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Sample records for receptors ppars prostaglandin

  1. Peroxisome Proliferators-Activated Receptor (PPAR Modulators and Metabolic Disorders

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    Min-Chul Cho

    2008-01-01

    Full Text Available Overweight and obesity lead to an increased risk for metabolic disorders such as impaired glucose regulation/insulin resistance, dyslipidemia, and hypertension. Several molecular drug targets with potential to prevent or treat metabolic disorders have been revealed. Interestingly, the activation of peroxisome proliferator-activated receptor (PPAR, which belongs to the nuclear receptor superfamily, has many beneficial clinical effects. PPAR directly modulates gene expression by binding to a specific ligand. All PPAR subtypes (α,γ, and σ are involved in glucose metabolism, lipid metabolism, and energy balance. PPAR agonists play an important role in therapeutic aspects of metabolic disorders. However, undesired effects of the existing PPAR agonists have been reported. A great deal of recent research has focused on the discovery of new PPAR modulators with more beneficial effects and more safety without producing undesired side effects. Herein, we briefly review the roles of PPAR in metabolic disorders, the effects of PPAR modulators in metabolic disorders, and the technologies with which to discover new PPAR modulators.

  2. Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders

    International Nuclear Information System (INIS)

    Agarwal, Swati; Yadav, Anuradha; Chaturvedi, Rajnish Kumar

    2017-01-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and they serve to be a promising therapeutic target for several neurodegenerative disorders, which includes Parkinson disease, Alzheimer's disease, Huntington disease and Amyotrophic Lateral Sclerosis. PPARs play an important role in the downregulation of mitochondrial dysfunction, proteasomal dysfunction, oxidative stress, and neuroinflammation, which are the major causes of the pathogenesis of neurodegenerative disorders. In this review, we discuss about the role of PPARs as therapeutic targets in neurodegenerative disorders. Several experimental approaches suggest potential application of PPAR agonist as well as antagonist in the treatment of neurodegenerative disorders. Several epidemiological studies found that the regular usage of PPAR activating non-steroidal anti-inflammatory drugs is effective in decreasing the progression of neurodegenerative diseases including PD and AD. We also reviewed the neuroprotective effects of PPAR agonists and associated mechanism of action in several neurodegenerative disorders both in vitro as well as in vivo animal models. - Highlights: • Peroxisome -activated receptors (PPARs) serve to be a promising therapeutic target for several neurodegenerative disorders. • PPAR agonist as well as provides neuroprotection in vitro as well as in vivo animal models of neurodegenerative disorders. • PPAR activating anti-inflammatory drugs use is effective in decreasing progression of neurodegenerative diseases.

  3. Putative role of prostaglandin receptor in intracerebral hemorrhage

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    Shekher eMohan

    2012-10-01

    Full Text Available Each year, approximately 795,000 people experience a new or recurrent stroke. Of all strokes, 84% are ischemic, 13% are intracerebral hemorrhage (ICH strokes and 3% are subarachnoid hemorrhage (SAH strokes. Despite the decreased incidence of ischemic stroke, there has been no change in the incidence of hemorrhagic stroke in the last decade. ICH is a devastating disease 37-38% of patients between the ages of 45-64 die within 30 days. In an effort to prevent ischemic and hemorrhagic strokes we and others have been studying the role of prostaglandins and their receptors. Prostaglandins are bioactive lipids derived from the metabolism of arachidonic acid. They sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. Most prostaglandins are produced from specific enzymes and act upon cells via distinct G-protein coupled receptors. The presence of multiple prostaglandin receptor’s cross-reactivity and coupling to different signal transduction pathways allow differentiated cells to respond to prostaglandins in a unique manner. Due to the number of prostaglandin receptors, prostaglandin-dependent signaling can function either to promote neuronal survival or injury following acute excitotoxicity, hypoxia, and stress induced by ICH. To better understand the mechanisms of neuronal survival and neurotoxicity mediated by prostaglandin receptors, it is essential to understand downstream signaling. Several groups including ours have discovered unique roles for prostaglandin receptors in rodent models of ischemic stroke, excitotoxicity, and Alzheimer disease, highlighting the emerging role of prostaglandin receptor signaling in hemorrhagic stroke with a focus on cyclic-adenosine monophosphate (cAMP and calcium (Ca2+ signaling. We review current ICH data and discuss future directions notably on prostaglandin receptors, which may lead to the development of unique therapeutic targets against hemorrhagic stroke and

  4. Revealing a steroid receptor ligand as a unique PPAR[gamma] agonist

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    Lin, Shengchen; Han, Ying; Shi, Yuzhe; Rong, Hui; Zheng, Songyang; Jin, Shikan; Lin, Shu-Yong; Lin, Sheng-Cai; Li, Yong (Pitt); (Xiamen)

    2012-06-28

    Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) regulates metabolic homeostasis and is a molecular target for anti-diabetic drugs. We report here the identification of a steroid receptor ligand, RU-486, as an unexpected PPAR{gamma} agonist, thereby uncovering a novel signaling route for this steroid drug. Similar to rosiglitazone, RU-486 modulates the expression of key PPAR{gamma} target genes and promotes adipocyte differentiation, but with a lower adipogenic activity. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for RU-486 in the PPAR{gamma} ligand-binding pocket with distinctive properties and epitopes, providing the molecular mechanisms for the discrimination of RU-486 from thiazolidinediones (TZDs) drugs. Our findings together indicate that steroid compounds may represent an alternative approach for designing non-TZD PPAR{gamma} ligands in the treatment of insulin resistance.

  5. Peroxisome proliferators-activated receptor (PPAR) regulation in cardiac metabolism and disease

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    el Azzouzi, H.

    2009-01-01

    Peroxisome proliferators-activated receptors (PPARs) are members of the nuclear receptor family of ligand activated transcription factors and consist of the three isoforms, PPAR, PPAR/ and PPAR. Considerable evidence has established the importance of PPARs in myocardial lipid homeostasis and

  6. Prostaglandins and prostaglandin receptor antagonism in migraine

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    Antonova, Maria

    2013-01-01

    Human models of headache may contribute to understanding of prostaglandins' role in migraine pathogenesis. The current thesis investigated the migraine triggering effect of prostaglandin E2 (PGE2) in migraine patients without aura, the efficacy of a novel EP4 receptor antagonist, BGC20....... The infusion of PGE2 caused the immediate migraine-like attacks and vasodilatation of the middle cerebral artery in migraine patients without aura. The highly specific and potent EP4 receptor antagonist, BGC20-1531, was not able to attenuate PGE2-induced headache and vasodilatation of both intra- and extra......-cerebral arteries. The intravenous infusion of PGF2α did not induce headache or statistically significant vasoconstriction of cerebral arteries in healthy volunteers. Novel data on PGE2-provoked immediate migraine-like attacks suggest that PGE2 may be one of the important final products in the pathogenesis...

  7. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS AS PROMISING NEW MEDICATIONS FOR DRUG ADDICTION: PRECLINICAL EVIDENCE

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    Foll, Bernard Le; Ciano, Patricia Di; Panlilio, Leigh V.; Goldberg, Steven R.; Ciccocioppo, Roberto

    2013-01-01

    This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together this preclinical data indicates that PPAR agonists are promising new medications for drug addiction treatment. PMID:23614675

  8. Pharmacologic implications of peroxisome proliferator activated receptors (PPAR Implicaciones farmacológicas de los receptores activados por los proliferadores de peroxisomas (PPAR

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    Luis Carlos Mejía Rivera

    2001-01-01

    Full Text Available PPAR are a group of proteins, members of the receptors located within the nucleus. These receptors modulate DNA transcriptional activity by binding to specific response elements on target genes. To date, three main types of PPAR have been identified designed α, δand γthese receptors are involved in the regulation of diferent metabolic processes, being the group of receptors more intensely studied. PPARαare greatly involved in both catabolism of fatty acids and transport of extracellular lipids; fibrates, their agonists, are of proved usefulness in some dyslipidemias. Thiazolidinediones used as antihyperglicemiant agents are PPARγagonists, but their relationship with carbohydrate metabolism is not yet clear; nevertheless, their use in the management of type 2 diabetes mellitus is of increasing importance. On the other hand, nonsteroidal anti-inflammatory agents are somehow related with PPARδfunctions; up to date a molecular and epidemiologic relationship of these drugs and receptors with colon cancer has been established. Los receptores activados por los proliferadores de peroxisomas (PPAR son un grupo de proteínas pertenecientes a la familia de receptores de ubicación nuclear que se comportan como factores que modulan la transcripción del DNA al unirse a elementos de respuesta específicos de ciertos genes blanco. Hasta el momento se han descrito tres tipos principales de PPAR designados como α, δ, y γ; estos receptores se encuentran involucrados en la regulación de diferentes procesos metabólicos; por esto se han convertido en uno de los grupos de receptores más intensamente estudiados. Los PPARα participan tanto en el catabolismo de los ácidos grasos como en el transporte extracelular de lípidos; los fibratos, sus agonistas, tienen utilidad ampliamente demostrada en el manejo de algunas dislipidemias. Las tiazolidindionas utilizadas como fármacos antihiperglicemiantes son agonistas de los PPARγ; todav

  9. Peroxisome Proliferator-Activated Receptors (PPARs as Potential Inducers of Antineoplastic Effects in CNS Tumors

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    Lars Tatenhorst

    2008-01-01

    Full Text Available The peroxisome proliferator-activated receptors (PPARs are ligand-inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS. The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studies dealing with the influence of PPARs on treatment of tumor cells in vitro. Remarkably, studies examining the effects of these drugs in vivo are just beginning to emerge. However, the agonists of PPARs, in particular the thiazolidinediones, seem to be promising candidates for new approaches in human CNS tumor therapy.

  10. Effect of PPAR γ activators on hypertrophic cardiac myocytes in vitro

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    Wu Shimin; Zhou Xin; Ye Ping; Wang Qiong; Gao Yue; Liu Yongxue

    2004-01-01

    Objective: To investigate the effects of peroxisome proliferator-activated receptor γ (PPAR γ) activators pioglitazone and 15-deoxy-Δ 12,14 prostaglandin J 2 (15d-PGJ 2 ) on hypertrophic cardiac myocytes (MC) of neonatal rats in vitro. Methods; With the stimulation of angiotensin II(Ang II), a model of hypertrophy of MC was established. With the method of reverse transcription-polymerase chain reaction (RT-PCR), mRNA expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was amplified; with the aid of NIH Image J software the surface area of MC was analyzed and with 3 H-leucine incorporation, the synthesizing rate of protein in MC was measured. Results: Increases in surface area of MC, mRNA expression of ANP and BNP and 3 H-leucine incorporation in MC were observed in the model of cardiac hypertrophy. Pioglitazone and 15d-PGJ 2 , two kinds of PPAR γ activators, inhibited the above changes in a dose-dependent manner. Conclusion: It is suggested that PPAR γ activators inhibit hypertrophy of cardiac myocytes and PPAR γ-dependent pathway be involved in the inhibitory course

  11. Activated AMPK inhibits PPAR-{alpha} and PPAR-{gamma} transcriptional activity in hepatoma cells.

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    Sozio, Margaret S; Lu, Changyue; Zeng, Yan; Liangpunsakul, Suthat; Crabb, David W

    2011-10-01

    AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPAR-α) are critical regulators of short-term and long-term fatty acid oxidation, respectively. We examined whether the activities of these molecules were coordinately regulated. H4IIEC3 cells were transfected with PPAR-α and PPAR-γ expression plasmids and a peroxisome-proliferator-response element (PPRE) luciferase reporter plasmid. The cells were treated with PPAR agonists (WY-14,643 and rosiglitazone), AMPK activators 5-aminoimidazole-4-carboxamide riboside (AICAR) and metformin, and the AMPK inhibitor compound C. Both AICAR and metformin decreased basal and WY-14,643-stimulated PPAR-α activity; compound C increased agonist-stimulated reporter activity and partially reversed the effect of the AMPK activators. Similar effects on PPAR-γ were seen, with both AICAR and metformin inhibiting PPRE reporter activity. Compound C increased basal PPAR-γ activity and rosiglitazone-stimulated activity. In contrast, retinoic acid receptor-α (RAR-α), another nuclear receptor that dimerizes with retinoid X receptor (RXR), was largely unaffected by the AMPK activators. Compound C modestly increased AM580 (an RAR agonist)-stimulated activity. The AMPK activators did not affect PPAR-α binding to DNA, and there was no consistent correlation between effects of the AMPK activators and inhibitor on PPAR and the nuclear localization of AMPK-α subunits. Expression of either a constitutively active or dominant negative AMPK-α inhibited basal and WY-14,643-stimulated PPAR-α activity and basal and rosiglitazone-stimulated PPAR-γ activity. We concluded that the AMPK activators AICAR and metformin inhibited transcriptional activities of PPAR-α and PPAR-γ, whereas inhibition of AMPK with compound C activated both PPARs. The effects of AMPK do not appear to be mediated through effects on RXR or on PPAR/RXR binding to DNA. These effects are independent of kinase activity and instead appear to

  12. Activation of peroxisome proliferator-activated receptors (PPARs) by their ligands and protein kinase A activators

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    Lazennec, Gwendal; Canaple, Laurence; Saugy, Damien; Wahli, Walter

    2000-01-01

    The nuclear peroxisome proliferator-activated receptors (PPARs) α, β and γ activate the transcription of multiple genes involved in lipid metabolism. Several natural and synthetic ligands have been identified for each PPAR isotype but little is known about the phosphorylation state of these receptors. We show here that activators of protein kinase A (PKA) can enhance mouse PPAR activity in the absence and the presence of exogenous ligands in transient transfection experiments. The activation function 1 (AF-1) of PPARs was dispensable for transcriptional enhancement, whereas the activation function 2 (AF-2) was required for this effect. We also show that several domains of PPAR can be phosphorylated by PKA in vitro. Moreover, gel experiments suggest that PKA stabilizes binding of the liganded PPAR to DNA. PKA inhibitors decreased not only the kinase dependent induction of PPARs but also their ligand-dependent induction, suggesting that the ligands may also mobilize the PKA pathway to lead to maximal transcriptional induction by PPARs. Moreover, comparing PPARα KO with PPARα wild-type mice, we show that the expression of the ACO gene can be regulated by PKA-activated PPARα in liver. These data demonstrate that the PKA pathway is an important modulator of PPAR activity and we propose a model associating this pathway in the control of fatty acid β-oxidation under conditions of fasting, stress and exercise. PMID:11117527

  13. Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures

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    Oyama, Takuji; Toyota, Kenji; Waku, Tsuyoshi; Hirakawa, Yuko; Nagasawa, Naoko; Kasuga, Jun-ichi; Hashimoto, Yuichi; Miyachi, Hiroyuki; Morikawa, Kosuke

    2009-01-01

    The structures of the ligand-binding domains (LBDs) of human peroxisome proliferator-activated receptors (PPARα, PPARγ and PPARδ) in complexes with a pan agonist, an α/δ dual agonist and a PPARδ-specific agonist were determined. The results explain how each ligand is recognized by the PPAR LBDs at an atomic level. Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family, which is defined as transcriptional factors that are activated by the binding of ligands to their ligand-binding domains (LBDs). Although the three PPAR subtypes display different tissue distribution patterns and distinct pharmacological profiles, they all are essentially related to fatty-acid and glucose metabolism. Since the PPARs share similar three-dimensional structures within the LBDs, synthetic ligands which simultaneously activate two or all of the PPARs could be potent candidates in terms of drugs for the treatment of abnormal metabolic homeostasis. The structures of several PPAR LBDs were determined in complex with synthetic ligands, derivatives of 3-(4-alkoxyphenyl)propanoic acid, which exhibit unique agonistic activities. The PPARα and PPARγ LBDs were complexed with the same pan agonist, TIPP-703, which activates all three PPARs and their crystal structures were determined. The two LBD–ligand complex structures revealed how the pan agonist is adapted to the similar, but significantly different, ligand-binding pockets of the PPARs. The structures of the PPARδ LBD in complex with an α/δ-selective ligand, TIPP-401, and with a related δ-specific ligand, TIPP-204, were also determined. The comparison between the two PPARδ complexes revealed how each ligand exhibits either a ‘dual selective’ or ‘single specific’ binding mode

  14. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) γ activators and pan-PPAR partial agonists

    NARCIS (Netherlands)

    Liberato, Marcelo Vizoná; Nascimento, Alessandro S; Ayers, Steven D; Lin, Jean Z; Cvoro, Aleksandra; Silveira, Rodrigo L; Martínez, Leandro; Souza, Paulo C T; Saidemberg, Daniel; Deng, Tuo; Amato, Angela Angelica; Togashi, Marie; Hsueh, Willa A; Phillips, Kevin; Palma, Mário Sérgio; Neves, Francisco A R; Skaf, Munir S; Webb, Paul; Polikarpov, Igor

    2012-01-01

    Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of

  15. Prostaglandin Receptor Signaling in Disease

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    Toshiyuki Matsuoka

    2007-01-01

    Full Text Available Prostanoids, consisting of the prostaglandins (PGs and the thromboxanes (TXs, are a group of lipid mediators formed in response to various stimuli. They include PGD2, PGE2, PGF2α, PGI2, and TXA2. They are released outside of the cells immediately after synthesis, and exert their actions by binding to a G-protein coupled rhodopsin-type receptor on the surface of target cells. There are eight types of the prostanoid receptors conserved in mammals from mouse to human. They are the PGD receptor (DP, four subtypes of the PGE receptor (EP1, EP2, EP3, and EP4, the PGF receptor (FP, PGI receptor (IP, and TXA receptor (TP. Recently, mice deficient in each of these prostanoid receptors were generated and subjected to various experimental models of disease. These studies have revealed the roles of PG receptor signaling in various pathological conditions, and suggest that selective manipulation of the prostanoid receptors may be beneficial in treatment of the pathological conditions. Here we review these recent findings of roles of prostanoid receptor signaling and their therapeutic implications.

  16. The Role of PPAR Receptors and Leukotriene B4 Receptors in Mediating the Effects of LY293111 in Pancreatic Cancer

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    Thomas E. Adrian

    2008-01-01

    Full Text Available Pancreatic cancer is a devastating disease in which current therapies are inadequate. Separate lines of research have identified the 5-lipoxygenase/leukotriene B4 receptor pathway and the PPAR pathway as potential targets for prevention or treatment of this disease. LY293111 was originally designed as a potent leukotriene B4 receptor antagonist for treatment of inflammatory conditions. LY293111 was also known to have inhibitory effects on 5-lipoxygenase, which is upstream of the production of leukotrienes. LY293111 was shown to have potent anticancer effects in pancreatic cancer and several other solid malignancies, where it caused cell cycle arrest and marked apoptosis. Subsequently, it came to light that LY293111 exhibited PPAR agonist activity in addition to its effects on the 5-lipoxygenase pathway. This raises the question of which of the two targets is of greatest importance with regard to the anticancer effects of this agent. The evidence to date is not conclusive, but suggests that the effects of LY293111 may be mediated by both LTB4 receptors and PPAR.

  17. Peroxisome Proliferator-Activated Receptor (PPAR) in Regenerative Medicine: Molecular Mechanism for PPAR in Stem Cells' Adipocyte Differentiation.

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    Xie, Qiang; Tian, Taoran; Chen, Zhaozhao; Deng, Shuwen; Sun, Ke; Xie, Jing; Cai, Xiaoxiao

    2016-01-01

    Regenerative medicine plays an indispensable role in modern medicine and many trials and researches have therefore been developed to fit our medical needs. Tissue engineering has proven that adipose tissue can widely be used and brings advantages to regenerative medicine. Moreover, a trait of adipose stem cells being isolated and grown in vitro is a cornerstone to various applications. Since the adipose tissue has been widely used in regenerative medicine, numerous studies have been conducted to seek methods for gaining more adipocytes. To investigate molecular mechanism for adipocyte differentiation, peroxisome proliferator-activated receptor (PPAR) has been widely studied to find out its functional mechanism, as a key factor for adipocyte differentiation. However, the precise molecular mechanism is still unknown. This review thus summarizes recent progress on the study of molecular mechanism and role of PPAR in adipocyte differentiation.

  18. PPAR, PTEN, and the Fight against Cancer

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    Rosemary E. Teresi

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptor gamma (PPAR is a ligand-activated transcription factor, which belongs to the family of nuclear hormone receptors. Recent in vitro studies have shown that PPAR can regulate the transcription of phosphatase and tensin homolog on chromosome ten (PTEN, a known tumor suppressor. PTEN is a susceptibility gene for a number of disorders, including breast and thyroid cancer. Activation of PPAR through agonists increases functional PTEN protein levels that subsequently induces apoptosis and inhibits cellular growth, which suggests that PPAR may be a tumor suppressor. Indeed, several in vivo studies have demonstrated that genetic alterations of PPAR can promote tumor progression. These results are supported by observations of the beneficial effects of PPAR agonists in the in vivo cancer setting. These studies signify the importance of PPAR and PTEN's interaction in cancer prevention.

  19. Time-Dependent Vascular Effects of Endocannabinoids Mediated by Peroxisome Proliferator-Activated Receptor Gamma (PPAR

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    Saoirse E. O'Sullivan

    2009-01-01

    Full Text Available The aim of the present study was to examine whether endocannabinoids cause PPAR-mediated vascular actions. Functional vascular studies were carried out in rat aortae. Anandamide and N-arachidonoyl-dopamine (NADA, but not palmitoylethanolamide, caused significant vasorelaxation over time (2 hours. Vasorelaxation to NADA, but not anandamide, was inhibited by CB1 receptor antagonism (AM251, 1 M, and vasorelaxation to both anandamide and NADA was inhibited by PPAR antagonism (GW9662, 1 M. Pharmacological inhibition of de novo protein synthesis, nitric oxide synthase, and super oxide dismutase abolished the responses to anandamide and NADA. Removal of the endothelium partly inhibited the vasorelaxant responses to anandamide and NADA. Inhibition of fatty acid amide hydrolase (URB597, 1 M inhibited the vasorelaxant response to NADA, but not anandamide. These data indicate that endocannabinoids cause time-dependent, PPAR-mediated vasorelaxation. Activation of PPAR in the vasculature may represent a novel mechanism by which endocannabinoids are involved in vascular regulation.

  20. Angiotensin II receptor blocker telmisartan enhances running endurance of skeletal muscle through activation of the PPAR-δ/AMPK pathway.

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    Feng, Xiaoli; Luo, Zhidan; Ma, Liqun; Ma, Shuangtao; Yang, Dachun; Zhao, Zhigang; Yan, Zhencheng; He, Hongbo; Cao, Tingbing; Liu, Daoyan; Zhu, Zhiming

    2011-07-01

    Clinical trials have shown that angiotensin II receptor blockers reduce the new onset of diabetes in hypertensives; however, the underlying mechanisms remain unknown. We investigated the effects of telmisartan on peroxisome proliferator activated receptor γ (PPAR-δ) and the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway in cultured myotubes, as well as on the running endurance of wild-type and PPAR-δ-deficient mice. Administration of telmisartan up-regulated levels of PPAR-δ and phospho-AMPKα in cultured myotubes. However, PPAR-δ gene deficiency completely abolished the telmisartan effect on phospho-AMPKαin vitro. Chronic administration of telmisartan remarkably prevented weight gain, enhanced running endurance and post-exercise oxygen consumption, and increased slow-twitch skeletal muscle fibres in wild-type mice, but these effects were absent in PPAR-δ-deficient mice. The mechanism is involved in PPAR-δ-mediated stimulation of the AMPK pathway. Compared to the control mice, phospho-AMPKα level in skeletal muscle was up-regulated in mice treated with telmisartan. In contrast, phospho-AMPKα expression in skeletal muscle was unchanged in PPAR-δ-deficient mice treated with telmisartan. These findings highlight the ability of telmisartan to improve skeletal muscle function, and they implicate PPAR-δ as a potential therapeutic target for the prevention of type 2 diabetes. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  1. Structural insights into human peroxisome proliferator activated receptor delta (PPAR-delta selective ligand binding.

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    Fernanda A H Batista

    Full Text Available Peroxisome proliferator activated receptors (PPARs δ, α and γ are closely related transcription factors that exert distinct effects on fatty acid and glucose metabolism, cardiac disease, inflammatory response and other processes. Several groups developed PPAR subtype specific modulators to trigger desirable effects of particular PPARs without harmful side effects associated with activation of other subtypes. Presently, however, many compounds that bind to one of the PPARs cross-react with others and rational strategies to obtain highly selective PPAR modulators are far from clear. GW0742 is a synthetic ligand that binds PPARδ more than 300-fold more tightly than PPARα or PPARγ but the structural basis of PPARδ:GW0742 interactions and reasons for strong selectivity are not clear. Here we report the crystal structure of the PPARδ:GW0742 complex. Comparisons of the PPARδ:GW0742 complex with published structures of PPARs in complex with α and γ selective agonists and pan agonists suggests that two residues (Val312 and Ile328 in the buried hormone binding pocket play special roles in PPARδ selective binding and experimental and computational analysis of effects of mutations in these residues confirms this and suggests that bulky substituents that line the PPARα and γ ligand binding pockets as structural barriers for GW0742 binding. This analysis suggests general strategies for selective PPARδ ligand design.

  2. Steroid receptor coactivator 1 deficiency increases MMTV-neu mediated tumor latency and differentiation specific gene expression, decreases metastasis, and inhibits response to PPAR ligands

    International Nuclear Information System (INIS)

    Han, Ji Seung; Crowe, David L

    2010-01-01

    The peroxisome proliferator activated receptor (PPAR) subgroup of the nuclear hormone receptor superfamily is activated by a variety of natural and synthetic ligands. PPARs can heterodimerize with retinoid X receptors, which have homology to other members of the nuclear receptor superfamily. Ligand binding to PPAR/RXRs results in recruitment of transcriptional coactivator proteins such as steroid receptor coactivator 1 (SRC-1) and CREB binding protein (CBP). Both SRC-1 and CBP are histone acetyltransferases, which by modifying nucleosomal histones, produce more open chromatin structure and increase transcriptional activity. Nuclear hormone receptors can recruit limiting amounts of coactivators from other transcription factor binding sites such as AP-1, thereby inhibiting the activity of AP-1 target genes. PPAR and RXR ligands have been used in experimental breast cancer therapy. The role of coactivator expression in mammary tumorigenesis and response to drug therapy has been the subject of recent studies. We examined the effects of loss of SRC-1 on MMTV-neu mediated mammary tumorigenesis. SRC-1 null mutation in mammary tumor prone mice increased the tumor latency period, reduced tumor proliferation index and metastasis, inhibited response to PPAR and RXR ligands, and induced genes involved in mammary gland differentiation. We also examined human breast cancer cell lines overexpressing SRC-1 or CBP. Coactivator overexpression increased cellular proliferation with resistance to PPAR and RXR ligands and remodeled chromatin of the proximal epidermal growth factor receptor promoter. These results indicate that histone acetyltransferases play key roles in mammary tumorigenesis and response to anti-proliferative therapies

  3. PPARs and the Cardiovascular System

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    Hamblin, Milton; Chang, Lin; Fan, Yanbo; Zhang, Jifeng

    2009-01-01

    Abstract Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone-receptor superfamily. Originally cloned in 1990, PPARs were found to be mediators of pharmacologic agents that induce hepatocyte peroxisome proliferation. PPARs also are expressed in cells of the cardiovascular system. PPARγ appears to be highly expressed during atherosclerotic lesion formation, suggesting that increased PPARγ expression may be a vascular compensatory response. Also, ligand-activated PPARγ decreases the inflammatory response in cardiovascular cells, particularly in endothelial cells. PPARα, similar to PPARγ, also has pleiotropic effects in the cardiovascular system, including antiinflammatory and antiatherosclerotic properties. PPARα activation inhibits vascular smooth muscle proinflammatory responses, attenuating the development of atherosclerosis. However, PPARδ overexpression may lead to elevated macrophage inflammation and atherosclerosis. Conversely, PPARδ ligands are shown to attenuate the pathogenesis of atherosclerosis by improving endothelial cell proliferation and survival while decreasing endothelial cell inflammation and vascular smooth muscle cell proliferation. Furthermore, the administration of PPAR ligands in the form of TZDs and fibrates has been disappointing in terms of markedly reducing cardiovascular events in the clinical setting. Therefore, a better understanding of PPAR-dependent and -independent signaling will provide the foundation for future research on the role of PPARs in human cardiovascular biology. Antioxid. Redox Signal. 11, 1415–1452. PMID:19061437

  4. Intestinal tumor suppression in ApcMin/+ mice by prostaglandin D2 receptor PTGDR

    International Nuclear Information System (INIS)

    Tippin, Brigette L; Kwong, Alan M; Inadomi, Michael J; Lee, Oliver J; Park, Jae Man; Materi, Alicia M; Buslon, Virgilio S; Lin, Amy M; Kudo, Lili C; Karsten, Stanislav L; French, Samuel W; Narumiya, Shuh; Urade, Yoshihiro; Salido, Eduardo; Lin, Henry J

    2014-01-01

    Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D 2 ) caused more adenomas in Apc Min/+ mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D 2 (PGD 2 ) binds to the prostaglandin D 2 receptor known as PTGDR (or DP1). PGD 2 metabolites bind to peroxisome proliferator-activated receptor γ (PPARG). We hypothesized that Ptgdr or Pparg knockouts may raise numbers of tumors, if these receptors take part in tumor suppression by PGD 2 . To assess, we produced Apc Min/+ mice with and without Ptgdr knockouts (147 mice). In separate experiments, we produced Apc Min/+ mice expressing transgenic lipocalin-type prostaglandin D synthase (PTGDS), with and without heterozygous Pparg knockouts (104 mice). Homozygous Ptgdr knockouts raised total numbers of tumors by 30–40% at 6 and 14 weeks. Colon tumors were not affected. Heterozygous Pparg knockouts alone did not affect tumor numbers in Apc Min/+ mice. As mentioned above, our Pparg knockout assessment also included mice with highly expressed PTGDS transgenes. Apc Min/+ mice with transgenic PTGDS had fewer large adenomas (63% of control) and lower levels of v-myc avian myelocytomatosis viral oncogene homolog (MYC) mRNA in the colon. Heterozygous Pparg knockouts appeared to blunt the tumor-suppressing effect of transgenic PTGDS. However, tumor suppression by PGD 2 was more clearly mediated by receptor PTGDR in our experiments. The suppression mechanism did not appear to involve changes in microvessel density or slower proliferation of tumor cells. The data support a role for PGD 2 signals acting through PTGDR in suppression of intestinal tumors

  5. Statins Activate Human PPAR Promoter and Increase PPAR mRNA Expression and Activation in HepG2 Cells

    Directory of Open Access Journals (Sweden)

    Makoto Seo

    2008-01-01

    Full Text Available Statins increase peroxisome proliferator-activated receptor (PPAR mRNA expression, but the mechanism of this increased PPAR production remains elusive. To examine the regulation of PPAR production, we examined the effect of 7 statins (atorvastatin, cerivastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin on human PPAR promoter activity, mRNA expression, nuclear protein levels, and transcriptional activity. The main results are as follows. (1 Majority of statins enhanced PPAR promoter activity in a dose-dependent manner in HepG2 cells transfected with the human PPAR promoter. This enhancement may be mediated by statin-induced HNF-4. (2 PPAR mRNA expression was increased by statin treatment. (3 The PPAR levels in nuclear fractions were increased by statin treatment. (4 Simvastatin, pravastatin, and cerivastatin markedly enhanced transcriptional activity in 293T cells cotransfected with acyl-coenzyme A oxidase promoter and PPAR/RXR expression vectors. In summary, these data demonstrate that PPAR production and activation are upregulated through the PPAR promoter activity by statin treatment.

  6. PPAR{gamma} regulates the expression of cholesterol metabolism genes in alveolar macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Baker, Anna D.; Malur, Anagha; Barna, Barbara P.; Kavuru, Mani S. [Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, East Carolina University (United States); Malur, Achut G. [Department of Microbiology and Immunology, East Carolina University (United States); Thomassen, Mary Jane, E-mail: thomassenm@ecu.edu [Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, East Carolina University (United States); Department of Microbiology and Immunology, East Carolina University (United States)

    2010-03-19

    Peroxisome proliferator-activated receptor-gamma (PPAR{gamma}) is a nuclear transcription factor involved in lipid metabolism that is constitutively expressed in the alveolar macrophages of healthy individuals. PPAR{gamma} has recently been implicated in the catabolism of surfactant by alveolar macrophages, specifically the cholesterol component of surfactant while the mechanism remains unclear. Studies from other tissue macrophages have shown that PPAR{gamma} regulates cholesterol influx, efflux, and metabolism. PPAR{gamma} promotes cholesterol efflux through the liver X receptor-alpha (LXR{alpha}) and ATP-binding cassette G1 (ABCG1). We have recently shown that macrophage-specific PPAR{gamma} knockout (PPAR{gamma} KO) mice accumulate cholesterol-laden alveolar macrophages that exhibit decreased expression of LXR{alpha} and ABCG1 and reduced cholesterol efflux. We hypothesized that in addition to the dysregulation of these cholesterol efflux genes, the expression of genes involved in cholesterol synthesis and influx was also dysregulated and that replacement of PPAR{gamma} would restore regulation of these genes. To investigate this hypothesis, we have utilized a Lentivirus expression system (Lenti-PPAR{gamma}) to restore PPAR{gamma} expression in the alveolar macrophages of PPAR{gamma} KO mice. Our results show that the alveolar macrophages of PPAR{gamma} KO mice have decreased expression of key cholesterol synthesis genes and increased expression of cholesterol receptors CD36 and scavenger receptor A-I (SRA-I). The replacement of PPAR{gamma} (1) induced transcription of LXR{alpha} and ABCG1; (2) corrected suppressed expression of cholesterol synthesis genes; and (3) enhanced the expression of scavenger receptors CD36. These results suggest that PPAR{gamma} regulates cholesterol metabolism in alveolar macrophages.

  7. FOXC1 Regulates Expression of Prostaglandin Receptors Leading to an Attenuated Response to Latanoprost.

    Science.gov (United States)

    Doucette, Lance P; Footz, Tim; Walter, Michael A

    2018-05-01

    This study examines the effect of FOXC1 on the prostaglandin pathway in order to explore FOXC1's role in the prostaglandin-resistant glaucoma phenotype commonly seen in Axenfeld-Rieger syndrome. Binding and transcriptional activity of FOXC1 to the gene coding for the EP3 prostaglandin receptor (PTGER3) were evaluated through ChIP-qPCR and luciferase-based assays. Immortalized trabecular meshwork cells (TM1) and HeLa cells had FOXC1 mRNA reduced via siRNA interference. qPCR and Western blot experiments were conducted to examine the changes in prostaglandin receptor expression brought about by lowered FOXC1. TM1 cells were then treated with 10 μM latanoprost acid and/or an siRNA for FOXC1. The expression of fibronectin and matrix metalloproteinase 9 were evaluated via qPCR in each treatment condition. ChIP-qPCR and luciferase experiments confirmed that FOXC1 binds to and activates transcription of the EP3 gene prostaglandin receptor. qPCR and Western experiments in HeLa and TM1 cells showed that FOXC1 siRNA knockdown results in significantly lowered EP3 levels (protein and RNA). In addition, RNA levels of the other prostaglandin receptor genes EP1 (PTGER1), EP2 (PTGER2), EP4 (PTGER4), and FP (PTGFR) were altered when FOXC1 was knocked down in TM1 and HeLa cells. Analysis of fibronectin expression in TM1 cells after treatment with 10 μM latanoprost acid showed a statistically significant increase in expression; this increase was abrogated by cotreatment with a siRNA for FOXC1. We show the abrogation of latanoprost signalling when FOXC1 is knocked down via siRNA in a trabecular meshwork cell line. We propose that the lower levels of active FOXC1 in Axenfeld-Rieger syndrome patients with glaucoma account for the lack of response to prostaglandin-based medications.

  8. PPAR-γ in the Cardiovascular System

    Directory of Open Access Journals (Sweden)

    Sheng Zhong Duan

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptor-γ (PPAR-γ, an essential transcriptional mediator of adipogenesis, lipid metabolism, insulin sensitivity, and glucose homeostasis, is increasingly recognized as a key player in inflammatory cells and in cardiovascular diseases (CVD such as hypertension, cardiac hypertrophy, congestive heart failure, and atherosclerosis. PPAR-γ agonists, the thiazolidinediones (TZDs, increase insulin sensitivity, lower blood glucose, decrease circulating free fatty acids and triglycerides, lower blood pressure, reduce inflammatory markers, and reduce atherosclerosis in insulin-resistant patients and animal models. Human genetic studies on PPAR-γ have revealed that functional changes in this nuclear receptor are associated with CVD. Recent controversial clinical studies raise the question of deleterious action of PPAR-γ agonists on the cardiovascular system. These complex interactions of metabolic responsive factors and cardiovascular disease promise to be important areas of focus for the future.

  9. PPAR-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic β-cells.

    Directory of Open Access Journals (Sweden)

    Hyo-Sup Kim

    Full Text Available BACKGROUND: It has been reported that peroxisome proliferator-activated receptor (PPAR-γ and their synthetic ligands have direct effects on pancreatic β-cells. We investigated whether PPAR-γ activation stimulates insulin secretion through the up-regulation of GPR40 in pancreatic β-cells. METHODS: Rat insulinoma INS-1 cells and primary rat islets were treated with rosiglitazone (RGZ and/or adenoviral PPAR-γ overexpression. OLETF rats were treated with RGZ. RESULTS: PPAR-γ activation with RGZ and/or adenoviral PPAR-γ overexpression increased free fatty acid (FFA receptor GPR40 expression, and increased insulin secretion and intracellular calcium mobilization, and was blocked by the PLC inhibitors, GPR40 RNA interference, and GLUT2 RNA interference. As a downstream signaling pathway of intracellular calcium mobilization, the phosphorylated levels of CaMKII and CREB, and the downstream IRS-2 and phospho-Akt were significantly increased. Despite of insulin receptor RNA interference, the levels of IRS-2 and phospho-Akt was still maintained with PPAR-γ activation. In addition, the β-cell specific gene expression, including Pdx-1 and FoxA2, increased in a GPR40- and GLUT2-dependent manner. The levels of GPR40, phosphorylated CaMKII and CREB, and β-cell specific genes induced by RGZ were blocked by GW9662, a PPAR-γ antagonist. Finally, PPAR-γ activation up-regulated β-cell gene expressions through FoxO1 nuclear exclusion, independent of the insulin signaling pathway. Based on immunohistochemical staining, the GLUT2, IRS-2, Pdx-1, and GPR40 were more strongly expressed in islets from RGZ-treated OLETF rats compared to control islets. CONCLUSION: These observations suggest that PPAR-γ activation with RGZ and/or adenoviral overexpression increased intracellular calcium mobilization, insulin secretion, and β-cell gene expression through GPR40 and GLUT2 gene up-regulation.

  10. Fatty Acid Amide Hydrolase (FAAH) Inhibition Enhances Memory Acquisition through Activation of PPAR-alpha Nuclear Receptors

    Science.gov (United States)

    Mazzola, Carmen; Medalie, Julie; Scherma, Maria; Panlilio, Leigh V.; Solinas, Marcello; Tanda, Gianluigi; Drago, Filippo; Cadet, Jean Lud; Goldberg, Steven R.; Yasar, Sevil

    2009-01-01

    Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB[subscript 1]-receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for alpha-type peroxisome proliferator-activated nuclear receptors, PPAR-alpha) when and where they are naturally released in the brain.…

  11. Pharmacological and expression profile of the prostaglandin I(2) receptor in the rat craniovascular system

    DEFF Research Database (Denmark)

    Myren, Maja; Olesen, Jes; Gupta, Saurabh

    2012-01-01

    Activation of the trigeminal nerve terminals around cerebral and meningeal arteries is thought to be an important patho-mechanism in migraine. Vasodilatation of the cranial arteries may also play a role in increasing nociception. Prostaglandin I(2) (PGI(2)) is capable of inducing a headache...... in healthy volunteers, a response that is likely to be mediated by the prostaglandin I(2) receptor (IP). This study investigates the functional and molecular characteristics of the IP receptor in the rat craniovascular system. In the closed cranial window model, iloprost, an IP receptor agonist, dilated...

  12. Regulation of PPAR{gamma} function by TNF-{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Ye Jianping [Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808 (United States)], E-mail: yej@pbrc.edu

    2008-09-26

    The nuclear receptor PPAR{gamma} is a lipid sensor that regulates lipid metabolism through gene transcription. Inhibition of PPAR{gamma} activity by TNF-{alpha} is involved in pathogenesis of insulin resistance, atherosclerosis, inflammation, and cancer cachexia. PPAR{gamma} activity is regulated by TNF-{alpha} at pre-translational and post-translational levels. Activation of serine kinases including IKK, ERK, JNK, and p38 may be involved in the TNF-regulation of PPAR{gamma}. Of the four kinases, IKK is a dominant signaling molecule in the TNF-regulation of PPAR{gamma}. IKK acts through at least two mechanisms: inhibition of PPAR{gamma} expression and activation of PPAR{gamma} corepressor. In this review article, literature is reviewed with a focus on the mechanisms of PPAR{gamma} inhibition by TNF-{alpha}.

  13. GQ-16, a Novel Peroxisome Proliferator-activated Receptor gamma (PPAR gamma) Ligand, Promotes Insulin Sensitization without Weight Gain

    NARCIS (Netherlands)

    Amato, Angelica A.; Rajagopalan, Senapathy; Lin, Jean Z.; Carvalho, Bruno M.; Figueira, Ana C. M.; Lu, Jenny; Ayers, Stephen D.; Mottin, Melina; Silveira, Rodrigo L.; Telles de Souza, Paulo; Mourao, Rosa H. V.; Saad, Mario J. A.; Togashi, Marie; Simeoni, Luiz A.; Abdalla, Dulcineia S. P.; Skaf, Munir S.; Polikparpov, Igor; Lima, Maria C. A.; Galdino, Suely L.; Brennan, Richard G.; Baxter, John D.; Pitta, Ivan R.; Webb, Paul; Phillips, Kevin J.; Neves, Francisco A. R.

    2012-01-01

    The recent discovery that peroxisome proliferator-activated receptor gamma (PPAR gamma) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report

  14. Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-γ activation

    International Nuclear Information System (INIS)

    Moriuchi, Akie; Yamasaki, Hironori; Shimamura, Mika; Kita, Atsushi; Kuwahara, Hironaga; Fujishima, Keiichiro; Satoh, Tsuyoshi; Fukushima, Keiko; Fukushima, Tetsuya; Hayakawa, Takao; Mizuguchi, Hiroyuki; Nagayama, Yuji; Abiru, Norio; Kawasaki, Eiji; Eguchi, Katsumi

    2007-01-01

    Adiponectin, an adipose tissue-specific plasma protein, has been shown to ameliorate insulin resistance and inhibit the process of atherosclerosis. Recently, several reports have stated that angiotensin type 1 receptor blockers (ARBs), increase adiponectin plasma level, and ameliorate insulin resistance. Telmisartan, a subclass of ARBs, has been shown to be a partial agonist of the peroxisome proliferator-activated receptor (PPAR)-γ, and to increase the plasma adiponectin level. However, the transcriptional regulation of the human adiponectin gene by telmisartan has not been determined yet. To elucidate the effect of telmisartan on adiponectin, the stimulatory regulation of human adiponectin gene by telmisartan was investigated in 3T3-L1 adipocytes, utilizing adenovirus-mediated luciferase reporter gene-transferring technique. This study indicates that telmisartan may stimulate adiponectin transcription independent of PPAR

  15. The PPAR{gamma} ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V., E-mail: lstewart@mmc.edu

    2010-12-10

    The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPAR{gamma} ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPAR{gamma} ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPAR{gamma} ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPAR{gamma}. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPAR{gamma} and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

  16. Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury

    Science.gov (United States)

    Glushakov, Alexander V.; Fazal, Jawad A.; Narumiya, Shuh; Doré, Sylvain

    2014-01-01

    Brain injuries promote upregulation of so-called proinflammatory prostaglandins, notably prostaglandin E2 (PGE2), leading to overactivation of a class of its cognate G-protein-coupled receptors, including EP1, which is considered a promising target for treatment of ischemic stroke. However, the role of the EP1 receptor is complex and depends on the type of brain injury. This study is focused on the investigation of the role of the EP1 receptor in a controlled cortical impact (CCI) model, a preclinical model of traumatic brain injury (TBI). The therapeutic effects of post-treatments with a widely studied EP1 receptor antagonist, SC-51089, were examined in wildtype and EP1 receptor knockout C57BL/6 mice. Neurological deficit scores (NDS) were assessed 24 and 48 h following CCI or sham surgery, and brain immunohistochemical pathology was assessed 48 h after surgery. In wildtype mice, CCI resulted in an obvious cortical lesion and localized hippocampal edema with an associated significant increase in NDS compared to sham-operated animals. Post-treatments with the selective EP1 receptor antagonist SC-51089 or genetic knockout of EP1 receptor had no significant effects on cortical lesions and hippocampal swelling or on the NDS 24 and 48 h after CCI. Immunohistochemistry studies revealed CCI-induced gliosis and microglial activation in selected ipsilateral brain regions that were not affected by SC-51089 or in the EP1 receptor-deleted mice. This study provides further clarification on the respective contribution of the EP1 receptor in TBI and suggests that, under this experimental paradigm, the EP1 receptor would have limited effects in modulating acute neurological and anatomical pathologies following contusive brain trauma. Findings from this protocol, in combination with previous studies demonstrating differential roles of EP1 receptor in ischemic, neurotoxic, and hemorrhagic conditions, provide scientific background and further clarification of potential therapeutic

  17. COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells.

    Science.gov (United States)

    Ramer, Robert; Heinemann, Katharina; Merkord, Jutta; Rohde, Helga; Salamon, Achim; Linnebacher, Michael; Hinz, Burkhard

    2013-01-01

    The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-γ in cannabidiol's proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662 (PPAR-γ antagonist), and siRNA targeting COX-2 and PPAR-γ. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-γ mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-γ mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PG) among which PGD(2) and 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) caused a translocation of PPAR-γ to the nucleus and induced a PPAR-γ-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-γ in tumor tissue and tumor regression that was reversible by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-γ and a subsequent nuclear translocation of PPAR-γ by COX-2-dependent PGs.

  18. PPAR2Pro12Ala Polymorphism and Human Health

    Directory of Open Access Journals (Sweden)

    Weimin He

    2009-01-01

    Full Text Available The nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPAR is an important transcription factor regulating adipocyte differentiation, lipid and glucose homeostasis, and insulin sensitivity. Numerous genetic mutations of PPAR have been identified and these mutations positively or negatively regulate insulin sensitivity. Among these, a relatively common polymorphism of PPAR, Pro12Ala of PPAR2, the isoform expressed only in adipose tissue has been shown to be associated with lower body mass index, enhanced insulin sensitivity, and resistance to the risk of type 2 diabetes in human subjects carrying this mutation. Subsequent studies in different ethnic populations, however, have revealed conflicting results, suggesting a complex interaction between the PPAR2 Pro12Ala polymorphism and environmental factors such as the ratio of dietary unsaturated fatty acids to saturated fatty acids and/or between the PPAR2 Pro12Ala polymorphism and genetic factors such as polymorphic mutations in other genes. In addition, this polymorphic mutation in PPAR2 is associated with other aspects of human diseases, including cancers, polycystic ovary syndrome, Alzheimer disease and aging. This review will highlight findings from recent studies.

  19. Abscisic Acid Regulates Inflammation via Ligand-binding Domain-independent Activation of Peroxisome Proliferator-activated Receptor γ*

    Science.gov (United States)

    Bassaganya-Riera, Josep; Guri, Amir J.; Lu, Pinyi; Climent, Montse; Carbo, Adria; Sobral, Bruno W.; Horne, William T.; Lewis, Stephanie N.; Bevan, David R.; Hontecillas, Raquel

    2011-01-01

    Abscisic acid (ABA) has shown efficacy in the treatment of diabetes and inflammation; however, its molecular targets and the mechanisms of action underlying its immunomodulatory effects remain unclear. This study investigates the role of peroxisome proliferator-activated receptor γ (PPAR γ) and lanthionine synthetase C-like 2 (LANCL2) as molecular targets for ABA. We demonstrate that ABA increases PPAR γ reporter activity in RAW 264.7 macrophages and increases ppar γ expression in vivo, although it does not bind to the ligand-binding domain of PPAR γ. LANCL2 knockdown studies provide evidence that ABA-mediated activation of macrophage PPAR γ is dependent on lancl2 expression. Consistent with the association of LANCL2 with G proteins, we provide evidence that ABA increases cAMP accumulation in immune cells. ABA suppresses LPS-induced prostaglandin E2 and MCP-1 production via a PPAR γ-dependent mechanism possibly involving activation of PPAR γ and suppression of NF-κB and nuclear factor of activated T cells. LPS challenge studies in PPAR γ-expressing and immune cell-specific PPAR γ null mice demonstrate that ABA down-regulates toll-like receptor 4 expression in macrophages and T cells in vivo through a PPAR γ-dependent mechanism. Global transcriptomic profiling and confirmatory quantitative RT-PCR suggest novel candidate targets and demonstrate that ABA treatment mitigates the effect of LPS on the expression of genes involved in inflammation, metabolism, and cell signaling, in part, through PPAR γ. In conclusion, ABA decreases LPS-mediated inflammation and regulates innate immune responses through a bifurcating pathway involving LANCL2 and an alternative, ligand-binding domain-independent mechanism of PPAR γ activation. PMID:21088297

  20. Abscisic acid regulates inflammation via ligand-binding domain-independent activation of peroxisome proliferator-activated receptor gamma.

    Science.gov (United States)

    Bassaganya-Riera, Josep; Guri, Amir J; Lu, Pinyi; Climent, Montse; Carbo, Adria; Sobral, Bruno W; Horne, William T; Lewis, Stephanie N; Bevan, David R; Hontecillas, Raquel

    2011-01-28

    Abscisic acid (ABA) has shown efficacy in the treatment of diabetes and inflammation; however, its molecular targets and the mechanisms of action underlying its immunomodulatory effects remain unclear. This study investigates the role of peroxisome proliferator-activated receptor γ (PPAR γ) and lanthionine synthetase C-like 2 (LANCL2) as molecular targets for ABA. We demonstrate that ABA increases PPAR γ reporter activity in RAW 264.7 macrophages and increases ppar γ expression in vivo, although it does not bind to the ligand-binding domain of PPAR γ. LANCL2 knockdown studies provide evidence that ABA-mediated activation of macrophage PPAR γ is dependent on lancl2 expression. Consistent with the association of LANCL2 with G proteins, we provide evidence that ABA increases cAMP accumulation in immune cells. ABA suppresses LPS-induced prostaglandin E(2) and MCP-1 production via a PPAR γ-dependent mechanism possibly involving activation of PPAR γ and suppression of NF-κB and nuclear factor of activated T cells. LPS challenge studies in PPAR γ-expressing and immune cell-specific PPAR γ null mice demonstrate that ABA down-regulates toll-like receptor 4 expression in macrophages and T cells in vivo through a PPAR γ-dependent mechanism. Global transcriptomic profiling and confirmatory quantitative RT-PCR suggest novel candidate targets and demonstrate that ABA treatment mitigates the effect of LPS on the expression of genes involved in inflammation, metabolism, and cell signaling, in part, through PPAR γ. In conclusion, ABA decreases LPS-mediated inflammation and regulates innate immune responses through a bifurcating pathway involving LANCL2 and an alternative, ligand-binding domain-independent mechanism of PPAR γ activation.

  1. Identification and characterization of PPAR? ligands in the hippocampus

    OpenAIRE

    Roy, Avik; Kundu, Madhuchhanda; Jana, Malabendu; Mishra, Rama K.; Yung, Yeni; Luan, Chi-Hao; Gonzalez, Frank J.; Pahan, Kalipada

    2016-01-01

    Peroxisome proliferator-activated receptor alpha (PPAR?) regulates hepatic fatty acid catabolism and mediates the metabolic response to starvation. Recently, we have found that PPAR? is constitutively activated in nuclei of hippocampal neurons and controls plasticity via direct transcriptional activation of CREB. Here, three endogenous ligands of PPAR?, 3-hydroxy-(2,2)-dimethyl butyrate, hexadecanamide, and 9-octadecenamide were discovered in mouse brain hippocampus. Mass spectrometric detect...

  2. Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors (PPARs in Dysregulated Metabolic Homeostasis, Inflammation and Cancer: Current Evidence and Future Perspectives

    Directory of Open Access Journals (Sweden)

    Antonio Simone Laganà

    2016-06-01

    Full Text Available Background: Peroxisome proliferator-activated receptors (PPARs have demonstrated a lot of important effects in the regulation of glucose and lipid metabolism and in the correct functioning of adipose tissue. Recently, many studies have evaluated a possible effect of PPARs on tumor cells. The purpose of this review is to describe the effects of PPARs, their action and their future prospective; Methods: Narrative review aimed to synthesize cutting-edge evidence retrieved from searches of computerized databases; Results: PPARs play a key role in metabolic diseases, which include several cardiovascular diseases, insulin resistance, type 2 diabetes, metabolic syndrome, impaired immunity and the increasing risk of cancer; in particular, PPARα and PPARβ/δ mainly enable energy combustion, while PPARγ contributes to energy storage by enhancing adipogenesis; Conclusion: PPAR agonists could represent interesting types of molecules that can treat not only metabolic diseases, but also inflammation and cancer. Additional research is needed for the identification of high-affinity, high-specificity agonists for the treatment of obesity, type 2 diabetes (T2DM and other metabolic diseases. Further studies are needed also to elucidate the role of PPARs in cancer.

  3. PPARs: Key Regulators of Airway Inflammation and Potential Therapeutic Targets in Asthma

    Directory of Open Access Journals (Sweden)

    Asoka Banno

    2018-01-01

    Full Text Available Asthma affects approximately 300 million people worldwide, significantly impacting quality of life and healthcare costs. While current therapies are effective in controlling many patients' symptoms, a large number continue to experience exacerbations or treatment-related adverse effects. Alternative therapies are thus urgently needed. Accumulating evidence has shown that the peroxisome proliferator-activated receptor (PPAR family of nuclear hormone receptors, comprising PPARα, PPARβ/δ, and PPARγ, is involved in asthma pathogenesis and that ligand-induced activation of these receptors suppresses asthma pathology. PPAR agonists exert their anti-inflammatory effects primarily by suppressing pro-inflammatory mediators and antagonizing the pro-inflammatory functions of various cell types relevant to asthma pathophysiology. Experimental findings strongly support the potential clinical benefits of PPAR agonists in the treatment of asthma. We review current literature, highlighting PPARs' key role in asthma pathogenesis and their agonists' therapeutic potential. With additional research and rigorous clinical studies, PPARs may become attractive therapeutic targets in this disease.

  4. The prostaglandin EP1 receptor potentiates kainate receptor activation via a protein kinase C pathway and exacerbates status epilepticus

    Science.gov (United States)

    Rojas, Asheebo; Gueorguieva, Paoula; Lelutiu, Nadia; Quan, Yi; Shaw, Renee; Dingledine, Raymond

    2014-01-01

    Prostaglandin E2 (PGE2) regulates membrane excitability, synaptic transmission, plasticity, and neuronal survival. The consequences of PGE2 release following seizures has been the subject of much study. Here we demonstrate that the prostaglandin E2 receptor 1 (EP1, or Ptger1) modulates native kainate receptors, a family of ionotropic glutamate receptors widely expressed throughout the central nervous system. Global ablation of the EP1 gene in mice (EP1-KO) had no effect on seizure threshold after kainate injection but reduced the likelihood to enter status epilepticus. EP1-KO mice that did experience typical status epilepticus had reduced hippocampal neurodegeneration and a blunted inflammatory response. Further studies with native prostanoid and kainate receptors in cultured cortical neurons, as well as with recombinant prostanoid and kainate receptors expressed in Xenopus oocytes, demonstrated that EP1 receptor activation potentiates heteromeric but not homomeric kainate receptors via a second messenger cascade involving phospholipase C, calcium and protein kinase C. Three critical GluK5 C-terminal serines underlie the potentiation of the GluK2/GluK5 receptor by EP1 activation. Taken together, these results indicate that EP1 receptor activation during seizures, through a protein kinase C pathway, increases the probability of kainic acid induced status epilepticus, and independently promotes hippocampal neurodegeneration and a broad inflammatory response. PMID:24952362

  5. The effect of quercetin and kaempferol aglycones and glucuronides on peroxisome proliferator-activated receptor-gamma (PPAR-¿)

    NARCIS (Netherlands)

    Beekmann, K.; Rubió, L.; Haan, de L.H.J.; Actis Goretta, L.; Burg, van der B.; Bladeren, van P.J.; Rietjens, I.M.C.M.

    2015-01-01

    The consumption of dietary flavonoids has been associated with a variety of health benefits, including effects mediated by the activation of peroxisome proliferator-activated receptor-gamma (PPAR-¿). Flavonoids are extensively metabolized during and after uptake and there is little known on the

  6. The role of the prostaglandin D2 receptor, DP, in eosinophil trafficking

    DEFF Research Database (Denmark)

    Schratl, Petra; Royer, Julia F; Kostenis, Evi

    2007-01-01

    of DP has remained unclear. We report in this study that, in addition to CRTH2, the DP receptor plays an important role in eosinophil trafficking. First, we investigated the release of eosinophils from bone marrow using the in situ perfused guinea pig hind limb preparation. PGD2 induced the rapid......Prostaglandin (PG) D2 is a major mast cell product that acts via two receptors, the D-type prostanoid (DP) and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptors. Whereas CRTH2 mediates the chemotaxis of eosinophils, basophils, and Th2 lymphocytes, the role...

  7. Activation of RXR–PPAR heterodimers by organotin environmental endocrine disruptors

    Science.gov (United States)

    le Maire, Albane; Grimaldi, Marina; Roecklin, Dominique; Dagnino, Sonia; Vivat-Hannah, Valérie; Balaguer, Patrick; Bourguet, William

    2009-01-01

    The nuclear receptor retinoid X receptor-α (RXR-α)–peroxisome proliferator-activated receptor-γ (PPAR-γ) heterodimer was recently reported to have a crucial function in mediating the deleterious effects of organotin compounds, which are ubiquitous environmental contaminants. However, because organotins are unrelated to known RXR-α and PPAR-γ ligands, the mechanism by which these compounds bind to and activate the RXR-α–PPAR-γ heterodimer at nanomolar concentrations has remained elusive. Here, we show that tributyltin (TBT) activates all three RXR–PPAR-α, -γ, -δ heterodimers, primarily through its interaction with RXR. In addition, the 1.9 Å resolution structure of the RXR-α ligand-binding domain in complex with TBT shows a covalent bond between the tin atom and residue Cys 432 of helix H11. This interaction largely accounts for the high binding affinity of TBT, which only partly occupies the RXR-α ligand-binding pocket. Our data allow an understanding of the binding and activation properties of the various organotins and suggest a mechanism by which these tin compounds could affect other nuclear receptor signalling pathways. PMID:19270714

  8. PPARs Signaling and Cancer in the Gastrointestinal System

    Directory of Open Access Journals (Sweden)

    Valerio Pazienza

    2012-01-01

    Full Text Available Nowadays, the study of the peroxisome proliferators activated receptors (PPARs as potential targets for cancer prevention and therapy has gained a strong interest. From a biological point of view, the overall responsibility of PPARs in cancer development and progression is still controversial since several studies report both antiproliferative and tumor-promoting actions for these signaling molecules in human cancer cells and animal models. In this paper, we discuss PPARs functions in the context of different types of gastrointestinal cancer.

  9. Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Garrido-Gil Pablo

    2012-02-01

    Full Text Available Abstract Background Several recent studies have shown that angiotensin type 1 receptor (AT1 antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ. PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions. Methods We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a-null mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662. Results We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a-null mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co

  10. PHARMACOGENOMICS OF PROSTAGLANDIN AND LEUKOTRIENE RECEPTORS

    Directory of Open Access Journals (Sweden)

    José Antonio Cornejo-García

    2016-09-01

    Full Text Available Individual genetic background together with environmental effects are thought to be behind many human complex diseases. A number of genetic variants, mainly single nucleotide polymorphisms (SNPs, have been shown to be associated with various pathological and inflammatory conditions, representing potential therapeutic targets. Prostaglandins (PTGs and leukotrienes (LTs are eicosanoids derived from arachidonic acid and related polyunsaturated fatty acids that participate in both normal homeostasis and inflammatory conditions. These bioactive lipid mediators are synthesised through two major multistep enzymatic pathways: PTGs by cyclooxygenase and LTs by 5-lipoxygenase. The main physiological effects of PTGs include vasodilation and vascular leakage (PTGE2; mast cell maturation, eosinophil recruitment and allergic responses (PTGD2; vascular and respiratory smooth muscle contraction (PTGF2, and inhibition of platelet aggregation (PTGI2. LTB4 is mainly involved in neutrophil recruitment, vascular leakage, and epithelial barrier function, whereas cysteinyl LTs (CysLTs (LTC4, LTD4 and LTE4 induce bronchoconstriction and neutrophil extravasation, and also participate in vascular leakage. PTGs and LTs exert their biological functions by binding to cognate receptors, which belong to the seven transmembrane, G protein-coupled receptor superfamily. SNPs in genes encoding these receptors may influence their functionality and have a role in disease susceptibility and drug treatment response. In this review we summarize SNPs in PTGs and LTs receptors and their relevance in human diseases. We also provide information on gene expression. Finally, we speculate on future directions for this topic.

  11. Restoration of Endothelial Function in Pparα−/− Mice by Tempol

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    Neerupma Silswal

    2015-01-01

    Full Text Available Peroxisome proliferator activated receptor alpha (PPARα is one of the PPAR isoforms belonging to the nuclear hormone receptor superfamily that regulates genes involved in lipid and lipoprotein metabolism. PPARα is present in the vascular wall and is thought to be involved in protection against vascular disease. To determine if PPARα contributes to endothelial function, conduit and cerebral resistance arteries were studied in Pparα−/− mice using isometric and isobaric tension myography, respectively. Aortic contractions to PGF2α and constriction of middle cerebral arteries to phenylephrine were not different between wild type (WT and Pparα−/−; however, relaxation/dilation to acetylcholine (ACh was impaired. There was no difference in relaxation between WT and Pparα−/− aorta to treatment with a nitric oxide (NO surrogate indicating impairment in endothelial function. Endothelial NO levels as well as NO synthase expression were reduced in Pparα−/− aortas, while superoxide levels were elevated. Two-week feeding with the reactive oxygen species (ROS scavenger, tempol, normalized ROS levels and rescued the impaired endothelium-mediated relaxation in Pparα−/− mice. These results suggest that Pparα−/− mice have impaired endothelial function caused by decreased NO bioavailability. Therefore, activation of PPARα receptors may be a therapeutic target for maintaining endothelial function and protection against cardiovascular disease.

  12. Examination of adipose depot-specific PPAR moieties

    Energy Technology Data Exchange (ETDEWEB)

    Dodson, M.V., E-mail: dodson@wsu.edu [Department of Animal Sciences, Washington State University, Pullman, WA 99164 (United States); Vierck, J.L. [Department of Animal Sciences, Washington State University, Pullman, WA 99164 (United States); Hausman, G.J. [USDA-ARS, Richard B. Russell Agricultural Research Station, Athens, GA 30604 (United States); Guan, L.L. [Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, T6G 2P5 Canada (Canada); Fernyhough, M.E. [The Hartz Mountain Corporation, Secaucus, NJ 07094 (United States); Poulos, S.P. [The Coca-Cola Company, Research and Technology, Atlanta, GA 30313 (United States); Mir, P.S. [Agriculture and Agri-Food Canada Research Centre, Lethbridge, CA T1J 4B1 (United States); Jiang, Z. [Department of Animal Sciences, Washington State University, Pullman, WA 99164 (United States)

    2010-04-02

    Molecular mechanisms of peroxisome proliferator activated receptors (PPARs) are being defined rapidly, as illustrated by the volume of papers published. Much of the research is directed towards a clinical end-point/application; however, the non-homogeneous nature of adipose depots in laboratory animals is spurring similar research in domestic meat animals (such as beef cattle). Moreover, the size of adipose depots in meat animals remains an attractive feature for using them to obtain cells for PPAR research. Examination of meat-animal depot-specific PPAR moieties may provide novel information about adipocyte regulation that might be extrapolated to all animals.

  13. Examination of adipose depot-specific PPAR moieties

    International Nuclear Information System (INIS)

    Dodson, M.V.; Vierck, J.L.; Hausman, G.J.; Guan, L.L.; Fernyhough, M.E.; Poulos, S.P.; Mir, P.S.; Jiang, Z.

    2010-01-01

    Molecular mechanisms of peroxisome proliferator activated receptors (PPARs) are being defined rapidly, as illustrated by the volume of papers published. Much of the research is directed towards a clinical end-point/application; however, the non-homogeneous nature of adipose depots in laboratory animals is spurring similar research in domestic meat animals (such as beef cattle). Moreover, the size of adipose depots in meat animals remains an attractive feature for using them to obtain cells for PPAR research. Examination of meat-animal depot-specific PPAR moieties may provide novel information about adipocyte regulation that might be extrapolated to all animals.

  14. Effects of Rosiglitazone on the Expression of PPAR-γ and on the ...

    African Journals Online (AJOL)

    Purpose: Peroxisome proliferator-activated receptor (PPAR)-γ ligand is known to repress the expression of pro-inflammatory mediators. However, it is unclear how it affects PPAR-γ expression and the inflammatory response in the human lung. We investigated the effects of rosiglitazone (synthetic PPAR-γ ligand) on the ...

  15. Activation of peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) suppresses postprandial lipidemia through fatty acid oxidation in enterocytes

    Energy Technology Data Exchange (ETDEWEB)

    Kimura, Rino [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Takahashi, Nobuyuki, E-mail: nobu@kais.kyoto-u.ac.jp [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Murota, Kaeko [Department of Life Science, School of Science and Engineering, Kinki University, Osaka 770-8503 (Japan); Yamada, Yuko [Laboratory of Physiological Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Niiya, Saori; Kanzaki, Noriyuki; Murakami, Yoko [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Moriyama, Tatsuya [Department of Applied Cell Biology, Graduate School of Agriculture, Kinki University, Nara 631-8505 (Japan); Goto, Tsuyoshi; Kawada, Teruo [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan)

    2011-06-24

    Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of fatty acid oxidation-related genes in human intestinal epithelial Caco-2 cells. {yields} PPAR{alpha} activation also increased oxygen consumption rate and CO{sub 2} production and decreased secretion of triglyceride and ApoB from Caco-2 cells. {yields} Orally administration of bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and CO{sub 2} production in small intestinal epithelial cells. {yields} Treatment with bezafibrate decreased postprandial serum concentration of triglyceride after oral injection of olive oil in mice. {yields} It suggested that intestinal lipid metabolism regulated by PPAR{alpha} activation suppresses postprandial lipidemia. -- Abstract: Activation of peroxisome proliferator-activated receptor (PPAR)-{alpha} which regulates lipid metabolism in peripheral tissues such as the liver and skeletal muscle, decreases circulating lipid levels, thus improving hyperlipidemia under fasting conditions. Recently, postprandial serum lipid levels have been found to correlate more closely to cardiovascular diseases than fasting levels, although fasting hyperlipidemia is considered an important risk of cardiovascular diseases. However, the effect of PPAR{alpha} activation on postprandial lipidemia has not been clarified. In this study, we examined the effects of PPAR{alpha} activation in enterocytes on lipid secretion and postprandial lipidemia. In Caco-2 enterocytes, bezafibrate, a potent PPAR{alpha} agonist, increased mRNA expression levels of fatty acid oxidation-related genes, such as acyl-CoA oxidase, carnitine palmitoyl transferase, and acyl-CoA synthase, and oxygen consumption rate (OCR) and suppressed secretion levels of both triglycerides and apolipoprotein B into the basolateral side. In vivo experiments revealed that feeding high-fat-diet containing bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and

  16. Prostaglandins and their receptors in insect biology

    Directory of Open Access Journals (Sweden)

    David eStanley

    2011-12-01

    Full Text Available We treat the biological significance of prostaglandins (PGs and their known receptors in insect biology. PGs and related eicosanoids are oxygenated derivatives of arachidonic acid (AA and two other C20 polyunsaturated fatty acids. PGs are mostly appreciated in the context of biomedicine, but a growing body of literature indicates the biological significance of these compounds extends throughout the animal kingdom, and possibly beyond. PGs act in several crucial areas of insect biology. In reproduction, a specific PG, PGE2, releases oviposition behavior in most crickets and a few other insect species; PGs also mediate events in egg development in some species, which may represent all insects. PGs play major roles in modulating fluid secretion in Malpighian tubules, rectum and salivary glands, although, again, this has been studied in only a few insect species that may represent the Class. Insect immunity is a very complex defense system. PGs and other eicosanoids mediate a large number of immune reactions to infection and invasion. The actions of most PGs are mediated by specific receptors. Biomedical research has discovered a great deal of knowledge about PG receptors in mammals, including their structures, pharmacology, molecular biology and cellular locations. Studies of PG receptors in insects lag behind the biomedical background, however, recent results hold the promise of accelerated research in this area. A PG receptor has been identified in a class of lepidopteran hemocytes and experimentally linked to the release of prophenoloxidase. We conclude that research into PGs and their receptors in insects will lead to important advances in our understanding of insect biology.

  17. Evolutionary Pattern and Regulation Analysis to Support Why Diversity Functions Existed within PPAR Gene Family Members

    Directory of Open Access Journals (Sweden)

    Tianyu Zhou

    2015-01-01

    Full Text Available Peroxisome proliferators-activated receptor (PPAR gene family members exhibit distinct patterns of distribution in tissues and differ in functions. The purpose of this study is to investigate the evolutionary impacts on diversity functions of PPAR members and the regulatory differences on gene expression patterns. 63 homology sequences of PPAR genes from 31 species were collected and analyzed. The results showed that three isolated types of PPAR gene family may emerge from twice times of gene duplication events. The conserved domains of HOLI (ligand binding domain of hormone receptors domain and ZnF_C4 (C4 zinc finger in nuclear in hormone receptors are essential for keeping basic roles of PPAR gene family, and the variant domains of LCRs may be responsible for their divergence in functions. The positive selection sites in HOLI domain are benefit for PPARs to evolve towards diversity functions. The evolutionary variants in the promoter regions and 3′ UTR regions of PPARs result into differential transcription factors and miRNAs involved in regulating PPAR members, which may eventually affect their expressions and tissues distributions. These results indicate that gene duplication event, selection pressure on HOLI domain, and the variants on promoter and 3′ UTR are essential for PPARs evolution and diversity functions acquired.

  18. Evolutionary Pattern and Regulation Analysis to Support Why Diversity Functions Existed within PPAR Gene Family Members.

    Science.gov (United States)

    Zhou, Tianyu; Yan, Xiping; Wang, Guosong; Liu, Hehe; Gan, Xiang; Zhang, Tao; Wang, Jiwen; Li, Liang

    2015-01-01

    Peroxisome proliferators-activated receptor (PPAR) gene family members exhibit distinct patterns of distribution in tissues and differ in functions. The purpose of this study is to investigate the evolutionary impacts on diversity functions of PPAR members and the regulatory differences on gene expression patterns. 63 homology sequences of PPAR genes from 31 species were collected and analyzed. The results showed that three isolated types of PPAR gene family may emerge from twice times of gene duplication events. The conserved domains of HOLI (ligand binding domain of hormone receptors) domain and ZnF_C4 (C4 zinc finger in nuclear in hormone receptors) are essential for keeping basic roles of PPAR gene family, and the variant domains of LCRs may be responsible for their divergence in functions. The positive selection sites in HOLI domain are benefit for PPARs to evolve towards diversity functions. The evolutionary variants in the promoter regions and 3' UTR regions of PPARs result into differential transcription factors and miRNAs involved in regulating PPAR members, which may eventually affect their expressions and tissues distributions. These results indicate that gene duplication event, selection pressure on HOLI domain, and the variants on promoter and 3' UTR are essential for PPARs evolution and diversity functions acquired.

  19. PPAR-α Ligands as Potential Therapeutic Agents for Wet Age-Related Macular Degeneration

    Directory of Open Access Journals (Sweden)

    Marisol del V Cano

    2008-01-01

    Full Text Available The peroxisome proliferator-activated receptors (PPAR's are members of the steroid/thyroid nuclear receptor, superfamily of transcription factors. There are currently three known PPAR subtypes, α, β, and γ. The PPARs are now recognized participants in a number of biological pathways some of which are implicated in the pathogenesis of age-related macular degeneration (AMD. These include immune modulation, lipid regulation, and oxidant/antioxidant pathways important to the onset and progression of “dry” AMD, and vascular endothelial growth factor (VEGF mediated pathways that stimulate choroidal neovascularization (CNV, characteristic of “wet” AMD. PPAR-α is found in retina and also on vascular cells important to formation of CNV. At this time, however, relatively little is known about potential contributions of PPAR-α to the pathogenesis of dry and wet AMD. This review examines current literature for potential roles of PPAR-α in the pathogenesis and potential treatment of AMD with emphasis on prevention and treatment of wet AMD.

  20. Peroxisome Proliferator-Activated Receptor ß/ (PPARß/) but Not PPAR Serves as a Plasma Free Fatty Acid Sensor in Liver

    NARCIS (Netherlands)

    Sanderson, L.; Degerhardt, T.; Desvergne, B.; Koppen, A.; Kalkhoven, E.; Müller, M.R.; Kersten, A.H.

    2009-01-01

    Peroxisome proliferator-activated receptor alpha (PPAR alpha) is an important transcription factor in liver that can be activated physiologically by fasting or pharmacologically by using high-affinity synthetic agonists. Here we initially set out to elucidate the similarities in gene induction

  1. PPARs, Obesity, and Inflammation

    Directory of Open Access Journals (Sweden)

    Rinke Stienstra

    2007-01-01

    Full Text Available The worldwide prevalence of obesity and related metabolic disorders is rising rapidly, increasing the burden on our healthcare system. Obesity is often accompanied by excess fat storage in tissues other than adipose tissue, including liver and skeletal muscle, which may lead to local insulin resistance and may stimulate inflammation, as in steatohepatitis. In addition, obesity changes the morphology and composition of adipose tissue, leading to changes in protein production and secretion. Some of these secreted proteins, including several proinflammatory mediators, may be produced by macrophages resident in the adipose tissue. The changes in inflammatory status of adipose tissue and liver with obesity feed a growing recognition that obesity represents a state of chronic low-level inflammation. Various molecular mechanisms have been implicated in obesity-induced inflammation, some of which are modulated by the peroxisome proliferator-activated receptors (PPARs. PPARs are ligand-activated transcription factors involved in the regulation of numerous biological processes, including lipid and glucose metabolism, and overall energy homeostasis. Importantly, PPARs also modulate the inflammatory response, which makes them an interesting therapeutic target to mitigate obesity-induced inflammation and its consequences. This review will address the role of PPARs in obesity-induced inflammation specifically in adipose tissue, liver, and the vascular wall.

  2. 15-Deoxy-Δ{sup 12,14}-prostaglandin J{sub 2} inhibits IL-13 production in T cells via an NF-κB-dependent mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Doyle, Marie-Christine; Tremblay, Sarah [Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke (QC), Canada J1K 2R1 (Canada); Dumais, Nancy, E-mail: nancy.dumais@usherbrooke.ca [Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke (QC), Canada J1K 2R1 (Canada)

    2013-02-15

    Highlights: ► 15d-PGJ{sub 2} decreased IL-13 mRNA transcription and secretion in activated T cells. ► IL-13 inhibition by 15d-PGJ{sub 2} is independent of PPAR-γ. ► The nuclear factor-κB mediates the 15d-PGJ{sub 2}-dependent down regulation of IL-13. -- Abstract: Interleukin (IL)-13 is a cytokine produced by activated CD4{sup +} T cells that plays a critical role in promoting allergic responses and tumor cell growth. The 15-deoxy-Δ{sup 12,14}-prostaglandin J{sub 2} (15d-PGJ{sub 2}) is a natural ligand for the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ), a known regulator of anti-inflammatory activities. We determined the effects of 15d-PGJ{sub 2} on IL-13 expression in the Jurkat E6.1 T-cell line and in peripheral blood mononuclear cells. Semi-quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay revealed that treatment of activated T cells with 15d-PGJ{sub 2} significantly decreased IL-13 mRNA transcription and secretion, respectively. This inhibition by 15d-PGJ{sub 2} was independent of PPAR-γ since treatment with GW9662, an irreversible antagonist of the nuclear receptor, produced no effect. Our data also revealed the involvement of nuclear factor-κB in mediating 15d-PGJ{sub 2}-dependent down regulation of IL-13 expression. Collectively, these results demonstrate the potential of 15d-PGJ{sub 2} in attenuating expression and production of IL-13 in activated T cells.

  3. Attenuation of Immune-Mediated Renal Injury by Telmisartan, an Angiotensin Receptor Blocker and a Selective PPAR-γ Activator

    Directory of Open Access Journals (Sweden)

    Yuki Hamano

    2011-09-01

    Full Text Available Background/Aims: Anti-glomerular basement membrane (GBM nephritis is characterized by activation of the renin-angiotensin system. This study aimed to determine the question of whether a temporary angiotensin II blockade at the initial stage of anti-GBM nephritis is able to attenuate the disease as well as differences in renoprotection among angiotensin II receptor blockers (ARBs with distinct peroxisome proliferator-activated receptor (PPAR-γ-modulating activities. Methods: C57BL/6J mice were immunized with rabbit IgG, followed by intravenous injection of rabbit anti-mouse antibodies. Mice were then treated with telmisartan, losartan, and telmisartan + GW9662 (a PPAR-γ antagonist for 5 days, or hydralazine for 9 days. On days 8 and 13, mice were sacrificed to obtain tissues for histological analysis. Results: The temporary administration of telmisartan significantly suppressed glomerular damage compared to hydralazine. Losartan showed a similar effect but was less effective. Co-administration of GW9662 attenuated the renoprotective effect of telmisartan, almost to levels observed with losartan. In particular, it limited the decreased infiltration of inflammatory cells and preservation of capillaries in the glomeruli induced by telmisartan. Conclusion: Temporary angiotensin II blockade at the initial stage of anti-GBM disease dramatically inhibited its progression. In addition to a class effect of ARBs, telmisartan modified inflammation and endothelial damage in the kidney through its PPAR-γ-agonistic action.

  4. Telmisartan prevented cognitive decline partly due to PPAR-γ activation

    International Nuclear Information System (INIS)

    Mogi, Masaki; Li Jianmei; Tsukuda, Kana; Iwanami, Jun; Min, Li-Juan; Sakata, Akiko; Fujita, Teppei; Iwai, Masaru; Horiuchi, Masatsugu

    2008-01-01

    Telmisartan is a unique angiotensin receptor blocker (ARB) and partial agonist of peroxisome proliferator-activated receptor (PPAR)-γ. Here, we investigated the preventive effect of telmisartan on cognitive decline in Alzheimer disease. In ddY mice, intracerebroventricular injection of Aβ 1-40 significantly attenuated their cognitive function evaluated by shuttle avoidance test. Pretreatment with a non-hypotensive dose of telmisartan significantly inhibited such cognitive decline. Interestingly, co-treatment with GW9662, a PPAR-γ antagonist, partially inhibited this improvement of cognitive decline. Another ARB, losartan, which has less PPAR-γ agonistic effect, also inhibited Aβ-injection-induced cognitive decline; however the effect was smaller than that of telmisartan and was not affected by GW9662. Immunohistochemical staining for Aβ showed the reduced Aβ deposition in telmisartan-treated mice. However, this reduction was not observed in mice co-administered GW9662. These findings suggest that ARB has a preventive effect on cognitive impairment in Alzheimer disease, and telmisartan, with PPAR-γ activation, could exert a stronger effect

  5. Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.

    Directory of Open Access Journals (Sweden)

    Katrin Hack

    Full Text Available We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787 retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration.

  6. Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats

    DEFF Research Database (Denmark)

    Boberg, Julie; Metzdorff, Stine Broeng; Wortziger, Rasmus Henrik Sorgenfryd

    2008-01-01

    of obesity and insulin resistance. These effects could be related to chemical interaction with nuclear receptors such as the peroxisome proliferator activated receptors (PPARs). As several testosterone-reducing drugs are PPAR activators, we aimed to examine whether four PPAR agonists were able to affect...

  7. Activation of Central PPAR-γ Attenuates Angiotensin II-Induced Hypertension

    Science.gov (United States)

    Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Guo, Fang; Johnson, Alan Kim; Felder, Robert B

    2015-01-01

    Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg/min) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2 and angiotensin II type-1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension. PMID:26101342

  8. Prenatal polycyclic aromatic hydrocarbon, adiposity, peroxisome proliferator-activated receptor (PPAR γ methylation in offspring, grand-offspring mice.

    Directory of Open Access Journals (Sweden)

    Zhonghai Yan

    Full Text Available Greater levels of prenatal exposure to polycyclic aromatic hydrocarbon (PAH have been associated with childhood obesity in epidemiological studies. However, the underlying mechanisms are unclear.We hypothesized that prenatal PAH over-exposure during gestation would lead to weight gain and increased fat mass in offspring and grand-offspring mice. Further, we hypothesized that altered adipose gene expression and DNA methylation in genes important to adipocyte differentiation would be affected.Pregnant dams were exposed to a nebulized PAH mixture versus negative control aerosol 5 days a week, for 3 weeks. Body weight was recorded from postnatal day (PND 21 through PND60. Body composition, adipose cell size, gene expression of peroxisome proliferator-activated receptor (PPAR γ, CCAAT/enhancer-binding proteins (C/EBP α, cyclooxygenase (Cox-2, fatty acid synthase (FAS and adiponectin, and DNA methylation of PPAR γ, were assayed in both the offspring and grand-offspring adipose tissue.Offspring of dams exposed to greater PAH during gestation had increased weight, fat mass, as well as higher gene expression of PPAR γ, C/EBP α, Cox2, FAS and adiponectin and lower DNA methylation of PPAR γ. Similar differences in phenotype and DNA methylation extended through the grand-offspring mice.Greater prenatal PAH exposure was associated with increased weight, fat mass, adipose gene expression and epigenetic changes in progeny.

  9. PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression possibly through PPAR{gamma} activation in the liver

    Energy Technology Data Exchange (ETDEWEB)

    Oishi, Katsutaka, E-mail: k-ooishi@aist.go.jp [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Uchida, Daisuke [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki (Japan); Ohkura, Naoki [Department of Clinical Molecular Biology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa (Japan); Horie, Shuichi [Department of Clinical Biochemistry, Kagawa Nutrition University, Sakado, Saitama (Japan)

    2010-10-15

    Research highlights: {yields} PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression. {yields} Hepatic expressions of PPAR{gamma} and PCG-1{alpha} are induced by a ketogenic diet. {yields} PPAR{gamma} antagonist attenuates a ketogenic diet-induced PAI-1 expression. {yields} Ketogenic diet advances the phase of circadian clock in a PPAR{alpha}-independent manner. -- Abstract: An increased level of plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular diseases, and PAI-1 gene expression is under the control of molecular circadian clocks in mammals. We recently showed that PAI-1 expression is augmented in a phase-advanced circadian manner in mice fed with a ketogenic diet (KD). To determine whether peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) is involved in hypofibrinolytic status induced by a KD, we examined the expression profiles of PAI-1 and circadian clock genes in PPAR{alpha}-null KD mice. Chronic administration of bezafibrate induced the PAI-1 gene expression in a PPAR{alpha}-dependent manner. Feeding with a KD augmented the circadian expression of PAI-1 mRNA in the hearts and livers of wild-type (WT) mice as previously described. The KD-induced mRNA expression of typical PPAR{alpha} target genes such as Cyp4A10 and FGF21 was damped in PPAR{alpha}-null mice. However, plasma PAI-1 concentrations were significantly more elevated in PPAR{alpha}-null KD mice in accordance with hepatic mRNA levels. These observations suggest that PPAR{alpha} activation is dispensable for KD-induced PAI-1 expression. We also found that hyperlipidemia, fatty liver, and the hepatic expressions of PPAR{gamma} and its coactivator PCG-1{alpha} were more effectively induced in PPAR{alpha}-null, than in WT mice on a KD. Furthermore, KD-induced hepatic PAI-1 expression was significantly suppressed by supplementation with bisphenol A diglycidyl ether, a PPAR{gamma} antagonist, in both WT and PPAR

  10. 15-Deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} impairs the functions of histone acetyltransferases through their insolubilization in cells

    Energy Technology Data Exchange (ETDEWEB)

    Hironaka, Asako [Department of Biochemistry, Nara Medical University, Shijo-Cho 840, Kashihara, Nara 634-8521 (Japan); Morisugi, Toshiaki; Kawakami, Tetsuji [Department of Oral and Maxillofacial Surgery, Nara Medical University, Shijo-Cho 840, Kashihara, Nara 634-8521 (Japan); Miyagi, Ikuko [Laboratory of Biometabolic Chemistry, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-Cho, Okinawa 903-0215 (Japan); Tanaka, Yasuharu, E-mail: yatanaka@med.u-ryukyu.ac.jp [Laboratory of Biometabolic Chemistry, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-Cho, Okinawa 903-0215 (Japan)

    2009-12-11

    The cyclopentenonic prostaglandin 15-deoxy-{Delta}{sup 12,14}-PG J{sub 2} (15d-PGJ{sub 2}) is a metabolite derived from PGD{sub 2}. Although 15d-PGJ{sub 2} has been demonstrated to be a potent ligand for peroxisome proliferator activated receptor {gamma} (PPAR{gamma}), the functions are not fully understood. In order to examine the effect of 15d-PGJ{sub 2} on histone acetyltransferases (HATs), several lines of cell including mouse embryonic fibroblast (MEF) cells were exposed to 15d-PGJ{sub 2}. Three types of HAT, p300, CREB-binding protein (CBP), and p300/CBP-associated factor (PCAF), selectively disappeared from the soluble fraction in time- and dose-dependent manners. Inversely, HATs in the insoluble fraction increased, suggesting their conformational changes. The decrease in the soluble form of HATs resulted in the attenuation of NF-{kappa}B-, p53-, and heat shock factor-dependent reporter gene expressions, implying that the insoluble HATs are inactive. The resultant insoluble PCAF and p300 seemed to be digested by proteasome, because proteasome inhibitors caused the accumulation of insoluble HATs. Taken together, these results indicate that 15d-PGJ{sub 2} attenuates some gene expressions that require HATs. This inhibitory action of 15d-PGJ{sub 2} on the function of HATs was independent of PPAR{gamma}, because PPAR{gamma} agonists could not mimick 15d-PGJ{sub 2} and PPAR{gamma} antagonists did not inhibit 15d-PGJ{sub 2}.

  11. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist inhibits collagen synthesis in human hypertrophic scar fibroblasts by targeting Smad3 via miR-145

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Hua-Yu; Li, Chao; Zheng, Zhao; Zhou, Qin; Guan, Hao; Su, Lin-Lin; Han, Jun-Tao; Zhu, Xiong-Xiang; Wang, Shu-yue; Li, Jun, E-mail: lijunfmmu@163.com; Hu, Da-Hai, E-mail: hudahaifmmu@aliyun.com

    2015-03-27

    The transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ) functions to regulate cell differentiation and lipid metabolism. Recently, its agonist has been documented to regulate extracellular matrix production in human dermal fibroblasts. This study explored the underlying molecular mechanisms and gene interactions in hypertrophic scar fibroblasts (HSFBs) in vitro. HSFBs were cultured and treated with or without PPAR-γ agonist or antagonist for gene expression. Bioinformatical analysis predicted that miR-145 could target Smad3 expression. Luciferase assay was used to confirm such an interaction. The data showed that PPAR-γ agonist troglitazone suppressed expression of Smad3 and Col1 in HSFBs. PPAR-γ agonist induced miR-145 at the gene transcriptional level, which in turn inhibited Smad3 expression and Col1 level in HSFBs. Furthermore, ELISA data showed that Col1 level in HSFBs was controlled by a feedback regulation mechanism involved in PPAR-γ agonist and antagonist-regulated expression of miR-145 and Smad3 in HSFBs. These findings indicate that PPAR-γ-miR-145-Smad3 axis plays a role in regulation of collagen synthesis in HSFBs. - Highlights: • PPAR-γ agonist inhibits collagen synthesis in HSFBs. • Smad3 and type I collagen expression are decreased by PPAR-γ agonist. • miR-145 expression is increased by PPAR-γ agonist in HSFBs. • Increased miR-145 inhibits collagen synthesis by targeting Smad3. • miR-145 regulates collagen synthesis.

  12. Genetic Manipulations of PPARs: Effects on Obesity and Metabolic Disease

    Directory of Open Access Journals (Sweden)

    Yaacov Barak

    2007-01-01

    Full Text Available The interest in genetic manipulations of PPARs is as old as their discovery as receptors of ligands with beneficial clinical activities. Considering the effects of PPAR ligands on critical aspects of systemic physiology, including obesity, lipid metabolism, insulin resistance, and diabetes, gene knockout (KO in mice is the ideal platform for both hypothesis testing and discovery of new PPAR functions in vivo. With the fervent pursuit of the magic bullet to eradicate the obesity epidemic, special emphasis has been placed on the impacts of PPARs on obesity and its associated diseases. As detailed in this review, understanding how PPARs regulate gene expression and basic metabolic pathways is a necessary intermediate en route to deciphering their effects on obesity. Over a decade and dozens of genetic modifications of PPARs into this effort, valuable lessons have been learned, but we are left with more questions to be answered. These lessons and future prospects are the subject of this review.

  13. A role for central nervous system PPAR-γ in the regulation of energy balance.

    Science.gov (United States)

    Ryan, Karen K; Li, Bailing; Grayson, Bernadette E; Matter, Emily K; Woods, Stephen C; Seeley, Randy J

    2011-05-01

    The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that is activated by lipids to induce the expression of genes involved in lipid and glucose metabolism, thereby converting nutritional signals into metabolic consequences. PPAR-γ is the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs, which have been widely prescribed to treat type 2 diabetes mellitus. A common side effect of treatment with TZDs is weight gain. Here we report a previously unknown role for central nervous system (CNS) PPAR-γ in the regulation of energy balance. We found that both acute and chronic activation of CNS PPAR-γ, by either TZDs or hypothalamic overexpression of a fusion protein consisting of PPAR-γ and the viral transcriptional activator VP16 (VP16-PPAR-γ), led to positive energy balance in rats. Blocking the endogenous activation of CNS PPAR-γ with pharmacological antagonists or reducing its expression with shRNA led to negative energy balance, restored leptin sensitivity in high-fat-diet (HFD)-fed rats and blocked the hyperphagic response to oral TZD treatment. These findings have implications for the widespread clinical use of TZD drugs and for understanding the etiology of diet-induced obesity.

  14. Hypoxia-inducible Lipid Droplet-associated (HILPDA) Is a Novel Peroxisome Proliferator-activated Receptor (PPAR) Target Involved in Hepatic Triglyceride Secretion

    NARCIS (Netherlands)

    Mattijsen, F.; Georgiadi, A.; Andasarie, T.; Szalowska, E.; Zota, A.; Krones-Herzig, A.; Kersten, A.H.

    2014-01-01

    Peroxisome proliferator-activated receptors (PPARs) play major roles in the regulation of hepatic lipid metabolism through the control of numerous genes involved in processes such as lipid uptake and fatty acid oxidation. Here we identify hypoxia-inducible lipid droplet-associated (Hilpda/Hig2) as a

  15. PPAR-γ and CYP46A1 genes polymorphism is associated with ...

    African Journals Online (AJOL)

    Syed Tasleem Raza

    2016-04-30

    Apr 30, 2016 ... Abstract Background: Involvement of genetic factors like gene polymorphisms was found to con- ... PPAR-c is a type II nuclear receptor which is encoded by the PPAR-c ... nificantly associated with diabetic retinopathy [10,11].

  16. Deletion of PPAR-γ in immune cells enhances susceptibility to antiglomerular basement membrane disease

    Directory of Open Access Journals (Sweden)

    Cristen Chafin

    2010-10-01

    Full Text Available Cristen Chafin2, Sarah Muse2, Raquel Hontecillas5, Josep Bassaganya-Riera5, David L Caudell2, Samuel K Shimp III4, M Nichole Rylander4, John Zhang6, Liwu Li3, Christopher M Reilly1,21Virginia College of Osteopathic Medicine, 2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; 3Department of Biological Sciences, 4Department of Mechanical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; 5Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; 6Medical University of SC, Charleston, SC, USAAbstract: Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR-γ has been shown to be immunoregulatory in autoimmune diseases by inhibiting production of a number of inflammatory mediators. We investigated whether PPAR-γ gene deletion in hematopoietic cells would alter disease pathogenesis in the antiglomerular basement membrane (anti-GBM mouse model. PPAR-γ+/+ and PPAR-γ-/- mice were immunized with rabbit antimouse GBM antibodies and lipopolysaccharide and evaluated for two weeks. Although both the PPAR-γ+/+ and PPAR-γ-/- mice had IgG deposition in the glomerulus and showed proteinuria two weeks after injection, glomerular and tubulointerstitial disease in PPAR-γ-/- mice were significantly more severe compared with the PPAR-γ+/+ animals. We observed that the PPAR-γ-/- mice had decreased CD4+CD25+ regulatory T cells and an increased CD8+:CD4+ ratio as compared with the PPAR-γ+/+ mice, suggesting that PPAR-γ has a role in the regulation of T cells. Furthermore, plasma interleukin-6 levels were significantly increased in the PPAR-γ-/- mice at two weeks as compared with the PPAR-γ+/+ animals. Taken together, these studies show that

  17. Antidepressant-like effect of atorvastatin in the forced swimming test in mice: the role of PPAR-gamma receptor and nitric oxide pathway.

    Science.gov (United States)

    Shahsavarian, Arash; Javadi, Shiva; Jahanabadi, Samane; Khoshnoodi, Mina; Shamsaee, Javad; Shafaroodi, Hamed; Mehr, Shahram Ejtemaei; Dehpour, Ahmadreza

    2014-12-15

    Atorvastatin is a synthetic and lipophilic statin which has been reported to have a positive role in reducing depression. The potential antidepressant-like effects of atorvastatin and the possible involvement of peroxisome proliferator-activated receptor gamma (PPAR_γ) and nitric oxide system were determined using forced swimming test (FST) in mice was studied. Atorvastatin (0.01, 0.1 and 1 mg/kg, p.o.) was administered 1 h before FST. To assess the involvement of PPAR_γ in the possible antidepressant effect of atorvastatin, pioglitazone, a PPAR_γ agonist (5 mg/kg), and GW-9662, a specific PPAR_γ antagonist (2 mg/kg), was co-administered with atorvastatin (0.01 mg/kg, p.o.) and then FST was performed. The possible role of nitric oxide pathway was determined by using co-administration of a non-specific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.p.), and a NO precursor, L-arginine (750 mg/kg, i.p.) with sub-effective doses of atorvastatin and pioglitazone. Immobility time was significantly decreased after atorvastatin administration (0.1 and 1 mg/kg, p.o.). Administration of pioglitazone or L-NAME in combination with the sub-effective dose of atorvastatin (0.01 mg/kg, p.o.) reduced the immobility time in the FST compared to drugs alone, showing the participation of these pathways; while co-administration of non-effective doses of atorvastatin and pioglitazone with GW9662 or L-arginine reversed antidepressant-like effect of atorvastatin in FST. Data from concurrent use of GW9662 and atorvastatin also demonstrated that the antidepressant effect of atorvastatin was significantly reversed by GW9662. The antidepressant-like effect of atorvastatin on mice in the FST is mediated at least in part through PPARreceptors and NO pathway. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. PPAR Agonists and Metabolic Syndrome: An Established Role?

    Directory of Open Access Journals (Sweden)

    Margherita Botta

    2018-04-01

    Full Text Available Therapeutic approaches to metabolic syndrome (MetS are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome proliferator-activated receptors (PPARs are involved in the metabolic regulation of lipid and lipoprotein levels, i.e., triglycerides (TGs, blood glucose, and abdominal adiposity. PPARs may be classified into the α, β/δ and γ subtypes. The PPAR-α agonists, mainly fibrates (including newer molecules such as pemafibrate and omega-3 fatty acids, are powerful TG-lowering agents. They mainly affect TG catabolism and, particularly with fibrates, raise the levels of high-density lipoprotein cholesterol (HDL-C. PPAR-γ agonists, mainly glitazones, show a smaller activity on TGs but are powerful glucose-lowering agents. Newer PPAR-α/δ agonists, e.g., elafibranor, have been designed to achieve single drugs with TG-lowering and HDL-C-raising effects, in addition to the insulin-sensitizing and antihyperglycemic effects of glitazones. They also hold promise for the treatment of non-alcoholic fatty liver disease (NAFLD which is closely associated with the MetS. The PPAR system thus offers an important hope in the management of atherogenic dyslipidemias, although concerns regarding potential adverse events such as the rise of plasma creatinine, gallstone formation, drug–drug interactions (i.e., gemfibrozil and myopathy should also be acknowledged.

  19. Immunoregulatory mechanisms of macrophage PPAR-γ in mice with experimental inflammatory bowel disease.

    Science.gov (United States)

    Hontecillas, R; Horne, W T; Climent, M; Guri, A J; Evans, C; Zhang, Y; Sobral, B W; Bassaganya-Riera, J

    2011-05-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) is widely expressed in macrophages and has been identified as a putative target for the development of novel therapies against inflammatory bowel disease (IBD). Computational simulations identified macrophages as key targets for therapeutic interventions against IBD. This study aimed to characterize the mechanisms underlying the beneficial effects of macrophage PPAR-γ in IBD. Macrophage-specific PPAR-γ deletion significantly exacerbated clinical activity and colonic pathology, impaired the splenic and mesenteric lymph node regulatory T-cell compartment, increased percentages of lamina propria (LP) CD8+ T cells, increased surface expression of CD40, Ly6C, and Toll-like receptor 4 (TLR-4) in LP macrophages, and upregulated expression of colonic IFN-γ, CXCL9, CXCL10, IL-22, IL1RL1, CCR1, suppressor of cytokine signaling 3, and MHC class II in mice with IBD. Moreover, macrophage PPAR-γ was required for accelerating pioglitazone-mediated recovery from dextran sodium sulfate (DSS) colitis, providing a cellular target for the anti-inflammatory effects of PPAR-γ agonists in IBD.

  20. Examining the safety of PPAR agonists - current trends and future prospects.

    Science.gov (United States)

    Bortolini, Michele; Wright, Matthew B; Bopst, Martin; Balas, Bogdana

    2013-01-01

    The peroxisome proliferator-activated receptor (PPAR)-α and -γ agonists, fibrates and glitazones, are effective treatments for dyslipidemia and type 2 diabetes mellitus, respectively, but exhibit class-related, as well as compound-specific safety characteristics. This article reviews the profiles of PPAR-α, PPAR-γ, and dual PPAR-α/γ agonists with regard to class-related and compound-specific efficacy and adverse effects. We explore how learnings from first-generation drugs are being applied to develop safer PPAR-targeted therapies. The finding that rosiglitazone may increase risk for cardiovascular events has led to regulatory guidelines requiring demonstration of cardiovascular safety in appropriate outcome trials for new type 2 diabetes mellitus drugs. The emerging data on the possibly increased risk of bladder cancer with pioglitazone may prompt the need for post-approval safety studies for new drugs. Since PPAR-α and -γ affect key cardiometabolic risk factors (diabetic dyslipidemia, insulin resistance, hyperglycemia, and inflammation) in a complementary fashion, combining their benefits has emerged as a particularly attractive option. New PPAR-targeted therapies that balance the relative potency and/or activity toward PPAR-α and -γ have shown promise in retaining efficacy while reducing potential side effects.

  1. Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements.

    Science.gov (United States)

    Keller, H; Givel, F; Perroud, M; Wahli, W

    1995-07-01

    Peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs) are nuclear hormone receptors that are activated by fatty acids and 9-cis-retinoic acid, respectively. PPARs and RXRs form heterodimers that activate transcription by binding to PPAR response elements (PPREs) in the promoter of target genes. The PPREs described thus far consist of a direct tandem repeat of the AGGTCA core element with one intervening nucleotide. We show here that the vitellogenin A2 estrogen response element (ERE) can also function as a PPRE and is bound by a PPAR/RXR heterodimer. Although this heterodimer can bind to several other ERE-related palindromic response elements containing AGGTCA half-sites, only the ERE is able to confer transactivation of test reporter plasmids, when the ERE is placed either close to or at a distance from the transcription initiation site. Examination of natural ERE-containing promoters, including the pS2, very-low-density apolipoprotein II and vitellogenin A2 genes, revealed considerable differences in the binding of PPAR/RXR heterodimers to these EREs. In their natural promoter context, these EREs did not allow transcriptional activation by PPARs/RXRs. Analysis of this lack of stimulation of the vitellogenin A2 promoter demonstrated that PPARs/RXRs bind to the ERE but cannot transactivate due to a nonpermissive promoter structure. As a consequence, PPARs/RXRs inhibit transactivation by the estrogen receptor through competition for ERE binding. This is the first example of signaling cross-talk between PPAR/RXR and estrogen receptor.

  2. 15-Deoxy-Δ12,14-prostaglandin J2 and thiazolidinediones transactivate epidermal growth factor and platelet-derived growth factor receptors in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Ichiki, Toshihiro; Tokunou, Tomotake; Fukuyama, Kae; Iino, Naoko; Masuda, Satoko; Takeshita, Akira

    2004-01-01

    Proliferation of vascular smooth muscle cells (VSMCs) is induced by various mitogens through activation of extracellular signal-regulated protein kinase (ERK) pathway. We recently reported that peroxisome proliferator-activated receptor (PPAR)γ activators such as 15-deoxy-Δ 12,14 -prostaglandin J2 (15-d-PGJ2) and thiazolidinediones (TZDs) activated MEK/ERK pathway through phosphatidylinositol 3-kinase (PI3-K) and induced proliferation of VSMCs. However, the precise mechanisms of PPARγ activators-induced activation of PI3-K/ERK pathway have not been determined. We examined whether transactivation of growth factor receptor is involved in this process. Stimulation of VSMCs with 15-d-PGJ2 or TZDs for 15 min induced phosphorylation of ERK1/2 and Akt. 15-d-PGJ2- or TZDs-induced phosphorylation of ERK1/2 and Akt was inhibited by AG1478, an inhibitor of epidermal growth factor receptor (EGF-R) as well as AG1295, an inhibitor of platelet derived growth factor receptor (PDGF-R). 15-d-PGJ2-induced phosphorylation of both EGF-R and PDGF-R. GM6001, a matrix metalloproteinase inhibitor, and PP2, a Src family protein kinase inhibitor, suppressed 15-d-PGJ2- and TZDs-induced phosphorylation of EGF-R and PDGFβ-R as well as activation of ERK1/2 and Akt. PDGFβ-R was co-immunoprecipitated with EGF-R, regardless of the presence or absence of 15-d-PGJ2. These data suggest that 15-d-PGJ2 and TZDs activate PI3-K/ERK pathway through Src family kinase- and matrix metalloproteinase-dependent transactivation of EGF-R and PDGF-R. Both receptors seemed to associate constitutively. This novel signaling mechanisms may contribute to diverse biological functions of PPARγ activators

  3. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yasuko Kitagishi

    2013-10-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer.

  4. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Matsuda, Satoru, E-mail: smatsuda@cc.nara-wu.ac.jp; Kitagishi, Yasuko [Department of Food Science and Nutrition, Nara Women’s University, Kita-Uoya Nishimachi, Nara 630-8506 (Japan)

    2013-10-21

    Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer.

  5. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    International Nuclear Information System (INIS)

    Matsuda, Satoru; Kitagishi, Yasuko

    2013-01-01

    Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer

  6. Should We Use PPAR Agonists to Reduce Cardiovascular Risk?

    Directory of Open Access Journals (Sweden)

    Jennifer G. Robinson

    2008-01-01

    Full Text Available Trials of peroxisome proliferator-activated receptor (PPAR agonists have shown mixed results for cardiovascular prevention. Fibrates are PPAR- agonists that act primarily to improve dyslipidemia. Based on low- and high-density lipoprotein cholesterol (LDL and HDL effects, gemfibrozil may be of greater cardiovascular benefit than expected, fenofibrate performed about as expected, and bezafibrate performed worse than expected. Increases in both cardiovascular and noncardiovascular serious adverse events have been observed with some fibrates. Thiazolidinediones (TZDs are PPAR- agonists used to improve impaired glucose metabolism but also influence lipids. Pioglitazone reduces atherosclerotic events in diabetic subjects, but has no net cardiovascular benefit due to increased congestive heart failure risk. Rosiglitazone may increase the risk of atherosclerotic events, and has a net harmful effect on the cardiovascular system when congestive heart failure is included. The primary benefit of TZDs appears to be the prevention of diabetic microvascular complications. Dual PPAR-/ agonists have had unacceptable adverse effects but more selective agents are in development. PPAR- and pan-agonists are also in development. It will be imperative to prove that future PPAR agonists not only prevent atherosclerotic events but also result in a net reduction on total cardiovascular events without significant noncardiovascular adverse effects with long-term use.

  7. Effects of peroxisome proliferator activated receptors (PPAR-γ and -α agonists on cochlear protection from oxidative stress.

    Directory of Open Access Journals (Sweden)

    Marijana Sekulic-Jablanovic

    Full Text Available Various insults cause ototoxicity in mammals by increasing oxidative stress leading to apoptosis of auditory hair cells (HCs. The thiazolidinediones (TZDs; e.g., pioglitazone and fibrate (e.g., fenofibrate drugs are used for the treatment of diabetes and dyslipidemia. These agents target the peroxisome proliferator-activated receptors, PPARγ and PPARα, which are transcription factors that influence glucose and lipid metabolism, inflammation, and organ protection. In this study, we explored the effects of pioglitazone and other PPAR agonists to prevent gentamicin-induced oxidative stress and apoptosis in mouse organ of Corti (OC explants. Western blots showed high levels of PPARγ and PPARα proteins in mouse OC lysates. Immunofluorescence assays indicated that PPARγ and PPARα proteins are present in auditory HCs and other cell types in the mouse cochlea. Gentamicin treatment induced production of reactive oxygen species (ROS, lipid peroxidation, caspase activation, PARP-1 cleavage, and HC apoptosis in cultured OCs. Pioglitazone mediated its anti-apoptotic effects by opposing the increase in ROS induced by gentamicin, which inhibited the subsequent formation of 4-hydroxy-2-nonenal (4-HNE and activation of pro-apoptotic mediators. Pioglitazone mediated its effects by upregulating genes that control ROS production and detoxification pathways leading to restoration of the reduced:oxidized glutathione ratio. Structurally diverse PPAR agonists were protective of HCs. Pioglitazone (PPARγ-specific, tesaglitazar (PPARγ/α-specific, and fenofibric acid (PPARα-specific all provided >90% protection from gentamicin toxicity by regulation of overlapping subsets of genes controlling ROS detoxification. This study revealed that PPARs play important roles in the cochlea, and that PPAR-targeting drugs possess therapeutic potential as treatment for hearing loss.

  8. The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation

    Czech Academy of Sciences Publication Activity Database

    Wang, X.; Shaw, D.K.; Hammond, H.L.; Sutterwala, F.S.; Rayamajhi, M.; Shirey, K.A.; Perkins, D.J.; Bonventre, J.V.; Velayutham, T.S.; Evans, S.M.; Rodino, K.G.; VieBrock, L.; Scanlon, K.M.; Carbonetti, N.H.; Carlyon, J.A.; Miao, E.A.; McBride, J.W.; Kotsyfakis, Michalis; Pedra, J. H. F.

    2016-01-01

    Roč. 12, č. 8 (2016), č. článku e1005803. E-ISSN 1553-7374 Institutional support: RVO:60077344 Keywords : Rickettsial agents * Anaplasma phagocytophilum * prostaglandin E2-EP3 Receptor Axis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.003, year: 2015

  9. Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

    DEFF Research Database (Denmark)

    Uller, Lena; Mathiesen, Jesper Mosolff; Alenmyr, Lisa

    2007-01-01

    BACKGROUND: Mast cell-derived prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells......, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist...... in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model. RESULTS: TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other...

  10. Synthesis of Phthalimide Derivatives as Potential PPAR-γ Ligands

    Directory of Open Access Journals (Sweden)

    So Hyeon Eom

    2016-06-01

    Full Text Available Paecilocin A, a phthalide derivative isolated from the jellyfish-derived fungus Paecilomyces variotii, activates PPAR-γ (Peroxisome proliferator-activated receptor gamma in rat liver Ac2F cells. Based on a SAR (Structure-activity relationships study and in silico analysis of paecilocin A-mimetic derivatives, additional N-substituted phthalimide derivatives were synthesized and evaluated for PPAR-γ agonistic activity in both murine liver Ac2F cells and in human liver HepG2 cells by luciferase assay, and for adipogenic activity in 3T3-L1 cells. Docking simulation indicated PD6 was likely to bind most strongly to the ligand binding domain of PPAR-γ by establishing crucial H-bonds with key amino acid residues. However, in in vitro assays, PD1 and PD2 consistently displayed significant PPAR-γ activation in Ac2F and HepG2 cells, and adipogenic activity in 3T3-L1 preadipocytes.

  11. PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

    International Nuclear Information System (INIS)

    Rogue, Alexandra; Anthérieu, Sébastien; Vluggens, Aurore; Umbdenstock, Thierry; Claude, Nancy; Moureyre-Spire, Catherine de la; Weaver, Richard J.; Guillouzo, André

    2014-01-01

    Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis. Conclusion: Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients. - Highlights: • There is no pharmacological agent approved for the treatment of NAFLD. • This study demonstrates that PPAR agonists can reduce fatty acid-induced steatosis. • Some nuclear receptors appear to be potent actors in the control

  12. PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

    Energy Technology Data Exchange (ETDEWEB)

    Rogue, Alexandra [Inserm UMR 991, 35043 Rennes Cedex (France); Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex (France); Biologie Servier, Gidy (France); Anthérieu, Sébastien; Vluggens, Aurore [Inserm UMR 991, 35043 Rennes Cedex (France); Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex (France); Umbdenstock, Thierry [Technologie Servier, Orléans (France); Claude, Nancy [Institut de Recherches Servier, Courbevoie (France); Moureyre-Spire, Catherine de la; Weaver, Richard J. [Biologie Servier, Gidy (France); Guillouzo, André, E-mail: Andre.Guillouzo@univ-rennes1.fr [Inserm UMR 991, 35043 Rennes Cedex (France); Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex (France)

    2014-04-01

    Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis. Conclusion: Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients. - Highlights: • There is no pharmacological agent approved for the treatment of NAFLD. • This study demonstrates that PPAR agonists can reduce fatty acid-induced steatosis. • Some nuclear receptors appear to be potent actors in the control

  13. Prostaglandins in Cancer Cell Adhesion, Migration, and Invasion

    Directory of Open Access Journals (Sweden)

    David G. Menter

    2012-01-01

    Full Text Available Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer. Cyclooxygenase-2 (COX-2 and microsomal prostaglandin E2 synthase-1 (mPGES-1 are upregulated in inflammation and cancer. This results in the production of prostaglandin E2 (PGE2, which binds to and activates G-protein-coupled prostaglandin E1-4 receptors (EP1-4. Selectively targeting the COX-2/mPGES-1/PGE2/EP1-4 axis of the prostaglandin pathway can reduce the adhesion, migration, invasion, and angiogenesis. Once stimulated by prostaglandins, cadherin adhesive connections between epithelial or endothelial cells are lost. This enables cells to invade through the underlying basement membrane and extracellular matrix (ECM. Interactions with the ECM are mediated by cell surface integrins by “outside-in signaling” through Src and focal adhesion kinase (FAK and/or “inside-out signaling” through talins and kindlins. Combining the use of COX-2/mPGES-1/PGE2/EP1-4 axis-targeted molecules with those targeting cell surface adhesion receptors or their downstream signaling molecules may enhance cancer therapy.

  14. Identification of plant extracts with potential antidiabetic properties: effect on human peroxisome proliferator-activated receptor (PPAR), adipocyte differentiation and insulin-stimulated glucose uptake

    DEFF Research Database (Denmark)

    Christensen, Kathrine B; Minet, Ariane; Svenstrup, Henrik

    2009-01-01

    Thiazolidinediones (TZDs) are insulin sensitizing drugs used to treat type 2 diabetes. The primary target of the TZDs is the peroxisome proliferator-activated receptor (PPAR) gamma, a key regulator of adipogenesis and glucose homeostasis. Currently prescribed TZDs are full PPARgamma agonists, and...

  15. PPAR Agonists for the Prevention and Treatment of Lung Cancer

    Directory of Open Access Journals (Sweden)

    Sowmya P. Lakshmi

    2017-01-01

    Full Text Available Lung cancer is the most common and most fatal of all malignancies worldwide. Furthermore, with more than half of all lung cancer patients presenting with distant metastases at the time of initial diagnosis, the overall prognosis for the disease is poor. There is thus a desperate need for new prevention and treatment strategies. Recently, a family of nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs, has attracted significant attention for its role in various malignancies including lung cancer. Three PPARs, PPARα, PPARβ/δ, and PPARγ, display distinct biological activities and varied influences on lung cancer biology. PPARα activation generally inhibits tumorigenesis through its antiangiogenic and anti-inflammatory effects. Activated PPARγ is also antitumorigenic and antimetastatic, regulating several functions of cancer cells and controlling the tumor microenvironment. Unlike PPARα and PPARγ, whether PPARβ/δ activation is anti- or protumorigenic or even inconsequential currently remains an open question that requires additional investigation. This review of current literature emphasizes the multifaceted effects of PPAR agonists in lung cancer and discusses how they may be applied as novel therapeutic strategies for the disease.

  16. Prostaglandins - universal biological regulators in the human body (literature review

    Directory of Open Access Journals (Sweden)

    О. V. Tymoshchuk

    2018-02-01

    Full Text Available Recently, researchers of different industries pay great attention to the problem of prostaglandins. Objective: to study and systematize the basic questions of structure, biological action and metabolism of prostaglandins in the human body and using their analogues in pharmacy through the domestic and foreign literature data analysis. Prostaglandins – biologically active substances which are similar in effect to hormones, but are synthesized in cells of different tissues. Prostaglandins as universal cellular mediators are widely distributed in the body, synthesized in small amounts in almost all tissues, have both local and systemic effects. For each prostaglandin there is a target organ. On chemical structure they are small molecules related to eicosanoids - a group of fat-like substances (lipids. Depending on the chemical structure prostaglandins are divided into series (A, B, C, D, E, F, G, H, I and J and three groups (1–3; type F isomers are to be indicated by additional letters α and β. Prostaglandins have an extremely wide range of physiological effects in the body and have three main functions: supporting, molecular, neurotransmitter. Most prostaglandins interact with specific receptors of plasma membranes, but some prostaglandins (group A can act without receptors. There is no stock of prostaglandins in the body, their life cycle is short, and they are quickly produced in response to biological stimulants exposure, have their effect in extremely small quantity and are rapidly inactivated in the bloodstream. Due to the extremely rapid breakdown of prostaglandins in the body they work near their place of secretion. Preparations of prostaglandins and their derivatives are used in experimental and clinical medicine for abortion and induction of labor, treatment of stomach ulcers, asthma, certain heart diseases, congenital heart defects in newborns, glaucoma, atherosclerosis, rheumatic and neurological diseases, kidney diseases, diabetes

  17. PPARs Link Early Life Nutritional Insults to Later Programmed Hypertension and Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    You-Lin Tain

    2015-12-01

    Full Text Available Hypertension is an important component of metabolic syndrome. Adulthood hypertension and metabolic syndrome can be programmed in response to nutritional insults in early life. Peroxisome proliferator-activated receptors (PPARs serve as a nutrient-sensing signaling linking nutritional programming to hypertension and metabolic syndrome. All three members of PPARs, PPARα, PPARβ/δ, and PPARγ, are expressed in the kidney and involved in blood pressure control. This review provides an overview of potential clinical applications of targeting on the PPARs in the kidney to prevent programmed hypertension and metabolic syndrome, with an emphasis on the following areas: mechanistic insights to interpret programmed hypertension; the link between the PPARs, nutritional insults, and programmed hypertension and metabolic syndrome; the impact of PPAR signaling pathway in a maternal high-fructose model; and current experimental studies on early intervention by PPAR modulators to prevent programmed hypertension and metabolic syndrome. Animal studies employing a reprogramming strategy via targeting PPARs to prevent hypertension have demonstrated interesting results. It is critical that the observed effects on developmental reprogramming in animal models are replicated in human studies, to halt the globally-growing epidemic of metabolic syndrome-related diseases.

  18. Activation of PPAR by Rosiglitazone Does Not Negatively Impact Male Sex Steroid Hormones in Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Mahmoud Mansour

    2009-01-01

    Full Text Available Peroxisome proliferator-activated receptor gamma (PPAR activation decreased serum testosterone (T in women with hyperthecosis and/or polycystic ovary syndrome and reduced the conversion of androgens to estradiol (E2 in female rats. This implies modulation of female sex steroid hormones by PPAR. It is not clear if PPAR modulates sex steroid hormones in diabetic males. Because PPAR activation by thiazolidinedione increased insulin sensitivity in type 2 diabetes, understanding the long term impact of PPAR activation on steroid sex hormones in males is critical. Our objective was to determine the effect of PPAR activation on serum and intratesticular T, luteinizing hormone (LH, follicle stimulating hormone (FSH and E2 concentrations in male Zucker diabetic fatty (ZDF rats treated with the PPAR agonist rosiglitazone (a thiazolidinedione. Treatment for eight weeks increased PPAR mRNA and protein in the testis and elevated serum adiponectin, an adipokine marker for PPAR activation. PPAR activation did not alter serum or intratesticular T concentrations. In contrast, serum T level but not intratesticular T was reduced by diabetes. Neither diabetes nor PPAR activation altered serum E2 or gonadotropins FSH and LH concentrations. The results suggest that activation of PPAR by rosiglitazone has no negative impact on sex hormones in male ZDF rats.

  19. Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

    Directory of Open Access Journals (Sweden)

    Högberg Thomas

    2007-02-01

    Full Text Available Abstract Background Mast cell-derived prostaglandin D2 (PGD2, may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2, a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology. Methods Affinity for and antagonistic potency of TM30089 on many mouse receptors including thromboxane A2 receptor mTP, CRTH2 receptor, and selected anaphylatoxin and chemokines receptors were determined in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model. Results TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other receptors including the related anaphylatoxin C3a and C5a receptors, selected chemokine receptors and the cyclooxygenase isoforms 1 and 2 which are all recognized players in allergic diseases. Furthermore, TM30089 and ramatroban, the latter used as a reference herein, similarly inhibited asthma pathology in vivo by reducing peribronchial eosinophilia and mucus cell hyperplasia. Conclusion This is the first report to demonstrate anti-allergic efficacy in vivo of a highly selective small molecule CRTH2 antagonist. Our data suggest that CRTH2 antagonism alone is effective in mouse allergic airway inflammation even to the extent that this mechanism can explain the efficacy of ramatroban.

  20. Retinoid X receptor and peroxisome proliferator-activated receptor activate an estrogen responsive gene independent of the estrogen receptor.

    Science.gov (United States)

    Nuñez, S B; Medin, J A; Braissant, O; Kemp, L; Wahli, W; Ozato, K; Segars, J H

    1997-03-14

    Estrogen receptors regulate transcription of genes essential for sexual development and reproductive function. Since the retinoid X receptor (RXR) is able to modulate estrogen responsive genes and both 9-cis RA and fatty acids influenced development of estrogen responsive tumors, we hypothesized that estrogen responsive genes might be modulated by RXR and the fatty acid receptor (peroxisome proliferator-activated receptor, PPAR). To test this hypothesis, transfection assays in CV-1 cells were performed with an estrogen response element (ERE) coupled to a luciferase reporter construct. Addition of expression vectors for RXR and PPAR resulted in an 11-fold increase in luciferase activity in the presence of 9-cis RA. Furthermore, mobility shift assays demonstrated binding of RXR and PPAR to the vitellogenin A2-ERE and an ERE in the oxytocin promoter. Methylation interference assays demonstrated that specific guanine residues required for RXR/PPAR binding to the ERE were similar to residues required for ER binding. Moreover, RXR domain-deleted constructs in transfection assays showed that activation required RXR since an RXR delta AF-2 mutant completely abrogated reporter activity. Oligoprecipitation binding studies with biotinylated ERE and (35)S-labeled in vitro translated RXR constructs confirmed binding of delta AF-2 RXR mutant to the ERE in the presence of baculovirus-expressed PPAR. Finally, in situ hybridization confirmed RXR and PPAR mRNA expression in estrogen responsive tissues. Collectively, these data suggest that RXR and PPAR are present in reproductive tissues, are capable of activating estrogen responsive genes and suggest that the mechanism of activation may involve direct binding of the receptors to estrogen response elements.

  1. Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Yuting [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Zhou, Lubing [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Gunnet, Joseph W [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Wines, Pamela G [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Cryan, Ellen V [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Demarest, Keith T [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States)

    2006-06-23

    HM74A is a G protein-coupled receptor for nicotinic acid (niacin), which has been used clinically to treat dyslipidemia for decades. The molecular mechanisms whereby niacin exerts its pleiotropic effects on lipid metabolism remain largely unknown. In addition, the most common side effect in niacin therapy is skin flushing that is caused by prostaglandin release, suggesting that the phospholipase A{sub 2} (PLA{sub 2})/arachidonic acid (AA) pathway is involved. Various eicosanoids have been shown to activate peroxisome-proliferator activated receptors (PPAR) that play a diverse array of roles in lipid metabolism. To further elucidate the potential roles of HM74A in mediating the therapeutic effects and/or side effects of niacin, we sought to explore the signaling events upon HM74A activation. Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells. Activation of HM74A also led to Ca{sup 2+}-mobilization and enhanced bradykinin-promoted Ca{sup 2+}-mobilization through Gi protein. While HM74A increased ERK1/2 activation by the bradykinin receptor, it had no effects on UTP-promoted ERK1/2 activation.Furthermore, UTP- and bradykinin-mediated AA release was significantly decreased in the presence of both MAPK kinase inhibitor PD 098059 and PKC inhibitor GF 109203X. However, the synergistic effects of HM74A were not dramatically affected by co-treatment with both inhibitors, indicating the cross-talk occurred at the receptor level. Finally, stimulation of A431 cells transiently transfected with PPRE-luciferase with AA significantly induced luciferase activity, mimicking the effects of PPAR{gamma} agonist rosiglitazone, suggesting that alteration of AA signaling pathway can regulate gene expression via endogenous PPARs.

  2. Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor delta-mediated transactivation

    DEFF Research Database (Denmark)

    Krogsdam, Anne-M; Nielsen, Curt A F; Neve, Søren

    2002-01-01

    delta-RXR alpha heterodimer bound to an acyl-CoA oxidase (ACO)-type peroxisome-proliferator response element recruited a glutathione S-transferase-NCoR fusion protein in a ligand-independent manner. Contrasting with most other nuclear receptors, PPAR delta was found to interact equally well......The nuclear receptor corepressor (NCoR) was isolated as a peroxisome-proliferator-activated receptor (PPAR) delta interacting protein using the yeast two-hybrid system. NCoR interacted strongly with the ligand-binding domain of PPAR delta, whereas interactions with the ligand-binding domains...

  3. Leptin rapidly activates PPARs in C2C12 muscle cells

    International Nuclear Information System (INIS)

    Bendinelli, Paola; Piccoletti, Roberta; Maroni, Paola

    2005-01-01

    Experimental evidence suggests that leptin operates on the tissues, including skeletal muscle, also by modulating gene expression. Using electrophoretic mobility shift assays, we have shown that physiological doses of leptin promptly increase the binding of C2C12 cell nuclear extracts to peroxisome proliferator-activated receptor (PPAR) response elements in oligonucleotide probes and that all three PPAR isoforms participate in DNA-binding complexes. We pre-treated C2C12 cells with AACOCF 3 , a specific inhibitor of cytosolic phospholipase A 2 (cPLA 2 ), an enzyme that supplies ligands to PPARs, and found that it abrogates leptin-induced PPAR DNA-binding activity. Leptin treatment significantly increased cPLA 2 activity, evaluated as the release of [ 3 H]arachidonic acid from pre-labelled C2C12 cells, as well as phosphorylation. Further, using MEK1 inhibitor PD-98059 we showed that leptin activates cPLA 2 through ERK induction. These results support a direct effect of leptin on skeletal muscle cells, and suggest that the hormone may modulate muscle transcription also by precocious activation of PPARs through ERK-cPLA 2 pathway

  4. Prostaglandin E2 stimulates Fas ligand expression via the EP1 receptor in colon cancer cells.

    LENUS (Irish Health Repository)

    O'Callaghan, G

    2012-02-03

    Fas ligand (FasL\\/CD95L) is a member of the tumour necrosis factor superfamily that triggers apoptosis following crosslinking of the Fas receptor. Despite studies strongly implicating tumour-expressed FasL as a major inhibitor of the anti-tumour immune response, little is known about the mechanisms that regulate FasL expression in tumours. In this study, we show that the cyclooxygenase (COX) signalling pathway, and in particular prostaglandin E(2) (PGE(2)), plays a role in the upregulation of FasL expression in colon cancer. Suppression of either COX-2 or COX-1 by RNA interference in HCA-7 and HT29 colon tumour cells reduced FasL expression at both the mRNA and protein level. Conversely, stimulation with PGE(2) increased FasL expression and these cells showed increased cytotoxicity against Fas-sensitive Jurkat T cells. Prostaglandin E(2)-induced FasL expression was mediated by signalling via the EP1 receptor. Moreover, immunohistochemical analysis using serial sections of human colon adenocarcinomas revealed a strong positive correlation between COX-2 and FasL (r=0.722; P<0.0001) expression, and between EP1 receptor and FasL (r=0.740; P<0.0001) expression, in the tumour cells. Thus, these findings indicate that PGE(2) positively regulates FasL expression in colon tumour cells, adding another pro-neoplastic activity to PGE(2).

  5. The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation.

    Directory of Open Access Journals (Sweden)

    Xiaowei Wang

    2016-08-01

    Full Text Available Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2 via cyclooxygenase 2 (COX2 and the membrane associated prostaglandin E synthase-1 (mPGES-1. PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2 was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum.

  6. Treatment of Obesity-Related Complications with Novel Classes of Naturally Occurring PPAR Agonists.

    Science.gov (United States)

    Bassaganya-Riera, Josep; Guri, Amir J; Hontecillas, Raquel

    2011-01-01

    The prevalence of obesity and its associated comorbidities has grown to epidemic proportions in the US and worldwide. Thus, developing safe and effective therapeutic approaches against these widespread and debilitating diseases is important and timely. Activation of peroxisome proliferator-activated receptors (PPARs) α, γ, and δ through several classes of pharmaceuticals can prevent or treat a variety of metabolic and inflammatory diseases, including type II diabetes (T2D). Thus, PPARs represent important molecular targets for developing novel and better treatments for a wide range of debilitating and widespread obesity-related diseases and disorders. However, available PPAR γ agonistic drugs such as Avandia have significant adverse side effects, including weight gain, fluid retention, hepatotoxicity, and congestive heart failure. An alternative to synthetic agonists of PPAR γ is the discovery and development of naturally occurring and safer nutraceuticals that may be dual or pan PPAR agonists. The purpose of this paper is to summarize the health effects of three plant-derived PPAR agonists: abscisic acid (ABA), punicic acid (PUA), and catalpic acid (CAA) in the prevention and treatment of chronic inflammatory and metabolic diseases and disorders.

  7. Co-factors necessary for PPAR mediated transactivation of endogenous target genes

    DEFF Research Database (Denmark)

    Grøntved, Lars; Nielsen, Ronni; Stunnenberg, Henk

    of endogenous target gene in different cell types are elusive. To mutually compare the ability of the PPAR subtypes to activate endogenous target genes in a given cell, PPARa, PPARb/d and PPARg2 were HA tagged and rapidly, equally and synchronously expressed using adenoviral delivery. Within a few hours after...... subtype specific activation of target genes. Accumulating evidence suggests that transcriptional co-factors can function as master regulators for nuclear receptors and impose promoter selectivity. To study co-factor necessity for PPAR mediated transactivation of endogenous target genes, specific co...

  8. Liver X receptor and peroxisome proliferator-activated receptor as integrators of lipid homeostasis and immunity.

    Science.gov (United States)

    Kidani, Yoko; Bensinger, Steven J

    2012-09-01

    Lipid metabolism has emerged as an important modulator of innate and adaptive immune cell fate and function. The lipid-activated transcription factors peroxisome proliferator-activated receptor (PPAR) α, β/δ, γ and liver X receptor (LXR) are members of the nuclear receptor superfamily that have a well-defined role in regulating lipid homeostasis and metabolic diseases. Accumulated evidence over the last decade indicates that PPAR and LXR signaling also influence multiple facets of inflammation and immunity, thereby providing important crosstalk between metabolism and immune system. Herein, we provide a brief introduction to LXR and PPAR biology and review recent discoveries highlighting the importance of PPAR and LXR signaling in the modulation of normal and pathologic states of immunity. We also examine advances in our mechanistic understanding of how nuclear receptors impact immune system function and homeostasis. Finally, we discuss whether LXRs and PPARs could be pharmacologically manipulated to provide novel therapeutic approaches for modulation of the immune system under pathologic inflammation or in the context of allergic and autoimmune disease. © 2012 John Wiley & Sons A/S.

  9. Immunoregulatory mechanisms of macrophage PPAR γ in mice with experimental inflammatory bowel disease

    Science.gov (United States)

    Hontecillas, Raquel; Horne, William T.; Climent, Montse; Guri, Amir J.; Evans, C.; Zhang, Y.; Sobral, Bruno W.; Bassaganya-Riera, Josep

    2010-01-01

    Peroxisome proliferator-activated receptor γ (PPAR γ) is widely expressed in macrophages and has been identified as a putative target for the development of novel therapies against inflammatory bowel disease (IBD). Computational simulations identified macrophages as key targets for therapeutic interventions against IBD. This study aimed to characterize the mechanisms underlying the beneficial effects of macrophage PPAR γ in IBD. Macrophage-specific PPAR γ deletion significantly exacerbated clinical activity and colonic pathology, impaired the splenic and mesenteric lymph node regulatory T cell compartment, increased percentages of LP CD8+ T cells, increased surface expression of CD40, Ly6C, and TLR-4 in LP macrophages, and upregulated expression of colonic IFN-γ, CXCL9, CXCL10, IL-22, IL1RL1, CCR1, suppressor of cytokine signaling 3 and MCH class II in mice with IBD. Moreover, macrophage PPAR γ was required for accelerating pioglitazone-mediated recovery from DSS colitis, providing a cellular target for the anti-inflammatory effects of PPAR γ agonists in IBD. PMID:21068720

  10. 15-Deoxy-Δ12,14-Prostaglandin J2 regulates leukemia inhibitory factor signaling through JAK-STAT pathway in mouse embryonic stem cells

    International Nuclear Information System (INIS)

    Rajasingh, Johnson; Bright, John J.

    2006-01-01

    Embryonic stem (ES) cells are genetically normal, pluripotent cells, capable of self-renewal and differentiation into all cell lineages. While leukemia inhibitory factor (LIF) maintains pluripotency in mouse ES cells, retinoic acid and other nuclear hormones induce neuro-glial differentiation in mouse and human ES cells in culture. Peroxisome-proliferator-activated receptors (PPARs) are ligand-dependent nuclear receptor transcription factors that regulate cell growth and differentiation in many cell types. However, the role of PPARs in the regulation of ES cell growth and differentiation is not known. In this study, we show that LIF induces proliferation and self-renewal of mouse D3-ES cells in culture. However, treatment with 15-Deoxy-Δ 12,14 -Prostaglandin J 2 (15d-PGJ2), a natural ligand for PPARγ, or all-trans retinoic acid (ATRA) results in a dose-dependent decrease in proliferation and self-renewal in D3-ES cells. Immunoprecipitation and Western blot analyses showed that LIF induces tyrosine phosphorylation of JAK1, TYK2 and STAT3 in 30 min and treatment with 15d-PGJ2 or ATRA results in a dose-dependent decrease in LIF-induced phosphorylation of JAK1 and STAT3 in D3-ES cells. However, treatment of D3-ES cells with Ciglitazone or 15d-PGJ2 for 48 h in culture resulted in a dose-dependent increase in PPARγ protein expression. These results suggest that PPARγ agonists regulate LIF signaling through JAK-STAT pathway leading to growth and self-renewal of ES cells

  11. Fisetin up-regulates the expression of adiponectin in 3T3-L1 adipocytes via the activation of silent mating type information regulation 2 homologue 1 (SIRT1)-deacetylase and peroxisome proliferator-activated receptors (PPARs).

    Science.gov (United States)

    Jin, Taewon; Kim, Oh Yoen; Shin, Min-Jeong; Choi, Eun Young; Lee, Sung Sook; Han, Ye Sun; Chung, Ji Hyung

    2014-10-29

    Adiponectin, an adipokine, has been described as showing physiological benefits against obesity-related malfunctions and vascular dysfunction. Several natural compounds that promote the expression and secretion of adipokines in adipocytes could be useful for treating metabolic disorders. This study investigated the effect of fisetin, a dietary flavonoid, on the regulation of adiponectin in adipocytes using 3T3-L1 preadipocytes. The expression and secretion of adiponectin increased in 3T3-L1 cells upon treatment with fisetin in a dose-dependent manner. Fisetin-induced adiponectin secretion was inhibited by peroxisome proliferator-activated receptor (PPAR) antagonists. It was also revealed that fisetin increased the activities of PPARs and silent mating type information regulation 2 homologue 1 (SIRT1) in a dose-dependent manner. Furthermore, the up-regulation of adiponectin and the activation of PPARs induced by fisetin were prevented by a SIRT1 inhibitor. Fisetin also promoted deacetylation of PPAR γ coactivator 1 (PGC-1) and its interaction with PPARs. SIRT knockdown by siRNA significantly decreased both adiponectin production and PPARs-PGC-1 interaction. These results provide evidence that fisetin promotes the gene expression of adiponectin through the activation of SIRT1 and PPARs in adipocytes.

  12. The Role of PPARs in Placental Immunology: A Systematic Review of the Literature

    Directory of Open Access Journals (Sweden)

    Stefan Hutter

    2013-01-01

    Full Text Available Pregnancy is a state of immunotolerance, and pregnancy outcome is strongly linked to the correct activation and balancing of the maternal immune system. Besides abortion as possible result of improper early pregnancy development, other pregnancy associated conditions like preeclampsia (PE, intrauterine growth retardation (IUGR, preterm labour, or gestational diabetes mellitus (GDM are linked to immunologic overactivation and dysregulation. Both the innate and the adaptive immune system, and therefore B and T lymphocytes, natural killer cells (NK, macrophages and dendritic cells (DCs are all involved in trophoblast invasion, pregnancy maintenance, and development of pregnancy disorders. Peroxisome proliferator activated receptors (PPARs are nuclear transcription factors with three known isotypes: PPAR, PPARβ/δ, and PPARγ. They are expressed in most human organs and their function extends from regulating metabolism, homeostasis, and carcinogenesis to immune response. In the recent years, PPARs have been identified in most reproductive tissues and in all lines of immune cells. Only in few cases, the role of PPARs in reproductive immunology has been elucidated though the role of PPARs in immune answer and immunotolerance is evident. Within this paper we would like to give an update on today’s knowledge about PPARs and immune cells in reproduction and highlight interesting interferences in regard of future therapeutic targets.

  13. Activation of Penile Proadipogenic Peroxisome Proliferator-Activated Receptor with an Estrogen: Interaction with Estrogen Receptor Alpha during Postnatal Development

    Directory of Open Access Journals (Sweden)

    Mahmoud M. Mansour

    2008-01-01

    Full Text Available Exposure to the estrogen receptor alpha (ER ligand diethylstilbesterol (DES between neonatal days 2 to 12 induces penile adipogenesis and adult infertility in rats. The objective of this study was to investigate the in vivo interaction between DES-activated ER and the proadipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPAR. Transcripts for PPARs , , and and 1a splice variant were detected in Sprague-Dawley normal rat penis with PPAR predominating. In addition, PPAR1b and PPAR2 were newly induced by DES. The PPAR transcripts were significantly upregulated with DES and reduced by antiestrogen ICI 182, 780. At the cellular level, PPAR protein was detected in urethral transitional epithelium and stromal, endothelial, neuronal, and smooth muscular cells. Treatment with DES activated ER and induced adipocyte differentiation in corpus cavernosum penis. Those adipocytes exhibited strong nuclear PPAR expression. These results suggest a biological overlap between PPAR and ER and highlight a mechanism for endocrine disruption.

  14. Bixin regulates mRNA expression involved in adipogenesis and enhances insulin sensitivity in 3T3-L1 adipocytes through PPAR{gamma} activation

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Nobuyuki; Goto, Tsuyoshi; Taimatsu, Aki; Egawa, Kahori; Katoh, Sota; Kusudo, Tatsuya; Sakamoto, Tomoya; Ohyane, Chie; Lee, Joo-Young; Kim, Young-il; Uemura, Taku; Hirai, Shizuka [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011 (Japan); Kawada, Teruo, E-mail: fat@kais.kyoto-u.ac.jp [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011 (Japan)

    2009-12-25

    Insulin resistance is partly due to suppression of insulin-induced glucose uptake into adipocytes. The uptake is dependent on adipocyte differentiation, which is controlled at mRNA transcription level. The peroxisome proliferator-activated receptor (PPAR), a ligand-regulated nuclear receptor, is involved in the differentiation. Many food-derived compounds serve as ligands to activate or inactivate PPAR. In this study, we demonstrated that bixin and norbixin (annatto extracts) activate PPAR{gamma} by luciferase reporter assay using GAL4-PPAR chimera proteins. To examine the effects of bixin on adipocytes, 3T3-L1 adipocytes were treated with bixin or norbixin. The treatment induced mRNA expression of PPAR{gamma} target genes such as adipocyte-specific fatty acid-binding protein (aP2), lipoprotein lipase (LPL), and adiponectin in differentiated 3T3-L1 adipocytes and enhanced insulin-dependent glucose uptake. The observations indicate that bixin acts as an agonist of PPAR{gamma} and enhances insulin sensitivity in 3T3-L1 adipocytes, suggesting that bixin is a valuable food-derived compound as a PPAR ligand to regulate lipid metabolism and to ameliorate metabolic syndrome.

  15. Arctigenin promotes cholesterol efflux from THP-1 macrophages through PPAR-γ/LXR-α signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Xiaolin [Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai 200032 (China); Li, Qian [Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai (China); Pang, Liewen; Huang, Guoqian; Huang, Jiechun; Shi, Meng; Sun, Xiaotian [Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai 200032 (China); Wang, Yiqing [Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai 200032 (China)

    2013-11-15

    Highlights: •Arctigenin enhanced cholesterol efflux in oxLDL-loaded THP-1 macrophages. •The expression of ABCA1, ABCG1 and apoE was upregulated in arctigenin-treated cells. •Arctigenin promoted the expression of PPAR-γ and LXR-α. •Inhibition of PPAR-γ or LXR-α reversed arctigenin-mediated biological effects. •Arctigenin promotes cholesterol efflux via activation of PPAR-γ/LXR-α/ABCA1 pathway. -- Abstract: Cholesterol efflux from macrophages is a critical mechanism to prevent the development of atherosclerosis. Here, we sought to investigate the effects of arctigenin, a bioactive component of Arctium lappa, on the cholesterol efflux in oxidized low-density lipoprotein (oxLDL)-loaded THP-1 macrophages. Our data showed that arctigenin significantly accelerated apolipoprotein A-I- and high-density lipoprotein-induced cholesterol efflux in both dose- and time-dependent manners. Moreover, arctigenin treatment enhanced the expression of ATP binding cassette transporter A1 (ABCA1), ABCG1, and apoE, all of which are key molecules in the initial step of cholesterol efflux, at both mRNA and protein levels. Arctigenin also caused a concentration-dependent elevation in the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α). The arctigenin-mediated induction of ABCA1, ABCG1, and apoE was abolished by specific inhibition of PPAR-γ or LXR-α using small interfering RNA technology. Our results collectively indicate that arctigenin promotes cholesterol efflux in oxLDL-loaded THP-1 macrophages through upregulation of ABCA1, ABCG1 and apoE, which is dependent on the enhanced expression of PPAR-γ and LXR-α.

  16. Arctigenin promotes cholesterol efflux from THP-1 macrophages through PPAR-γ/LXR-α signaling pathway

    International Nuclear Information System (INIS)

    Xu, Xiaolin; Li, Qian; Pang, Liewen; Huang, Guoqian; Huang, Jiechun; Shi, Meng; Sun, Xiaotian; Wang, Yiqing

    2013-01-01

    Highlights: •Arctigenin enhanced cholesterol efflux in oxLDL-loaded THP-1 macrophages. •The expression of ABCA1, ABCG1 and apoE was upregulated in arctigenin-treated cells. •Arctigenin promoted the expression of PPAR-γ and LXR-α. •Inhibition of PPAR-γ or LXR-α reversed arctigenin-mediated biological effects. •Arctigenin promotes cholesterol efflux via activation of PPAR-γ/LXR-α/ABCA1 pathway. -- Abstract: Cholesterol efflux from macrophages is a critical mechanism to prevent the development of atherosclerosis. Here, we sought to investigate the effects of arctigenin, a bioactive component of Arctium lappa, on the cholesterol efflux in oxidized low-density lipoprotein (oxLDL)-loaded THP-1 macrophages. Our data showed that arctigenin significantly accelerated apolipoprotein A-I- and high-density lipoprotein-induced cholesterol efflux in both dose- and time-dependent manners. Moreover, arctigenin treatment enhanced the expression of ATP binding cassette transporter A1 (ABCA1), ABCG1, and apoE, all of which are key molecules in the initial step of cholesterol efflux, at both mRNA and protein levels. Arctigenin also caused a concentration-dependent elevation in the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α). The arctigenin-mediated induction of ABCA1, ABCG1, and apoE was abolished by specific inhibition of PPAR-γ or LXR-α using small interfering RNA technology. Our results collectively indicate that arctigenin promotes cholesterol efflux in oxLDL-loaded THP-1 macrophages through upregulation of ABCA1, ABCG1 and apoE, which is dependent on the enhanced expression of PPAR-γ and LXR-α

  17. ATP induced vasodilatation and purinergic receptors in the human leg: roles of nitric oxide, prostaglandins and adenosine

    DEFF Research Database (Denmark)

    Mortensen, Stefan P; Gonzalez-Alonso, Jose; Bune, Laurids

    2009-01-01

    .05) and was associated with a parallel lowering in leg vascular conductance and cardiac output and a compensatory increase in leg O2 extraction. Infusion of theophylline did not alter the ATP induced leg hyperemia or systemic variables. Real time PCR analysis of the mRNA content from the vastus lateralus muscle of 8...... subjects showed the highest expression of P2Y2 receptors of the 10 investigated P2 receptor subtypes. Immunohistochemistry showed that P2Y2 receptors were located in the endothelium of microvessels and smooth muscle cells, whereas P2X1 receptors were located in the endothelium and the sacrolemma....... Collectively, these results indicate that NO and prostaglandins, but not adenosine, play a role in ATP induced vasodilation in human skeletal muscle. The localization of the P2Y2 and P2X1 receptors suggest that these receptors may mediate ATP induced vasodilation in skeletal muscle. Key words: Skeletal Muscle...

  18. Modulation of PPAR-γ by Nutraceutics as Complementary Treatment for Obesity-Related Disorders and Inflammatory Diseases

    Directory of Open Access Journals (Sweden)

    D. Ortuño Sahagún

    2012-01-01

    Full Text Available A direct correlation between adequate nutrition and health is a universally accepted truth. The Western lifestyle, with a high intake of simple sugars, saturated fat, and physical inactivity, promotes pathologic conditions. The main adverse consequences range from cardiovascular disease, type 2 diabetes, and metabolic syndrome to several cancers. Dietary components influence tissue homeostasis in multiple ways and many different functional foods have been associated with various health benefits when consumed. Natural products are an important and promising source for drug discovery. Many anti-inflammatory natural products activate peroxisome proliferator-activated receptors (PPAR; therefore, compounds that activate or modulate PPAR-gamma (PPAR-γ may help to fight all of these pathological conditions. Consequently, the discovery and optimization of novel PPAR-γ agonists and modulators that would display reduced side effects is of great interest. In this paper, we present some of the main naturally derived products studied that exert an influence on metabolism through the activation or modulation of PPAR-γ, and we also present PPAR-γ-related diseases that can be complementarily treated with nutraceutics from functional foods.

  19. Atherogenic ω-6 Lipids Modulate PPAR- EGR-1 Crosstalk in Vascular Cells

    Directory of Open Access Journals (Sweden)

    Jia Fei

    2011-01-01

    Full Text Available Atherogenic ω-6 lipids are physiological ligands of peroxisome proliferator-activated receptors (PPARs and elicit pro- and antiatherogenic responses in vascular cells. The objective of this study was to investigate if ω-6 lipids modulated the early growth response-1 (Egr-1/PPAR crosstalk thereby altering vascular function. Rat aortic smooth muscle cells (RASMCs were exposed to ω-6 lipids, linoleic acid (LA, or its oxidized form, 13-HPODE (OxLA in the presence or absence of a PPARα antagonist (MK886 or PPARγ antagonist (GW9662 or PPAR-specific siRNA. Our results demonstrate that ω-6 lipids, induced Egr-1 and monocyte chemotactic protein-1 (MCP-1 mRNA and protein levels at the acute phase (1–4 hrs when PPARα was downregulated and at subacute phase (4–12 hrs by modulating PPARγ, thus resulting in altered monocyte adhesion to RASMCs. We provide novel insights into the mechanism of action of ω-6 lipids on Egr-1/PPAR interactions in vascular cells and their potential in altering vascular function.

  20. Differential regulation of renal prostaglandin receptor mRNAs by dietary salt intake in the rat

    DEFF Research Database (Denmark)

    Jensen, B L; Mann, Birgitte; Skøtt, O

    1999-01-01

    and cells by ribonuclease protection assay and reverse transcription-polymerase chain reaction analysis. Functional correlates were studied by measurement of PGE2-induced cAMP formation and renin secretion in juxtaglomerular (JG) cells isolated from animals on various salt intakes. RESULTS: EP1 and EP3......BACKGROUND: In this study, we tested the hypothesis that prostaglandin (PG) receptor expression in the rat kidney is subject to physiological regulation by dietary salt intake. METHODS: Rats were fed diets with 0.02 or 4% NaCl for two weeks. PG receptor expression was assayed in kidney regions...... did not affect the expression of EP1 or IP receptors, whereas EP4 transcripts in glomeruli were increased twofold by salt deprivation. Consistent with this, we found that PGE2-evoked cAMP production and renin secretion by JG cells from salt-deprived animals were significantly higher compared...

  1. Functional Role of PPARs in Ruminants: Potential Targets for Fine-Tuning Metabolism during Growth and Lactation

    Science.gov (United States)

    Chen, Shuowen; Khan, Muhammad J.; Loor, Juan J.

    2013-01-01

    Characterization and biological roles of the peroxisome proliferator-activated receptor (PPAR) isotypes are well known in monogastrics, but not in ruminants. However, a wealth of information has accumulated in little more than a decade on ruminant PPARs including isotype tissue distribution, response to synthetic and natural agonists, gene targets, and factors affecting their expression. Functional characterization demonstrated that, as in monogastrics, the PPAR isotypes control expression of genes involved in lipid metabolism, anti-inflammatory response, development, and growth. Contrary to mouse, however, the PPARγ gene network appears to controls milk fat synthesis in lactating ruminants. As in monogastrics, PPAR isotypes in ruminants are activated by long-chain fatty acids, therefore, making them ideal candidates for fine-tuning metabolism in this species via nutrients. In this regard, using information accumulated in ruminants and monogastrics, we propose a model of PPAR isotype-driven biological functions encompassing key tissues during the peripartal period in dairy cattle. PMID:23737762

  2. Inverse Relationship between 15-Lipoxygenase-2 and PPAR-γ Gene Expression in Normal Epithelia Compared with Tumor Epithelia

    Directory of Open Access Journals (Sweden)

    Vemparala Subbarayan

    2005-03-01

    Full Text Available 15-Lipoxygenase-2 (15-LOX-2 synthesizes 15-S-hydroxyeicosatetraenoic acid (15-S-HETE, an endogenous ligand for the nuclear receptor, peroxisome proliferator-activated receptor-γ (PPAR-γ. Several studies have described an inverse relationship between 15-LOX-2 and PPAR-γ expression in normal versus tumor samples. To systematically determine if this is a ubiquitous phenomenon, we used a variety of epithelial and nonepithelial cells and some tissues to further evaluate the extent of this inverse relationship. The levels of mRNA or protein were measured by reverse transcriptase polymerase chain reaction or Western gray level intensity, whereas distribution was determined by in situ hybridization or immunofluorescence. 15-S-HETE was measured by liquid chromatography/tandem mass spectrometry. Normal epithelial cells/samples generally expressed high levels of 15-LOX-2 along with the enzyme product 15-S-HETE, but both levels were reduced in cancer cells/samples. In contrast, most cancer cells expressed high levels of PPAR-γ mRNA and protein, which were absent from normal epithelial cells. Overall, the inverse relationship between these two genes was primarily restricted to epithelial samples. Forced expression of PPAR-γ reduced 15-LOX-2 protein levels in normal cells, whereas forced expression of 15-LOX-2 in tumor cells suppressed PPAR-y protein levels. These results suggest that feedback mechanisms may contribute to the loss of 15-LOX-2 pathway components, which coincide with an increase in PPAR-γ in many epithelial cancers.

  3. PPAR-α, a lipid-sensing transcription factor, regulates blood-brain barrier efflux transporter expression.

    Science.gov (United States)

    More, Vijay R; Campos, Christopher R; Evans, Rebecca A; Oliver, Keith D; Chan, Gary Ny; Miller, David S; Cannon, Ronald E

    2017-04-01

    Lipid sensor peroxisome proliferator-activated receptor alpha (PPAR- α) is the master regulator of lipid metabolism. Dietary release of endogenous free fatty acids, fibrates, and certain persistent environmental pollutants, e.g. perfluoroalkyl fire-fighting foam components, are peroxisome proliferator-activated receptor alpha ligands. Here, we define a role for peroxisome proliferator-activated receptor alpha in regulating the expression of three ATP-driven drug efflux transporters at the rat and mouse blood-brain barriers: P-glycoprotein (Abcb1), breast cancer resistance protein (Bcrp/Abcg2), and multidrug resistance-associated protein 2 (Mrp2/Abcc2). Exposing isolated rat brain capillaries to linoleic acid, clofibrate, or PKAs increased the transport activity and protein expression of the three ABC transporters. These effects were blocked by the PPAR- α antagonist, GW6471. Dosing rats with 20 mg/kg or 200 mg/kg of clofibrate decreased the brain accumulation of the P-glycoprotein substrate, verapamil, by 50% (in situ brain perfusion; effects blocked by GW6471) and increased P-glycoprotein expression and activity in capillaries ex vivo. Fasting C57Bl/6 wild-type mice for 24 h increased both serum lipids and brain capillary P-glycoprotein transport activity. Fasting did not alter P-glycoprotein activity in PPAR- α knockout mice. These results indicate that hyperlipidemia, lipid-lowering fibrates and exposure to certain fire-fighting foam components activate blood-brain barrier peroxisome proliferator-activated receptor alpha, increase drug efflux transporter expression and reduce drug delivery to the brain.

  4. Calcitriol Inhibits HCV Infection via Blockade of Activation of PPAR and Interference with Endoplasmic Reticulum-Associated Degradation

    Directory of Open Access Journals (Sweden)

    Yu-Min Lin

    2018-01-01

    Full Text Available Vitamin D has been identified as an innate anti-hepatitis C virus (HCV agent but the possible mechanisms for this issue remain unclear. Here, we clarified the mechanisms of calcitriol-mediated inhibition of HCV infection. Calcitriol partially inhibited HCV infection, nitric oxide (NO release and lipid accumulation in Huh7.5 human hepatoma cells via the activation of vitamin D receptor (VDR. When cells were pretreated with the activators of peroxisome proliferator-activated receptor (PPAR-α (Wy14643 and -γ (Ly171883, the calcitriol-mediated HCV suppression was reversed. Otherwise, three individual stimulators of PPAR-α/β/γ blocked the activation of VDR. PPAR-β (linoleic acid reversed the inhibition of NO release, whereas PPAR-γ (Ly171883 reversed the inhibitions of NO release and lipid accumulation in the presence of calcitriol. The calcitriol-mediated viral suppression, inhibition of NO release and activation of VDR were partially blocked by an inhibitor of endoplasmic reticulum-associated degradation (ERAD, kifunensine. Furthermore, calcitriol blocked the HCV-induced expressions of apolipoprotein J and 78 kDa glucose-regulated protein, which was restored by pretreatment of kifunensine. These results indicated that the calcitriol-mediated HCV suppression was associated with the activation of VDR, interference with ERAD process, as well as blockades of PPAR, lipid accumulation and nitrative stress.

  5. PPAR ligands improve impaired metabolic pathways in fetal hearts of diabetic rats.

    Science.gov (United States)

    Kurtz, Melisa; Capobianco, Evangelina; Martinez, Nora; Roberti, Sabrina Lorena; Arany, Edith; Jawerbaum, Alicia

    2014-10-01

    In maternal diabetes, the fetal heart can be structurally and functionally affected. Maternal diets enriched in certain unsaturated fatty acids can activate the nuclear receptors peroxisome proliferator-activated receptors (PPARs) and regulate metabolic and anti-inflammatory pathways during development. Our aim was to investigate whether PPARα expression, lipid metabolism, lipoperoxidation, and nitric oxide (NO) production are altered in the fetal hearts of diabetic rats, and to analyze the putative effects of in vivo PPAR activation on these parameters. We found decreased PPARα expression in the hearts of male but not female fetuses of diabetic rats when compared with controls. Fetal treatments with the PPARα ligand leukotriene B4 upregulated the expression of PPARα and target genes involved in fatty acid oxidation in the fetal hearts. Increased concentrations of triglycerides, cholesterol, and phospholipids were found in the hearts of fetuses of diabetic rats. Maternal treatments with diets supplemented with 6% olive oil or 6% safflower oil, enriched in unsaturated fatty acids that can activate PPARs, led to few changes in lipid concentrations, but up-regulated PPARα expression in fetal hearts. NO production, which was increased in the hearts of male and female fetuses in the diabetic group, and lipoperoxidation, which was increased in the hearts of male fetuses in the diabetic group, was reduced by the maternal treatments supplemented with safflower oil. In conclusion, impaired PPARα expression, altered lipid metabolism, and increased oxidative and nitridergic pathways were evidenced in hearts of fetuses of diabetic rats and were regulated in a gender-dependent manner by treatments enriched with PPAR ligands. © 2014 Society for Endocrinology.

  6. PPAR gamma Pro(12)Ala polymorphism and risk of acute coronary syndrome in a prospective study of Danes

    DEFF Research Database (Denmark)

    Vogel, Ulla Birgitte; Segel, Stine; Dethlefsen, Claus

    2009-01-01

    Background: Acute coronary syndrome (ACS) is a major cause of morbidity and mortality in the western world. Peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a key role in the regulation of the energy balance, adipocyte differentiation and lipid biosynthesis. The aim...... was to investigate if the polymorphism PPAR gamma 2 Pro(12)Ala, which encodes a less efficient transcription factor, was associated with risk of acute coronary disease and if there were interactions between this polymorphism and factors that modify PPAR gamma activity, such as alcohol intake, smoking, and use of non...

  7. Immunoregulatory actions of epithelial cell PPAR gamma at the colonic mucosa of mice with experimental inflammatory bowel disease.

    Science.gov (United States)

    Mohapatra, Saroj K; Guri, Amir J; Climent, Montse; Vives, Cristina; Carbo, Adria; Horne, William T; Hontecillas, Raquel; Bassaganya-Riera, Josep

    2010-04-20

    Peroxisome proliferator-activated receptors are nuclear receptors highly expressed in intestinal epithelial cells (IEC) and immune cells within the gut mucosa and are implicated in modulating inflammation and immune responses. The objective of this study was to investigate the effect of targeted deletion of PPAR gamma in IEC on progression of experimental inflammatory bowel disease (IBD). In the first phase, PPAR gamma flfl; Villin Cre- (VC-) and PPAR gamma flfl; Villin Cre+ (VC+) mice in a mixed FVB/C57BL/6 background were challenged with 2.5% dextran sodium sulfate (DSS) in drinking water for 0, 2, or 7 days. VC+ mice express a transgenic recombinase under the control of the Villin-Cre promoter that causes an IEC-specific deletion of PPAR gamma. In the second phase, we generated VC- and VC+ mice in a C57BL/6 background that were challenged with 2.5% DSS. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to phenotypically characterize lymphocyte and macrophage populations in blood, spleen and mesenteric lymph nodes. Global gene expression analysis was profiled using Affymetrix microarrays. The IEC-specific deficiency of PPAR gamma in mice with a mixed background worsened colonic inflammatory lesions, but had no effect on disease activity (DAI) or weight loss. In contrast, the IEC-specific PPAR gamma null mice in C57BL/6 background exhibited more severe inflammatory lesions, DAI and weight loss in comparison to their littermates expressing PPAR gamma in IEC. Global gene expression profiling revealed significantly down-regulated expression of lysosomal pathway genes and flow cytometry results demonstrated suppressed production of IL-10 by CD4+ T cells in mesenteric lymph nodes (MLN) of IEC-specific PPAR gamma null mice. Our results demonstrate that adequate expression of PPAR gamma in IEC is required for the regulation of mucosal immune responses and prevention of experimental IBD, possibly by modulation of

  8. Immunoregulatory actions of epithelial cell PPAR gamma at the colonic mucosa of mice with experimental inflammatory bowel disease.

    Directory of Open Access Journals (Sweden)

    Saroj K Mohapatra

    Full Text Available BACKGROUND: Peroxisome proliferator-activated receptors are nuclear receptors highly expressed in intestinal epithelial cells (IEC and immune cells within the gut mucosa and are implicated in modulating inflammation and immune responses. The objective of this study was to investigate the effect of targeted deletion of PPAR gamma in IEC on progression of experimental inflammatory bowel disease (IBD. METHODOLOGY/PRINCIPAL FINDINGS: In the first phase, PPAR gamma flfl; Villin Cre- (VC- and PPAR gamma flfl; Villin Cre+ (VC+ mice in a mixed FVB/C57BL/6 background were challenged with 2.5% dextran sodium sulfate (DSS in drinking water for 0, 2, or 7 days. VC+ mice express a transgenic recombinase under the control of the Villin-Cre promoter that causes an IEC-specific deletion of PPAR gamma. In the second phase, we generated VC- and VC+ mice in a C57BL/6 background that were challenged with 2.5% DSS. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to phenotypically characterize lymphocyte and macrophage populations in blood, spleen and mesenteric lymph nodes. Global gene expression analysis was profiled using Affymetrix microarrays. The IEC-specific deficiency of PPAR gamma in mice with a mixed background worsened colonic inflammatory lesions, but had no effect on disease activity (DAI or weight loss. In contrast, the IEC-specific PPAR gamma null mice in C57BL/6 background exhibited more severe inflammatory lesions, DAI and weight loss in comparison to their littermates expressing PPAR gamma in IEC. Global gene expression profiling revealed significantly down-regulated expression of lysosomal pathway genes and flow cytometry results demonstrated suppressed production of IL-10 by CD4+ T cells in mesenteric lymph nodes (MLN of IEC-specific PPAR gamma null mice. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that adequate expression of PPAR gamma in IEC is required for the regulation of mucosal

  9. Immunoregulatory Actions of Epithelial Cell PPAR γ at the Colonic Mucosa of Mice with Experimental Inflammatory Bowel Disease

    Science.gov (United States)

    Mohapatra, Saroj K.; Guri, Amir J.; Climent, Montse; Vives, Cristina; Carbo, Adria; Horne, William T.; Hontecillas, Raquel; Bassaganya-Riera, Josep

    2010-01-01

    Background Peroxisome proliferator-activated receptors are nuclear receptors highly expressed in intestinal epithelial cells (IEC) and immune cells within the gut mucosa and are implicated in modulating inflammation and immune responses. The objective of this study was to investigate the effect of targeted deletion of PPAR γ in IEC on progression of experimental inflammatory bowel disease (IBD). Methodology/Principal Findings In the first phase, PPAR γ flfl; Villin Cre- (VC-) and PPAR γ flfl; Villin Cre+ (VC+) mice in a mixed FVB/C57BL/6 background were challenged with 2.5% dextran sodium sulfate (DSS) in drinking water for 0, 2, or 7 days. VC+ mice express a transgenic recombinase under the control of the Villin-Cre promoter that causes an IEC-specific deletion of PPAR γ. In the second phase, we generated VC- and VC+ mice in a C57BL/6 background that were challenged with 2.5% DSS. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to phenotypically characterize lymphocyte and macrophage populations in blood, spleen and mesenteric lymph nodes. Global gene expression analysis was profiled using Affymetrix microarrays. The IEC-specific deficiency of PPAR γ in mice with a mixed background worsened colonic inflammatory lesions, but had no effect on disease activity (DAI) or weight loss. In contrast, the IEC-specific PPAR γ null mice in C57BL/6 background exhibited more severe inflammatory lesions, DAI and weight loss in comparison to their littermates expressing PPAR γ in IEC. Global gene expression profiling revealed significantly down-regulated expression of lysosomal pathway genes and flow cytometry results demonstrated suppressed production of IL-10 by CD4+ T cells in mesenteric lymph nodes (MLN) of IEC-specific PPAR γ null mice. Conclusions/Significance Our results demonstrate that adequate expression of PPAR γ in IEC is required for the regulation of mucosal immune responses and prevention of

  10. Maraviroc attenuates trauma-hemorrhage-induced hepatic injury through PPAR gamma-dependent pathway in rats.

    Directory of Open Access Journals (Sweden)

    Fu-Chao Liu

    Full Text Available Maraviroc is a CC-chemokine receptor 5 (CCR5 antagonist with potent antiviral and cancer preventive effects. Recent evidence suggests that the co-existence of CCR5 in various cell types is involved in inflammation. However, the effects that CCR5 antagonists produce in trauma-hemorrhage remain unknown. The peroxisome proliferator-activated receptor gamma (PPAR(γ pathway exerts anti-inflammatory effects in injury. In this study, we hypothesized that maraviroc administration in male rats, after trauma-hemorrhage, decreases cytokine production and protects against hepatic injury through a PPAR(γ-dependent pathway. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35-40 mmHg for 90 minutes, followed by fluid resuscitation. During resuscitation, a single dose of maraviroc (3 mg/kg, intravenously with and without a PPAR(γ antagonist GW9662 (1 mg/kg, intravenously, GW9662 or vehicle was administered. Plasma alanine aminotransferase (ALT with aspartate aminotransferase (AST concentrations and various hepatic parameters were measured (n=8 rats/group at 24 hours after resuscitation. The results showed that trauma-hemorrhage increased hepatic myeloperoxidase activity, intercellular adhesion molecule-1 and interleukin-6 levels, and plasma ALT and AST concentrations. These parameters were significantly improved in the maraviroc-treated rats subjected to trauma-hemorrhage. Maraviroc treatment also increased hepatic PPAR(γ expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of GW9662 with maraviroc abolished the maraviroc-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of maraviroc administration on alleviation of hepatic injury after trauma-hemorrhage, which is, at least in part, through PPAR(γ-dependent pathway.

  11. Irbesartan increased PPAR{gamma} activity in vivo in white adipose tissue of atherosclerotic mice and improved adipose tissue dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Iwai, Masaru; Kanno, Harumi; Senba, Izumi; Nakaoka, Hirotomo; Moritani, Tomozo [Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295 (Japan); Horiuchi, Masatsugu, E-mail: horiuchi@m.ehime-u.ac.jp [Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295 (Japan)

    2011-03-04

    Research highlights: {yields} Atherosclerotic apolipoprotein E-deficient (ApoEKO) mice were treated with irbesartan. {yields} Irbesartan decreased white adipose tissue weight without affecting body weight. {yields} DNA-binding for PPAR{gamma} was increased in white adipose tissue in vivo by irbesartan. {yields} Irbesartan increased adipocyte number in white adipose tissue. {yields} Irbesatan increased the expression of adiponectin and leptin in white adipose tissue. -- Abstract: The effect of the PPAR{gamma} agonistic action of an AT{sub 1} receptor blocker, irbesartan, on adipose tissue dysfunction was explored using atherosclerotic model mice. Adult male apolipoprotein E-deficient (ApoEKO) mice at 9 weeks of age were treated with a high-cholesterol diet (HCD) with or without irbesartan at a dose of 50 mg/kg/day for 4 weeks. The weight of epididymal and retroperitoneal adipose tissue was decreased by irbesartan without changing food intake or body weight. Treatment with irbesartan increased the expression of PPAR{gamma} in white adipose tissue and the DNA-binding activity of PPAR{gamma} in nuclear extract prepared from adipose tissue. The expression of adiponectin, leptin and insulin receptor was also increased by irbesartan. These results suggest that irbesartan induced activation of PPAR{gamma} and improved adipose tissue dysfunction including insulin resistance.

  12. Peroxisome Proliferator-activated Receptor gamma Regulates Expression of the Anti-lipolytic G-protein-coupled Receptor 81 (GPR81/Gpr81)

    NARCIS (Netherlands)

    Jeninga, E.H.; Bugge, A.; Nielsen, R.; Kersten, A.H.; Hamers, N.; Dani, C.; Wabitsch, M.; Berger, R.; Stunnenberg, H.G.; Mandrup, S.; Kalkhoven, E.

    2009-01-01

    The ligand-inducible nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a key role in the differentiation, maintenance, and function of adipocytes and is the molecular target for the insulin-sensitizing thiazoledinediones (TZDs). Although a number of PPAR gamma

  13. Angiopoietin-like 4 mediates PPAR delta effect on lipoprotein lipase-dependent fatty acid uptake but not on beta-oxidation in myotubes.

    Directory of Open Access Journals (Sweden)

    Marius R Robciuc

    Full Text Available Peroxisome proliferator-activated receptor (PPAR delta is an important regulator of fatty acid (FA metabolism. Angiopoietin-like 4 (Angptl4, a multifunctional protein, is one of the major targets of PPAR delta in skeletal muscle cells. Here we investigated the regulation of Angptl4 and its role in mediating PPAR delta functions using human, rat and mouse myotubes. Expression of Angptl4 was upregulated during myotubes differentiation and by oleic acid, insulin and PPAR delta agonist GW501516. Treatment with GW501516 or Angptl4 overexpression inhibited both lipoprotein lipase (LPL activity and LPL-dependent uptake of FAs whereas uptake of BSA-bound FAs was not affected by either treatment. Activation of retinoic X receptor (RXR, PPAR delta functional partner, using bexarotene upregulated Angptl4 expression and inhibited LPL activity in a PPAR delta dependent fashion. Silencing of Angptl4 blocked the effect of GW501516 and bexarotene on LPL activity. Treatment with GW501516 but not Angptl4 overexpression significantly increased palmitate oxidation. Furthermore, Angptl4 overexpression did not affect the capacity of GW501516 to increase palmitate oxidation. Basal and insulin stimulated glucose uptake, glycogen synthesis and glucose oxidation were not significantly modulated by Angptl4 overexpression. Our findings suggest that FAs-PPARdelta/RXR-Angptl4 axis controls the LPL-dependent uptake of FAs in myotubes, whereas the effect of PPAR delta activation on beta-oxidation is independent of Angptl4.

  14. Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor Alpha Selective

    Energy Technology Data Exchange (ETDEWEB)

    Li, J.; Kennedy, L; Shi, Y; Tao, S; Ye, X; Chen, S; Wang, Y; Hernandez, A; Wang, W; et al.

    2010-01-01

    An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) {alpha} agonist, with an EC{sub 50} of 10 nM for human PPAR{alpha} and {approx}410-fold selectivity vs human PPAR{gamma} in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPAR{delta}. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPAR{alpha} ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPAR{alpha} in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.

  15. Anti-diabetic action of Punica granatum flower extract: Activation of PPAR-γ and identification of an active component

    International Nuclear Information System (INIS)

    Huang, Tom H.W.; Peng Gang; Kota, Bhavani P.; Li, George Q.; Yamahara, Johji; Roufogalis, Basil D.; Li Yuhao

    2005-01-01

    Peroxisome proliferator-activated receptor (PPAR)-γ activators are widely used in the treatment of type 2 diabetes because they improve the sensitivity of insulin receptors. Punica granatum flower (PGF) has been used as an anti-diabetic medicine in Unani medicinal literature. The mechanism of actions is, however, unknown. In the current study, we demonstrated that 6-week oral administration of methanol extract from PGF (500 mg/kg, daily) inhibited glucose loading-induced increase of plasma glucose levels in Zucker diabetic fatty rats (ZDF), a genetic animal model for type 2 diabetes, whereas it did not inhibit the increase in Zucker lean rats (ZL). The treatment did not lower the plasma glucose levels in fasted ZDF and ZL rats. Furthermore, RT-PCR results demonstrated that the PGF extract treatment in ZDF rats enhanced cardiac PPAR-γ mRNA expression and restored the down-regulated cardiac glucose transporter (GLUT)-4 (the insulin-dependent isoform of GLUTs) mRNA. These results suggest that the anti-diabetic activity of PGF extract may result from improved sensitivity of the insulin receptor. From the in vitro studies, we demonstrated that the PGF extract enhanced PPAR-γ mRNA and protein expression and increased PPAR-γ-dependent mRNA expression and activity of lipoprotein lipase in human THP-1-differentiated macrophage cells. Phytochemical investigation demonstrated that gallic acid in PGF extract is mostly responsible for this activity. Thus, our findings indicate that PPAR-γ is a molecular target for PGF extract and its prominent component gallic acid, and provide a better understanding of the potential mechanism of the anti-diabetic action of PGF

  16. The role of T cell PPAR gamma in mice with experimental inflammatory bowel disease.

    Science.gov (United States)

    Guri, Amir J; Mohapatra, Saroj K; Horne, William T; Hontecillas, Raquel; Bassaganya-Riera, Josep

    2010-06-10

    Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been shown to modulate macrophage and T cell-mediated inflammation. The objective of this study was to investigate the mechanisms by which the deletion of PPAR gamma in T cells modulates immune cell distribution and colonic gene expression and the severity of experimental IBD. PPAR gamma flfl; CD4 Cre+ (CD4cre) or Cre- (WT) mice were challenged with 2.5% dextran sodium sulfate in their drinking water for 0, 2, or 7 days. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to assess lymphocyte and macrophage populations in the blood, spleen, and mesenteric lymph nodes (MLN). Global gene expression in colonic mucosa was profiled using Affymetrix microarrays. The deficiency of PPAR gamma in T cells accelerated the onset of disease and body weight loss. Examination of colon histopathology revealed significantly greater epithelial erosion, leukocyte infiltration, and mucosal thickening in the CD4cre mice on day 7. CD4cre mice had more CD8+ T cells than WT mice and fewer CD4+ FoxP3+ regulatory T cells (Treg) and IL10+ CD4+ T cells in blood and MLN, respectively. Transcriptomic profiling revealed around 3000 genes being transcriptionally altered as a result of DSS challenge in CD4cre mice. These included up-regulated mRNA expression of adhesion molecules, proinflammatory cytokines interleukin-6 (IL-6) and IL-1beta, and suppressor of cytokine signaling 3 (SOCS-3) on day 7. Gene set enrichment analysis (GSEA) showed that the ribosome and Krebs cycle pathways were downregulated while the apoptosis pathway was upregulated in colons of mice lacking PPAR gamma in T cells. The expression of PPAR gamma in T cells is involved in preventing gut inflammation by regulating colonic expression of adhesion molecules and inflammatory mediators at later stages of disease while favoring the recruitment of Treg to the mucosal inductive

  17. The Role of T cell PPAR γ in mice with experimental inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    Hontecillas Raquel

    2010-06-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptor γ (PPAR γ is a nuclear receptor whose activation has been shown to modulate macrophage and T cell-mediated inflammation. The objective of this study was to investigate the mechanisms by which the deletion of PPAR γ in T cells modulates immune cell distribution and colonic gene expression and the severity of experimental IBD. Methods PPAR γ flfl; CD4 Cre+ (CD4cre or Cre- (WT mice were challenged with 2.5% dextran sodium sulfate in their drinking water for 0, 2, or 7 days. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to assess lymphocyte and macrophage populations in the blood, spleen, and mesenteric lymph nodes (MLN. Global gene expression in colonic mucosa was profiled using Affymetrix microarrays. Results The deficiency of PPAR γ in T cells accelerated the onset of disease and body weight loss. Examination of colon histopathology revealed significantly greater epithelial erosion, leukocyte infiltration, and mucosal thickening in the CD4cre mice on day 7. CD4cre mice had more CD8+ T cells than WT mice and fewer CD4+FoxP3+ regulatory T cells (Treg and IL10+CD4+ T cells in blood and MLN, respectively. Transcriptomic profiling revealed around 3000 genes being transcriptionally altered as a result of DSS challenge in CD4cre mice. These included up-regulated mRNA expression of adhesion molecules, proinflammatory cytokines interleukin-6 (IL-6 and IL-1β, and suppressor of cytokine signaling 3 (SOCS-3 on day 7. Gene set enrichment analysis (GSEA showed that the ribosome and Krebs cycle pathways were downregulated while the apoptosis pathway was upregulated in colons of mice lacking PPAR γ in T cells. Conclusions The expression of PPAR γ in T cells is involved in preventing gut inflammation by regulating colonic expression of adhesion molecules and inflammatory mediators at later stages of disease while favoring the recruitment

  18. Study of Arachidonic Acid Pathway in Human Bladder Tumor

    Directory of Open Access Journals (Sweden)

    Masahide Matsuyama

    2009-12-01

    Full Text Available Recent epidemiological studies and animal experiments have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs reduce the incidence of colorectal carcinoma. Cyclooxygenase (COX is the principal target of NSAIDs. COX is the first oxidase in the process of prostaglandin production from arachidonic acid. COX enzyme may be involved in the initiation and/or the promotion of tumorigenesis due to NSAIDs inhibition of COX. Lipoxygenase (LOX is also an initial enzyme in the pathway for producing leukotrienes from arachidonic acid. Similar to COX, LOX enzyme may also be involved in the initiation and/or promotion of tumorigenesis. Peroxisome proliferator activator-receptor (PPAR-γ is a ligand-activated transcriptional factor belonging to the steroid receptor superfamily. PPAR-γ plays a role in both adipocyte differentiation and tumorigenesis. PPAR-γ is one target for cell growth modulation of NSAIDs. In this review, we report the expression of COX-2, LOX and PPAR-γ in human bladder tumor tissues as well as the effects of COX-2 and LOX inhibitors and PPAR-γ ligand.

  19. Study of Arachidonic Acid Pathway in Human Bladder Tumor

    Directory of Open Access Journals (Sweden)

    Masahide Matsuyama

    2009-01-01

    Full Text Available Recent epidemiological studies and animal experiments have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs reduce the incidence of colorectal carcinoma. Cyclooxygenase (COX is the principal target of NSAIDs. COX is the first oxidase in the process of prostaglandin production from arachidonic acid. COX enzyme may be involved in the initiation and/or the promotion of tumorigenesis due to NSAIDs inhibition of COX. Lipoxygenase (LOX is also an initial enzyme in the pathway for producing leukotrienes from arachidonic acid. Similar to COX, LOX enzyme may also be involved in the initiation and/or promotion of tumorigenesis. Peroxisome proliferator activator-receptor (PPAR-γ is a ligand-activated transcriptional factor belonging to the steroid receptor superfamily. PPAR-γ plays a role in both adipocyte differentiation and tumorigenesis. PPAR-γ is one target for cell growth modulation of NSAIDs. In this review, we report the expression of COX-2, LOX and PPAR-γ in human bladder tumor tissues as well as the effects of COX-2 and LOX inhibitors and PPAR-γ ligand.

  20. Nicotinic Acid-Mediated Activation of Both Membrane and Nuclear Receptors towards Therapeutic Glucocorticoid Mimetics for Treating Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    W. Todd Penberthy

    2009-01-01

    Full Text Available Acute attacks of multiple sclerosis (MS are most commonly treated with glucocorticoids, which can provide life-saving albeit only temporary symptomatic relief. The mechanism of action (MOA is now known to involve induction of indoleamine 2,3-dioxygenase (IDO and interleukin-10 (IL-10, where IL-10 requires subsequent heme oxygenase-1 (HMOX-1 induction. Ectopic expression studies reveal that even small changes in expression of IDO, HMOX-1, or mitochondrial superoxide dismutase (SOD2 can prevent demyelination in experimental autoimmune encephalomyelitis (EAE animal models of MS. An alternative to glucocorticoids is needed for a long-term treatment of MS. A distinctly short list of endogenous activators of both membrane G-protein-coupled receptors and nuclear peroxisome proliferating antigen receptors (PPARs demonstrably ameliorate EAE pathogenesis by MOAs resembling that of glucocorticoids. These dual activators and potential MS therapeutics include endocannabinoids and the prostaglandin 15-deoxy-Δ12,14-PGJ2. Nicotinamide profoundly ameliorates and prevents autoimmune-mediated demyelination in EAE via maintaining levels of nicotinamide adenine dinucleotide (NAD, without activating PPAR nor any G-protein-coupled receptor. By comparison, nicotinic acid provides even greater levels of NAD than nicotinamide in many tissues, while additionally activating the PPAR-dependent pathway already shown to provide relief in animal models of MS after activation of GPR109a/HM74a. Thus nicotinic acid is uniquely suited for providing therapeutic relief in MS. However nicotinic acid is unexamined in MS research. Nicotinic acid penetrates the blood brain barrier, cures pellagric dementia, has been used for over 50 years clinically without toxicity, and raises HDL concentrations to a greater degree than any pharmaceutical, thus providing unparalleled benefits against lipodystrophy. Summary analysis reveals that the expected therapeutic benefits of high-dose nicotinic

  1. Evaluation of glucose metabolism and reproductive hormones in polycystic ovary syndrome on the basis of peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala genotype.

    Science.gov (United States)

    Tok, E C; Aktas, A; Ertunc, D; Erdal, E M; Dilek, S

    2005-06-01

    Peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala polymorphism has been suggested as a protective factor for polycystic ovary syndrome (PCOS). In this study, we aimed to investigate metabolic features and reproductive hormones in women with PCOS and compare these features with control women on the basis of Pro12Ala genotype. This study involved 60 randomly selected women with PCOS and 60 controls. Main outcome measures were anthropometric measures, variables of glucose metabolism and reproductive hormones. All the patients were genotyped for Pro12Ala variant of PPAR-gamma2 gene. Patients with Pro12Ala polymorphism were more obese in both groups. Furthermore, they had lower fasting insulin levels, were less insulin-resistant and were less glucose-intolerant as demonstrated by 2 h glucose concentrations. However, there was no difference in reproductive hormone levels on the basis of Pro12Ala genotype. Both control women and women with PCOS had significant differences in glucose metabolism on the basis of PPAR-gamma2 Pro12Ala polymorphism. Pro12Ala variant may break the process that leads to PCOS in susceptible women, instead of being a direct causal relationship between Pro12Ala polymorphism and PCOS.

  2. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR γ activators and pan-PPAR partial agonists.

    Directory of Open Access Journals (Sweden)

    Marcelo Vizoná Liberato

    Full Text Available Thiazolidinediones (TZDs act through peroxisome proliferator activated receptor (PPAR γ to increase insulin sensitivity in type 2 diabetes (T2DM, but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD and found that the ligand binding pocket (LBP is occupied by bacterial medium chain fatty acids (MCFAs. We verified that MCFAs (C8-C10 bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5, linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/β-sheet region and the helix (H 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPARγ modulators with useful clinical profiles among natural products.

  3. Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene in relation to insulin sensitivity among glucose tolerant caucasians

    DEFF Research Database (Denmark)

    Ek, J; Andersen, G; Urhammer, S A

    2001-01-01

    We examined whether the Pro12-Ala polymorphism of the human peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene was related to altered insulin sensitivity among glucose-tolerant subjects or a lower accumulated incidence or prevalence of IGT and Type II (non-insulin-dependent) dia......-insulin-dependent) diabetes mellitus among Scandinavian Caucasians....

  4. Prostaglandin E(2) stimulates glutamate receptor-dependent astrocyte neuromodulation in cultured hippocampal cells.

    Science.gov (United States)

    Sanzgiri, R P; Araque, A; Haydon, P G

    1999-11-05

    Recent Ca(2+) imaging studies in cell culture and in situ have shown that Ca(2+) elevations in astrocytes stimulate glutamate release and increase neuronal Ca(2+) levels, and that this astrocyte-neuron signaling can be stimulated by prostaglandin E(2) (PGE(2)). We investigated the electrophysiological consequences of the PGE(2)-mediated astrocyte-neuron signaling using whole-cell recordings on cultured rat hippocampal cells. Focal application of PGE(2) to astrocytes evoked a Ca(2+) elevation in the stimulated cell by mobilizing internal Ca(2+) stores, which further propagated as a Ca(2+) wave to neighboring astrocytes. Whole-cell recordings from neurons revealed that PGE(2) evoked a slow inward current in neurons adjacent to astrocytes. This neuronal response required the presence of an astrocyte Ca(2+) wave and was mediated through both N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors. Taken together with previous studies, these data demonstrate that PGE(2)-evoked Ca(2+) elevations in astrocyte cause the release of glutamate which activates neuronal ionotropic receptors. Copyright 1999 John Wiley & Sons, Inc.

  5. The Role of Peroxisome Proliferator-Activated Receptors in the Development and Physiology of Gametes and Preimplantation Embryos

    Directory of Open Access Journals (Sweden)

    Jaou-Chen Huang

    2008-01-01

    Full Text Available In several species, a family of nuclear receptors, the peroxisome proliferator-activated receptors (PPARs composed of three isotypes, is expressed in somatic cells and germ cells of the ovary as well as the testis. Invalidation of these receptors in mice or stimulation of these receptors in vivo or in vitro showed that each receptor has physiological roles in the gamete maturation or the embryo development. In addition, synthetic PPARγ ligands are recently used to induce ovulation in women with polycystic ovary disease. These results reveal the positive actions of PPAR in reproduction. On the other hand, xenobiotics molecules (in herbicides, plasticizers, or components of personal care products, capable of activating PPAR, may disrupt normal PPAR functions in the ovary or the testis and have consequences on the quality of the gametes and the embryos. Despite the recent data obtained on the biological actions of PPARs in reproduction, relatively little is known about PPARs in gametes and embryos. This review summarizes the current knowledge on the expression and the function of PPARs as well as their partners, retinoid X receptors (RXRs, in germ cells and preimplantation embryos. The effects of natural and synthetic PPAR ligands will also be discussed from the perspectives of reproductive toxicology and assisted reproductive technology.

  6. Screening of Peroxisome Proliferator-Activated Receptors (PPARs) α, γ and α Gene Polymorphisms for Obesity and Metabolic Syndrome Association in the Multi-Ethnic Malaysian Population.

    Science.gov (United States)

    Chia, Phee-Phee; Fan, Sook-Ha; Say, Yee-How

    2015-11-05

    This study aimed to investigate the association of peroxisome proliferator-activated receptor (PPAR) genes PPARα L162V, PPARγ2 C161T and PPARδ T294C single nucleotide polymorphisms (SNPs) with obesity and metabolic syndrome (Met-S) in a multi-ethnic population in Kampar, Malaysia. Socio-demographic data, anthropometric and biochemical measurements (plasma lipid profile, adiponectin and interleukin-6 [IL-6] levels) were taken from 307 participants (124 males; 180 obese; 249 Met-S; 97 Malays, 85 ethnic Chinese, 55 ethnic Indians). The overall minor allele frequencies were .08, .22 and .30 for PPAR α L162V, γ C161T, δ T294C, respectively. All SNPs were not associated with obesity, Met-S and obesity with/without Met-S by χ(2) analysis, ethnicity-stratified and logistic regression analyses. Nevertheless, participants with V162 allele of PPARα had significantly higher IL-6, while those with T161 allele of PPARγ2 had significantly lower HOMA-IR. All PPAR SNPs were not associated with obesity and Met-S in the suburban population of Kampar, Malaysia, where only PPARα V162 and PPARγ2 T161 alleles were associated with plasma IL-6 and HOMA-IR, respectively.

  7. Activated prostaglandin D2 receptors on macrophages enhance neutrophil recruitment into the lung

    Science.gov (United States)

    Jandl, Katharina; Stacher, Elvira; Bálint, Zoltán; Sturm, Eva Maria; Maric, Jovana; Peinhaupt, Miriam; Luschnig, Petra; Aringer, Ida; Fauland, Alexander; Konya, Viktoria; Dahlen, Sven-Erik; Wheelock, Craig E.; Kratky, Dagmar; Olschewski, Andrea; Marsche, Gunther; Schuligoi, Rufina; Heinemann, Akos

    2016-01-01

    Background Prostaglandin (PG) D2 is an early-phase mediator in inflammation, but its action and the roles of the 2 D-type prostanoid receptors (DPs) DP1 and DP2 (also called chemoattractant receptor–homologous molecule expressed on TH2 cells) in regulating macrophages have not been elucidated to date. Objective We investigated the role of PGD2 receptors on primary human macrophages, as well as primary murine lung macrophages, and their ability to influence neutrophil action in vitro and in vivo. Methods In vitro studies, including migration, Ca2+ flux, and cytokine secretion, were conducted with primary human monocyte-derived macrophages and neutrophils and freshly isolated murine alveolar and pulmonary interstitial macrophages. In vivo pulmonary inflammation was assessed in male BALB/c mice. Results Activation of DP1, DP2, or both receptors on human macrophages induced strong intracellular Ca2+ flux, cytokine release, and migration of macrophages. In a murine model of LPS-induced pulmonary inflammation, activation of each PGD2 receptor resulted in aggravated airway neutrophilia, tissue myeloperoxidase activity, cytokine contents, and decreased lung compliance. Selective depletion of alveolar macrophages abolished the PGD2-enhanced inflammatory response. Activation of PGD2 receptors on human macrophages enhanced the migratory capacity and prolonged the survival of neutrophils in vitro. In human lung tissue specimens both DP1 and DP2 receptors were located on alveolar macrophages along with hematopoietic PGD synthase, the rate-limiting enzyme of PGD2 synthesis. Conclusion For the first time, our results show that PGD2 markedly augments disease activity through its ability to enhance the proinflammatory actions of macrophages and subsequent neutrophil activation. PMID:26792210

  8. PPAR Agonists: Potential as Therapeutics for Neovascular Retinopathies

    Directory of Open Access Journals (Sweden)

    Harrihar A. Pershadsingh

    2008-01-01

    Full Text Available The angiogenic, neovascular proliferative retinopathies, proliferative diabetic retinopathy (PDR, and age-dependent macular degeneration (AMD complicated by choroidal neovascularization (CNV, also termed exudative or “wet” AMD, are common causes of blindness. The antidiabetic thiazolidinediones (TZDs, rosiglitazone, and troglitazone are PPAR agonists with demonstrable antiproliferative, and anti-inflammatory effects, in vivo, were shown to ameliorate PDR and CNV in rodent models, implying the potential efficacy of TZDs for treating proliferative retinopathies in humans. Activation of the angiotensin II type 1 receptor (AT1-R propagates proinflammatory and proliferative pathogenic determinants underlying PDR and CNV. The antihypertensive dual AT1-R blocker (ARB, telmisartan, recently was shown to activate PPAR and improve glucose and lipid metabolism and to clinically improve PDR and CNV in rodent models. Therefore, the TZDs and telmisartan, clinically approved antidiabetic and antihypertensive drugs, respectively, may be efficacious for treating and attenuating PDR and CNV humans. Clinical trials are needed to test these possibilities.

  9. Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor

    International Nuclear Information System (INIS)

    Yan Zhencheng; Liu Daoyan; Zhang Lili; Shen Chenyi; Ma Qunli; Cao Tingbing; Wang Lijuan; Nie Hai; Zidek, Walter; Tepel, Martin; Zhu Zhiming

    2007-01-01

    Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-δ (PPAR-δ)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow or a high-fat diet without and with regular endurance exercise. Exercise in rats on high-fat diet significantly reduced visceral fat mass, blood pressure, and adipocyte size (each p < 0.05). Adipocyte hypertrophy induced by high-fat diet was accompanied by increased CB1 expression in adipose tissue, whereas exercise significantly reduced CB1 expression (each p < 0.05). CB1 receptor expression and adipocyte differentiation were directly regulated by PPAR-δ. Adipocyte hypertrophy induced by high-fat diet was accompanied by reduced PPAR-δ. Furthermore, selective silencing of PPAR-δ by RNA interference in 3T3-L1-preadipocyte cells significantly increased CB1 expression from 1.00 ± 0.06 (n = 3) to 1.91 ± 0.06 (n = 3; p < 0.01) and increased adipocyte differentiation, whereas adenovirus-mediated overexpression of PPAR-δ significantly reduced CB1 expression to 0.39 ± 0.03 (n = 3; p < 0.01) and reduced adipocyte differentiation. In the presence of the CB1 antagonist rimonabant adipocyte differentiation in stimulated 3T3 L1 preadipocyte cells was significantly reduced. The study indicates that high-fat diet-induced hypertrophy of adipocytes is associated with increased CB1 receptor expression which is directly regulated by PPAR-δ. Both CB1 and PPAR-δ are intimately involved in therapeutic interventions against a most important cardiovascular risk factor

  10. A Role for PPAR/ in Ocular Angiogenesis

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    David Bishop-Bailey

    2008-01-01

    Full Text Available The uses of highly selective PPAR/ ligands and PPAR/ knockout mice have shown a direct ability of PPAR/ to regulate angiogenesis in vitro and in vivo in animal models. PPAR/ ligands induce the proangiogenic growth factor VEGF in many cells and tissues, though its actions in the eye are not known. However, virtually, all tissue components of the eye express PPAR/. Both angiogenesis and in particular VEGF are not only critical for the development of the retina, but they are also a central component in many common pathologies of the eye, including diabetic retinopathy and age-related macular degeneration, the most common causes of blindness in the Western world. This review, therefore, will discuss the recent evidence of PPAR/-mediated angiogenesis and VEGF release in the context of ocular disorders.

  11. The molecular mechanisms of action of PPAR-γ agonists in the treatment of corneal alkali burns (Review)

    Science.gov (United States)

    Zhou, Hongyan; Zhang, Wensong; Bi, Miaomiao; Wu, Jie

    2016-01-01

    Corneal alkali burns (CAB) are characterized by injury-induced inflammation, fibrosis and neovascularization (NV), and may lead to blindness. This review evaluates the current knowledge of the molecular mechanisms responsible for CAB. The processes of cytokine production, chemotaxis, inflammatory responses, immune response, cell signal transduction, matrix metalloproteinase production and vascular factors in CAB are discussed. Previous evidence indicates that peroxisome proliferator-activated receptor γ (PPAR-γ) agonists suppress immune responses, inflammation, corneal fibrosis and NV. This review also discusses the role of PPAR-γ as an anti-inflammatory, anti-fibrotic and anti-angiogenic agent in the treatment of CAB, as well as the potential role of PPAR-γ in the pathological process of CAB. There have been numerous studies evaluating the clinical profiles of CAB, and the aim of this systematic review was to summarize the evidence regarding the treatment of CAB with PPAR-γ agonists. PMID:27499172

  12. Pre-treatment with Toll-like receptor 4 antagonist inhibits lipopolysaccharide-induced preterm uterine contractility, cytokines, and prostaglandins in rhesus monkeys

    Science.gov (United States)

    Adams Waldorf, Kristina M.; Persing, David; Novy, Miles J.; Sadowsky, Drew W.; Gravett, Michael G.

    2009-01-01

    Intra-uterine infection, which occurs in the majority of early preterm births, triggers an immune response culminating in preterm labor. We hypothesized that blockade of lipopolysaccharide (LPS)-induced immune responses by a Toll-like receptor 4 antagonist (TLR4A) would prevent elevations in amniotic fluid (AF) cytokines, prostaglandins, and uterine contractility. Chronically catheterized rhesus monkeys at 128-147 days gestation received intra-amniotic infusions of either: 1) saline (n=6), 2) LPS (0.15-10μg; n=4), or 3) TLR4A pre-treatment with LPS (10 μg) one hour later (n=4). AF cytokines, prostaglandins, and uterine contractility were compared using oneway ANOVA with Bonferroni-adjusted pairwise comparisons. Compared to saline controls, LPS induced significant elevations in AF IL-8, TNF-α, PGE2, PGF2α, and uterine contractility (p<0.05). In contrast, TLR4A pre-treatment inhibited LPS-induced uterine activity and was associated with significantly lower AF IL-8, TNF-α, PGE2, and PGF2α versus LPS alone (p<0.05). Toll-like receptor antagonists, together with antibiotics, may delay or prevent infection-associated preterm birth. PMID:18187405

  13. PPARs Expression in Adult Mouse Neural Stem Cells: Modulation of PPARs during Astroglial Differentiaton of NSC

    Directory of Open Access Journals (Sweden)

    A. Cimini

    2007-01-01

    Full Text Available PPAR isotypes are involved in the regulation of cell proliferation, death, and differentiation, with different roles and mechanisms depending on the specific isotype and ligand and on the differentiated, undifferentiated, or transformed status of the cell. Differentiation stimuli are integrated by key transcription factors which regulate specific sets of specialized genes to allow proliferative cells to exit the cell cycle and acquire specialized functions. The main differentiation programs known to be controlled by PPARs both during development and in the adult are placental differentiation, adipogenesis, osteoblast differentiation, skin differentiation, and gut differentiation. PPARs may also be involved in the differentiation of macrophages, brain, and breast. However, their functions in this cell type and organs still awaits further elucidation. PPARs may be involved in cell proliferation and differentiation processes of neural stem cells (NSC. To this aim, in this work the expression of the three PPAR isotypes and RXRs in NSC has been investigated.

  14. Characterization of P2Y receptors mediating ATP induced relaxation in guinea pig airway smooth muscle: involvement of prostaglandins and K+ channels.

    Science.gov (United States)

    Montaño, Luis M; Cruz-Valderrama, José E; Figueroa, Alejandra; Flores-Soto, Edgar; García-Hernández, Luz M; Carbajal, Verónica; Segura, Patricia; Méndez, Carmen; Díaz, Verónica; Barajas-López, Carlos

    2011-10-01

    In airway smooth muscle (ASM), adenosine 5'-triphosphate (ATP) induces a relaxation associated with prostaglandin production. We explored the role of K(+) currents (I (K)) in this relaxation. ATP relaxed the ASM, and this effect was abolished by indomethacin. Removal of airway epithelium slightly diminished the ATP-induced relaxation at lower concentration without modifying the responses to ATP at higher concentrations. ATPγS and UTP induced a concentration-dependent relaxation similar to ATP; α,β-methylene-ATP was inactive from 1 to 100 μM. Suramin or reactive blue 2 (RB2), P2Y receptor antagonists, did not modify the relaxation, but their combination significantly reduced this effect of ATP. The relaxation was also inhibited by N-ethylmaleimide (NEM; which uncouples G proteins). In myocytes, the ATP-induced I (K) increment was not modified by suramin or RB2 but the combination of both drugs abolished it. This increment in the I (K) was also completely nullified by NEM and SQ 22,536. 4-Amynopyridine or iberiotoxin diminished the ATP-induced I (K) increment, and the combination of both substances diminished ATP-induced relaxation. The presence of P2Y(2) and P2Y(4) receptors in smooth muscle was corroborated by Western blot and confocal images. In conclusion, ATP: (1) produces relaxation by inducing the production of bronchodilator prostaglandins in airway smooth muscle, most likely by acting on P2Y(4) and P2Y(2) receptors; (2) induces I (K) increment through activation of the delayed rectifier K(+) channels and the high-conductance Ca(2+)-dependent K(+) channels, therefore both channels are implicated in the ATP-induced relaxation; and (3) this I (K) increment is mediated by prostaglandin production which in turns increase cAMP signaling pathway.

  15. Salvianolic acid B accelerated ABCA1-dependent cholesterol efflux by targeting PPAR-γ and LXRα

    Energy Technology Data Exchange (ETDEWEB)

    Yue, Jianmei [Department of Endocrinology, Shandong Province Hospital Affiliated to Shandong University, 324# Jing 5 Road, Jinan 255021 (China); Department of Endocrinology, The First Hospital of Zibo, 4# E Mei Shan Dong Road, Zibo 255200 (China); Li, Bo, E-mail: libosubmit@163.com [Department of Cardiology, Central Hospital of Zibo, 54# Gong Qing Tuan Xi Road, Zibo, Shandong Province (China); Jing, Qingping [Department of Endocrinology, The First Hospital of Zibo, 4# E Mei Shan Dong Road, Zibo 255200 (China); Guan, Qingbo, E-mail: guanqingbosubmit@163.com [Department of Endocrinology, Shandong Province Hospital Affiliated to Shandong University, 324# Jing 5 Road, Jinan 255021 (China)

    2015-07-03

    Objectives: Cholesterol efflux has been thought to be the main and basic mechanism by which free cholesterol is transferred from extra hepatic cells to the liver or intestine for excretion. Salvianolic acid B (Sal B) has been widely used for the prevention and treatment of atherosclerotic diseases. Here, we sought to investigate the effects of Sal B on the cholesterol efflux in THP-1 macrophages. Methods: After PMA-stimulated THP-1 cells were exposed to 50 mg/L of oxLDL and [{sup 3}H] cholesterol (1.0 μCi/mL) for another 24 h, the effect of Sal B on cholesterol efflux was evaluated in the presence of apoA-1, HDL{sub 2} or HDL{sub 3}. The expression of ATP binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor-gamma (PPAR-γ), and liver X receptor-alpha (LXRα) was detected both at protein and mRNA levels in THP-1 cells after the stimulation of Sal B. Meanwhile, specific inhibition of PPAR-γ and LXRα were performed to investigate the mechanism. Results: The results showed that Sal B significantly accelerated apoA-I- and HDL-mediated cholesterol efflux in both dose- and time-dependent manners. Meanwhile, Sal B treatment also enhanced the expression of ABCA1 at both mRNA and protein levels. Then the data demonstrated that Sal B increased the expression of PPAR-γ and LXRα. And the application of specific agonists and inhibitors of further confirmed that Sal exert the function through PPAR-γ and LXRα. Conclusion: These results demonstrate that Sal B promotes cholesterol efflux in THP-1 macrophages through ABCA1/PPAR-γ/LXRα pathway. - Highlights: • Sal B promotes the expression of ABCA1. • Sal B promotes cholesterol efflux in macrophages. • Sal B promotes the expression of ABCA1 and cholesterol efflux through PPAR-γ/LXRα signaling pathway.

  16. Salacia oblonga root improves postprandial hyperlipidemia and hepatic steatosis in Zucker diabetic fatty rats: Activation of PPAR

    International Nuclear Information System (INIS)

    Hsun-Wei Huang, Tom; Peng Gang; Qian Li, George; Yamahara, Johji; Roufogalis, Basil D.; Li Yuhao

    2006-01-01

    Salacia oblonga (SO) root is an Ayurvedic medicine with anti-diabetic and anti-obese properties. Peroxisome proliferator-activated receptor (PPAR)-α, a nuclear receptor, plays an important role in maintaining the homeostasis of lipid metabolism. Here, we demonstrate that chronic oral administration of the water extract from the root of SO to Zucker diabetic fatty (ZDF) rats, a genetic model of type 2 diabetes and obesity, lowered plasma triglyceride and total cholesterol (TC) levels, increased plasma high-density lipoprotein levels and reduced the liver contents of triglyceride, non-esterified fatty acids (NEFA) and the ratio of fatty droplets to total tissue. By contrast, the extract had no effect on plasma triglyceride and TC levels in fasted ZDF rats. After olive oil administration to ZDF the extract also inhibited the increase in plasma triglyceride levels. These results suggest that SO extract improves postprandial hyperlipidemia and hepatic steatosis in ZDF rats. Additionally, SO treatment enhanced hepatic expression of PPAR-α mRNA and protein, and carnitine palmitoyltransferase-1 and acyl-CoA oxidase mRNAs in ZDF rats. In vitro, SO extract and its main component mangiferin activated PPAR-α luciferase activity in human embryonic kidney 293 cells and lipoprotein lipase mRNA expression and enzyme activity in THP-1 differentiated macrophages; these effects were completely suppressed by a selective PPAR-α antagonist MK-886. The findings from both in vivo and in vitro suggest that SO extract functions as a PPAR-α activator, providing a potential mechanism for improvement of postprandial hyperlipidemia and hepatic steatosis in diabetes and obesity

  17. Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A

    International Nuclear Information System (INIS)

    Tang, Yuting; Zhou, Lubing; Gunnet, Joseph W.; Wines, Pamela G.; Cryan, Ellen V.; Demarest, Keith T.

    2006-01-01

    HM74A is a G protein-coupled receptor for nicotinic acid (niacin), which has been used clinically to treat dyslipidemia for decades. The molecular mechanisms whereby niacin exerts its pleiotropic effects on lipid metabolism remain largely unknown. In addition, the most common side effect in niacin therapy is skin flushing that is caused by prostaglandin release, suggesting that the phospholipase A 2 (PLA 2 )/arachidonic acid (AA) pathway is involved. Various eicosanoids have been shown to activate peroxisome-proliferator activated receptors (PPAR) that play a diverse array of roles in lipid metabolism. To further elucidate the potential roles of HM74A in mediating the therapeutic effects and/or side effects of niacin, we sought to explore the signaling events upon HM74A activation. Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells. Activation of HM74A also led to Ca 2+ -mobilization and enhanced bradykinin-promoted Ca 2+ -mobilization through Gi protein. While HM74A increased ERK1/2 activation by the bradykinin receptor, it had no effects on UTP-promoted ERK1/2 activation.Furthermore, UTP- and bradykinin-mediated AA release was significantly decreased in the presence of both MAPK kinase inhibitor PD 098059 and PKC inhibitor GF 109203X. However, the synergistic effects of HM74A were not dramatically affected by co-treatment with both inhibitors, indicating the cross-talk occurred at the receptor level. Finally, stimulation of A431 cells transiently transfected with PPRE-luciferase with AA significantly induced luciferase activity, mimicking the effects of PPARγ agonist rosiglitazone, suggesting that alteration of AA signaling pathway can regulate gene expression via endogenous PPARs

  18. Characterization of the promoter of human CRTh2, a prostaglandin D{sub 2} receptor

    Energy Technology Data Exchange (ETDEWEB)

    Quapp, Russell; Madsen, Norman [Department of Medicine, Division of Pulmonary Medicine, Pulmonary Research Group, 574B Heritage Medical Research Centre, University of Alberta, Edmonton, AB, T6G 2S2 (Canada); Cameron, Lisa [Department of Medicine, Division of Pulmonary Medicine, Pulmonary Research Group, 574B Heritage Medical Research Centre, University of Alberta, Edmonton, AB, T6G 2S2 (Canada)

    2007-11-30

    Chemoattractant-receptor homologous molecule expressed on Th2 cells (CRTh2) is a receptor for prostaglandin (PG)D{sub 2}, a lipid mediator involved in allergic inflammation. CRTh2 is expressed by Th2 cells, eosinophils and basophils and PDG{sub 2}-CRTh2 signaling induces calcium mobilization, cell migration and expression of the Th2 cytokines IL-4, IL-5, and IL-13. Despite the role of CRTh2 in allergic inflammation, transcriptional regulation of this gene has not been studied. Here, we demonstrated that a reporter construct of the CRTh2 promoter was induced following T cell stimulation. This activity could be further enhanced by over-expression of GATA-3, but not NFAT2 or STAT6. Electromobility shift assay demonstrated GATA-3 binding to a probe from the CRTh2 promoter. This study provides the first detailed analysis of transcriptional regulation of the human CRTh2 promoter. These findings may help identify strategies to attenuate expression of this gene and influence the maintenance and proliferation of Th2 cells in allergic inflammation.

  19. Specific binding of prostaglandin E2 to membrane preparations from human skin: receptor modulation by UVB-irradiation and chemical agents

    International Nuclear Information System (INIS)

    Lord, J.T.; Ziboh, V.A.

    1979-01-01

    Human skin membranes bind prostaglandin E2 (PGE2) with high affinity and specificity. This binding is inhibited by trypsin or heat treatment suggesting that PGE2 receptors have protein components. Exposure of the membranes to ultraviolet irradiation (UVB) resulted in the loss of the membrane binding capacity for PGE2. This UVB-inhibitory effect could be prevented by a known protein sulfhydryl-oxidizing agent and a known lipid anti-oxidant

  20. Arctigenin promotes cholesterol efflux from THP-1 macrophages through PPAR-γ/LXR-α signaling pathway.

    Science.gov (United States)

    Xu, Xiaolin; Li, Qian; Pang, Liewen; Huang, Guoqian; Huang, Jiechun; Shi, Meng; Sun, Xiaotian; Wang, Yiqing

    2013-11-15

    Cholesterol efflux from macrophages is a critical mechanism to prevent the development of atherosclerosis. Here, we sought to investigate the effects of arctigenin, a bioactive component of Arctium lappa, on the cholesterol efflux in oxidized low-density lipoprotein (oxLDL)-loaded THP-1 macrophages. Our data showed that arctigenin significantly accelerated apolipoprotein A-I- and high-density lipoprotein-induced cholesterol efflux in both dose- and time-dependent manners. Moreover, arctigenin treatment enhanced the expression of ATP binding cassette transporter A1 (ABCA1), ABCG1, and apoE, all of which are key molecules in the initial step of cholesterol efflux, at both mRNA and protein levels. Arctigenin also caused a concentration-dependent elevation in the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α). The arctigenin-mediated induction of ABCA1, ABCG1, and apoE was abolished by specific inhibition of PPAR-γ or LXR-α using small interfering RNA technology. Our results collectively indicate that arctigenin promotes cholesterol efflux in oxLDL-loaded THP-1 macrophages through upregulation of ABCA1, ABCG1 and apoE, which is dependent on the enhanced expression of PPAR-γ and LXR-α. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention?

    Directory of Open Access Journals (Sweden)

    Tenenbaum Alexander

    2012-11-01

    Full Text Available Abstract All fibrates are peroxisome proliferators-activated receptors (PPARs-alpha agonists with ability to decrease triglyceride and increase high density lipoprotein- cholesterol (HDL-C. However, bezafibrate has a unique characteristic profile of action since it activates all three PPAR subtypes (alpha, gamma and delta at comparable doses. Therefore, bezafibrate operates as a pan-agonist for all three PPAR isoforms. Selective PPAR gamma agonists (thiazolidinediones are used to treat type 2 diabetes mellitus (T2DM. They improve insulin sensitivity by up-regulating adipogenesis, decreasing free fatty acid levels, and reversing insulin resistance. However, selective PPAR gamma agonists also cause water retention, weight gain, peripheral edema, and congestive heart failure. The expression of PPAR beta/ delta in essentially all cell types and tissues (ubiquitous presence suggests its potential fundamental role in cellular biology. PPAR beta/ delta effects correlated with enhancement of fatty acid oxidation, energy consumption and adaptive thermogenesis. Together, these data implicate PPAR beta/delta in fuel combustion and suggest that pan-PPAR agonists that include a component of PPAR beta/delta activation might offset some of the weight gain issues seen with selective PPAR gamma agonists, as was demonstrated by bezafibrate studies. Suggestively, on the whole body level all PPARs acting as one orchestra and balanced pan-PPAR activation seems as an especially attractive pharmacological goal. Conceptually, combined PPAR gamma and alpha action can target simultaneously insulin resistance and atherogenic dyslipidemia, whereas PPAR beta/delta properties may prevent the development of overweight. Bezafibrate, as all fibrates, significantly reduced plasma triglycerides and increased HDL-C level (but considerably stronger than other major fibrates. Bezafibrate significantly decreased prevalence of small, dense low density lipoproteins particles, remnants

  2. Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention?

    Science.gov (United States)

    Tenenbaum, Alexander; Fisman, Enrique Z

    2012-11-14

    All fibrates are peroxisome proliferators-activated receptors (PPARs)-alpha agonists with ability to decrease triglyceride and increase high density lipoprotein- cholesterol (HDL-C). However, bezafibrate has a unique characteristic profile of action since it activates all three PPAR subtypes (alpha, gamma and delta) at comparable doses. Therefore, bezafibrate operates as a pan-agonist for all three PPAR isoforms. Selective PPAR gamma agonists (thiazolidinediones) are used to treat type 2 diabetes mellitus (T2DM). They improve insulin sensitivity by up-regulating adipogenesis, decreasing free fatty acid levels, and reversing insulin resistance. However, selective PPAR gamma agonists also cause water retention, weight gain, peripheral edema, and congestive heart failure. The expression of PPAR beta/ delta in essentially all cell types and tissues (ubiquitous presence) suggests its potential fundamental role in cellular biology. PPAR beta/ delta effects correlated with enhancement of fatty acid oxidation, energy consumption and adaptive thermogenesis. Together, these data implicate PPAR beta/delta in fuel combustion and suggest that pan-PPAR agonists that include a component of PPAR beta/delta activation might offset some of the weight gain issues seen with selective PPAR gamma agonists, as was demonstrated by bezafibrate studies. Suggestively, on the whole body level all PPARs acting as one orchestra and balanced pan-PPAR activation seems as an especially attractive pharmacological goal. Conceptually, combined PPAR gamma and alpha action can target simultaneously insulin resistance and atherogenic dyslipidemia, whereas PPAR beta/delta properties may prevent the development of overweight. Bezafibrate, as all fibrates, significantly reduced plasma triglycerides and increased HDL-C level (but considerably stronger than other major fibrates). Bezafibrate significantly decreased prevalence of small, dense low density lipoproteins particles, remnants, induced

  3. Radioiodsodestannylation. Convenient synthesis of a high affinity thromboxane A2/prostaglandin H2 receptor antagonist

    International Nuclear Information System (INIS)

    Mais, D.E.; Hamanaka, Nobuyuki

    1991-01-01

    Radioiodination of methyl-7-[(2R, 2S, 5R)-6,6-dimethyl-3-(4-trimethylstannylbenzenesulfononylamino3S) bicyclo[3.1.1]hept-2-yl]-5(Z)-heptenoate with [ 125 I] Na using a modification of the chloramine-T method in organic solvent is simple with high yields and site specific. The product, following hydrolysis of the ester, 7-[(2R, 2S, 3S, 5R)-6,6-dimethyl-3-(4[ 125 I]-iodobenzenesulfonylamino) bicyclo[3.1.1]hept-2-yl]-5(Z)-heptenoic acid [( 125 I]-ISAP), was purified by HPLC. The high specific activity and specific binding will make the ligand a useful tool for the characterization of thromboxane A 2 /prostaglandin H 2 receptors. (author)

  4. Opposite Interplay Between the Canonical WNT/β-Catenin Pathway and PPAR Gamma: A Potential Therapeutic Target in Gliomas.

    Science.gov (United States)

    Vallée, Alexandre; Lecarpentier, Yves; Guillevin, Rémy; Vallée, Jean-Noël

    2018-06-01

    In gliomas, the canonical Wingless/Int (WNT)/β-catenin pathway is increased while peroxisome proliferator-activated receptor gamma (PPAR-γ) is downregulated. The two systems act in an opposite manner. This review focuses on the interplay between WNT/β-catenin signaling and PPAR-γ and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/β-catenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis, tumor growth, and angiogenesis. Activation of PPAR-γ agonists inhibits various signaling pathways such as the JAK/STAT, WNT/β-catenin, and PI3K/Akt pathways, which reduces tumor growth, cell proliferation, cell invasiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs, curcumin, antipsychotic drugs, adiponectin, and sulforaphane downregulate the WNT/β-catenin pathway through the upregulation of PPAR-γ and thus appear to provide an interesting therapeutic approach for gliomas. Temozolomide (TMZ) is an antiangiogenic agent. The downstream action of this opposite interplay may explain the TMZ-resistance often reported in gliomas.

  5. Prostaglandin potentiates 5-HT responses in stomach and ileum innervating visceral afferent sensory neurons

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sojin; Jin, Zhenhua; Lee, Goeun [Department of Physiology, School of Medicine, Kyung Hee University, Seoul 130-701 (Korea, Republic of); Park, Yong Seek; Park, Cheung-Seog [Department of Microbiology, School of Medicine, Kyung Hee University, Seoul 130-701 (Korea, Republic of); Jin, Young-Ho, E-mail: jinyh@khu.ac.kr [Department of Physiology, School of Medicine, Kyung Hee University, Seoul 130-701 (Korea, Republic of)

    2015-01-02

    Highlights: • Prostaglandin E2 (PGE{sub 2}) effect was tested on visceral afferent neurons. • PGE{sub 2} did not evoke response but potentiated serotonin (5-HT) currents up to 167%. • PGE{sub 2}-induced potentiation was blocked by E-prostanoid type 4 receptors antagonist. • PGE{sub 2} effect on 5-HT response was also blocked by protein kinase A inhibitor KT5720. • Thus, PGE{sub 2} modulate visceral afferent neurons via synergistic signaling with 5-HT. - Abstract: Gastrointestinal disorder is a common symptom induced by diverse pathophysiological conditions that include food tolerance, chemotherapy, and irradiation for therapy. Prostaglandin E{sub 2} (PGE{sub 2}) level increase was often reported during gastrointestinal disorder and prostaglandin synthetase inhibitors has been used for ameliorate the symptoms. Exogenous administration of PGE{sub 2} induces gastrointestinal disorder, however, the mechanism of action is not known. Therefore, we tested PGE{sub 2} effect on visceral afferent sensory neurons of the rat. Interestingly, PGE{sub 2} itself did not evoked any response but enhanced serotonin (5-HT)-evoked currents up to 167% of the control level. The augmented 5-HT responses were completely inhibited by a 5-HT type 3 receptor antagonist, ondansetron. The PGE{sub 2}-induced potentiation were blocked by a selective E-prostanoid type4 (EP{sub 4}) receptors antagonist, L-161,982, but type1 and 2 receptor antagonist AH6809 has no effect. A membrane permeable protein kinase A (PKA) inhibitor, KT5720 also inhibited PGE{sub 2} effects. PGE{sub 2} induced 5-HT current augmentation was observed on 15% and 21% of the stomach and ileum projecting neurons, respectively. Current results suggest a synergistic signaling in visceral afferent neurons underlying gastrointestinal disorder involving PGE{sub 2} potentiation of 5-HT currents. Our findings may open a possibility for screen a new type drugs with lower side effects than currently using steroidal prostaglandin

  6. Circadian rhythms, Wnt/beta-catenin pathway and PPAR alpha/gamma profiles in diseases with primary or secondary cardiac dysfunction

    Directory of Open Access Journals (Sweden)

    Yves eLecarpentier

    2014-11-01

    Full Text Available Circadian clock mechanisms are far-from-equilibrium dissipative structures. Peroxisome proliferator-activated receptors (PPAR alpha, beta/delta and gamma play a key role in metabolic regulatory processes, particularly in heart muscle. Links between circadian rhythms (CRs and PPARs have been established. Mammalian CRs involve at least two critical transcription factors, CLOCK and BMAL1 (Gekakis et al., 1998; Hogenesch et al., 1998. PPAR gamma plays a major role in both glucose and lipid metabolisms and presents circadian properties which coordinate the interplay between metabolism and CRs. PPAR gamma is a major component of the vascular clock. Vascular PPAR gamma is a peripheral regulator of cardiovascular rhythms controlling circadian variations in blood pressure and heart rate through BMAL1. We focused our review on diseases with abnormalities of CRs and with primary or secondary cardiac dysfunction. Moreover, these diseases presented changes in the Wnt/beta-catenin pathway and PPARs, according to two opposed profiles. Profile 1 was defined as follows: inactivation of the Wnt/beta-catenin pathway with increased expression of PPAR gamma. Profile 2 was defined as follows: activation of the Wnt/beta-catenin pathway with decreased expression of PPAR gamma. A typical profile 1 disease is arrhythmogenic right ventricular cardiomyopathy, a genetic cardiac disease which presents mutations of the desmosomal proteins and is mainly characterized by fatty acid accumulation in adult cardiomyocytes mainly in the right ventricle. The link between PPAR gamma dysfunction and desmosomal genetic mutations occurs via inactivation of the Wnt/beta-catenin pathway presenting oscillatory properties. A typical profile 2 disease is type 2 diabetes, with activation of the Wnt/beta-catenin pathway and decreased expression of PPAR gamma. CRs abnormalities are present in numerous pathologies such as cardiovascular diseases, sympathetic/parasympathetic dysfunction

  7. The Pro12Ala Polymorphism of PPAR-γ Gene Is Associated with Sepsis Disease Severity and Outcome in Chinese Han Population

    Directory of Open Access Journals (Sweden)

    Guoda Ma

    2014-01-01

    Full Text Available Peroxisome proliferator-activated receptor-γ (PPAR-γ is a ligand-binding nuclear receptor, and its activation plays a prominent role in regulating the inflammatory response. Therefore, PPAR-γ has been suggested as a candidate gene for sepsis. In the present study, we investigated the association between the Pro12Ala polymorphism of PPAR-γ and sepsis in a Han Chinese population. A total of 308 patients with sepsis and 345 healthy controls were enrolled in this study. Genotyping was performed using the polymerase chain reaction-ligation detection reaction (PCR-LDR method. No significant differences were detected in the allele and genotype distributions of the PPAR-γ Pro12Ala SNP between septic patients and controls (P=0.622 for genotype; P=0.629 for allele. However, stratification by subtypes (sepsis, septic shock, and severe sepsis revealed a statistically significant difference in the frequency of the Ala allele and Ala-carrier genotype between the patients with the sepsis subtype and the healthy controls (P=0.014 for allele and P=0.012, for genotype. Moreover, significant differences were found in the frequency of the Ala allele and genotype between the sepsis survivors and nonsurvivors (all P=0.002. In the survivors, the PPAR-γ Pro12Ala genotype was significantly associated with decreased disease severity and recovery time (all P<0.001. Thus, genetic polymorphism is thought to play a role in the development and outcome of sepsis.

  8. Extensive mapping of PPAR binding to genomic DNA

    DEFF Research Database (Denmark)

    Nielsen, Ronni; Pedersen, Thomas Åskov; Trindade, Luisa

    processes such as adaptation to fasting and cold, muscle isotype switching and adipogenesis, underscoring the metabolic importance of these transcription factors. Although the PPARs have been subject to intensive studies for almost two decades, far from all PPAR target genes are known. In addition, only few...... analysis of the regulatory networks controlled by PPAR transcription factors, thereby allowing for a better understanding of PPAR biology. - Adenoviral expression PPARg2 and RXR induce transcription from a wide range of hepatocyte as well as non-hepatocyte PPAR target genes in the murine AML-12 hepatoma...... cell line. Only very few PPAR target genes are not induced by PPARg2/RXR. - ChIP-on-chip analysis shows ~1200 peaks on chr. 7 & 8 by peak detection software. 80% of selected peaks were positive in single ChIP experiments.   - PPARg2/RXR are recruited to DNA elements near several genes on chr. 7 & 8...

  9. Peroxisome Proliferator-Activated Receptor- Is a Potent Target for Prevention and Treatment in Human Prostate and Testicular Cancer

    Directory of Open Access Journals (Sweden)

    Masahide Matsuyama

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptor- (PPAR- is a ligand-activated transcriptional factor belonging to steroid receptor superfamily. PPAR- plays a role in both adipocyte differentiation and tumorigenesis. Up to date, PPAR- is expressed in various cancer tissues, and PPAR- ligand induces growth arrest of these cancer cells. In this study, we examined the expression of PPAR- in prostate cancer (PC and testicular cancer (TC by RT-PCR and immunohistochemistry, and we also examined the effect of PPAR- ligand in these cells by MTT assay, hoechest staining, and flow cytometry. PPAR- expression was significantly more extensive and intense in malignant tissues than in normal tissues. PPAR- ligand induced the reduction of malignant cell viability through apoptosis. These results demonstrated that the generated PPAR- in PC and TC cells might play an important role in the tumorigenesis. PPAR- may become a new target in the treatment of PC and TC.

  10. Peroxisome proliferator-activated receptors (PPARs-independent functions of fish oil on glucose and lipid metabolism in diet-induced obese mice

    Directory of Open Access Journals (Sweden)

    Wakutsu Masaki

    2010-09-01

    Full Text Available Abstract Background Fish oil is known to improve lifestyle-related diseases. These effects occur partly via activation of PPARs by the n-3 polyunsaturated fatty acids included abundantly in fish oil. We investigated fish oil functions on glucose and lipid metabolism that are both dependent on and independent of PPARs pathway. Methods Mice were fed a diet containing 30 en% beef tallow (B diet for twelve weeks to induce obesity. The mice were then divided into two groups which were fed either a B diet or a diet containing 30 en% fish oil (F diet. Each group was further divided into two groups which were administered PPARα and γ antagonists or vehicle once a day for three weeks. Results The F diet groups showed lower triglyceride levels in plasma and liver than the B diet groups, but PPARs antagonists did not affect the triglyceride levels in either diet groups. The F diet groups also showed improvement of glucose tolerance compared with the B diet groups. However, PPARs antagonists made glucose tolerance worse in the F diet group but improved it in the B diet group. Therefore, by the administration of antagonists, glucose tolerance was inversely regulated between the B and F diets, and hypolipidemic action in the plasma and liver of the F diet group was not affected. Conclusion These results suggest that fish oil decreases lipid levels in plasma and liver via PPARs pathway-independent mechanism, and that glucose tolerance is inversely regulated by PPARs antagonists under diets containing different oils.

  11. Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.

    Directory of Open Access Journals (Sweden)

    Li-Song Zhang

    Full Text Available As important members of nuclear receptor superfamily, Peroxisome proliferator-activated receptors (PPAR play essential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms. The PPAR receptors have 3 identified subtypes: PPARα, PPARβ and PPARγ, all of which have been treated as attractive targets for developing drugs to treat type 2 diabetes. Due to the undesirable side-effects, many PPAR agonists including PPARα/γ and PPARβ/γ dual agonists are stopped by US FDA in the clinical trials. An alternative strategy is to design novel pan-agonist that can simultaneously activate PPARα, PPARβ and PPARγ. Under such an idea, in the current study we adopted the core hopping algorithm and glide docking procedure to generate 7 novel compounds based on a typical PPAR pan-agonist LY465608. It was observed by the docking procedures and molecular dynamics simulations that the compounds generated by the core hopping and glide docking not only possessed the similar functions as the original LY465608 compound to activate PPARα, PPARβ and PPARγ receptors, but also had more favorable conformation for binding to the PPAR receptors. The additional absorption, distribution, metabolism and excretion (ADME predictions showed that the 7 compounds (especially Cpd#1 hold high potential to be novel lead compounds for the PPAR pan-agonist. Our findings can provide a new strategy or useful insights for designing the effective pan-agonists against the type 2 diabetes.

  12. Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis.

    Science.gov (United States)

    Vallée, Alexandre; Lecarpentier, Yves; Guillevin, Rémy; Vallée, Jean-Noël

    2017-10-27

    Radiation therapy induces DNA damage and inflammation leading to fibrosis. Fibrosis can occur 4 to 12 months after radiation therapy. This process worsens with time and years. Radiation-induced fibrosis is characterized by fibroblasts proliferation, myofibroblast differentiation, and synthesis of collagen, proteoglycans and extracellular matrix. Myofibroblasts are non-muscle cells that can contract and relax. Myofibroblasts evolve towards irreversible retraction during fibrosis process. In this review, we discussed the interplays between transforming growth factor-β1 (TGF-β1), canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR γ) in regulating the molecular mechanisms underlying the radiation-induced fibrosis, and the potential role of PPAR γ agonists. Overexpression of TGF-β and canonical WNT/β-catenin pathway stimulate fibroblasts accumulation and myofibroblast differentiation whereas PPAR γ expression decreases due to the opposite interplay of canonical WNT/β-catenin pathway. Both TGF-β1 and canonical WNT/β-catenin pathway stimulate each other through the Smad pathway and non-Smad pathways such as phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) signaling. WNT/β-catenin pathway and PPAR γ interact in an opposite manner. PPAR γ agonists decrease β-catenin levels through activation of inhibitors of the WNT pathway such as Smad7, glycogen synthase kinase-3 (GSK-3 β) and dickkopf-related protein 1 (DKK1). PPAR γ agonists also stimulate phosphatase and tensin homolog (PTEN) expression, which decreases both TGF-β1 and PI3K/Akt pathways. PPAR γ agonists by activating Smad7 decrease Smads pathway and then TGF-β signaling leading to decrease radiation-induced fibrosis. TGF-β1 and canonical WNT/β-catenin pathway promote radiation-induced fibrosis whereas PPAR γ agonists can prevent radiation-induced fibrosis.

  13. Voluntary exercise prevents colonic inflammation in high-fat diet-induced obese mice by up-regulating PPAR-γ activity

    International Nuclear Information System (INIS)

    Liu, Wei-Xin; Wang, Ting; Zhou, Feng; Wang, Ying; Xing, Jun-Wei; Zhang, Shen; Gu, Shou-Zhi; Sang, Li-Xuan; Dai, Cong; Wang, Hai-Lan

    2015-01-01

    Obesity is associated with increased colonic inflammation, which elevates the risk of colon cancer. Although exercise exerts anti-inflammatory actions in multiple chronic diseases associated with inflammation, it is unknown whether this strategy prevents colonic inflammation in obesity. We hypothesized that voluntary exercise would suppress colonic inflammation in high-fat diet (HFD)-induced obesity by modulation of peroxisome proliferator-activated receptor (PPAR)-γ. Male C57Bl/6J mice fed either a control diet (6.5% fat, CON) or a high-fat diet (24% fat, HFD) were divided into sedentary, voluntary exercise or voluntary exercise with PPAR-γ antagonist GW9662 (10 mg/kg/day). All interventions took place for 12 weeks. Compared with CON-sedentary group, HFD-sedentary mice gained significantly more body weight and exhibited metabolic disorders. Molecular studies revealed that HFD-sedentary mice had increased expression of inflammatory mediators and activation of nuclear factor (NF)-κB in the colons, which were associated with decreased expression and activity of PPAR-γ. Voluntary exercise markedly attenuated body weight gain, improved metabolic disorders, and normalized the expression of inflammatory mediators and activation of NF-κB in the colons in HFD-mice while having no effects in CON-animals. Moreover, voluntary exercise significantly increased expression and activity of PPAR-γ in the colons in both HFD- and CON-animals. However, all of these beneficial effects induced by voluntary exercise were abolished by GW9662, which inhibited expression and activity of PPAR-γ. The results suggest that decreased PPAR-γ activity in the colon of HFD-induced obesity may facilitate the inflammatory response and colon carcinogenesis. Voluntary exercise prevents colonic inflammation in HFD-induced obesity by up-regulating PPAR-γ activity. - Highlights: • Obesity down-regulates PPAR-γ in the colon. • Down-regulated colonic PPAR-γ may facilitate inflammatory

  14. Voluntary exercise prevents colonic inflammation in high-fat diet-induced obese mice by up-regulating PPAR-γ activity

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Wei-Xin, E-mail: weixinliu@yahoo.com [Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning (China); Wang, Ting; Zhou, Feng; Wang, Ying; Xing, Jun-Wei; Zhang, Shen [Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning (China); Gu, Shou-Zhi [Department of Anatomy, Seirei Christopher College, Hamamatsu 433-8558 (Japan); Sang, Li-Xuan [Department of Cadre Ward II, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning (China); Dai, Cong [Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning (China); Wang, Hai-Lan [Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510300, Guangdong (China)

    2015-04-10

    Obesity is associated with increased colonic inflammation, which elevates the risk of colon cancer. Although exercise exerts anti-inflammatory actions in multiple chronic diseases associated with inflammation, it is unknown whether this strategy prevents colonic inflammation in obesity. We hypothesized that voluntary exercise would suppress colonic inflammation in high-fat diet (HFD)-induced obesity by modulation of peroxisome proliferator-activated receptor (PPAR)-γ. Male C57Bl/6J mice fed either a control diet (6.5% fat, CON) or a high-fat diet (24% fat, HFD) were divided into sedentary, voluntary exercise or voluntary exercise with PPAR-γ antagonist GW9662 (10 mg/kg/day). All interventions took place for 12 weeks. Compared with CON-sedentary group, HFD-sedentary mice gained significantly more body weight and exhibited metabolic disorders. Molecular studies revealed that HFD-sedentary mice had increased expression of inflammatory mediators and activation of nuclear factor (NF)-κB in the colons, which were associated with decreased expression and activity of PPAR-γ. Voluntary exercise markedly attenuated body weight gain, improved metabolic disorders, and normalized the expression of inflammatory mediators and activation of NF-κB in the colons in HFD-mice while having no effects in CON-animals. Moreover, voluntary exercise significantly increased expression and activity of PPAR-γ in the colons in both HFD- and CON-animals. However, all of these beneficial effects induced by voluntary exercise were abolished by GW9662, which inhibited expression and activity of PPAR-γ. The results suggest that decreased PPAR-γ activity in the colon of HFD-induced obesity may facilitate the inflammatory response and colon carcinogenesis. Voluntary exercise prevents colonic inflammation in HFD-induced obesity by up-regulating PPAR-γ activity. - Highlights: • Obesity down-regulates PPAR-γ in the colon. • Down-regulated colonic PPAR-γ may facilitate inflammatory

  15. Characterization of biosynthesis and modes of action of prostaglandin E2 and prostacyclin in guinea pig mesenteric lymphatic vessels.

    Science.gov (United States)

    Rehal, Sonia; Blanckaert, Pauline; Roizes, Simon; von der Weid, Pierre-Yves

    2009-12-01

    Rhythmical transient constrictions of the lymphatic vessels provide the means for efficient lymph drainage and interstitial tissue fluid balance. This activity is critical during inflammation, to avoid or limit oedema resulting from increased vascular permeability, mediated by the release of various inflammatory mediators. In this study, we investigated the mechanisms by which prostaglandin E(2) (PGE(2)) and prostacyclin modulate lymphatic contractility in isolated guinea pig mesenteric lymphatic vessels. Quantitative RT-PCR was used to assess the expression of mRNA for enzymes and receptors involved in the production and action of PGE(2) and prostacyclin in mesenteric collecting lymphatic vessels. Frequency and amplitude of lymphatic vessel constriction were measured in the presence of these prostaglandins and the role of their respective EP and IP receptors assessed. Prostaglandin E(2) and prostacyclin decreased concentration-dependently the frequency, without affecting the amplitude, of lymphatic constriction. Data obtained in the presence of the EP(4) receptor antagonists, GW627368x (1 microM) and AH23848B (30 microM) and the IP receptor antagonist CAY10441 (0.1 microM) suggest that PGE(2) predominantly activates EP(4), whereas prostacyclin mainly stimulates IP receptors. Inhibition of responses to either prostaglandin with H89 (10 microM) or glibenclamide (1 microM) suggested a role for the activation of protein kinase A and ATP-sensitive K(+) channels. Our findings characterized the inhibition of lymphatic pumping induced by PGE(2) or prostacyclin in guinea pig mesenteric lymphatics. This action is likely to impair oedema resolution and to contribute to the pro-inflammatory actions of these prostaglandins.

  16. Prostaglandins and Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Mohammad Javad Fattahi

    2012-01-01

    Full Text Available Rheumatoid arthritis (RA is a chronic, autoimmune, and complex inflammatory disease leading to bone and cartilage destruction, whose cause remains obscure. Accumulation of genetic susceptibility, environmental factors, and dysregulated immune responses are necessary for mounting this self-reacting disease. Inflamed joints are infiltrated by a heterogeneous population of cellular and soluble mediators of the immune system, such as T cells, B cells, macrophages, cytokines, and prostaglandins (PGs. Prostaglandins are lipid inflammatory mediators derived from the arachidonic acid by multienzymatic reactions. They both sustain homeostatic mechanisms and mediate pathogenic processes, including the inflammatory reaction. They play both beneficial and harmful roles during inflammation, according to their site of action and the etiology of the inflammatory response. With respect to the role of PGs in inflammation, they can be effective mediators in the pathophysiology of RA. Thus the use of agonists or antagonists of PG receptors may be considered as a new therapeutic protocol in RA. In this paper, we try to elucidate the role of PGs in the immunopathology of RA.

  17. PPAR γ is highly expressed in F4/80hi adipose tissue macrophages and dampens adipose-tissue inflammation

    Science.gov (United States)

    Bassaganya-Riera, Josep; Misyak, Sarah; Guri, Amir J.; Hontecillas, Raquel

    2009-01-01

    Macrophage infiltration into adipose tissue is a hallmark of obesity. We recently reported two phenotypically distinct subsets of adipose tissue macrophages (ATM) based on the surface expression of the glycoprotein F4/80 and responsiveness to treatment with a peroxisome proliferator-activated receptor (PPAR) γ agonist. Hence, we hypothesized that F4/80hi and F4/80lo ATM differentially express PPAR γ. This study phenotypically and functionally characterizes F4/80hi and F4/80lo ATM subsets during obesity. Changes in gene expression were also examined on sorted F4/80lo and F4/80hi ATM by quantitative real-time RT-PCR. We show that while F4/80lo macrophages predominate in adipose tissue of lean mice, obesity causes accumulation of both F4/80lo and F4/80hi ATM. Moreover, accumulation of F4/80hi ATM in adipose tissue is associated with impaired glucose tolerance. Phenotypically, F4/80hi ATM express greater amounts of CD11c, MHC II, CD49b, and CX3CR1 and produce more TNF-α, MCP-1, and IL-10 than F4/80lo ATM. Gene expression analyses of the sorted populations revealed that only the F4/80lo population produced IL-4, whereas the F4/80hi ATM expressed greater amounts of PPAR γ, δ, CD36 and toll-like receptor-4. In addition, the deficiency of PPAR γ in immune cells favors expression of M1 and impairs M2 macrophage marker expression in adipose tissue. Thus, PPAR γ is differentially expressed in F4/80hi versus F4/80low ATM subsets and its deficiency favors a predominance of M1 markers in WAT. PMID:19423085

  18. PPAR gamma is highly expressed in F4/80(hi) adipose tissue macrophages and dampens adipose-tissue inflammation.

    Science.gov (United States)

    Bassaganya-Riera, Josep; Misyak, Sarah; Guri, Amir J; Hontecillas, Raquel

    2009-01-01

    Macrophage infiltration into adipose tissue is a hallmark of obesity. We recently reported two phenotypically distinct subsets of adipose tissue macrophages (ATM) based on the surface expression of the glycoprotein F4/80 and responsiveness to treatment with a peroxisome proliferator-activated receptor (PPAR) gamma agonist. Hence, we hypothesized that F4/80(hi) and F4/80(lo) ATM differentially express PPAR gamma. This study phenotypically and functionally characterizes F4/80(hi) and F4/80(lo) ATM subsets during obesity. Changes in gene expression were also examined on sorted F4/80(lo) and F4/80(hi) ATM by quantitative real-time RT-PCR. We show that while F4/80(lo) macrophages predominate in adipose tissue of lean mice, obesity causes accumulation of both F4/80(lo) and F4/80(hi) ATM. Moreover, accumulation of F4/80(hi) ATM in adipose tissue is associated with impaired glucose tolerance. Phenotypically, F4/80(hi) ATM express greater amounts of CD11c, MHC II, CD49b, and CX3CR1 and produce more TNF-alpha, MCP-1, and IL-10 than F4/80(lo) ATM. Gene expression analyses of the sorted populations revealed that only the F4/80(lo) population produced IL-4, whereas the F4/80(hi) ATM expressed greater amounts of PPAR gamma, delta, CD36 and toll-like receptor-4. In addition, the deficiency of PPAR gamma in immune cells favors expression of M1 and impairs M2 macrophage marker expression in adipose tissue. Thus, PPAR gamma is differentially expressed in F4/80(hi) versus F4/80(low) ATM subsets and its deficiency favors a predominance of M1 markers in WAT.

  19. Time-dependent therapeutic roles of nitazoxanide on high-fat diet/streptozotocin-induced diabetes in rats: effects on hepatic peroxisome proliferator-activated receptor-gamma receptors.

    Science.gov (United States)

    Elaidy, Samah M; Hussain, Mona A; El-Kherbetawy, Mohamed K

    2018-05-01

    Targeting peroxisome proliferator-activated receptor-gamma (PPAR-γ) is an approved strategy in facing insulin resistance (IR) for diabetes mellitus (DM) type 2. The PPAR-γ modulators display improvements in the insulin-sensitizing and adverse effects of the traditional thiazolidinediones. Nitazoxanide (NTZ) is proposed as a PPARreceptor ligand with agonistic post-transcriptional effects. Currently, NTZ antidiabetic activities versus pioglitazone (PIO) in a high-fat diet/streptozotocin rat model of type 2 diabetes was explored. Diabetic adult male Wistar rats were treated orally with either PIO (2.7 mg·kg -1 ·day -1 ) or NTZ (200 mg·kg -1 ·day -1 ) for 14, 21, and 28 days. Body masses, fasting blood glucose, IR, lipid profiles, and liver and kidney functions of rats were assayed. Hepatic glucose metabolism and PPAR-γ protein expression levels as well as hepatic, pancreatic, muscular, and renal histopathology were evaluated. Significant time-dependent euglycemic and insulin-sensitizing effects with preservation of liver and kidney functions were offered by NTZ. Higher hepatic levels of glucose-6-phosphatase and glucose-6-phosphate dehydrogenase enzymes and PPAR-γ protein expressions were acquired by NTZ and PIO, respectively. NTZ could be considered an oral therapeutic strategy for DM type 2. Further systematic NTZ/PPARreceptor subtype molecular activations are recommended. Simultaneous use of NTZ with other approved antidiabetics should be explored.

  20. Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b

    Directory of Open Access Journals (Sweden)

    Lee Robert E

    2006-01-01

    Full Text Available Abstract Background There have been indications that common Angiotensin Receptor Blockers (ARBs may be exerting anti-inflammatory actions by directly modulating the immune system. We decided to use molecular modelling to rapidly assess which of the potential targets might justify the expense of detailed laboratory validation. We first studied the VDR nuclear receptor, which is activated by the secosteroid hormone 1,25-dihydroxyvitamin-D. This receptor mediates the expression of regulators as ubiquitous as GnRH (Gonadatrophin hormone releasing hormone and the Parathyroid Hormone (PTH. Additionally we examined Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma, which affects the function of phagocytic cells, and the C-CChemokine Receptor, type 2b, (CCR2b, which recruits monocytes to the site of inflammatory immune challenge. Results Telmisartan was predicted to strongly antagonize (Ki≈0.04nmol the VDR. The ARBs Olmesartan, Irbesartan and Valsartan (Ki≈10 nmol are likely to be useful VDR antagonists at typical in-vivo concentrations. Candesartan (Ki≈30 nmol and Losartan (Ki≈70 nmol may also usefully inhibit the VDR. Telmisartan is a strong modulator of PPARgamma (Ki≈0.3 nmol, while Losartan (Ki≈3 nmol, Irbesartan (Ki≈6 nmol, Olmesartan and Valsartan (Ki≈12 nmol also seem likely to have significant PPAR modulatory activity. Olmesartan andIrbesartan (Ki≈9 nmol additionally act as antagonists of a theoretical modelof CCR2b. Initial validation of this CCR2b model was performed, and a proposed model for the AngiotensinII Type1 receptor (AT2R1 has been presented. Conclusion Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the

  1. Prostaglandin E2 produced by Entamoeba histolytica binds to EP4 receptors and stimulates interleukin-8 production in human colonic cells.

    Science.gov (United States)

    Dey, Indranil; Chadee, Kris

    2008-11-01

    Entamoeba histolytica pathogenesis in the colon occurs in a stepwise fashion. It begins with colonization of the mucin layer, which is followed by stimulation of a proinflammatory response that causes nonspecific tissue damage that may facilitate parasite invasion of the underlying colonic mucosa. Unfortunately, the parasite and/or host factors that stimulate a proinflammatory response in the gut are poorly understood. In this study, we found that live E. histolytica or secretory or proteins (SP) and soluble ameba components (SAP) can markedly increase interleukin-8 (IL-8) mRNA expression and protein production in colonic epithelial cells. The IL-8-stimulating molecule produced by live amebae was identified as prostaglandin E(2) (PGE(2)) as trophozoites treated with cyclooxygenase inhibitors inhibited the biosynthesis of PGE(2) and eliminated IL-8 production induced by live parasites or ameba components. Moreover, using specific prostaglandin EP2 and EP4 receptor agonists and antagonists, we found that PGE(2) binds exclusively through EP4 receptors in colonic epithelial cells to stimulate IL-8 production. Silencing of EP4 receptors with EP4 small interfering RNA completely eliminated SP- and SAP-induced IL-8 production. These studies identified bioactive PGE(2) as a one of the major virulence factors produced by E. histolytica that can stimulate the potent neutrophil chemokine and activator IL-8, which can trigger an acute host inflammatory response. Thus, the induction of IL-8 production in response to E. histolytica-derived PGE(2) may be a mechanism that explains the initiation and amplification of acute inflammation associated with intestinal amebiasis.

  2. Peroxisome proliferator-activated receptor ligands regulate lipid content, metabolism, and composition in fetal lungs of diabetic rats.

    Science.gov (United States)

    Kurtz, M; Capobianco, E; Careaga, V; Martinez, N; Mazzucco, M B; Maier, M; Jawerbaum, A

    2014-03-01

    Maternal diabetes impairs fetal lung development. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors relevant in lipid homeostasis and lung development. This study aims to evaluate the effect of in vivo activation of PPARs on lipid homeostasis in fetal lungs of diabetic rats. To this end, we studied lipid concentrations, expression of lipid metabolizing enzymes and fatty acid composition in fetal lungs of control and diabetic rats i) after injections of the fetuses with Leukotriene B4 (LTB4, PPARα ligand) or 15deoxyΔ(12,14)prostaglandin J2 (15dPGJ2, PPARγ ligand) and ii) fed during pregnancy with 6% olive oil- or 6% safflower oil-supplemented diets, enriched with PPAR ligands were studied. Maternal diabetes increased triglyceride concentrations and decreased expression of lipid-oxidizing enzymes in fetal lungs of diabetic rats, an expression further decreased by LTB4 and partially restored by 15dPGJ2 in lungs of male fetuses in the diabetic group. In lungs of female fetuses in the diabetic group, maternal diets enriched with olive oil increased triglyceride concentrations and fatty acid synthase expression, while those enriched with safflower oil increased triglyceride concentrations and fatty acid transporter expression. Both olive oil- and safflower oil-supplemented diets decreased cholesterol and cholesteryl ester concentrations and increased the expression of the reverse cholesterol transporter ATP-binding cassette A1 in fetal lungs of female fetuses of diabetic rats. In fetal lungs of control and diabetic rats, the proportion of polyunsaturated fatty acids increased with the maternal diets enriched with olive and safflower oils. Our results revealed important changes in lipid metabolism in fetal lungs of diabetic rats, and in the ability of PPAR ligands to modulate the composition of lipid species relevant in the lung during the perinatal period.

  3. Sex steroid receptor expression in the oviduct and uterus of sheep with estrus synchronized with progestagen or prostaglandin analogues.

    Science.gov (United States)

    García-Palencia, P; Sánchez, M A; Nieto, A; Vilar, M P; González, M; Veiga-Lopez, A; González-Bulnes, A; Flores, J M

    2007-01-01

    The objective of this study was to investigate differences in the expression of estrogen receptor-alpha (ERalpha), progesterone receptor (PR) and the proliferative indexes (Ki-67), in the uterus and oviduct of sheep with estrus synchronized either by prostaglandin analogues (Group PA, n=27) or by treatment with progestagens (Group P, n=29) on days 4 and 7 (day 0=estrus), when the embryos were collected. Immunohistochemical methods were used to quantify ERalpha, PR and Ki-67 in six superficial and deep compartments in the uterus and oviduct. The expression of ERalpha was significantly (Pprogesterone treated ewes than in the PA Group in the superficial gland (Psheep with synchronization of estrus with progestagens showed a reduction of ERalpha and PR protein expression in most of oviductal and uterine cells.

  4. Cow's milk increases the activities of human nuclear receptors peroxisome proliferator-activated receptors alpha and delta and retinoid X receptor alpha involved in the regulation of energy homeostasis, obesity, and inflammation.

    Science.gov (United States)

    Suhara, W; Koide, H; Okuzawa, T; Hayashi, D; Hashimoto, T; Kojo, H

    2009-09-01

    The nuclear peroxisome proliferator-activated receptors (PPAR) have been shown to play crucial roles in regulating energy homeostasis including lipid and carbohydrate metabolism, inflammatory responses, and cell proliferation, differentiation, and survival. Because PPAR agonists have the potential to prevent or ameliorate diseases such as hyperlipidemia, diabetes, atherosclerosis, and obesity, we have explored new natural agonists for PPAR. For this purpose, cow's milk was tested for agonistic activity toward human PPAR subtypes using a reporter gene assay. Milk increased human PPARalpha activity in a dose-dependent manner with a 3.2-fold increase at 0.5% (vol/vol). It also enhanced human PPARdelta activity in a dose-dependent manner with an 11.5-fold increase at 0.5%. However, it only slightly affected human PPARgamma activity. Ice cream, butter, and yogurt also increased the activities of PPARalpha and PPARdelta, whereas vegetable cream affected activity of PPARdelta but not PPARalpha. Skim milk enhanced the activity of PPAR to a lesser degree than regular milk. Milk and fresh cream increased the activity of human retinoid X receptor (RXR)alpha as well as PPARalpha and PPARdelta, whereas neither affected vitamin D3 receptor, estrogen receptors alpha and beta, or thyroid receptors alpha and beta. Both milk and fresh cream were shown by quantitative real-time PCR to increase the quantity of mRNA for uncoupling protein 2 (UCP2), an energy expenditure gene, in a dose-dependent manner. The increase in UCP2 mRNA was found to be reduced by treatment with PPARdelta-short interfering (si)RNA. This study unambiguously clarified at the cellular level that cow's milk increased the activities of human PPARalpha, PPARdelta, and RXRalpha. The possible role in enhancing the activities of PPARalpha, PPARdelta, and RXRalpha, and the health benefits of cow's milk were discussed.

  5. Role of Peroxisome Proliferator-Activated Receptor γ in Ocular Diseases

    Directory of Open Access Journals (Sweden)

    Su Zhang

    2015-01-01

    Full Text Available Peroxisome proliferator-activated receptor γ (PPAR γ, a member of the nuclear receptor superfamily, is a ligand-activated transcription factor that plays an important role in the control of a variety of physiological processes. The last decade has witnessed an increasing interest for the role played by the agonists of PPAR γ in antiangiogenesis, antifibrosis, anti-inflammation effects and in controlling oxidative stress response in various organs. As the pathologic mechanisms of major blinding diseases, such as age-related macular degeneration (AMD, diabetic retinopathy (DR, keratitis, and optic neuropathy, often involve neoangiogenesis and inflammation- and oxidative stress-mediated cell death, evidences are accumulating on the potential benefits of PPAR γ to improve or prevent these vision threatening eye diseases. In this paper we describe what is known about the role of PPAR γ in the ocular pathophysiological processes and PPAR γ agonists as novel adjuvants in the treatment of eye diseases.

  6. Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-[gamma

    Energy Technology Data Exchange (ETDEWEB)

    Casimiro-Garcia, Agustin; Filzen, Gary F.; Flynn, Declan; Bigge, Christopher F.; Chen, Jing; Davis, Jo Ann; Dudley, Danette A.; Edmunds, Jeremy J.; Esmaeil, Nadia; Geyer, Andrew; Heemstra, Ronald J.; Jalaie, Mehran; Ohren, Jeffrey F.; Ostroski, Robert; Ellis, Teresa; Schaum, Robert P.; Stoner, Chad (Pfizer)

    2013-03-07

    Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPAR{gamma} confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPAR{gamma} activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC{sub 50} = 1.6 nM) with partial PPAR{gamma} agonism (EC{sub 50} = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

  7. Stable expression of lipocalin-type prostaglandin D synthase in cultured preadipocytes impairs adipogenesis program independently of endogenous prostanoids

    Energy Technology Data Exchange (ETDEWEB)

    Hossain, Mohammad Salim; Chowdhury, Abu Asad; Rahman, Mohammad Sharifur [Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-cho, Matsue, Shimane 690-8504 (Japan); Nishimura, Kohji [Department of Molecular and Functional Genomics, Center for Integrated Research in Science, Shimane University, 1060 Nishikawatsu-cho, Matsue, Shimane 690-8504 (Japan); Jisaka, Mitsuo; Nagaya, Tsutomu [Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-cho, Matsue, Shimane 690-8504 (Japan); Shono, Fumiaki [Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiro-cho, Tokushima-shi, Tokushima 770-8514 (Japan); Yokota, Kazushige, E-mail: yokotaka@life.shimane-u.ac.jp [Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-cho, Matsue, Shimane 690-8504 (Japan)

    2012-02-15

    Lipocalin-type prostaglandin D synthase (L-PGDS) expressed preferentially in adipocytes is responsible for the synthesis of PGD{sub 2} and its non-enzymatic dehydration products, PGJ{sub 2} series, serving as pro-adipogenic factors. However, the role of L-PGDS in the regulation of adipogenesis is complex because of the occurrence of several derivatives from PGD{sub 2} and their distinct receptor subtypes as well as other functions such as a transporter of lipophilic molecules. To manipulate the expression levels of L-PGDS in cultured adipocytes, cultured preadipogenic 3T3-L1 cells were transfected stably with a mammalian expression vector having cDNA encoding murine L-PGDS oriented in the sense direction. The isolated cloned stable transfectants with L-PGDS expressed higher levels of the transcript and protein levels of L-PGDS, and synthesized PGD{sub 2} from exogenous arachidonic acid at significantly higher levels. By contrast, the synthesis of PGE{sub 2} remained unchanged, indicating no influence on the reactions of cyclooxygenase (COX) and PGE synthase. Furthermore, the ability of those transfectants to synthesize {Delta}{sup 12}-PGJ{sub 2} increased more greatly during the maturation phase. The sustained expression of L-PGDS in cultured stable transfectants hampered the storage of fats during the maturation phase of adipocytes, which was accompanied by the reduced gene expression of adipocyte-specific markers reflecting the down-regulation of the adipogenesis program. The suppressed adipogenesis was not rescued by either exogenous aspirin or peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonists including troglitazone and {Delta}{sup 12}-PGJ{sub 2}. Taken together, the results indicate the negative regulation of the adipogenesis program by the enhanced expression of L-PGDS through a cellular mechanism involving the interference of the PPAR{gamma} signaling pathway without the contribution of endogenous pro-adipogenic prostanoids

  8. The Multiple Faces of Prostaglandin E2 G-Protein Coupled Receptor Signaling during the Dendritic Cell Life Cycle

    Directory of Open Access Journals (Sweden)

    Alessandra Cambi

    2013-03-01

    Full Text Available Many processes regulating immune responses are initiated by G-protein coupled receptors (GPCRs and report biochemical changes in the microenvironment. Dendritic cells (DCs are the most potent antigen-presenting cells and crucial for the regulation of innate and adaptive immune responses. The lipid mediator Prostaglandin E2 (PGE2 via four GPCR subtypes (EP1-4 critically regulates DC generation, maturation and migration. The role of PGE2 signaling in DC biology was unraveled by the characterization of EP receptor subtype expression in DC progenitor cells and DCs, the identification of the signaling pathways initiated by these GPCR subtypes and the classification of DC responses to PGE2 at different stages of differentiation. Here, we review the advances in PGE2 signaling in DCs and describe the efforts still to be made to understand the spatio-temporal fine-tuning of PGE2 responses by DCs.

  9. Weight-loss changes PPAR expression, reduces atherosclerosis and improves cardiovascular function in obese insulin-resistant mice

    Energy Technology Data Exchange (ETDEWEB)

    Verreth, Wim; Verhamme, Peter; Pelat, Michael; Ganame, Javier; Bielicki, John K.; Mertens, Ann; Quarck, Rozenn; Benhabiles, Nora; Marguerie, Gerard; Mackness, Bharti; Mackness, Mike; Ninio, Ewa; Herregods, Marie-Christine; Balligand, Jean-Luc; Holvoet, Paul

    2003-09-01

    Weight-loss in obese insulin-resistant, but not in insulin-sensitive, persons reduces CHD risk. It is not known to what extent changes in the adipose gene expression profile are important for reducing CHD risk. We studied the effect of diet restriction-induced weight-loss on gene expression in adipose tissue, atherosclerosis and cardiovascular function in mice with combined leptin and LDL-receptor deficiency. Obesity, hypertriglyceridemia and insulin-resistance are associated with hypertension, impaired left ventricle function and accelerated atherosclerosis in those mice. Diet restriction during 12 weeks caused a 45% weight-loss and changes in the gene expression in adipose tissue of PPARa and PPAR? and of key genes regulating glucose transport and insulin sensitivity, lipid metabolism, oxidative stress and inflammation, most of which are under the transcriptional control of PPARs. These changes were associated with increased insulin-sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. Thus, induction of PPARa and PPAR? in adipose tissue is a key mechanism for reducing atherosclerosis and improving cardiovascular function resulting from weight-loss. Our observations point to the critical role of PPARs in the pathogenesis of cardiovascular features of the metabolic syndrome.

  10. Identification and characterization of a putative human platelet thromboxane A2/prostaglandin H2 receptor

    International Nuclear Information System (INIS)

    Saussy, D.L. Jr.

    1986-01-01

    The thromboxane A 2 (TXA 2 ) analog, 9,11-dimethylmethano-11,12-methano-16-(3-iodo-4-hydroxyphenyl)-13,14-dihydro-13-aza-15αβ-omega-tetranor TXA 2 (I-PTA-OH) was characterized as a competitive antagonist of TXA 2 mimetic-induced platelet aggregation, with a K/sub d/ of 190 nM in platelet rich plasma. This antagonism was specific for the putative thromboxane A 2 /prostaglandin H 2 (TXA 2 /PGH 2 ) receptor, since I-PTA-OH had no inhibitory effects on platelet aggregation stimulated by agonists which act independently of TXA 2 /PGH 2 , and did not inhibit platelet TXA 2 synthesis. [ 125 I]-PTA-OH binding to a particulate fraction from human platelets was saturable, displaceable, and linear with protein concentration. Scatchard analysis of equilibrium binding revealed a single class of high affinity binding sites, with a K/sub d/ of 30 +/- 4 nM and a B/sub max/ of 1.8 +/- 0.3 pmol/mg protein. Kinetic analysis yielded a k 1 of 1.35 x 10 6 M -1 x min -1 and a k√ 1 of 0.032 min -1 , K/sub d/ = k√ 1 /k 1 = 24 nM. The subcellular localization of the putative TXA 2 /PGH 2 receptor was determined using [ 125 I]-PTA-OH binding as a marker for the receptor. [ 125 I]-PTA-OH binding as a marker for the receptor. [ 125 I]-PTA-OH binding, was coenriched with markers for plasma membranes and dense tubular system; but not with markers for cytoplasmic constituents, mitochondria, or granules

  11. Oxytocin induces prostaglandin F2 alpha release in pregnant cows: influence of gestational age and oxytocin receptor concentrations.

    Science.gov (United States)

    Fuchs, A R; Rollyson, M K; Meyer, M; Fields, M J; Minix, J M; Randel, R D

    1996-03-01

    Brahman cows with known breeding dates received i.v. injections of either 10 or 100 IU oxytocin (OT) on Days 50, 150, 250, or 280 of gestation (n = 6 for each stage). Concentrations of the prostaglandin (PG) F2 alpha metabolite, 13,14-dihydro-15-keto-prostaglandin (PGFM), and OT were measured in samples of peripheral plasma collected at 15-min intervals for 1 h before and 1 h after treatment and then at 30-min intervals for 3 h. Plasma progesterone was measured daily for 14 days after OT injections on Days 50 and 250 of gestation. The increase in plasma OT after injection was dose-dependent (p = 0.001) but not affected by stage of gestation. Plasma PGFM increased after OT in a dose- and stage-dependent manner (p = 0.0001). At Day 280, the increase in plasma PGFM after 100 IU OT was sevenfold greater than at Day 50. Plasma progesterone declined significantly during the 7th to 12th days postinjection and returned to normal pregnancy values by the 14th day (4.4 +/- 0.3 ng/ml) except in two cows treated on Day 50 of gestation that later aborted. In these, plasma progesterone was significantly lower, 2.6 +/- 0.1 ng/ml. In a second experiment, the concentration of OT receptors was determined in endometrium collected from purebred Angus or Hereford cows slaughtered on Days 50, 150, 250, and 280 of gestation (n = 3 or 4 at each stage). Endometrial concentrations of OT receptor changed as a function of gestational age, increasing sixfold from Day 50 to Day 280, which was parallel to the increase by OT of plasma PGFM. Thus, endometrial OT receptors are functionally coupled to PGF2 alpha release during pregnancy, and their concentration determines the magnitude of OT-induced PGF2 alpha release during gestation. Consequently, endogenous OT is a factor in the regulation of PGF2 alpha release from the bovine uterus during pregnancy and parturition.

  12. Differential activation of catalase expression and activity by PPAR agonists: Implications for astrocyte protection in anti-glioma therapy☆

    Science.gov (United States)

    Khoo, Nicholas K.H.; Hebbar, Sachin; Zhao, Weiling; Moore, Steven A.; Domann, Frederick E.; Robbins, Mike E.

    2013-01-01

    Glioma survival is dismal, in part, due to an imbalance in antioxidant expression and activity. Peroxisome proliferator-activated receptor (PPAR) agonists have antineoplastic properties which present new redox-dependent targets for glioma anticancer therapies. Herein, we demonstrate that treatment of primary cultures of normal rat astrocytes with PPAR agonists increased the expression of catalase mRNA protein, and enzymatic activity. In contrast, these same agonists had no effect on catalase expression and activity in malignant rat glioma cells. The increase in steady-state catalase mRNA observed in normal rat astrocytes was due, in part, to de novo mRNA synthesis as opposed to increased catalase mRNA stability. Moreover, pioglitazone-mediated induction of catalase activity in normal rat astrocytes was completely blocked by transfection with a PPARγ-dominant negative plasmid. These data suggest that defects in PPAR-mediated signaling and gene expression may represent a block to normal catalase expression and induction in malignant glioma. The ability of PPAR agonists to differentially increase catalase expression and activity in normal astrocytes but not glioma cells suggests that these compounds might represent novel adjuvant therapeutic agents for the treatment of gliomas. PMID:24024139

  13. Muscarinic M1 receptor inhibition reduces gastroduodenal bicarbonate secretion and promotes gastric prostaglandin E2 synthesis in healthy volunteers

    DEFF Research Database (Denmark)

    Mertz-Nielsen, A; Hillingsø, Jens; Eskerod, O

    1995-01-01

    stimulated gastric and basal duodenal bicarbonate secretion by about 50% (p basal and vagally stimulated PGE2 output increased significantly (p ...The selective muscarinic M1 receptor antagonist, pirenzepine, considerably stimulates duodenal mucosal bicarbonate secretion in the rat and increases gastric luminal release of prostaglandin E2 (PGE2) in humans. This study, therefore, looked at the effect of pirenzepine on bicarbonate secretion...... sham feeding and acid exposure (HCl 0.1 M; 20 ml; 5 min) of the duodenal bulb increased mucosal bicarbonate secretion from 191 (14) mumol/cm x h to 266 (27) mumol/cm x h (p basal and vagally...

  14. The PPAR alpha agonist gemfibrozil is an ineffective treatment for spinal cord injured mice.

    Science.gov (United States)

    Almad, Akshata; Lash, A Todd; Wei, Ping; Lovett-Racke, Amy E; McTigue, Dana M

    2011-12-01

    Peroxisome Proliferator Activated Receptor (PPAR)-α is a key regulator of lipid metabolism and recent studies reveal it also regulates inflammation in several different disease models. Gemfibrozil, an agonist of PPAR-α, is a FDA approved drug for hyperlipidemia and has been shown to inhibit clinical signs in a rodent model of multiple sclerosis. Since many studies have shown improved outcome from spinal cord injury (SCI) by anti-inflammatory and neuroprotective agents, we tested the efficacy of oral gemfibrozil given before or after SCI for promoting tissue preservation and behavioral recovery after spinal contusion injury in mice. Unfortunately, the results were contrary to our hypothesis; in our first attempt, gemfibrozil treatment exacerbated locomotor deficits and increased tissue pathology after SCI. In subsequent experiments, the behavioral effects were not replicated but histological outcomes again were worse. We also tested the efficacy of a different PPAR-α agonist, fenofibrate, which also modulates immune responses and is beneficial in several neurodegenerative disease models. Fenofibrate treatment did not improve recovery, although there was a slight trend for a modest increase in histological tissue sparing. Based on our results, we conclude that PPAR-α agonists yield either no effect or worsen recovery from spinal cord injury, at least at the doses and the time points of drug delivery tested here. Further, patients sustaining spinal cord injury while taking gemfibrozil might be prone to exacerbated tissue damage. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Prostaglandin E2 potentiation of P2X3 receptor mediated currents in dorsal root ganglion neurons

    Directory of Open Access Journals (Sweden)

    Huang Li-Yen

    2007-08-01

    Full Text Available Abstract Prostaglandin E2 (PGE2 is a well-known inflammatory mediator that enhances the excitability of DRG neurons. Homomeric P2X3 and heteromeric P2X2/3 receptors are abundantly expressed in dorsal root ganglia (DRG neurons and participate in the transmission of nociceptive signals. The interaction between PGE2 and P2X3 receptors has not been well delineated. We studied the actions of PGE2 on ATP-activated currents in dissociated DRG neurons under voltage-clamp conditions. PGE2 had no effects on P2X2/3 receptor-mediated responses, but significantly potentiated fast-inactivating ATP currents mediated by homomeric P2X3 receptors. PGE2 exerted its action by activating EP3 receptors. To study the mechanism underlying the action of PGE2, we found that the adenylyl cyclase activator, forskolin and the membrane-permeable cAMP analogue, 8-Br-cAMP increased ATP currents, mimicking the effect of PGE2. In addition, forskolin occluded the enhancement produced by PGE2. The protein kinase A (PKA inhibitors, H89 and PKA-I blocked the PGE2 effect. In contrast, the PKC inhibitor, bisindolymaleimide (Bis did not change the potentiating action of PGE2. We further showed that PGE2 enhanced α,β-meATP-induced allodynia and hyperalgesia and the enhancement was blocked by H89. These observations suggest that PGE2 binds to EP3 receptors, resulting in the activation of cAMP/PKA signaling pathway and leading to an enhancement of P2X3 homomeric receptor-mediated ATP responses in DRG neurons.

  16. Functional reconstitution of prostaglandin E receptor from bovine adrenal medulla with guanine nucleotide binding proteins

    International Nuclear Information System (INIS)

    Negishi, M.; Ito, S.; Yokohama, H.; Hayashi, H.; Katada, T.; Ui, M.; Hayaishi, O.

    1988-01-01

    Prostaglandin E 2 (PEG 2 ) was found to bind specifically to a 100,000 x g pellet prepared from bovine adrenal medulla. The PGE receptor was associated with a GTP-binding protein (G-protein) and could be covalently cross-linked with this G-protein by dithiobis(succinimidyl propionate) in the 100,000 x g pellet. In order to characterize the G-protein associated with the PGE receptor and reconstitute these proteins in phospholipid vesicles, the authors purified the G-protein to apparent homogeneity from the 100,000 x g pellet. The G-protein served as a substrate of pertussis toxin but differed in its α subunit from two known pertussis toxin substrate G-proteins (G/sub i/ and G 0 ) purified from bovine brain. The molecular weight of the α subunit was 40,000, which is between those of G/sub i/ and G 0 . The purified protein was also distinguished immunologically from G/sub i/ and G 0 and was referred to as G/sub am/. Reconstitution of the PGE receptor with pure C/sub am/, G/sub i/, or G 0 in phospholipid vesicles resulted in a remarkable restoration of [ 3 H]PGE 2 binding activity in a GTP-dependent manner. The efficiency of these three G-proteins in this capacity was roughly equal. When pertussis toxin- or N-ethylmaleimide-treated G-proteins, instead of the native ones, were reconstituted into vesicles, the restoration of binding activity was no longer observed. These results indicate that the PGE receptor can couple functionally with G/sub am/, G/sub i/, or G 0 in phospholipid vesicles and suggest that G/sub am/ may be involved in signal transduction of the PGE receptor in bovine adrenal medulla

  17. Rosiglitazone, a Peroxisome Proliferator-Activated Receptor (PPAR)-γ Agonist, Attenuates Inflammation Via NF-κB Inhibition in Lipopolysaccharide-Induced Peritonitis.

    Science.gov (United States)

    Zhang, Yun-Fang; Zou, Xun-Liang; Wu, Jun; Yu, Xue-Qing; Yang, Xiao

    2015-12-01

    We assessed the anti-inflammatory effect of peroxisome proliferator-activated receptor (PPAR)-γ agonist, rosiglitazone, in a lipopolysaccharide (LPS)-induced peritonitis rat model. LPS was intraperitoneally injected into rats to establish peritonitis model. Male Sprague-Dawley (SD) rats were assigned to normal saline (the solvent of LPS), LPS, rosiglitazone plus LPS, and rosiglitazone alone. A simple peritoneal equilibrium test was performed with 20 ml 4.25 % peritoneal dialysis fluid. We measured the leukocyte count in dialysate and ultrafiltration volume. Peritoneal membrane histochemical staining was performed, and peritoneal thickness was assessed. CD40 and intercellular adhesion molecule-1 messenger RNA (ICAM-1 mRNA) levels in rat visceral peritoneum were detected by reverse transcription (RT)-PCR. IL-6 in rat peritoneal dialysis effluent was measured using enzyme-linked immunosorbent assay. The phosphorylation of NF-κB-p65 and IκBα was analyzed by Western blot. LPS administration resulted in increased peritoneal thickness and decreased ultrafiltration volume. Rosiglitazone pretreatment significantly decreased peritoneal thickness. In addition to CD40 and ICAM-1 mRNA expression, the IL-6, p-p65, and p-IκBα protein expressions were enhanced in LPS-administered animals. Rosiglitazone pretreatment significantly decreased ICAM-1 mRNA upregulation, secretion of IL-6 protein, and phosphorylation of NF-κB-p65 and IκBα without decreasing CD40 mRNA expression. Rosiglitazone has a protective effect in peritonitis, simultaneously decreasing NF-κB phosphorylation, suggesting that NF-κB signaling pathway mediated peritoneal inflammation induced by LPS. PPAR-γ might be considered a potential therapeutic target against peritonitis.

  18. Antidiabetic effects of chamomile flowers extract in obese mice through transcriptional stimulation of nutrient sensors of the peroxisome proliferator-activated receptor (PPAR family.

    Directory of Open Access Journals (Sweden)

    Christopher Weidner

    Full Text Available Given the significant increases in the incidence of metabolic diseases, efficient strategies for preventing and treating of these common disorders are urgently needed. This includes the development of phytopharmaceutical products or functional foods to prevent or cure metabolic diseases. Plant extracts from edible biomaterial provide a potential resource of structurally diverse molecules that can synergistically interfere with complex disorders. In this study we describe the safe application of ethanolic chamomile (Matricaria recutita flowers extract (CFE for the treatment and prevention of type 2 diabetes and associated disorders. We show in vitro that this extract activates in particular nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ and its isotypes. In a cellular context, in human primary adipocytes CFE administration (300 µg/ml led to specific expression of target genes of PPARγ, whereas in human hepatocytes CFE-induced we detected expression changes of genes that were regulated by PPARα. In vivo treatment of insulin-resistant high-fat diet (HFD-fed C57BL/6 mice with CFE (200 mg/kg/d for 6 weeks considerably reduced insulin resistance, glucose intolerance, plasma triacylglycerol, non-esterified fatty acids (NEFA and LDL/VLDL cholesterol. Co-feeding of lean C57BL/6 mice a HFD with 200 mg/kg/d CFE for 20 weeks showed effective prevention of fatty liver formation and hepatic inflammation, indicating additionally hepatoprotective effects of the extract. Moreover, CFE treatment did not reveal side effects, which have otherwise been associated with strong synthetic PPAR-targeting molecules, such as weight gain, liver disorders, hemodilution or bone cell turnover. Taken together, modulation of PPARs and other factors by chamomile flowers extract has the potential to prevent or treat type 2 diabetes and related disorders.

  19. Prostaglandin E and F2 alpha receptors in human myometrium during the menstrual cycle and in pregnancy and labor

    International Nuclear Information System (INIS)

    Giannopoulos, G.; Jackson, K.; Kredentser, J.; Tulchinsky, D.

    1985-01-01

    The binding of prostaglandins E1 and F2 alpha has been studied in the human myometrium and cervix during the menstrual cycle and in the myometrium of pregnant patients at term before and during labor. Tritium-labeled prostaglandin E1 and F2 alpha binding was saturable and reversible. Scatchard analysis of tritium-labeled prostaglandin E1 binding was linear, which suggests a single class of high-affinity binding sites with an estimated apparent equilibrium dissociation constant of 2.5 to 5.4 nmol/L and inhibitor affinities of 0.9, 273, 273, and 217 nmol/L for prostaglandins E2, A1, B1, and F2 alpha, respectively. Scatchard analysis of tritium-labeled prostaglandin F2 alpha, binding was also linear, but the affinity of these binding sites was much lower, with an average dissociation constant of 50 nmol/L and inhibitor affinities of 1.6, 2.2, and 11.2 nmol/L for prostaglandins E1, E2, and A1, respectively. In nonpregnant patients, the concentrations and affinities of tritium-labeled prostaglandin E1 binding sites were similar in the myometrium during the proliferative and secretory phases of the menstrual cycle, but the concentration of these sites was much lower in the cervix. The concentration of the tritium-labeled prostaglandin E1 binding sites was significantly lower in the myometrium of pregnant patients at term than in the myometrium of nonpregnant patients. The concentrations and affinities of tritium-labeled prostaglandin E1 binding sites were not significantly different in the upper and lower myometrium of pregnant patients at term or in the myometrium of such patients before and during labor. The concentrations of the tritium-labeled prostaglandin F2 alpha binding sites during the menstrual cycle and in pregnancy at term were similar to those of tritium-labeled prostaglandin E1 binding sites

  20. Prostaglandin E and F2 alpha receptors in human myometrium during the menstrual cycle and in pregnancy and labor

    Energy Technology Data Exchange (ETDEWEB)

    Giannopoulos, G.; Jackson, K.; Kredentser, J.; Tulchinsky, D.

    1985-12-15

    The binding of prostaglandins E1 and F2 alpha has been studied in the human myometrium and cervix during the menstrual cycle and in the myometrium of pregnant patients at term before and during labor. Tritium-labeled prostaglandin E1 and F2 alpha binding was saturable and reversible. Scatchard analysis of tritium-labeled prostaglandin E1 binding was linear, which suggests a single class of high-affinity binding sites with an estimated apparent equilibrium dissociation constant of 2.5 to 5.4 nmol/L and inhibitor affinities of 0.9, 273, 273, and 217 nmol/L for prostaglandins E2, A1, B1, and F2 alpha, respectively. Scatchard analysis of tritium-labeled prostaglandin F2 alpha, binding was also linear, but the affinity of these binding sites was much lower, with an average dissociation constant of 50 nmol/L and inhibitor affinities of 1.6, 2.2, and 11.2 nmol/L for prostaglandins E1, E2, and A1, respectively. In nonpregnant patients, the concentrations and affinities of tritium-labeled prostaglandin E1 binding sites were similar in the myometrium during the proliferative and secretory phases of the menstrual cycle, but the concentration of these sites was much lower in the cervix. The concentration of the tritium-labeled prostaglandin E1 binding sites was significantly lower in the myometrium of pregnant patients at term than in the myometrium of nonpregnant patients. The concentrations and affinities of tritium-labeled prostaglandin E1 binding sites were not significantly different in the upper and lower myometrium of pregnant patients at term or in the myometrium of such patients before and during labor. The concentrations of the tritium-labeled prostaglandin F2 alpha binding sites during the menstrual cycle and in pregnancy at term were similar to those of tritium-labeled prostaglandin E1 binding sites.

  1. Liver X Receptor (LXR) activation negatively regulates visfatin expression in macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Mayi, Therese Hervee; Rigamonti, Elena [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France); Pattou, Francois [Univ Lille Nord de France, F-59000 Lille (France); Department of Endocrine Surgery, University Hospital, Lille (France); U859 Biotherapies for Diabetes, INSERM, Lille (France); Staels, Bart, E-mail: bart.staels@pasteur-lille.fr [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France); Chinetti-Gbaguidi, Giulia [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France)

    2011-01-07

    Research highlights: {yields} Synthetic LXR ligands decreased visfatin expression in human macrophages. {yields} LXR activation leads to a modest and transient decrease of NAD{sup +} concentration. {yields} LXR activation decreased PPAR{gamma}-induced visfatin in human macrophages. -- Abstract: Adipose tissue macrophages (ATM) are the major source of visfatin, a visceral fat adipokine upregulated during obesity. Also known to play a role in B cell differentiation (pre-B cell colony-enhancing factor (PBEF)) and NAD biosynthesis (nicotinamide phosphoribosyl transferase (NAMPT)), visfatin has been suggested to play a role in inflammation. Liver X Receptor (LXR) and Peroxisome Proliferator-Activated Receptor (PPAR){gamma} are nuclear receptors expressed in macrophages controlling the inflammatory response. Recently, we reported visfatin as a PPAR{gamma} target gene in human macrophages. In this study, we examined whether LXR regulates macrophage visfatin expression. Synthetic LXR ligands decreased visfatin gene expression in a LXR-dependent manner in human and murine macrophages. The decrease of visfatin mRNA was paralleled by a decrease of protein secretion. Consequently, a modest and transient decrease of NAD{sup +} concentration was observed. Interestingly, LXR activation decreased the PPAR{gamma}-induced visfatin gene and protein secretion in human macrophages. Our results identify visfatin as a gene oppositely regulated by the LXR and PPAR{gamma} pathways in human macrophages.

  2. Activation of PPAR{delta} up-regulates fatty acid oxidation and energy uncoupling genes of mitochondria and reduces palmitate-induced apoptosis in pancreatic {beta}-cells

    Energy Technology Data Exchange (ETDEWEB)

    Wan, Jun; Jiang, Li; Lue, Qingguo; Ke, Linqiu [Department of Endocrinology, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041 (China); Li, Xiaoyu [State Key Laboratory of Oral Diseases, Sichuan University, No. 14, 3rd Section, Renmin South Road, Chengdu, Sichuan 610041 (China); Tong, Nanwei, E-mail: buddyjun@hotmail.com [Department of Endocrinology, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041 (China)

    2010-01-15

    Recent evidence indicates that decreased oxidative capacity, lipotoxicity, and mitochondrial aberrations contribute to the development of insulin resistance and type 2 diabetes. The goal of this study was to investigate the effects of peroxisome proliferator-activated receptor {delta} (PPAR{delta}) activation on lipid oxidation, mitochondrial function, and insulin secretion in pancreatic {beta}-cells. After HIT-T15 cells (a {beta}-cell line) were exposed to high concentrations of palmitate and GW501516 (GW; a selective agonist of PPAR{delta}), we found that administration of GW increased the expression of PPAR{delta} mRNA. GW-induced activation of PPAR{delta} up-regulated carnitine palmitoyltransferase 1 (CPT1), long-chain acyl-CoA dehydrogenase (LCAD), pyruvate dehydrogenase kinase 4 (PDK4), and uncoupling protein 2 (UCP2); alleviated mitochondrial swelling; attenuated apoptosis; and reduced basal insulin secretion induced by increased palmitate in HIT cells. These results suggest that activation of PPAR{delta} plays an important role in protecting pancreatic {beta}-cells against aberrations caused by lipotoxicity in metabolic syndrome and diabetes.

  3. Novel time-dependent vascular actions of {delta}{sup 9}-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma

    Energy Technology Data Exchange (ETDEWEB)

    O' Sullivan, Saoirse E [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Tarling, Elizabeth J [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Bennett, Andrew J [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Kendall, David A [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Randall, Michael D [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom)

    2005-11-25

    Cannabinoids have widespread effects on the cardiovascular system, only some of which are mediated via G-protein-coupled cell surface receptors. The active ingredient of cannabis, {delta}{sup 9}-tetrahydrocannabinol (THC), causes acute vasorelaxation in various arteries. Here we show for the first time that THC also causes slowly developing vasorelaxation through activation of peroxisome proliferator-activated receptors gamma (PPAR{gamma}). In vitro, THC (10 {mu}M) caused time-dependent vasorelaxation of rat isolated arteries. Time-dependent vasorelaxation to THC was similar to that produced by the PPAR{gamma} agonist rosiglitazone and was inhibited by the PPAR{gamma} antagonist GW9662 (1 {mu}M), but not the cannabinoid CB{sub 1} receptor antagonist AM251 (1 {mu}M). Time-dependent vasorelaxation to THC requires an intact endothelium, nitric oxide, production of hydrogen peroxide, and de novo protein synthesis. In transactivation assays in cultured HEK293 cells, THC-activated PPAR{gamma}, transiently expressed in combination with retinoid X receptor {alpha} and a luciferase reporter gene, in a concentration-dependent manner (100 nM-10 {mu}M). In vitro incubation with THC (1 or 10 {mu}M, 8 days) stimulated adipocyte differentiation in cultured 3T3L1 cells, a well-accepted property of PPAR{gamma} ligands. The present results provide strong evidence that THC is a PPAR{gamma} ligand, stimulation of which causes time-dependent vasorelaxation, implying some of the pleiotropic effects of cannabis may be mediated by nuclear receptors.

  4. A role for prostaglandins in rapid cycling suggested by episode-specific gene expression shifts in peripheral blood mononuclear cells

    DEFF Research Database (Denmark)

    Gurvich, Artem; Begemann, Martin; Dahm, Liane

    2014-01-01

    and quantitative real-time reverse transcriptase polymerase chain reaction for prostaglandin D2 synthase (PTGDS), aldo-ketoreductase family 1, member C3 (AKR1C3), cyclooxygenase-2 (PAN means all splice variants) (COX2PAN ), prostaglandin-endoperoxide synthase 2 (PTGS2), and purinergic receptor P2X, ligand...

  5. Role of Peroxisome Proliferator-Activated Receptors in Inflammation Control

    Directory of Open Access Journals (Sweden)

    Jihan Youssef

    2004-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs were discovered over a decade ago, and were classified as orphan members of the nuclear receptor superfamily. To date, three PPAR subtypes have been discovered and characterized (PPARα, β/δ, γ. Different PPAR subtypes have been shown to play crucial roles in important diseases and conditions such as obesity, diabetes, atherosclerosis, cancer, and fertility. Among the most studied roles of PPARs is their involvement in inflammatory processes. Numerous studies have revealed that agonists of PPARα and PPARγ exert anti-inflammatory effects both in vitro and in vivo. Using the carrageenan-induced paw edema model of inflammation, a recent study in our laboratories showed that these agonists hinder the initiation phase, but not the late phase of the inflammatory process. Furthermore, in the same experimental model, we recently also observed that activation of PPARδ exerted an anti-inflammatory effect. Despite the fact that exclusive dependence of these effects on PPARs has been questioned, the bulk of evidence suggests that all three PPAR subtypes, PPARα,δ,γ, play a significant role in controlling inflammatory responses. Whether these subtypes act via a common mechanism or are independent of each other remains to be elucidated. However, due to the intensity of research efforts in this area, it is anticipated that these efforts will result in the development of PPAR ligands as therapeutic agents for the treatment of inflammatory diseases.

  6. Partial purification and identification of the thrombozane A2/prostaglandin H2 receptor protein in human platelets

    International Nuclear Information System (INIS)

    Lim, C.T.; Kattelman, E.J.; Arora, S.K.; Venton, D.L.; Le Breton, G.C.

    1986-01-01

    The thromboxane A 2 /prostaglandin H 2 (TXA 2 /PGH 2 ) receptor antagonist [ 3 H]-13-azaprostanoic acid (13-APA) was used to identify and purify the platelet TXA 2 /PGH 2 receptor protein. Optimal solubilization of the 13-APA binding protein was achieved by extraction with 3-[(3-cholamidopropyl)dimethyl-ammonio]-1-propanesulfonate (CHAPS) detergent. Preliminary purification of the crude solubilized membrane fraction was performed by gel filtration chromatography using a Sepharose 4B column. Further purification was accomplished by high performance liquid chromatography (HPLC) using a Synchropak GPC-500 column. The HPLC protein profile revealed two protein peaks, only one of which was enriched in [ 3 H]-13-APA. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of this peak revealed two bands with molecular weights of 65,000 and 60,000 daltons. In binding studies using the 60,000 dalton-enriched subfraction, unlabelled 13-APA, the TXA 2 /PGH 2 mimetic U46619 and the TXA 2 /PGH 2 antagonist SQ 29,548 all competed for [ 3 H]-13-APA binding whereas TXB 2 did not compete for binding. Heat denaturation of this subfraction resulted in a complete loss of binding activity. These findings indicate that a protein of approximately 60,000 daltons represents the human platelet TXA 2 /PGH 2 receptor

  7. Prostaglandin synthesis and catabolism in the gastric mucosa: studies in normal rabbits and rabbits immunized with prostaglandin E2

    International Nuclear Information System (INIS)

    Redfern, J.S.

    1988-01-01

    Antral and fundic mucosal homogenates obtained from prostaglandin E2-immunized rabbits converted 14C-arachidonic acid to prostaglandin E2, 6-keto prostaglandin F1 alpha, prostaglandin F2 alpha, and prostaglandin D2. Percentage conversion of 14C-arachidonic acid to these prostaglandin products was not significantly different in prostaglandin E2-immunized rabbits compared with control rabbits (thyroglobulin-immunized and unimmunized rabbits combined). Synthesis of 6-keto prostaglandin F1 alpha, prostaglandin E2 and 13,14-dihydro 15-keto prostaglandin E2 from endogenous arachidonic acid after vortex mixing fundic mucosal homogenates was similar in prostaglandin E2 immunized rabbits and control rabbits. Both in prostaglandin E2-immunized rabbits and controls, 3H-prostaglandin E2 was catabolized extensively by the fundic mucosa, whereas 3H-6-keto prostaglandin F1 alpha, 3H-prostaglandin F2 alpha, and 3H-prostaglandin D2 were not catabolized to any appreciable extent. The rate of catabolism of PGs was not significantly different in prostaglandin E2-immunized rabbits and control rabbits, with the exception of prostaglandin F2 alpha which was catabolized slightly more rapidly in prostaglandin E2-immunized rabbits. These results indicate that development of gastric ulcers in prostaglandin E2-immunized rabbits is not associated with an alteration in the capacity of the gastric mucosa to synthesize or catabolize prostaglandins

  8. Pioglitazone Attenuates Drug-Eluting Stent-Induced Proinflammatory State in Patients by Blocking Ubiquitination of PPAR

    Directory of Open Access Journals (Sweden)

    Zhongxia Wang

    2016-01-01

    Full Text Available The inflammatory response after polymer-based drug-eluting stent (DES placement has recently emerged as a major concern. The biologic roles of peroxisome proliferator-activated receptor-γ (PPAR-γ activators thiazolidinedione (TZD remain controversial in cardiovascular disease. Herein, we investigated the antiinflammatory effects of pioglitazone (PIO on circulating peripheral blood mononuclear cells (MNCs in patients after coronary DES implantation. Methods and Results. Twenty-eight patients with coronary artery disease and who underwent DES implantations were randomly assigned to pioglitazone (30 mg/d; PIO or placebo (control; Con treatment in addition to optimal standard therapy. After 12 weeks of treatment, plasma concentrations of high-sensitivity C-reactive protein (hs-CRP, interleukin-6 (IL-6, tumor necrosis factor-α (TNF-α, and matrix metalloproteinase-9 (MMP-9 were significantly decreased in PIO group compared to the Con group (P=0.035, 0.011, 0.008, and 0.012, resp.. DES-induced mRNA expressions of IL-6, TNF-α, and MMP-9 in circulating MNC were significantly blocked by PIO (P=0.031, 0.012, and 0.007, resp.. In addition, PIO markedly inhibited DES-enhanced NF-κB function and DES-blocked PPAR-γ activity. Mechanically, DES induced PPAR-γ ubiquitination and degradation in protein level, which can be totally reversed by PIO. Conclusion. PIO treatment attenuated DES-induced PPAR loss, NF-κB activation, and proinflammation, indicating that PIO may have a novel direct protective role in modulating proinflammation in DES era.

  9. Glucose-induced metabolic memory in Schwann cells: prevention by PPAR agonists.

    Science.gov (United States)

    Kim, Esther S; Isoda, Fumiko; Kurland, Irwin; Mobbs, Charles V

    2013-09-01

    A major barrier in reversing diabetic complications is that molecular and pathologic effects of elevated glucose persist despite normalization of glucose, a phenomenon referred to as metabolic memory. In the present studies we have investigated the effects of elevated glucose on Schwann cells, which are implicated in diabetic neuropathy. Using quantitative PCR arrays for glucose and fatty acid metabolism, we have found that chronic (>8 wk) 25 mM high glucose induces a persistent increase in genes that promote glycolysis, while inhibiting those that oppose glycolysis and alternate metabolic pathways such as fatty acid metabolism, the pentose phosphate pathway, and trichloroacetic acid cycle. These sustained effects were associated with decreased peroxisome proliferator-activated receptor (PPAR)γ binding and persistently increased reactive oxygen species, cellular NADH, and altered DNA methylation. Agonists of PPARγ and PPARα prevented select effects of glucose-induced gene expression. These observations suggest that Schwann cells exhibit features of metabolic memory that may be regulated at the transcriptional level. Furthermore, targeting PPAR may prevent metabolic memory and the development of diabetic complications.

  10. EP3 receptors inhibit antidiuretic-hormone-dependent sodium transport across frog skin epithelium

    DEFF Research Database (Denmark)

    Rytved, Klaus A.; Nielsen, Robert

    1999-01-01

    Antidiuretic hormone; tight epithelium; prostaglandin receptors; sulprostone; misoprostol; cAMP; cellular Ca2+......Antidiuretic hormone; tight epithelium; prostaglandin receptors; sulprostone; misoprostol; cAMP; cellular Ca2+...

  11. Implication of prostaglandins and histamine H1 and H2 receptors in radiation-induced temperature responses of rats

    International Nuclear Information System (INIS)

    Kandasamy, S.B.; Hunt, W.A.; Mickley, G.A.

    1988-01-01

    Exposure of rats to 1-15 Gy gamma radiation ( 60 Co) induced hyperthermia, whereas 20-200 Gy induced hypothermia. Exposure either to the head or to the whole body to 10 Gy induced hyperthermia, while body-only exposure produced hypothermia. This observation indicates that radiation-induced fever is a result of a direct effect on the brain. The hyperthermia due to 10 Gy was significantly attenuated by the pre- or post-treatment with a cyclooxygenase inhibitor, indomethacin. Hyperthermia was also altered by the central administration of a mu-receptor antagonist naloxone but only at low doses of radiation. These findings suggest that radiation-induced hyperthermia may be mediated through the synthesis and release of prostaglandins in the brain and to a lesser extent to the release of endogenous opioid peptides. The release of histamine acting on H1 and H2 receptors may be involved in radiation-induced hypothermia, since both the H1 receptor antagonist, mepyramine, and H2 receptor antagonist, cimetidine, antagonized the hypothermia. The results of these studies suggest that the release of neurohumoral substances induced by exposure to ionizing radiation is dose dependent and has different consequences on physiological processes such as the regulation of body temperature. Furthermore, the antagonism of radiation-induced hyperthermia by indomethacin may have potential therapeutic implications in the treatment of fever resulting from accidental irradiations

  12. Peroxisome proliferator-activated receptor delta activation leads to increased transintestinal cholesterol efflux

    NARCIS (Netherlands)

    Vrins, Carlos L. J.; van der Velde, Astrid E.; van den Oever, Karin; Levels, Johannes H. M.; Huet, Stephane; Elferink, Ronald P. J. Oude; Kuipers, Folkert; Groen, Albert K.

    2009-01-01

    Peroxisome proliferator-activated receptor delta (PPAR delta) is involved in regulation of energy homeostasis. Activation of PPAR delta markedly increases fecal neutral sterol secretion, the last step in reverse cholesterol transport. This phenomenon can neither be explained by increased

  13. The role of prostaglandins in spinal transmission of the exercise pressor reflex in decerebrate rats

    Science.gov (United States)

    Stone, Audrey J.; Copp, Steven W.; Kaufman, Marc P.

    2014-01-01

    Previous studies found that prostaglandins in skeletal muscle play a role in evoking the exercise pressor reflex; however the role played by prostaglandins in the spinal transmission of the reflex is not known. We determined, therefore, whether or not spinal blockade of cyclooxygenase (COX) activity and/or spinal blockade of endoperoxide receptor (EP) 2 or EP4 receptors attenuated the exercise pressor reflex in decerebrate rats. We first established that intrathecal doses of a non-specific COX inhibitor Ketorolac (100ug in 10ul), a COX-2 specific inhibitor Celecoxib (100μg in 10μl), an EP2 antagonist PF-04418948 (10μg in 10μl), and an EP4 antagonist L-161,982 (4μg in 10μl) effectively attenuated the pressor responses to intrathecal injections of Arachidonic Acid (100μg in 10μl), EP2 agonist Butaprost (4ng in 10 μl), and EP4 agonist TCS 2510 (6.25μg in 2.5 μl), respectively. Once effective doses were established, we statically contracted the hindlimb before and after intrathecal injections of Ketorolac, Celecoxib, the EP2 antagonist and the EP4 antagonist. We found that Ketorolac significantly attenuated the pressor response to static contraction (before Ketorolac: 23±5 mmHg, after Ketorolac 14±5 mmHg; preflex, and that the spinal prostaglandins produced by this enzyme are most likely activating spinal EP4 receptors, but not EP2 receptors. PMID:25003710

  14. Citreoviridin induces triglyceride accumulation in hepatocytes through inhibiting PPAR-α in vivo and in vitro.

    Science.gov (United States)

    Feng, Chang; Li, Dandan; Jiang, Liping; Liu, Xiaofang; Li, Qiujuan; Geng, Chengyan; Sun, Xiance; Yang, Guang; Yao, Xiaofeng; Chen, Min

    2017-08-01

    Citreoviridin (CIT) is a mycotoxin produced by Penicillum citreonigrum, Aspergillus terreus and Eupenicillium ochrosalmoneum. CIT occurs naturally in moldy rice and corn. CIT is associated with the development of atherosclerosis in the general population. Alteration in hepatic lipid metabolism is a pathogenic factor in atherosclerosis. However the effect and the underlying mechanism of CIT on hepatic lipid metabolism are largely unknown. In this study, we reported that CIT induced triglyceride accumulation in mice liver and human liver HepG2 cells as shown in oil red O staining. CIT (0.1 mg/kg-0.3 mg/kg) for 6 weeks elevated liver triglyceride contents in mice. CIT inhibited the transactivation activity of peroxisome proliferator-activated receptor-α (PPAR-α) in hepatocyte in vivo and in vitro, as shown by the reduced mRNA levels of PPAR-α target genes which play key roles in lipid metabolism in various aspects. PPAR-α agonist fenofibrate attenuated CIT-induced triglyceride accumulation in HepG2 cells. Furthermore, CIT increased serum total cholesterol/high-density lipoprotein cholesterol ratio, a strong risk factor for cardiovascular disease. In summary, we reported that CIT induced PPAR-α-dependent hepatic triglyceride accumulation and dyslipidemia. Our data will provide new mechanistic insights into CIT-induced lipid alterations. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening

    DEFF Research Database (Denmark)

    Markt, Patrick; Petersen, Rasmus K; Flindt, Esben N

    2008-01-01

    Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow base...

  16. Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor [alpha] Selective Agonist 2-((3-((2-(4-Chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic Acid (BMS-687453)

    Energy Technology Data Exchange (ETDEWEB)

    Li, Jun; Kennedy, Lawrence J.; Shi, Yan; Tao, Shiwei; Ye, Xiang-Yang; Chen, Stephanie Y.; Wang, Ying; Hernndez, Andrs S.; Wang, Wei; Devasthale, Pratik V.; Chen, Sean; Lai, Zhi; Zhang, Hao; Wu, Shung; Smirk, Rebecca A.; Bolton, Scott A.; Ryono, Denis E.; Zhang, Huiping; Lim, Ngiap-Kie; Chen, Bang-Chi; Locke, Kenneth T.; O’Malley, Kevin M.; Zhang, Litao; Srivastava, Rai Ajit; Miao, Bowman; Meyers, Daniel S.; Monshizadegan, Hossain; Search, Debra; Grimm, Denise; Zhang, Rongan; Harrity, Thomas; Kunselman, Lori K.; Cap, Michael; Kadiyala, Pathanjali; Hosagrahara, Vinayak; Zhang, Lisa; Xu, Carrie; Li, Yi-Xin; Muckelbauer, Jodi K.; Chang, Chiehying; An, Yongmi; Krystek, Stanley R.; Blanar, Michael A.; Zahler, Robert; Mukherjee, Ranjan; Cheng, Peter T.W.; Tino, Joseph A. (BMS)

    2010-04-12

    An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) {alpha} agonist, with an EC{sub 50} of 10 nM for human PPAR{alpha} and 410-fold selectivity vs human PPAR{gamma} in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPAR{delta}. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPAR{alpha} ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPAR{alpha} in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.

  17. Microarray evaluation of EP4 receptor-mediated prostaglandin E2 suppression of 3T3-L1 adipocyte differentiation

    International Nuclear Information System (INIS)

    Sugimoto, Yukihiko; Tsuboi, Hiroaki; Okuno, Yasushi; Tamba, Shigero; Tsuchiya, Soken; Tsujimoto, Gozo; Ichikawa, Atsushi

    2004-01-01

    Prostaglandin E 2 (PGE 2 ) has been shown to negatively regulate adipogenesis. To explore to what extent PGE 2 inhibits the differentiation of cells to adipocytes and to examine whether its effect could be due to EP4 receptor signaling, we used microarrays to analyze the gene expression profiles of 3T3-L1 cells exposed to a differentiation cocktail supplemented with PGE 2 , AE1-329 (an EP4 agonist), or vehicle. The differentiation-associated responses in genes such as adipocytokines and enzymes related to lipid metabolism were largely weakened upon PGE 2 treatment. In particular, the expression of peroxisome proliferator activated receptor-γ and CCAAT/enhancer binding protein-α, genes playing a central role in adipogenesis, was greatly suppressed. PGE 2 appears to be ineffective to a subclass of insulin target genes such as hexokinase 2 and phosphofructokinase. Similar responses were produced in the differentiation-associated genes upon AE1-329 treatment. These results suggest that PGE 2 inhibits a crucial step of the adipocyte differentiation process by acting on the EP4 receptor in 3T3-L1 cells

  18. Prostaglandins in the kidney: developments since Y2K.

    Science.gov (United States)

    Nasrallah, Rania; Clark, Jordan; Hébert, Richard L

    2007-10-01

    There are five major PGs (prostaglandins/prostanoids) produced from arachidonic acid via the COX (cyclo-oxygenase) pathway: PGE(2), PGI(2) (prostacyclin), PGD(2), PGF(2alpha) and TXA(2) (thromboxane A(2)). They exert many biological effects through specific G-protein-coupled membrane receptors, namely EP (PGE(2) receptor), IP (PGI(2) receptor), DP (PGD(2) receptor), FP (PGF(2alpha) receptor) and TP (TXA(2) receptor) respectively. PGs are implicated in physiological and pathological processes in all major organ systems, including cardiovascular function, gastrointestinal responses, reproductive processes, renal effects etc. This review highlights recent insights into the role of each prostanoid in regulating various aspects of renal function, including haemodynamics, renin secretion, growth responses, tubular transport processes and cell fate. A thorough review of the literature since Y2K (year 2000) is provided, with a general overview of PGs and their synthesis enzymes, and then specific considerations of each PG/prostanoid receptor system in the kidney.

  19. High sugar intake and development of skeletal muscle insulin resistance and inflammation in mice: a protective role for PPAR- δ agonism.

    Science.gov (United States)

    Benetti, Elisa; Mastrocola, Raffaella; Rogazzo, Mara; Chiazza, Fausto; Aragno, Manuela; Fantozzi, Roberto; Collino, Massimo; Minetto, Marco A

    2013-01-01

    Peroxisome Proliferator Activated Receptor (PPAR)- δ agonists may serve for treating metabolic diseases. However, the effects of PPAR- δ agonism within the skeletal muscle, which plays a key role in whole-body glucose metabolism, remain unclear. This study aimed to investigate the signaling pathways activated in the gastrocnemius muscle by chronic administration of the selective PPAR- δ agonist, GW0742 (1 mg/kg/day for 16 weeks), in male C57Bl6/J mice treated for 30 weeks with high-fructose corn syrup (HFCS), the major sweetener in foods and soft-drinks (15% wt/vol in drinking water). Mice fed with the HFCS diet exhibited hyperlipidemia, hyperinsulinemia, hyperleptinemia, and hypoadiponectinemia. In the gastrocnemius muscle, HFCS impaired insulin and AMP-activated protein kinase signaling pathways and reduced GLUT-4 and GLUT-5 expression and membrane translocation. GW0742 administration induced PPAR- δ upregulation and improvement in glucose and lipid metabolism. Diet-induced activation of nuclear factor-κB and expression of inducible-nitric-oxide-synthase and intercellular-adhesion-molecule-1 were attenuated by drug treatment. These effects were accompanied by reduction in the serum concentration of interleukin-6 and increase in muscular expression of fibroblast growth factor-21. Overall, here we show that PPAR- δ activation protects the skeletal muscle against the metabolic abnormalities caused by chronic HFCS exposure by affecting multiple levels of the insulin and inflammatory cascades.

  20. In Silico Identification of Potent PPAR-γ Agonists from Traditional Chinese Medicine: A Bioactivity Prediction, Virtual Screening, and Molecular Dynamics Study

    Directory of Open Access Journals (Sweden)

    Kuan-Chung Chen

    2014-01-01

    Full Text Available The peroxisome proliferator-activated receptors (PPARs related to regulation of lipid metabolism, inflammation, cell proliferation, differentiation, and glucose homeostasis by controlling the related ligand-dependent transcription of networks of genes. They are used to be served as therapeutic targets against metabolic disorder, such as obesity, dyslipidemia, and diabetes; especially, PPAR-γ is the most extensively investigated isoform for the treatment of dyslipidemic type 2 diabetes. In this study, we filter compounds of traditional Chinese medicine (TCM using bioactivities predicted by three distinct prediction models before the virtual screening. For the top candidates, the molecular dynamics (MD simulations were also utilized to investigate the stability of interactions between ligand and PPAR-γ protein. The top two TCM candidates, 5-hydroxy-L-tryptophan and abrine, have an indole ring and carboxyl group to form the H-bonds with the key residues of PPAR-γ protein, such as residues Ser289 and Lys367. The secondary amine group of abrine also stabilized an H-bond with residue Ser289. From the figures of root mean square fluctuations (RMSFs, the key residues were stabilized in protein complexes with 5-Hydroxy-L-tryptophan and abrine as control. Hence, we propose 5-hydroxy-L-tryptophan and abrine as potential lead compounds for further study in drug development process with the PPAR-γ protein.

  1. Ω-3 fatty acids prevent hepatic steatosis, independent of PPAR-α activity, in a murine model of parenteral nutrition-associated liver disease.

    Science.gov (United States)

    Prince, Esther; Lazare, Farrah B; Treem, William R; Xu, Jiliu; Iqbal, Jahangir; Pan, Xiaoyue; Josekutty, Joby; Walsh, Meghan; Anderson, Virginia; Hussain, M Mahmood; Schwarz, Steven M

    2014-07-01

    ω-3 Fatty acids (FAs), natural ligands for the peroxisome proliferator-activated receptor-α (PPAR-α), attenuate parenteral nutrition-associated liver disease (PNALD). However, the mechanisms underlying the protective role of ω-3 FAs are still unknown. The aim of this study was to determine the effects of ω-3 FAs on hepatic triglyceride (TG) accumulation in a murine model of PNALD and to investigate the role of PPAR-α and microsomal triglyceride transfer protein (MTP) in this experimental setting. 129S1/SvImJ wild-type or 129S4/SvJaePparatm/Gonz/J PPAR-α knockout mice were fed chow and water (controls); oral, fat-free PN solution only (PN-O); PN-O plus intraperitoneal (IP) ω-6 FA-predominant supplements (PN-ω-6); or PN-O plus IP ω-3 FA (PN-ω-3). Control and PN-O groups received sham IP injections of 0.9% NaCl. Hepatic histology, TG and cholesterol, MTP activity, and PPAR-α messenger RNA were assessed after 19 days. In all experimental groups, PN feeding increased hepatic TG and MTP activity compared with controls. Both PN-O and PN-ω-6 groups accumulated significantly greater amounts of TG when compared with PN-ω-3 mice. Studies in PPAR-α null animals showed that PN feeding increases hepatic TG as in wild-type mice. PPAR-α null mice in the PN-O and PN-ω-6 groups demonstrated variable degrees of hepatic steatosis, whereas no evidence of hepatic fat accumulation was found after 19 days of oral PN plus IP ω-3 FAs. PN induces TG accumulation (steatosis) in wild-type and PPAR-α null mice. In PN-fed wild-type and PPAR-α null mice given IP ω-3 FAs, reduced hepatic TG accumulation and absent steatosis are found. Prevention of steatosis by ω-3 FAs results from PPAR-α-independent pathways. © 2013 American Society for Parenteral and Enteral Nutrition.

  2. Effects of pioglitazone mediated activation of PPAR-γ on CIDEC and obesity related changes in mice.

    Directory of Open Access Journals (Sweden)

    Bilal Haider Shamsi

    Full Text Available OBJECTIVE: Obesity is a metabolic disorder that can lead to high blood pressure, increased blood cholesterol and triglycerides, insulin resistance, and diabetes mellitus. The aim was to study the effects of pioglitazone mediated sensitization of peroxisome proliferator-activated receptor gamma (PPAR-γ on the relationship of Cell death-inducing DFFA-like effector C (CIDEC with obesity related changes in mice. METHODS: Sixty C57B/L6 mice weighing 10-12g at 3 weeks of age were randomly divided into 3 groups. Mice in Group 1 were fed on normal diet (ND while Group 2 mice were given high fat diet (HFD, and Group 3 mice were given high fat diet and treated with Pioglitazone (HFD+P. Body weight, length and level of blood sugar were measured weekly. Quantitative real-time PCR, fluorescence microscopy, and ELISA were performed to analyze the expression of CIDEC and PPAR-γ in visceral adipose tissue (VAT and subcutaneous adipose tissue (SAT. RESULTS: Body weight and length of mice increased gradually with time in all groups. Blood sugar in HFD mice started to increase significantly from the mid of late phase of obesity while pioglitazone attenuated blood sugar level in HFD+P mice. The mRNA expressions and protein levels of PPAR-γ and CIDEC genes started to increase in HFD mice as compared to ND mice and decreased gradually during the late phase of obesity in VAT. Pioglitazone enhanced the expression of PPAR-γ and CIDEC genes in HFD+P mice even during the late phase of obesity. CONCLUSION: It is insinuated that VAT is associated with late phase obesity CIDEC decrease and insulin resistance, while pioglitazone enhances CIDEC through activation of PPAR-γ, increases its expression, and decreases lipolysis, hence preventing an increase of blood sugar in mice exposed to HFD.

  3. Oleamide activates peroxisome proliferator-activated receptor gamma (PPARγ in vitro

    Directory of Open Access Journals (Sweden)

    Dionisi Mauro

    2012-05-01

    Full Text Available Abstract Background Oleamide (ODA is a fatty acid primary amide first identified in the cerebrospinal fluid of sleep-deprived cats, which exerts effects on vascular and neuronal tissues, with a variety of molecular targets including cannabinoid receptors and gap junctions. It has recently been reported to exert a hypolipidemic effect in hamsters. Here, we have investigated the nuclear receptor family of peroxisome proliferator-activated receptors (PPARs as potential targets for ODA action. Results Activation of PPARα, PPARβ and PPARγ was assessed using recombinant expression in Chinese hamster ovary cells with a luciferase reporter gene assay. Direct binding of ODA to the ligand binding domain of each of the three PPARs was monitored in a cell-free fluorescent ligand competition assay. A well-established assay of PPARγ activity, the differentiation of 3T3-L1 murine fibroblasts into adipocytes, was assessed using an Oil Red O uptake-based assay. ODA, at 10 and 50 μM, was able to transactivate PPARα, PPARβ and PPARγ receptors. ODA bound to the ligand binding domain of all three PPARs, although complete displacement of fluorescent ligand was only evident for PPARγ, at which an IC50 value of 38 μM was estimated. In 3T3-L1 cells, ODA, at 10 and 20 μM, induced adipogenesis. Conclusions We have, therefore, identified a novel site of action of ODA through PPAR nuclear receptors and shown how ODA should be considered as a weak PPARγ ligand in vitro.

  4. Expression of prostanoid receptors in human ductus arteriosus

    Science.gov (United States)

    Leonhardt, Andreas; Glaser, Alexander; Wegmann, Markus; Schranz, Dietmar; Seyberth, Hannsjörg; Nüsing, Rolf

    2003-01-01

    Prostaglandins play a major role in maintaining ductal patency in utero. Ductal tone is regulated by both locally released and circulating vasodilatory prostaglandins. In infants with ductus arteriosus-dependent congenital heart disease, ductal patency is maintained by intravenous administration of prostaglandin (PG) E1. Little information is available regarding the expression of prostaglandin receptors in man. By means of RT–PCR and immunohistochemistry we studied the expression of the PGI2 receptor (IP), the four different PGE2 receptors (EP1, EP2, EP3 and EP4), and the receptors for thromboxane (Tx) A2 (TP), PGD2 (DP) and PGF2α (FP) in the ductus arteriosus of three newborn infants with ductus arteriosus-dependent congenital heart disease and intravenous infusion of PGE1 and of one 8 month old child with a patent ductus arteriosus. The EP3, EP4, FP, IP and TP receptor were markedly expressed at the mRNA and protein level, whereas the EP2 receptor was weakly expressed and the EP1 receptor was detected in two out of four tissue specimens only. The DP receptor was not detected in any of the samples. The most pronounced expression, which was located in the media of the ductus arteriosus, was observed for the EP4 and TP receptors followed by IP and FP receptor protein. These data indicate that ductal patency during the infusion of PGE1 in infants with ductus arteriosus-dependent congenital heart disease might be mediated by the EP4 and IP receptor. The data further suggest that a heterogeneous population of prostanoid receptors may contribute to the regulation of ductus arteriosus tone in humans. PMID:12598419

  5. TLR4/MyD88/NF-κB signaling and PPAR-γ within the paraventricular nucleus are involved in the effects of telmisartan in hypertension

    Energy Technology Data Exchange (ETDEWEB)

    Li, Hong-Bao; Li, Xiang; Huo, Chan-Juan; Su, Qing; Guo, Jing [Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Health Science Center, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an 710061 (China); Yuan, Zu-Yi [Department of Cardiovascular Medicine, First Affiliated Hospital of Medical College of Xi' an Jiaotong University, Xi' an 710061 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Shi, Xiao-Lian, E-mail: shxl@mail.xjtu.edu.cn [Department of Pharmacology, School of Basic Medical Sciences, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Liu, Jin-Jun, E-mail: jupet@163.com [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Health Science Center, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an 710061 (China)

    2016-08-15

    Previous findings from our laboratory and others indicate that the main therapeutic effect of angiotensin II type 1 receptor (AT1-R) antagonists is to decrease blood pressure and exert anti-inflammatory effects in the cardiovascular system. In this study, we determined whether AT1-R antagonist telmisartan within the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and hypothalamic inflammation via both the TLR4/MyD88/NF-κB signaling pathway and peroxisome proliferator-activated receptor-γ (PPAR-γ) in the PVN in hypertensive rats. Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were treated for 4 weeks through bilateral PVN infusion with the AT1-R antagonist telmisartan (TEL, 10 μg/h), or losartan (LOS, 20 μg/h), or the PPAR-γ antagonist GW9662 (GW, 100 μg/h), or vehicle via osmotic minipump. Mean arterial pressure (MAP) was recorded by a tail-cuff occlusion method. PVN tissue and blood were collected for the measurement of AT1-R, PPAR-γ, pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6), inducible nitric oxide synthase (iNOS), TLR4, MyD88, nuclear factor-kappa B (NF-κB) activity and plasma norepinephrine (NE), respectively. Hypertensive rats exhibited significantly higher level of AT1-R and lower level of PPAR-γ in the PVN. PVN treatment with TEL attenuated MAP, improved cardiac hypertrophy, reduced TNF-α, IL-1β, IL-6, iNOS levels, and plasma NE in SHR but not in WKY rats. These results were associated with reduced TLR4, MyD88 and NF-κB levels and increased PPAR-γ level in the PVN of hypertensive rats. Our findings suggest that TLR4/MyD88/NF-κB signaling and PPAR-γ within the PVN are involved in the beneficial effects of telmisartan in hypertension. - Highlights: • PVN infusion of TEL in spontaneously hypertensive rats is reported. • PVN infusion of TEL attenuates hypertension and proinflammatory cytokines in PVN. • PVN blockade of AT1-R attenuates

  6. Telmisartan, a possible PPAR-δ agonist, reduces TNF-α-stimulated VEGF-C production by inhibiting the p38MAPK/HSP27 pathway in human proximal renal tubular cells

    Energy Technology Data Exchange (ETDEWEB)

    Kimura, Hideki, E-mail: hkimura@u-fukui.ac.jp [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan); Department of Clinical Laboratories and Nephrology, University of Fukui Hospital, Fukui (Japan); Mikami, Daisuke; Kamiyama, Kazuko [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan); Sugimoto, Hidehiro [Department of Clinical Laboratories and Nephrology, University of Fukui Hospital, Fukui (Japan); Kasuno, Kenji; Takahashi, Naoki [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan); Yoshida, Haruyoshi [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan); Division of Nephrology, Obama Municipal Hospital, Obama, Fukui (Japan); Iwano, Masayuki [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan)

    2014-11-14

    Highlights: • TNF-α increased VEGF-C expression by enhancing phosphorylation of p38MAPK and HSP27. • Telmisartan decreased TNF-α-stimulated expression of VEGF-C. • Telmisartan suppressed TNF-α-induced phosphorylation of p38MAPK and HSP27. • Telmisartan activated endogenous PPAR-δ protein. • Telmisartan suppressed p38MAPK phosphorylation in a PPAR-δ-dependent manner. - Abstract: Vascular endothelial growth factor-C (VEGF-C) is a main inducer of inflammation-associated lymphangiogenesis in various inflammatory disorders including chronic progressive kidney diseases, for which angiotensin II receptor type 1 blockers (ARBs) are widely used as the main treatment. Although proximal renal tubular cells may affect the formation of lymphatic vessels in the interstitial area by producing VEGF-C, the molecular mechanisms of VEGF-C production and its manipulation by ARB have not yet been examined in human proximal renal tubular epithelial cells (HPTECs). In the present study, TNF-α dose-dependently induced the production of VEGF-C in HPTECs. The TNF-α-induced production of VEGF-C was mediated by the phosphorylation of p38MAPK and HSP27, but not by that of ERK or NFkB. Telmisartan, an ARB that can activate the peroxisome proliferator-activated receptor (PPAR), served as a PPAR-δ activator and reduced the TNF-α-stimulated production of VEGF-C. This reduction was partially attributed to a PPAR-δ-dependent decrease in p38MAPK phosphorylation. Our results indicate that TNF-α induced the production of VEGF-C in HPTECs by activating p38MAPK/HSP27, and this was partially inhibited by telmisartan in a PPAR-δ dependent manner. These results provide a novel insight into inflammation-associated lymphangiogenesis.

  7. Topical Rosiglitazone Treatment Improves Ulcerative Colitis by Restoring Peroxisome Proliferator-Activated Receptor-gamma Activity

    DEFF Research Database (Denmark)

    Pedersen, G.; Brynskov, Jørn

    2010-01-01

    OBJECTIVES: Impaired epithelial expression of peroxisome proliferator-activated receptor-gamma (PPAR gamma) has been described in animal colitis models and briefly in patients with ulcerative colitis, but the functional significance in humans is not well defined. We examined PPAR gamma expression...

  8. Bezafibrate induces a mitochondrial derangement in human cell lines: a PPAR-independent mechanism for a peroxisome proliferator.

    Science.gov (United States)

    Scatena, R; Bottoni, P; Vincenzoni, F; Messana, I; Martorana, G E; Nocca, G; De Sole, P; Maggiano, N; Castagnola, M; Giardina, B

    2003-11-01

    Bezafibrate is a hypolipidemic drug that belongs to the group of peroxisome proliferators because it binds to peroxisome proliferator-activated receptors type alpha (PPARs). Peroxisome proliferators produce a myriad of extraperoxisomal effects, which are not necessarily dependent on their interaction with PPARs. An investigation on the peculiar activities of bezafibrate could clarify some of the molecular events and the relationship with the biochemical and pharmacological properties of this class of compounds. In this view, the human acute promyelocytic leukemia HL-60 cell line and human rabdomiosarcoma TE-671 cell line were cultured in media containing bezafibrate and a number of observations such as spectrophotometric analysis of mitochondrial respiratory chain enzymes, NMR metabolite determinations, phosphofructokinase enzymatic analysis, and differentiation assays were carried on. Bezafibrate induced a derangement of NADH cytochrome c reductase activity accompanied by metabolic alterations, mainly a shift to anaerobic glycolysis and an increase of fatty acid oxidation, as shown by NMR analysis of culture supernatants where acetate, lactate, and alanine levels increased. On the whole, the present results suggest a biochemical profile and a therapeutic role of this class of PPARs ligands more complex than those previously proposed.

  9. Gemfibrozil, a lipid lowering drug, inhibits the activation of primary human microglia via peroxisome proliferator-activated receptor β.

    Science.gov (United States)

    Jana, Malabendu; Pahan, Kalipada

    2012-08-01

    Microglial activation participates in the pathogenesis of various neuroinflammatory and neurodegenerative diseases. However, mechanisms by which microglial activation could be controlled are poorly understood. Peroxisome proliferator-activated receptors (PPAR) are transcription factors belonging to the nuclear receptor super family with diverse effect. This study underlines the importance of PPARβ/δ in mediating the anti-inflammatory effect of gemfibrozil, an FDA-approved lipid-lowering drug, in primary human microglia. Bacterial lipopolysachharides (LPS) induced the expression of various proinflammatory molecules and upregulated the expression of microglial surface marker CD11b in human microglia. However, gemfibrozil markedly suppressed proinflammatory molecules and CD11b in LPS-stimulated microglia. Human microglia expressed PPAR-β and -γ, but not PPAR-α. Interestingly, either antisense knockdown of PPAR-β or antagonism of PPAR-β by a specific chemical antagonist abrogated gemfibrozil-mediated inhibition of microglial activation. On the other hand, blocking of PPAR-α and -γ had no effect on gemfibrozil-mediated anti-inflammatory effect in microglia. These results highlight the fact that gemfibrozil regulates microglial activation by inhibiting inflammatory gene expression in a PPAR-β dependent pathway and further reinforce its therapeutic application in several neuroinflammatory and neurodegenerative diseases.

  10. Different populations of prostaglandin EP3 receptor-expressing preoptic neurons project to two fever-mediating sympathoexcitatory brain regions.

    Science.gov (United States)

    Nakamura, Y; Nakamura, K; Morrison, S F

    2009-06-30

    The central mechanism of fever induction is triggered by an action of prostaglandin E(2) (PGE(2)) on neurons in the preoptic area (POA) through the EP3 subtype of prostaglandin E receptor. EP3 receptor (EP3R)-expressing POA neurons project directly to the dorsomedial hypothalamus (DMH) and to the rostral raphe pallidus nucleus (rRPa), key sites for the control of thermoregulatory effectors. Based on physiological findings, we hypothesize that the febrile responses in brown adipose tissue (BAT) and those in cutaneous vasoconstrictors are controlled independently by separate neuronal pathways: PGE(2) pyrogenic signaling is transmitted from EP3R-expressing POA neurons via a projection to the DMH to activate BAT thermogenesis and via another projection to the rRPa to increase cutaneous vasoconstriction. In this case, DMH-projecting and rRPa-projecting neurons would constitute segregated populations within the EP3R-expressing neuronal group in the POA. Here, we sought direct anatomical evidence to test this hypothesis with a double-tracing experiment in which two types of the retrograde tracer, cholera toxin b-subunit (CTb), conjugated with different fluorophores were injected into the DMH and the rRPa of rats and the resulting retrogradely labeled populations of EP3R-immunoreactive neurons in the POA were identified with confocal microscopy. We found substantial numbers of EP3R-immunoreactive neurons in both the DMH-projecting and the rRPa-projecting populations. However, very few EP3R-immunoreactive POA neurons were labeled with both the CTb from the DMH and that from the rRPa, although a substantial number of neurons that were not immunoreactive for EP3R were double-labeled with both CTbs. The paucity of the EP3R-expressing neurons that send collaterals to both the DMH and the rRPa suggests that pyrogenic signals are sent independently to these caudal brain regions from the POA and that such pyrogenic outputs from the POA reflect different control mechanisms for BAT

  11. Arterial portography using prostaglandin E1

    International Nuclear Information System (INIS)

    Seo, Heung Suk; Kim, Hyung Sik; Lee, Seung Chul; Lee, Seung Ro; Hahm, Chang Kok; Kim, Jung Jin; Cho, Suk Shin

    1987-01-01

    A total of 110 arterial portographies via superior mesenteric artery were performed on 100 patients at Hanyang University Hospital in the past 2 years. There were 20 control portographies and 90 portographies using prostaglandin E 1 Twenty μg prostaglandin E 1 was injected for 30 seconds in the superior mesenteric artery 30 seconds before injection of contrast media. Both control and prostaglandin E 1 portograms were evaluated for quality of opacification and side effects of prostaglandin E 1 were recorded. The results were as follows; 1.The appearance time and optimal opacification time of the portal vein system were obtained approximately 6 seconds earlier in the prostaglandin E 1 portograms than in the control portograms. 2.The incidence of opacification of the intrahepatic portal veins was greater in the prostaglandin E 1 portograms than in the control portograms. 3.The main portal vein and intrahepatic portal veins were more clearly opacified in the prostaglandin... portograms than in the control portograms. 4.The prostaglandin E 1 portograms provided clearer and more detailed opacification of the portal vein system than the control portograms in the same patients. 5.There was a minimal decrease in blood pressure with a concomitant small rise in heart rate and mild abdominal pain following the prostaglandin E 1 injection. The authors found arterial portography using prostaglandin E 1 simple, safe and useful for clear and detailed visualization of the portal vein system

  12. Bone formation induced in an infant by systemic prostaglandin-E2 administration

    DEFF Research Database (Denmark)

    Jørgensen, H R; Svanholm, H; Høst, A

    1988-01-01

    We report a case of long-term systemic administration of prostaglandin E2 (PGE2) to a newborn infant with ductus-dependent congenital heart disease. After 46 days of treatment, radiography showed cortical hyperostosis of the long bones. The child died 62 days after discontinuation of prostaglandin...... treatment. Histologic examination of tubular bones showed hyperostosis presumably due to prostaglandin-induced rapid formation of primitive bone. The additional finding of extensive resorption of the outer cortical surface and bone formation at the inner surface suggested a reversible phase after...

  13. High Sugar Intake and Development of Skeletal Muscle Insulin Resistance and Inflammation in Mice: A Protective Role for PPAR-δ Agonism

    Directory of Open Access Journals (Sweden)

    Elisa Benetti

    2013-01-01

    Full Text Available Peroxisome Proliferator Activated Receptor (PPAR-δ agonists may serve for treating metabolic diseases. However, the effects of PPAR-δ agonism within the skeletal muscle, which plays a key role in whole-body glucose metabolism, remain unclear. This study aimed to investigate the signaling pathways activated in the gastrocnemius muscle by chronic administration of the selective PPAR-δ agonist, GW0742 (1 mg/kg/day for 16 weeks, in male C57Bl6/J mice treated for 30 weeks with high-fructose corn syrup (HFCS, the major sweetener in foods and soft-drinks (15% wt/vol in drinking water. Mice fed with the HFCS diet exhibited hyperlipidemia, hyperinsulinemia, hyperleptinemia, and hypoadiponectinemia. In the gastrocnemius muscle, HFCS impaired insulin and AMP-activated protein kinase signaling pathways and reduced GLUT-4 and GLUT-5 expression and membrane translocation. GW0742 administration induced PPAR-δ upregulation and improvement in glucose and lipid metabolism. Diet-induced activation of nuclear factor-κB and expression of inducible-nitric-oxide-synthase and intercellular-adhesion-molecule-1 were attenuated by drug treatment. These effects were accompanied by reduction in the serum concentration of interleukin-6 and increase in muscular expression of fibroblast growth factor-21. Overall, here we show that PPAR-δ activation protects the skeletal muscle against the metabolic abnormalities caused by chronic HFCS exposure by affecting multiple levels of the insulin and inflammatory cascades.

  14. The effect of PPAR-γ agonist on 18F-FDG uptake in tumor and macrophages and tumor cells

    International Nuclear Information System (INIS)

    Kim, Se-Lim; Kim, Eun-Mi; Cheong, Su-Jin; Lee, Chang-Moon; Kim, Dong Wook; Jeong, Hwan-Jeong; Lim, Seok Tae; Sohn, Myung-Hee; Yim, Chang Yeol

    2009-01-01

    Purpose: The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors, and its role in adipogenesis and glucose metabolism has been well established. PPAR-γ agonists have been shown to inhibit many cytokines and to have anti-inflammatory effects. In pathologic conditions, enhanced fluoro-2-deoxy-D-glucose (FDG) uptake is observed not only in malignant tumors but also in inflammatory lesions, and this uptake occurs through the glucose transporter in these cells. Thus, the present study was undertaken to investigate the potential of using PPAR-γ's glucose uptake ability as a diagnostic tool to differentiate between macrophage and tumor cells. Materials and Methods: Cellular uptake studies were carried out on macrophage and two tumor cell lines for comparison by using 18 F-FDG. Western blot analysis was performed to determine the expression levels of both the glucose transporter and hexokinase protein. To confirm the possibility of differentiation between tumor and inflammatory lesions using rosiglitazone based on in vitro studies, 18 F-FDG (3.7x10 6 Bq) uptake in A549 and RAW 264.7 xenograft mice was compared. Results: The cellular uptake study findings were quite different for macrophages and tumor cells. 18 F-FDG uptakes by macrophages decreased by about 60% but was increased twofold in tumor cells after rosiglitazone treatment. Moreover, the expressions of proteins related to glucose uptake correlated well with cellular glucose accumulation in both cell types. Higher tumor uptake was observed after the injection of rosiglitazone in A549 xenograft mice (1.58±0.55 to 4.66±1.16), but no significant change of 18 F-FDG uptake was shown in RAW 264.7 xenograft mice (4.04±1.16 to 4.00±0.14). Conclusion: The present study demonstrates the roles of PPAR-γ agonist on FDG uptake in macrophages and tumor cells in vitro and in vivo. Our findings suggest that rosiglitazone has the

  15. Gemfibrozil, a lipid-lowering drug, increases myelin genes in human oligodendrocytes via peroxisome proliferator-activated receptor-β.

    Science.gov (United States)

    Jana, Malabendu; Mondal, Susanta; Gonzalez, Frank J; Pahan, Kalipada

    2012-10-05

    An increase in CNS remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis. Earlier studies have shown that gemfibrozil, a lipid-lowering drug, has anti-inflammatory properties. The current study identified another novel property of gemfibrozil in stimulating the expression of myelin-specific genes (myelin basic protein, myelin oligodendrocyte glycoprotein, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, and proteolipid protein (PLP)) in primary human oligodendrocytes, mixed glial cells, and spinal cord organotypic cultures. Although gemfibrozil is a known activator of peroxisome proliferator-activated receptor-α (PPAR-α), we were unable to detect PPAR-α in either gemfibrozil-treated or untreated human oligodendrocytes, and gemfibrozil increased the expression of myelin genes in oligodendrocytes isolated from both wild type and PPAR-α(-/-) mice. On the other hand, gemfibrozil markedly increased the expression of PPAR-β but not PPAR-γ. Consistently, antisense knockdown of PPAR-β, but not PPAR-γ, abrogated the stimulatory effect of gemfibrozil on myelin genes in human oligodendrocytes. Gemfibrozil also did not up-regulate myelin genes in oligodendroglia isolated from PPAR-β(-/-) mice. Chromatin immunoprecipitation analysis showed that gemfibrozil induced the recruitment of PPAR-β to the promoter of PLP and myelin oligodendrocyte glycoprotein genes in human oligodendrocytes. Furthermore, gemfibrozil treatment also led to the recruitment of PPAR-β to the PLP promoter in vivo in the spinal cord of experimental autoimmune encephalomyelitis mice and suppression of experimental autoimmune encephalomyelitis symptoms in PLP-T cell receptor transgenic mice. These results suggest that gemfibrozil stimulates the expression of myelin genes via PPAR-β and that gemfibrozil, a prescribed drug for humans, may find further therapeutic use in demyelinating diseases.

  16. Association between PPAR-γ2 Pro12Ala genotype and insulin resistance is modified by circulating lipids in Mexican children

    Science.gov (United States)

    Stryjecki, Carolina; Peralta-Romero, Jesus; Alyass, Akram; Karam-Araujo, Roberto; Suarez, Fernando; Gomez-Zamudio, Jaime; Burguete-Garcia, Ana; Cruz, Miguel; Meyre, David

    2016-01-01

    The Pro12Ala (rs1801282) polymorphism in peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) has been convincingly associated with insulin resistance (IR) and type 2 diabetes (T2D) among Europeans, in interaction with a high-fat diet. Mexico is disproportionally affected by obesity and T2D however, whether the Pro12Ala polymorphism is associated with early metabolic complications in this population is unknown. We assessed the association of PPAR-γ2 Pro12Ala with metabolic traits in 1457 Mexican children using linear regression models. Interactions between PPAR-γ2 Pro12Ala and circulating lipids on metabolic traits were determined by adding an interaction term to regression models. We observed a high prevalence of overweight/obesity (49.2%), dyslipidemia (34.9%) and IR (11.1%). We detected nominally significant/significant interactions between lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol), the PPAR-γ2 Pro12Ala genotype and waist-to-hip ratio, fasting insulin, HOMA-IR and IR (9.30 × 10−4  ≤ Pinteraction ≤ 0.04). Post-hoc subgroup analyses evidenced that the association between the PPAR-γ2 Pro12Ala genotype and fasting insulin, HOMA-IR and IR was restricted to children with total cholesterol or LDL-cholesterol values higher than the median (0.02 ≤ P ≤ 0.03). Our data support an association of the Pro12Ala polymorphism with IR in Mexican children and suggest that this relationship is modified by dyslipidemia. PMID:27075119

  17. Role of prostaglandins in spinal transmission of the exercise pressor reflex in decerebrated rats.

    Science.gov (United States)

    Stone, A J; Copp, S W; Kaufman, M P

    2014-09-26

    Previous studies found that prostaglandins in skeletal muscle play a role in evoking the exercise pressor reflex; however the role played by prostaglandins in the spinal transmission of the reflex is not known. We determined, therefore, whether or not spinal blockade of cyclooxygenase (COX) activity and/or spinal blockade of endoperoxide (EP) 2 or 4 receptors attenuated the exercise pressor reflex in decerebrated rats. We first established that intrathecal doses of a non-specific COX inhibitor Ketorolac (100 μg in 10 μl), a COX-2-specific inhibitor Celecoxib (100 μg in 10 μl), an EP2 antagonist PF-04418948 (10 μg in 10 μl), and an EP4 antagonist L-161,982 (4 μg in 10 μl) effectively attenuated the pressor responses to intrathecal injections of arachidonic acid (100 μg in 10 μl), EP2 agonist Butaprost (4 ng in 10 μl), and EP4 agonist TCS 2510 (6.25 μg in 2.5 μl), respectively. Once effective doses were established, we statically contracted the hind limb before and after intrathecal injections of Ketorolac, Celecoxib, the EP2 antagonist and the EP4 antagonist. We found that Ketorolac significantly attenuated the pressor response to static contraction (before Ketorolac: 23 ± 5 mmHg, after Ketorolac 14 ± 5 mmHg; preflex, and that the spinal prostaglandins produced by this enzyme are most likely activating spinal EP4 receptors, but not EP2 receptors. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. Hesperidin produces cardioprotective activity via PPAR-γ pathway in ischemic heart disease model in diabetic rats.

    Directory of Open Access Journals (Sweden)

    Yogeeta O Agrawal

    Full Text Available The present study investigated the effect of hesperidin, a natural flavonoid, in cardiac ischemia and reperfusion (I/R injury in diabetic rats. Male Wistar rats with diabetes were divided into five groups and were orally administered saline once daily (IR-sham and IR-control, Hesperidin (100 mg/kg/day; IR-Hesperidin, GW9962 (PPARreceptor antagonist, or combination of both for 14 days. On the 15th day, in the IR-control and IR-treatment groups, rats were subjected to left anterior descending (LAD coronary artery occlusion for 45 minutes followed by a one-hour reperfusion. Haemodynamic parameters were recorded and rats were sacrificed; hearts were isolated for biochemical, histopathological, ultrastructural and immunohistochemistry. In the IR-control group, significant ventricular dysfunctions were observed along with enhanced expression of pro-apoptotic protein Bax. A decline in cardiac injury markers lactate dehydrogenase activity, CK-MB and increased content of thiobarbituric acid reactive substances, a marker of lipid peroxidation, and TNF-α were observed. Hesperidin pretreatment significantly improved mean arterial pressure, reduced left ventricular end-diastolic pressure, and improved both inotropic and lusitropic function of the heart (+LVdP/dt and -LVdP/dt as compared to IR-control. Furthermore, hesperidin treatment significantly decreased the level of thiobarbituric acid reactive substances and reversed the activity of lactate dehydrogenase towards normal value. Hesperidin showed anti-apoptotic effects by upregulating Bcl-2 protein and decreasing Bax protein expression. Additionally, histopathological and ultrastructural studies reconfirmed the protective action of hesperidin. On the other hand, GW9662, selective PPARreceptor antagonist, produced opposite effects and attenuated the hesperidin induced improvements. The study for the first time evidence the involvement of PPAR-γ pathway in the cardioprotective activity of

  19. Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats

    International Nuclear Information System (INIS)

    Boberg, Julie; Metzdorff, Stine; Wortziger, Rasmus; Axelstad, Marta; Brokken, Leon; Vinggaard, Anne Marie; Dalgaard, Majken; Nellemann, Christine

    2008-01-01

    Endocrine disrupting chemicals can induce malformations and impairment of reproductive function in experimental animals and may have similar effects in humans. Recently, the environmental obesogen hypothesis was proposed, suggesting that environmental chemicals contribute to the development of obesity and insulin resistance. These effects could be related to chemical interaction with nuclear receptors such as the peroxisome proliferator activated receptors (PPARs). As several testosterone-reducing drugs are PPAR activators, we aimed to examine whether four PPAR agonists were able to affect fetal testosterone production and masculinization of rats. Additionally, we wished to examine whether these chemicals affected fetal plasma levels of insulin and leptin, which play important roles in the developmental programming of the metabolic system. Pregnant Wistar rats were exposed from gestation day (GD) 7-21 to diisobutyl phthalate (DiBP), butylparaben, perfluorooctanoate, or rosiglitazone (600, 100, 20, or 1 mg/kg bw/day, respectively). Endocrine endpoints were studied in offspring at GD 19 or 21. DiBP, butylparaben and rosiglitazone reduced plasma leptin levels in male and female offspring. DiBP and rosiglitazone additionally reduced fetal plasma insulin levels. In males, DiBP reduced anogenital distance, testosterone production and testicular expression of Insl-3 and genes related to steroidogenesis. PPARα mRNA levels were reduced by DiBP at GD 19 in testis and liver. In females, DiBP increased anogenital distance and increased ovarian aromatase mRNA levels. This study reveals new targets for phthalates and parabens in fetal male and female rats and contributes to the increasing concern about adverse effects of human exposure to these compounds

  20. Genotyping of PPAR-γ gene polymorphism in Egyptian neonates affected with sepsis disease and its severity

    Directory of Open Access Journals (Sweden)

    Rabah M. Shawky

    2018-07-01

    Full Text Available Background: Peroxisome Proliferator-Activated Receptor gamma (PPARγ is a ligand-dependent transcription factor involved in inflammatory process. PPAR-γ gene was mentioned as having a modulating role in the pathological status of sepsis.The present study aimed to make a correlation between The Pro12Ala polymorphism in PPAR-γ gene and occurrence of neonatal sepsis and its severity among a sample of Egyptian neonates suffering sepsis. Subjects and methods: This case-control study included 30 neonates (11 females and19 males newly admitted with neonatal sepsis at the intensive care unit (NICU (mean age 10.3 days ± 6.23. The control group included 50 age and sex matched neonates (23 females and 27 males (mean age 10.20 days ± 5.36 days. All the neonates (preterm and full term included were with clinical signs and laboratory data consistent with neonatal sepsis. Genotyping for PPARγ gene region harboring the Pro12Ala variant locus were carried out using Tetra ARMS technique. Results: About 56.7% of the patients group was homozygote (GG for polymorphic locus (coding for Alanine/Alanine while 30% was heterozygote for polymorphic locus (CG (coding for Proline/Alanine and up to 13.3% was homozygote for the polymorphic locus (CC (coding for Proline/Proline. Compared to the control group where homozygotes for CC were the most prevalent (90% and the CG were 10% with absence of GG genotypes. There was a strong statistical significant difference between patients and the normal control group as regards prevalence of PPAR-γ gene polymorphism in occurrence of neonatal sepsis and its severity. Also, there were strong relation between genotype GG and low birth weight, neonatal fever, prematurity and depressed neonatal reflexes. Conclusion: PPAR-γ gene has been suggested to be a candidate gene for neonatal sepsis. Therefore, Pro12Ala polymorphism might be useful in predicting the risk factor of neonatal sepsis and its severity. Keywords: Sepsis, PPAR

  1. Molecular Recognition of PPAR gamma by Kinase Cdk5/p25: Insights from a Combination of Protein-Protein Docking and Adaptive Biasing Force Simulations

    NARCIS (Netherlands)

    Mottin, Melina; Telles de Souza, Paulo C; Skaf, Munir S

    2015-01-01

    The peroxisome proliferator-activated receptor gamma (PPAR gamma) is an important transcription factor that plays a major role in the regulation of glucose and lipid metabolisms and has, therefore, many implications in modern-life metabolic disorders such as diabetes, obesity, and cardiovascular

  2. Prostaglandin D2 Inhibits Hair Growth and Is Elevated in Bald Scalp of Men with Androgenetic Alopecia

    Science.gov (United States)

    Garza, Luis A.; Liu, Yaping; Yang, Zaixin; Alagesan, Brinda; Lawson, John A.; Norberg, Scott M.; Loy, Dorothy E.; Zhao, Tailun; Blatt, Hanz B.; Stanton, David C.; Carrasco, Lee; Ahluwalia, Gurpreet; Fischer, Susan M.; FitzGerald, Garret A.; Cotsarelis, George

    2012-01-01

    Testosterone is necessary for the development of male pattern baldness, known as androgenetic alopecia (AGA); yet, the mechanisms for decreased hair growth in this disorder are unclear. We show that prostaglandin D2 synthase (PTGDS) is elevated at the mRNA and protein levels in bald scalp compared to haired scalp of men with AGA. The product of PTGDS enzyme activity, prostaglandin D2 (PGD2), is similarly elevated in bald scalp. During normal follicle cycling in mice, Ptgds and PGD2 levels increase immediately preceding the regression phase, suggesting an inhibitory effect on hair growth. We show that PGD2 inhibits hair growth in explanted human hair follicles and when applied topically to mice. Hair growth inhibition requires the PGD2 receptor G protein (heterotrimeric guanine nucleotide)–coupled receptor 44 (GPR44), but not the PGD2 receptor 1 (PTGDR). Furthermore, we find that a transgenic mouse, K14-Ptgs2, which targets prostaglandin-endoperoxide synthase 2 expression to the skin, demonstrates elevated levels of PGD2 in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA. These results define PGD2 as an inhibitor of hair growth in AGA and suggest the PGD2-GPR44 pathway as a potential target for treatment. PMID:22440736

  3. Gemfibrozil, a Lipid-lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-activated Receptor-β*

    Science.gov (United States)

    Jana, Malabendu; Mondal, Susanta; Gonzalez, Frank J.; Pahan, Kalipada

    2012-01-01

    An increase in CNS remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis. Earlier studies have shown that gemfibrozil, a lipid-lowering drug, has anti-inflammatory properties. The current study identified another novel property of gemfibrozil in stimulating the expression of myelin-specific genes (myelin basic protein, myelin oligodendrocyte glycoprotein, 2′,3′-cyclic-nucleotide 3′-phosphodiesterase, and proteolipid protein (PLP)) in primary human oligodendrocytes, mixed glial cells, and spinal cord organotypic cultures. Although gemfibrozil is a known activator of peroxisome proliferator-activated receptor-α (PPAR-α), we were unable to detect PPAR-α in either gemfibrozil-treated or untreated human oligodendrocytes, and gemfibrozil increased the expression of myelin genes in oligodendrocytes isolated from both wild type and PPAR-α(−/−) mice. On the other hand, gemfibrozil markedly increased the expression of PPAR-β but not PPAR-γ. Consistently, antisense knockdown of PPAR-β, but not PPAR-γ, abrogated the stimulatory effect of gemfibrozil on myelin genes in human oligodendrocytes. Gemfibrozil also did not up-regulate myelin genes in oligodendroglia isolated from PPAR-β(−/−) mice. Chromatin immunoprecipitation analysis showed that gemfibrozil induced the recruitment of PPAR-β to the promoter of PLP and myelin oligodendrocyte glycoprotein genes in human oligodendrocytes. Furthermore, gemfibrozil treatment also led to the recruitment of PPAR-β to the PLP promoter in vivo in the spinal cord of experimental autoimmune encephalomyelitis mice and suppression of experimental autoimmune encephalomyelitis symptoms in PLP-T cell receptor transgenic mice. These results suggest that gemfibrozil stimulates the expression of myelin genes via PPAR-β and that gemfibrozil, a prescribed drug for humans, may find further therapeutic use in demyelinating diseases. PMID:22879602

  4. Effect of folic acid and vitamin B12 on the expression of PPAR?, caspase-3 and caspase-8 mRNA in the abdominal aortas of rats with hyperlipidemia

    OpenAIRE

    LV, FENG-HUA; GAO, JIAN-ZHI; TENG, QING-LEI; ZHANG, JIN-YING

    2013-01-01

    Hyperlipidemia may lead to endothelial injury, due to its effects on homocysteine and vascular endothelial growth factor in the serum, and the mRNA expression levels of peroxisome proliferator-activated receptor-? (PPAR?), and caspase-3 and -8 in the vascular wall. In order to prevent and mitigate the high-fat state that results from endothelial injury, this study examined the effect of folic acid (FA) and vitamin B12 (VB12) on the expression of PPAR? and caspase-3 and -8 mRNA in the abdomina...

  5. Radiation-induced changes in production of prostaglandins Fsub(2α), E, and thromboxane B2 in guinea pig parenchymal lung tissues

    International Nuclear Information System (INIS)

    Steel, L.K.; Catravas, G.N.

    1982-01-01

    At 1 hour to 4 days after unilateral exposure of guinea pigs to a single dose (0.5, 1.5, or 3.0 Gy) of gamma-radiation, changes were detected in prostaglandin and thromboxane concentrations in parenchymal lung tissues. At 1-3 hours after exposure, tissue levels of PGFsub(2α), PGE, and thromboxane B 2 were significantly elevated in animals receiving 3.0 Gy, with the magnitude of alteration revealing a radiation dose effect. By 24 hours, tissue prostaglandin and thromboxane levels returned to near control values. Lung tissue synthesis of prostaglandins in response to H-1 receptor stimulation by the exogenous addition of histamine revealed similar radiation dose effects. The carboxylic acid ionophore A23187, exogenously applied to lung tissues, revealed a transient peak of increased sensitivity to ionophore stimulation for TxB 2 synthesis at 24 hours and for PGFsub(2α) at 72 hours post-irradiation. The data suggest that significant alterations in prostaglandin and thromboxane concentrations in parenchymal lung tissues occur following irradiation, in a dose-dependent manner, and that altered responsiveness to H-1 receptor stimulation and divalent cation transport also occur

  6. Peroxisome Proliferator-Activated Receptor Genetic Polymorphisms and Nonalcoholic Fatty Liver Disease: Any Role in Disease Susceptibility?

    Directory of Open Access Journals (Sweden)

    Paola Dongiovanni

    2013-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD defines a wide spectrum of liver diseases that extend from simple steatosis, that is, increased hepatic lipid content, to nonalcoholic steatohepatitis (NASH, a condition that may progress to cirrhosis with its associated complications. Nuclear hormone receptors act as intracellular lipid sensors that coordinate genetic networks regulating lipid metabolism and energy utilization. This family of transcription factors, in particular peroxisome proliferator-activated receptors (PPARs, represents attractive drug targets for the management of NAFLD and NASH, as well as related conditions such as type 2 diabetes and the metabolic syndrome. The impact on the regulation of lipid metabolism observed for PPARs has led to the hypothesis that genetic variants within the human PPARs genes may be associated with human disease such as NAFLD, the metabolic syndrome, and/or coronary heart disease. Here we review the available evidence on the association between PPARs genetic polymorphism and the susceptibility to NAFLD and NASH, and we provide a meta-analysis of the available evidence. The impact of PPAR variants on the susceptibility to NASH in specific subgroup of patients, and in particular on the response to therapies, especially those targeting PPARs, represents promising new areas of investigation.

  7. Prostaglandin E2 EP2 Receptor Deletion Attenuates Intracerebral Hemorrhage-Induced Brain Injury and Improves Functional Recovery

    Directory of Open Access Journals (Sweden)

    Jenna L. Leclerc

    2015-04-01

    Full Text Available Intracerebral hemorrhage (ICH is a devastating type of stroke characterized by bleeding into the brain parenchyma and secondary brain injury resulting from strong neuroinflammatory responses to blood components. Production of prostaglandin E2 (PGE2 is significantly upregulated following ICH and contributes to this inflammatory response in part through its E prostanoid receptor subtype 2 (EP2. Signaling through the EP2 receptor has been shown to affect outcomes of many acute and chronic neurological disorders; although, not yet explored in the context of ICH. Wildtype (WT and EP2 receptor knockout (EP2−/− mice were subjected to ICH, and various anatomical and functional outcomes were assessed by histology and neurobehavioral testing, respectively. When compared with age-matched WT controls, EP2−/− mice had 41.9 ± 4.7% smaller ICH-induced brain lesions and displayed significantly less ipsilateral hemispheric enlargement and incidence of intraventricular hemorrhage. Anatomical outcomes correlated with improved functional recovery as identified by neurological deficit scoring. Histological staining was performed to begin investigating the mechanisms involved in EP2-mediated neurotoxicity after ICH. EP2−/− mice exhibited 45.5 ± 5.8% and 41.4 ± 8.1% less blood and ferric iron accumulation, respectively. Furthermore, significantly less striatal and cortical microgliosis, striatal and cortical astrogliosis, blood–brain barrier breakdown, and peripheral neutrophil infiltration were seen in EP2−/− mice. This study is the first to suggest a deleterious role for the PGE2-EP2 signaling axis in modulating brain injury, inflammation, and functional recovery following ICH. Targeting the EP2 G protein-coupled receptor may represent a new therapeutic avenue for the treatment of hemorrhagic stroke.

  8. High expression of liver histone deacetylase 3 contributes to high-fat-diet-induced metabolic syndrome by suppressing the PPAR-γ and LXR-α-pathways in E3 rats.

    Science.gov (United States)

    Li, Dongmin; Wang, Xuan; Ren, Wuchao; Ren, Juan; Lan, Xi; Wang, Feimiao; Li, Hongmin; Zhang, Fujun; Han, Yan; Song, Tianbao; Holmdahl, Rikard; Lu, Shemin

    2011-09-15

    In the previous experiment, we found that there was a different response between E3 rats and DA.1U rats to high-fat-diet-induced metabolic syndrome (HFD-MetS). The aim of this study was to explore the cause and molecular mechanism of the genetic difference in susceptibility to metabolic syndrome in E3 rats as compared with DA.1U rats. Firstly, a 12-week HFD-MetS model in E3 and DA.1U rats was carried out and assessed. Then, the expression of key insulin signaling molecules, metabolic nuclear receptors, metabolic key enzymes and histone deacetylases (Hdacs) was determined by different methods. Finally, the effects of overexpression and disruption of Hdac3 on metabolic nuclear receptors were analyzed in CBRH-7919 cells and primarily-hepatic cells from DA.1U and E3 rats. We found that E3 rats were susceptible, while DA.1U rats were resisted to HFD-MetS. The expression of liver X receptor α,β (LXR-α,β), farnesoid X receptor (FXR), peroxisome proliferator activated receptor γ (PPAR-γ) and cholesterol 7α-hydroxylase (CYP7A1) increased markedly in DA.1U rat liver, whereas they decreased significantly in E3 rats. The expression of Hdac3 increased by HFD treatment in both E3 and DA.1U rat livers, but the constitutive Hdac3 expression was lower in DA.IU rat liver than in E3 rat liver. Importantly, overexpression of Hdac3 could downregulate the expression of LXR-α, PPAR-γ and CYP7A1 in both CBRH-7919 cells and primarily cultured hepatic cells from DA.IU rats. On the contrary, disruption of Hdac3 by shRNA upregulated the expression of LXR-α, PPAR-γ and CYP7A1 in both CBRH-7919 cells and primarily cultured hepatic cells from E3 rats. The results suggested that a high constitutive expression of Hdac3 inhibiting the expression of PPAR-γ, LXR-α and CYP7A1 in liver contributes to HFD-MetS in E3 rats. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  9. Effects of the PPAR-β agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination

    Directory of Open Access Journals (Sweden)

    Honegger Paul

    2009-05-01

    Full Text Available Abstract Background Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS. Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-γ (IFN-γ and lipopolysaccharide (LPS. Peroxisome proliferator-associated receptor (PPAR pathways are involved in the control of the inflammatory processes, and PPAR-β seems to play an important role in the regulation of central inflammation. In addition, PPAR-β agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE, an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-β agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-γ and LPS. Methods Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-γ and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG. The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, inducible NO synthase (i-NOS, PPAR-β, PPAR-γ, glial fibrillary acidic protein (GFAP, myelin basic protein (MBP, and high molecular weight neurofilament protein (NF-H. GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4 and ED1 labeling. Results GW 501516 decreased the IFN-γ-induced up-regulation of TNF-α and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-β agonist. However, it increased IL

  10. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor.

    Science.gov (United States)

    Göttlicher, M; Widmark, E; Li, Q; Gustafsson, J A

    1992-01-01

    Peroxisome proliferators such as clofibric acid, nafenopin, and WY-14,643 have been shown to activate PPAR (peroxisome proliferator-activated receptor), a member of the steroid nuclear receptor superfamily. We have cloned the cDNA from the rat that is homologous to that from the mouse [Issemann, I. & Green, S. (1990) Nature (London) 347, 645-650], which encodes a 97% similar protein with a particularly well-conserved putative ligand-binding domain. To search for physiologically occurring activators, we established a transcriptional transactivation assay by stably expressing in CHO cells a chimera of rat PPAR and the human glucocorticoid receptor that activates expression of the placental alkaline phosphatase reporter gene under the control of the mouse mammary tumor virus promoter. Testing of compounds related to lipid metabolism or peroxisomal proliferation revealed that 150 microM concentrations of arachidonic or linoleic acid but not of dehydroepiandrosterone, cholesterol, or 25-hydroxy-cholesterol, activate the receptor chimera. In addition, saturated fatty acids induce the reporter gene. Shortening the chain length to n = 6 or introduction of an omega-terminal carboxylic group abolished the activation potential of the fatty acid. In conclusion, the present results indicate that fatty acids can regulate gene expression mediated by a member of the steroid nuclear receptor superfamily. Images PMID:1316614

  11. Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-{gamma}-dependent activity

    Energy Technology Data Exchange (ETDEWEB)

    Toyama, Kensuke; Nakamura, Taishi; Kataoka, Keiichiro [Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan); Yasuda, Osamu [Department of Cardiovascular Clinical and Translational Research, Kumamoto University Hospital, Kumamoto (Japan); Fukuda, Masaya; Tokutomi, Yoshiko; Dong, Yi-Fei [Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan); Ogawa, Hisao [Department of Cardiovascular Medicine, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan); Kim-Mitsuyama, Shokei, E-mail: kimmitsu@gpo.kumamoto-u.ac.jp [Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan)

    2011-07-08

    Highlights: {yields} Telmisartan, an angiotensin receptor blocker, acts as a partial PPAR{gamma} agonist. {yields} The protective effects of telmisartan against diabetic vascular injury were associated with attenuation of vascular NF{kappa}B activation and TNF {alpha}. {yields} PPAR{gamma} activity of telmisartan was involved in the normalization of vascular PPAR{gamma} downregulation in diabetic mice. {yields} We provided the first evidence indicating that PPAR{gamma} activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. -- Abstract: Experimental and clinical data support the notion that peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) activation is associated with anti-atherosclerosis as well as anti-diabetic effect. Telmisartan, an angiotensin receptor blocker (ARB), acts as a partial PPAR{gamma} agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPAR{gamma} activation. We compared the effects of telmisartan, telmisartan combined with GW9662 (a PPAR{gamma} antagonist), and losartan with no PPAR{gamma} activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NF{kappa}B) activation and tumor necrosis factor {alpha}. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPAR{gamma} activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation of

  12. Combination Therapy of PPAR Ligands and Inhibitors of Arachidonic Acid in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jordi Tauler

    2008-01-01

    Full Text Available Lung cancer is the leading cause of cancer death in the United States and five-year survival remains low. Numerous studies have shown that chronic inflammation may lead to progression of carcinogenesis. As a result of inflammatory stimulation, arachidonic acid (AA metabolism produces proliferation mediators through complex and dynamic interactions of the products of the LOX/COX enzymes. One important mediator in the activation of the AA pathways is the nuclear protein PPAR. Targeting LOX/COX enzymes and inducing activation of PPAR have resulted in significant reduction of cell growth in lung cancer cell lines. However, specific COX-inhibitors have been correlated with an increased cardiovascular risk. Clinical applications are still being explored with a novel generation of dual LOX/COX inhibitors. PPAR activation through synthetic ligands (TZDs has revealed a great mechanistic complexity since effects are produced through PPAR-dependent and -independent mechanisms. Furthermore, PPAR could also be involved in regulation of COX-2. Overexpression of PPAR has reported to play a role in control of invasion and differentiation. Exploring the function of PPAR, in this new context, may provide a better mechanistic model of its role in cancer and give an opportunity to design a more efficient therapeutic approach in combination with LOX/COX inhibitors.

  13. Expression of Peroxisomes-Proliferate Activated Receptors-γ in Diabetics, Obese and Normal Subjects

    International Nuclear Information System (INIS)

    Afzal, N.

    2016-01-01

    Background: Current research in type 2 diabetes mellitus focuses on the role of Peroxisome-Proliferator Activated Receptors (PPARs) in the pathogenesis of the Insulin Resistance Syndrome (IRS), which are pre-diabetic lesion and the hallmark of fully developed type 2 diabetes mellitus. This study aims at identifying the abnormal status of the PPAR-g in adipose tissues of type 2 diabetes mellitus patients, when compared with matched normal controls. Methods: This cross-sectional study was conducted in Ayub Medical College, Abbottabad, from 2012 to 2014. Sample included three equal groups of patients. Group-1 with diagnosed type 2 diabetes mellitus, aged 40-65 years, acting as the test group, Group-2 included non-diabetic obese, and Group-3 with normal subjects. Transcription Factor Assay for Peroxisome Proliferator Activated Receptor Gamma (gamma PPAR) was done on ELISA Technique from Nuclear Extract procured from Adipose Tissue of the subjects. Results: Mean age of enrolled participants was 48.93 SD±6.52.years. Patients ranged between ages of 40 years to 67 years. The mean values of PPAR in normal, obese and diabetic group were 1.72 SD±0.28, 1.282 SE±0.18 and 1.283 SE±0.18 respectively. The difference in mean values of PPAR was significant ρ<0.05. Conclusion: The levels of PPAR-g in patients with type 2 Diabetes Mellitus and Obese cases are significantly lower than normal controls. (author)

  14. Association of Pro12Ala polymorphism of PPAR-γ2 Gene and diabetic retinopathy in type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Yong-Qing Liu

    2013-06-01

    Full Text Available AIM: To observe the relationship between Prol2Ala polymorphism of peroxisome proliferator activated receptor-γ2(PPAR-γ2gene and diabetic retinopathy(DRwith type 2 diabetic mellitus(T2DMof the Han nationality in Shanxi province. METHODS: Totally 90 patients with T2DM were selected into our research, who were at the age of 40 to 70 years old, diabetic duration from 10 to 20 years, blood pressure PPAR-γ2 gene were determined by polymerase chain reaction-restriction fragment length polymorphisms(PCR-RFLPassay in all the patients. RESULTS: PCR results showed that there were 2 alleles and 3 genotypes in the groups. The frequency of genotype PP, PA, AA were 40.0%, 53.3%, 6.7% in NDR group, 70.0%, 30.0%, 0.0% in BDR group, 76.7%, 23.3%, 0% in PDR group, respectively. The allele frequency(χ2=10.208and gene frequency(χ2=10.351were statistically significant(PCONCLUSION: The alanine variant of Prol2Ala polymorphism of PPAR-γ2 gene is associated with DR in type 2 diabetes among the Hans in Shanxi area, and the Ala allele might be a protective factor for the development of diabetic retinopathy.

  15. Misoprostol inhibits gastric mucosal release of endogenous prostaglandin E2 and thromboxane B2 in healthy volunteers

    DEFF Research Database (Denmark)

    Mertz-Nielsen, A; Eskerod, O; Bukhave, K

    1995-01-01

    Prostaglandin analogues of the E-series theoretically offer the ideal antiulcer drugs. Peptic ulcer healing with prostaglandin analogues is, however, no better than would be predicted from their ability to inhibit gastric acid secretion and they are less effective than histamine H2 receptor...... antagonists in preventing ulcer relapse. It could be that prostaglandin analogues inhibit gastric mucosal synthesis or release of endogenous eicosanoids, thereby abrogating their own effects. This study, therefore, examined how a single therapeutic dose (200 micrograms) of misoprostol, a synthetic analogue...... blind, cross over design. In each subject misoprostol or placebo was instilled in randomised order into the stomach, which was subsequently perfused with isotonic mannitol. Misoprostol significantly decreased basal as well as acid stimulated output of PGE2 and TXB2, without affecting output of LTB4...

  16. PPAR-γ Silencing Inhibits the Apoptosis of A549 Cells by Upregulating Bcl-2

    Directory of Open Access Journals (Sweden)

    Jingyu YANG

    2013-03-01

    Full Text Available Background and objective Drug resistance is the one of primary causes of death in patients with lung cancer, PPAR-γ could induce the apoptosis and reverse drug resistance. The aim of this study is to investigate the expression of PPAR-γ on cisplatin sensitivity and apoptosis response of human lung cancer cell line A549. Methods Reconstruction of PPAR-γ silencing A549 cells (A549/PPAR-γ(- by siRNA. MTT assay was employed to determine the effect of cisplatin on the proliferation of A549/PPAR-γ(-, flow cytometry to determine the effect of cisplatin on the cell apoptosis, Western blot to determine the change of phosphorylation of Akt, caspase-3 and expression of bcl-2/bax. Finally, RT-PCR was employed to determine the transcriptional level of bcl-2. Results Two PPAR-γ silencing A549 cell clones were established successfully, and the expression of PPAR-γ was downregulated significantly as confirmed by RT-PCR and Western blot. After PPAR-γ silencing, the resistance of these two A549 clones to cisplatin was increased by 1.29-fold and 1.60-fold respectively. Flow cytometry showed that the apoptosis rate was decreased, and Western Blot showed that the phosphorylation of Akt and expression of bcl-2/bax were upregulated, caspase-3 was downregulated. Finally, RT-PCR showed that the transcriptional level of bcl-2 was upregulated as well. Conclusion Downregulation of PPAR-γ in A549 cells led to increase of cisplatin resistance. One of the mechanisms was upregulatin of phosphorylation of Akt and expression of bcl-2, which inhibited the apoptosis of cells. The downregulation of PPAR-γ is a possible mechanism that leads to the clinical drug resistance of cancer.

  17. Catalposide is a natural agonistic ligand of peroxisome proliferator-activated receptor-{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ji Hae; Jun, Hee-jin; Hoang, Minh-Hien; Jia, Yaoyao [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Han, Xiang Hua [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Dong-Ho [Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Lee, Hak-Ju [Division of Green Business Management, Department of Forest Resources Utilization, Korean Forest Research Institute, Seoul 130-712 (Korea, Republic of); Hwang, Bang Yeon, E-mail: byhwang@chungbuk.ac.kr [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Sung-Joon, E-mail: junelee@korea.ac.kr [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer Catalposide is a novel ligand for PPAR{alpha}. Black-Right-Pointing-Pointer Cell stimulated with catalposide improved fatty acid uptake, regulated target genes in fatty acid {beta}-oxidation and synthesis. Black-Right-Pointing-Pointer Catalposdie reduces hepatic triacylglycerides. Black-Right-Pointing-Pointer Theses demonstrate catalposide could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: Peroxisome proliferator-activated receptor-alpha (PPAR{alpha}) is a nuclear receptor that regulates the expression of genes related to cellular lipid uptake and oxidation. Thus, PPAR{alpha} agonists may be important in the treatment of hypertriglyceridemia and hepatic steatosis. In this study, we demonstrated that catalposide is a novel natural PPAR{alpha} agonist, identified from reporter gene assay-based activity screening with approximately 900 natural plant and seaweed extracts. Results of time-resolved fluorescence resonance energy transfer analyses suggested that the compound interacted directly with the ligand-binding domain of PPAR{alpha}. Cultured hepatocytes stimulated with catalposide exhibited significantly reduced cellular triglyceride concentrations, by 21%, while cellular uptake of fatty acids was increased, by 70% (P < 0.05). Quantitative PCR analysis revealed that the increase in cellular fatty acid uptake was due to upregulation of fatty acid transporter protein-4 (+19% vs. the control) in cells stimulated with catalposide. Additionally, expression of genes related to fatty acid oxidation and high-density lipoprotein metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed. In conclusion, catalposide is hypolipidemic by activation of PPAR{alpha} via a ligand-mediated mechanism that modulates the expression of in lipid metabolism genes in hepatocytes.

  18. Peroxisome Proliferator-Activated Receptor-alpha Gene Level Differently Affects Lipid Metabolism and Inflammation in Apolipoprotein E2 Knock-In Mice

    NARCIS (Netherlands)

    Lalloyer, Fanny; Wouters, Kristiaan; Baron, Morgane; Caron, Sandrine; Vallez, Emmanuelle; Vanhoutte, Jonathan; Bauge, Eric; Shiri-Sverdlov, Ronit; Hofker, Marten; Staels, Bart; Tailleux, Anne

    Objective-Peroxisome proliferator-activated receptor-alpha (PPAR alpha) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPAR alpha is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence

  19. Radiation-induced changes in production of prostaglandins Fsub(2. cap alpha. ), E, and thromboxane B/sub 2/ in guinea pig parenchymal lung tissues

    Energy Technology Data Exchange (ETDEWEB)

    Steel, L K; Catravas, G N [Armed Forces Radiobiology Research Inst., Bethesda, MD (USA)

    1982-11-01

    At 1 hour to 4 days after unilateral exposure of guinea pigs to a single dose (0.5, 1.5, or 3.0 Gy) of gamma-radiation, changes were detected in prostaglandin and thromboxane concentrations in parenchymal lung tissues. At 1-3 hours after exposure, tissue levels of PGFsub(2..cap alpha..), PGE, and thromboxane B/sub 2/ were significantly elevated in animals receiving 3.0 Gy, with the magnitude of alteration revealing a radiation dose effect. By 24 hours, tissue prostaglandin and thromboxane levels returned to near control values. Lung tissue synthesis of prostaglandins in response to H-1 receptor stimulation by the exogenous addition of histamine revealed similar radiation dose effects. The carboxylic acid ionophore A23187, exogenously applied to lung tissues, revealed a transient peak of increased sensitivity to ionophore stimulation for TxB/sub 2/ synthesis at 24 hours and for PGFsub(2..cap alpha..) at 72 hours post-irradiation. The data suggest that significant alterations in prostaglandin and thromboxane concentrations in parenchymal lung tissues occur following irradiation, in a dose-dependent manner, and that altered responsiveness to H-1 receptor stimulation and divalent cation transport also occur.

  20. Induction of mitochondrial biogenesis and respiration is associated with mTOR regulation in hepatocytes of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA)

    Energy Technology Data Exchange (ETDEWEB)

    Hagland, Hanne R.; Nilsson, Linn I.H. [Department of Biomedicine, University of Bergen (Norway); Burri, Lena [Institute of Medicine, University of Bergen, Haukeland University Hospital (Norway); Nikolaisen, Julie [Department of Biomedicine, University of Bergen (Norway); Berge, Rolf K. [Institute of Medicine, University of Bergen, Haukeland University Hospital (Norway); Department of Heart Disease, Haukeland University Hospital (Norway); Tronstad, Karl J., E-mail: karl.tronstad@biomed.uib.no [Department of Biomedicine, University of Bergen (Norway)

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer We investigated mechanisms of mitochondrial regulation in rat hepatocytes. Black-Right-Pointing-Pointer Tetradecylthioacetic acid (TTA) was employed to activate mitochondrial oxidation. Black-Right-Pointing-Pointer Mitochondrial biogenesis and respiration were induced. Black-Right-Pointing-Pointer It was confirmed that PPAR target genes were induced. Black-Right-Pointing-Pointer The mechanism involved activation mTOR. -- Abstract: The hypolipidemic effect of peroxisome proliferator-activated receptor (PPAR) activators has been explained by increasing mitochondrial fatty acid oxidation, as observed in livers of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA). PPAR-activation does, however, not fully explain the metabolic adaptations observed in hepatocytes after treatment with TTA. We therefore characterized the mitochondrial effects, and linked this to signalling by the metabolic sensor, the mammalian target of rapamycin (mTOR). In hepatocytes isolated from TTA-treated rats, the changes in cellular content and morphology were consistent with hypertrophy. This was associated with induction of multiple mitochondrial biomarkers, including mitochondrial DNA, citrate synthase and mRNAs of mitochondrial proteins. Transcription analysis further confirmed activation of PPAR{alpha}-associated genes, in addition to genes related to mitochondrial biogenesis and function. Analysis of mitochondrial respiration revealed that the capacity of both electron transport and oxidative phosphorylation were increased. These effects coincided with activation of the stress related factor, ERK1/2, and mTOR. The protein level and phosphorylation of the downstream mTOR actors eIF4G and 4E-BP1 were induced. In summary, TTA increases mitochondrial respiration by inducing hypertrophy and mitochondrial biogenesis in rat hepatocytes, via adaptive regulation of PPARs as well as mTOR.

  1. The Effect of Resveratrol and Quercetin Treatment on PPAR Mediated Uncoupling Protein (UCP- 1, 2, and 3 Expression in Visceral White Adipose Tissue from Metabolic Syndrome Rats

    Directory of Open Access Journals (Sweden)

    Vicente Castrejón-Tellez

    2016-07-01

    Full Text Available Uncoupling proteins (UCPs are members of the mitochondrial anion carrier superfamily involved in the control of body temperature and energy balance regulation. They are currently proposed as therapeutic targets for treating obesity and metabolic syndrome (MetS. We studied the gene expression regulation of UCP1, -2, and -3 in abdominal white adipose tissue (WAT from control and MetS rats treated with two doses of a commercial mixture of resveratrol (RSV and quercetin (QRC. We found that UCP2 was the predominantly expressed isoform, UCP3 was present at very low levels, and UCP1 was undetectable. The treatment with RSV + QRC did not modify UCP3 levels; however, it significantly increased UCP2 mRNA in control and MetS rats in association with an increase in oleic and linoleic fatty acids. WAT from MetS rats showed a significantly increased expression of peroxisome proliferator-activated receptor (PPAR-α and PPAR-γ when compared to the control group. Furthermore, PPAR-α protein levels were increased by the highest dose of RSV + QRC in the control and MetS groups. PPAR-γ expression was only increased in the control group. We conclude that the RSV + QRC treatment leads to overexpression of UCP2, which is associated with an increase in MUFA and PUFA, which might increase PPAR-α expression.

  2. Activation of PPARs α, β/δ, and γ Impairs TGF-β1-Induced Collagens' Production and Modulates the TIMP-1/MMPs Balance in Three-Dimensional Cultured Chondrocytes

    Directory of Open Access Journals (Sweden)

    Paul-Emile Poleni

    2010-01-01

    Full Text Available Background and Purpose. We investigated the potency of Peroxisome Proliferators-Activated Receptors (PPARs α, β/δ, and γ agonists to modulate Transforming Growth Factor-β1 (TGF-β1- induced collagen production or changes in Tissue Inhibitor of Matrix Metalloproteinase- (TIMP- 1/Matrix Metalloproteinase (MMP balance in rat chondrocytes embedded in alginate beads. Experimental Approach. Collagen production was evaluated by quantitative Sirius red staining, while TIMP-1 protein levels and global MMP (-1, -2, -3, -7, and -9 or specific MMP-13 activities were measured by ELISA and fluorigenic assays in culture media, respectively. Levels of mRNA for type II collagen, TIMP-1, and MMP-3 & 13 were quantified by real-time PCR. Key Results. TGF-β1 increased collagen deposition and type II collagen mRNA levels, while inducing TIMP-1 mRNA and protein expression. In contrast, it decreased global MMP or specific MMP-13 activities, while decreasing MMP-3 or MMP-13 mRNA levels. PPAR agonists reduced most of the effects of TGF-β1 on changes in collagen metabolism and TIMP-1/MMP balance in rat in a PPAR-dependent manner, excepted for Wy14643 on MMP activities. Conclusions and Implications. PPAR agonists reduce TGF-β1-modulated ECM turnover and inhibit chondrocyte activities crucial for collagen biosynthesis, and display a different inhibitory profile depending on selectivity for PPAR isotypes.

  3. Overproduction of altered VLDL in an insulin-resistance rat model: Influence of SREBP-1c and PPAR-α.

    Science.gov (United States)

    Lucero, Diego; Miksztowicz, Verónica; Macri, Vanesa; López, Gustavo H; Friedman, Silvia; Berg, Gabriela; Zago, Valeria; Schreier, Laura

    2015-01-01

    In insulin-resistance, VLDL presents alterations that increase its atherogenic potential. The mechanism by which insulin-resistance promotes the production of altered VLDL is still not completely understood. The aim of this study was to evaluate the relationship between the expression of sterol regulatory element binding protein 1c (SREBP-1c) and of peroxisome proliferator-activated receptor-α (PPAR-α), with the features of composition and size of VLDL in an insulin-resistance rat model induced by a sucrose rich diet (SRD). The study was conducted on 12 male Wistar rats (180g) receiving SRD (12 weeks) and 12 controls. Lipid profile, free fatty acids, glucose, and insulin were measured. Lipid content in liver and visceral fat were assessed. Isolated VLDL (d<1.006g/ml) was characterized by its chemical composition and size by HPLC. The respective hepatic expression of SREBP-1c and PPAR-α was determined (Western blot). As expected, SRD had elevated triglycerides (TG), free fatty acids and insulin levels, and decreased HDL-cholesterol (p<0.05), together with augmented hepatic and visceral fat (p<0.05). SRD showed higher VLDL total mass - with increased TG content - and predominance of large VLDL (p<0.05). SRD showed an increase in SREBP-1c (precursor and mature forms) and decreased PPAR-α expression (p<0.045). SREBP-1c forms were positively associated with VLDL total mass (p<0.04), VLDL-TG% (p<0.019), and large VLDL% (p<0.002). On the other hand, PPAR-α correlated negatively with VLDL total mass (p=0.05), VLDL-TG% (p=0.005), and large VLDL% (p=0.002). Insulin-resistance, by coordinated activation of SREBP-1c and reduction of PPAR-α, could promote the secretion of larger and TG over-enriched VLDL particles, with greater atherogenic capacity. Copyright © 2014 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

  4. Activation of peroxisome proliferator-activated receptor-{alpha} enhances fatty acid oxidation in human adipocytes

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joo-Young; Hashizaki, Hikari; Goto, Tsuyoshi; Sakamoto, Tomoya; Takahashi, Nobuyuki [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Kawada, Teruo, E-mail: fat@kais.kyoto-u.ac.jp [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan)

    2011-04-22

    Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of adipocyte differentiation marker genes and GPDH activity in human adipocytes. {yields} PPAR{alpha} activation also increased insulin-dependent glucose uptake in human adipocytes. {yields} PPAR{alpha} activation did not affect lipid accumulation in human adipocytes. {yields} PPAR{alpha} activation increased fatty acid oxidation through induction of fatty acid oxidation-related genes in human adipocytes. -- Abstract: Peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) is a key regulator for maintaining whole-body energy balance. However, the physiological functions of PPAR{alpha} in adipocytes have been unclarified. We examined the functions of PPAR{alpha} using human multipotent adipose tissue-derived stem cells as a human adipocyte model. Activation of PPAR{alpha} by GW7647, a potent PPAR{alpha} agonist, increased the mRNA expression levels of adipocyte differentiation marker genes such as PPAR{gamma}, adipocyte-specific fatty acid-binding protein, and lipoprotein lipase and increased both GPDH activity and insulin-dependent glucose uptake level. The findings indicate that PPAR{alpha} activation stimulates adipocyte differentiation. However, lipid accumulation was not changed, which is usually observed when PPAR{gamma} is activated. On the other hand, PPAR{alpha} activation by GW7647 treatment induced the mRNA expression of fatty acid oxidation-related genes such as CPT-1B and AOX in a PPAR{alpha}-dependent manner. Moreover, PPAR{alpha} activation increased the production of CO{sub 2} and acid soluble metabolites, which are products of fatty acid oxidation, and increased oxygen consumption rate in human adipocytes. The data indicate that activation of PPAR{alpha} stimulates both adipocyte differentiation and fatty acid oxidation in human adipocytes, suggesting that PPAR{alpha} agonists could improve insulin resistance without lipid accumulation in adipocytes. The expected

  5. PPAR alpha-activation results in enhanced carnitine biosynthesis and OCTN2-mediated hepatic carnitine accumulation

    NARCIS (Netherlands)

    van Vlies, Naomi; Ferdinandusse, Sacha; Turkenburg, Marjolein; Wanders, Ronald J. A.; Vaz, Frédéric M.

    2007-01-01

    In fasted rodents hepatic carnitine concentration increases considerably which is not observed in PPAR alpha-/- mice, indicating that PPAR alpha is involved in carnitine homeostasis. To investigate the mechanisms underlying the PPAR alpha-dependent hepatic carnitine accumulation we measured

  6. Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    Eric R Kallwitz; Alan McLachlan; Scott J Cotler

    2008-01-01

    Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and can result in nonalcoholic steatohepatitis (NASH) and progressive liver disease including cirrhosis and hepatocellular carcinoma. A growing body of literature implicates the peroxisorne proliferators- activated receptors (PPARs) in the pathogenesis and treatment of NAFLD. These nuclear hormone receptors impact on hepatic triglyceride accumulation and insulin resistance. The aim of this review is to describe the data linking PPARα and PPARγ to NAFLD/NASH and to discuss the use of PPAR ligands for the treatment of NASH.

  7. Curcumin Protects Neuron against Cerebral Ischemia-Induced Inflammation through Improving PPAR-Gamma Function

    OpenAIRE

    Zun-Jing Liu; Wei Liu; Lei Liu; Cheng Xiao; Yu Wang; Jing-Song Jiao

    2013-01-01

    Cerebral ischemia is the most common cerebrovascular disease worldwide. Recent studies have demonstrated that curcumin had beneficial effect to attenuate cerebral ischemic injury. However, it is unclear how curcumin protects against cerebral ischemic injury. In the present study, using rat middle cerebral artery occlusion model, we found that curcumin was a potent PPAR ? agonist in that it upregulated PPAR ? expression and PPAR ? -PPRE binding activity. Administration of curcumin markedly dec...

  8. Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR

    Science.gov (United States)

    Lee, Hong Jin; Ju, Jihyeung; Paul, Shiby; So, Jae-Young; DeCastro, Andrew; Smolarek, Amanda; Lee, Mao-Jung; Yang, Chung S.; Newmark, Harold L.; Suh, Nanjoo

    2009-01-01

    Purpose Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of α-tocopherol (vitamin E) have been studied for decades, recent intervention studies with α-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of 4 isoforms, α, β, γ, and δ variants, and recent attention is being made to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in γ- and δ-tocopherols against mammary tumorigenesis. Experimental Design Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in γ- and δ-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells. Results Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3 and peroxisome proliferator activated receptor-γ (PPAR-γ), and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that γ- and δ-tocopherols, but not α-tocopherol, activated PPAR-γ and antagonized estrogen action in breast cancer. Conclusion The results suggest that γ- and δ-tocopherols may be effective agents for the prevention of breast cancer. PMID:19509159

  9. Kinetics of prostaglandin E2 and thromboxane A2 synthesis and suppression of PHA-stimulated peripheral blood mononuclear leucocytes.

    Science.gov (United States)

    Awara, W; Hillier, K; Jones, D

    1986-12-01

    The immunomodulatory effects of thromboxane A2 and prostaglandin E2 on peripheral blood mononuclear leucocytes stimulated with PHA in vitro, and the relationship of this to the time-course of their synthesis in culture, were investigated using prostaglandin E2, a thromboxane A2 synthesis inhibitor (UK37248), a thromboxane A2 mimic (U46619) and a thromboxane A2 receptor blocker (EP045). The inhibitory effect of prostaglandin E2 on PHA-induced human peripheral blood mononuclear leucocyte proliferation diminishes if the addition of PGE2 is delayed. If added 4 hr after a maximum concentration of PHA (5 micrograms/ml), the effect of PGE2 was reduced by 60%. If a submaximal concentration of PHA (1 microgram/ml) was used, the effect of PGE2 was not reduced if added 4 hr later but fell by about 60% after 16 hr. UK37248 moderately inhibited PHA-induced activation while substantially inhibiting thromboxane A2 synthesis and simultaneously enhancing PGE2 synthesis. The enhanced accumulation of PGE2 occurs while sensitivity to PGE2 is dropping. U46619, exogenously applied as a thromboxane A2 mimic, inhibited PHA-induced activation at concentrations that did not significantly alter PGE2 synthesis. EP045, which may modulate the effects of endogenous thromboxane A2 by blocking receptors, did not alter PHA-induced activation. We conclude that thromboxane A2 may have a role in inhibiting PHA-induced activation on the basis of the effect of U46619. However, this study highlights difficulties in utilizing prostaglandin and thromboxane receptor and synthesis inhibitors to examine their endogenous role in the modulation of mitogen-induced activation in vitro. If sensitivity to the purported endogenous substance is limited to the early stages of culture and if only low levels are synthesized at this early stage, then blocking drugs would have little effect.

  10. Peroxisome Proliferator-Activated Receptor-γ in Thyroid Autoimmunity

    Directory of Open Access Journals (Sweden)

    Silvia Martina Ferrari

    2015-01-01

    Full Text Available Peroxisome proliferator-activated receptor- (PPAR- γ expression has been shown in thyroid tissue from patients with thyroiditis or Graves’ disease and furthermore in the orbital tissue of patients with Graves’ ophthalmopathy (GO, such as in extraocular muscle cells. An increasing body of evidence shows the importance of the (C-X-C motif receptor 3 (CXCR3 and cognate chemokines (C-X-C motif ligand (CXCL9, CXCL10, and CXCL11, in the T helper 1 immune response and in inflammatory diseases such as thyroid autoimmune disorders. PPAR-γ agonists show a strong inhibitory effect on the expression and release of CXCR3 chemokines, in vitro, in various kinds of cells, such as thyrocytes, and in orbital fibroblasts, preadipocytes, and myoblasts from patients with GO. Recently, it has been demonstrated that rosiglitazone is involved in a higher risk of heart failure, stroke, and all-cause mortality in old patients. On the contrary, pioglitazone has not shown these effects until now; this favors pioglitazone for a possible use in patients with thyroid autoimmunity. However, further studies are ongoing to explore the use of new PPAR-γ agonists in the treatment of thyroid autoimmune disorders.

  11. Lack of association between the Pro12Ala polymorphism of the PPAR-gamma 2 gene and type 2 diabetes mellitus in the Qatari consanguineous population.

    Science.gov (United States)

    Badii, Ramin; Bener, Abdulbari; Zirie, Mahmoud; Al-Rikabi, Ammar; Simsek, Mehmet; Al-Hamaq, Abdulla O A A; Ghoussaini, Maya; Froguel, Philippe; Wareham, Nick J

    2008-03-01

    Peroxisome proliferators-activated receptor gamma (PPAR gamma) is a nuclear hormone receptor that serves as a master regulator for adipocytes-specific genes contributing to adipocytes differentiation, insulin sensitivity and lipid metabolism. The substitution of proline to alanine at codon 12 of the PPAR gamma 2 gene (Pro12Ala polymorphism) is most widely studied, and the associations with diabetes, obesity, and other clinical parameters have been reported and discussed in several ethnic groups. Among native Qatar ethnicity, however, there is no report about this polymorphism. The aim of this study was to estimate the allele frequency of the Pro12Ala polymorphism of PPAR gamma 2 gene among Qatari population and investigate the association between this polymorphism and obesity or type 2 diabetes. This is a matched case-control study. It was carried out among diabetic patients and healthy subjects at the Primary Healthcare Clinics, and the survey was conducted from February 2003 to March 2006 in Qatari male and female nationals aged 35 to 60 years. The study was based on matched age, sex, and ethnicity of 400 cases (with diabetes) and 450 controls (without diabetes). Face-to-face interviews were based on a questionnaire that included variables such as age, sex, sociodemographic status, body mass index (BMI), and obesity. Their health status was assessed by medical conditions, family history, and blood pressure measurements. The allele frequency of Pro12Ala polymorphism in PPAR gamma 2 gene among Qataris is lower than that in many Caucasian ethnic groups. No association is seen between the Pro12Ala and type 2 Diabetes (0.055 vs 0.059, OR = 1.1311, P = 0.669). Nearly half of the diabetic type 2 patients (48.5%) were obese (BMI > 30) compared to nondiabetic subjects (29.8%) (P Qatar.

  12. Palmitic acid suppresses apolipoprotein M gene expression via the pathway of PPAR{sub β/δ} in HepG2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Guanghua; Shi, Yuanping; Zhang, Jun; Mu, Qinfeng; Qin, Li; Zheng, Lu; Feng, Yuehua [Comprehensive Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou 213003 (China); Berggren-Söderlund, Maria; Nilsson-Ehle, Peter [Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, S-221 85 Lund (Sweden); Zhang, Xiaoying, E-mail: zhangxy6689996@163.com [Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213003 (China); Xu, Ning, E-mail: ning.xu@med.lu.se [Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, S-221 85 Lund (Sweden)

    2014-02-28

    Highlights: • Palmitic acid significantly inhibited APOM gene expression in HepG2 cells. • Palmitic acid could obviously increase PPARB/D mRNA levels in HepG2 cells. • PPAR{sub β/δ} antagonist, GSK3787, had no effect on APOM expression. • GSK3787 could reverse the palmitic acid-induced down-regulation of APOM expression. • Palmitic acid induced suppression of APOM expression is mediated via the PPAR{sub β/δ} pathway. - Abstract: It has been demonstrated that apolipoprotein M (APOM) is a vasculoprotective constituent of high density lipoprotein (HDL), which could be related to the anti-atherosclerotic property of HDL. Investigation of regulation of APOM expression is of important for further exploring its pathophysiological function in vivo. Our previous studies indicated that expression of APOM could be regulated by platelet activating factor (PAF), transforming growth factors (TGF), insulin-like growth factor (IGF), leptin, hyperglycemia and etc., in vivo and/or in vitro. In the present study, we demonstrated that palmitic acid could significantly inhibit APOM gene expression in HepG2 cells. Further study indicated neither PI-3 kinase (PI3K) inhibitor LY294002 nor protein kinase C (PKC) inhibitor GFX could abolish palmitic acid induced down-regulation of APOM expression. In contrast, the peroxisome proliferator-activated receptor beta/delta (PPAR{sub β/δ}) antagonist GSK3787 could totally reverse the palmitic acid-induced down-regulation of APOM expression, which clearly demonstrates that down-regulation of APOM expression induced by palmitic acid is mediated via the PPAR{sub β/δ} pathway.

  13. Nifedipine, a calcium channel blocker, inhibits advanced glycation end product (AGE)-elicited mesangial cell damage by suppressing AGE receptor (RAGE) expression via peroxisome proliferator-activated receptor-gamma activation

    International Nuclear Information System (INIS)

    Matsui, Takanori; Yamagishi, Sho-ichi; Takeuchi, Masayoshi; Ueda, Seiji; Fukami, Kei; Okuda, Seiya

    2009-01-01

    The interaction between advanced glycation end products (AGE) and their receptor RAGE mediates the progressive alteration in renal architecture and loss of renal function in diabetic nephropathy. Oxidative stress generation and inflammation also play a central role in diabetic nephropathy. This study investigated whether and how nifedipine, a calcium channel blocker (CCB), blocked the AGE-elicited mesangial cell damage in vitro. Nifedipine, but not amlodipine, a control CCB, down-regulated RAGE mRNA levels and subsequently reduced reactive oxygen species (ROS) generation in AGE-exposed mesangial cells. AGE increased mRNA levels of vascular cell adhesion molecule-1 (VCAM-1) and induced monocyte chemoattractant protein-1 (MCP-1) production in mesangial cells, both of which were prevented by the treatment with nifedipine, but not amlodipine. The beneficial effects of nifedipine on AGE-exposed mesangial cells were blocked by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPAR-γ). Although nifedipine did not affect expression levels of PPAR-γ, it increased the PPAR-γ transcriptional activity in mesangial cells. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-inflammatory agent against AGE by suppressing RAGE expression in cultured mesangial cells via PPAR-γ activation.

  14. Bone changes from prostaglandin therapy

    International Nuclear Information System (INIS)

    Poznanski, A.K.; Fernbach, S.K.; Berry, T.E.; Northwestern Univ., Chicago, IL

    1985-01-01

    Prostaglandin E therapy in infants causes periosteal elevation. Although the changes usually take 30-40 days to become visible, we have seen them as early as nine days. In 15 infants who had prostaglandin E therapy for over six days, three developed periosteal elevation. Three other cases are described in greater detail, with long-term follow-up in two in which the bone remodeled to normal. Gallium scan in one showed increased uptake in areas involved. The periosteal cloaking may mimic Caffey disease but the pattern of involvement is different, since the mandible, which is commonly affected in Caffey disease, is rarely involved in prostaglandin E therapy. (orig.)

  15. Effect of Persea americana (avocado) fruit extract on the level of expression of adiponectin and PPAR-γ in rats subjected to experimental hyperlipidemia and obesity.

    Science.gov (United States)

    Padmanabhan, Monika; Arumugam, Geetha

    2014-06-01

    Persea americana, commonly known as avocado, is traditionally consumed fruit which possesses body fat lowering capacity. Adiponectin plays an important role in regulating obesity. In this study, the effect of hydro-alcoholic fruit extract of P. americana (HAEPA) on the level of blood lipids, glutathione, lipid peroxidation products, adiponectin and peroxisome proliferator activated receptor (PPAR)-γ expressions was investigated in rats fed a high-fat diet (HFD). Male Sprague Dawley rats were divided into four groups: groups 1 and 2 were fed normal rat chow (5% fat) and groups 3 and 4 were fed HFD (23% fat) for a period of 14 weeks. In addition, groups 2 and 4 rats were administered orally with 100 mg/kg body weight of HAEPA from third week. After 14 weeks, rats were sacrificed, and serum/plasma levels of total cholesterol, phospholipids, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and adiponectin were determined. The mRNA expression of adiponectin, PPAR-γ and protein expression of PPAR-γ were also evaluated. The body mass index (BMI), total fat pad mass and adiposity index were significantly decreased in HAEPA co-administered rats than in HFD-fed rats. The levels of LDL and lipid peroxides were significantly higher in HFD group than in HFD+HAEPA group. Levels of reduced glutathione, adiponectin, mRNA expression of adiponectin, PPAR-γ and protein expression of PPAR-γ were found to be increased in HFD+HAEPA group than in HFD group. The hypolipidemic effect of HAEPA is also evidenced by the histological observations in liver, heart and adipose tissue. The results indicate that HAEPA exhibits hypolipidemic activity probably by increasing the mRNA expression of adiponectin and PPAR-γ, which reduce the risk of hyperlipidemia and obesity.

  16. Fruit extracts of Momordica charantia potentiate glucose uptake and up-regulate Glut-4, PPAR gamma and PI3K.

    Science.gov (United States)

    Kumar, Ramadhar; Balaji, S; Uma, T S; Sehgal, P K

    2009-12-10

    Momordica charantia fruit is a widely used traditional medicinal herb as, anti-diabetic, anti-HIV, anti-ulcer, anti-inflammatory, anti-leukemic, anti-microbial, and anti-tumor. The present study is undertaken to investigate the possible mode of action of fruit extracts derived from Momordica charantia (MC) and study its pharmacological effects for controlling diabetic mellitus. Effects of aqueous and chloroform extracts of Momordica charantia fruit on glucose uptake and up-regulation of glucose transporter (Glut-4), peroxisome proliferator activator receptor gamma (PPAR gamma) and phosphatidylinositol-3 kinase (PI3K), were investigated to show its efficacy as a hypoglycaemic agent. Dose dependent glucose uptake assay was performed on L6 myotubes using 2-deoxy-D-[1-(3)H] glucose. Up-regulatory effects of the extracts on the mRNA expression level of Glut-4, PPAR gamma and PI3K have been studied. The association of Momordica charantia with the aqueous and chloroform extracts of Momordica charantia fruit at 6 microg/ml has shown significant up-regulatory effect, respectively, by 3.6-, 2.8- and 3.8-fold on the battery of targets Glut-4, PPAR gamma and PI3K involved in glucose transport. The up-regulation of glucose uptake was comparable with insulin and rosiglitazone which was approximately 2-fold over the control. Moreover, the inhibitory effect of the cyclohexamide on Momordica charantia fruit extract mediated glucose uptake suggested the requirement of new protein synthesis for the enhanced glucose uptake. This study demonstrated the significance of Glut-4, PPAR gamma and PI3K up-regulation by Momordica charantia in augmenting the glucose uptake and homeostasis.

  17. Prostaglandin E2 Prevents Hyperosmolar-Induced Human Mast Cell Activation through Prostanoid Receptors EP2 and EP4

    Science.gov (United States)

    Torres-Atencio, Ivonne; Ainsua-Enrich, Erola; de Mora, Fernando; Picado, César; Martín, Margarita

    2014-01-01

    Background Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB. Objective This study aimed to evaluate the protective effect of PGE2 on osmotically activated mast cells, as a model of exercise-induced bronchoconstriction. Methods We used LAD2, HMC-1, CD34-positive, and human lung mast cell lines. Cells underwent a mannitol challenge, and the effects of PGE2 and prostanoid receptor (EP) antagonists for EP1–4 were assayed on the activated mast cells. Beta-hexosaminidase release, protein phosphorylation, and calcium mobilization were assessed. Results Mannitol both induced mast cell degranulation and activated phosphatidyl inositide 3-kinase and mitogen-activated protein kinase (MAPK) pathways, thereby causing de novo eicosanoid and cytokine synthesis. The addition of PGE2 significantly reduced mannitol-induced degranulation through EP2 and EP4 receptors, as measured by beta-hexosaminidase release, and consequently calcium influx. Extracellular-signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 phosphorylation were diminished when compared with mannitol activation alone. Conclusions Our data show a protective role for the PGE2 receptors EP2 and EP4 following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition. PMID:25329458

  18. 15-Deoxy-Δ12,14-prostaglandin J2 inhibits macrophage colonization by Salmonella enterica serovar Typhimurium.

    Directory of Open Access Journals (Sweden)

    Michelle M C Buckner

    Full Text Available 15-deoxy-Δ(12,14-prostaglandin J2 (15d-PGJ2 is an anti-inflammatory downstream product of the cyclooxygenase enzymes. It has been implicated to play a protective role in a variety of inflammatory mediated diseases, including rheumatoid arthritis, neural damage, and myocardial infarctions. Here we show that 15d-PGJ2 also plays a role in Salmonella infection. Salmonella enterica Typhimurium is a Gram-negative facultative intracellular pathogen that is able to survive and replicate inside phagocytic immune cells, allowing for bacterial dissemination to systemic sites. Salmonella species cause a wide range of morbidity and mortality due to gastroenteritis and typhoid fever. Previously we have shown that in mouse models of typhoid fever, Salmonella infection causes a major perturbation in the prostaglandin pathway. Specifically, we saw that 15d-PGJ2 production was significantly increased in both liver and feces. In this work we show that 15d-PGJ2 production is also significantly increased in macrophages infected with Salmonella. Furthermore, we show that the addition of 15d-PGJ2 to Salmonella infected RAW264.7, J774, and bone marrow derived macrophages is sufficient to significantly reduce bacterial colonization. We also show evidence that 15d-PGJ2 is reducing bacterial uptake by macrophages. 15d-PGJ2 reduces the inflammatory response of these infected macrophages, as evidenced by a reduction in the production of cytokines and reactive nitrogen species. The inflammatory response of the macrophage is important for full Salmonella virulence, as it can give the bacteria cues for virulence. The reduction in bacterial colonization is independent of the expression of Salmonella virulence genes SPI1 and SPI2, and is independent of the 15d-PGJ2 ligand PPAR-γ. 15d-PGJ2 also causes an increase in ERK1/2 phosphorylation in infected macrophages. In conclusion, we show here that 15d-PGJ2 mediates the outcome of bacterial infection, a previously unidentified

  19. The MAPK-dependent regulation of the Jagged/Notch gene expression by VEGF, bFGF or PPAR gamma mediated angiogenesis in HUVEC

    DEFF Research Database (Denmark)

    Kiec-Wilk, B; Grzybowska-Galuszka, J; Polus, A

    2010-01-01

    The Jagged-Notch signalling, plays a crucial role in cell differentiation. Angiogenesis, is regulated by VEGF, bFGF as well as by the free fatty acid metabolites , which are regulators of transcription factors such as peroxisome proliferation activating receptors (PPARs). The study analyzed...... the signalling pathways involved in the regulation of Jagged-1/Notch-4 expression in endothelial cells (HUVECs) in response to VEGF, bFGF and PPAR-gamma exogenous activator - ciglitazone. HUVECs were incubated with investigated substances for 24 hours, with or without the presence of the MAP-kinases inhibitors...... were used. Jagged-1 and Notch-4 gene expression was determined using quantitative Real-Time PCR. The Jagged-1/Notch-4 protein expression was compared by flow cytometry, when the phosphorylation-dependent activation of kinases was estimated by Western-blot method. The opposite effect of VEGF, b...

  20. Does prostaglandin D2 hold the cure to male pattern baldness?

    Science.gov (United States)

    Nieves, Ashley; Garza, Luis A

    2014-04-01

    Lipids in the skin are the most diverse in the entire human body. Their bioactivity in health and disease is underexplored. Prostaglandin D2 has recently been identified as a factor which is elevated in the bald scalp of men with androgenetic alopecia (AGA) and has the capacity to decrease hair lengthening. An enzyme which synthesizes it, prostaglandin D2 synthase (PTGDS or lipocalin-PGDS), is hormone responsive in multiple other organs. PGD2 has two known receptors, GPR44 and PTGDR. GPR44 was found to be necessary for the decrease in hair growth by PGD2 . This creates an exciting opportunity to perhaps create novel treatments for AGA, which inhibit the activity of PTGDS, PGD2 or GPR44. This review discusses the current knowledge surrounding PGD2 , and future steps needed to translate these findings into novel therapies for patients with AGA. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Effect of PPAR-α and -γ agonist on the expression of visfatin, adiponectin, and TNF-α in visceral fat of OLETF rats

    International Nuclear Information System (INIS)

    Choi, K.C.; Ryu, O.H.; Lee, K.W.; Kim, H.Y.; Seo, J.A.; Kim, S.G.; Kim, N.H.; Choi, D.S.; Baik, S.H.; Choi, K.M.

    2005-01-01

    A variety of adipocytokines and peptides secreted from adipocytes have been considered to play a crucial role in obesity, insulin resistance, and type 2 diabetes. Recently, visfatin, a new adipocytokine, known as a pre-B cell colony-enhancing factor, has been isolated from visceral fat deposits. It has been shown to activate insulin receptors in a manner different from insulin. To understand the role of adipocytokines in improving insulin sensitivity via activation of the nuclear receptor peroxisome proliferator-activated receptor-α (PPAR-α) and -γ (PPAR-γ), we examined the expression of visfatin, adiponectin, and TNF-α in visceral fat depots of Otsuka Long-Evans Tokushima fatty (OLETF) rats from early to advanced diabetic stage (from 28 to 40 weeks of age). Serum glucose and insulin concentrations significantly (P < 0.05) decreased in rosiglitazone or fenofibrate-treated OLETF rats compared to untreated OLETF rats. Rosiglitazone significantly increased serum adiponectin concentration from 20 to 40 weeks of age (P < 0.05), whereas fenofibrate reduced TNF-α concentration. The expression of visfatin and adiponectin mRNA in visceral fat deposits was elevated by rosiglitazone or fenofibrate treatments when compared to untreated OLETF rats (P < 0.05), whereas, TNF-α mRNA was down-regulated by these drugs (P < 0.05). These results suggest that rosiglitazone and fenofibrate may prevent type 2 diabetes by regulating adipocytokines including visfatin, adiponectin, and TNF-α

  2. The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR

    Science.gov (United States)

    Ren, Tingting; Zhu, Juanjuan; Zhu, Lili; Cheng, Mingliang

    2017-01-01

    Nonalcoholic steatohepatitis (NASH) is liver inflammation and a major threat to public health. Several pharmaceutical agents have been used for NASH therapy but their high-rate side effects limit the use. Blueberry juice and probiotics (BP) have anti-inflammation and antibacterial properties, and may be potential candidates for NASH therapy. To understand the molecular mechanism, Sprague Dawley rats were used to create NASH models and received different treatments. Liver tissues were examined using HE (hematoxylin and eosin) and ORO (Oil Red O) stain, and serum biochemical indices were measured. The levels of peroxisome proliferators-activated receptor (PPAR)-α, sterol regulatory element binding protein-1c (SREBP-1c), Patatin-like phospholipase domain-containing protein 3 (PNPLA-3), inflammatory cytokines and apoptosis biomarkers in liver tissues were measured by qRT-PCR and Western blot. HE and ORO analysis indicated that the hepatocytes were seriously damaged with more and larger lipid droplets in NASH models while BP reduced the number and size of lipid droplets (p < 0.05). Meanwhile, BP increased the levels of SOD (superoxide dismutase), GSH (reduced glutathione) and HDL-C (high-density lipoprotein cholesterol), and reduced the levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), TG (triglycerides), LDL-C (low-density lipoprotein cholesterol) and MDA (malondialdehyde) in NASH models (p < 0.05). BP increased the level of PPAR-α (Peroxisome proliferator-activated receptor α), and reduced the levels of SREBP-1c (sterol regulatory element binding protein-1c) and PNPLA-3 (Patatin-like phospholipase domain-containing protein 3) (p < 0.05). BP reduced hepatic inflammation and apoptosis by affecting IL-6 (interleukin 6), TNF-α (Tumor necrosis factor α), caspase-3 and Bcl-2 in NASH models. Furthermore, PPAR-α inhibitor increased the level of SREBP-1c and PNPLA-3. Therefore, BP prevents NASH progression by affecting SREBP-1c/PNPLA-3 pathway

  3. Peroxisome Proliferator-Activated Receptor-γ Ligands: Potential Pharmacological Agents for Targeting the Angiogenesis Signaling Cascade in Cancer

    Directory of Open Access Journals (Sweden)

    Costas Giaginis

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptor-γ (PPAR-γ has currently been considered as molecular target for the treatment of human metabolic disorders. Experimental data from in vitro cultures, animal models, and clinical trials have shown that PPAR-γ ligand activation regulates differentiation and induces cell growth arrest and apoptosis in a variety of cancer types. Tumor angiogenesis constitutes a multifaceted process implicated in complex downstream signaling pathways that triggers tumor growth, invasion, and metastasis. In this aspect, accumulating in vitro and in vivo studies have provided extensive evidence that PPAR-γ ligands can function as modulators of the angiogenic signaling cascade. In the current review, the crucial role of PPAR-γ ligands and the underlying mechanisms participating in tumor angiogenesis are summarized. Targeting PPAR-γ may prove to be a potential therapeutic strategy in combined treatments with conventional chemotherapy; however, special attention should be taken as there is also substantial evidence to support that PPAR-γ ligands can enhance angiogenic phenotype in tumoral cells.

  4. Tartrazine and the prostaglandin system.

    Science.gov (United States)

    Gerber, J G; Payne, N A; Oelz, O; Nies, A S; Oates, J A

    1979-04-01

    The effect of tartrazine on prostaglandin production was evaluated in several in vitro systems in order to elucidate the interrelationship between aspirin-sensitive asthma and tartrazine. Unlike the nonsteroidal anti-inflammatory drugs, tartrazine did not inhibit cyclooxygenase activity in sheep seminal vesicles, guinea pig lung microsomes, and human platelets. Tartrazine had no effect on the activation of acyl hydrolase, which is the rate-limiting step in prostaglandin production. The major metabolite of tartrazine, sulfanilic acid, also had no inhibitory effect on the sheep seminal vesicle cyclooxygenase. In view of these findings, if there is a cross-sensitivity between tartrazine and aspirin in aspirin-sensitive asthmatics, it is unlikely to be on the basis of prostaglandin inhibition.

  5. Quercetin enhances adiponectin secretion by a PPAR-gamma independent mechanism

    DEFF Research Database (Denmark)

    Wein, Silvia; Behm, Norma; Petersen, Rasmus Koefoed

    2010-01-01

    To study possible insulin sensitizing, anti-inflammatory and anti-oxidative effects of the flavonol quercetin, rats were fed a high-fat diet (19%, w/w) with (HFQ) or without (HF) 0.03% quercetin or a flavonoid-poor low-fat (5%, w/w) maintenance diet (LF) over 4 weeks. Body weight was measured...... and WAT mRNA levels of adiponectin were elevated compared with the HF group, however, PPAR-gamma mRNA concentration in WAT was decreased (HFQ vs. HF). Compared to both other groups quercetin feeding significantly reduced oxidative stress, measured by plasma 8-iso-PGF(2alpha), while body weight gain, body...... composition and plasma leptin levels were not affected. Neither quercetin nor its metabolites induced PPAR-gamma-mediated transactivation in vitro. Adiponectin stimulating effects of quercetin are PPAR-gamma-independent and prevent impairment of insulin sensitivity without affecting body weight...

  6. Prevotella intermedia induces prostaglandin E2 via multiple signaling pathways.

    Science.gov (United States)

    Guan, S-M; Fu, S-M; He, J-J; Zhang, M

    2011-01-01

    Prostaglandin E(2) (PGE(2)) plays important roles in the bone resorption of inflammatory diseases such as rheumatoid arthritis and periodontitis via specific prostaglandin receptors (i.e., EP1-EP4). In this study, the authors examined whether Prevotella intermedia regulates PGE(2) production and EP expression in human periodontal ligament fibroblasts (hPDLs); they also explored the potential signaling pathways involved in PGE(2) production. P. intermedia induced PGE(2) production and cyclooxygenase-2 (COX-2) expression in a dose- and time-dependent manner. Indomethacin and NS-398 completely abrogated the P. intermedia-induced PGE(2) production without modulating COX-2 expression. Specific inhibitors of extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, phosphatidylinositol 3-kinase, and protein kinase C--but not c-AMP and protein kinase A--significantly attenuated the P. intermedia-induced COX-2 and PGE(2) expression. P. intermedia reduced EP1 expression in a concentration- and time-dependent manner. The results indicate that the COX-2-dependent induction of PGE(2) by P. intermedia in hPDLs is mediated by multiple signaling pathways.

  7. PPAR/RXR Regulation of Fatty Acid Metabolism and Fatty Acid -Hydroxylase (CYP4 Isozymes: Implications for Prevention of Lipotoxicity in Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    James P. Hardwick

    2009-01-01

    Full Text Available Fatty liver disease is a common lipid metabolism disorder influenced by the combination of individual genetic makeup, drug exposure, and life-style choices that are frequently associated with metabolic syndrome, which encompasses obesity, dyslipidemia, hypertension, hypertriglyceridemia, and insulin resistant diabetes. Common to obesity related dyslipidemia is the excessive storage of hepatic fatty acids (steatosis, due to a decrease in mitochondria -oxidation with an increase in both peroxisomal -oxidation, and microsomal -oxidation of fatty acids through peroxisome proliferator activated receptors (PPARs. How steatosis increases PPAR activated gene expression of fatty acid transport proteins, peroxisomal and mitochondrial fatty acid -oxidation and -oxidation of fatty acids genes regardless of whether dietary fatty acids are polyunsaturated (PUFA, monounsaturated (MUFA, or saturated (SFA may be determined by the interplay of PPARs and HNF4 with the fatty acid transport proteins L-FABP and ACBP. In hepatic steatosis and steatohepatitis, the -oxidation cytochrome P450 CYP4A gene expression is increased even with reduced hepatic levels of PPAR. Although numerous studies have suggested the role ethanol-inducible CYP2E1 in contributing to increased oxidative stress, Cyp2e1-null mice still develop steatohepatitis with a dramatic increase in CYP4A gene expression. This strongly implies that CYP4A fatty acid -hydroxylase P450s may play an important role in the development of steatohepatitis. In this review and tutorial, we briefly describe how fatty acids are partitioned by fatty acid transport proteins to either anabolic or catabolic pathways regulated by PPARs, and we explore how medium-chain fatty acid (MCFA CYP4A and long-chain fatty acid (LCFA CYP4F -hydroxylase genes are regulated in fatty liver. We finally propose a hypothesis that increased CYP4A expression with a decrease in CYP4F genes may promote the progression of steatosis to

  8. Synthesis and evaluation of fatty acid amides on the N-oleoylethanolamide-like activation of peroxisome proliferator activated receptor α.

    Science.gov (United States)

    Takao, Koichi; Noguchi, Kaori; Hashimoto, Yosuke; Shirahata, Akira; Sugita, Yoshiaki

    2015-01-01

    A series of fatty acid amides were synthesized and their peroxisome proliferator-activated receptor α (PPAR-α) agonistic activities were evaluated in a normal rat liver cell line, clone 9. The mRNAs of the PPAR-α downstream genes, carnitine-palmitoyltransferase-1 and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase, were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR) as PPAR-α agonistic activities. We prepared nine oleic acid amides. Their PPAR-α agonistic activities were, in decreasing order, N-oleoylhistamine (OLHA), N-oleoylglycine, Oleamide, N-oleoyltyramine, N-oleoylsertonin, and Olvanil. The highest activity was found with OLHA. We prepared and evaluated nine N-acylhistamines (N-acyl-HAs). Of these, OLHA, C16:0-HA, and C18:1Δ(9)-trans-HA showed similar activity. Activity due to the different chain length of the saturated fatty acid peaked at C16:0-HA. The PPAR-α antagonist, GW6471, inhibited the induction of the PPAR-α downstream genes by OLHA and N-oleoylethanolamide (OEA). These data suggest that N-acyl-HAs could be considered new PPAR-α agonists.

  9. Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-delta

    DEFF Research Database (Denmark)

    Yan, Zhen Cheng; Liu, Dao Yan; Zhang, Li Li

    2007-01-01

    Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-delta (PPAR-delta)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow...... or a high-fat diet without and with regular endurance exercise. Exercise in rats on high-fat diet significantly reduced visceral fat mass, blood pressure, and adipocyte size (each p...

  10. Neuroprotección conferida por agonistas PPARs E IGF-1 y su impacto en vías de supervivencia en dos modelos in vitro de la enfermedad de Krabbe

    OpenAIRE

    Martínez Galarza, David Ernesto

    2014-01-01

    La enfermedad de Krabbe (KD, del inglés Krabbe disease) es un desorden neurodegenerativo fatal, causado por mutaciones en el gen para la enzima lisosomal galactocerebrosidasa (GALC), con la consecuente acumulación de galactosilesfingosina (psicosina), esfingolípido altamente tóxico, que genera muerte severa de oligodendrocitos y otros tipos celulares. Los Receptores Activados por el Proliferador Peroxisomal (PPARs), son receptores nucleares conformados por al menos tres tipos: PPARα PPARγ ...

  11. Low Concentrations of o,p’-DDT Inhibit Gene Expression and Prostaglandin Synthesis by Estrogen Receptor-Independent Mechanism in Rat Ovarian Cells

    Science.gov (United States)

    Liu, Jing; Zhao, Meirong; Zhuang, Shulin; Yang, Yan; Yang, Ye; Liu, Weiping

    2012-01-01

    o,p’-DDT is an infamous xenoestrogen as well as a ubiquitous and persistent pollutant. Biomonitoring studies show that women have been internally exposed to o,p’-DDT at range of 0.3–500 ng/g (8.46×10−10 M−1.41×10−6 M) in blood and other tissues. However, very limited studies have investigated the biological effects and mechanism(s) of o,p’-DDT at levels equal to or lower than current exposure levels in human. In this study, using primary cultures of rat ovarian granulosa cells, we determined that very low doses of o,p’-DDT (10−12−10−8 M) suppressed the expression of ovarian genes and production of prostaglandin E2 (PGE2). In vivo experiments consistently demonstrated that o,p’-DDT at 0.5–1 mg/kg inhibited the gene expression and PGE2 levels in rat ovary. The surprising results from the receptor inhibitors studies showed that these inhibitory effects were exerted independently of either classical estrogen receptors (ERs) or G protein-coupled receptor 30 (GPR30). Instead, o,p’-DDT altered gene expression or hormone action via inhibiting the activation of protein kinase A (PKA), rather than protein kinase C (PKC). We further revealed that o,p’-DDT directly interfered with the PKA catalytic subunit. Our novel findings support the hypothesis that exposure to low concentrations of o,p’-DDT alters gene expression and hormone synthesis through signaling mediators beyond receptor binding, and imply that the current exposure levels of o,p’-DDT observed in the population likely poses a health risk to female reproduction. PMID:23209616

  12. The role of prostaglandins in livestock production | Okon | Global ...

    African Journals Online (AJOL)

    ... synthesized) fashion. Prostaglandins are therefore regarded as essential mediators of female reproductive processes, hence, this paper seeks to review the role of Prostaglandins which is exploited in livestock production especially oestrus synchronization and induced parturition. KEYWORDS: Prostaglandins, Production ...

  13. Mice lacking prostaglandin E receptor subtype 4 manifest disrupted lipid metabolism attributable to impaired triglyceride clearance.

    Science.gov (United States)

    Cai, Yin; Ying, Fan; Song, Erfei; Wang, Yu; Xu, Aimin; Vanhoutte, Paul M; Tang, Eva Hoi-Ching

    2015-12-01

    Upon high-fat feeding, prostaglandin E receptor subtype 4 (EP4)-knockout mice gain less body weight than their EP4(+/+) littermates. We investigated the cause of the lean phenotype. The mice showed a 68.8% reduction in weight gain with diminished fat mass that was not attributable to reduced food intake, fat malabsorption, or increased energy expenditure. Plasma triglycerides in the mice were elevated by 244.9%. The increase in plasma triglycerides was independent of changes in hepatic very low density lipoprotein (VLDL)-triglyceride production or intestinal chylomicron-triglyceride synthesis. However, VLDL-triglyceride clearance was drastically impaired in the EP4-knockout mice. The absence of EP4 in mice compromised the activation of lipoprotein lipase (LPL), the key enzyme responsible for trafficking of plasma triglycerides into peripheral tissues. Deficiency in EP4 reduced hepatic mRNA expression of the transcriptional factor cAMP response element binding protein H (by 36.8%) and LPL activators, including apolipoprotein (Apo)a5 (by 40.2%) and Apoc2 (by 61.3%). In summary, the lean phenotype of EP4-deficient mice resulted from reduction in adipose tissue and accretion of other peripheral organs caused by impaired triglyceride clearance. The findings identify a new metabolic dimension in the physiologic role played by endogenous EP4. © FASEB.

  14. Development of PPAR-agonist GW0742 as antidiabetic drug: study in animals

    Directory of Open Access Journals (Sweden)

    Niu HS

    2015-10-01

    Full Text Available Ho-Shan Niu,1 Po-Ming Ku,2,3 Chiang-Shan Niu,1 Juei-Tang Cheng,3,4 Kung-Shing Lee5–71Department of Nursing, Tzu Chi College of Technology, Hualien City, 2Department of Cardiology, 3Department of Medical Research, Chi-Mei Medical Center, Yong Kang, Tainan City, 4Institute of Medical Sciences, Chang Jung Christian University, Guiren, Tainan City, 5Department of Surgery, Division of Neurosurgery, Pingtung Hospital, 6Department of Surgery, Kaohsiung Medical University, 7School of Medicine, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung City, TaiwanBackground: The development of new drugs for the treatment of diabetes mellitus (DM is critically important. Insulin resistance (IR is one of the main problems associated with type-2 DM (T2DM seen in clinics. GW0742, a selective peroxisome proliferator-activated receptor (PPAR-δ agonist, has been shown to ameliorate metabolic abnormalities including IR in skeletal muscle in mice fed high-fructose corn syrup. However, the influence of GW0742 on systemic insulin sensitivity has still not been elucidated. Therefore, it is important to investigate the effect of GW0742 on systemic IR in diabetic rats for the development of new drugs.Methods: The present study used a T2DM animal model to compare the effect of GW0742 on IR using homeostasis model assessment-IR (HOMA-IR and hyperinsulinemic euglycemic clamping. Additionally, the insulinotropic action of GW0742 was investigated in type-1 DM (T1DM rats. Changes in the protein expression of glucose transporter 4 (GLUT4 and phosphoenolpyruvate carboxykinase (PEPCK in skeletal muscle and in liver, respectively, were also identified by Western blots.Results: GW0742 attenuated the increased HOMA-IR in diabetic rats fed a fructose-rich diet. This action was blocked by GSK0660 at the dose sufficient to inhibit PPAR-δ. Improvement of IR by GW0742 was also characterized in diabetic rats using hyperinsulinemic euglycemic clamping. Additionally, an

  15. Increased renin production in mice with deletion of peroxisome proliferator-activated receptor-gamma in juxtaglomerular cells

    DEFF Research Database (Denmark)

    Desch, Michael; Schreiber, Andrea; Schweda, Frank

    2010-01-01

    We recently found that endogenous (free fatty acids) and pharmacological (thiazolidinediones) agonists of nuclear receptor Peroxisome proliferator-activated receptor (PPAR)gamma stimulate renin transcription. In addition, the renin gene was identified as a direct target of PPARgamma. The mouse re...

  16. PPAR Gamma in Neuroblastoma: The Translational Perspectives of Hypoglycemic Drugs

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    Serena Vella

    2016-01-01

    Full Text Available Neuroblastoma (NB is the most common and aggressive pediatric cancer, characterized by a remarkable phenotypic diversity and high malignancy. The heterogeneous clinical behavior, ranging from spontaneous remission to fatal metastatic disease, is attributable to NB biology and genetics. Despite major advances in therapies, NB is still associated with a high morbidity and mortality. Thus, novel diagnostic, prognostic, and therapeutic approaches are required, mainly to improve treatment outcomes of high-risk NB patients. Among neuroepithelial cancers, NB is the most studied tumor as far as PPAR ligands are concerned. PPAR ligands are endowed with antitumoral effects, mainly acting on cancer stem cells, and constitute a possible add-on therapy to antiblastic drugs, in particular for NB with unfavourable prognosis. While discussing clinical background, this review will provide a synopsis of the major studies about PPAR expression in NB, focusing on the potential beneficial effects of hypoglycemic drugs, thiazolidinediones and metformin, to reduce the occurrence of relapses as well as tumor regrowth in NB patients.

  17. The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells

    International Nuclear Information System (INIS)

    Cherukuri, Durga Prasad; Chen, Xiao B.O.; Goulet, Anne-Christine; Young, Robert N.; Han, Yongxin; Heimark, Ronald L.; Regan, John W.; Meuillet, Emmanuelle; Nelson, Mark A.

    2007-01-01

    Accumulating evidence indicates that elevated levels of prostaglandin E 2 (PGE 2 ) can increase intestinal epithelial cell proliferation, and thus play a role in colorectal tumorigenesis. PGE 2 exerts its effects through four G-protein-coupled PGE receptor (EP) subtypes, named the EP1, EP2, EP3, and EP4. Increased phosphorylation of extracellular regulated kinases (ERK1/2) is required for PGE 2 to stimulate cell proliferation of human colon cancer cells. However, the EP receptor(s) that are involved in this process remain unknown. We provide evidence that L-161,982, a selective EP4 receptor antagonist, completely blocks PGE 2 -induced ERK phosphorylation and cell proliferation of HCA-7 cells. In order to identify downstream target genes of ERK1/2 signaling, we found that PGE 2 induces expression of early growth response gene-1 (EGR-1) downstream of ERK1/2 and regulates its expression at the level of transcription. PGE 2 treatment induces phosphorylation of cyclic AMP response element binding protein (CREB) at Ser133 residue and CRE-mediated luciferase activity in HCA-7 cells. Studies with dominant-negative CREB mutant (ACREB) provide clear evidence for the involvement of CREB in PGE 2 driven egr-1 transcription in HCA-7 cells. In conclusion, this study reveals that egr-1 is a target gene of PGE 2 in HCA-7 cells and is regulated via the newly identified EP4/ERK/CREB pathway. Finally our results support the notion that antagonizing EP4 receptors may provide a novel therapeutic approach to the treatment of colon cancer

  18. Impaired leukocyte influx in cervix of postterm women not responding to prostaglandin priming

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    Masironi Britt

    2008-09-01

    Full Text Available Abstract Background Prolonged pregnancies are associated with increased rate of maternal and fetal complications. Post term women could be divided into at least two subgroups, one where parturition is possible to induce by prostaglandins and one where it is not. Our aim was to study parameters in cervical biopsies in women with spontaneous delivery at term (controls and compare to those that are successfully induced post term (responders, and those that are not induced (non-responders, by local prostaglandin treatment. Methods Stromal parameters examined in this study were the accumulation of leukocytes (CD45, CD68, mRNAs and/or proteins for the extracellular matrix degrading enzymes (matrix metalloproteinase (MMP-2, MMP-8 and MMP-9, their inhibitors (tissue inhibitor of MMP (TIMP-1 and TIMP-2, interleukin-8 (IL-8, the platelet activating factor-receptor (PAF-R, syndecan-1 and estrogen binding receptors (estrogen receptor (ERα, ERβ and G-coupled protein receptor (GPR 30 as well as the proliferation marker Ki-67. Results The influx of leukocytes as assessed by CD45 was strongest in the responders, thereafter in the controls and significantly lower in the non-responders. IL-8, PAF-R and MMP-9, all predominantly expressed in leukocytes, showed significantly reduced immunostaining in the group of non-responders, while ERα and GPR30 were more abundant in the non-responders, as compared to the controls. Conclusion The impaired leukocyte influx, as reflected by the reduced number of CD45 positive cells as well as decreased immunostaining of IL-8, PAF-R and MMP-9 in the non-responders, could be one explanation of the failed ripening of the cervix in post term women. If the decreased leukocyte influx is a primary explanation to absent ripening or secondary, as a result of other factors, is yet to be established.

  19. Prostaglandin levels and lysosomal enzyme activities in irradiated rats

    International Nuclear Information System (INIS)

    Trocha, P.J.; Catravas, G.N.

    1980-01-01

    Whole-body irradiation of rats results in the release of hydrolases from lysosomes, an increase in lysosomal enzyme activities, and changes in the prostaglandin levels in spleen and liver tissues. A transient increase in the concentration of prostaglandins E and F and leakage of lysosomal hydrolases occurred in both spleen and liver tissues 3-6 hours after the animals were irradiated. Maximal values for hydrolase activities, prostaglandin E and F content, and release of lysosomal enzymes were found 4 days postirradiation in rat spleens whereas in the liver only slight increases were observed at this time period for prostaglandin F levels. On day 7 there was a final rise in the spleen's prostaglandin E and F concentrations and leakage of hydrolases from the lysosomes before returning to near normal values on day 11. The prostaglandin F concentration in liver was also slightly elevated on the 7th day after irradiation and then decreased to control levels. (author)

  20. Prostaglandin receptor EP3 regulates cell proliferation and migration with impact on survival of endometrial cancer patients.

    Science.gov (United States)

    Zhu, Junyan; Trillsch, Fabian; Mayr, Doris; Kuhn, Christina; Rahmeh, Martina; Hofmann, Simone; Vogel, Marianne; Mahner, Sven; Jeschke, Udo; von Schönfeldt, Viktoria

    2018-01-02

    Prostaglandin E2 (PGE2) receptor 3 (EP3) regulates tumor cell proliferation, migration, and invasion in numerous cancers. The role of EP3 as a prognostic biomarker in endometrial cancer remains unclear. The primary aim of this study was to analyze the prognostic significance of EP3 expression in endometrial cancer. We analyzed the EP3 expression of 140 endometrial carcinoma patients by immunohistochemistry. RL95-2 endometrial cancer cell line was chosen from four endometrial cancer cell lines (RL95-2, Ishikawa, HEC-1-A, and HEC-1-B) according to EP3 expression level. Treated with PGE2 and EP3 antagonist, RL95-2 cells were investigated by MTT, BrdU, and wound healing assay for functional assessment of EP3. EP3 staining differed significantly according to WHO tumor grading in both whole cohort (p = 0.01) and the subgroup of endometrioid carcinoma (p = 0.01). Patients with high EP3 expression in their respective tumors had impaired progression-free survival as well as overall survival in both cohorts above. EP3 expression in the overall cohort was identified as an independent prognostic marker for progression-free survival (HR 1.014, 95%CI 1.003-1.024, p = 0.01) when adjusted for age, stage, grading, and recurrence. Treatment with EP3 antagonists induced upregulation of estrogen receptor β and decreased activity of Ras and led to attenuated proliferation and migration of RL95-2 cells. EP3 seems to play a crucial role in endometrial cancer progression. In the context of limited systemic treatment options for endometrial cancer, this explorative analysis identifies EP3 as a potential target for diagnostic workup and therapy.

  1. Catalpic acid decreases abdominal fat deposition, improves glucose homeostasis and upregulates PPAR alpha expression in adipose tissue.

    Science.gov (United States)

    Hontecillas, Raquel; Diguardo, Maggie; Duran, Elisa; Orpi, Marcel; Bassaganya-Riera, Josep

    2008-10-01

    Catalpic acid (CAT) is a conjugated linolenic acid (CLN) isomer containing trans-9, trans-11, cis-13 double bonds in an 18-carbon chain and it is found primarily in the seed oil of ornamental and medicinal trees and shrubs of the family Bignoniaceae. The objective of this study was to investigate whether CAT decreases obesity and ameliorates insulin sensitivity and glucose tolerance in mice fed high-fat diets. To test the efficacy of CAT in decreasing obesity and diabetes we used both a model of diet-induced obesity (DIO) and a genetic model of obesity (i.e., mice lacking the leptin receptor). Blood was collected on days 0, 7, 14, 21 and 28 for determining fasting glucose and insulin concentrations in plasma. In addition, a glucose tolerance test was administered on day 28. We found that dietary CAT (1g/100g) decreased fasting plasma glucose and insulin concentrations, ameliorated the glucose normalizing ability following glucose challenge and decreased abdominal white adipose tissue accumulation. In white adipose tissue (WAT), CAT upregulated peroxisome proliferator-activated receptor (PPAR) alpha and its responsive genes [i.e., stearoyl-coenzyme A desaturase (SCD1) and enoyl-coenzyme A hydratase (ECH)], increased concentrations of high-density lipoprotein (HDL) cholesterol and decreased plasma triglyceride (TG) levels. CAT decreased abdominal fat deposition, increased HDL cholesterol, decreased TG concentrations, decreased glucose and insulin homeostasis and modulated WAT gene expression in a manner reminiscent of the actions of the PPAR alpha-activating fibrate class of lipid-lowering drugs.

  2. DMPD: Anti-inflammatory actions of PPAR ligands: new insights on cellular andmolecular mechanisms. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17981503 Anti-inflammatory actions of PPAR ligands: new insights on cellular andmol...) (.html) (.csml) Show Anti-inflammatory actions of PPAR ligands: new insights on cellular andmolecular mech...anisms. PubmedID 17981503 Title Anti-inflammatory actions of PPAR ligands: new insight

  3. Regulation of the human SLC25A20 expression by peroxisome proliferator-activated receptor alpha in human hepatoblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Tachibana, Keisuke, E-mail: nya@phs.osaka-u.ac.jp [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); Takeuchi, Kentaro; Inada, Hirohiko [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); Yamasaki, Daisuke [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); The Center for Advanced Medical Engineering and Informatics, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Ishimoto, Kenji [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Tanaka, Toshiya; Hamakubo, Takao; Sakai, Juro; Kodama, Tatsuhiko [Laboratory for System Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo 153-8904 (Japan); Doi, Takefumi [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); The Center for Advanced Medical Engineering and Informatics, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan)

    2009-11-20

    Solute carrier family 25, member 20 (SLC25A20) is a key molecule that transfers acylcarnitine esters in exchange for free carnitine across the mitochondrial membrane in the mitochondrial {beta}-oxidation. The peroxisome proliferator-activated receptor alpha (PPAR{alpha}) is a ligand-activated transcription factor that plays an important role in the regulation of {beta}-oxidation. We previously established tetracycline-regulated human cell line that can be induced to express PPAR{alpha} and found that PPAR{alpha} induces the SLC25A20 expression. In this study, we analyzed the promoter region of the human slc25a20 gene and showed that PPAR{alpha} regulates the expression of human SLC25A20 via the peroxisome proliferator responsive element.

  4. PPAR-δ Agonist With Mesenchymal Stem Cells Induces Type II Collagen-Producing Chondrocytes in Human Arthritic Synovial Fluid.

    Science.gov (United States)

    Heck, Bruce E; Park, Joshua J; Makani, Vishruti; Kim, Eun-Cheol; Kim, Dong Hyun

    2017-08-01

    Osteoarthritis (OA) is an inflammatory joint disease characterized by degeneration of articular cartilage within synovial joints. An estimated 27 million Americans suffer from OA, and the population is expected to reach 67 million in the United States by 2030. Thus, it is urgent to find an effective treatment for OA. Traditional OA treatments have no disease-modifying effect, while regenerative OA therapies such as autologous chondrocyte implantation show some promise. Nonetheless, current regenerative therapies do not overcome synovial inflammation that suppresses the differentiation of mesenchymal stem cells (MSCs) to chondrocytes and the expression of type II collagen, the major constituent of functional cartilage. We discovered a synergistic combination that overcame synovial inflammation to form type II collagen-producing chondrocytes. The combination consists of peroxisome proliferator-activated receptor (PPAR) δ agonist, human bone marrow (hBM)-derived MSCs, and hyaluronic acid (HA) gel. Interestingly, those individual components showed their own strong enhancing effects on chondrogenesis. GW0742, a PPAR-δ agonist, greatly enhanced MSC chondrogenesis and the expression of type II collagen and glycosaminoglycan (GAG) in hBM-MSC-derived chondrocytes. GW0742 also increased the expression of transforming growth factor β that enhances chondrogenesis and suppresses cartilage fibrillation, ossification, and inflammation. HA gel also increased MSC chondrogenesis and GAG production. However, neither GW0742 nor HA gel could enhance the formation of type II collagen-producing chondrocytes from hBM-MSCs within human OA synovial fluid. Our data demonstrated that the combination of hBM-MSCs, PPAR-δ agonist, and HA gel significantly enhanced the formation of type II collagen-producing chondrocytes within OA synovial fluid from 3 different donors. In other words, the novel combination of PPAR-δ agonist, hBM-MSCs, and HA gel can overcome synovial inflammation to form

  5. Structural Features and Transcriptional Activity of Chicken PPARs (α, β, and γ

    Directory of Open Access Journals (Sweden)

    Ichiro Takada

    2013-01-01

    Full Text Available While an understanding of lipid metabolism in chickens is critical for a further improvement of food production, there are few studies concerning differences in lipid metabolism mechanisms between chickens and other species at a molecular level. Chickens have three PPAR gene subtypes (α, β, and γ that function differently from those present in humans and mice. The chicken PPAR-gamma (cPPARγ gene is shorter than that in humans and lacks a γ2 isoform. Moreover, in serum-free media, cPPARγ shows high transcriptional activity without exogenous ligands. Luciferase reporter assays were used to examine the effect of sera on cPPAR transcriptional activities and showed that adult bovine serum and chicken serum highly activate cPPARα and β functions. Moreover, we found that bezafibrate induces the transactivation function of cPPARβ, but not human PPARδ (human PPARβ ortholog. This ligand selectivity relies on one amino acid residue (chicken: Val419, human: Met444. These results show the possibilities for unique functions of cPPARs on chicken-specific lipid glucose metabolism. As such, a better understanding of the molecular mechanisms of lipid metabolism in chickens could result in higher productivity for the poultry industry.

  6. Alpha 1-adrenergic receptor-mediated phosphoinositide hydrolysis and prostaglandin E2 formation in Madin-Darby canine kidney cells. Possible parallel activation of phospholipase C and phospholipase A2

    International Nuclear Information System (INIS)

    Slivka, S.R.; Insel, P.A.

    1987-01-01

    alpha 1-Adrenergic receptors mediate two effects on phospholipid metabolism in Madin-Darby canine kidney (MDCK-D1) cells: hydrolysis of phosphoinositides and arachidonic acid release with generation of prostaglandin E2 (PGE2). The similarity in concentration dependence for the agonist (-)-epinephrine in eliciting these two responses implies that they are mediated by a single population of alpha 1-adrenergic receptors. However, we find that the kinetics of the two responses are quite different, PGE2 production occurring more rapidly and transiently than the hydrolysis of phosphoinositides. The antibiotic neomycin selectively decreases alpha 1-receptor-mediated phosphatidylinositol 4,5-bisphosphate hydrolysis without decreasing alpha 1-receptor-mediated arachidonic acid release and PGE2 generation. In addition, receptor-mediated inositol trisphosphate formation is independent of extracellular calcium, whereas release of labeled arachidonic acid is largely calcium-dependent. Moreover, based on studies obtained with labeled arachidonic acid, receptor-mediated generation of arachidonic acid cannot be accounted for by breakdown of phosphatidylinositol monophosphate, phosphatidylinositol bisphosphate, or phosphatidic acid. Further studies indicate that epinephrine produces changes in formation or turnover of several classes of membrane phospholipids in MDCK cells. We conclude that alpha 1-adrenergic receptors in MDCK cells appear to regulate phospholipid metabolism by the parallel activation of phospholipase C and phospholipase A2. This parallel activation of phospholipases contrasts with models described in other systems which imply sequential activation of phospholipase C and diacylglycerol lipase or phospholipase A2

  7. Prostaglandin F2α–F-Prostanoid Receptor Signalling Promotes Neutrophil Chemotaxis via Chemokine (CXC motif) Ligand-1 in Endometrial Adenocarcinoma

    Science.gov (United States)

    Wallace, Alison E; Sales, Kurt J; Catalano, Roberto D; Anderson, Richard A; Williams, Alistair RW; Wilson, Martin R; Schwarze, Jurgen; Wang, Hongwei; Rossi, Adriano G; Jabbour, Henry N

    2009-01-01

    The prostaglandin F2α (PGF2α) receptor (FP) is elevated in endometrial adenocarcinoma. This study found that PGF2α signalling via FP regulates expression of chemokine (C-X-C motif) ligand 1 (CXCL1) in endometrial adenocarcinoma cells. Expression of CXCL1 and its receptor, CXCR2, are elevated in cancer tissue as compared to normal endometrium and localised to glandular epithelium, endothelium and stroma. Treatment of Ishikawa cells stably transfected with the FP receptor (FPS cells) with 100nM PGF2α increased CXCL1 promoter activity, mRNA and protein expression, and these effects were abolished by co-treatment of cells with FP antagonist or chemical inhibitors of Gq, EGFR and ERK. Similarly, CXCL1 was elevated in response to 100 nM PGF2α in endometrial adenocarcinoma explant tissue. CXCL1 is a potent neutrophil chemoattractant. The expression of CXCR2 colocalised to neutrophils in endometrial adenocarcinoma and increased neutrophils were present in endometrial adenocarcinoma compared with normal endometrium. Conditioned media from PGF2α-treated FPS cells stimulated neutrophil chemotaxis which could be abolished by CXCL1 protein immunoneutralisation of the conditioned media or antagonism of CXCR2. Finally, xenograft tumours in nude mice arising from inoculation with FPS cells showed increased neutrophil infiltration compared to tumours arising from wild-type cells or following treatment of mice bearing FPS tumours with CXCL1-neutralising antibody. In conclusion, our results demonstrate a novel PGF2α-FP pathway that may regulate the inflammatory microenvironment in endometrial adenocarcinoma via neutrophil chemotaxis. PMID:19549892

  8. Peroxisome Proliferator-Activated Receptor-γ in Amyotrophic Lateral Sclerosis and Huntington’s Disease

    Directory of Open Access Journals (Sweden)

    Mahmoud Kiaei

    2008-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a debilitating and one of the most common adult-onset neurodegenerative diseases with the prevalence of about 5 per 100 000 individuals. It results in the progressive loss of upper and lower motor neurons and leads to gradual muscle weakening ultimately causing paralysis and death. ALS has an obscure cause and currently no effective treatment exists. In this review, a potentially important pathway is described that can be activated by peroxisome proliferator-activated receptor-γ (PPAR-γ agonists and has the ability to block the neuropathological damage caused by inflammation in ALS and possibly in other neudegenerative diseases like Huntington's disease (HD. Neuroinflammation is a common pathological feature in neurodegenerative diseases. Therefore, PPAR-γ agonists are thought to be neuroprotective in ALS and HD. We and others have tested the neuroprotective effect of pioglitazone (Actos, a PPAR-γ agonist, in G93A SOD1 transgenic mouse model of ALS and found significant increase in survival of G93A SOD1 mice. These findings suggest that PPAR-γ may be an important regulator of neuroinflammation and possibly a new target for the development of therapeutic strategies for ALS. The involvement of PPAR-γ in HD is currently under investigation, one study finds that the treatment with rosiglitazone had no protection in R6/2 transgenic mouse model of HD. PPAR-γ coactivator-1α (PGC-1α is a transcriptional coactivator that works together with combination of other transcription factors like PPAR-γ in the regulation of mitochondrial biogenesis. Therefore, PPAR-γ is a possible target for ALS and HD as it functions as transcription factor that interacts with PGC-1α. In this review, the role of PPAR-γ in ALS and HD is discussed based on the current literature and hypotheses.

  9. Transcription control and neuronal differentiation by agents that activate the LXR nuclear receptor family.

    Science.gov (United States)

    Schmidt, A; Vogel, R; Holloway, M K; Rutledge, S J; Friedman, O; Yang, Z; Rodan, G A; Friedman, E

    1999-09-10

    LXR and PPAR receptors belong to the nuclear receptor superfamily of transcriptional activating factors. Using ligand-dependent transcription assays, we found that 5-tetradecyloxy-2-furancarboxylic acid (TOFA) transactivates chimeric receptors composed of the glucocorticoid receptor DNA binding domain and the ligand binding regions of PPARalpha, PPARbeta (NUC-1) and LXRbeta (NER) receptors. In the same assays, ligands for PPARs (oleic acid, WY-14643 and L-631,033) and LXRs (hydroxycholesterols) maintain their respective receptor selectivity. TOFA and hydroxycholesterols also stimulate transcription from a minimal fibrinogen promoter that is under the control of AP-1 or NF-kappaB transcription factor binding sites. In addition to their effects on transcription, these LXRbeta activators induce neuronal differentiation in rat pheochromocytoma cells. TOFA and the natural LXR agonist, 22 (R)-hydroxycholesterol, stimulate neurite outgrowth in 55 and 28% of cells, respectively. No neurite outgrowth was induced by the related 22(S)-hydroxycholesterol, which does not activate the LXR family. These results suggest that the hydroxycholesterol signaling pathway has a complex effect on transcription that mediates the activity of TOFA and hydroxycholesterol on neuronal differentiation in pheochromocytoma cells.

  10. Vitamin D deficiency impairs glucose-stimulated insulin secretion and increases insulin resistance by reducing PPAR-γ expression in nonobese Type 2 diabetic rats.

    Science.gov (United States)

    Park, Sunmin; Kim, Da Sol; Kang, Suna

    2016-01-01

    Human studies have provided relatively strong associations of poor vitamin D status with Type 2 diabetes but do not explain the nature of the association. Here, we explored the physiological pathways that may explain how vitamin D status modulates energy, lipid and glucose metabolisms in nonobese Type 2 diabetic rats. Goto-Kakizaki (GK) rats were fed high-fat diets containing 25 (VD-low), 1000 (VD-normal) or 10,000 (VD-high) cholecalciferol-IU/kg diet for 8 weeks. Energy expenditure, insulin resistance, insulin secretory capacity and lipid metabolism were measured. Serum 25-OH-D levels, an index of vitamin D status, increased dose dependently with dietary vitamin D. VD-low resulted in less fat oxidation without a significant difference in energy expenditure and less lean body mass in the abdomen and legs comparison to the VD-normal group. In comparison to VD-low, VD-normal had lower serum triglycerides and intracellular fat accumulation in the liver and skeletal muscles which was associated with down-regulation of the mRNA expressions of sterol regulatory element binding protein-1c and fatty acid synthase and up-regulation of gene expressions of peroxisome proliferator-activated receptors (PPAR)-α and carnitine palmitoyltransferase-1. In euglycemic hyperinsulinemic clamp, whole-body and hepatic insulin resistance was exacerbated in the VD-low group but not in the VD-normal group, possibly through decreasing hepatic insulin signaling and PPAR-γ expression in the adipocytes. In 3T3-L1 adipocytes 1,25-(OH)2-D (10 nM) increased triglyceride accumulation by elevating PPAR-γ expression and treatment with a PPAR-γ antagonist blocked the triglyceride deposition induced by 1,25-(OH)2-D treatment. VD-low impaired glucose-stimulated insulin secretion in hyperglycemic clamp and decreased β-cell mass by decreasing β-cell proliferation. In conclusion, vitamin D deficiency resulted in the dysregulation of glucose metabolism in GK rats by simultaneously increasing insulin

  11. Effect of Pranayama on Ppar-γ, Nf-κB Expressions and Red Complex Microorganisms in Patients with Chronic Periodontitis - A Clinical Trial.

    Science.gov (United States)

    Mahendra, Jaideep; Mahendra, Little; Ananthalakshmi, R; Parthiban, Prathahini S; Cherukuri, Sandhya; Junaid, Mohammed

    2017-06-01

    Sudarshankriya pranayama is the control of breathing movements to regulate the energy flow throughout the body, which has shown to positively affect immune function, autonomic nervous system and psychologic-neuro pathways. The practice of pranayama has been proven to show several benefits such as reduction in stress levels, relieves anxiety and depression, increase in antioxidant levels, reduces insulin resistance and improves respiratory function. The objective of the study was to evaluate the levels of Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ), Nuclear Factor-Kappa B (NF-κB) and the presence of Red Complex Microorganisms (RCM) such as Treponema denticola , Porphyromonas gingivalis and Tannerella forsythia in the subgingivalpl aque samples of chronic periodontitis subjects before and after intervention with pranayama as an adjunct to Scaling and Root Planing (SRP). A total of 30 subjects (control group) were treated with SRP and 30 subjects (pranayama group) underwent SRP and pranayama for three months. Probing Pocket Depth (PPD), Clinical Attachment Level (CAL), Bleeding Index (BI) and Plaque Index (PI) were recorded and the presence of PPAR-γ, NF-κB and RCM were assessed at baseline and after three months using polymerase chain reaction. ANCOVA test was done to compare the clinical parameters between the groups. Fisher's Exact test was done to identify RCM and Mann-Whitney and Wilcoxon-signed test was used to identify the expression of NF-κB and PPAR-γ in the plaque samples. The change in the mean CAL from baseline to third month was significantly higher in pranayama group compared to control group (p≤0.05). There was a statistically significant reduction in the expression of NF-κB and increase in PPAR-γ expression levels in pranayama group on comparison with the control group (p<0.001). The reduction in number of positive samples with T.denticola , P.gingivalis and T.forsythia at third month post-intervention did not affect the change

  12. The nuclear receptor PPARγ as a therapeutic target for cerebrovascular and brain dysfunction in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Nektaria Nicolakakis

    2010-05-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are ligand-activated nuclear transcription factors that regulate peripheral lipid and glucose metabolism. Three subtypes make up the PPAR family (α, γ, β/δ, and synthetic ligands for PPARα (fibrates and PPARγ (Thiazolidinediones, TZDs are currently prescribed for the respective management of dyslipidemia and type 2 diabetes. In contrast to the well characterized action of PPARs in the periphery, little was known about the presence or function of these receptors in the brain and cerebral vasculature, until fairly recently. Indeed, research in the last decade has uncovered these receptors in most brain cell types, and has shown that their activation, particularly that of PPARγ, is implicated in normal brain and cerebrovascular physiology, and confers protection under pathological conditions. Notably, accumulating evidence has highlighted the therapeutic potential of PPARγ ligands in the treatment of brain disorders such as Alzheimer’s disease (AD, leading to the testing of the TZDs pioglitazone and rosiglitazone in AD clinical trials. This review will focus on the benefits of PPARγ agonists for vascular, neuronal and glial networks, and assess the value of these compounds as future AD therapeutics in light of evidence from transgenic mouse models and recent clinical trials.

  13. Prostaglandin Hsynthase immunoreactivity in human gut. An immunohistochemical study

    DEFF Research Database (Denmark)

    Mikkelsen, Hanne Birte; Rumessen, Jüri Johannes; Qvortrup, Klaus

    1991-01-01

    Anatomy, prostaglandin H-synthase, smooth muscle cells, intestine, muscularis externa, immunohistochemistry......Anatomy, prostaglandin H-synthase, smooth muscle cells, intestine, muscularis externa, immunohistochemistry...

  14. Role of contractile prostaglandins and Rho-kinase in growth factor-induced airway smooth muscle contraction

    Directory of Open Access Journals (Sweden)

    Zaagsma Johan

    2005-07-01

    Full Text Available Abstract Background In addition to their proliferative and differentiating effects, several growth factors are capable of inducing a sustained airway smooth muscle (ASM contraction. These contractile effects were previously found to be dependent on Rho-kinase and have also been associated with the production of eicosanoids. However, the precise mechanisms underlying growth factor-induced contraction are still unknown. In this study we investigated the role of contractile prostaglandins and Rho-kinase in growth factor-induced ASM contraction. Methods Growth factor-induced contractions of guinea pig open-ring tracheal preparations were studied by isometric tension measurements. The contribution of Rho-kinase, mitogen-activated protein kinase (MAPK and cyclooxygenase (COX to these reponses was established, using the inhibitors Y-27632 (1 μM, U-0126 (3 μM and indomethacin (3 μM, respectively. The Rho-kinase dependency of contractions induced by exogenously applied prostaglandin F2α (PGF2α and prostaglandin E2 (PGE2 was also studied. In addition, the effects of the selective FP-receptor antagonist AL-8810 (10 μM and the selective EP1-antagonist AH-6809 (10 μM on growth factor-induced contractions were investigated, both in intact and epithelium-denuded preparations. Growth factor-induced PGF2α-and PGE2-release in the absence and presence of Y-27632, U-0126 and indomethacin, was assessed by an ELISA-assay. Results Epidermal growth factor (EGF-and platelet-derived growth factor (PDGF-induced contractions of guinea pig tracheal smooth muscle preparations were dependent on Rho-kinase, MAPK and COX. Interestingly, growth factor-induced PGF2α-and PGE2-release from tracheal rings was significantly reduced by U-0126 and indomethacin, but not by Y-27632. Also, PGF2α-and PGE2-induced ASM contractions were largely dependent on Rho-kinase, in contrast to other contractile agonists like histamine. The FP-receptor antagonist AL-8810 (10 μM significantly

  15. Produtos naturais ativadores de PPAR e marcadores associados ao processo inflamatório na Síndrome Metabólica

    Directory of Open Access Journals (Sweden)

    L.F. Brito

    2013-01-01

    Full Text Available O processo inflamatório é o elo entre a síndrome metabólica e as doenças cardiovasculares. Para verificar a presença e o grau da inflamação, vários biomarcadores têm sido propostos e investigados. Este trabalho tem como objetivo revisar as recentes pesquisas que associam alguns marcadores expressos no tecido adiposo, enfatizando, dentre eles, a adiponectina, a resistina, a leptina e o transportador de glicose GLUT-4 na síndrome metabólica, a relação da inflamação decorrente desse conjunto de desordens metabólicas sob os receptores proliferadores peroxissomais (PPARs, bem como o efeito de diferentes extratos vegetais e produtos naturais bioativos na ativação desses receptores.

  16. Lipids and addiction: how sex steroids, prostaglandins, and cannabinoids interact with drugs of abuse.

    Science.gov (United States)

    Leishman, Emma; Kokesh, Kevin J; Bradshaw, Heather B

    2013-04-01

    Lipidomics aims to identify and characterize all endogenous species of lipids and understand their roles in cellular signaling and, ultimately, the functioning of the organism. We are on the cusp of fully understanding the functions of many of the lipid signaling systems that have been identified for decades (e.g., steroids, prostaglandins), whereas our understanding of newer lipid signaling systems (e.g., endocannabinoids, N-acyl amides) still lags considerably behind. With an emphasis on their roles in the neurophysiology of addiction, we will examine three classes of lipids--sex steroids, prostaglandins, and cannabinoids--and how they work synergistically in the neurocircuitry of motivation. We will first give a brief overview of the biosynthesis for each class of lipid and its receptors, and then summarize what is known about the collective roles of the lipids in cocaine and alcohol abuse. This approach provides a novel view of lipid signaling as a class of molecules and their synergistic roles in addiction. © 2013 New York Academy of Sciences.

  17. Atorvastatin Inhibits the HIF1α-PPAR Axis, Which Is Essential for Maintaining the Function of Human Induced Pluripotent Stem Cells.

    Science.gov (United States)

    Nakashima, Yoshiki; Miyagi-Shiohira, Chika; Noguchi, Hirofumi; Omasa, Takeshi

    2018-06-19

    We herein report a novel mechanism of action of statin preparations using a new drug discovery method. Milk fat globule-EGF factor 8 protein (MFG-E8) was identified from the secretory component of mouse embryonic fibroblast (MEF) as a cell adhesion-promoting factor effective for screening active cellular agents of human induced pluripotent stem cells (hiPSCs) in vitro using electrochemical impedance. Our analyses showed that atorvastatin did not cause death in myocardial cells differentiated from hiPSCs but reduced the pluripotent cell survival in vitro when using serum- and albumin-free media, and inhibited the ability to form teratomas in mice. This result could have been already the cytopathic effect of atorvastatin, and complete elimination of hiPSCs was confirmed in the xenotransplantation assay. The administration of atorvastatin to hiPSCs caused the expression of hypoxia inducible factor (HIF)1α mRNA to be unchanged at 6 hr and downregulated at 24 hr. In addition, the inhibition of the survival of hiPSCs was confirmed by HIF1α-peroxisome proliferator-activated receptor (PPAR) axis inhibition. These results suggest that the addition of atorvastatin to hiPSC cultures reduces the survival of pluripotent cells by suppressing the HIF1α-PPAR axis. In summary, the HIF1α-PPAR axis has an important role in maintaining the survival of pluripotent hiPSCs. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Inhibitors of Fatty Acid Synthesis Induce PPAR α -Regulated Fatty Acid β -Oxidative Genes: Synergistic Roles of L-FABP and Glucose.

    Science.gov (United States)

    Huang, Huan; McIntosh, Avery L; Martin, Gregory G; Petrescu, Anca D; Landrock, Kerstin K; Landrock, Danilo; Kier, Ann B; Schroeder, Friedhelm

    2013-01-01

    While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor- α (PPAR α ) in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High (20 mM) but not physiological (6 mM) glucose conferred on both TOFA and C75 the ability to induce PPAR α transcription of the fatty acid β -oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type (WT) mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associated with an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding protein facilitating TOFA and C75-mediated induction of PPAR α in the context of high glucose at levels similar to those in uncontrolled diabetes.

  19. Transcriptional activation of peroxisome proliferator-activated receptor-γ requires activation of both protein kinase A and Akt during adipocyte differentiation

    International Nuclear Information System (INIS)

    Kim, Sang-pil; Ha, Jung Min; Yun, Sung Ji; Kim, Eun Kyoung; Chung, Sung Woon; Hong, Ki Whan; Kim, Chi Dae; Bae, Sun Sik

    2010-01-01

    Research highlights: → Elevated cAMP activates both PKA and Epac. → PKA activates CREB transcriptional factor and Epac activates PI3K/Akt pathway via Rap1. → Akt modulates PPAR-γ transcriptional activity in concert with CREB. -- Abstract: Peroxisome proliferator-activated receptor-γ (PPAR-γ) is required for the conversion of pre-adipocytes. However, the mechanism underlying activation of PPAR-γ is unclear. Here we showed that cAMP-induced activation of protein kinase A (PKA) and Akt is essential for the transcriptional activation of PPAR-γ. Hormonal induction of adipogenesis was blocked by a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), by a protein kinase A (PKA) inhibitor (H89), and by a Rap1 inhibitor (GGTI-298). Transcriptional activity of PPAR-γ was markedly enhanced by 3-isobutyl-1-methylxanthine (IBMX), but not insulin and dexamethasone. In addition, IBMX-induced PPAR-γ transcriptional activity was blocked by PI3K/Akt, PKA, or Rap1 inhibitors. 8-(4-Chlorophenylthio)-2'-O-methyl-cAMP (8-pCPT-2'-O-Me-cAMP) which is a specific agonist for exchanger protein directly activated by cAMP (Epac) significantly induced the activation of Akt. Furthermore, knock-down of Akt1 markedly attenuated PPAR-γ transcriptional activity. These results indicate that both PKA and Akt signaling pathways are required for transcriptional activation of PPAR-γ, suggesting post-translational activation of PPAR-γ might be critical step for adipogenic gene expression.

  20. Lycium chinense Improves Post-Menopausal Obesity via Regulation of PPAR-γ and Estrogen Receptor-α/β Expressions.

    Science.gov (United States)

    Kim, Mi Hye; Kim, Eun-Jung; Choi, You Yeon; Hong, Jongki; Yang, Woong Mo

    2017-01-01

    The fruit of Lycium chinense Miller (Solanaceae) is used as a functional food and a medicinal herb for treating many specific health concerns. Weight gain induced by estrogen deficiency is a problem for post-menopausal women around the globe. The present study investigates the effects of aqueous extract of L. chinense (LC) on post-menopausal obesity. Female C57BL/6 mice were ovariectomized and fed on high-fat diet (HFD) for 12 weeks to induce post-menopausal obesity. LC extract (1[Formula: see text]mg/kg and 10[Formula: see text]mg/kg) was orally administrated for 6 weeks with continuous HFD feeding. Ovarian adipose tissues and uterus were weighed. Serum triglyceride, cholesterol, LDL-cholesterol and fasting glucose levels were analyzed. The expressions of adipocyte-specific factors and estrogen receptors (ERs) were investigated. Additionally, lipid accumulation was confirmed in differentiated 3T3-L1 adipocytes. Increased body weight due to post-menopausal obesity was ameliorated about 14.7% and 17.76% by treatment of 1[Formula: see text]mg/kg and 10[Formula: see text]mg/kg LC, respectively. LC treatment reduced both of serum lipid and fasting blood glucose levels. Adipocyte hypertrophy and fatty liver were ameliorated in LC-treated groups. In LC-treated adipocyte cells, lipid accumulation was significantly inhibited. The expression of perilipin in adipose tissues was decreased by LC. In addition, expression of PPAR-[Formula: see text] protein was down-regulated in adipose tissues and differentiated adipocytes, while GLUT4 expression was increased in adipose tissues by LC treatment. Moreover, LC treatment up-regulated the expressions of ER-[Formula: see text]/[Formula: see text] accompanied with increased uterine weight. These results showed the ameliorative effects of LC on overweight after menopause. Post-menopausal obesity may be improved by LC treatment.

  1. Utilization of a single antiserum for the direct radioimmunoassay of prostaglandins E and F in semen and prostaglandin F in amniotic fluid

    International Nuclear Information System (INIS)

    Clarke, A.H.; Ing, R.M.Y.; Jones, W.R.; Llewellyn-Jones, D.; Shutt, D.A.

    1974-01-01

    Antibodies to both prostaglandin F (PGF) and prostaglandin E (PGE) were raised in rabbits after they were immunized with prostaglandin F/sub 2a/ conjugated to bovine serum albumin (PGF/sub 2a/--BSA). The antisera were group specific although the antibodies to the F group of prostaglandins showed greater specificity than those to the E group. The antisera were sufficiently specific however to allow the direct radioimmunoassay of PGF and PGE in human semen and PGF in amniotic fluid during induced abortion. Specificity of the direct radioimmunoassay was checked by chromatographic separation of the prostaglandins prior to analysis. Estimation of the prostaglandins in the semen of 30 men attending the infertility clinic showed that 19 of the men had normal semen levels of PGE and PGF of 68 +- 7 (SE) and 6.0 +- 0.6 μg/ml respectively, as compared with data on normal fertile males, whilst the other 11 men had lower levels of 16 +- 2 (SE) and 0.8 +- 0.1 μg/ml respectively. Application of the method to amniotic fluid showed that the PGF concentration in amniotic fluid during the induction of abortion with extra-ovular saline increased from less than 0.6 ng/ml to 6.4 ng/ml when the induction-abortion intervals ranged from 6 to 48 hours. (U.S.)

  2. Genomic organization of the mouse peroxisome proliferator-activated receptor beta/delta gene

    DEFF Research Database (Denmark)

    Larsen, Leif K; Amri, Ez-Zoubir; Mandrup, Susanne

    2002-01-01

    Peroxisome proliferator-activated receptor (PPAR) beta/delta is ubiquitously expressed, but the level of expression differs markedly between different cell types. In order to determine the molecular mechanisms governing PPARbeta/delta gene expression, we have isolated and characterized the mouse...

  3. PPAR-gamma activation is associated with reduced liver ischemia-reperfusion injury and altered tissue-resident macrophages polarization in a mouse model.

    Science.gov (United States)

    Linares, Ivan; Farrokhi, Kaveh; Echeverri, Juan; Kaths, Johan Moritz; Kollmann, Dagmar; Hamar, Matyas; Urbanellis, Peter; Ganesh, Sujani; Adeyi, Oyedele A; Yip, Paul; Selzner, Markus; Selzner, Nazia

    2018-01-01

    PPAR-gamma (γ) is highly expressed in macrophages and its activation affects their polarization. The effect of PPAR-γ activation on Kupffer cells (KCs) and liver ischemia-reperfusion injury (IRI) has not yet been evaluated. We investigated the effect of PPAR-γ activation on KC-polarization and IRI. Seventy percent (70%) liver ischemia was induced for 60mins. PPAR-γ-agonist or vehicle was administrated before reperfusion. PPAR-γ-antagonist was used to block PPAR-γ activation. Liver injury, necrosis, and apoptosis were assessed post-reperfusion. Flow-cytometry determined KC-phenotypes (pro-inflammatory Nitric Oxide +, anti-inflammatory CD206+ and anti-inflammatory IL-10+). Liver injury assessed by serum AST was significantly decreased in PPAR-γ-agonist versus control group at all time points post reperfusion (1hr: 3092±105 vs 4469±551; p = 0.042; 6hr: 7041±1160 vs 12193±1143; p = 0.015; 12hr: 5746±328 vs 8608±1259; p = 0.049). Furthermore, liver apoptosis measured by TUNEL-staining was significantly reduced in PPAR-γ-agonist versus control group post reperfusion (1hr:2.46±0.49 vs 6.90±0.85%;p = 0.001; 6hr:26.40±2.93 vs 50.13±8.29%; p = 0.048). H&E staining demonstrated less necrosis in PPAR-γ-agonist versus control group (24hr:26.66±4.78 vs 45.62±4.57%; p = 0.032). The percentage of pro-inflammatory NO+ KCs was significantly lower at all post reperfusion time points in the PPAR-γ-agonist versus control group (1hr:28.49±4.99 vs 53.54±9.15%; p = 0.040; 6hr:5.51±0.54 vs 31.12±9.58%; p = 0.009; 24hr:4.15±1.50 vs 17.10±4.77%; p = 0.043). In contrast, percentage of anti-inflammatory CD206+ KCs was significantly higher in PPAR-γ-agonist versus control group prior to IRI (8.62±0.96 vs 4.88 ±0.50%; p = 0.04). Administration of PPAR-γ-antagonist reversed the beneficial effects on AST, apoptosis, and pro-inflammatory NO+ KCs. PPAR-γ activation reduces IRI and decreases the pro-inflammatory NO+ Kupffer cells. PPAR-γ activation can become an

  4. Peroxisome proliferator-activated receptors (PPAR) agonists affect cell viability, apoptosis and expression of cell cycle related proteins in cell lines of glial brain tumors

    Czech Academy of Sciences Publication Activity Database

    Straková, N.; Ehrmann, J.; Bartoš, Jan; Malíková, J.; Doležel, Jaroslav; Kolář, Z.

    2005-01-01

    Roč. 52, - (2005), s. 126-136 ISSN 0028-2685 Institutional research plan: CEZ:AV0Z50380511; CEZ:AV0Z5038910 Keywords : PPAR * glioplasma * cell cycle Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.731, year: 2005

  5. Involvement of the Retinoid X Receptor Ligand in the Anti-Inflammatory Effect Induced by Peroxisome Proliferator-Activated Receptor Agonist In Vivo

    Directory of Open Access Journals (Sweden)

    Atsuki Yamamoto

    2011-01-01

    Full Text Available Peroxisome proliferator-activated receptor γ (PPARγ forms a heterodimeric DNA-binding complex with retinoid X receptors (RXRs. It has been reported that the effect of the PPAR agonist is reduced in hepatocyte RXR-deficient mice. Therefore, it is suggested that the endogenous RXR ligand is involved in the PPARγ agonist-induced anti-inflammatory effect. However, the participation of the RXR ligand in the PPARγ-induced anti-inflammatory effect is unknown. Here, we investigated the influence of RXR antagonist on the anti-inflammatory effect of PPARγ agonist pioglitazone in carrageenan test. In addition, we also examined the influence of PPAR antagonist on the anti-inflammatory effect induced by RXR agonist NEt-3IP. The RXR antagonist suppressed the antiedema effect of PPARγ agonist. In addition, the anti-inflammatory effect of RXR agonist was suppressed by PPARγ antagonist. PPARγ agonist-induced anti-inflammatory effects were reversed by the RXR antagonist. Thus, we showed that the endogenous RXR ligand might contribute to the PPARγ agonist-induced anti-inflammatory effect.

  6. Cytotoxic activities of amentoflavone against human breast and cervical cancers are mediated by increasing of PTEN expression levels due to peroxisomes proliferate-activated receptor {gamma} activation

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Eunjung; Shin, Soyoung; Lee, Jeeyoung; Lee, So Jung; Kim, Jinkyoung; Yoon, Doyoung; Kim, Yangmee [Konkuk Univ., Seoul (Korea, Republic of); Woo, Eunrhan [Chosun Univ., Gwangju (Korea, Republic of)

    2012-07-15

    Human peroxisomes proliferate-activated receptor gamma (hPPAR{gamma}) has been implicated in numerous pathologies, including obesity, diabetes, and cancer. Previously, we verified that amentoflavone is an activator of hPPAR{gamma} and probed the molecular basis of its action. In this study, we investigated the mechanism of action of amentoflavone in cancer cells and demonstrated that amentoflavone showed strong cytotoxicity against MCF-7 and HeLa cancer cell lines. We showed that hPPAR{gamma} expression in MCF-7 and HeLa cells is specifically stimulated by amentoflavone, and suggested that amentoflavone-induced cytotoxic activities are mediated by activation of hPPAR{gamma} in these two cancer cell lines. Moreover, amentoflavone increased PTEN levels in these two cancer cell lines, indicating that the cytotoxic activities of amentoflavone are mediated by increasing of PTEN expression levels due to hPPAR{gamma} activation.

  7. Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors.

    Science.gov (United States)

    Melis, Miriam; Pillolla, Giuliano; Luchicchi, Antonio; Muntoni, Anna Lisa; Yasar, Sevil; Goldberg, Steven R; Pistis, Marco

    2008-12-17

    Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-alpha triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-alpha in the brain and provide a potential new target for the treatment of nicotine addiction.

  8. Metabolomics: An Essential Tool to Understand the Function of Peroxisome Proliferator–Activated Receptor Alpha

    Science.gov (United States)

    Montanez, Jessica E.; Peters, Jeffrey M.; Correll, Jared B.; Gonzalez, Frank J.; Patterson, Andrew D.

    2013-01-01

    The peroxisome proliferator–activated receptor (PPAR) family of nuclear hormone transcription factors (PPARα, PPARβ/δ, and PPARγ) is regulated by a wide array of ligands including natural and synthetic chemicals. PPARs have important roles in control of energy metabolism and are known to influence inflammation, differentiation, carcinogenesis, and chemical toxicity. As such, PPARs have been targeted as therapy for common disorders such as cancer, metabolic syndrome, obesity, and diabetes. The recent application of metabolomics, or the global, unbiased measurement of small molecules found in biofluids, or extracts from cells, tissues, or organisms, has advanced our understanding of the varied and important roles that the PPARs have in normal physiology as well as in pathophysiological processes. Continued development and refinement of analytical platforms, and the application of new bioinformatics strategies, have accelerated the widespread use of metabolomics and have allowed further integration of small molecules into systems biology. Recent studies using metabolomics to understand PPARα function, as well as to identify PPARα biomarkers associated with drug efficacy/toxicity and drug-induced liver injury, will be discussed. PMID:23197196

  9. Impaired peroxisome proliferator-activated receptor γ function through mutation of a conserved salt bridge (R425C) in familial partial lipodystrophy

    NARCIS (Netherlands)

    Jeninga, E.H.; van Beekum, P.O; van Dijk, A.D.J.; Hamers, N.; Bonvin, A.M.J.J.; Berger, R.; Kalkhoven, E.

    2007-01-01

    The nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ plays a key role in the regulation of glucose and lipid metabolism in adipocytes by regulating their differentiation, maintenance, and function. A heterozygous mutation in the PPARG gene, which changes an arginine residue at

  10. Altered aortic and cremaster muscle prostaglandin synthesis in diabetic rats

    International Nuclear Information System (INIS)

    Myers, T.O.; Messina, E.J.; Rodrigues, A.M.; Gerritsen, M.E.

    1985-01-01

    Alterations in the synthesis and release of prostaglandins have been reported in humans and animal models of diabetes mellitus. In the present study synthesis and release of prostaglandins by thoracic aorta and cremaster muscle of rats with streptozotocin-induced diabetes of 8 wk duration was compared with age-matched controls. Prostaglandin synthesis was assessed by the measurement of immunoreactive prostaglandin E2 (PGE2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) release and by quantifying metabolism of exogenous [1- 14 C]arachidonic acid by thoracic aortic rings and minced cremaster muscle. These studies indicate that diminished prostacyclin (PGI2) and/or PGE2 production is not a general feature of all diabetic vascular tissues, suggesting that large and small blood vessels may not be similarly affected by diabetes in regard to the metabolism of exogenous arachidonic acid and the synthesis and release of prostaglandins. Furthermore, the vascular changes often observed in conjunction with diabetes, i.e., alterations in vascular reactivity and microangiopathy in small blood vessels and atherosclerosis of large blood vessels may be related in some way to the segmental differences observed in prostaglandin synthesis

  11. Peroxisome proliferator-activated receptor-gamma agonists suppress tissue factor overexpression in rat balloon injury model with paclitaxel infusion.

    Directory of Open Access Journals (Sweden)

    Jun-Bean Park

    Full Text Available The role and underlying mechanisms of rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-γ agonist, on myocardial infarction are poorly understood. We investigated the effects of this PPAR-γ agonist on the expression of tissue factor (TF, a primary molecule for thrombosis, and elucidated its underlying mechanisms. The PPAR-γ agonist inhibited TF expression in response to TNF-α in human umbilical vein endothelial cells, human monocytic leukemia cell line, and human umbilical arterial smooth muscle cells. The overexpression of TF was mediated by increased phosphorylation of mitogen-activated protein kinase (MAPK, which was blocked by the PPAR-γ agonist. The effective MAPK differed depending on each cell type. Luciferase and ChIP assays showed that transcription factor, activator protein-1 (AP-1, was a pivotal target of the PPAR-γ agonist to lower TF transcription. Intriguingly, two main drugs for drug-eluting stent, paclitaxel or rapamycin, significantly exaggerated thrombin-induced TF expression, which was also effectively blocked by the PPAR-γ agonist in all cell types. This PPAR-γ agonist did not impair TF pathway inhibitor (TFPI in three cell types. In rat balloon injury model (Sprague-Dawley rats, n = 10/group with continuous paclitaxel infusion, the PPAR-γ agonist attenuated TF expression by 70±5% (n = 4; P<0.0001 in injured vasculature. Taken together, rosiglitazone reduced TF expression in three critical cell types involved in vascular thrombus formation via MAPK and AP-1 inhibitions. Also, this PPAR-γ agonist reversed the paclitaxel-induced aggravation of TF expression, which suggests a possibility that the benefits might outweigh its risks in a group of patients with paclitaxel-eluting stent implanted.

  12. Statins and PPAR{alpha} agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, Timothy E [Department of Safety Assessment, Merck Research Laboratories, WP45-319, Merck Research Laboratories, West Point, PA 19486 (United States); Zhang, Xiaohua [Department of Biometrics Research, Merck Research Laboratories, West Point, PA 19486 (United States); Shi, Shu [Department of Safety Assessment, Merck Research Laboratories, WP45-319, Merck Research Laboratories, West Point, PA 19486 (United States); Umbenhauer, Diane R [Department of Safety Assessment, Merck Research Laboratories, WP45-319, Merck Research Laboratories, West Point, PA 19486 (United States)

    2005-11-01

    Statins and fibrates (weak PPAR{alpha} agonists) are prescribed for the treatment of lipid disorders. Both drugs cause myopathy, but with a low incidence, 0.1-0.5%. However, combined statin and fibrate therapy can enhance myopathy risk. We tested the myotoxic potential of PPAR subtype selective agonists alone and in combination with statins in a differentiated rat myotube model. A pharmacologically potent experimental PPAR{alpha} agonist, Compound A, induced myotoxicity as assessed by TUNEL staining at a minimum concentration of 1 nM, while other weaker PPAR{alpha} compounds, for example, WY-14643, Gemfibrozil and Bezafibrate increased the percentage of TUNEL-positive nuclei at micromolar concentrations. In contrast, the PPAR{gamma} agonist Rosiglitazone caused little or no cell death at up to 10 {mu}M and the PPAR{delta} ligand GW-501516 exhibited comparatively less myotoxicity than that seen with Compound A. An experimental statin (Compound B) and Atorvastatin also increased the percentage of TUNEL-positive nuclei and co-treatment with WY-14643, Gemfibrozil or Bezafibrate had less than a full additive effect on statin-induced cell killing. The mechanism of PPAR{alpha} agonist-induced cell death was different from that of statins. Unlike statins, Compound A and WY-14643 did not activate caspase 3/7. In addition, mevalonate and geranylgeraniol reversed the toxicity caused by statins, but did not prevent the cell killing induced by WY-14643. Furthermore, unlike statins, Compound A did not inhibit the isoprenylation of rab4 or rap1a. Interestingly, Compound A and Compound B had differential effects on ATP levels. Taken together, these observations support the hypothesis that in rat myotube cultures, PPAR{alpha} agonism mediates in part the toxicity response to PPAR{alpha} compounds. Furthermore, PPAR{alpha} agonists and statins cause myotoxicity through distinct and independent pathways.

  13. Intracrine prostaglandin E2 pro-tumoral actions in prostate epithelial cells originate from non-canonical pathways.

    Science.gov (United States)

    Madrigal-Martínez, Antonio; Fernández-Martínez, Ana B; Lucio Cazaña, Francisco J

    2018-04-01

    Prostaglandin E 2 (PGE 2 ) increases cell proliferation and stimulates migratory and angiogenic abilities in prostate cancer cells. However, the effects of PGE 2 on non-transformed prostate epithelial cells are unknown, despite the fact that PGE 2 overproduction has been found in benign hyperplastic prostates. In the present work we studied the effects of PGE 2 in immortalized, non-malignant prostate epithelial RWPE-1 cells and found that PGE 2 increased cell proliferation, cell migration, and production of vascular endothelial growth factor-A, and activated in vitro angiogenesis. These actions involved a non-canonic intracrine mechanism in which the actual effector was intracellular PGE 2 (iPGE 2 ) instead of extracellular PGE 2 : inhibition of the prostaglandin uptake transporter (PGT) or antagonism of EP receptors prevented the effects of PGE 2 , which indicated that PGE 2 activity depended on its carrier-mediated translocation from the outside to the inside of cells and that EP receptors located intracellularly (iEP) mediated the effects of PGE 2 . iPGE 2 acted through transactivation of epidermal growth factor-receptor (EGFR) by iEP, leading to increased expression and activity of hypoxia-inducible factor-1α (HIF-1α). Interestingly, iPGE 2 also mediates the effects of PGE 2 on prostate cancer PC3 cells through the axis iPGE 2 -iEP receptors-EGFR-HIF-1α. Thus, this axis might be responsible for the growth-stimulating effects of PGE 2 on prostate epithelial cells, thereby contributing to prostate proliferative diseases associated with chronic inflammation. Since this PGT-dependent non-canonic intracrine mechanism of PGE 2 action operates in both benign and malignant prostate epithelial cells, PGT inhibitors should be tested as a novel therapeutic modality to treat prostate proliferative disease. © 2017 Wiley Periodicals, Inc.

  14. Influence of endogenous pyrogen on the cerebral prostaglandin-synthetase system.

    Science.gov (United States)

    Ziel, R; Krupp, P

    1976-11-15

    The biotransformation of arachidonic acid to prostaglandins in vitro is specifically augmented by endogenous pyrogen to a degree depending on the concentration applied, providing that the microsomal fraction of the cerebral cortex is used as prostaglandin-synthetase system. This effect is inhibited by non-steroidal anti-inflammatory agents. These findings are compatible with the hypothesis that prostaglandins might act as mediators of the febrile reaction induced by endogenous pyrogen.

  15. Food Components Modulate Obesity and Energy Metabolism via the Transcriptional Regulation of Lipid-Sensing Nuclear Receptors.

    Science.gov (United States)

    Goto, Tsuyoshi; Takahashi, Nobuyuki; Kawada, Teruo

    2015-01-01

    Obesity is a major risk factor for chronic diseases such as diabetes, cardiovascular diseases, and hypertension. Many modern people have a tendency to overeat owing to stress and loosening of self-control. Moreover, energy expenditure varies greatly among individuals. Scientific reduction of obesity is important under these circumstances. Furthermore, recent research on molecular levels has clarified the differentiation of adipocytes, the level of subsequent fat accumulation, and the secretion of the biologically active adipokines by adipocytes. Adipose tissues and obesity have become the most important target for the prevention and treatment of many chronic diseases. We have identified various food-derived compounds modulating nuclear receptors, especially peroxisome proliferators-activated receptor(PPAR), in the regulation of energy metabolism and obesity. In this review, we discuss the PPARs that are most important in obesity and energy metabolism.

  16. Carbonic anhydrase III regulates peroxisome proliferator-activated receptor-{gamma}2

    Energy Technology Data Exchange (ETDEWEB)

    Mitterberger, Maria C. [Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, 6020 Innsbruck (Austria); Kim, Geumsoo [Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-8012 (United States); Rostek, Ursula [Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, 6020 Innsbruck (Austria); Levine, Rodney L. [Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-8012 (United States); Zwerschke, Werner, E-mail: werner.zwerschke@oeaw.ac.at [Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, 6020 Innsbruck (Austria)

    2012-05-01

    Carbonic anhydrase III (CAIII) is an isoenzyme of the CA family. Because of its low specific anhydrase activity, physiological functions in addition to hydrating CO{sub 2} have been proposed. CAIII expression is highly induced in adipogenesis and CAIII is the most abundant protein in adipose tissues. The function of CAIII in both preadipocytes and adipocytes is however unknown. In the present study we demonstrate that adipogenesis is greatly increased in mouse embryonic fibroblasts (MEFs) from CAIII knockout (KO) mice, as demonstrated by a greater than 10-fold increase in the induction of fatty acid-binding protein-4 (FABP4) and increased triglyceride formation in CAIII{sup -/-} MEFs compared with CAIII{sup +/+} cells. To address the underlying mechanism, we investigated the expression of the two adipogenic key regulators, peroxisome proliferator-activated receptor-{gamma}2 (PPAR{gamma}2) and CCAAT/enhancer binding protein-{alpha}. We found a considerable (approximately 1000-fold) increase in the PPAR{gamma}2 expression in the CAIII{sup -/-} MEFs. Furthermore, RNAi-mediated knockdown of endogenous CAIII in NIH 3T3-L1 preadipocytes resulted in a significant increase in the induction of PPAR{gamma}2 and FABP4. When both CAIII and PPAR{gamma}2 were knocked down, FABP4 was not induced. We conclude that down-regulation of CAIII in preadipocytes enhances adipogenesis and that CAIII is a regulator of adipogenic differentiation which acts at the level of PPAR{gamma}2 gene expression. -- Highlights: Black-Right-Pointing-Pointer We discover a novel function of Carbonic anhydrase III (CAIII). Black-Right-Pointing-Pointer We show that CAIII is a regulator of adipogenesis. Black-Right-Pointing-Pointer We demonstrate that CAIII acts at the level of PPAR{gamma}2 gene expression. Black-Right-Pointing-Pointer Our data contribute to a better understanding of the role of CAIII in fat tissue.

  17. DNA sequence variants in PPARGC1A, a gene encoding a coactivator of the ω-3 LCPUFA sensing PPAR-RXR transcription complex, are associated with NV AMD and AMD-associated loci in genes of complement and VEGF signaling pathways.

    Directory of Open Access Journals (Sweden)

    John Paul SanGiovanni

    Full Text Available Increased intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFAs and use of peroxisome proliferator activator receptor (PPAR-activating drugs are associated with attenuation of pathologic retinal angiogenesis. ω-3 LCPUFAs are endogenous agonists of PPARs. We postulated that DNA sequence variation in PPAR gamma (PPARG co-activator 1 alpha (PPARGC1A, a gene encoding a co-activator of the LCPUFA-sensing PPARG-retinoid X receptor (RXR transcription complex, may influence neovascularization (NV in age-related macular degeneration (AMD.We applied exact testing methods to examine distributions of DNA sequence variants in PPARGC1A for association with NV AMD and interaction of AMD-associated loci in genes of complement, lipid metabolism, and VEGF signaling systems. Our sample contained 1858 people from 3 elderly cohorts of western European ancestry. We concurrently investigated retinal gene expression profiles in 17-day-old neonatal mice on a 2% LCPUFA feeding paradigm to identify LCPUFA-regulated genes both associated with pathologic retinal angiogenesis and known to interact with PPARs or PPARGC1A.A DNA coding variant (rs3736265 and a 3'UTR-resident regulatory variant (rs3774923 in PPARGC1A were independently associated with NV AMD (exact P = 0.003, both SNPs. SNP-SNP interactions existed for NV AMD (P<0.005 with rs3736265 and a AMD-associated variant in complement factor B (CFB, rs512559. PPARGC1A influences activation of the AMD-associated complement component 3 (C3 promoter fragment and CFB influences activation and proteolysis of C3. We observed interaction (P ≤ 0.003 of rs3736265 with a variant in vascular endothelial growth factor A (VEGFA, rs3025033, a key molecule in retinal angiogenesis. Another PPARGC1A coding variant (rs8192678 showed statistical interaction with a SNP in the VEGFA receptor fms-related tyrosine kinase 1 (FLT1, rs10507386; P ≤ 0.003. C3 expression was down-regulated 2-fold in retinas of ω-3 LCPUFA-fed mice

  18. DNA sequence variants in PPARGC1A, a gene encoding a coactivator of the ω-3 LCPUFA sensing PPAR-RXR transcription complex, are associated with NV AMD and AMD-associated loci in genes of complement and VEGF signaling pathways.

    Science.gov (United States)

    SanGiovanni, John Paul; Chen, Jing; Sapieha, Przemyslaw; Aderman, Christopher M; Stahl, Andreas; Clemons, Traci E; Chew, Emily Y; Smith, Lois E H

    2013-01-01

    Increased intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFAs) and use of peroxisome proliferator activator receptor (PPAR)-activating drugs are associated with attenuation of pathologic retinal angiogenesis. ω-3 LCPUFAs are endogenous agonists of PPARs. We postulated that DNA sequence variation in PPAR gamma (PPARG) co-activator 1 alpha (PPARGC1A), a gene encoding a co-activator of the LCPUFA-sensing PPARG-retinoid X receptor (RXR) transcription complex, may influence neovascularization (NV) in age-related macular degeneration (AMD). We applied exact testing methods to examine distributions of DNA sequence variants in PPARGC1A for association with NV AMD and interaction of AMD-associated loci in genes of complement, lipid metabolism, and VEGF signaling systems. Our sample contained 1858 people from 3 elderly cohorts of western European ancestry. We concurrently investigated retinal gene expression profiles in 17-day-old neonatal mice on a 2% LCPUFA feeding paradigm to identify LCPUFA-regulated genes both associated with pathologic retinal angiogenesis and known to interact with PPARs or PPARGC1A. A DNA coding variant (rs3736265) and a 3'UTR-resident regulatory variant (rs3774923) in PPARGC1A were independently associated with NV AMD (exact P = 0.003, both SNPs). SNP-SNP interactions existed for NV AMD (Pcomplement factor B (CFB, rs512559). PPARGC1A influences activation of the AMD-associated complement component 3 (C3) promoter fragment and CFB influences activation and proteolysis of C3. We observed interaction (P ≤ 0.003) of rs3736265 with a variant in vascular endothelial growth factor A (VEGFA, rs3025033), a key molecule in retinal angiogenesis. Another PPARGC1A coding variant (rs8192678) showed statistical interaction with a SNP in the VEGFA receptor fms-related tyrosine kinase 1 (FLT1, rs10507386; P ≤ 0.003). C3 expression was down-regulated 2-fold in retinas of ω-3 LCPUFA-fed mice - these animals also showed 70% reduction in retinal NV (P

  19. Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling

    Directory of Open Access Journals (Sweden)

    Helle Sadam

    2018-03-01

    Full Text Available Background: Neuropathological findings support an autoimmune etiology as an underlying factor for loss of orexin-producing neurons in spontaneous narcolepsy type 1 (narcolepsy with cataplexy; sNT1 as well as in Pandemrix influenza vaccine-induced narcolepsy type 1 (Pdmx-NT1. The precise molecular target or antigens for the immune response have, however, remained elusive. Methods: Here we have performed a comprehensive antigenic repertoire analysis of sera using the next-generation phage display method - mimotope variation analysis (MVA. Samples from 64 children and adolescents were analyzed: 10 with Pdmx-NT1, 6 with sNT1, 16 Pandemrix-vaccinated, 16 H1N1 infected, and 16 unvaccinated healthy individuals. The diagnosis of NT1 was defined by the American Academy of Sleep Medicine international criteria of sleep disorders v3. Findings: Our data showed that although the immunoprofiles toward vaccination were generally similar in study groups, there were also striking differences in immunoprofiles between sNT1 and Pdmx-NT1 groups as compared with controls. Prominent immune response was observed to a peptide epitope derived from prostaglandin D2 receptor (DP1, as well as peptides homologous to B cell lymphoma 6 protein. Further validation confirmed that these can act as true antigenic targets in discriminating NT1 diseased along with a novel epitope of hemagglutinin of H1N1 to delineate exposure to H1N1. Interpretation: We propose that DP1 is a novel molecular target of autoimmune response and presents a potential diagnostic biomarker for NT1. DP1 is involved in the regulation of non-rapid eye movement (NREM sleep and thus alterations in its functions could contribute to the disturbed sleep regulation in NT1 that warrants further studies. Together our results also show that MVA is a helpful method for finding novel peptide antigens to classify human autoimmune diseases, possibly facilitating the design of better therapies. Keywords: Narcolepsy type 1

  20. Spinal antinflammatory action of Diclofenac.

    Science.gov (United States)

    Sandri, Alberto

    2016-06-01

    Diclofenac is a non-steroidal antinflammatory drug (NSAID) that finds indication in the treatment of debilitating pathologies characterized by chronic pain sustained by inflammation, such as in rheumatic disease (rheumatoid arthritis or osteoarthritis) or periarthritis, bursitis, tendonitis, myositis and sciatica. Its properties differentiate it from other NSAIDs. In fact, diclofenac's increased effect on spinal nociception and chronic neuro-inflammatory pain may be referred to: 1) its synergistic effects on peroxisome proliferator-activated receptor-γ (PPAR- γ) activation and prostaglandin synthesis inhibition (COX-2 inhibition); 2) its capacity of suppressing neuronal hyperexcitability through the blockage of neuronal K+ channels in a concentration-dependant manner; and 3) its facility to cross the blood-brain barrier.

  1. Wake-promoting effects of ONO-4127Na, a prostaglandin DP1 receptor antagonist, in hypocretin/orexin deficient narcoleptic mice.

    Science.gov (United States)

    Sagawa, Yohei; Sato, Masatoshi; Sakai, Noriaki; Chikahisa, Sachiko; Chiba, Shintaro; Maruyama, Takashi; Yamamoto, Junki; Nishino, Seiji

    2016-11-01

    Prostaglandin (PG)D2 is an endogenous sleep substance, and a series of animal studies reported that PGD2 or PGD2 receptor (DP1) agonists promote sleep, while DP1 antagonists promote wakefulness. This suggests the possibility of use of PG DP1 antagonists as wake-promoting compounds. We therefore evaluated the wake-promoting effects of ONO-4127Na, a DP1 antagonist, in a mouse model of narcolepsy (i.e., orexin/ataxin-3 transgenic mice) and compared those to effects of modafinil. ONO-4127Na perfused in the basal forebrain (BF) area potently promoted wakefulness in both wild type and narcoleptic mice, and the wake-promoting effects of ONO-4127Na at 2.93 × 10(-4) M roughly corresponded to those of modafinil at 100 mg/kg (p.o.). The wake promoting effects of ONO-4127Na was observed both during light and dark periods, and much larger effects were seen during the light period when mice slept most of the time. ONO-4127Na, when perfused in the hypothalamic area, had no effects on sleep. We further demonstrated that wake-promoting effects of ONO-4127Na were abolished in DP1 KO mice, confirming that the wake-promoting effect of ONO-4127Na is mediated by blockade of the PG DP1 receptors located in the BF area. ONO-4127Na reduced DREM, an EEG/EMG assessment of behavioral cataplexy in narcoleptic mice, suggesting that ONO-4127Na is likely to have anticataplectic effects. DP1 antagonists may be a new class of compounds for the treatment of narcolepsy-cataplexy, and further studies are warranted. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Thermodynamics in Gliomas: Interactions between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma

    Directory of Open Access Journals (Sweden)

    Alexandre Vallée

    2017-05-01

    Full Text Available Gliomas cells are the site of numerous metabolic and thermodynamics abnormalities with an increasing entropy rate which is characteristic of irreversible processes driven by changes in Gibbs energy, heat production, intracellular acidity, membrane potential gradient, and ionic conductance. We focus our review on the opposing interactions observed in glioma between the canonical WNT/beta-catenin pathway and PPAR gamma and their metabolic and thermodynamic implications. In gliomas, WNT/beta-catenin pathway is upregulated while PPAR gamma is downregulated. Upregulation of WNT/beta-catenin signaling induces changes in key metabolic enzyme that modify their thermodynamics behavior. This leads to activation pyruvate dehydrogenase kinase 1(PDK-1 and monocarboxylate lactate transporter 1 (MCT-1. Consequently, phosphorylation of PDK-1 inhibits pyruvate dehydrogenase complex (PDH. Thus, a large part of pyruvate cannot be converted into acetyl-CoA in mitochondria and in TCA (tricarboxylic acid cycle. This leads to aerobic glycolysis despite the availability of oxygen, named Warburg effect. Cytoplasmic pyruvate is, in major part, converted into lactate. The WNT/beta-catenin pathway induces also the transcription of genes involved in cell proliferation, cell invasiveness, nucleotide synthesis, tumor growth, and angiogenesis, such as c-Myc, cyclin D1, PDK. In addition, in gliomas cells, PPAR gamma is downregulated, leading to a decrease in insulin sensitivity and an increase in neuroinflammation. Moreover, PPAR gamma contributes to regulate some key circadian genes. Abnormalities in the regulation of circadian rhythms and dysregulation in circadian clock genes are observed in gliomas. Circadian rhythms are dissipative structures, which play a key role in far-from-equilibrium thermodynamics through their interactions with WNT/beta-catenin pathway and PPAR gamma. In gliomas, metabolism, thermodynamics, and circadian rhythms are tightly interrelated.

  3. Involvement of prostaglandins and histamine in radiation-induced temperature responses in rats

    International Nuclear Information System (INIS)

    Kandasamy, S.B.; Hunt, W.A.

    1990-01-01

    Exposure of rats to 1-15 Gy of gamma radiation induced hyperthermia, whereas exposure to 20-150 Gy produced hypothermia. Since radiation exposure induced the release of prostaglandins (PGs) and histamine, the role of PGs and histamine in radiation-induced temperature changes was examined. Radiation-induced hyper- and hypothermia were antagonized by pretreatment with indomethacin, a cyclooxygenase inhibitor. Intracerebroventricular administration of PGE2 and PGD2 induced hyper- and hypothermia, respectively. Administration of SC-19220, a specific PGE2 antagonist, attenuated PGE2- and radiation-induced hyperthermia, but it did not antagonize PGD2- or radiation-induced hypothermia. Consistent with an apparent role of histamine in hypothermia, administration of disodium cromoglycate (a mast cell stabilizer), mepyramine (H1-receptor antagonist), or cimetidine (H2-receptor antagonist) attenuated PGD2- and radiation-induced hypothermia. These results suggest that radiation-induced hyperthermia is mediated via PGE2 and that radiation-induced hypothermia is mediated by another PG, possibly PGD2, via histamine

  4. Ccl22/MDC, is a prostaglandin dependent pyrogen, acting in the anterior hypothalamus to induce hyperthermia via activation of brown adipose tissue.

    Science.gov (United States)

    Osborn, Olivia; Sanchez-Alavez, Manuel; Dubins, Jeffrey S; Gonzalez, Alejandro Sanchez; Morrison, Brad; Hadcock, John R; Bartfai, Tamas

    2011-03-01

    CC Chemokine ligand 22 (Ccl22) is a selective, high affinity ligand at the CC chemokine receptor 4 (Ccr4). We have identified cDNAs encoding both ligand and receptor of the Ccl22-Ccr4 pair in cDNA libraries of the anterior hypothalamus/pre-optic area (AH/POA) by PCR. The AH/POA is the key brain region where endogenous pyrogens have been shown to act on warm sensitive neurons to affect thermogenesis in brown adipose tissue (BAT) and other thermogenically responsive tissues. We show that functional Ccr4 receptors are present in the AH/POA neurons as injection of Ccl22 into the POA but not to other hypothalamic nuclei induces an increase in core body temperature as measured by radiotelemetry. Indomethacin (5 mg/kg s.c) pre-treatment markedly reduced the hyperthermia evoked by POA injection of Ccl22 (10 ng/0.5 ul) and thus suggests that this hyperthermia is mediated through cyclooxygenase activation and thus likely through the formation and action of the pyrogen prostaglandin E2. The temperature elevation involves a decrease in the respiratory exchange ratio and increased activation of the brown adipose tissue as demonstrated by ¹⁸F-FDG-PET imaging. We describe a novel role to the ligand Ccl22 and its receptor Ccr4 in the anterior hypothalamus in temperature regulation that depends on the synthesis of the endogenous pyrogen, prostaglandin E2. Copyright © 2010 Elsevier Ltd. All rights reserved.

  5. Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR-α/sirtuin 1/PGC-1α pathway.

    Science.gov (United States)

    Liu, Guang-Zhong; Hou, Ting-Ting; Yuan, Yue; Hang, Peng-Zhou; Zhao, Jing-Jing; Sun, Li; Zhao, Guan-Qi; Zhao, Jing; Dong, Jing-Mei; Wang, Xiao-Bing; Shi, Hang; Liu, Yong-Wu; Zhou, Jing-Hua; Dong, Zeng-Xiang; Liu, Yang; Zhan, Cheng-Chuang; Li, Yue; Li, Wei-Min

    2016-03-01

    Atrial metabolic remodelling is critical for the process of atrial fibrillation (AF). The PPAR-α/sirtuin 1 /PPAR co-activator α (PGC-1α) pathway plays an important role in maintaining energy metabolism. However, the effect of the PPAR-α agonist fenofibrate on AF is unclear. Therefore, the aim of this study was to determine the effect of fenofibrate on atrial metabolic remodelling in AF and explore its possible mechanisms of action. The expression of metabolic proteins was examined in the left atria of AF patients. Thirty-two rabbits were divided into sham, AF (pacing with 600 beats·min(-1) for 1 week), fenofibrate treated (pretreated with fenofibrate before pacing) and fenofibrate alone treated (for 2 weeks) groups. HL-1 cells were subjected to rapid pacing in the presence or absence of fenofibrate, the PPAR-α antagonist GW6471 or sirtuin 1-specific inhibitor EX527. Metabolic factors, circulating biochemical metabolites, atrial electrophysiology, adenine nucleotide levels and accumulation of glycogen and lipid droplets were assessed. The PPAR-α/sirtuin 1/PGC-1α pathway was significantly inhibited in AF patients and in the rabbit/HL-1 cell models, resulting in a reduction of key downstream metabolic factors; this effect was significantly restored by fenofibrate. Fenofibrate prevented the alterations in circulating biochemical metabolites, reduced the level of adenine nucleotides and accumulation of glycogen and lipid droplets, reversed the shortened atrial effective refractory period and increased risk of AF. Fenofibrate inhibited atrial metabolic remodelling in AF by regulating the PPAR-α/sirtuin 1/PGC-1α pathway. The present study may provide a novel therapeutic strategy for AF. © 2016 The British Pharmacological Society.

  6. Essential Oil of Pinus koraiensis Exerts Antiobesic and Hypolipidemic Activity via Inhibition of Peroxisome Proliferator-Activated Receptors Gamma Signaling.

    Science.gov (United States)

    Ko, Hyun-Suk; Lee, Hyo-Jeong; Lee, Hyo-Jung; Sohn, Eun Jung; Yun, Miyong; Lee, Min-Ho; Kim, Sung-Hoon

    2013-01-01

    Our group previously reported that essential oil of Pinus koraiensis (EOPK) exerts antihyperlipidemic effects via upregulation of low-density lipoprotein receptor and inhibition of acyl-coenzyme A. In the present study, we investigated the antiobesity and hypolipidemic mechanism of EOPK using in vitro 3T3-L1 cells and in vivo HFD-fed rats. EOPK markedly suppressed fat accumulation and intracellular triglyceride associated with downregulation of adipogenic transcription factor expression, including PPAR γ and CEBP α in the differentiated 3T3-L1 adipocytes. Additionally, EOPK attenuated the expression levels of FABP and GPDH as target genes of PPAR γ during adipocyte differentiation. Furthermore, PPAR γ inhibitor GW9662 enhanced the decreased expression of FABP and PPAR γ and fat accumulation induced by EOPK. To confirm the in vitro activity of EOPK, animal study was performed by administering normal diet, HFD, and/or EOPK at the dose of 100 or 200 mg/kg for 6 weeks. Consistently, EOPK significantly suppressed body weight gain, serum triglyceride, total cholesterol, LDL cholesterol, and AI value and increased HDL cholesterol in a dose-dependent manner. Immunohistochemistry revealed that EOPK treatment abrogated the expression of PPAR γ in the liver tissue sections of EOPK-treated rats. Taken together, our findings suggest that EOPK has the antiobesic and hypolipidemic potential via inhibition of PPAR γ -related signaling.

  7. Prostaglandins and complement changes in some conditions related to inflammation. [Mice

    Energy Technology Data Exchange (ETDEWEB)

    Eisen, V.; Walker, D.I.; Binysh, S.G.; Tedder, R.S.

    1977-01-01

    Exposure to ionizing radiation produces several systemic and local reactions which could be mediated by prostaglandins. Prostaglandin levels were therefore studied in blood and tissues of mice which had been exposed to x-rays. Significant increases were found in spleens after 200 to 700 R, and in lungs after 600 to 700 R. These changes were most pronounced 4 to 7 days after irradiation. Ionizing radiation promptly and potently reduced the activity of prostaglandin dehydrogenase in the spleen, whereas prostaglandin synthesis was less affected. Evidence was obtained for the activation and consumption of haemolytic complement in serum in the course of heart-lung operations involving extracorporeal circulation. Activation involved primarily the classical pathway, and only slightly the alternate pathway.

  8. Telmisartan prevents weight gain and obesity through activation of peroxisome proliferator-activated receptor-delta-dependent pathways

    DEFF Research Database (Denmark)

    He, Hongbo; Yang, Dachun; Ma, Liqun

    2010-01-01

    Telmisartan shows antihypertensive and several pleiotropic effects that interact with metabolic pathways. In the present study we tested the hypothesis that telmisartan prevents adipogenesis in vitro and weight gain in vivo through activation of peroxisome proliferator-activated receptor (PPAR)-d...

  9. Identification and expression analysis of peroxisome proliferator-activated receptors cDNA in a reptile, the leopard gecko (Eublepharis macularius).

    Science.gov (United States)

    Kato, Keisuke; Oka, Yoshitaka; Park, Min Kyun

    2008-05-01

    Despite the physiological and evolutionary significance of lipid metabolism in amniotes, the molecular mechanisms involved have been unclear in reptiles. To elucidate this, we investigated peroxisome proliferators-activated receptors (PPARs) in the leopard gecko (Eublepharis macularius). PPARs belong to a nuclear hormone-receptor family mainly involved in lipid metabolism. Although PPARs have been widely studied in mammals, little information about them is yet available from reptiles. We identified in the leopard gecko partial cDNA sequences of PPARalpha and beta, and full sequences of two isoforms of PPARgamma. This is the first report of reptilian PPARgamma mRNA isoforms. We also evaluated the organ distribution of expression of these genes by using RT-PCR and competitive PCR. The expression level of PPARalpha mRNA was highest in the large intestine, and moderate in the liver and kidney. The expression level of PPARbeta mRNA was highest in the kidney and large intestine, and moderate in the liver. Similarly to the expression of human PPARgamma isoforms, PPARgammaa was expressed ubiquitously, whereas the expression of PPARgammab was restricted. The highest levels of their expression, however, were observed in the large intestine, rather than in the adipose tissue as in mammals. Taken together, these results showed that the profile of PPARbeta mRNA expression in the leopard gecko is similar to that in mammals, and that those of PPAR alpha and gamma are species specific. This may reflect adaptation to annual changes in lipid storage due to seasonal food availability.

  10. Problems connected with the production of highly specific antisera against prostaglandin E2 (PGE2) and prostaglandin A2 (PGA2) for radioimmunoassay

    International Nuclear Information System (INIS)

    Kopp, H.G.; Vetter, W.; Siegenthaler, W.

    1978-01-01

    To obtain sensitive and specific antisera against PGE 2 and PGA 2 these substances were coupled to thyroglobulin (Tg). Coupling reactions were performed by using either a hydroxy-succinimide-ester as intermediate step leading to a complex carrying 170mol PGE 2 per mol Tg (''PGE 2 -OSU-Tg'') and 240mol PGA 2 per mol Tg (''PGA 2 -OSU-Tg''), or N, N'-carbonyl-diimidazole resulting in ''PGE 2 -CDI-Tg'' (400mol PGE 2 per mol Tg) and ''PGA 2 -CDI-Tg'' (600mol PGA 2 per mol Tg). Two tracer systems ( 3 H-prostaglandin and 125 I-histamine-prostaglandin) were used for analysis of antibody activity. The PGE 2 -CDI-Tg and PGA 2 -CDI-Tg complexes were both poor immunogens in rabbits. The PGE 2 -OSU-Tg and PGA 2 -OSU-Tg conjugates were injected in rabbits and in guinea-pigs. These two compounds resulted in very high antibody titres in both animal species. However, in guinea-pigs a markedly higher antibody sensitivity and antibody specificity were observed than in rabbits. Our results indicate that the guinea-pig may be the animal of choice for immunization against prostaglandins. Antibody specificity of guinea-pig antisera may be high enough to measure the concentration of PGE 2 and PGA 2 in the presence of other prostaglandins or prostaglandin metabolites. (author)

  11. Problems connected with the production of highly specific antisera against prostaglandin E2 (PGE2) and prostaglandin A2 (PGA2) for radioimmunoassay

    International Nuclear Information System (INIS)

    Kopp, H.G.; Vetter, W.; Siegenthaler, W.

    1977-01-01

    To obtain sensitive and specific antisera against PGE 2 and PGA 2 these substances were coupled to thyroglobulin (Tg). Coupling reactions were either performed by using a hydroxysuccinimideester as intermediate step leading to a complex carrying 170 mol PGE 2 per mol Tg ('PGE 2 -OSU-Tg') and 240 mol PGA 2 per mol Tg ('PGA 2 -OSU-Tg') or alternatively by using N,N'-carbonyl-diimidazole resulting in 'PGE 2 -CDI-Tg' (400 mol PGE 2 per mol Tg) and 'PGA 2 -CDI-Tg' (600 mol PGA 2 per mol Tg). Two tracer systems ( 3 H-prostaglandin, 125 I-histamine-prostaglandin) were used for analysis of antibody activity. Both PGE 2 - and PGA 2 -CDI-Tg complexes were poor immunogens in rabbits. The PGE 2 - and PGA 2 -OSU-Tg conjugates were injected both in rabbits and in guinea pigs. These two compounds resulted in very high antibody titers in both animal species. However, in guinea pigs markedly higher antibody sensitivity and antibody specificity were observed than in rabbits. Our results indicate that the guinea pig may be the animal of choice for immunization against prostaglandins. Antibody specificity of guinea pig antisera may be perhaps high enough to measure the concentration of PGE 2 and PGA 2 in the presence of other prostaglandins or prostaglandin metabolites. (orig.) [de

  12. Circadian and estral changes in the hypothalamic prostaglandin e content and [h]prostaglandin e binding in female rats.

    Science.gov (United States)

    Bommelaer-Bayet, M C; Wisner, A; Renard, C A; Levi, F A; Dray, F

    1990-04-01

    Abstract Prostaglandin E(2), (PGE(2)) is involved in the luteinizing hormone-releasing hormone-stimulated luteinizing hormone surge in female rats and may act via specific membrane receptors. The following studies were performed to determine whether there were any changes in the hypothalamic PGE(2) binding and/or PGE(2) content which were specific to proestrus and not to the rest of the estrous cycle. Groups of female Wistar rats were sacrificed at 3-h intervals throughout the estrous cycle to determine both the circadian and circaestral changes in the hypothalamic PGE(2) content and [(3)H]PGE(2) binding. The hypothalamic PGE(2) content was maximal at 1700 h on each of the 4 consecutive days of the estrous cycle but was independent of the stage of the cycle. [(3)H]PGE(2) binding also displayed a circadian rhythm; the lowest binding occurred near the circadian peak of PGE(2), suggesting that the PGE(2) binding sites were occupied by endogenous PGE(2). Since such circadian rhythms were not observed in the hypothalamus of male rats, they may be under the control of ovarian steroids. Also, since PGE(2) binding and the PGE(2) content both exhibit a diurnal pattern independent of the day of the cycle, there may be changes in the PGE(2) receptor-mediated process coupled to an adenylyl cyclase which could explain the luteinizing hormone surge in proestrus.

  13. Peroxisome proliferator-activated receptor {alpha} agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease

    Energy Technology Data Exchange (ETDEWEB)

    Antonelli, Alessandro, E-mail: a.antonelli@med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Ferrari, Silvia Martina, E-mail: sm.ferrari@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Frascerra, Silvia, E-mail: lafrasce@gmail.com [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Corrado, Alda, E-mail: dala_res@hotmail.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Pupilli, Cinzia, E-mail: c.pupilli@dfc.unifi.it [Endocrinology Unit, Azienda Ospedaliera Careggi and University of Florence, Viale Morgagni 85, I-50134, Florence (Italy); Bernini, Giampaolo, E-mail: g.bernini@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Benvenga, Salvatore, E-mail: s.benvenga@me.nettuno.it [Department of Clinical and Experimental Medicine, Section of Endocrinology, University of Messina, Piazza Pugliatti 1, I-98122, Messina (Italy); Ferrannini, Ele, E-mail: eferrannini@med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Fallahi, Poupak, E-mail: poupak@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy)

    2011-07-01

    Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR){alpha} activation on the prototype Th1 [chemokine (C-X-C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C-C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells. The role of PPAR{alpha} and PPAR{gamma} activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN){gamma} and tumor necrosis factor (TNF){alpha}. IFN{gamma} stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNF{alpha} alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFN{gamma} and TNF{alpha} had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPAR{alpha} activators inhibited the secretion of both chemokines (stimulated with IFN{gamma} and TNF{alpha}) at a level higher (for CXCL10, about 60-72%) than PPAR{gamma} agonists (about 25-35%), which were confirmed to inhibit CXCL10, but not CCL2. Our data show that CCL2 is modulated by IFN{gamma} and TNF{alpha} in GD and normal thyrocytes. Furthermore we first show that PPAR{alpha} activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPAR{alpha} may be involved in the modulation of the immune response in the thyroid.

  14. Peroxisome proliferator-activated receptor: effects on nutritional homeostasis, obesity and diabetes mellitus Receptores activados por los proliferadores de peroxisomas: implicaciones sobre la homeostasis nutricional, en la obesidad y en la diabetes mellitus

    OpenAIRE

    M. Viana Abranches; F. C. Esteves de Oliveira; J. Bressan

    2011-01-01

    The obesity and the metabolic disorders associated characterize the metabolic syndrome, which has increased at an alarming rate around the world. It is known that environmental and genetic factors are involved in the genesis of obesity. Peroxisome Proliferator-Activated Receptors (PPARs) stand out among these factors. They compose the nuclear receptor superfamily and there are in three isoforms (PPARα,PPARβ/δ and PPARγ), which play an important role in the regulation of...

  15. Assessment of chitosan-affected metabolic response by peroxisome proliferator-activated receptor bioluminescent imaging-guided transcriptomic analysis.

    Directory of Open Access Journals (Sweden)

    Chia-Hung Kao

    Full Text Available Chitosan has been widely used in food industry as a weight-loss aid and a cholesterol-lowering agent. Previous studies have shown that chitosan affects metabolic responses and contributes to anti-diabetic, hypocholesteremic, and blood glucose-lowering effects; however, the in vivo targeting sites and mechanisms of chitosan remain to be clarified. In this study, we constructed transgenic mice, which carried the luciferase genes driven by peroxisome proliferator-activated receptor (PPAR, a key regulator of fatty acid and glucose metabolism. Bioluminescent imaging of PPAR transgenic mice was applied to report the organs that chitosan acted on, and gene expression profiles of chitosan-targeted organs were further analyzed to elucidate the mechanisms of chitosan. Bioluminescent imaging showed that constitutive PPAR activities were detected in brain and gastrointestinal tract. Administration of chitosan significantly activated the PPAR activities in brain and stomach. Microarray analysis of brain and stomach showed that several pathways involved in lipid and glucose metabolism were regulated by chitosan. Moreover, the expression levels of metabolism-associated genes like apolipoprotein B (apoB and ghrelin genes were down-regulated by chitosan. In conclusion, these findings suggested the feasibility of PPAR bioluminescent imaging-guided transcriptomic analysis on the evaluation of chitosan-affected metabolic responses in vivo. Moreover, we newly identified that downregulated expression of apoB and ghrelin genes were novel mechanisms for chitosan-affected metabolic responses in vivo.

  16. Close teamwork between Nrf2 and peroxiredoxins 1 and 6 for the regulation of prostaglandin D2 and E2 production in macrophages in acute inflammation.

    Science.gov (United States)

    Ishii, Tetsuro

    2015-11-01

    Inflammation is a complex biological self-defense reaction triggered by tissue damage or infection by pathogens. Acute inflammation is regulated by the time- and cell type-dependent production of cytokines and small signaling molecules including reactive oxygen species and prostaglandins. Recent studies have unveiled the important role of the transcription factor Nrf2 in the regulation of prostaglandin production through transcriptional regulation of peroxiredoxins 1 and 6 (Prx1 and Prx6) and lipocalin-type prostaglandin D synthase (L-PGDS). Prx1 and Prx6 are multifunctional proteins important for cell protection against oxidative stress, but also work together to facilitate production of prostaglandins E2 and D2 (PGE2 and PGD2). Prx1 secreted from cells under mild oxidative stress binds Toll-like receptor 4 and induces NF-κB activation, important for the expression of cyclooxygenase-2 and microsomal PGE synthase-1 (mPGES-1) expression. The activated MAPKs p38 and ERK phosphorylate Prx6, leading to NADPH oxidase-2 activation, which contributes to production of PGD2 by hematopoietic prostaglandin D synthase (H-PGDS). PGD2 and its end product 15-deoxy-∆(12,14)-prostaglandin J2 (15d-PGJ2) activate Nrf2 thereby forming a positive feedback loop for further production of PGD2 by L-PGDS. Maintenance of cellular glutathione levels is an important role of Nrf2 not only for cell protection but also for the synthesis of prostaglandins, as mPGES-1 and H-PGDS require glutathione for their activities. This review is aimed at describing the functions of Prx1 and Prx6 in the regulation of PGD2 and PGE2 production in acute inflammation in macrophages and the importance of 15d-PGJ2 as an intrinsic Nrf2 activator. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Do stress responses promote leukemia progression? An animal study suggesting a role for epinephrine and prostaglandin-E2 through reduced NK activity.

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    Shelly Inbar

    2011-04-01

    Full Text Available In leukemia patients, stress and anxiety were suggested to predict poorer prognosis. Oncological patients experience ample physiological and psychological stress, potentially leading to increased secretion of stress factors, including epinephrine, corticosteroids, and prostaglandins. Here we tested whether environmental stress and these stress factors impact survival of leukemia-challenged rats, and studied mediating mechanisms. F344 rats were administered with a miniscule dose of 60 CRNK-16 leukemia cells, and were subjected to intermittent forced swim stress or to administration of physiologically relevant doses of epinephrine, prostaglandin-E(2 or corticosterone. Stress and each stress factor, and/or their combinations, doubled mortality rates when acutely applied simultaneously with, or two or six days after tumor challenge. Acute administration of the β-adrenergic blocker nadolol diminished the effects of environmental stress, without affecting baseline survival rates. Prolonged β-adrenergic blockade or COX inhibition (using etodolac also increased baseline survival rates, possibly by blocking tumor-related or normal levels of catecholamines and prostaglandins. Searching for mediating mechanisms, we found that each of the stress factors transiently suppressed NK activity against CRNK-16 and YAC-1 lines on a per NK basis. In contrast, the direct effects of stress factors on CRNK-16 proliferation, vitality, and VEGF secretion could not explain or even contradicted the in vivo survival findings. Overall, it seems that environmental stress, epinephrine, and prostaglandins promote leukemia progression in rats, potentially through suppressing cell mediated immunity. Thus, patients with hematological malignancies, which often exhibit diminished NK activity, may benefit from extended β-blockade and COX inhibition.

  18. Prostaglandin H synthase immunoreactivity in human gut. An immunohistochemical study

    DEFF Research Database (Denmark)

    Mikkelsen, H B; Rumessen, J J; Qvortrup, Klaus

    1991-01-01

    Prostaglandins exhibit a variety of actions on intestinal smooth muscle depending upon the type, dose and muscle layer studied. As the cellular origin of prostaglandin H (PGH) synthase has not been established with certainty in the human gut wall, we studied the localization of PGH synthase...

  19. Potential effects of curcumin on peroxisome proliferator-activated receptor-gamma in vitro and in vivo

    Science.gov (United States)

    Natural peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists are found in food and may be important for health through their anti-inflammatory properties. Curcumin (Cur) is a bright yellow spice, derived from the rhizome of Curcuma longa Linn. It has been shown to have many biologi...

  20. Prostaglandin E2 facilitates neurite outgrowth in a motor neuron-like cell line, NSC-34

    Directory of Open Access Journals (Sweden)

    Hiroshi Nango

    2017-10-01

    Full Text Available Prostaglandin E2 (PGE2 exerts various biological effects by binding to E-prostanoid receptors (EP1-4. Although recent studies have shown that PGE2 induces cell differentiation in some neuronal cells such as mouse DRG neurons and sensory neuron-like ND7/23 cells, it is unclear whether PGE2 plays a role in differentiation of motor neurons. In the present study, we investigated the mechanism of PGE2-induced differentiation of motor neurons using NSC-34, a mouse motor neuron-like cell line. Exposure of undifferentiated NSC-34 cells to PGE2 and butaprost, an EP2-selective agonist, resulted in a reduction of MTT reduction activity without increase the number of propidium iodide-positive cells and in an increase in the number of neurite-bearing cells. Sulprostone, an EP1/3 agonist, also significantly lowered MTT reduction activity by 20%; however, no increase in the number of neurite-bearing cells was observed within the concentration range tested. PGE2-induced neurite outgrowth was attenuated significantly in the presence of PF-0441848, an EP2-selective antagonist. Treatment of these cells with dibutyryl-cAMP increased the number of neurite-bearing cells with no effect on cell proliferation. These results suggest that PGE2 promotes neurite outgrowth and suppresses cell proliferation by activating the EP2 subtype, and that the cAMP-signaling pathway is involved in PGE2-induced differentiation of NSC-34 cells. Keywords: Prostaglandin E2, E-prostanoid receptors, Motor neuron, Neurite outgrowth, cAMP

  1. Changes in the Th1 : Th2 Cytokine Bias in Pregnancy and the Effects of the Anti-Inflammatory Cyclopentenone Prostaglandin 15-Deoxy-Δ12,14-Prostaglandin J2

    Directory of Open Access Journals (Sweden)

    Lynne Sykes

    2012-01-01

    Full Text Available Pregnancy is a complex immunological state in which a bias towards T helper 2 (Th2 protects the fetus. Evidence suggests that proinflammatory cytokines increase the risk of poor neonatal outcome, independently of the direct effect of preterm labour. The anti-inflammatory prostaglandin 15-deoxy-Δ12,14-Prostaglandin J2 (15dPGJ2 inhibits nuclear factor Kappa B (NF-κB in amniocytes and myocytes in vitro and is a ligand for the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 receptor. Here we examine the Th1:Th2 cytokine bias in pregnancy and whether 15dPGJ2 could be used to inhibit the production of the proinflammatory cytokines through inhibition of NF-κB while simultaneously promoting Th2 interleukin 4 (IL-4 synthesis via CRTH2 in T helper cells. Peripheral blood mononuclear cells (PBMCs from women at 28 weeks, term pre-labour, term labour as well as non-pregnant female controls were cultured with 15dPGJ2 or vehicle control and stimulated with phorbol myristyl acetate (PMA/ionomycin. The percentage of CD4+ cells producing interferon gamma (IFN-γ and tumor necrosis factor alpha (TNF-α in response to PMA/ionomycin was significantly reduced in pregnancy. 15dPGJ2 reduced IFN-γ and TNF-α production in stimulated T helper cells, but did not alter IL-4 production in CRTH2+ve cells. 15dPGJ2 also reduced phospho-p65 in stimulated PBMCs. In summary, 15dPGJ2 suppresses the Th1 response of PBMCs during pregnancy and active labour whilst maintaining the Th2 response suggesting a therapeutic benefit in reducing neonatal morbidity in inflammation-induced PTL.

  2. Inhibitory effect on hepatitis B virus in vitro by a peroxisome proliferator-activated receptor-{gamma} ligand, rosiglitazone

    Energy Technology Data Exchange (ETDEWEB)

    Wakui, Yuta; Inoue, Jun [Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai 980-8574 (Japan); Ueno, Yoshiyuki, E-mail: yueno@mail.tains.tohoku.ac.jp [Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai 980-8574 (Japan); Fukushima, Koji; Kondo, Yasuteru; Kakazu, Eiji; Obara, Noriyuki; Kimura, Osamu; Shimosegawa, Tooru [Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai 980-8574 (Japan)

    2010-05-28

    Although chronic infection of hepatitis B virus (HBV) is currently managed with nucleot(s)ide analogues or interferon-{alpha}, the control of HBV infection still remains a clinical challenge. Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor, that plays a role in glucose and lipid metabolism, immune reactions, and inflammation. In this study, the suppressive effect of PPAR ligands on HBV replication was examined in vitro using a PPAR{alpha} ligand, bezafibrate, and a PPAR{gamma} ligand, rosiglitazone. The effects were examined in HepG2 cells transfected with a plasmid containing 1.3-fold HBV genome. Whereas bezafibrate showed no effect against HBV replication, rosiglitazone reduced the amount of HBV DNA, hepatitis B surface antigen, and hepatitis B e antigen in the culture supernatant. Southern blot analysis showed that the replicative intermediates of HBV in the cells were also inhibited. It was confirmed that GW9662, an antagonist of PPAR{gamma}, reduced the suppressive effect of rosiglitazone on HBV. Moreover, rosiglitazone showed a synergistic effect on HBV replication with lamivudine or interferon-{alpha}-2b. In conclusion, this study showed that rosiglitazone inhibited the replication of HBV in vitro, and suggested that the combination therapy of rosiglitazone and nucleot(s)ide analogues or interferon could be a therapeutic option for chronic HBV infection.

  3. Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans.

    Directory of Open Access Journals (Sweden)

    Marc R Van Gilst

    2005-02-01

    Full Text Available Mammalian nuclear hormone receptors (NHRs, such as liver X receptor, farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs, precisely control energy metabolism. Consequently, these receptors are important targets for the treatment of metabolic diseases, including diabetes and obesity. A thorough understanding of NHR fat regulatory networks has been limited, however, by a lack of genetically tractable experimental systems. Here we show that deletion of the Caenorhabditis elegans NHR gene nhr-49 yielded worms with elevated fat content and shortened life span. Employing a quantitative RT-PCR screen, we found that nhr-49 influenced the expression of 13 genes involved in energy metabolism. Indeed, nhr-49 served as a key regulator of fat usage, modulating pathways that control the consumption of fat and maintain a normal balance of fatty acid saturation. We found that the two phenotypes of the nhr-49 knockout were linked to distinct pathways and were separable: The high-fat phenotype was due to reduced expression of enzymes in fatty acid beta-oxidation, and the shortened adult life span resulted from impaired expression of a stearoyl-CoA desaturase. Despite its sequence relationship with the mammalian hepatocyte nuclear factor 4 receptor, the biological activities of nhr-49 were most similar to those of the mammalian PPARs, implying an evolutionarily conserved role for NHRs in modulating fat consumption and composition. Our findings in C. elegans provide novel insights into how NHR regulatory networks are coordinated to govern fat metabolism.

  4. Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans.

    Science.gov (United States)

    Van Gilst, Marc R; Hadjivassiliou, Haralambos; Jolly, Amber; Yamamoto, Keith R

    2005-02-01

    Mammalian nuclear hormone receptors (NHRs), such as liver X receptor, farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs), precisely control energy metabolism. Consequently, these receptors are important targets for the treatment of metabolic diseases, including diabetes and obesity. A thorough understanding of NHR fat regulatory networks has been limited, however, by a lack of genetically tractable experimental systems. Here we show that deletion of the Caenorhabditis elegans NHR gene nhr-49 yielded worms with elevated fat content and shortened life span. Employing a quantitative RT-PCR screen, we found that nhr-49 influenced the expression of 13 genes involved in energy metabolism. Indeed, nhr-49 served as a key regulator of fat usage, modulating pathways that control the consumption of fat and maintain a normal balance of fatty acid saturation. We found that the two phenotypes of the nhr-49 knockout were linked to distinct pathways and were separable: The high-fat phenotype was due to reduced expression of enzymes in fatty acid beta-oxidation, and the shortened adult life span resulted from impaired expression of a stearoyl-CoA desaturase. Despite its sequence relationship with the mammalian hepatocyte nuclear factor 4 receptor, the biological activities of nhr-49 were most similar to those of the mammalian PPARs, implying an evolutionarily conserved role for NHRs in modulating fat consumption and composition. Our findings in C. elegans provide novel insights into how NHR regulatory networks are coordinated to govern fat metabolism.

  5. Do prostaglandins affect cellular radiosensitivity in vitro

    International Nuclear Information System (INIS)

    Millar, B.C.; Jinks, S.

    1984-01-01

    The authors were unable to detect any change in the in vitro radiation response of mouse fibrosarcoma cells, HSDM 1 C 1 , which secrete 2 μg PGE 2 /mg cell protein/24 h, in the presence of the prostaglandin biosynthesis inhibitor flurbiprofen. Furthermore, addition of exogenous PGE 1 or PGA 2 to cultures of Chinese hamster cells was similarly without effect on radiation response. Although a high concentration of PGA 2 inhibited the growth of Chinese hamster cells in vitro this effect disappeared upon removal of the prostaglandin. The implications of these results for radiotherapy are discussed. (author)

  6. Regulation of cyclic AMP metabolism by prostaglandins in rabbit cortical collecting tubule cells

    International Nuclear Information System (INIS)

    Sonnenburg, W.K.

    1987-01-01

    In the rabbit cortical collecting tubule (RCCT), prostaglandin E 1 (PGE 1 ) and prostaglandin E 2 (PGE 2 ) at 1 nM inhibit arginine-vasopressin (AVP)-induced water reabsorption, while 100 nM PGE 1 and PGE 2 alone stimulate water reabsorption. Reported here are studies designed to investigate the molecular basis for the biphasic physiological action of PGE 1 and PGE 2 in the collecting duct. In freshly isolated RCCT cells, PGE 1 , PGE 2 , and 16,16-dimethyl-PGE 2 (DM-PGE 2 ) stimulated cAMP synthesis at concentrations ranging from 0.1 to 10 M. Other prostaglandins including the synthetic PGE 2 analogue, sulprostone, failed to stimulate cAMP synthesis. Moreover, sulprostone did not antagonize PGE 2 -stimulated cAMP formation. In contrast, PGE 2 and sulprostone at concentrations ranging from 1 to 100 nM, inhibited AVP-induced cAMP accumulation in freshly isolated RCCT cells. PGE 2 , PGE 1 , DM-PGE 2 and sulprostone at 100 nM were equally effective in inhibiting AVP-induced cAMP formation. Moreover sulprostone inhibited AVP-stimulated adenylate cyclase activity. These results suggest that PGE derivatives mediate either inhibition or activation of adenylate cyclase by stimulating different PGE receptors. To further test this concept, PGE 2 binding to freshly isolated RCCT cell membranes was characterized. Two different classes of PGE 2 binding were detected. / 3 H/PGE 2 binding to the high affinity class of sites was increased by the GTP-analogue, GTP S, while pertussis toxin pretreatment blocked the stimulatory action. In contrast, / 3 H/ PGE 2 binding to the low affinity class of sites was decreased by GTP S; this inhibitory effect was not blocked by pertussis toxin pretreatment

  7. Exposure to rosiglitazone, a PPAR-γ agonist, in late gestation reduces the abundance of factors regulating cardiac metabolism and cardiomyocyte size in the sheep fetus.

    Science.gov (United States)

    Lie, Shervi; Hui, Melisa; McMillen, I Caroline; Muhlhausler, Beverly S; Posterino, Giuseppe S; Dunn, Stacey L; Wang, Kimberley C; Botting, Kimberley J; Morrison, Janna L

    2014-03-15

    It is unknown whether cardiomyocyte hypertrophy and the transition to fatty acid oxidation as the main source of energy after birth is dependent on the maturation of the cardiomyocytes' metabolic system, or on the limitation of substrate availability before birth. This study aimed to investigate whether intrafetal administration of a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, rosiglitazone, during late gestation can stimulate the expression of factors regulating cardiac growth and metabolism in preparation for birth, and the consequences of cardiac contractility in the fetal sheep at ∼140 days gestation. The mRNA expression and protein abundance of key factors regulating growth and metabolism were quantified using quantitative RT-PCR and Western blot analysis, respectively. Cardiac contractility was determined by measuring the Ca(2+) sensitivity and maximum Ca(2+)-activated force of skinned cardiomyocyte bundles. Rosiglitazone-treated fetuses had a lower cardiac abundance of insulin-signaling molecules, including insulin receptor-β, insulin receptor substrate-1 (IRS-1), phospho-IRS-1 (Tyr-895), phosphatidylinositol 3-kinase (PI3K) regulatory subunit p85, PI3K catalytic subunit p110α, phospho-3-phosphoinositide-dependent protein kinase 1 (Ser-241), protein kinase B (Akt-1), phospho-Akt (Ser-273), PKCζ, phospho-PKCζ(Thr-410), Akt substrate 160 kDa (AS160), phospho-AS160 (Thr-642), and glucose transporter type-4. Additionally, cardiac abundance of regulators of fatty acid β-oxidation, including adiponectin receptor 1, AMPKα, phospho-AMPKα (Thr-172), phospho-acetyl CoA carboxylase (Ser-79), carnitine palmitoyltransferase-1, and PGC-1α was lower in the rosiglitazone-treated group. Rosiglitazone administration also resulted in a decrease in cardiomyocyte size. Rosiglitazone administration in the late-gestation sheep fetus resulted in a decreased abundance of factors regulating cardiac glucose uptake, fatty acid β-oxidation, and

  8. Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ.

    Directory of Open Access Journals (Sweden)

    Till Adhikary

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are nuclear receptors with essential functions in lipid, glucose and energy homeostasis, cell differentiation, inflammation and metabolic disorders, and represent important drug targets. PPARs heterodimerize with retinoid X receptors (RXRs and can form transcriptional activator or repressor complexes at specific DNA elements (PPREs. It is believed that the decision between repression and activation is generally governed by a ligand-mediated switch. We have performed genomewide analyses of agonist-treated and PPARβ/δ-depleted human myofibroblasts to test this hypothesis and to identify global principles of PPARβ/δ-mediated gene regulation. Chromatin immunoprecipitation sequencing (ChIP-Seq of PPARβ/δ, H3K4me3 and RNA polymerase II enrichment sites combined with transcriptional profiling enabled the definition of 112 bona fide PPARβ/δ target genes showing either of three distinct types of transcriptional response: (I ligand-independent repression by PPARβ/δ; (II ligand-induced activation and/or derepression by PPARβ/δ; and (III ligand-independent activation by PPARβ/δ. These data identify PPRE-mediated repression as a major mechanism of transcriptional regulation by PPARβ/δ, but, unexpectedly, also show that only a subset of repressed genes are activated by a ligand-mediated switch. Our results also suggest that the type of transcriptional response by a given target gene is connected to the structure of its associated PPRE(s and the biological function of its encoded protein. These observations have important implications for understanding the regulatory PPAR network and PPARβ/δ ligand-based drugs.

  9. Angiotensin II potentiates prostaglandin stimulation of cyclic AMP levels in intact bovine adrenal medulla cells but not adenylate cyclase in permeabilized cells.

    Science.gov (United States)

    Boarder, M R; Plevin, R; Marriott, D B

    1988-10-25

    The level of cyclic AMP in primary cultures of bovine adrenal medulla cells is elevated by prostaglandin E1. Angiotensin II is commonly reported to act on receptors linked to phosphoinositide metabolism or to inhibition of adenylate cyclase. We have investigated the effect of angiotensin II on prostaglandin E1-stimulated cyclic AMP levels in these primary cultures. Rather than reducing cyclic AMP levels, we have found that angiotensin II powerfully potentiates prostaglandin E1-stimulated cyclic AMP accumulation in intact cells, both in the presence and absence of phosphodiesterase inhibitors. The 50% maximal response was similar to that for stimulation of phosphoinositide breakdown by angiotensin II in these cultures. The potentiation of stimulated cyclic AMP levels was seen, although to a smaller maximum, with the protein kinase C (Ca2+/phospholipid-dependent enzyme) activating phorbol ester tetradecanoyl phorbolacetate and with the synthetic diacylglycerol 1-oleoyl-2-acetylglycerol; pretreatment (24 h) with active phorbol ester, which would be expected to diminish protein kinase C levels, attenuated the angiotensin II potentiation of cyclic AMP. Using digitonin-permeabilized cells we showed that adenylate cyclase activity was stimulated by prostaglandin E1 with the same dose-response relationship as was cyclic AMP accumulation in intact cells, but the permeabilized cells showed no response to angiotensin II. The results are discussed with respect to the hypothesis that the angiotensin II influence on cyclic AMP levels is mediated, in part, by diacylglycerol stimulation of protein kinase C.

  10. Haplotypes of the porcine peroxisome proliferator-activated receptor delta gene are associated with backfat thickness

    Directory of Open Access Journals (Sweden)

    Blöcker Helmut

    2009-11-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptor delta belongs to the nuclear receptor superfamily of ligand-inducible transcription factors. It is a key regulator of lipid metabolism. The peroxisome proliferator-activated receptor delta gene (PPARD has been assigned to a region on porcine chromosome 7, which harbours a quantitative trait locus for backfat. Thus, PPARD is considered a functional and positional candidate gene for backfat thickness. The purpose of this study was to test this candidate gene hypothesis in a cross of breeds that were highly divergent in lipid deposition characteristics. Results Screening for genetic variation in porcine PPARD revealed only silent mutations. Nevertheless, significant associations between PPARD haplotypes and backfat thickness were observed in the F2 generation of the Mangalitsa × Piétrain cross as well as a commercial German Landrace population. Haplotype 5 is associated with increased backfat in F2 Mangalitsa × Piétrain pigs, whereas haplotype 4 is associated with lower backfat thickness in the German Landrace population. Haplotype 4 and 5 carry the same alleles at all but one SNP. Interestingly, the opposite effects of PPARD haplotypes 4 and 5 on backfat thickness are reflected by opposite effects of these two haplotypes on PPAR-δ mRNA levels. Haplotype 4 significantly increases PPAR-δ mRNA levels, whereas haplotype 5 decreases mRNA levels of PPAR-δ. Conclusion This study provides evidence for an association between PPARD and backfat thickness. The association is substantiated by mRNA quantification. Further studies are required to clarify, whether the observed associations are caused by PPARD or are the result of linkage disequilibrium with a causal variant in a neighbouring gene.

  11. Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension.

    Science.gov (United States)

    Avouac, Jerome; Konstantinova, Irena; Guignabert, Christophe; Pezet, Sonia; Sadoine, Jeremy; Guilbert, Thomas; Cauvet, Anne; Tu, Ly; Luccarini, Jean-Michel; Junien, Jean-Louis; Broqua, Pierre; Allanore, Yannick

    2017-11-01

    To evaluate the antifibrotic effects of the pan-peroxisome proliferator-activated receptor (PPAR) agonist IVA337 in preclinical mouse models of pulmonary fibrosis and related pulmonary hypertension (PH). IVA337 has been evaluated in the mouse model of bleomycin-induced pulmonary fibrosis and in Fra-2 transgenic mice, this latter being characterised by non-specific interstitial pneumonia and severe vascular remodelling of pulmonary arteries leading to PH. Mice received two doses of IVA337 (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. IVA337 demonstrated at a dose of 100 mg/kg a marked protection from the development of lung fibrosis in both mouse models compared with mice receiving 30 mg/kg of IVA337 or vehicle. Histological score was markedly reduced by 61% in the bleomycin model and by 50% in Fra-2 transgenic mice, and total lung hydroxyproline concentrations decreased by 28% and 48%, respectively, as compared with vehicle-treated mice. IVA337 at 100 mg/kg also significantly decreased levels of fibrogenic markers in lesional lungs of both mouse models. In addition, IVA337 substantially alleviated PH in Fra-2 transgenic mice by improving haemodynamic measurements and vascular remodelling. In primary human lung fibroblasts, IVA337 inhibited in a dose-dependent manner fibroblast to myofibroblasts transition induced by TGF-β and fibroblast proliferation mediated by PDGF. We demonstrate that treatment with 100 mg/kg IVA337 prevents lung fibrosis in two complementary animal models and substantially attenuates PH in the Fra-2 mouse model. These findings confirm that the pan-PPAR agonist IVA337 is an appealing therapeutic candidate for these cardiopulmonary involvements. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  12. NAD(P)H oxidase/nitric oxide interactions in peroxisome proliferator activated receptor (PPAR)α-mediated cardiovascular effects

    International Nuclear Information System (INIS)

    Newaz, Mohammad; Blanton, Ahmad; Fidelis, Paul; Oyekan, Adebayo

    2005-01-01

    Activation of peroxisome proliferator activated receptor (PPAR)α and its protective role in cardiovascular function has been reported but the exact mechanism(s) involved is not clear. As we have shown that PPARα ligands increased nitric oxide (NO) production and cardiovascular function is controlled by a balance between NO and free radicals, we hypothesize that PPARα activation tilts the balance between NO and free radicals and that this mechanism defines the protective effects of PPARα ligands on cardiovascular system. Systolic blood pressure (SBP) was greater in PPARα knockout (KO) mice compared with its wild type (WT) litter mates (130 ± 10 mmHg versus 107 ± 4 mmHg). L-NAME (100 mg/L p.o.), the inhibitor of NO production abolished the difference between PPARα KO and WT mice. In kidney homogenates, tissue lipid hydroperoxide generation was greater in KO mice (11.8 ± 1.4 pM/mg versus 8.3 ± 0.6 pM/mg protein). This was accompanied by a higher total NOS activity (46 ± 6%, p 2+ -dependent NOS activity in kidney homogenates of untreated PPARα WT compared with the KO mice. Clofibrate, a PPARα ligand, increased NOS activity in WT but not KO mice. Bezafibrate (30 mg/kg) reduced SBP in conscious rats (19 ± 4%, p < 0.05), increased urinary NO excretion (4.06 ± 0.53-7.07 ± 1.59 μM/24 h; p < 0.05) and reduced plasma 8-isoprostane level (45.8 ± 15 μM versus 31.4 ± 8 μM), and NADP(H) oxidase activity (16 ± 5%). Implantation of DOCA pellet (20 mg s.c.) in uninephrectomized mice placed on 1% NaCl drinking water increased SBP by a margin that was markedly greater in KO mice (193 ± 13 mmHg versus 130 ± 12 mmHg). In the rat, DOCA increased SBP and NAD(P)H oxidase activity and both effects were diminished by clofibrate. In addition, clofibrate reduced ET-1 production in DOCA/salt hypertensive rats. Thus, apart from inhibition of ET-1 production, PPARα activation exerts protective actions in hypertension via a mechanism that involves NO production and

  13. A Mixture of Extracts of Kochia scoparia and Rosa multiflora with PPAR α/γ Dual Agonistic Effects Prevents Photoaging in Hairless Mice

    Science.gov (United States)

    Jeon, Hyerin; Kim, Dong Hye; Nho, Youn-Hwa; Park, Ji-Eun; Kim, Su-Nam; Choi, Eung Ho

    2016-01-01

    Activation of peroxisome proliferator-activated receptors (PPAR) α/γ is known to inhibit the increases in matrix metalloproteinase (MMP) and reactive oxygen species (ROS) induced by ultraviolet light (UV). Extracts of natural herbs, such as Kochia scoparia and Rosa multiflora, have a PPAR α/γ dual agonistic effect. Therefore, we investigated whether and how they have an antiaging effect on photoaging skin. Eighteen-week-old hairless mice were irradiated with UVA 14 J/cm2 and UVB 40 mJ/cm2 three times a week for 8 weeks. A mixture of extracts of Kochia scoparia and Rosa multiflora (KR) was topically applied on the dorsal skin of photoaging mice twice a day for 8 weeks. Tesaglitazar, a known PPAR α/γ agonist, and vehicle (propylene glycol:ethanol = 7:3, v/v) were applied as positive and negative controls, respectively. Dermal effects (including dermal thickness, collagen density, dermal expression of procollagen 1 and collagenase 13) and epidermal effects (including skin barrier function, epidermal proliferation, epidermal differentiation, and epidermal cytokines) were measured and compared. In photoaging murine skin, KR resulted in a significant recovery of dermal thickness as well as dermal fibroblasts, although it did not change dermal collagen density. KR increased the expression of dermal transforming growth factor (TGF)-β. The dermal effects of KR were explained by an increase in procollagen 1 expression, induced by TGF-β, and a decrease in MMP-13 expression. KR did not affect basal transepidermal water loss (TEWL) or stratum corneum (SC) integrity, but did decrease SC hydration. It also did not affect epidermal proliferation or epidermal differentiation. KR decreased the expression of epidermal interleukin (IL)-1α. Collectively, KR showed possible utility as a therapeutic agent for photoaging skin, with few epidermal side effects such as epidermal hyperplasia or poor differentiation. PMID:27854351

  14. A Mixture of Extracts of Kochia scoparia and Rosa multiflora with PPAR α/γ Dual Agonistic Effects Prevents Photoaging in Hairless Mice

    Directory of Open Access Journals (Sweden)

    Hyerin Jeon

    2016-11-01

    Full Text Available Activation of peroxisome proliferator-activated receptors (PPAR α/γ is known to inhibit the increases in matrix metalloproteinase (MMP and reactive oxygen species (ROS induced by ultraviolet light (UV. Extracts of natural herbs, such as Kochia scoparia and Rosa multiflora, have a PPAR α/γ dual agonistic effect. Therefore, we investigated whether and how they have an antiaging effect on photoaging skin. Eighteen-week-old hairless mice were irradiated with UVA 14 J/cm2 and UVB 40 mJ/cm2 three times a week for 8 weeks. A mixture of extracts of Kochia scoparia and Rosa multiflora (KR was topically applied on the dorsal skin of photoaging mice twice a day for 8 weeks. Tesaglitazar, a known PPAR α/γ agonist, and vehicle (propylene glycol:ethanol = 7:3, v/v were applied as positive and negative controls, respectively. Dermal effects (including dermal thickness, collagen density, dermal expression of procollagen 1 and collagenase 13 and epidermal effects (including skin barrier function, epidermal proliferation, epidermal differentiation, and epidermal cytokines were measured and compared. In photoaging murine skin, KR resulted in a significant recovery of dermal thickness as well as dermal fibroblasts, although it did not change dermal collagen density. KR increased the expression of dermal transforming growth factor (TGF-β. The dermal effects of KR were explained by an increase in procollagen 1 expression, induced by TGF-β, and a decrease in MMP-13 expression. KR did not affect basal transepidermal water loss (TEWL or stratum corneum (SC integrity, but did decrease SC hydration. It also did not affect epidermal proliferation or epidermal differentiation. KR decreased the expression of epidermal interleukin (IL-1α. Collectively, KR showed possible utility as a therapeutic agent for photoaging skin, with few epidermal side effects such as epidermal hyperplasia or poor differentiation.

  15. Glial cell line-derived neurotrophic factor protects against high-fat diet-induced hepatic steatosis by suppressing hepatic PPAR-γ expression.

    Science.gov (United States)

    Mwangi, Simon Musyoka; Peng, Sophia; Nezami, Behtash Ghazi; Thorn, Natalie; Farris, Alton B; Jain, Sanjay; Laroui, Hamed; Merlin, Didier; Anania, Frank; Srinivasan, Shanthi

    2016-01-15

    Glial cell line-derived neurotrophic factor (GDNF) protects against high-fat diet (HFD)-induced hepatic steatosis in mice, however, the mechanisms involved are not known. In this study we investigated the effects of GDNF overexpression and nanoparticle delivery of GDNF in mice on hepatic steatosis and fibrosis and the expression of genes involved in the regulation of hepatic lipid uptake and de novo lipogenesis. Transgenic overexpression of GDNF in liver and other metabolically active tissues was protective against HFD-induced hepatic steatosis. Mice overexpressing GDNF had significantly reduced P62/sequestosome 1 protein levels suggestive of accelerated autophagic clearance. They also had significantly reduced peroxisome proliferator-activated receptor-γ (PPAR-γ) and CD36 gene expression and protein levels, and lower expression of mRNA coding for enzymes involved in de novo lipogenesis. GDNF-loaded nanoparticles were protective against short-term HFD-induced hepatic steatosis and attenuated liver fibrosis in mice with long-standing HFD-induced hepatic steatosis. They also suppressed the liver expression of steatosis-associated genes. In vitro, GDNF suppressed triglyceride accumulation in Hep G2 cells through enhanced p38 mitogen-activated protein kinase-dependent signaling and inhibition of PPAR-γ gene promoter activity. These results show that GDNF acts directly in the liver to protect against HFD-induced cellular stress and that GDNF may have a role in the treatment of nonalcoholic fatty liver disease.

  16. Prostaglandin E and the local immune response in chronic periodontal disease

    International Nuclear Information System (INIS)

    Loening, T.; Albers, H.-K.; Lisboa, B.P.; Burkhardt, A.; Caselitz, J.

    1980-01-01

    The local immune reaction of progressive chronic periodontal disease may be particularly influenced by macrophages and macrophage-derived factors. Among these substances the prostaglandins and lysosomal enzymes may play an important pathogenetic role. Parallel immunohistochemical and radioimmunological studies were done to investigate the relatiships of the immune-competent cells and the inflammatory mediators in gingival tissues. The radioimmunological analysis revealed that prostaglandin E increases markedly in the established gingival lesions. Immunohistochemically prostaglandin E was mainly localized within macrophage-like cells. Cytoplasmic lysozyme could be detected in these cells, too. On the other hand, the B-cell response is the prominent feature in established chronic periodontal disease. However, there is apparently a disturbed B-cell reaction as indicated by the irregular IgG-subclass pattern and by the production of mainly monomeric IgA. The possible interactions of macrophages and especially B-cells via prostaglandin E-mediated mechanisms are discussed. (author)

  17. Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator-activated receptor γ function (P465L PPARγ) in mice

    NARCIS (Netherlands)

    Gray, S.L.; Dalla Nora, E.; Grosse, J.; Manieri, M.; Stoeger, T.; Medina-Gomez, G.; Burling, K.; Wattler, S.; Russ, A.; Yeo, G.S.H.; Chatterjee, V.K.; O'Rahilly, S.; Voshol, P.J.; Cinti, S.; Vidal-Puig, A.

    2006-01-01

    Peroxisome proliferator-activated receptor (PPAR)γ is a key transcription factor facilitating fat deposition in adipose tissue through its proadipogenic and lipogenic actions. Human patients with dominant-negative mutations in PPARγ display lipodystrophy and extreme insulin resistance. For this

  18. Do prostaglandins affect cellular radiosensitivity in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Millar, B.C.; Jinks, S. (Institute of Cancer Research, Sutton (UK). Surrey Branch)

    1984-10-01

    The authors were unable to detect any change in the in vitro radiation response of mouse fibrosarcoma cells, HSDM/sub 1/C/sub 1/, which secrete 2 ..mu..g PGE/sub 2//mg cell protein/24 h, in the presence of the prostaglandin biosynthesis inhibitor flurbiprofen. Furthermore, addition of exogenous PGE/sub 1/ or PGA/sub 2/ to cultures of Chinese hamster cells was similarly without effect on radiation response. Although a high concentration of PGA/sub 2/ inhibited the growth of Chinese hamster cells in vitro this effect disappeared upon removal of the prostaglandin. The implications of these results for radiotherapy are discussed.

  19. Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats

    Science.gov (United States)

    Rojas, Asheebo; Ganesh, Thota; Manji, Zahra; O’neill, Theon; Dingledine, Raymond

    2016-01-01

    Survivors of exposure to an organophosphorus nerve agent may develop a number of complications including long-term cognitive deficits (Miyaki et al., 2005; Nishiwaki et al., 2001). We recently demonstrated that inhibition of the prostaglandin E2 receptor, EP2, attenuates neuroinflammation and neurodegeneration caused by status epilepticus (SE) induced by the soman analog, diisopropylfluorophosphate (DFP), which manifest within hours to days of the initial insult. Here, we tested the hypothesis that DFP exposure leads to a loss of cognitive function in rats that is blocked by early, transient EP2 inhibition. Adult male Sprague-Dawley rats were administered vehicle or the competitive EP2 antagonist, TG6-10-1, (ip) at various times relative to DFP-induced SE. DFP administration resulted in prolonged seizure activity as demonstrated by cortical electroencephalography (EEG). A single intraperitoneal injection of TG6-10-1 or vehicle 1 h prior to DFP did not alter the development of seizures, the latency to SE or the duration of SE. Rats administered six injections of TG6-10-1 starting 90 min after the onset of DFP-induced SE could discriminate between a novel and familiar object 6–12 weeks after SE, unlike vehicle treated rats which showed no preference for the novel object. By contrast, behavioral changes in the light-dark box and open field assays were not affected by TG6-10-1. Delayed mortality after DFP was also unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor may prevent SE-induced memory impairment in rats caused by exposure to a high dose of DFP. PMID:27477533

  20. Energy Balance, Myostatin, and GILZ: Factors Regulating Adipocyte Differentiation in Belly and Bone

    Directory of Open Access Journals (Sweden)

    Xingming Shi

    2007-01-01

    Full Text Available Peroxisome proliferator-activated receptor gamma (PPAR-γ belongs to the nuclear hormone receptor subfamily of transcription factors. PPARs are expressed in key target tissues such as liver, fat, and muscle and thus they play a major role in the regulation of energy balance. Because of PPAR-γ's role in energy balance, signals originating from the gut (e.g., GIP, fat (e.g., leptin, muscle (e.g., myostatin, or bone (e.g., GILZ can in turn modulate PPAR expression and/or function. Of the two PPAR-γ isoforms, PPAR-γ2 is the key regulator of adipogenesis and also plays a role in bone development. Activation of this receptor favors adipocyte differentiation of mesenchymal stem cells, while inhibition of PPAR-γ2 expression shifts the commitment towards the osteoblastogenic pathway. Clinically, activation of this receptor by antidiabetic agents of the thiazolidinedione class results in lower bone mass and increased fracture rates. We propose that inhibition of PPAR-γ2 expression in mesenchymal stem cells by use of some of the hormones/factors mentioned above may be a useful therapeutic strategy to favor bone formation.

  1. PPAR agonists in modulating the inflammatory properties of macrophages

    OpenAIRE

    Paukkeri, Erja-Leena

    2015-01-01

    PPAR-agonistien vaikutukset makrofagien aktivaatioon Tulehdus on keskeinen tekijä sekä perinteisten tulehdussairauksien, kuten nivelreuman, että lihavuuteen liittyvien sairauksien, kuten aikuistyypin diabeteksen ja sydän- ja verisuonisairauksien, tautiprosesseissa. Nivelreumassa liiallinen tulehdusreaktio aiheuttaa kudostuhoa ja kipua sekä hankaloittaa potilaan kykyä työskennellä ja toimia yhteiskunnassa. Lihavuuteen liittyvä tulehdus on voimakkuudeltaan hiljaisempaa kuin nivelreumassa, m...

  2. AUGMENTATIVE EFFECT OF PROSTAGLANDIN E1 ON PENTOBARBITAL HYPNOSIS MEDIATED BY 5-HT IN CHICKS

    Directory of Open Access Journals (Sweden)

    Amalendu Chanda

    2012-01-01

    Full Text Available Prostaglandins (PG are present in different tissues specially in brain tissues endowed with different central nervous system activities. Similarly, 5-hydroxytryptamine (5-HT a biogenic amine with its presence in different central and peripheral tissues as neurotransmitter plays an important role in the regulation of physiological functions specially hypnosis, convulsions, analgesia in rats, mice, cats and chicks etc. Pentobarbitone (PB induced sleep appear to be a serotonergic modulator activity in different animals. PGE1 potentiates the pentobarbitone hypnosis also mediated through serotonin. In the present study, PGE1 induced sleeping time in chicks was evaluated. Drugs affecting 5-HT synthesis, metabolism and receptor activity modulate the potentiating response, while adrenergic receptor antagonists did not showed any response. This study suggest that PGE1 potentiate PB induced sleep through serotonergic signaling pathway as PGE1 increased 5-HT synthesis rate in chick brain.

  3. Peroxisome Proliferator-Activated Receptors as Mediators of Phthalate-Induced Effects in the Male and Female Reproductive Tract: Epidemiological and Experimental Evidence

    Directory of Open Access Journals (Sweden)

    Giuseppe Latini

    2008-01-01

    Full Text Available There is growing evidence that male as well as female reproductive function has been declining in human and wildlife populations over the last 40 years. Several factors such as lifestyle or environmental xenobiotics other than genetic factors may play a role in determining adverse effects on reproductive health. Among the environmental xenobiotics phthalates, a family of man-made pollutants are suspected to interfere with the function of the endocrine system and therefore to be endocrine disruptors. The definition of endocrine disruption is today extended to broader endocrine regulations, and includes activation of metabolic sensors, such as the peroxisome proliferator-activated receptors (PPARs. Toxicological studies have shown that phthalates can activate a subset of PPARs. Here, we analyze the epidemiological and experimental evidence linking phthalate exposure to both PPAR activation and adverse effects on male and female reproductive health.

  4. Anti-kindling Effect of Bezafibrate, a Peroxisome Proliferator-activated Receptors Alpha Agonist, in Pentylenetetrazole Induced Kindling Seizure Model.

    Science.gov (United States)

    Saha, Lekha; Bhandari, Swati; Bhatia, Alka; Banerjee, Dibyajyoti; Chakrabarti, Amitava

    2014-12-01

    Studies in the animals suggested that Peroxisome proliferators activated receptors (PPARs) may be involved in seizure control and selective agonists of PPAR α or PPAR γ raise seizure thresholds. The present study was contemplated with the aim of evaluating the anti kindling effects and the mechanism of bezafibrate, a Peroxisome proliferator-activated receptors α (PPAR-α) agonist in pentylenetetrazole (PTZ) induced kindling model of seizures in rats. In a PTZ kindled Wistar rat model, different doses of bezafibrate (100 mg/kg, 200 mg/kg and 300 mg/kg) were administered intraperitoneally 30 minutes before the PTZ injection. The PTZ injection was given on alternate day till the animal became fully kindled or till 10 weeks. The parameters measured were the latency to develop kindling and incidence of kindling, histopathological study of hippocampus, hippocampal lipid peroxidation studies, serum neuron specific enolase, and hippocampal DNA fragmentation study. In this study, bezafibrate significantly reduced the incidence of kindling in PTZ treated rats and exhibited a marked prolongation in the latencies to seizures. In the present study bezafibrate decreased the thiobarbituric acid-reactive substance i.e. Malondialdehyde levels, increased the reduced glutathione levels, catalase and superoxide dismutase activity in the brain. This added to its additional neuroprotective effects. Bezafibrate also reduced the neuronal damage and apoptosis in hippocampal area of the brain. Therefore bezafibrate exerted anticonvulsant properties in PTZ induced kindling model in rats. These findings may provide insights into the understanding of the mechanism of bezafibrate as an anti kindling agent and could offer a useful support to the basic antiepileptic therapy in preventing the development of PTZ induced seizures, suggesting its potential for therapeutic applications in temporal lobe epilepsy.

  5. Peroxisome proliferator-activated receptor-gamma as a potential therapeutic target in the treatment of preeclampsia.

    LENUS (Irish Health Repository)

    McCarthy, Fergus P

    2012-01-31

    Preeclampsia is a multisystemic disorder of pregnancy characterized by hypertension, proteinuria, and maternal endothelial dysfunction. It is a major cause of maternal and perinatal morbidity and mortality and is thought to be attributable, in part, to inadequate trophoblast invasion. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor expressed in trophoblasts, and the vasculature of which activation has been shown to improve endothelium-dependent vasodilatation in hypertensive conditions. We investigated the effects of the administration of a PPAR-gamma agonist using the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. The selective PPAR-gamma agonist, rosiglitazone, was administered to pregnant rats that had undergone RUPP surgery. To investigate whether any observed beneficial effects of PPAR-gamma activation were mediated by the antioxidant enzyme, heme oxygenase 1, rosiglitazone was administered in combination with the heme oxygenase 1 inhibitor tin-protoporphyrin IX. RUPP rats were characterized by hypertension, endothelial dysfunction, and elevated microalbumin:creatinine ratios. Rosiglitazone administration ameliorated hypertension, improved vascular function, and reduced the elevated microalbumin:creatinine ratio in RUPP rats. With the exception of microalbumin:creatinine ratio, these beneficial effects were abrogated in the presence of the heme oxygenase 1 inhibitor. Administration of a PPAR-gamma agonist prevented the development of several of the pathophysiological characteristics associated with the RUPP model of preeclampsia, via a heme oxygenase 1-dependent pathway. The findings from this study provide further insight into the underlying etiology of preeclampsia and a potential therapeutic target for the treatment of preeclampsia.

  6. Implication of the Pro12Ala polymorphism of the PPAR-gamma 2 gene in type 2 diabetes and obesity in the French population

    Directory of Open Access Journals (Sweden)

    Charles Marie-Aline

    2005-03-01

    Full Text Available Abstract Background The Pro12Ala Single Nucleotide Polymorphism (SNP of the Peroxisome Proliferator-Activated Receptor gamma 2 (PPAR-gamma 2 has been associated with insulin resistance and type 2 diabetes (T2D and also inconsistently with obesity. The aim of this study was to evaluate the impact of this SNP with regards to T2D and childhood and adult obesity in the French Caucasian population. Methods We conducted three independent case/control studies encompassing 2126 cases and 1124 controls. Results We found a significant association between PPAR-gamma 2 Pro12Ala SNP and T2D (p = 0.04, OR = 1.37, which was stronger when the T2D cohort was stratified according to the obesity status (p = 0.03, OR = 1.81 in obese T2D subjects. In contrast, there was no association between the Pro12Ala SNP and childhood and adulthood obesity. In normal glucose tolerant obese adults (but not in lean subjects, the Pro12 allele was associated with a significant increase in fasting insulin levels (p = 0.01, and in insulin resistance estimated by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR (p = 0.003, after adjustment for age, gender and BMI. We didn't detect evidence for an interaction effect between the Pro12Ala SNP and the obesity status with respect to the HOMA-IR index in normal glucose tolerant children, but we found a borderline interaction (p = 0.06 in normal glucose tolerant adults. Conclusion Our results showed that the Pro12Ala polymorphism is not associated with childhood or adult obesity in the French Caucasian population. In contrast, we confirm a contribution of the PPAR-gamma 2 Pro12 allele in the genetic risk forT2D, especially in obese subjects, where this allele worsens insulin resistanceand increases fasting insulin levels.

  7. The effects of photosensitizing antibiotics and ultraviolet irradiation on the biosynthesis of prostaglandins

    International Nuclear Information System (INIS)

    Lord, J.T.; Ziboh, V.A.; Blick, G.; Poitier, J.; Kursunoglu, I.; Penneys, N.S.

    1978-01-01

    Oxygenation of arachidonic acid in vitro by calf skin microsomal acetone powder was enhanced by UV-irradiation at wavelengths of 254 and 360 nm. Further enhancement of the oxygenation reaction was observed in the presence of two photosensitizing cyclic antibiotics, tetracycline and demethylchlortetracycline. To test whether or not the oxygenation of arachidonic acid was related to the biosynthesis of prostaglandins, [I- 14 C]-arachidonic acid was incubated with calf skin acetone powder in the presence of UV-irradiation and the cyclic antibiotics. Prostaglandin biosynthesis from arachidonic acid by the calf skin microsomal acetone powder was enhanced after exposure to UV-irradiation at 254 nm and moderately at 360 nm. Incubation in the presence of demethylchlortetra-cycline (0.2 mM) increased prostaglandin biosynthesis approximately 95% over control by UV-irradiation at 254 nm. No significant stimulation of prostaglandin biosynthesis was observed at 360 nm. Non-photosensitizing antibiotics had no effect either on the oxygenation of arachidonic acid or on the biosynthesis of prostaglandin with or without UV-irradiation. It is suggested that the inflammatory reactions associated with these photo-reactive antibiotics may in part, be via the biosynthesis and release of the prostaglandins which are known to produce cutaneous inflammatory reactions. (author)

  8. Role of the ERC motif in the proximal part of the second intracellular loop and the C-terminal domain of the human prostaglandin F2alpha receptor (hFP-R) in G-protein coupling control.

    Science.gov (United States)

    Pathe-Neuschäfer-Rube, Andrea; Neuschäfer-Rube, Frank; Püschel, Gerhard P

    2005-05-15

    The human FP-R (F2alpha prostaglandin receptor) is a Gq-coupled heptahelical ectoreceptor, which is of significant medical interest, since it is a potential target for the treatment of glaucoma and preterm labour. On agonist exposure, it mediates an increase in intracellular inositol phosphate formation. Little is known about the structures that govern the agonist-dependent receptor activation. In other prostanoid receptors, the C-terminal domain has been inferred in the control of agonist-dependent receptor activation. A DRY motif at the beginning of the second intracellular loop is highly conserved throughout the G-protein-coupled receptor family and appears to be crucial for controlling agonist-dependent receptor activation. It is replaced by an ERC motif in the FP-R and no evidence for the relevance of this motif in ligand-dependent activation of prostanoid receptors has been provided so far. The aim of the present study was to elucidate the potential role of the C-terminal domain and the ERC motif in agonist-controlled intracellular signalling in FP-R mutants generated by site-directed mutagenesis. It was found that substitution of the acidic Glu(132) in the ERC motif by a threonine residue led to full constitutive activation, whereas truncation of the receptor's C-terminal domain led to partial constitutive activation of all three intracellular signal pathways that had previously been shown to be activated by the FP-R, i.e. inositol trisphosphate formation, focal adhesion kinase activation and T-cell factor signalling. Inositol trisphosphate formation and focal adhesion kinase phosphorylation were further enhanced by ligand binding in cells expressing the truncation mutant but not the E132T (Glu132-->Thr) mutant. Thus C-terminal truncation appeared to result in a receptor with partial constitutive activation, whereas substitution of Glu132 by threonine apparently resulted in a receptor with full constitutive activity.

  9. Thermodynamics in Neurodegenerative Diseases: Interplay Between Canonical WNT/Beta-Catenin Pathway-PPAR Gamma, Energy Metabolism and Circadian Rhythms.

    Science.gov (United States)

    Vallée, Alexandre; Lecarpentier, Yves; Guillevin, Rémy; Vallée, Jean-Noël

    2018-03-23

    Entropy production rate is increased by several metabolic and thermodynamics abnormalities in neurodegenerative diseases (NDs). Irreversible processes are quantified by changes in the entropy production rate. This review is focused on the opposing interactions observed in NDs between the canonical WNT/beta-catenin pathway and PPAR gamma and their metabolic and thermodynamic implications. In amyotrophic lateral sclerosis and Huntington's disease, WNT/beta-catenin pathway is upregulated, whereas PPAR gamma is downregulated. In Alzheimer's disease and Parkinson's disease, WNT/beta-catenin pathway is downregulated while PPAR gamma is upregulated. The dysregulation of the canonical WNT/beta-catenin pathway is responsible for the modification of thermodynamics behaviors of metabolic enzymes. Upregulation of WNT/beta-catenin pathway leads to aerobic glycolysis, named Warburg effect, through activated enzymes, such as glucose transporter (Glut), pyruvate kinase M2 (PKM2), pyruvate dehydrogenase kinase 1(PDK1), monocarboxylate lactate transporter 1 (MCT-1), lactic dehydrogenase kinase-A (LDH-A) and inactivation of pyruvate dehydrogenase complex (PDH). Downregulation of WNT/beta-catenin pathway leads to oxidative stress and cell death through inactivation of Glut, PKM2, PDK1, MCT-1, LDH-A but activation of PDH. In addition, in NDs, PPAR gamma is dysregulated, whereas it contributes to the regulation of several key circadian genes. NDs show many dysregulation in the mediation of circadian clock genes and so of circadian rhythms. Thermodynamics rhythms operate far-from-equilibrium and partly regulate interactions between WNT/beta-catenin pathway and PPAR gamma. In NDs, metabolism, thermodynamics and circadian rhythms are tightly interrelated.

  10. Plasma 8-iso-Prostaglandin F2α concentrations and outcomes after acute intracerebral hemorrhage.

    Science.gov (United States)

    Du, Quan; Yu, Wen-Hua; Dong, Xiao-Qiao; Yang, Ding-Bo; Shen, Yong-Feng; Wang, Hao; Jiang, Li; Du, Yuan-Feng; Zhang, Zu-Yong; Zhu, Qiang; Che, Zhi-Hao; Liu, Qun-Jie

    2014-11-01

    Higher plasma 8-iso-Prostaglandin F2α concentrations have been associated with poor outcome of severe traumatic brain injury. We further investigated the relationships between plasma 8-iso-Prostaglandin F2α concentrations and clinical outcomes in patients with acute intracerebral hemorrhage. Plasma 8-iso-Prostaglandin F2α concentrations of 128 consecutive patients and 128 sex- and gender-matched healthy subjects were measured by enzyme-linked immunosorbent assay. We assessed their relationships with disease severity and clinical outcomes including 1-week mortality, 6-month mortality and unfavorable outcome (modified Rankin Scale score>2). Plasma 8-iso-Prostaglandin F2α concentrations were substantially higher in patients than in healthy controls. Plasma 8-iso-Prostaglandin F2α concentrations were positively associated with National Institutes of Health Stroke Scale (NIHSS) scores and hematoma volume using a multivariate linear regression. It emerged as an independent predictor for clinical outcomes of patients using a forward stepwise logistic regression. ROC curves identified the predictive values of plasma 8-iso-Prostaglandin F2α concentrations, and found its predictive value was similar to NIHSS scores and hematoma volumes. However, it just numerically added the predictive values of NIHSS score and hematoma volume. Increased plasma 8-iso-Prostaglandin F2α concentrations are associated with disease severity and clinical outcome after acute intracerebral hemorrhage. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Effect of Selective Prostaglandin E2 EP2 Receptor Agonist CP-533,536 on Voiding Efficiency in Rats with Midodrine-Induced Functional Urethral Obstruction.

    Science.gov (United States)

    Kurihara, Ryoko; Imazumi, Katsunori; Takamatsu, Hajime; Ishizu, Kenichiro; Yoshino, Taiji; Masuda, Noriyuki

    2016-05-01

    We investigated the effect of the selective prostaglandin E2 EP2 receptor agonist CP-533,536 on voiding efficiency in rats with midodrine-induced functional urethral obstruction. The effect of CP-533,536 (0.03-0.3 mg/kg, intravenous [i.v.]) on urethral perfusion pressure (UPP) was investigated in anesthetized rats pre-treated with midodrine (1 mg/kg, i.v.), which forms an active metabolite that acts as an α1 -adrenoceptor agonist. The effect of CP-533,536 (0.03-0.3 mg/kg, i.v.) on cystometric parameters was also investigated in anesthetized rats. In addition, the effect of CP-533,536 (0.03-0.3 mg/kg, i.v.) on residual urine volume (RV) and voiding efficiency (VE) was investigated in conscious rats treated with midodrine (1 mg/kg, i.v.). CP-533,536 dose-dependently decreased UPP elevated by midodrine in anesthetized rats. In contrast, CP-533,536 did not affect maximum voiding pressure, intercontraction interval, or intravesical threshold pressure. In conscious rats, midodrine (1 mg/kg, i.v.) markedly increased RV and reduced VE. CP-533,536 dose-dependently ameliorated increases in RV and decreases in VE induced by midodrine. These results suggest that a selective EP2 receptor agonist could ameliorate the elevation of RV and improve the reduction of VE in rats with functional urethral obstruction caused by stimulation of α1 -adrenoceptors. The mechanism of action might be not potentiation of bladder contraction but rather preferential relief of urethral constriction. © 2014 Wiley Publishing Asia Pty Ltd.

  12. Prostaglandin E2 Regulates Liver versus Pancreas Cell Fate Decisions and Endodermal Outgrowth

    Science.gov (United States)

    Nissim, Sahar; Sherwood, Richard I.; Wucherpfennig, Julia; Saunders, Diane; Harris, James M.; Esain, Virginie; Carroll, Kelli J.; Frechette, Gregory M.; Kim, Andrew J.; Hwang, Katie L.; Cutting, Claire C.; Elledge, Susanna; North, Trista E.; Goessling, Wolfram

    2014-01-01

    SUMMARY The liver and pancreas arise from common endodermal progenitors. How these distinct cell fates are specified is poorly understood. Here, we describe prostaglandin E2 (PGE2) as a regulator of endodermal fate specification during development. Modulating PGE2 activity has opposing effects on liver-versus-pancreas specification in zebrafish embryos as well as mouse endodermal progenitors. The PGE2 synthetic enzyme cox2a and receptor ep2a are patterned such that cells closest to PGE2 synthesis acquire a liver fate whereas more distant cells acquire a pancreas fate. PGE2 interacts with the bmp2b pathway to regulate fate specification. At later stages of development, PGE2 acting via the ep4a receptor promotes outgrowth of both the liver and pancreas. PGE2 remains important for adult organ growth, as it modulates liver regeneration. This work provides in vivo evidence that PGE2 may act as a morphogen to regulate cell fate decisions and outgrowth of the embryonic endodermal anlagen. PMID:24530296

  13. The Value of Intravenous Prostaglandin E2 after Intra-uterine Death

    African Journals Online (AJOL)

    1974-09-21

    Sep 21, 1974 ... ficantly smaller doses of prostaglandins can achieve deli- very of the fetus and an intravenous route will be the method of choice. However, in cases of rhesus iso- immunisation, where larger doses of prostaglandin are required, with correspondingly more severe side-effects, the extra-amniotic route may be ...

  14. Nuclear Receptor Cofactors in PPARγ-Mediated Adipogenesis and Adipocyte Energy Metabolism

    Directory of Open Access Journals (Sweden)

    Emily Powell

    2007-01-01

    Full Text Available Transcriptional cofactors are integral to the proper function and regulation of nuclear receptors. Members of the peroxisome proliferator-activated receptor (PPAR family of nuclear receptors are involved in the regulation of lipid and carbohydrate metabolism. They modulate gene transcription in response to a wide variety of ligands, a process that is mediated by transcriptional coactivators and corepressors. The mechanisms by which these cofactors mediate transcriptional regulation of nuclear receptor function are still being elucidated. The rapidly increasing array of cofactors has brought into focus the need for a clear understanding of how these cofactors interact in ligand- and cell-specific manners. This review highlights the differential effects of the assorted cofactors regulating the transcriptional action of PPARγ and summarizes the recent advances in understanding the physiological functions of corepressors and coactivators.

  15. Mode of action of ethyl tertiary-butyl ether hepatotumorigenicity in the rat: Evidence for a role of oxidative stress via activation of CAR, PXR and PPAR signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Kakehashi, Anna, E-mail: anna@med.osaka-cu.ac.jp [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Hagiwara, Akihiro; Imai, Norio [DIMS Institute of Medical Science, Inc., 64 Goura, Nishiazai, Azai-cho, Ichinomiya, Aichi 491-0113 (Japan); Nagano, Kasuke [Nagano Toxicologic-Pathology Consulting, Ochiai, Hadano, Kanagawa 257-0025 (Japan); Nishimaki, Fukumi [Biofuel Assessment Group, New Fuels Dept., Japan Petroleum Energy Center (JPEC), 4-3-9 Toranomon, Minato-ku, Tokyo 105-0001 (Japan); Banton, Marcy [Toxicology and Risk Assessment, LyondellBasell Industries, LyondellBasell Corporate HSE/Product Safety, One Houston Center, Suite 700, 1221 McKinney Street, Houston, TX 770 10 (United States); Wei, Min [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Fukushima, Shoji [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Japan Bioassay Research Center, Japan Industrial Safety and Health Association, 2445 Hirasawa, Hadano, Kanagawa 257-0011 (Japan); Wanibuchi, Hideki [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan)

    2013-12-01

    To elucidate possible mode of action (MOA) and human relevance of hepatotumorigenicity in rats for ethyl tertiary-butyl ether (ETBE), male F344 rats were administered ETBE at doses of 0, 150 and 1000 mg/kg body weight twice a day by gavage for 1 and 2 weeks. For comparison, non-genotoxic carcinogen phenobarbital (PB) was applied at a dose of 500 ppm in diet. Significant increase of P450 total content and hydroxyl radical levels by low, high doses of ETBE and PB treatments at weeks 1 and 2, and 8-OHdG formation at week 2, accompanied accumulation of CYP2B1/2B2, CYP3A1/3A2 and CYP2C6, and downregulation of DNA oxoguanine glycosylase 1, induction of apoptosis and cell cycle arrest in hepatocytes, respectively. Up-regulation of CYP2E1 and CYP1A1 at weeks 1 and 2, and peroxisome proliferation at week 2 were found in high dose ETBE group. Results of proteome analysis predicted activation of upstream regulators of gene expression altered by ETBE including constitutive androstane receptor (CAR), pregnane-X-receptor (PXR) and peroxisome proliferator-activated receptors (PPARs). These results indicate that the MOA of ETBE hepatotumorigenicity in rats may be related to induction of oxidative stress, 8-OHdG formation, subsequent cell cycle arrest, and apoptosis, suggesting regenerative cell proliferation after week 2, predominantly via activation of CAR and PXR nuclear receptors by a mechanism similar to that of PB, and differentially by activation of PPARs. The MOA for ETBE hepatotumorigenicity in rats is unlikely to be relevant to humans. - Highlights: • We focus on MOA and human relevance of hepatotumorigenicity in rats for ETBE. • ETBE was administered to F344 rats for 1 and 2 weeks. • Oxidative stress formation, proliferation and apoptosis in the liver are analyzed. • ETBE-induced changes of gene and protein expression in the liver are examined. • The effects are compared with those induced by non-genotoxic carcinogen PB.

  16. Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-α-mediated downregulation of cholesterol 7α-hydroxylase and sterol 27-hydroxylase expression

    NARCIS (Netherlands)

    Post, S.M.; Duez, H.; Gervois, P.P.; Staels, B.; Kuipers, F.; Princen, H.M.G.

    2001-01-01

    Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased

  17. Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase expression

    NARCIS (Netherlands)

    Post, SM; Duez, H; Gervois, PP; Staels, B; Kuipers, F; Princen, HMG

    2001-01-01

    Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased

  18. Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1.

    Science.gov (United States)

    Li, Fengyin; He, Bing; Ma, Xiaoke; Yu, Shuyang; Bhave, Rupali R; Lentz, Steven R; Tan, Kai; Guzman, Monica L; Zhao, Chen; Xue, Hai-Hui

    2017-09-07

    Effective treatment of chronic myelogenous leukemia (CML) largely depends on the eradication of CML leukemic stem cells (LSCs). We recently showed that CML LSCs depend on Tcf1 and Lef1 factors for self-renewal. Using a connectivity map, we identified prostaglandin E1 (PGE1) as a small molecule that partly elicited the gene expression changes in LSCs caused by Tcf1/Lef1 deficiency. Although it has little impact on normal hematopoiesis, we found that PGE1 treatment impaired the persistence and activity of LSCs in a pre-clinical murine CML model and a xenograft model of transplanted CML patient CD34 + stem/progenitor cells. Mechanistically, PGE1 acted on the EP4 receptor and repressed Fosb and Fos AP-1 factors in a β-catenin-independent manner. Misoprostol, an FDA-approved EP4 agonist, conferred similar protection against CML. These findings suggest that activation of this PGE1-EP4 pathway specifically targets CML LSCs and that the combination of PGE1/misoprostol with conventional tyrosine-kinase inhibitors could provide effective therapy for CML. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Liver steatosis study_PFAA treated Wild type and PPAR KO mouse data

    Data.gov (United States)

    U.S. Environmental Protection Agency — Data set 1 consists of the experimental data for the Wild Type and PPAR KO animal study and includes data used to prepare Figures 1-4 and Table 1 of the Das et al,...

  20. Prostaglandin E2 release from dermis regulates sodium permeability of frog skin epithelium

    DEFF Research Database (Denmark)

    Rytved, Klaus A.; Brodin, Birger; Nielsen, Robert

    1995-01-01

    Arachidonic acid, cAMP, epithelium, frog skin, intracellular calcium, prostaglandin E*U2, sodium transport, tight epithelium.......Arachidonic acid, cAMP, epithelium, frog skin, intracellular calcium, prostaglandin E*U2, sodium transport, tight epithelium....

  1. A positive feedback loop between progesterone and microsomal prostaglandin E synthase-1-mediated PGE2 promotes production of both in mouse granulosa cells.

    Science.gov (United States)

    Tamura, Kazuhiro; Naraba, Hiroaki; Hara, Takahiko; Nakamura, Kota; Yoshie, Mikihiro; Kogo, Hiroshi; Tachikawa, Eiichi

    2016-03-01

    Microsomal prostaglandin E synthase-1 (mPGES-1) is primarily expressed in granulosa cells (GCs) in the preovulatory follicle. Both prostaglandin E2 (PGE2) and progesterone (P4) are implicated in various reproductive functions. Here, we demonstrate that mPges-1 may be a direct downstream target gene of the P4 receptor and P4-stimulated PGE2 secretion can stimulate P4 production in a newly generated mouse GC line (GtsT). Treatment of GtsT cells with a P4 receptor agonist, norgestrel, markedly increased mPGES-1 expression detected by RT-PCR analysis. PGE2 secretion measured by an enzyme-linked immunosorbent assay was enhanced by P4 treatment. Luciferase assays revealed that the proximal promoter region of the mPges-1 gene was responsible for the effects of P4 treatment. Conversely, PGE2 treatment stimulated P4 secretion, which coordinated with mRNA expression of steroidogenic acute regulatory protein. Taken together, P4 may regulate mPGES-1 expression to increase PGE2 secretion and in turn P4 production. An autocrine loop between P4 and PGE2 might function to maintain the increased levels of both in GCs. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Prostaglandin production by melanocytic cells and the effect of alpha-melanocyte stimulating hormone.

    Science.gov (United States)

    Nicolaou, Anna; Estdale, Sian E; Tsatmali, Marina; Herrero, Daniel Pascual; Thody, Anthony J

    2004-07-16

    Prostaglandins are potent mediators of the inflammatory response and are also involved in cancer development. In this study, we show that human melanocytes and FM55 melanoma cells express cyclooxygenase-1 and -2 (COX-1 and -2) and thus have the capability to produce prostaglandins. The FM55 cells produced predominantly PGE2 and PGF2alpha, whereas the HaCaT keratinocyte cell line produced mainly PGE2. The anti-inflammatory peptide, alpha-melanocyte stimulating hormone (alpha-MSH), reduced prostaglandin production in FM55 and HaCaT cells and reversed the effect of the pro-inflammatory cytokine TNF-alpha in the former. These results indicate that melanocytes produce prostaglandins and that alpha-MSH, by inhibiting this response, may play an important role in regulating inflammatory responses in the skin.

  3. Misoprostol, an anti-ulcer agent and PGE2 receptor agonist, protects against cerebral ischemia

    OpenAIRE

    Li, Jun; Liang, Xibin; Wang, Qian; Breyer, Richard M.; McCullough, Louise; Andreasson, Katrin

    2008-01-01

    Induction of COX-2 activity in cerebral ischemia results in increased neuronal injury and infarct size. Recent studies investigating neurotoxic mechanisms of COX-2 demonstrate both toxic and paradoxically protective effects of downstream prostaglandin receptor signaling pathways. We tested whether misoprostol, a PGE2 receptor agonist that is utilized clinically as an anti-ulcer agent and signals through the protective PGE2 EP2, EP3, and EP4 receptors, would reduce brain injury in the murine m...

  4. Peroxisome Proliferator-Activated Receptor -β/δ, -γ Agonists and Resveratrol Modulate Hypoxia Induced Changes in Nuclear Receptor Activators of Muscle Oxidative Metabolism

    Directory of Open Access Journals (Sweden)

    Timothy R. H. Regnault

    2010-01-01

    Full Text Available PPAR-α, PPAR-β, and PPAR-γ, and RXR in conjunction with PGC-1α and SIRT1, activate oxidative metabolism genes determining insulin sensitivity. In utero, hypoxia is commonly observed in Intrauterine Growth Restriction (IUGR, and reduced insulin sensitivity is often observed in these infants as adults. We sought to investigate how changes in oxygen tension might directly impact muscle PPAR regulation of oxidative genes. Following eight days in culture at 1% oxygen, C2C12 muscle myoblasts displayed a reduction of PGC-1α, PPAR-α, and RXR-α mRNA, as well as CPT-1b and UCP-2 mRNA. SIRT1 and PGC-1α protein was reduced, and PPAR-γ protein increased. The addition of a PPAR-β agonist (L165,041 for the final 24 hours of 1% treatment resulted in increased levels of UCP-2 mRNA and protein whereas Rosiglitazone induced SIRT1, PGC-1α, RXR-α, PPAR-α, CPT-1b, and UCP-2 mRNA and SIRT1 protein. Under hypoxia, Resveratrol induced SIRT1, RXR-α, PPAR-α mRNA, and PPAR-γ and UCP-2 protein. These findings demonstrate that hypoxia alters the components of the PPAR pathway involved in muscle fatty acid oxidative gene transcription and translation. These results have implications for understanding selective hypoxia adaptation and how it might impact long-term muscle oxidative metabolism and insulin sensitivity.

  5. A novel antipyretic action of 15-deoxy-Delta12,14-prostaglandin J2 in the rat brain.

    Science.gov (United States)

    Mouihate, Abdeslam; Boissé, Lysa; Pittman, Quentin J

    2004-02-11

    Fever is an important part of the host defense response, yet fever can be detrimental if it is uncontrolled. We provide the first evidence that 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), can attenuate the febrile response to lipopolysaccharide (LPS) in rats via an action on the brain. Furthermore, we show that PPARgamma is expressed in the hypothalamus, an important locus in the brain for fever generation. In addition, 15d-PGJ2 and its synthesizing enzyme (PGD2 synthase) were present in rat cerebrospinal fluid, and their levels were enhanced in response to systemic injection of LPS. The antipyretic effect of 15d-PGJ2 was associated with reduction in LPS-stimulated cyclooxygenase-2 expression in the hypothalamus but not in p44/p42 mitogen-activated protein kinase phosphorylation or in the expression of the PPARgamma. Thus it is likely that there is a parallel induction of an endogenous prostanoid pathway in the brain capable of limiting deleterious actions of the proinflammatory prostaglandin E2-dependent pathway.

  6. Some effects of prostaglandins E1 and E2 and of endotoxin injected into the hypothalamus of young chicks: dissociation between endotoxin fever and the effects of prostaglandins.

    Science.gov (United States)

    Artunkal, A A; Marley, E; Stephenson, J D

    1977-09-01

    Prostaglandins E1 and E2 elevated body temperature of young chicks when injected into the hypothalamus at thermoneutrality (31 degrees C). In contrast, they lowered body temperature when so injected below thermoneutrality (16degreesC): the relation of the fall in body temperature to increased heat loss and decreased heat production was examined. 2 The above effects below thermoneutrality were potentiated by pretreatment with inhibitors of prostaglandin synthetase and possible reasons for this potentation are given. 3 The O-somatic antigen of Shigella dysenteriae consistently evoked hyperthermia when injected into the hypothalamus, irrespective of whether the chicks were within or below thermoneutrality. 4 Pretreatment with prostaglandin synthetase inhibitors failed to prevent the onset of endotoxin fever; however, duration of the fever, induced by intrahypothalamic injection of the O-somatic antigen of Shigella dysenteriae was reduced. 5 The intrahypothalamic injection, belwo thermoneutrality of prostaglandins E1, E2, noradrenaline, 5-hydroxytryptamine or carbachol reversed endotoxin fever, inducing even substantial falls in body temperature. 6 While the results cast some doubts on the role of prostaglandins of the E series as mediators of endotoxin fever in chicks, they cannot be eliminated as mediators until the significance of the reduction in duration of the pyrexic response by indomethacin and 5,8,11,14-eicosatetraynoic acid, and the degree of synthesis inhibition attained, are known.

  7. Chloroquine, quinine, procaine, quinidine, tricyclic antidepressants, and methylxanthines as prostaglandin agonists and antagonists.

    Science.gov (United States)

    Manku, M S; Horrobin, D F

    1976-11-20

    Chloroquine, quanine, procaine, quinidine, clomipramine, theophylline, and caffeine have been shown to be strong prostaglandin antagonists and weak agonists. The antagonist effect is clearly demonstrable at concentrations reached in human plasma when the drugs are used therapeutically. This suggests that prostaglandins are important in several situations in which their role has hitherto been unsuspected. New approaches to the development of prostaglandin antagonists and new uses for established drugs are indicated. In a preliminary study chloroquine has been successfully used to close patent ductus arteriosus in three infants.

  8. The effect of n-3 long chain fatty acids supplementation on plasma peroxisome proliferator activated receptor gamma and thyroid hormones in obesity

    Directory of Open Access Journals (Sweden)

    Parizad Taraghijou

    2012-01-01

    Full Text Available Background: Peroxisome proliferator-activated receptor gamma (PPAR γ is a transcription factor, which is abundantly expressed in adipose tissue and has a direct link to adiposity. It seems that long-chain polyunsaturated fatty acids (LC-PUFAs can regulate PPAR γ expression. The purpose of this study was to investigate the effects of n-3LC PUFA supplementation on plasma levels of PPAR γ and thyroid hormones in obesity. Materials and Methods: In a randomized double-blind controlled trial, 66 subjects with obesity were assigned to 2 groups. Participants in intervention group consumed omega3 capsules contained 1000 mg n-3 fatty acids (180 mg of eicosapentaenoic acid [EPA] and 120 mg of docosahexaenoic acid [DHA] and placebo group consumed placebo capsules contained paraffin twice a day for 4 wk. Fasting blood samples and weight measurements were collected at the baseline and at the end of the trial. Plasma PPAR γ and thyroid hormones were measured by ELISA. Data were analyzed using a repeated measure model-two factor for comparing two groups in two times. Results: No significant changes were observed in PPAR γ levels between and within the groups after supplementation (P>0.05. N-3LC PUFA supplementation significantly increased T4 levels after 4 wk (P<0.05 but T3 and TSH did not change significantly. Conclusion: Our study showed that n-3LC PUFAs supplementation increased T4 levels. However, no significant changes in T3, TSH and PPAR γ plasma levels were observed in obese adults.

  9. Oxymatrine attenuates hepatic steatosis in non-alcoholic fatty liver disease rats fed with high fructose diet through inhibition of sterol regulatory element binding transcription factor 1 (Srebf1) and activation of peroxisome proliferator activated receptor alpha (Pparα).

    Science.gov (United States)

    Shi, Li-juan; Shi, Lei; Song, Guang-yao; Zhang, He-fang; Hu, Zhi-juan; Wang, Chao; Zhang, Dong-hui

    2013-08-15

    The aim of this study was to examine the therapeutic effect of oxymatrine, a monomer isolated from the medicinal plant Sophora flavescens Ait, on the hepatic lipid metabolism in non-alcoholic fatty liver (NAFLD) rats and to explore the potential mechanism. Rats were fed with high fructose diet for 8 weeks to establish the NAFLD model, then were given oxymatrine treatment (40, 80, and 160 mg/kg, respectively) for another 8 weeks. Body weight gain, liver index, serum and liver lipids, and histopathological evaluation were measured. Enzymatic activity and gene expression of the key enzymes involved in the lipogenesis and fatty acid oxidation were assayed. The results showed that oxymatrine treatment reduced body weight gain, liver weight, liver index, dyslipidemia, and liver triglyceride level in a dose dependant manner. Importantly, the histopathological examination of liver confirmed that oxymatrine could decrease the liver lipid accumulation. The treatment also decreased the fatty acid synthase (FAS) enzymatic activity and increased the carnitine palmitoyltransferase 1A (CPT1A) enzymatic activity. Besides, oxymatrine treatment decreased the mRNA expression of sterol regulatory element binding transcription factor 1(Srebf1), fatty acid synthase (Fasn), and acetyl CoA carboxylase (Acc), and increased the mRNA expression of peroxisome proliferator activated receptor alpha (Pparα), carnitine palmitoyltransferase 1A (Cpt1a), and acyl CoA oxidase (Acox1) in high fructose diet induced NAFLD rats. These results suggested that the therapeutic effect of oxymatrine on the hepatic steatosis in high fructose diet induced fatty liver rats is partly due to down-regulating Srebf1 and up-regulating Pparα mediated metabolic pathways simultaneously. © 2013 Elsevier B.V. All rights reserved.

  10. Lipid-binding proteins modulate ligand-dependent trans-activation by peroxisome proliferator-activated receptors and localize to the nucleus as well as the cytoplasm

    DEFF Research Database (Denmark)

    Helledie, T; Antonius, M; Sorensen, R V

    2000-01-01

    Peroxisome proliferator-activated receptors (PPARs) are activated by a variety of fatty acids, eicosanoids, and hypolipidemic and insulin-sensitizing drugs. Many of these compounds bind avidly to members of a family of small lipid-binding proteins, the fatty acid-binding proteins (FABPs). Fatty...

  11. Tetrandrine has anti-adipogenic effect on 3T3-L1 preadipocytes through the reduced expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3

    International Nuclear Information System (INIS)

    Jang, Byeong-Churl

    2016-01-01

    Tetrandrine is a bisbenzylisoquinoline alkaloid isolated from the roots of Stephania tetrandra S. Moore and has been shown to possess anti-inflammatory and anti-cancerous activities. In this study, the effect of tetrandrine on adipogenesis in 3T3-L1 preadipocytes was investigated. Tetrandrine at 10 μM concentration strongly inhibited lipid accumulation and triglyceride (TG) synthesis during the differentiation of 3T3-L1 preadipocytes into adipocytes. On mechanistic levels, tetrandrine reduced not only the expressions of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), and perilipin A but also the phosphorylation levels of signal transducer and activator of transcription-3 (STAT-3) during 3T3-L1 adipocyte differentiation. Tetrandrine also reduced the mRNA expression of leptin, but not adiponectin, during 3T3-L1 adipocyte differentiation. Collectively, these findings show that tetrandrine has strong anti-adipogenic effect on 3T3-L1 preadipocytes and the effect is largely attributable to the reduced expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3. - Highlights: • Tetrandrine, a bisbenzylisoquinoline alkaloid, inhibits adipogenesis. • Tetrandrine inhibits C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3 in 3T3-L1 adipocytes. • Tetrandrine reduces leptin, but not adiponectin, expression in 3T3-L1 adipocytes. • Tetrandrine may thus have therapeutic potential against obesity.

  12. Tetrandrine has anti-adipogenic effect on 3T3-L1 preadipocytes through the reduced expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Byeong-Churl, E-mail: jangbc123@gw.kmu.ac.kr

    2016-08-05

    Tetrandrine is a bisbenzylisoquinoline alkaloid isolated from the roots of Stephania tetrandra S. Moore and has been shown to possess anti-inflammatory and anti-cancerous activities. In this study, the effect of tetrandrine on adipogenesis in 3T3-L1 preadipocytes was investigated. Tetrandrine at 10 μM concentration strongly inhibited lipid accumulation and triglyceride (TG) synthesis during the differentiation of 3T3-L1 preadipocytes into adipocytes. On mechanistic levels, tetrandrine reduced not only the expressions of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), and perilipin A but also the phosphorylation levels of signal transducer and activator of transcription-3 (STAT-3) during 3T3-L1 adipocyte differentiation. Tetrandrine also reduced the mRNA expression of leptin, but not adiponectin, during 3T3-L1 adipocyte differentiation. Collectively, these findings show that tetrandrine has strong anti-adipogenic effect on 3T3-L1 preadipocytes and the effect is largely attributable to the reduced expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3. - Highlights: • Tetrandrine, a bisbenzylisoquinoline alkaloid, inhibits adipogenesis. • Tetrandrine inhibits C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3 in 3T3-L1 adipocytes. • Tetrandrine reduces leptin, but not adiponectin, expression in 3T3-L1 adipocytes. • Tetrandrine may thus have therapeutic potential against obesity.

  13. Clofibric acid, a peroxisome proliferator-activated receptor alpha ligand, inhibits growth of human ovarian cancer.

    Science.gov (United States)

    Yokoyama, Yoshihito; Xin, Bing; Shigeto, Tatsuhiko; Umemoto, Mika; Kasai-Sakamoto, Akiko; Futagami, Masayuki; Tsuchida, Shigeki; Al-Mulla, Fahd; Mizunuma, Hideki

    2007-04-01

    Recent reports have shown that peroxisome proliferator-activated receptor (PPAR)alpha ligands reduce growth of some types of malignant tumors and prevent carcinogenesis. In this study, we investigated the inhibitory effect of clofibric acid (CA), a ligand for PPARalpha on growth of ovarian malignancy, in in vivo and in vitro experiments using OVCAR-3 and DISS cells derived from human ovarian cancer and aimed to elucidate the molecular mechanism of its antitumor effect. CA treatment significantly suppressed the growth of OVCAR-3 tumors xenotransplanted s.c. and significantly prolonged the survival of mice with malignant ascites derived from DISS cells as compared with control. CA also dose-dependently inhibited cell proliferation of cultured cell lines. CA treatment increased the expression of carbonyl reductase (CR), which promotes the conversion of prostaglandin E(2) (PGE(2)) to PGF(2alpha), in implanted OVCAR-3 tumors as well as cultured cells. CA treatment decreased PGE(2) level as well as vascular endothelial growth factor (VEGF) amount in both of OVCAR-3-tumor and DISS-derived ascites. Reduced microvessel density and induced apoptosis were found in solid OVCAR-3 tumors treated by CA. Transfection of CR expression vector into mouse ovarian cancer cells showed significant reduction of PGE(2) level as well as VEGF expression. These results indicate that CA produces potent antitumor effects against ovarian cancer in conjunction with a reduction of angiogenesis and induction of apoptosis. We conclude that CA could be an effective agent in ovarian cancer and should be tested alone and in combination with other anticancer drugs.

  14. Structural features of subtype-selective EP receptor modulators.

    Science.gov (United States)

    Markovič, Tijana; Jakopin, Žiga; Dolenc, Marija Sollner; Mlinarič-Raščan, Irena

    2017-01-01

    Prostaglandin E2 is a potent endogenous molecule that binds to four different G-protein-coupled receptors: EP1-4. Each of these receptors is a valuable drug target, with distinct tissue localisation and signalling pathways. We review the structural features of EP modulators required for subtype-selective activity, as well as the structural requirements for improved pharmacokinetic parameters. Novel EP receptor subtype selective agonists and antagonists appear to be valuable drug candidates in the therapy of many pathophysiological states, including ulcerative colitis, glaucoma, bone healing, B cell lymphoma, neurological diseases, among others, which have been studied in vitro, in vivo and in early phase clinical trials. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. Endogenous opioids: role in prostaglandin-dependent and -independent fever.

    Science.gov (United States)

    Fraga, Daniel; Machado, Renes R; Fernandes, Luíz C; Souza, Glória E P; Zampronio, Aleksander R

    2008-02-01

    This study evaluated the participation of mu-opioid-receptor activation in body temperature (T(b)) during normal and febrile conditions (including activation of heat conservation mechanisms) and in different pathways of LPS-induced fever. The intracerebroventricular treatment of male Wistar rats with the selective opioid mu-receptor-antagonist cyclic d-Phe-Cys-Try-d-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP; 0.1-1.0 microg) reduced fever induced by LPS (5.0 microg/kg) but did not change T(b) at ambient temperatures of either 20 degrees C or 28 degrees C. The subcutaneous, intracerebroventricular, and intrahypothalamic injection of morphine (1.0-10.0 mg/kg, 3.0-30.0 microg, and 1-100 ng, respectively) produced a dose-dependent increase in T(b). Intracerebroventricular morphine also produced a peripheral vasoconstriction. Both effects were abolished by CTAP. CTAP (1.0 microg icv) reduced the fever induced by intracerebroventricular administration of TNF-alpha (250 ng), IL-6 (300 ng), CRF (2.5 microg), endothelin-1 (1.0 pmol), and macrophage inflammatory protein (500 pg) and the first phase of the fever induced by PGF(2alpha) (500.0 ng) but not the fever induced by IL-1beta (3.12 ng) or PGE(2) (125.0 ng) or the second phase of the fever induced by PGF(2alpha). Morphine-induced fever was not modified by the cyclooxygenase (COX) inhibitor indomethacin (2.0 mg/kg). In addition, morphine injection did not induce the expression of COX-2 in the hypothalamus, and CTAP did not modify PGE(2) levels in cerebrospinal fluid or COX-2 expression in the hypothalamus after LPS injection. In conclusion, our results suggest that LPS and endogenous pyrogens (except IL-1beta and prostaglandins) recruit the opioid system to cause a mu-receptor-mediated fever.

  16. Modulation of enhanced vascular permeability by prostaglandins through alterations in blood flow (hyperemia). [/sup 85/Sr tracer technique

    Energy Technology Data Exchange (ETDEWEB)

    Johnston, M G; Hay, J B; Movat, H Z

    1976-11-01

    The enhanced vascular permeability induced by histamine or bradykinin in the skin of the guinea-pig and rabbit was significantly augmented by small amounts of prostaglandins of the E type. When injected alone these prostaglandins had little effect on vascular permeability. Furthermore, E type prostaglandins were found to be more potent at inducing hyperemia than either histamine or bradykinin. Prostaglandin F/sub 2/ alpha did not enhance the vascular permeability induced by histamine or bradykinin nor did it produce hyperemia in the skin. In the rat, prostaglandins alone enhanced vascular permeability but they also increased the effect of histamine, serotonin and bradykinin. Using /sup 85/Sr-microspheres to measure blood flow a correlation was found between the degree of hyperemia produced by prostaglandins and the degree to which they augmented enhanced vascular permeability due to histamine, serotonin or bradykinin. Prostaglandins therefore can directly mimic the hyperemia of the inflammatory process and can also modulate the changes in vascular permeability caused by other mediators of inflammation.

  17. Artesunate inhibits adipogeneis in 3T3-L1 preadipocytes by reducing the expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Byeong-Churl, E-mail: jangbc123@gw.kmu.ac.kr

    2016-05-20

    Differentiation of preadipocyte, also called adipogenesis, leads to the phenotype of mature adipocyte. However, excessive adipogenesis is closely linked to the development of obesity. Artesunate, one of artemisinin-type sesquiterpene lactones from Artemisia annua L., is known for anti-malarial and anti-cancerous activities. In this study, we investigated the effect of artesunate on adipogenesis in 3T3-L1 preadipocytes. Artesunate strongly inhibited lipid accumulation and triglyceride (TG) synthesis during the differentiation of 3T3-L1 preadipocytes into adipocytes at 5 μM concentration. Artesunate at 5 μM also reduced not only the expressions of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), and perilipin A but also the phosphorylation levels of signal transducer and activator of transcription-3 (STAT-3) during adipocyte differentiation. Moreover, artesunate at 5 μM reduced leptin, but not adiponectin, mRNA expression during adipocyte differentiation. Taken together, these findings demonstrate that artesunate inhibits adipogenesis in 3T3-L1 preadipoytes through the reduced expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3. -- Highlights: •Artesunate, an artemisinin derivative, inhibits adipogenesis. •Artesunate inhibits C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3 in 3T3-L1 adipocytes. •Artesunate reduces leptin, but not adiponectin, expression in 3T3-L1 adipocytes. •Artesunate thus may have therapeutic potential against obesity.

  18. Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH.

    Science.gov (United States)

    Rashid, Jahidur; Alobaida, Ahmad; Al-Hilal, Taslim A; Hammouda, Samia; McMurtry, Ivan F; Nozik-Grayck, Eva; Stenmark, Kurt R; Ahsan, Fakhrul

    2018-06-28

    Peroxisome-proliferator-activated-receptor-gamma (PPAR-γ) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH). Rosiglitazone, an oral antidiabetic and PPAR-γ agonist, has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Here, we sought to test the hypothesis that rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. We have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% ± 6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells. All in all, data generated using intact animal and cellular models point to the conclusion that PLGA particles of an antidiabetic drug can be used for the treatment of a different disease, PAH. Copyright © 2018 Elsevier B.V. All rights reserved.

  19. The introduction of tritium label into natural and modified prostaglandins

    International Nuclear Information System (INIS)

    Shevchenko, V.P.; Bezuglov, V.V.; Nagayev, I.Y.; Myasoedov, N.F.

    1989-01-01

    Studies on the role of the nature of both heterogeneous catalysts and the solvent on the reduction selectively of 5,6-double bonds showed that the largest yield could be obtained by using the Lindlar catalyst and ethyl acetate. The use of different isotopes of hydrogen in the protium-deuterium-tritium series markedly decreased the hydrogenation reaction rate, but the selectivity of the process practically remained unaltered. Homogeneous catalysts were also used in the production of natural tritium-labelled prostaglandins and of their fluorine and deoxy analogues. The label was introduced by selective hydrogenation in the presence of (Ph 3 P) 3 RhCl and dioxane as solvent. Different ways have been studied of tritium-label introduction into prostaglandins modified at the carboxyl group. The synthesis of similar preparations was performed either by selective dehalogenation in the presence of heterogeneous catalysts treated with quinoline or triethylamine, or by condensation of prostaglandins at the carboxyl group by tritium-labelled amino acid. (author). 4 refs.; 1 fig

  20. Effects of PPARs agonists on cardiac metabolism in littermate and cardiomyocyte-specific PPAR-γ-knockout (CM-PGKO mice.

    Directory of Open Access Journals (Sweden)

    Michelangela Barbieri

    Full Text Available Understanding the molecular regulatory mechanisms controlling for myocardial lipid metabolism is of critical importance for the development of new therapeutic strategies for heart diseases. The role of PPARγ and thiazolidinediones in regulation of myocardial lipid metabolism is controversial. The aim of our study was to assess the role of PPARγ on myocardial lipid metabolism and function and differentiate local/from systemic actions of PPARs agonists using cardiomyocyte-specific PPARγ -knockout (CM-PGKO mice. To this aim, the effect of PPARγ, PPARγ/PPARα and PPARα agonists on cardiac function, intra-myocyte lipid accumulation and myocardial expression profile of genes and proteins, affecting lipid oxidation, uptake, synthesis, and storage (CD36, CPT1MIIA, AOX, FAS, SREBP1-c and ADPR was evaluated in cardiomyocyte-specific PPARγ-knockout (CM-PGKO and littermate control mice undergoing standard and high fat diet (HFD. At baseline, protein levels and mRNA expression of genes involved in lipid uptake, oxidation, synthesis, and accumulation of CM-PGKO mice were not significantly different from those of their littermate controls. At baseline, no difference in myocardial lipid content was found between CM-PGKO and littermate controls. In standard condition, pioglitazone and rosiglitazone do not affect myocardial metabolism while, fenofibrate treatment significantly increased CD36 and CPT1MIIA gene expression. In both CM-PGKO and control mice submitted to HFD, six weeks of treatment with rosiglitazone, fenofibrate and pioglitazone lowered myocardial lipid accumulation shifting myocardial substrate utilization towards greater contribution of glucose. In conclusion, at baseline, PPARγ does not play a crucial role in regulating cardiac metabolism in mice, probably due to its low myocardial expression. PPARs agonists, indirectly protect myocardium from lipotoxic damage likely reducing fatty acids delivery to the heart through the actions on adipose

  1. Paricalcitol attenuates lipopolysaccharide-induced inflammation and apoptosis in proximal tubular cells through the prostaglandin E₂ receptor EP4

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    Yu Ah Hong

    2017-06-01

    Full Text Available Background: Vitamin D is considered to exert a protective effect on various renal diseases but its underlying molecular mechanism remains poorly understood. This study aimed to determine whether paricalcitol attenuates inflammation and apoptosis during lipopolysaccharide (LPS-induced renal proximal tubular cell injury through the prostaglandin E₂ (PGE₂ receptor EP4. Methods: Human renal tubular epithelial (HK-2 cells were pretreated with paricalcitol (2 ng/mL for 1 hour and exposed to LPS (1 μg/mL. The effects of paricalcitol pretreatment in relation to an EP4 blockade using AH-23848 or EP4 small interfering RNA (siRNA were investigated. Results: The expression of cyclooxygenase-2, PGE₂, and EP4 were significantly increased in LPS-exposed HK-2 cells treated with paricalcitol compared with cells exposed to LPS only. Paricalcitol prevented cell death induced by LPS exposure, and the cotreatment of AH-23848 or EP4 siRNA offset these cell-protective effects. The phosphorylation and nuclear translocation of p65 nuclear factor-kappaB (NF-κB were decreased and the phosphorylation of Akt was increased in LPS-exposed cells with paricalcitol treatment. AH-23848 or EP4 siRNA inhibited the suppressive effects of paricalcitol on p65 NF-κB nuclear translocation and the activation of Akt. The production of proinflammatory cytokines and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were attenuated by paricalcitol in LPS exposed HK-2 cells. The cotreatment with an EP4 antagonist abolished these anti-inflammatory and antiapoptotic effects. Conclusion: EP4 plays a pivotal role in anti-inflammatory and antiapoptotic effects through Akt and NF-κB signaling after paricalcitol pretreatment in LPS-induced renal proximal tubule cell injury.

  2. Peroxisome proliferator-activated receptor gamma signaling in human sperm physiology.

    Science.gov (United States)

    Liu, Li-Li; Xian, Hua; Cao, Jing-Chen; Zhang, Chong; Zhang, Yong-Hui; Chen, Miao-Miao; Qian, Yi; Jiang, Ming

    2015-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the PPARs, which are transcription factors of the steroid receptor superfamily. PPARγ acts as an important molecule for regulating energy homeostasis, modulates the hypothalamic-pituitary-gonadal (HPG) axis, and is reciprocally regulated by HPG. In the human, PPARγ protein is highly expressed in ejaculated spermatozoa, implying a possible role of PPARγ signaling in regulating sperm energy dissipation. PPARγ protein is also expressed in Sertoli cells and germ cells (spermatocytes). Its activation can be induced during capacitation and the acrosome reaction. This mini-review will focus on how PPARγ signaling may affect fertility and sperm quality and the potential reversibility of these adverse effects.

  3. Stimulation of Oxytocin Receptor during Early Reperfusion Period Protects the Heart against Ischemia/Reperfusion Injury: the Role of Mitochondrial ATPSensitive Potassium Channel, Nitric Oxide, and Prostaglandins

    Directory of Open Access Journals (Sweden)

    Alireza Imani

    2015-10-01

    Full Text Available Postconditioning is a simple and safe strategy for cardioprotection and infarct size limitation. Ourprevious study showed that oxytocin (OT exerts postconditioning effect on ischemic/reperfused isolated ratheart. The aim of this study was to investigate the involvement of OT receptor, mitochondrial ATP-sensitivepotassium channel (mKATP, nitric oxide (NO and cyclooxygenase (COX pathways in OTpostconditioning. Isolated rat hearts were divided into10 groups and underwent 30 min of regional ischemiafollowed by 120 min of reperfusion (n =6. In I/R (ischemia/reperfusion group, ischemia and reperfusionwere induced without any treatment. In OT group, oxytocin was perfused 5 min prior to beginning ofreperfusion for 25 min. In groups 3-6, atosiban (oxytocin receptor blocker, L-NAME (N-Nitro-L-ArginineMethyl Ester, non-specific nitric oxide synthase inhibitor, 5-HD (5-hydroxydecanoate, mKATP inhibitorand indomethacin (cyclooxygenase inhibitor were infused prior to oxytocin administration. In others, thementioned inhibitors were perfused prior to ischemia without oxytocin infusion. Infarct size, ventricularhemodynamic, coronary effluent, malondialdehyde (MDA and lactate dehydrogenase (LDH were measuredat the end of reperfusion. OT perfusion significantly reduced infarct size, MDA and LDH in comparison withIR group. Atosiban, 5HD, L-NAME and indomethacin abolished the postconditioning effect of OT. Perfusionof the inhibitors alone prior to ischemia had no effect on infarct size, hemodynamic parameters, coronaryeffluent and biochemical markers as compared with I/R group. In conclusion, this study indicates thatpostconditioning effects of OT are mediated by activation of mKATP and production of NO andProstaglandins (PGs.

  4. Effects of indomethacin on plasma homovanillic acid concentration in normal subjects: a study of prostaglandin-dopamine interactions.

    Science.gov (United States)

    Kahn, R S; Davidson, M; Kanof, P; McQueeney, R T; Singh, R R; Davis, K L

    1991-01-01

    In laboratory animals, prostaglandins have been shown to act as endogenous neuromodulators of central dopamine (DA) activity. To examine the interaction between prostaglandins and DA in man, the effect of a prostaglandin synthesis inhibitor, indomethacin, was studied on plasma concentrations of the DA metabolite, homovanillic acid (pHVA). Indomethacin (150 mg PO) as compared to placebo significantly elevated mean pHVA concentrations in eight normal subjects. Results of this study support the hypothesis that, as in animals, inhibition of prostaglandin synthesis increases central DA turnover in man.

  5. CRPS: A contingent hypothesis with prostaglandins as crucial conversion factor.

    Science.gov (United States)

    van der Veen, Phe

    2015-11-01

    CRPS is an acute pain disease expressed as chronic pain with a severe loss of tissue and function. CRPS usually occurs after minor injuries and then progresses in a way that is scarcely controllable, or completely uncontrollable. This article addresses the functional control mechanism of a biological organism, a comparison of techniques, and the way the negative feedback mechanisms fail in regulated feedback systems. The measurement and regulation system is controlled at the local, regional, and central levels in a biological system. Locally generated substances such as prostaglandins and hormones, as well as the central nervous system, play important roles in this process. Prostaglandins fulfil many conversion functions and are involved in vasoactive processes, pain, and inflammation. They play an intermediating role between the activity of the autonomic nervous system and local occurrences. The insufficiently explored conversion function of prostaglandins as a ubiquitously present cofactor may be related to the development of CRPS at sites which have had minor injuries in the past. Chronic Regional Pain Syndrome (CRPS) is a moderately prevalent disease, which occurs more frequently with age. Even though there are diseases known to have a precipitating effect on the aetiology of CRPS, for example Carpal tunnel syndrome, the mechanism of onset is unknown. The disease falls under the category of chronic pain, and seldom has an effective treatment based on scientific research. The economic and psychosocial aspects of the disease are substantial. CRPS is the final position of a positive feedback measurement and control system. Homoeostasis is directed by measurement and control processes. In electronics, a rapid conversion system, which quickly adapts to changing circumstances, superimposed with a delayed conversion system, which ensures a stable basis of homoeostasis. Measured changes are compensatorily controlled. An analogy is expected for a Complex Adaptive System

  6. Prostaglandin E2 and the protein kinase A pathway mediate arachidonic acid induction of c-fos in human prostate cancer cells

    Science.gov (United States)

    Chen, Y.; Hughes-Fulford, M.

    2000-01-01

    Arachidonic acid (AA) is the precursor for prostaglandin E2 (PGE2) synthesis and increases growth of prostate cancer cells. To further elucidate the mechanisms involved in AA-induced prostate cell growth, induction of c-fos expression by AA was investigated in a human prostate cancer cell line, PC-3. c-fos mRNA was induced shortly after addition of AA, along with a remarkable increase in PGE2 production. c-fos expression and PGE2 production induced by AA was blocked by a cyclo-oxygenase inhibitor, flurbiprofen, suggesting that PGE2 mediated c-fos induction. Protein kinase A (PKA) inhibitor H-89 abolished induction of c-fos expression by AA, and partially inhibited PGE2 production. Protein kinase C (PKC) inhibitor GF109203X had no significant effect on c-fos expression or PGE2 production. Expression of prostaglandin (EP) receptors, which mediate signal transduction from PGE2 to the cells, was examined by reverse transcription polymerase chain reaction in several human prostate cell lines. EP4 and EP2, which are coupled to the PKA signalling pathway, were expressed in all cells tested. Expression of EP1, which activates the PKC pathway, was not detected. The current study showed that induction of the immediate early gene c-fos by AA is mediated by PGE2, which activates the PKA pathway via the EP2/4 receptor in the PC-3 cells.

  7. Activation of peroxisome proliferator-activated receptor-alpha and -gamma in auricular tissue from heart failure patients.

    Science.gov (United States)

    Gómez-Garre, Dulcenombre; Herraíz, Marta; González-Rubio, Ma Luisa; Bernal, Rosa; Aragoncillo, Paloma; Carbonell, Amparo; Rufilanchas, Juan José; Fernández-Cruz, Arturo

    2006-03-01

    Peroxisome proliferator-activated receptors (PPARs), key transcriptional regulators of lipid and energy metabolism in cardiomyocytes, have recently been proposed to modulate cardiovascular pathophysiological responses in experimental models. However, there is little information about the functional activity of PPARs in human heart failure. To investigate PPAR-alpha and -gamma expression and activity, and the association with ET-1 production and fibrosis, in cardiac biopsies from patients with end-stage heart failure due to ischemic cardiomyopathy (ICM) in comparison and from non-failing donor hearts. All samples were obtained during cardiac transplantation. Morphological analysis (by Masson trichrome and image analysis) did not detect fibrosis in the left atrium from non-failing donors (NFLA) or from ICM patients (FLA). However, left ventricles from failing hearts (FLV) contained a greater number of fibrotic areas (NFLA: 3.21+/-1.15, FLA: 1.63+/-0.83, FLV: 14.5+/-3.45%; n = 9, PPPAP-gamma mRNA (by RT-PCR) and protein (by Western blot) levels were higher in the ventricles from failing hearts compared with the atrium from failing and non-failing hearts. Electrophoretic mobility shift assays showed that PPAR-alpha and PPAP-gamma were not activated in the ventricles (NFLA: 1.00+/-0.11, FLA: 1.89+/-0.24, FLV: 0.95+/-0.07; n = 9, PPPAP-gamma are selectively activated in the atria from ICM patients and might be functionally important in the maintenance of atrial morphology.

  8. Characterization of a thromboxane A2/prostaglandin H2 receptor in guinea pig lung membranes using a radioiodinated thromboxane mimetic

    International Nuclear Information System (INIS)

    Saussy, D.L. Jr.; Mais, D.E.; Dube, G.P.; Magee, D.E.; Brune, K.A.; Kurtz, W.L.; Williams, C.M.

    1991-01-01

    Thromboxane A2 (TXA2) and prostaglandin H2 (PGH2) are potent constrictors of airway smooth muscle and may mediate some of the pulmonary effects of leukotrienes. To date, the TXA2/PGH2 receptor in lung has not been well characterized. In this report, we describe the evaluation of the TXA2/PGH2 receptor in guinea pig lung membranes using the new radiolabeled TXA2 mimetic [1S(1 alpha,2 beta(5Z),3 alpha(1E,3S*),4 alpha)]-7-[3-(3-hydroxy-4-(4'- iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-h eptenoic acid (IBOP). IBOP elicited a dose-dependent contraction of guinea pig lung parenchymal strips (EC50 = 3.03 +/- 0.97 nM, three experiments), which was blocked by the TXA2/PGH2 antagonists SQ29548 (pKB = 7.44 +/- 0.2, three experiments), BM13505 (pKB = 6.29 +/- 0.26, three experiments), and I-PTA-OH (pKB = 5.82 +/- 0.36, three experiments). In radioligand binding studies, the binding of [125I]IBOP to guinea pig lung membranes prepared from perfused lungs was saturable, displaceable, and dependent upon protein concentration. Binding was optimal at pH 6.5 and was enhanced by the addition of mono- and divalent cations. The standard assay buffer was 25 mM 3-(N-morpholino)propanesulfonic acid, pH 6.5, 100 mM NaCl, 5 mM MgCl2. Binding was inhibited by pretreatment with dithiothreitol, N-ethylmaleimide, or beta-mercaptoethanol. Binding was unaffected by the addition of guanine nucleotide analogs at concentrations up to 300 microM. Analysis of the time course of binding of [125]IBOP at 30 degrees yielded k-1 = 0.0447 min-1, k1 = 2.49 x 10(8) M-1 min-1, and Kd = k-1/k1 = 180 pM. Computer analysis of equilibrium binding studies using nonlinear methods (LUNDON-1) revealed a single class of noninteracting binding sites with a Kd of 86.9 +/- 11.9 pM and a Bmax of 81.8 +/- 7.7 fmol/mg of protein (three experiments)

  9. Inhibition of prostaglandin synthesis after metabolism of menadione by cultured porcine endothelial cells

    International Nuclear Information System (INIS)

    Barchowsky, A.; Tabrizi, K.; Kent, R.S.; Whorton, A.R.

    1989-01-01

    We have examined the effects of menadione on porcine aortic endothelial cell prostaglandin synthesis. Addition of 1-20 microM menadione caused a dose- and time-dependent inhibition of stimulated prostaglandin synthesis with an IC50 of 5 microM at 15 min. Concentrations greater than 100 microM menadione were necessary to increase 51 Cr release from prelabeled cells. Recovery of enzyme inactivated by menadione required a 6-h incubation in 1% serum. In a microsomal preparation, menadione was shown to have no direct effect on conversion of arachidonic acid to prostaglandins. In intact cells menadione caused only a 40% inhibition of the conversion of PGH2 to prostacyclin. Enzymes involved in the incorporation and the release of arachidonic acid were not affected by menadione (20 microM, 15 min). Menadione undergoes oxidation/reduction reactions in intact cells leading to partial reduction of oxygen-forming, reactive oxygen species. In our cells menadione was found to increase KCN-resistant oxygen consumption. Further, an increased accumulation of H 2 O 2 was observed with a time course consistent with menadione-induced inhibition of prostaglandin synthesis. We conclude that menadione at sublethal doses caused inhibition of prostaglandin synthesis. The mechanism involves inactivation of PGH2 synthase by a reactive species resulting from metabolism of menadione by endothelial cells

  10. Matrix metalloproteinase-12 gene regulation by a PPAR alpha agonist in human monocyte-derived macrophages

    International Nuclear Information System (INIS)

    Souissi, Imen Jguirim; Billiet, Ludivine; Cuaz-Perolin, Clarisse; Slimane, Mohamed-Naceur; Rouis, Mustapha

    2008-01-01

    MMP-12, a macrophage-specific matrix metalloproteinase with large substrate specificity, has been reported to be highly expressed in mice, rabbits and human atherosclerotic lesions. Increased MMP-12 from inflammatory macrophages is associated with several degenerative diseases such as atherosclerosis. In this manuscript, we show that IL-1β, a proinflammatory cytokine found in atherosclerotic plaques, increases both mRNA and protein levels of MMP-12 in human monocyte-derived macrophages (HMDM). Since peroxisome proliferator-activated receptors (PPARs), such as PPARα and PPARγ, are expressed in macrophages and because PPAR activation exerts an anti-inflammatory effect on vascular cells, we have investigated the effect of PPARα and γ isoforms on MMP-12 regulation in HMDM. Our results show that MMP-12 expression (mRNA and protein) is down regulated in IL-1β-treated macrophages only in the presence of a specific PPARα agonist, GW647, in a dose-dependent manner. In contrast, this inhibitory effect was abolished in IL-1β-stimulated peritoneal macrophages isolated from PPARα -/- mice and treated with the PPARα agonist, GW647. Moreover, reporter gene transfection experiments using different MMP-12 promoter constructs showed a reduction of the promoter activities by ∼ 50% in IL-1β-stimulated PPARα-pre-treated cells. However, MMP-12 promoter analysis did not reveal the presence of a PPRE response element. The IL-1β effect is known to be mediated through the AP-1 binding site. Mutation of the AP-1 site, located at - 81 in the MMP-12 promoter region relative to the transcription start site, followed by transfection analysis, gel shift and ChIP experiments revealed that the inhibitory effect was the consequence of the protein-protein interaction between GW 647-activated PPARα and c-Fos or c-Jun transcription factors, leading to inhibition of their binding to the AP-1 motif. These studies suggest that PPARα agonists may be used therapeutically, not only for lipid

  11. Radioimmunoassay determination of urinary prostaglandins in patients with progressive systemic sclerosis

    International Nuclear Information System (INIS)

    Ramirez P, P.; Erbessd, M.L.; Mares, G.; Recinos, G.; Graef S, A.; Lavalle, C.

    1985-01-01

    The results of urinary determinations of E-2 prostaglandines by radioimmunoassay (RIA) in 24-hour urine are presented for three groups: progressive systemic sclerotic patients with normotension and with elevated or normal APR, progressive systemic sclerotic patients with hypertension and with normal or low APR, control group of normal subjects. In a recent report of progressive systemic sclerosis in patients we demonstrated changes in the urine concentratrion of APR levels, sodium excretion and in total blood volume. Based on these findings we felt the need to perform quantifications of E-2 prostaglandines (PGE-2) in 24-hour recently taken urine samples stored at 70 0 and measure the sodium amounts excreted in the urine. We concluded that urinary determination of E-2 prostaglandines was the most suitable for our study as it allowed the establishment of relationships between APR, aldosterone and metabolic sodium balance. (author)

  12. [Ocular Surface Evaluation in Patients Treated with Prostaglandin Analogues Considering Preservative Agent].

    Science.gov (United States)

    Mlčáková, E; Mlčák, P; Karhanová, M; Langová, K; Marešová, K

    The aim of this study was to evaluate the ocular surface in patients treated with prostaglandin analogues considering contained preservative agent. 60 patients with glaucoma or ocular hypertension treated with prostaglandin analogue monotherapy were enrolled in this observational study. 20 patients with glaucoma suspect or ocular hypertension without local or systemic glaucoma medication formed the control group. Demographic data and medical history were recorded for each participant. Patients filled in the Ocular surface disease index© (OSDI) questionnaire and underwent an ophthalmological examination including assessment of conjunctival hyperaemia according to Efron, tear film break up time (BUT) and fluorescein staining according to the Oxford grading scheme. Treated participants were divided into 3 groups according to the preservative contained in the currently used prostaglandin analogue: the preservative-free group (18 patients), the polyquaternium group (17 patients) and the benzalkonium chloride (BAK) group (25 patients). The control group had significantly lower fluorescein staining than the preservative-free group (p=0.001), the polyquaternium group (p=0.007) and the BAK group (p=0.002). The conjunctival hyperaemia was significantly lower in the preservative-free group compared to the polyquaternium group (p=0.011). There was no significant difference among the other groups. The difference neither in the OSDI score nor in the BUT was statistically important. This study confirmed that the ocular surface is worse in patients treated with prostaglandin analogue monotherapy than in people without glaucoma medication. A significant difference among treated patients depending on a preservative agent was not proved.Key words: benzalkonium chloride, glaucoma, ocular surface disease, preservatives, prostaglandin analogues.

  13. Cross-talk between an activator of nuclear receptors-mediated transcription and the D1 dopamine receptor signaling pathway.

    Science.gov (United States)

    Schmidt, Azriel; Vogel, Robert; Rutledge, Su Jane; Opas, Evan E; Rodan, Gideon A; Friedman, Eitan

    2005-03-01

    Nuclear receptors are transcription factors that usually interact, in a ligand-dependent manner, with specific DNA sequences located within promoters of target genes. The nuclear receptors can also be controlled in a ligand-independent manner via the action of membrane receptors and cellular signaling pathways. 5-Tetradecyloxy-2-furancarboxylic acid (TOFA) was shown to stimulate transcription from the MMTV promoter via chimeric receptors that consist of the DNA binding domain of GR and the ligand binding regions of the PPARbeta or LXRbeta nuclear receptors (GR/PPARbeta and GR/LXRbeta). TOFA and hydroxycholesterols also modulate transcription from NF-kappaB- and AP-1-controlled reporter genes and induce neurite differentiation in PC12 cells. In CV-1 cells that express D(1) dopamine receptors, D(1) dopamine receptor stimulation was found to inhibit TOFA-stimulated transcription from the MMTV promoter that is under the control of chimeric GR/PPARbeta and GR/LXRbeta receptors. Treatment with the D(1) dopamine receptor antagonist, SCH23390, prevented dopamine-mediated suppression of transcription, and by itself increased transcription controlled by GR/LXRbeta. Furthermore, combined treatment of CV-1 cells with TOFA and SCH23390 increased transcription controlled by the GR/LXRbeta chimeric receptor synergistically. The significance of this in vitro synergy was demonstrated in vivo, by the observation that SCH23390 (but not haloperidol)-mediated catalepsy in rats was potentiated by TOFA, thus showing that an agent that mimics the in vitro activities of compounds that activate members of the LXR and PPAR receptor families can influence D1 dopamine receptor elicited responses.

  14. The Kallikrein-Kinin System in Bartter's Syndrome and Its Response to Prostaglandin Synthetase Inhibition

    Science.gov (United States)

    Vinci, Joseph M.; Gill, John R.; Bowden, Robert E.; Pisano, John J.; Izzo, Joseph L.; Radfar, Nazam; Taylor, Addison A.; Zusman, Randall M.; Bartter, Frederic C.; Keiser, Harry R.

    1978-01-01

    The kallikrein-kinin system was characterized in seven patients with Bartter's syndrome on constant metabolic regimens before, during, and after treatment with prostaglandin synthetase inhibitors. Patients with Bartter's syndrome had high values for plasma bradykinin, plasma renin activity (PRA), urinary kallikrein, urinary immunoreactive prostaglandin E excretion, and urinary aldosterone; urinary kinins were subnormal and plasma prekallikrein was normal. Treatment with indomethacin or ibuprofen which decreased urinary immunoreactive prostaglandin E excretion by 67%, decreased mean PRA (patients recumbent) from 17.3±5.3 (S.E.M.) ng/ml per h to 3.3±1.1 ng/ml per h, mean plasma bradykinin (patients recumbent) from 15.4±4.4 ng/ml to 3.9±0.9 ng/ml, mean urinary kallikrein excretion from 24.8±3.2 tosyl-arginine-methyl ester units (TU)/day to 12.4±2.0 TU/day, but increased mean urinary kinin excretion from 3.8±1.3 μg/day to 8.5±2.5 μg/day. Plasma prekallikrein remained unchanged at 1.4 TU/ml. Thus, with prostaglandin synthetase inhibition, values for urinary kallikrein and kinin and plasma bradykinin returned to normal pari passu with changes in PRA, in aldosterone, and in prostaglandin E. The results suggest that, in Bartter's syndrome, prostaglandins mediate the low urinary kinins and the high plasma bradykinin, and that urinary kallikrein, which is aldosterone dependent, does not control kinin excretion. The high plasma bradykinin may be a cause of the pressor hyporesponsiveness to angiotensin II which characterizes the syndrome. PMID:96139

  15. N-Acetylcysteine enhances the action of anti-inflammatory drugs as suppressors of prostaglandin production in monocytes

    Directory of Open Access Journals (Sweden)

    Erica Hoffer

    2002-01-01

    Full Text Available The anti-inflammatory effect of non-steroidal anti-inflammatory drugs (NSAIDs is associated with inhibition of cyclooxygenase (COX, the rate-limiting enzyme responsible for the synthesis of prostaglandins. Since oxygen free radicals can act as second cellular messengers, especially to modulate the metabolism of arachidonic acid and the prostaglandin tract, it seems plausible that antioxidants might affect the production of prostaglandin by activated cells. This research is focused on the effect of the antioxidant N-acetylcysteine (NAC on the inhibition of prostaglandin E2 formation in activated monocytes by specific and non-specific COX inhibitors. We found that lipopolysaccharide-induced prostaglandin E2 formation was significantly reduced by rofecoxib and by diclofenac, two NSAIDs. Addition of NAC to each of these drugs enhanced the effect of the NSAIDs. These results suggest that one might expect either a potentiation of the anti-inflammatory effect of COX inhibitors by their simultaneous administration with NAC, or obtaining the same anti-inflammatory at lower drug levels.

  16. Role of adrenal hormones and prostaglandins in the control of mouse thymocytes lysis.

    Science.gov (United States)

    Durant, S; Seillan, C; Duval, D; Homo-Delarche, F

    1984-01-01

    The cytolytic actions of glucocorticoids and of agents increasing cyclic AMP were studied in vitro in thymocyte suspensions isolated from adrenalectomized or hydrocortisone-treated mice. Although considered as corticoresistant cells, the thymocytes isolated from hydrocortisone-treated mice were lysed to the same extent although more slowly in vitro by dexamethasone than whole thymocyte populations (i.e. corticosensitive cells). Moreover, these two cell populations were shown to contain comparable amounts of glucocorticoid receptors and to be almost equally sensitive to the metabolic effects of glucocorticoids when measured by inhibition of RNA and DNA synthesis. Studies performed with corticosensitive cells showed that prostaglandin E2, isoproterenol and dibutyrilcyclic AMP were also able to induce cell lysis and that, isoproterenol and dexamethasone exerted additive cytolytic action in vitro. In vivo experiments showed also an additive effect of steroids and isoproterenol on thymus atrophy. In contrast, cells isolated from hydrocortisone-treated animals were not sensitive to the cytotoxic action of prostaglandin E2, isoproterenol and dibutyril cyclic AMP. This difference between the two populations was not associated with any difference in the responsiveness of adenylate cyclase as determined following isoproterenol-induced accumulation of cyclic AMP. The cytolytic action of dexamethasone but also that of prostaglandin E2 and isoproterenol, could be blocked in the presence of cycloheximide, an inhibitor of protein synthesis, thus suggesting that glucocorticoids and agents increasing cyclic AMP control the synthesis of some proteins involved in the triggering of cell lysis. Among the hypotheses proposed to explain the differences between in vitro and in vivo sensitivity of lymphoid cell to glucocorticoids, it was suggested that the drug may in vivo indirectly control the viability or the proliferation of thymocytes through the release of other mediators. We have

  17. Single-nucleotide polymorphism of INS, INSR, IRS1, IRS2, PPAR-G ...

    Indian Academy of Sciences (India)

    2017-03-02

    Mar 2, 2017 ... Abstract. Polycystic ovary syndrome (PCOS) is the most common and a complex female endocrine disorder, and is one of the leading cause of female infertility. Here, we aimed to investigate the association of single-nucleotide polymorphism of INS, INSR,. IRS1, IRS2, PPAR-G and CAPN10 gene in the ...

  18. Peroxisome proliferator-activated receptors, estrogenic responses and biotransformation system in the liver of salmon exposed to tributyltin and second messenger activator

    Energy Technology Data Exchange (ETDEWEB)

    Pavlikova, Nela [Department of Biology, Norwegian University of Science and Technology (NTNU), Hogskoleringen 5, 7491 Trondheim (Norway); RECETOX Research Centre for Environmental Chemistry and Ecotoxicology, Masaryk University, Kamenice 3, CZ62500 Brno (Czech Republic); Kortner, Trond M. [Department of Biology, Norwegian University of Science and Technology (NTNU), Hogskoleringen 5, 7491 Trondheim (Norway); Arukwe, Augustine, E-mail: arukwe@bio.ntnu.no [Department of Biology, Norwegian University of Science and Technology (NTNU), Hogskoleringen 5, 7491 Trondheim (Norway)

    2010-08-15

    The mechanisms by which organotin compounds produce modulations of the endocrine systems and other biological responses are not fully understood. In this study, juvenile salmon were force-fed diet containing TBT (0: solvent control, 0.1, 1 and 10 mg/kg fish) for 72 h. Subsequently, fish exposed to solvent control and 10 mg TBT were exposed to waterborne concentration (200 {mu}g/l) of the adenylate cyclase (AC) stimulator, forskolin for 2 and 4 h. The overall aim of the study was to explore whether TBT endocrine disruptive effects involve second messenger activation. Liver was sampled from individual fish (n = 8) at the end of the exposures. The transcription patterns of peroxisome proliferator-activated receptor (PPAR) isotype and acyl-coenzyme A oxidase 1 (ACOX1), aromatase isoform, estrogen receptor-{alpha} (ER{alpha}), pregnane X receptor (PXR), CYP3A and glutathione S-transferase (GST) genes were measured by quantitative polymerase chain reaction (qPCR). Our data showed a consistent increase in PPAR{alpha}, PPAR{beta} and PPAR{gamma} mRNA and protein expression after TBT exposure that were inversely correlated with ACOX1 mRNA levels. Forskolin produced PPAR isotype-specific mRNA and protein effects that were modulated by TBT. ACOX1 expression was decreased (at 2 h) and increased (at 4 h) by forskolin and the presence of TBT potentiated these effects. TBT apparently increased mRNA and protein levels of cyp19a, compared to the solvent control, whereas cyp19b mRNA levels were unaffected by TBT treatment. Combined TBT and forskolin exposure produced respective decrease and increase of mRNA levels of cyp19a and cyp19b, compared with control. TBT decreased ER{alpha} mRNA at low dose (1 mg/kg) and forskolin exposure alone produced a consistent decrease of ER{alpha} mRNA levels that were not affected by the presence of TBT. Interestingly, PXR and CYP3A mRNA levels were differentially affected, either decreased or increased, after exposure to TBT and forskolin, singly

  19. Prostaglandin E2 regulates hematopoietic stem cell

    International Nuclear Information System (INIS)

    Wang Yingying; Zhou Daohong; Meng Aimin

    2013-01-01

    Prostaglandin E2 (PGE2) is a bioactive lipid molecule produced by cyclooxygenase (COX), which plays an important role on hematopoiesis. While it can block differentiation of myeloid progenitors but enhance proliferation of erythroid progenitors. Recent research found that PGE2 have the effects on hematopoietic stem cell (HSC) function and these effects were independent from effects on progenitor cells. Exposure of HSC cells to PGE2 in vitro can increase homing efficiency of HSC to the murine bone marrow compartment and decrease HSC apoptosis, meanwhile increase long-term stem cell engraftment. In-vivo treatment with PGE2 expands short-term HSC and engraftment in murine bone marrow but not long-term HSC.In addition, PGE2 increases HSC survival after radiation injury and enhance hematopoietic recovery, resulting maintains hematopoietic homeostasis. PGE2 regulates HSC homeostasis by reactive oxygen species and Wnt pathway. Clinical beneficial of 16, 16-dimethyl-prostaglandin E2 treatment to enhance engraftment of umbilical cord blood suggest important improvements to therapeutic strategies. (authors)

  20. Peroxisome Proliferator-Activated Receptor α Activation Suppresses Cytochrome P450 Induction Potential in Mice Treated with Gemfibrozil.

    Science.gov (United States)

    Shi, Cunzhong; Min, Luo; Yang, Julin; Dai, Manyun; Song, Danjun; Hua, Huiying; Xu, Gangming; Gonzalez, Frank J; Liu, Aiming

    2017-09-01

    Gemfibrozil, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely used for hypertriglyceridaemia and mixed hyperlipidaemia. Drug-drug interaction of gemfibrozil and other PPARα agonists has been reported. However, the role of PPARα in cytochrome P450 (CYP) induction by fibrates is not well known. In this study, wild-type mice were first fed gemfibrozil-containing diets (0.375%, 0.75% and 1.5%) for 14 days to establish a dose-response relationship for CYP induction. Then, wild-type mice and Pparα-null mice were treated with a 0.75% gemfibrozil-containing diet for 7 days. CYP3a, CYP2b and CYP2c were induced in a dose-dependent manner by gemfibrozil. In Pparα-null mice, their mRNA level, protein level and activity were induced more than those in wild-type mice. So, gemfibrozil induced CYP, and this action was inhibited by activated PPARα. These data suggested that the induction potential of CYPs was suppressed by activated PPARα, showing a potential role of this receptor in drug-drug interactions and metabolic diseases treated with fibrates. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  1. a randomised controlled trial oftwo prostaglandin regitnens

    African Journals Online (AJOL)

    Design. A prospective randomised controlled trial. Setting. Department of Obstetrics and Gynae- ... hours after the original administration of either prostaglandin regimen. If abortion had not taken place 36 .... Tygerberg Hospital for permission to publish, and Upjohn. (Pry) Ltd for supplying the Prepidil gel used in the study. 1.

  2. Synergistic Effects of PPARγ Ligands and Retinoids in Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Masahito Shimizu

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are members of the nuclear receptor superfamily. The activation of PPARs by their specific ligands is regarded as one of the promising strategies to inhibit cancer cell growth. However, recent clinical trials targeting several common cancers showed no beneficial effect when PPAR ligands are used as a monotherapy. Retinoid X receptors (RXRs, which play a critical role in normal cell proliferation as a master regulator for nuclear receptors, preferentially form heterodimers with PPARs. A malfunction of RXRα due to phosphorylation by the Ras/MAPK signaling pathway is associated with the development of certain types of human malignancies. The activation of PPARγ/RXR heterodimer by their respective ligands synergistically inhibits cell growth, while inducing apoptosis in human colon cancer cells when the phosphorylation of RXRα was inhibited. We herein review the synergistic antitumor effects produced by the combination of the PPAR, especially PPARγ, ligands plus other agents, especially retinoids, in a variety of human cancers. We also focus on the phosphorylation of RXRα because the inhibition of RXRα phosphorylation and the restoration of its physiological function may activate PPAR/RXR heterodimer and, therefore, be a potentially effective and critical strategy for the inhibition of cancer cell growth.

  3. Receptors involved in the modulation of guinea pig urinary bladder motility by prostaglandin D2

    Science.gov (United States)

    Guan, Na N; Svennersten, Karl; de Verdier, Petra J; Wiklund, N Peter; Gustafsson, Lars E

    2015-01-01

    Background and Purpose We have described a urothelium-dependent release of PGD2-like activity which had inhibitory effects on the motility of guinea pig urinary bladder. Here, we have pharmacologically characterized the receptors involved and localized the sites of PGD2 formation and of its receptors. Experimental Approach In the presence of selective DP and TP receptor antagonists alone or combined, PGD2 was applied to urothelium-denuded diclofenac-treated urinary bladder strips mounted in organ baths. Antibodies against PGD2 synthase and DP1 receptors were used with Western blots and for histochemistry. Key Results PGD2 inhibited nerve stimulation -induced contractions in strips of guinea pig urinary bladder with estimated pIC50 of 7.55 ± 0.15 (n = 13), an effect blocked by the DP1 receptor antagonist BW-A868C. After blockade of DP1 receptors, PGD2 enhanced the contractions, an effect abolished by the TP receptor antagonist SQ-29548. Histochemistry revealed strong immunoreactivity for PGD synthase in the urothelium/suburothelium with strongest reaction in the suburothelium. Immunoreactive DP1 receptors were found in the smooth muscle of the bladder wall with a dominant localization to smooth muscle membranes. Conclusions and Implications In guinea pig urinary bladder, the main effect of PGD2 is an inhibitory action via DP1 receptors localized to the smooth muscle, but an excitatory effect via TP receptors can also be evoked. The urothelium with its suburothelium might signal to the smooth muscle which is rich in PGD2 receptors of the DP1 type. The results are important for our understanding of regulation of bladder motility. PMID:25917171

  4. Chemical and protein structural basis for biological crosstalk between PPAR α and COX enzymes

    Science.gov (United States)

    Cleves, Ann E.; Jain, Ajay N.

    2015-02-01

    We have previously validated a probabilistic framework that combined computational approaches for predicting the biological activities of small molecule drugs. Molecule comparison methods included molecular structural similarity metrics and similarity computed from lexical analysis of text in drug package inserts. Here we present an analysis of novel drug/target predictions, focusing on those that were not obvious based on known pharmacological crosstalk. Considering those cases where the predicted target was an enzyme with known 3D structure allowed incorporation of information from molecular docking and protein binding pocket similarity in addition to ligand-based comparisons. Taken together, the combination of orthogonal information sources led to investigation of a surprising predicted relationship between a transcription factor and an enzyme, specifically, PPAR α and the cyclooxygenase enzymes. These predictions were confirmed by direct biochemical experiments which validate the approach and show for the first time that PPAR α agonists are cyclooxygenase inhibitors.

  5. Dominant role of prostaglandin E2 EP4 receptor in furosemide-induced salt-losing tubulopathy: a model for hyperprostaglandin E syndrome/antenatal Bartter syndrome

    DEFF Research Database (Denmark)

    Nüsing, Rolf M; Treude, Antje; Weissenberger, Christian

    2005-01-01

    Increased formation of prostaglandin E2 (PGE2) is a key part of hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS), a renal disease characterized by NaCl wasting, water loss, and hyperreninism. Inhibition of PGE2 formation by cyclo-oxygenase inhibitors significantly lowers patient...

  6. The roles of the cyclo-oxygenases types one and two in prostaglandin synthesis in human fetal membranes at term.

    Science.gov (United States)

    Sawdy, R J; Slater, D M; Dennes, W J; Sullivan, M H; Bennett, P R

    2000-01-01

    The aim of this study was to determine the relative contributions of cyclo-oxygenase (COX) types 1 and 2 to prostaglandin synthesis at term. Fetal membranes were collected from 6 pregnancies after elective caesarean section at term, prior to labour. The presence of COX-1 and COX-2 protein was determined using Western analysis. The relative contributions of the two isoforms of COX to prostaglandin synthesis were determined by incubation of fetal membrane discs with either a COX-2 selective inhibitor, SC236, or a COX-1 selective inhibitor, SC560, and measurement of prostaglandin release during 24 h using enzyme-linked immuno-sorbent assay (ELISA). Both COX-1 and COX-2 protein were demonstrated in amnion and chorion-decidua. The COX-2 selective inhibitor, SC-236, significantly reduced prostaglandin synthesis, both in its COX-2 specific and higher, non-specific concentration ranges. The COX-1 selective inhibitor, SC-560, had no effect upon prostaglandin synthesis in its COX-1 specific concentration range, but did significantly reduce prostaglandin synthesis at higher, non-selective concentrations. Fetal membranes contain both COX-1 and COX-2 at term, but only COX-2 contributes towards prostaglandin synthesis. COX-2 selective NSAI drugs will be as effective as non-selective agents in inhibition of fetal membrane prostaglandin synthesis and may represent a new strategy for tocolysis. Copyright 2000 Harcourt Publishers Ltd.

  7. Preventive effect of Dioscorea japonica on squamous cell carcinoma of mouse skin involving down-regulation of prostaglandin E2 synthetic pathway.

    Science.gov (United States)

    Tsukayama, Izumi; Toda, Keisuke; Takeda, Yasunori; Mega, Takuto; Tanaka, Mitsuki; Kawakami, Yuki; Takahashi, Yoshitaka; Kimoto, Masumi; Yamamoto, Kei; Miki, Yoshimi; Murakami, Makoto; Suzuki-Yamamoto, Toshiko

    2018-03-01

    Hyperproduced prostaglandin E 2 by cyclooxygenase-2 and microsomal prostaglandin E synthase-1 evokes several pathophysiological responses such as inflammation and carcinogenesis. Our recent study demonstrated that Dioscorea japonica extract suppressed the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 and induced apoptosis in lung carcinoma A549 cells. In the present study, we investigated the effects of Dioscorea japonica on squamous cell carcinoma of mouse skin. Dioscorea japonica feeding and Dioscorea japonica extract topical application suppressed the expression of cyclooxygenase-2, microsomal prostaglandin E synthase-1, interleukin-1β and interleukin-6 and inhibited tumor formation, hyperplasia and inflammatory cell infiltration. Immunohistochemical analyses showed the immunoreactivities of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in tumor keratinocytes and stronger immunoreactivities of cyclooxygenase-2 and hematopoietic prostaglandin D synthase in epidermal dendritic cells (Langerhans cells). Treatment with Dioscorea japonica decreased the immunoreactivity of cyclooxygenase-2 and microsomal prostaglandin E synthase-1. These results indicate that Dioscorea japonica may have inhibitory effects on inflammation and carcinogenesis via suppression of the prostaglandin E 2 synthetic pathway.

  8. Helicobacter pylori colonization ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism.

    Science.gov (United States)

    Bassaganya-Riera, Josep; Dominguez-Bello, Maria Gloria; Kronsteiner, Barbara; Carbo, Adria; Lu, Pinyi; Viladomiu, Monica; Pedragosa, Mireia; Zhang, Xiaoying; Sobral, Bruno W; Mane, Shrinivasrao P; Mohapatra, Saroj K; Horne, William T; Guri, Amir J; Groeschl, Michael; Lopez-Velasco, Gabriela; Hontecillas, Raquel

    2012-01-01

    There is an inverse secular trend between the incidence of obesity and gastric colonization with Helicobacter pylori, a bacterium that can affect the secretion of gastric hormones that relate to energy homeostasis. H. pylori strains that carry the cag pathogenicity island (PAI) interact more intimately with gastric epithelial cells and trigger more extensive host responses than cag(-) strains. We hypothesized that gastric colonization with H. pylori strains differing in cag PAI status exert distinct effects on metabolic and inflammatory phenotypes. To test this hypothesis, we examined metabolic and inflammatory markers in db/db mice and mice with diet-induced obesity experimentally infected with isogenic forms of H. pylori strain 26695: the cag PAI wild-type and its cag PAI mutant strain 99-305. H. pylori colonization decreased fasting blood glucose levels, increased levels of leptin, improved glucose tolerance, and suppressed weight gain. A response found in both wild-type and mutant H. pylori strain-infected mice included decreased white adipose tissue macrophages (ATM) and increased adipose tissue regulatory T cells (Treg) cells. Gene expression analyses demonstrated upregulation of gastric PPAR γ-responsive genes (i.e., CD36 and FABP4) in H. pylori-infected mice. The loss of PPAR γ in immune and epithelial cells in mice impaired the ability of H. pylori to favorably modulate glucose homeostasis and ATM infiltration during high fat feeding. Gastric infection with some commensal strains of H. pylori ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism and modulates macrophage and Treg cell infiltration into the abdominal white adipose tissue.

  9. ANGIOTENSIN RECEPTOR BLOCKERS WITH PLEIOTROPIC PROPERTIES: A NEW STANDARD IN CARDIOVASCULAR RISK MANAGEMENT AND TREATMENT OF HYPERTENSION

    Directory of Open Access Journals (Sweden)

    V. I. Podzolkov

    2017-01-01

    Full Text Available An increase in the activity of the renin-angiotensin-aldosterone system is one of the most important mechanisms for the realization of the cardiovascular continuum. The role that angiotensin receptor blockers play in achieving target figures of blood pressure and reducing cardiovascular risk is discussed. The importance of pleiotropic properties of angiotensin receptor blockers (in particular, activation of peroxisome proliferator-activated receptors gamma – PPAR-γ in the management of patients with insulin resistance, obesity, dyslipidemia is also covered. The evidence base for the use of telmisartan as a drug with pleiotropic effect in patients with arterial hypertension and associated diseases (diabetes mellitus, obesity, renal dysfunction is discussed. 

  10. Preferential binding of growth inhibitory prostaglandins by the target protein of a carcinogen

    Energy Technology Data Exchange (ETDEWEB)

    Khan, S.H.; Sorof, S. (Fox Chase Cancer Center, Philadelphia, PA (United States))

    1990-12-01

    Liver fatty acid binding protein (L-FABP) is the principal target protein of the hepatic carcinogen N-(2-fluorenyl)acetamide (2-acetylaminofluorene) in rat liver. In addition, the cyclopentenone prostaglandins (PG), PGA, PGJ{sub 2}, and {Delta}{sup 12}-PGJ{sub 2}, inhibit the growth of many cell types in vitro. This report describes the preferential binding of the growth inhibitory prostaglandins by L-FABP and the reversible inhibition of thymidine incorporation into DNA by PGA{sub 2} and {Delta}{sup 12}-PGJ{sub 2} in primary cultures of purified rat hepatocytes. As a model ligand, ({sup 3}H)PGA{sub 1} bound to L-FABP specifically, reversibly, rapidly, and with high affinity. Its dissociation constants were 134 nM (high affinity) and 3.6 {mu}M (low affinity). The high-affinity finding of ({sup 3}H)PGA{sup 1} correlated with their growth inhibitory activities reported previously and here. The in vitro actions of L-FABP are compatible with those of a specific and dissociable carrier of growth inhibitory prostaglandins in rat hepatocytes and suggest that the carcinogen may usurp the cellular machinery of the growth inhibitory prostaglandins.

  11. Abscisic acid synergizes with rosiglitazone to improve glucose tolerance, down-modulate macrophage accumulation in adipose tissue: possible action of the cAMP/PKA/PPAR γ axis

    Science.gov (United States)

    Guri, Amir J; Hontecillas, Raquel; Bassaganya-Riera, Josep

    2010-01-01

    Background & Aims Abscisic acid (ABA) is effective in preventing insulin resistance and obesity-related inflammation through a PPAR γ-dependent mechanism. The objective of this study was to assess the efficacy ABA in improving glucose homeostasis and suppress inflammation when administered in combination with rosiglitazone (Ros) and to determine whether PPAR γ activation by ABA is initiated via cAMP/protein kinase A (PKA) signaling. Methods Obese db/db mice were fed high-fat diets containing 0, 10, or 70 mg/kg Ros with and without racemic ABA (100 mg/kg) for 60 days. Glucose tolerance and fasting insulin levels were assessed at 6 and 8 weeks, respectively, and adipose tissue macrophage (ATM) infiltration was examined by flow cytometry. Gene expression was examined on white adipose tissue (WAT) and stromal vascular cells (SVCs) cultured with ABA, Ros, or an ABA/Ros combination. Results Both Ros and ABA improved glucose tolerance, and ABA decreased plasma insulin levels while having no effect on Ros-induced weight gain. ABA in combination with low-dose Ros (10 mg/kg; Roslo) synergistically inhibited ATM infiltration. Treatment of SVCs with Ros, ABA or ABA/Ros suppressed expression of the M1 marker CCL17. ABA and Ros synergistically increased PPAR γ activity and pretreatment with a cAMP-inhibitor or a PKA-inhibitor abrogated ABA-induced PPAR γ activation. Conclusions ABA and Ros act synergistically to modulate PPAR γ activity and macrophage accumulation in WAT and ABA enhances PPAR γ activity through a membrane-initiated mechanism dependent on cAMP/PKA signaling. PMID:20207056

  12. Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation

    Energy Technology Data Exchange (ETDEWEB)

    Matsui, Takanori [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan); Yamagishi, Sho-ichi, E-mail: shoichi@med.kurume-u.ac.jp [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan); Takeuchi, Masayoshi [Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa (Japan); Ueda, Seiji; Fukami, Kei; Okuda, Seiya [Department of Medicine, Kurume University School of Medicine, Kurume (Japan)

    2010-07-23

    Research highlights: {yields} Nifedipine inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma}. {yields} GW9662 treatment alone increased RAGE mRNA levels in tubular cells. {yields} Nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-{beta} gene expression in tubular cells, all of which were blocked by GW9662. -- Abstract: There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) interaction evokes oxidative stress generation and subsequently elicits inflammatory and fibrogenic reactions, thereby contributing to the development and progression of diabetic nephropathy. We have previously found that nifedipine, a calcium-channel blocker (CCB), inhibits the AGE-induced mesangial cell damage in vitro. However, effects of nifedipine on proximal tubular cell injury remain unknown. We examined here whether and how nifedipine blocked the AGE-induced tubular cell damage. Nifedipine, but not amlodipine, a control CCB, inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}). GW9662 treatment alone was found to increase RAGE mRNA levels in tubular cells. Further, nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-beta gene expression in tubular cells, all of which were blocked by GW9662. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-oxidative and anti-inflammatory agent against AGEs in tubular cells by suppressing RAGE expression

  13. Medicinal Product Use Reglandin D-(+ - Cloprostenol, Synthetic Analogue of Prostaglandins F2α Natural Body in Fighting with Anestrus Lute (CL in Cattle

    Directory of Open Access Journals (Sweden)

    George Florea Tobă

    2011-05-01

    Full Text Available The studies made by us are based on fundamental biological role of prostaglandin modulator of hormonal actions, influxs nerve transmission and cellular ionic exchange. One of the main actions of PGF2α is luteolyse, a process that includes the secretion of progesterone and regression yellow body. PGF2α is a luteolitic for almost species: cow, buffalo, sow, mare, sheep, rabbits, guinea pigs, hamsters and rats, except primates. At present it is considered that PGF2α have their specific receptors, which are fixed and through their model would enable guanidine monophosphate or cyclic GMP's Goldberg. The effect of ocitocic luteolitic and pharmacodynamics basis of PGF2α, used in breeding biotechnologies and hormonal therapy. In medicine veterinary prostaglandines are used after 1973. Were injected with 2 ml Reglandin (150 mg D-(+ - cloprostenol 24 women diagnosed with corpus luteum anestris and 22 females (87.5% came in to oestrus at a mean of 59 hours, and after an average interval of 70 hours.şi were artificially inseminated (AI a total of 20 female (83.33%.

  14. Prostaglandin E1 and prostaglandin F2 alpha in exudate in nickel allergy

    DEFF Research Database (Denmark)

    Lerche, A; Bisgaard, H; Kassis, V

    1989-01-01

    Ten nickel-allergic patients and 5 healthy control subjects participated in a study of the kinetics of the flux and concentration of migrated leukocytes and extracellular PGE1 and PGF2 alpha during a 48 h period, using a skin chamber technique. The patients were provided with two skin chambers, one...... with and one without nickel challenge. A higher flux of leukocytes, PGE1 and PGF2 alpha was observed during the second day of allergen exposure, while the concentrations probably due to dilution were unchanged or diminished, indicating an unspecific role of the prostaglandins during the contact allergic...

  15. Human alpha-fetoprotein and prostaglandins suppress human lymphocyte transformation by different mechanisms

    International Nuclear Information System (INIS)

    Yachnin, S.; Lester, E.P.

    1979-01-01

    The capacity of human alpha-fetoprotein (HAFP) to suppress human lymphocyte transformation is well established, although some investigators have reported negative results in their efforts to demonstrate this phenomenon. This discrepancy may reside in the fact that not all isolates of HAFP are potent inhibitors of lymphocyte transformation and that the immunosuppressive potency of various HAFP isolates may be correlated with the proportion of certain negatively charged HAFP isomers which they contain. The possibility was considered that noncovalent binding of low-molecular-weight, negatively charged molecules might be partially responsible. Since fatty acids, including certain prostaglandins (PG), are capable of binding to a partly related serum protein, namely, human serum albumin, and since certain prostaglandins are known to be potent suppressors of human lymphocyte transformation, a study was undertaken of the role which prostaglandins might play in HAFP-induced suppression of human lymphocyte transformation

  16. Effect of forskolin and prostaglandin E1 on stimulus secretion coupling in cultured bovine adrenal chromaffin cells.

    Science.gov (United States)

    Marriott, D; Adams, M; Boarder, M R

    1988-02-01

    Treatment of adrenal chromaffin cells with forskolin (0.1-10 microM) stimulated cyclic AMP levels, reduced the maximal stimulation of release of noradrenaline by nicotine, and increased release in response to elevated external potassium and the calcium ionophore A23187. The presence of the phosphodiesterase inhibitor Ro 20-17-24 with forskolin potentiated both the stimulation of cyclic AMP and the inhibition of nicotine-induced noradrenaline release. Dibutyryl cyclic AMP, and the elevation of cyclic AMP with prostaglandin E1, also attenuated nicotine-stimulated release. However, when the stimulation of intracellular cyclic AMP production by prostaglandin E1 was potentiated by low levels of forskolin, there was not a concomitant potentiation of effect on noradrenaline release. Dideoxyforskolin, an analogue of forskolin which does not stimulate adenylate cyclase, inhibited both potassium- and nicotine-stimulated release, probably by a mechanism unrelated to the action of forskolin in these experiments. Using Fura-2 to estimate free intracellular calcium levels, both forskolin and dideoxyforskolin (at 10 microM) reduced the calcium transient in response to nicotine. These results support a model in which elevation of cyclic AMP inhibits the activation of nicotinic receptors, but augments stimulus secretion coupling downstream of calcium entry. The data, however, do not indicate a simple relationship between total intracellular cyclic AMP levels and the attenuation of nicotinic stimulation of release.

  17. Vaginal prostaglandin gel to induce labour in women with one previous caesarean section.

    LENUS (Irish Health Repository)

    Agnew, G

    2012-02-01

    This retrospective study reviewed the mode of delivery when vaginal prostaglandins were used to induce labour in women with a single previous lower segment caesarean section. Over a 4-year period, PGE 2 gel was used cautiously in low doses in 54 women. Induction with PGE 2 gel was associated with an overall vaginal birth after caesarean section (VBAC) rate of 74%, which compared favourably with the 74% VBAC rate in women who went into spontaneous labour (n = 1969). There were no adverse outcomes recorded after the prostaglandin inductions but the number reported are too small to draw any conclusions about the risks, such as uterine rupture. We report our results because they may be helpful in assessing the chances of a successful VBAC in the uncommon clinical circumstances where prostaglandin induction is being considered.

  18. Values of Prostaglandin during Pre and Post-Partum and at parturition in buffaloes

    Directory of Open Access Journals (Sweden)

    R.M. Khattab

    2010-02-01

    Full Text Available This study was carried out at Mehallet Mousa Animal production Research station, Animal production Research institute- ministry of agriculture, Egypt. This work was carried out on ten late pregnant buffaloes for studying prostaglandin (PG F2α during pre and post partum periods. Blood samples were collected five days prepartum and one week postpartum. Prostaglandin was determined by Elisa (Enzyme-Limked immunosorbant Assay. The results, showed that the plasma prostaglandin levels on day three, two and one prepartum was higher than on day five prepartum. On The day of delivery (0 day a sudden sharp increase in PGF2& con concentration occurred (180.83±4.23 pg/ml followed by a gradual decrease in the plasma concentration. Of PGF2α on day four, five, six and seven postpartum, small respectively.

  19. Genome specific PPARαB duplicates in salmonids and insights into estrogenic regulation in brown trout.

    Science.gov (United States)

    Madureira, Tânia Vieira; Pinheiro, Ivone; de Paula Freire, Rafaelle; Rocha, Eduardo; Castro, Luis Filipe; Urbatzka, Ralph

    2017-06-01

    Peroxisome proliferator-activated receptors (PPARs) are key regulators of many processes in vertebrates, such as carbohydrate and lipid metabolism. PPARα, a member of the PPAR nuclear receptor gene subfamily (NR1C1), is involved in fatty acid metabolism, namely in peroxisomal β-oxidation. Two gene paralogues, pparαA and pparαB, were described in several teleost species with their origin dating back to the teleost-specific genome duplication (3R). Given the additional salmonid-specific genome duplication (4R), four genes could be theoretically anticipated for this gene subfamily. In this work, we examined the pparα gene repertoire in brown trout, Salmo trutta f. fario. Data disclosed two pparα-like sequences in brown trout. Phylogenetic analyses further revealed that the isolated genes are most likely genome pparαB duplicates, pparαBa and pparαBb, while pparαA is apparently absent in salmonids. Both genes showed a ubiquitous mRNA expression across a panel of 11 different organs. In vitro exposed primary brown trout hepatocytes strongly suggest that pparα gene paralogues are differently regulated by ethinylestradiol (EE2). PparαBb mRNA expression significantly decreased with dosage, reaching significance after exposure to 50μM EE2, while pparαBa mRNA increased, significant at 1μM EE2. The present data enhances the understanding of pparα function and evolution in teleost, and reinforces the evidence of a potential crosstalk between estrogenic and pparα signaling pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Prostaglandin E(2) synthase inhibition as a therapeutic target.

    Science.gov (United States)

    Iyer, Jitesh P; Srivastava, Punit K; Dev, Rishabh; Dastidar, Sunanda G; Ray, Abhijit

    2009-07-01

    Most NSAIDs function by inhibiting biosynthesis of PGE(2) by inhibition of COX-1 and/or COX-2. Since COX-1 has a protective function in the gastro-intestinal tract (GIT), non-selective inhibition of both cycloxy genases leads to moderate to severe gastro-intestinal intolerance. Attempts to identify selective inhibitors of COX-2, led to the identification of celecoxib and rofecoxib. However, long-term use of these drugs has serious adverse effects of sudden myocardial infarction and thrombosis. Drug-mediated imbalance in the levels of prostaglandin I(2) (PGI(2)) and thromboxane A(2) (TXA(2)) with a bias towards TXA(2) may be the primary reason for these events. This resulted in the drugs being withdrawn from the market, leaving a need for an effective and safe anti-inflammatory drug. Recently, the focus of research has shifted to enzymes downstream of COX in the prosta glandin biosynthetic pathway such as prostaglandin E(2) synthases. Microsomal prostaglandin E(2) synthase-1 (mPGES-1) specifically isomerizes PGH(2) to PGE(2), under inflammatory conditions. In this review, we examine the biology of mPGES-1 and its role in disease. Progress in designing molecules that can selectively inhibit mPGES-1 is reviewed. mPGES-1 has the potential to be a target for anti-inflammatory therapy, devoid of adverse GIT and cardiac effects and warrants further investigation.

  1. Indomethacin causes prostaglandin D(2)-like and eotaxin-like selective responses in eosinophils and basophils.

    Science.gov (United States)

    Stubbs, Victoria E L; Schratl, Petra; Hartnell, Adele; Williams, Timothy J; Peskar, Bernhard A; Heinemann, Akos; Sabroe, Ian

    2002-07-19

    We investigated the actions of a panel of nonsteroidal anti-inflammatory drugs on eosinophils, basophils, neutrophils, and monocytes. Indomethacin alone was a potent and selective inducer of eosinophil and basophil shape change. In eosinophils, indomethacin induced chemotaxis, CD11b up-regulation, respiratory burst, and L-selectin shedding but did not cause up-regulation of CD63 expression. Pretreatment of eosinophils with indomethacin also enhanced subsequent eosinophil shape change induced by eotaxin, although treatment with higher concentrations of indomethacin resulted in a decrease in the expression of the major eosinophil chemokine receptor, CCR3. Indomethacin activities and cell selectivity closely resembled those of prostaglandin D(2) (PGD(2)). Eosinophil shape change in response to eotaxin was inhibited by pertussis toxin, but indomethacin- and PGD(2)-induced shape change responses were not. Treatment of eosinophils with specific inhibitors of phospholipase C (U-73122), phosphatidylinositol 3-kinase (LY-294002), and p38 mitogen-activated protein kinase (SB-202190) revealed roles for these pathways in indomethacin signaling. Indomethacin and its analogues may therefore provide a structural basis from which selective PGD(2) receptor small molecule antagonists may be designed and which may have utility in the treatment of allergic inflammatory disease.

  2. Triptolide disrupts fatty acids and peroxisome proliferator-activated receptor (PPAR) levels in male mice testes followed by testicular injury: A GC–MS based metabolomics study

    International Nuclear Information System (INIS)

    Ma, Bo; Qi, Huanhuan; Li, Jing; Xu, Hong; Chi, Bo; Zhu, Jianwei; Yu, Lisha; An, Guohua; Zhang, Qi

    2015-01-01

    in maintaining normal function of the testis tissue, was observed in triptolide-treated mice. Additionally, the protein expressions of PPAR, a transcription factor known to play a pivotal role in lipid and energy metabolism was significantly decreased in the testis tissue of triptolide-treated mice. In summary, our study represents the first comprehensive GC–MS based metabolomics analysis of triptolide-induced testicular toxicity. We reported for the first time that exposure to triptolide led to marked changes of a panel of endogenous metabolites in both testis and serum. The impairment of spermatogenesis may be caused by abnormal lipid and energy metabolism in testis via the down-regulation of PPARs mediated by triptolide. The presence of research suggested that PPARs and its related fatty acids metabolism may serve as potential targets for intervention or treatment of male infertility induced by triptolide

  3. Effect of radioprotectant WR 2721 on cyclic nucleotides, prostaglandins, and lysosomes

    International Nuclear Information System (INIS)

    Trocha, P.J.; Catravas, G.N.

    1983-01-01

    Within 1 hr after ip injection of the radioprotectant WR 2721 into rats, splenic cGMP levels dropped and remained suppressed for 6 hr before returning to normal. However, if rats were exposed to ionizing radiation 30-40 min after WR 2721 treatment, they had higher cGMP levels at 3 hr postirradiation than the nonirradiUted, drug-treated controls, but the cGMP content was still found to be lower than that of the irradiated nondrug-treated controls. Radiation exposure of animals pretreated with WR 2721 also resulted in higher liver and spleen levels of cAMP and additional elevations in spleen prostaglandin content, compared with irradiated controls at 3-6 hr after radiation treatment. The secondary fluctuations of lysosomal enzyme activities, prostaglandin content, and cyclic nucleotide levels were also altered in irradiated rats pretreated with WR 2721 when compared with irradiated controls. Liver and spleen lysosomal β-glucuronidase activities, spleen cAMP and cGMP levels, and spleen prostaglandin concentrations were closer to physiological levels at 3 days postirradiation in rats given WR 2721 before the radiation treatment

  4. Urinary prostaglandin excretion in pregnancy: the effect of dietary sodium restriction.

    Science.gov (United States)

    Delemarre, F M; Thomas, C M; van den Berg, R J; Jongsma, H W; Steegers, E A

    2000-10-01

    Dietary sodium restriction results in activation of the renin-angiotensin-aldosterone-system. In the non-pregnant situation renin release in response to a low sodium diet is mediated by prostaglandins. We studied the effect of dietary sodium restriction on urinary prostaglandin metabolism in pregnancy. In a randomized, longitudinal study the excretion of urinary metabolites of prostacyclin (6-keto-PGF(1 alpha)and 2,3-dinor-6-keto-PGF(1 alpha)) and thromboxane A(2)(TxB(2)and 2,3-dinor-TxB(2)) was determined throughout pregnancy and post partum in 12 women on a low sodium diet and in 12 controls. In pregnancy the excretion of all urinary prostaglandins is increased. The 6-keto-PGF(1 alpha)/ TxB(2)-ratio as well as the 2, 3-dinor-6-keto-PGF(1 alpha)/ 2,3-dinor-TxB(2)-ratio did not significantly change in pregnancy. CONCLUISION Prostacyclin and thromboxane do not seem to play an important role in sodium balance during pregnancy. Copyright 2000 Harcourt Publishers Ltd.

  5. Cyclooxygenase-2 induction in macrophages is modulated by docosahexaenoic acid via interactions with free fatty acid receptor 4 (FFA4).

    Science.gov (United States)

    Li, Xinzhi; Yu, Ying; Funk, Colin D

    2013-12-01

    Cyclooxygenase-2 (COX-2)-derived prostaglandins are implicated in numerous inflammatory disorders. The purpose of these studies was to examine previously unexplored interactions between COX-2 induction and docosahexaenoic acid (DHA) via the free fatty acid receptor 4 (FFA4) signaling pathway in murine RAW 264.7 cells and peritoneal macrophages challenged with lipopolysaccharide (LPS). DHA dose (IC50=18 μM)- and time-dependently reduced COX-2 expression, without affecting COX-1. DHA (25 μM for 24 h) decreased LPS-induced prostaglandin E2 (PGE2) synthesis by 81%, primarily through reducing COX-2 (60%), as well as down-regulating microsomal prostaglandin E synthase-1 (46%), but independently of peroxisome proliferator-activated receptors. FFA4 knockdown abrogated DHA effects on COX-2 induction, PGE2 production, and interleukin 6 (IL-6) gene expression. In the presence of inhibitors of eicosanoid metabolism via COX-2, 12/15-lipoxygenase and CYP450s (rofecoxib (1 μM), PD146176 (2 μM), or MS-PPOH (20 μM)), DHA was still effective in attenuating COX-2 induction. Moreover, Toll-like receptor 4 signaling via Akt/JNK phosphorylation and p65 nuclear translocation was repressed by DHA-activated FFA4 coupling with β-arrestin 2, which was reversed by FFA4 knockdown. These data support DHA modulation of COX-2 expression and activity, in part, via FFA4, which provides a new mechanistic explanation for some of the anti-inflammatory effects of DHA.

  6. Radiation-induced increases in sensitivity of cataleptic behavior to haloperidol: possible involvement of prostaglandins

    International Nuclear Information System (INIS)

    Joseph, J.A.; Kandasamy, S.B.; Hunt, W.A.; Dalton, T.K.; Stevens, S.

    1988-01-01

    The effects of radiation exposure on haloperidol-induced catalepsy were examined in order to determine whether elevated prostaglandins, through an action on dopaminergic autoreceptors, could be involved in the radiation-induced increase in the potency of this neuroleptic. Cataleptic behavior was examined in animals irradiated with various doses of gamma photons (1-150 Gy) and pretreated with a subthreshold dose of haloperidol (0.1 mg/kg). This approach was chosen to maximize any synergistic effects of radiation and haloperidol. After irradiation with doses less than or equal to 30 Gy, the combined treatment of haloperidol and radiation produced catalepsy, whereas neither treatment alone had an effect. This observed catalepsy could be blocked with prior administration of indomethacin, a prostaglandin synthesis inhibitor. Animals exposed to doses of radiation less than or equal to 50 Gy and no haloperidol, however, displayed apparent catalepsy. This effect was also antagonized by indomethacin. Prostaglandins can induce catalepsy and when administered in subthreshold doses along with subthreshold doses of haloperidol, catalepsy was observed. In order to assess a possible action of prostaglandins and radiation on dopaminergic activity, the functioning of striatal dopaminergic autoreceptors was examined by determining the effects of varying concentrations of haloperidol on the K+-evoked release of dopamine from striatal slices obtained from parallel groups of animals treated as above. Results indicated that sensitivity to haloperidol increased (higher K+-evoked dopamine release) in slices from irradiated or prostaglandin-treated animals and that this increase in sensitivity was blocked by indomethacin

  7. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 inhibits adhesion of human endometriotic epithelial and stromal cells through suppression of integrin-mediated mechanisms.

    Science.gov (United States)

    Lee, JeHoon; Banu, Sakhila K; Burghardt, Robert C; Starzinski-Powitz, Anna; Arosh, Joe A

    2013-03-01

    Endometriosis is a chronic gynecological disease of reproductive age women characterized by the presence of functional endometrial tissues outside the uterine cavity. Interactions between the endometriotic cells and the peritoneal extracellular matrix proteins (ECM) are crucial mechanisms that allow adhesion of the endometriotic cells into peritoneal mesothelia. Prostaglandin E2 (PGE2) plays an important role in the pathogenesis of endometriosis. In previous studies, we have reported that selective inhibition of PGE2 receptors PTGER2 and PTGER4 decreases survival and invasion of human endometriotic epithelial and stromal cells through multiple mechanisms. Results of the present study indicates that selective inhibition of PTGER2- and PTGER4-mediated PGE2 signaling 1) decreases the expression and/or activity of specific integrin receptor subunits Itgb1 (beta1) and Itgb3 (beta3) but not Itgb5 (beta5), Itga1 (alpha1), Itga2 (alpha2), Itga5 (alpha5), and Itgav (alphav); 2) decreases integrin-signaling components focal adhesion kinase or protein kinase 2 (PTK2) and talin proteins; 3) inhibits interactions between Itgb1/Itgb3 subunits, PTK2, and talin and PTGER2/PTGER4 proteins through beta-arrestin-1 and Src kinase protein complex in human endometriotic epithelial cells 12Z and stromal cells 22B; and 4) decreases adhesion of 12Z and 22B cells to ECM collagen I, collagen IV, fibronectin, and vitronectin in a substrate-specific manner. These novel findings provide an important molecular framework for further evaluation of selective inhibition of PTGER2 and PTGER4 as potential nonsteroidal therapy to expand the spectrum of currently available treatment options for endometriosis in child-bearing age women.

  8. Metabolic syndrome and related variables, insulin resistance, leptin levels, and PPAR-γ2 and leptin gene polymorphisms in a pedigree of subjects with bipolar disorder

    Directory of Open Access Journals (Sweden)

    Trino Baptista

    2015-06-01

    Full Text Available Objective:Evidence points to a high prevalence of metabolic dysfunction in bipolar disorder (BD, but few studies have evaluated the relatives of subjects with BD. We conducted a cross-sectional study in an extended family of patients with BD type I.Methods:The available relatives of the same family were interviewed (DSM-IV-R and assessed in fasting conditions for body mass index, constituent variables of the metabolic syndrome (MS, leptin levels, insulin resistance index, and single nucleotide polymorphisms (SNPs for the leptin receptor and promoter and PPAR-γ2 genes. The frequency of MS was compared with that recorded in the local general population.Results:Ninety-three relatives of three adults with BD were evaluated (30 aged 18 years. The frequency of MS was similar to that of the general population. Significantly higher frequencies of abnormal glucose, total and low density cholesterol (LDL-c levels (all p < 0.05, waist circumference (p = 0.057, and leptin and insulin resistance values (in adults only were observed in the family. Adults with the QQ genotype of the leptin receptor displayed higher LDL-c levels than carriers of the R allele.Conclusions:The associations among BD consanguinity, familial hypercholesterolemia, and leptin receptor SNPs reported herein should be replicated and extended in other pedigrees.

  9. Involvement of prostaglandins F/sub 2α/ and E1 with rabbit endometrium

    International Nuclear Information System (INIS)

    Orlicky, D.J.

    1985-01-01

    Several growth factors and hormones are thought to play a role in the growth control of endometrial cells. The authors have shown that prostaglandin F/sub 2→/ (PGF/sub 2α/) is a growth factor for primary cultures of rabbit endometrium cultured in chemically-defined serum-free medium and that prostaglandin E 1 (PGE 1 ) antagonizes the PGF/sub 2→/ induction of growth. Both [ 3 H]PGF/sub 2α/ and [ 3 H]PGE 1 bind in a time and temperature dependent, dissociable, saturable and specific manner. The binding of [ 3 H]PGF/sub 2α/ and [ 3 H]PGE 1 can be both down and up regulated and is enzyme sensitive. PGE 1 stimulates intracellular cAMP synthesis and accumulation in a time and concentration dependent manner. PGF/sub 2α/ probably exerts its effects through an amiloride-sensitive intermediate. Both PGF/sub 2α/ and PGE 1 are constitutively synthesized by these primary cultures, and they have shown this synthesis to be both drug and hormone sensitive. They hypothesize that it is the ratio, rather than the absolute quantities, of PGF/sub 2α/ and PGE 1 which is of more importance in the regulation of endometrial cell growth. Furthermore, they believe this regulation of endometrial growth plays a role in control of proliferation during the decidual response and that a derangement in the ratio of these prostaglandins may lead to either infertility or hyperplasia. The ability of these cultures to synthesize prostaglandins in a hormonally regulatable manner may be of importance in the study of dysmenorrhea and uterine cramping as caused by the myometrial contracting prostaglandin, PGF/sub 2α/

  10. Stimulation of prostaglandin E2 production by phorbol esters and epidermal growth factor in porcine thyroid cells

    International Nuclear Information System (INIS)

    Kasai, K.; Hiraiwa, M.; Emoto, T.; Akimoto, K.; Takaoka, T.; Shimoda, S.I.

    1987-01-01

    Effects of phorbol esters and epidermal growth factor (EGF) on prostaglandin E 2 production by cultured porcine thyroid cells were examined. Both phorbol 12-myristate 13-acetate (PMA) and EGF stimulated prostaglandin E 2 production by the cells in dose related fashion. PMA stimulated prostaglandin E 2 production over fifty-fold with the dose of 10 -7 M compared with control. EGF (10 -7 M) also stimulated it about ten-fold. The ED 50 values of PMA and EGF were respectively around 1 x 10 -9 M and 5 x 10 -10 M. Thyroid stimulating hormone (TSH), however, did not stimulate prostaglandin E 2 production from 1 to 24-h incubation. The release of radioactivity from [ 3 H]-arachidonic acid prelabeled cells was also stimulated by PMA and EGF, but not by TSH. These results indicate that both PMA and EGF are potent stimulators of prostaglandin E 2 production, associated with the activity to stimulate arachidonic acid release in porcine thyroid cells. 36 references, 2 figures, 1 table

  11. Expression of Peroxisome Proliferator-Activated Receptor-γ in Key Neuronal Subsets Regulating Glucose Metabolism and Energy Homeostasis

    OpenAIRE

    Sarruf, David A.; Yu, Fang; Nguyen, Hong T.; Williams, Diana L.; Printz, Richard L.; Niswender, Kevin D.; Schwartz, Michael W.

    2008-01-01

    In addition to increasing insulin sensitivity and adipogenesis, peroxisome proliferator-activated receptor (PPAR)-γ agonists cause weight gain and hyperphagia. Given the central role of the brain in the control of energy homeostasis, we sought to determine whether PPARγ is expressed in key brain areas involved in metabolic regulation. Using immunohistochemistry, PPARγ distribution and its colocalization with neuron-specific protein markers were investigated in rat and mouse brain sections spa...

  12. Helicobacter pylori colonization ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism.

    Directory of Open Access Journals (Sweden)

    Josep Bassaganya-Riera

    Full Text Available BACKGROUND: There is an inverse secular trend between the incidence of obesity and gastric colonization with Helicobacter pylori, a bacterium that can affect the secretion of gastric hormones that relate to energy homeostasis. H. pylori strains that carry the cag pathogenicity island (PAI interact more intimately with gastric epithelial cells and trigger more extensive host responses than cag(- strains. We hypothesized that gastric colonization with H. pylori strains differing in cag PAI status exert distinct effects on metabolic and inflammatory phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, we examined metabolic and inflammatory markers in db/db mice and mice with diet-induced obesity experimentally infected with isogenic forms of H. pylori strain 26695: the cag PAI wild-type and its cag PAI mutant strain 99-305. H. pylori colonization decreased fasting blood glucose levels, increased levels of leptin, improved glucose tolerance, and suppressed weight gain. A response found in both wild-type and mutant H. pylori strain-infected mice included decreased white adipose tissue macrophages (ATM and increased adipose tissue regulatory T cells (Treg cells. Gene expression analyses demonstrated upregulation of gastric PPAR γ-responsive genes (i.e., CD36 and FABP4 in H. pylori-infected mice. The loss of PPAR γ in immune and epithelial cells in mice impaired the ability of H. pylori to favorably modulate glucose homeostasis and ATM infiltration during high fat feeding. CONCLUSIONS/SIGNIFICANCE: Gastric infection with some commensal strains of H. pylori ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism and modulates macrophage and Treg cell infiltration into the abdominal white adipose tissue.

  13. Molecular cloning and characterization of the porcine prostaglandin transporter (SLCO2A1: evaluation of its role in F4 mediated neonatal diarrhoea

    Directory of Open Access Journals (Sweden)

    Cox Eric

    2009-10-01

    Full Text Available Abstract Background Because prostaglandins are involved in many (pathophysiological processes, SLCO2A1 was already characterized in several species in an attempt to unravel specific processes/deficiencies. Here, we describe the molecular cloning and characterization of the porcine ortholog in order to evaluate its possible involvement in F4 enterotoxigenic E. coli mediated neonatal diarrhoea, based on a positional candidate gene approach study. Results Porcine SLCO2A1 is organized in 14 exons, containing an open reading frame of 1935 bp, encoding a 12-transmembrane organic anion cell surface transporter of 644 aa. The -388 to -5 upstream region comprises a (CpG48 island containing a number of conserved promoter elements, including a TATA box. A potential alternative promoter region was found in the conserved -973 to -700 upstream region. No consensus polyadenylation signal was discovered in the 3' UTR. Repeat sequences were found in 15% of all the non coding sequences. As expected for a multifunctional protein, a wide tissue distribution was observed. mRNA expression was found in the adrenal gland, bladder, caecum, colon (centripetal coil/centrifugal coil, diaphragm, duodenum, gallbladder, heart, ileum, jejunum, kidney, liver, longissimus dorsi muscle, lung, lymph node, mesenterium, rectum, spleen, stomach, tongue and ureter, but not in the aorta, oesophagus and pancreas. The promoter region and the exons (including the splice sites of SLCO2A1 were resequenced in 5 F4ab/ac receptor positive and 5 F4ab/ac receptor negative pigs. Two silent and 2 missense (both S → L at position 360 and 633 mutations were found, but none was associated with the F4ab/ac receptor phenotype. In addition, no phenotype associated differential mRNA expression or alternative/abberant splicing/polyadenylation was found in the jejunum. Conclusion The molecular cloning and characterization of porcine SLCO2A1 not only contributes to the already existing knowledge about the

  14. Prostaglandin E(2) mediates acid-induced heartburn in healthy volunteers.

    Science.gov (United States)

    Kondo, Takashi; Oshima, Tadayuki; Tomita, Toshihiko; Fukui, Hirokazu; Watari, Jiro; Okada, Hiroki; Kikuchi, Shojiro; Sasako, Mitsuru; Matsumoto, Takayuki; Knowles, Charles H; Miwa, Hiroto

    2013-03-15

    Prostaglandin E(2) (PGE(2)) plays a major role in pain processing and hypersensitivity. This study investigated whether PGE(2) levels are increased in the esophageal mucosa after acid infusion and whether increases in PGE(2) are associated with heartburn. Furthermore, expression of the PGE(2) receptor EP1 was investigated in human esophageal mucosa. Fourteen healthy male volunteers were randomized to 30-min lower esophageal acid (1% HCl) or saline perfusion. Before and after acid perfusion, endoscopic biopsies were taken from the distal esophagus. PGE(2) concentration (pg/mg protein) and EP1 mRNA and protein in biopsy samples were measured by ELISA, RT-PCR, and Western blotting. Symptom status of heartburn was evaluated with a validated categorical rating scale with a higher values corresponding to increasing intensity. PGE(2) levels in the esophageal mucosa significantly increased after acid infusion (before vs. after acid infusion: 23.2 ± 8.6 vs. 68.6 ± 18.3, P heartburn in the acid-infusion group was also significantly greater compared with saline (saline vs. acid infusion: 54.3 ± 13.1 vs. 178.5 ± 22.8, P heartburn.

  15. Effects of nonhypotensive endotoxemia in conscious rats: Role of prostaglandins

    International Nuclear Information System (INIS)

    Burnier, M.; Waeber, B.; Aubert, J.F.; Nussberger, J.; Brunner, H.R.

    1988-01-01

    A nonhypotensive dose of endotoxin was administered to normal conscious rats to evaluate the vascular and humoral effects of endotoxemia per se. Mean blood pressure and heart rate remained stable during the 45 min infusion of Escherichia coli endotoxin. However, a marked increase in plasma renin activity plasma epinephrine and plasma norepinephrine was observed during infusion in endotoxin-treated rats when compared with the vehicle-treated animals. In addition, the blood pressure response to exogenous norepinephrine was significantly reduced during nonhypotensive endotoxemia. Significant changes in regional blood flow distribution, as assessed by radiolabeled microspheres, were observed in endotoxemic rats; in particular a decrease in renal blood flow, and an increase in coronary blood flow were found. The role of prostaglandins in the vascular and humoral alterations induced by nonhypotensive endotoxemia was also examined. Pretreatment with indomethacin (5 mg) prevent the increase in plasma renin activity as well as plasma catecholamine levels. On the contrary, the decreased vascular reactivity and the reduction in renal blood flow observed during endotoxemia were not affected by prostaglandin synthesis inhibition. Thus significant vascular and humoral changes have been found during endotoxemia even in absence of hypotension. The humoral but not the vascular effects of endotoxemia were abolished when prostaglandin synthesis was inhibited

  16. Computational tool for immunotoxic assessment of pyrethroids toward adaptive immune cell receptors.

    Science.gov (United States)

    Kumar, Anoop; Behera, Padma Charan; Rangra, Naresh Kumar; Dey, Suddhasattya; Kant, Kamal

    2018-01-01

    Pyrethroids have prominently known for their insecticidal actions worldwide, but recent reports as anticancer and antiviral applications gained a lot of interest to further understand their safety and immunotoxicity. This encouraged us to carry out our present study to evaluate the interactions of pyrethroids toward adaptive immune cell receptors. Type 1 and Type 2 pyrethroids were tested on T (CD4 and CD8) and B (CD28 and CD45) immune cell receptors using Maestro 9.3 (Schrödinger, LLC, Cambridge, USA). In addition, top-ranked tested ligands were too explored for toxicity prediction in rodents using ProTOX tool. Pyrethroids (specifically type 2) such as fenvalerate (-5.534 kcal/mol: CD8), fluvalinate (-4.644 and - 4.431 kcal/mol: CD4 and CD45), and cypermethrin (-3.535 kcal/mol: CD28) have outcome in less energy or more affinity for B-cell and T-cell immune receptors which may later result in the immunosuppressive and hypersensitivity reactions. The current findings have uncovered that there is a further need to assess the Type 2 pyrethroids with wet laboratory experiments to understand the chemical nature of pyrethroid-induced immunotoxicity. Fenvalerate showed apex glide score toward CD8 immune receptor, while fluvalinate confirmed top-ranked binding with CD4 and CD45 immune proteinsIn addition, cypermethrin outcame in top glide score against CD28 immune receptorTop dock hits (Type 2) pyrethroids have shown probable toxicity targets toward AOFA: Amine oxidase (flavin-containing) A and PGH1: Prostaglandin G/H synthase 1, respectively. Abbreviations used: PDB: Protein Data Bank; AOFA: Amine oxidase (flavin-containing) A; PGH 1: Prostaglandin G/H synthase 1.

  17. The Natural Compound Dansameum Reduces foam Cell Formation by Downregulating CD36 and Peroxisome Proliferator-activated Receptor-gamma; Expression.

    Science.gov (United States)

    Park, Kang-Seo; Ahn, Sang Hyun; Lee, Kang Pa; Park, Sun-Young; Cheon, Jin Hong; Choi, Jun-Yong; Kim, Kibong

    2018-01-01

    Atherosclerosis-induced vascular disorders are major causes of death in most western countries. During the development of atherosclerotic lesions, foam cell formation is essential and formed through the expression of CD36 and the peroxisome proliferator-activated receptor gamma (PPAR-γ). To investigate whether dansameum extract (DSE) could show anti-atherosclerotic effect through down-regulating cellular redox state including CD36 and PARP-γ expression in oxidative low-density lipoprotein (oxLDL)-treated RAW264.7 cells and on differentiated foam cells in ApoE Knockout (ApoE-/-) mice. The Korean polyherbal medicine DSE was prepared from three plants in the following proportions: 40 g of Salvia miltiorrhiza root, 4 g of Amomumxanthioides fruit, and 4 g of Santalum album lignum. The immunohistochemistry and reverse transcription-polymerase chain reaction was used for analysis of protein and mRNA involved in foam cell formation. We first showed that effects of DSE on foam cell formation in both oxLDL-induced RAW264.7 cells and in blood vessels from apolipoprotein E deficientApoE-/- mice with high fat diet-fed. DSE treatment significantly reduced the expression of CD36 and PPAR-γ in oxLDL-stimulated RAW264.7 cells and ApoE-/-mice, in the latter case by regulating heme oxygenase-1. Furthermore, DSE treatment also reduced cellular lipid content in vitro and in vivo experiments. Our data suggest that DSE may have anti-atherosclerotic properties through regulating foam cell formation. Dansameum extract (DSE) Regulates the expression of CD36 and peroxisome proliferator-activated receptor gamma in oxidative low-density lipoprotein-stimulated RAW264.7 Cells and ApoE Knockout (ApoE Knockout [ApoE-/-]) miceDSE Regulates Cholesterol Levels in the Serum of ApoE-deficient (ApoE-/-) miceDSE Reduced the Formation of Foam Cells by Regulating heme oxygenase-1 in ApoE-/- mice with high fat diet-fed. Abbreviations used: DSE: Dansameum extract, PPAR-γ: Peroxisome proliferator

  18. Prostaglandin synthesis can be inhibited locally by infusion of NSAIDS through microdialysis catheters in human skeletal muscle

    DEFF Research Database (Denmark)

    Mikkelsen, Ulla Ramer; Helmark, Ida Carøe; Kjaer, Michael

    2008-01-01

    of nonsteroidal anti-inflammatory drugs (NSAIDs). However, to study the local role of prostaglandins, the formation of prostaglandins within the tissue must be controlled. Microdialysis enables determination of local concentrations of water-soluble substances within the tissue. In the present study......, the microdialysis method was used to infuse NSAIDs locally into human skeletal muscles producing a local block of prostaglandin formation. In addition, the graded blockade at various distances from the infusion site within the muscle during rest, exercise and recovery was determined. Microdialysis was performed...... in thigh muscles (vastus lateralis muscle) in six healthy men. One of the microdialysis catheters was used to block prostaglandin synthesis by infusion of the NSAID indomethacin. Additional catheters were placed 1 and 4 cm away from the infusion and in the contralateral leg (working control). Following 2 h...

  19. Cloning retinoid and peroxisome proliferator-activated nuclear receptors of the Pacific oyster and in silico binding to environmental chemicals.

    Directory of Open Access Journals (Sweden)

    Susanne Vogeler

    Full Text Available Disruption of nuclear receptors, a transcription factor superfamily regulating gene expression in animals, is one proposed mechanism through which pollution causes effects in aquatic invertebrates. Environmental pollutants have the ability to interfere with the receptor's functions through direct binding and inducing incorrect signals. Limited knowledge of invertebrate endocrinology and molecular regulatory mechanisms, however, impede the understanding of endocrine disruptive effects in many aquatic invertebrate species. Here, we isolated three nuclear receptors of the Pacific oyster, Crassostrea gigas: two isoforms of the retinoid X receptor, CgRXR-1 and CgRXR-2, a retinoic acid receptor ortholog CgRAR, and a peroxisome proliferator-activated receptor ortholog CgPPAR. Computer modelling of the receptors based on 3D crystal structures of human proteins was used to predict each receptor's ability to bind to different ligands in silico. CgRXR showed high potential to bind and be activated by 9-cis retinoic acid and the organotin tributyltin (TBT. Computer modelling of CgRAR revealed six residues in the ligand binding domain, which prevent the successful interaction with natural and synthetic retinoid ligands. This supports an existing theory of loss of retinoid binding in molluscan RARs. Modelling of CgPPAR was less reliable due to high discrepancies in sequence to its human ortholog. Yet, there are suggestions of binding to TBT, but not to rosiglitazone. The effect of potential receptor ligands on early oyster development was assessed after 24h of chemical exposure. TBT oxide (0.2μg/l, all-trans retinoic acid (ATRA (0.06 mg/L and perfluorooctanoic acid (20 mg/L showed high effects on development (>74% abnormal developed D-shelled larvae, while rosiglitazone (40 mg/L showed no effect. The results are discussed in relation to a putative direct (TBT disruption effect on nuclear receptors. The inability of direct binding of ATRA to CgRAR suggests

  20. Effects of ultraviolet irradiation on prostaglandin-E2 production by cultured corneal stromal cells

    International Nuclear Information System (INIS)

    Weinreb, R.N.; Yue, B.Y.J.T.; Peyman, G.A.

    1990-01-01

    The authors examined the effects of ultraviolet (UV) irradiation on the release of prostaglandin E 2 (PGE 2 ) by rabbit corneal stromal cells in culture. Considerable amounts of PGE 2 were present in the media of control corneal cultures following 1, 2, 4, 8 and 24 hr of incubation. Irradiation with UV-A (320-400 nm) for 30 min resulted in more than a 50% increase in PGE 2 release. Dexamethasone inhibited PGE 2 release by corneal stromal cells. It was, however, ineffective in protecting the cells from the UV-induced release of PGE 2 . (author)

  1. Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis.

    Science.gov (United States)

    Vallée, Alexandre; Vallée, Jean-Noël; Guillevin, Rémy; Lecarpentier, Yves

    2018-05-01

    Multiple sclerosis (MS) is marked by neuroinflammation and demyelination with loss of oligodendrocytes in the central nervous system. The immune response is regulated by WNT/beta-catenin pathway in MS. Activated NF-kappaB, a major effector of neuroinflammation, and upregulated canonical WNT/beta-catenin pathway positively regulate each other. Demyelinating events present an upregulation of WNT/beta-catenin pathway, whereas proper myelinating phases show a downregulation of WNT/beta-catenin pathway essential for the promotion of oligodendrocytes precursors cells proliferation and differentiation. The activation of WNT/beta-catenin pathway results in differentiation failure and impairment in remyelination. However, PI3K/Akt pathway and TCF7L2, two downstream targets of WNT/beta-catenin pathway, are upregulated and promote proper remyelination. The interactions of these signaling pathways remain unclear. PPAR gamma activation can inhibit NF-kappaB, and can also downregulate the WNT/beta-catenin pathway. PPAR gamma and canonical WNT/beta-catenin pathway act in an opposite manner. PPAR gamma agonists appear as a promising treatment for the inhibition of demyelination and the promotion of proper remyelination through the control of both NF-kappaB activity and canonical WNT/beta-catenin pathway.

  2. Urinary prostaglandin E and vasopressin excretion in essential fatty acid-deficient rats

    DEFF Research Database (Denmark)

    Hansen, Harald S.; Jensen, B.

    1983-01-01

    excretion of prostaglandin E (PGE), immunoreactive arginine vasopressin (iA VP), and kallikrein were determined. PGE was quantitated with a radioimmunoassay having 4.9% cross-reactivity with prostaglandin E (PGE). After 4 weeks on the diet, water consumption and urinary iAVP excretion increased....... Increased water consumption and increased urinary iAVP excretion seem to be early symptoms (after 4 weeks) of EFA deficiency, whereas decreased urine output and decreased urinary PGE excretion occur much later (after 10 weeks). Two energy% linolenate supplementation to a fat-free diet did not change...

  3. Development of novel non agoinst PPAR-gamma ligands for lung cancer treatment

    Science.gov (United States)

    2017-08-01

    AWARD NUMBER: W81XWH-15-1-0165 TITLE: Development of novel non-agoinst PPAR-gamma ligands for lung cancer treatment . PRINCIPAL INVESTIGATOR...factor PPARγ, the thiazolidinediones (TZDs), synergized with carboplatin treatment of lung cancer in vitro and in vivo. Unfortunately, the use of TZDs...novel therapeutics with potential in lung cancer , we have explored the role of these non- agonist PPARγ ligands in cancer treatment . We have

  4. Abscisic acid synergizes with rosiglitazone to improve glucose tolerance and down-modulate macrophage accumulation in adipose tissue: possible action of the cAMP/PKA/PPAR γ axis.

    Science.gov (United States)

    Guri, Amir J; Hontecillas, Raquel; Bassaganya-Riera, Josep

    2010-10-01

    Abscisic acid (ABA) is effective in preventing insulin resistance and obesity-related inflammation through a PPAR γ-dependent mechanism. The objective of this study was to assess the efficacy ABA in improving glucose homeostasis and suppress inflammation when administered in combination with rosiglitazone (Ros) and to determine whether PPAR γ activation by ABA is initiated via cAMP/protein kinase A (PKA) signaling. Obese db/db mice were fed high-fat diets containing 0, 10, or 70 mg/kg Ros with and without racemic ABA (100 mg/kg) for 60 days. Glucose tolerance and fasting insulin levels were assessed at 6 and 8 weeks, respectively, and adipose tissue macrophage (ATM) infiltration was examined by flow cytometry. Gene expression was examined on white adipose tissue (WAT) and stromal vascular cells (SVCs) cultured with ABA, Ros, or an ABA/Ros combination. Both Ros and ABA improved glucose tolerance, and ABA decreased plasma insulin levels while having no effect on Ros-induced weight gain. ABA in combination with low-dose Ros (10 mg/kg; Roslo) synergistically inhibited ATM infiltration. Treatment of SVCs with Ros, ABA or ABA/Ros suppressed expression of the M1 marker CCL17. ABA and Ros synergistically increased PPAR γ activity and pretreatment with a cAMP-inhibitor or a PKA-inhibitor abrogated ABA-induced PPAR γ activation. ABA and Ros act synergistically to modulate PPAR γ activity and macrophage accumulation in WAT and ABA enhances PPAR γ activity through a membrane-initiated mechanism dependent on cAMP/PKA signaling. Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  5. Peroxisome proliferator-activated receptors: bridging metabolic syndrome with molecular nutrition.

    Science.gov (United States)

    Guri, Amir J; Hontecillas, Raquel; Bassaganya-Riera, Josep

    2006-12-01

    Over recent years, obesity rates and the onset of obesity-induced chronic diseases have risen dramatically. The more we learn about the physiological and morphological changes that occur during obesity, the more it is becoming clear that obesity-related disorders can be traced back to adipocyte hypertrophy and inflammation at white adipose tissue (WAT). To combat this problem, the body has developed a regulatory system specifically designed at mediating the systemic response to obesity, utilizing free fatty acids (FFAs) and their metabolites as nutrient messengers to signal adaptations from peripheral tissues. These messages are predominantly interceded through the peroxisome proliferator-activated receptors (PPARs), a family of ligand-induced transcription factors that serve as a net of lipid sensors throughout the body. Understanding how and why nutrients, nutrient derivatives and metabolites exert their physiological effects are the key goals in the study of molecular nutrition. By learning about the mechanisms and tissue-specific effects of endogenous PPAR ligands and expanding our knowledge of the body's integrated homeostatic system, we will significantly increase our odds of designing safe and effective preventive and therapeutic interventions that keep us one step ahead of obesity-related diseases.

  6. Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP3 receptors.

    Science.gov (United States)

    Tunaru, Sorin; Althoff, Till F; Nüsing, Rolf M; Diener, Martin; Offermanns, Stefan

    2012-06-05

    Castor oil is one of the oldest drugs. When given orally, it has a laxative effect and induces labor in pregnant females. The effects of castor oil are mediated by ricinoleic acid, a hydroxylated fatty acid released from castor oil by intestinal lipases. Despite the wide-spread use of castor oil in conventional and folk medicine, the molecular mechanism by which ricinoleic acid acts remains unknown. Here we show that the EP(3) prostanoid receptor is specifically activated by ricinoleic acid and that it mediates the pharmacological effects of castor oil. In mice lacking EP(3) receptors, the laxative effect and the uterus contraction induced via ricinoleic acid are absent. Although a conditional deletion of the EP(3) receptor gene in intestinal epithelial cells did not affect castor oil-induced diarrhea, mice lacking EP(3) receptors only in smooth-muscle cells were unresponsive to this drug. Thus, the castor oil metabolite ricinoleic acid activates intestinal and uterine smooth-muscle cells via EP(3) prostanoid receptors. These findings identify the cellular and molecular mechanism underlying the pharmacological effects of castor oil and indicate a role of the EP(3) receptor as a target to induce laxative effects.

  7. Multiple roles of the prostaglandin D2 signaling pathway in reproduction.

    Science.gov (United States)

    Rossitto, Moïra; Ujjan, Safdar; Poulat, Francis; Boizet-Bonhoure, Brigitte

    2015-01-01

    Prostaglandins signaling molecules are involved in numerous physiological processes. They are produced by several enzyme-limited reactions upon fatty acids, which are catalyzed by two cyclooxygenases and prostaglandin synthases. In particular, the prostaglandins E2 (PGE2), D2 (PGD2), and F2 (PGF2 α) have been shown to be involved in female reproductive mechanisms. Furthermore, widespread expression of lipocalin- and hematopoietic-PGD2 synthases in the male reproductive tract supports the purported roles of PGD2 in the development of both embryonic and adult testes, sperm maturation, and spermatogenesis. In this review, we summarize the putative roles of PGD2 signaling and the roles of both PGD2 synthases in testicular formation and function. We review the data reporting the involvement of PGD2 signaling in the differentiation of Sertoli and germ cells of the embryonic testis. Furthermore, we discuss the roles of lipocalin-PGD2 synthase in steroidogenesis and spermatogenesis, in terms of lipid molecule transport and PGD2 production. Finally, we discuss the hypothesis that PGD2 signaling may be affected in certain reproductive diseases, such as infertility, cryptorchidism, and testicular cancer. © 2015 Society for Reproduction and Fertility.

  8. Maternal docosahexaenoic acid increases adiponectin and normalizes IUGR-induced changes in rat adipose deposition.

    Science.gov (United States)

    Bagley, Heidi N; Wang, Yan; Campbell, Michael S; Yu, Xing; Lane, Robert H; Joss-Moore, Lisa A

    2013-01-01

    Intrauterine growth restriction (IUGR) predisposes to obesity and adipose dysfunction. We previously demonstrated IUGR-induced increased visceral adipose deposition and dysregulated expression of peroxisome proliferator activated receptor- γ 2 (PPAR γ 2) in male adolescent rats, prior to the onset of obesity. In other studies, activation of PPAR γ increases subcutaneous adiponectin expression and normalizes visceral adipose deposition. We hypothesized that maternal supplementation with docosahexaenoic acid (DHA), a PPAR γ agonist, would normalize IUGR adipose deposition in association with increased PPAR γ , adiponectin, and adiponectin receptor expression in subcutaneous adipose. To test these hypotheses, we used a well-characterized model of uteroplacental-insufficiency-(UPI-) induced IUGR in the rat with maternal DHA supplementation. Our primary findings were that maternal DHA supplementation during rat pregnancy and lactation (1) normalizes IUGR-induced changes in adipose deposition and visceral PPAR γ expression in male rats and (2) increases serum adiponectin, as well as adipose expression of adiponectin and adiponectin receptors in former IUGR rats. Our novel findings suggest that maternal DHA supplementation may normalize adipose dysfunction and promote adiponectin-induced improvements in metabolic function in IUGR.

  9. Involvement of prostaglandins and histamine in nickel wire-induced acute inflammation in mice.

    Science.gov (United States)

    Hirasawa, Noriyasu; Goi, Yoshiaki; Tanaka, Rina; Ishihara, Kenji; Ohtsu, Hiroshi; Ohuchi, Kazuo

    2010-06-15

    The irritancy of Nickel (Ni) ions has been well documented clinically. However, the chemical mediators involved in the acute inflammation induced by solid Ni are not fully understood. We used the Ni wire-implantation model in mice and examined roles of prostaglandins and histamine in plasma leakage in the acute phase. The subcutaneous implantation of a Ni wire into the back of mice induced plasma leakage from 8 to 24 h and tissue necrosis around the wire at 3 days, whereas the implantation of an aluminum wire induced no such inflammatory responses. An increase in the mRNA for cyclooxygenase (COX)-2 and HDC in cells around the Ni wire was detected 4 h after the implantation. The leakage of plasma at 8 h was inhibited by indomethacin in a dose-dependent manner. Dexamethasone and the p38 MAP kinase inhibitor SB203580 also inhibited the exudation of plasma consistent with the inhibition of the expression of COX-2 mRNA. Furthermore, plasma leakage was partially but siginificantly reduced in histamine H1 receptor knockout mice and histidine decarboxylase (HDC) knockout mice but not in H2 receptor knockout mice. These results suggested that the Ni ions released from the wire induced the expression of COX-2 and HDC, resulting in an increase in vascular permeability during the acute phase of inflammation. (c) 2009 Wiley Periodicals, Inc.

  10. Effect of synthetic prostaglandin E1 analog on gastric emptying of meals in man.

    Science.gov (United States)

    Moore, J G; Alazraki, N; Clay, G D

    1986-01-01

    Forty-five subjects with healed duodenal ulcer were administered either a placebo or a low-dose or high-dose regimen of misoprostol, a synthetic PGE1 analog, in a double-blind, random, parallel-group design to assess the effect of this prostaglandin compound on the gastric emptying of liquid-solid meals. A dual-radionuclide technique to measure liquid- and solid-phase gastric emptying rates of physiological meals by external gamma camera imaging was used. All subjects had a pretreatment control (baseline) evaluation, followed one week later by a treatment-influenced emptying study. The results demonstrated that misoprostol did not significantly alter gastric emptying of either liquids or solids; however, these results cannot be extrapolated to other prostaglandin compounds because of the diverse and sometimes paradoxical effects of different prostaglandins on gastric motility.

  11. 9-Hydroxyprostaglandin dehydrogenase in rat kidney cortex converts prostaglandin I2 into 15-keto-13,14-dihydro 6-ketoprostaglandin E1.

    Science.gov (United States)

    Pace-Asciak, C R; Domazet, Z

    1984-11-14

    15-Keto-13,14-dihydro 6-ketoprostaglandin E1 was positively identified by gas chromatography-mass spectrometry with negative-ion chemical ionisation detection from samples of rat kidney high-speed supernatant incubated with prostaglandin I2 in the presence of NAD+. A decreased formation of this product was observed when NAD+ was substituted with NADP+ and none was observed in the absence of nucleotide or substrate prostaglandin I2. Experiments with [9 beta-3H]prostaglandin I2 showed a time- and concentration-dependent loss of tritium which appeared as tritiated water, typical of reaction of [9 beta-3H]prostaglandin substrates with the enzyme, 9-hydroxyprostaglandin dehydrogenase. Time-course measurements of the appearance of tritiated water showed similar rates with 6-keto[9 beta-3H]prostaglandin F1 alpha and 15-keto-13,14-dihydro 6-keto[9 beta-3H]prostaglandin F1 alpha as substrates. These experiments suggest that the transformation of prostaglandin I2 and 6-ketoprostaglandin F1 alpha into the 15-keto-13,14-dihydro 6-ketoprostaglandin E1 catabolite occurs in this in vitro preparation via the corresponding 15-keto-13,14-dihydro catabolite of 6-ketoprostaglandin F1 alpha.

  12. Effects of L-carnitine against oxidative stress in human hepatocytes: involvement of peroxisome proliferator-activated receptor alpha

    Directory of Open Access Journals (Sweden)

    Li Jin-Lian

    2012-03-01

    Full Text Available Abstract Background Excessive oxidative stress and lipid peroxidation have been demonstrated to play important roles in the production of liver damage. L-carnitine is a natural substance and acts as a carrier for fatty acids across the inner mitochondrial membrane for subsequent beta-oxidation. It is also an antioxidant that reduces metabolic stress in the cells. Recent years L-carnitine has been proposed for treatment of various kinds of disease, including liver injury. This study was conducted to evaluate the protective effect of L-carnitine against hydrogen peroxide (H2O2-induced cytotoxicity in a normal human hepatocyte cell line, HL7702. Methods We analyzed cytotoxicity using MTT assay and lactate dehydrogenase (LDH release. Antioxidant activity and lipid peroxidation were estimated by reactive oxygen species (ROS levels, activities and protein expressions of superoxide dismutase (SOD and catalase (CAT, and malondialdehyde (MDA formation. Expressions of peroxisome proliferator-activated receptor (PPAR-alpha and its target genes were evaluated by RT-PCR or western blotting. The role of PPAR-alpha in L-carnitine-enhanced expression of SOD and CAT was also explored. Statistical analysis was performed by a one-way analysis of variance, and its significance was assessed by Dennett's post-hoc test. Results The results showed that L-carnitine protected HL7702 cells against cytotoxity induced by H2O2. This protection was related to the scavenging of ROS, the promotion of SOD and CAT activity and expression, and the prevention of lipid peroxidation in cultured HL7702 cells. The decreased expressions of PPAR-alpha, carnitine palmitoyl transferase 1 (CPT1 and acyl-CoA oxidase (ACOX induced by H2O2 can be attenuated by L-carnitine. Besides, we also found that the promotion of SOD and CAT protein expression induced by L-carnitine was blocked by PPAR-alpha inhibitor MK886. Conclusions Taken together, our findings suggest that L-carnitine could protect HL

  13. Inhibition of prostaglandin synthesis after metabolism of menadione by cultured porcine endothelial cells.

    OpenAIRE

    Barchowsky, A; Tabrizi, K; Kent, R S; Whorton, A R

    1989-01-01

    We have examined the effects of menadione on porcine aortic endothelial cell prostaglandin synthesis. Addition of 1-20 microM menadione caused a dose- and time-dependent inhibition of stimulated prostaglandin synthesis with an IC50 of 5 microM at 15 min. Concentrations greater than 100 microM menadione were necessary to increase 51Cr release from prelabeled cells. Recovery of enzyme inactivated by menadione required a 6-h incubation in 1% serum. In a microsomal preparation, menadione was show...

  14. Doenjang, a Korean fermented soy food, exerts antiobesity and antioxidative activities in overweight subjects with the PPAR-γ2 C1431T polymorphism: 12-week, double-blind randomized clinical trial.

    Science.gov (United States)

    Cha, Youn-Soo; Park, Yongsoon; Lee, Myoungsook; Chae, Soo-Wan; Park, Kungmin; Kim, Yeonsoo; Lee, Haeng-Shin

    2014-01-01

    We examined the antiobesity and antioxidant effects of supplementation with doenjang, a fermented soybean paste, in overweight Koreans with the PPAR-γ2 C1431T polymorphism. Sixty overweight subjects were randomly assigned to consume either 9.8 g/day of doenjang or placebo for 12 weeks. Before and after the intervention, anthropometric and metabolic parameters, along with abdominal fat distribution and PPAR-γ2 polymorphisms, were measured. Fifty-one subjects completed the study, doenjang (n=26) and placebo (n=25) groups. Relative frequencies of the PPAR-γ2 genotypes CC, TC, and TT were 70% (n=41), 25.9% (15), and 3.4% (2), whereas those of the PPAR-γ2 alleles C and T were 81.6% and 18.4%. Visceral fat area (VFA) was significantly decreased by doenjang supplementation in subjects with a mutant T allele of PPAR-γ2 compared to those with a C allele after adjusting for age, sex, and body mass index. Plasma free fatty acid, insulin, and homeostatic model assessment insulin resistance (HOMA-IR) levels were also significantly increased in the doenjang group. Doenjang pills significantly activated radical clearance capacity (ORAC and DNA tail length) in subjects with the C allele. The catalase (CAT) activity was increased twofold in the doenjang-treated group with the C allele, but this phenomenon was reversed in those with the T allele. Doenjang-treated subjects tended to have low dietary carbohydrate and sodium intakes compared with those given placebo. We found that doenjang supplementation decreased visceral fat accumulation and aging most effectively in subjects with PPAR-γ polymorphisms. This study suggests that doenjang has antiobesity and antioxidative effects in overweight individuals with mutant alleles of PPAR-γ2.

  15. Efficacy of peroxisome proliferator activated receptor agonist in the treatment of virus-associated haemophagocytic syndrome in a rabbit model.

    Science.gov (United States)

    Hsieh, Wen-Chuan; Lan, Bau-Shin; Chen, Yi-Ling; Chang, Yao; Chuang, Huai-Chia; Su, Ih-Jen

    2010-01-01

    Virus-associated haemophagocytic syndrome (VAHS) is a fatal complication of viral infections, such as Epstein-Barr virus and H5N1 influenza, that results from macrophage activation and pro inflammatory cytokine injuries. The high comorbidity and mortality of current therapy urgently demands an ideal agent based on VAHS pathogenesis. Peroxisome proliferator activated receptor (PPAR) agonists, regulators of metabolic syndrome, can exhibit immunomodulatory effects on macrophage activation and cytokine secretion. In this study, we adopted rosiglitazone, a PPAR-gamma agonist, for VAHS control in a Herpesvirus papio (HVP)-infected rabbit model. Various doses of rosiglitazone were orally administered to rabbits on day 7 or day 20 after intravenous challenge with 5 x 10(7) copies of HVP. The rabbits that received 4 mg/day rosiglitazone had significantly increased survival when treated at an early stage of infection (P<0.01), whereas a higher dose (8 mg/day) was required at the advanced stage of the disease (P<0.05). All rosiglitazone-treated rabbits had significantly improved laboratory parameters and plasma tumour necrosis factor-alpha levels. Importantly, rosiglitazone could also inhibit viral replication in vitro and in vivo. PPAR agonists could represent a potentially new agent for the therapy of VAHS.

  16. Prostaglandin-associated periorbitopathy in latanoprost users

    Directory of Open Access Journals (Sweden)

    Nakakura S

    2014-12-01

    Full Text Available Shunsuke Nakakura,1 Minamai Yamamoto,1 Etsuko Terao,1 Nozomi Nagatomi,1 Naoko Matsuo,1 Yausko Fujisawa,1 Yuki Fujio,1 Hitoshi Tabuchi,1 Yoshiaki Kiuchi2 1Department of Ophthalmology, Saneikai Tsukazaki Hospital, Himeji, Japan; 2Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan Purpose: We investigated the incidence of prostaglandin-associated periorbitopathy (PAP in subjects with glaucoma treated with latanoprost ophthalmic solution.Subjects and methods: One eye and the forehead in 22 subjects were evaluated. All patients had used latanoprost for more than 1 year (range, 12 to 45 months; mean, 26.0 months and were prostaglandin F2α analogue treatment-naïve. Digital photographs of the subjects obtained before latanoprost therapy and at the last examination were compared retrospectively. Four signs of PAP (deepening of the upper eyelid sulcus (DUES, upper eyelid ptosis, flattening of the lower eyelid bags, and inferior scleral show and supplemental side effects around the eyelids (eyelash growth, poliosis, and eyelid pigmentation were judged to be negative or positive by three independent observers. If the observers unanimously rated a sign as positive, the result was defined as positive.Results: Twelve subjects (54.5% had no apparent signs. Three subjects were judged to have DUES (13.6%, and two subjects each were judged to have flattening of the lower eyelid bags and eyelid pigmentation (9.0%. The other signs were judged as positive in only one subject each, respectively (4.5%. A univariate logistic regression analysis showed no significant associations between any of the signs and age, sex, or the duration of therapy.Conclusion: Latanoprost induced DUES, upper eyelid ptosis, flattening of the lower eyelid bags, inferior scleral show, and supplemental side effects around the eyelids; however, the rates of such occurrence might be relatively low. Keywords: glaucoma

  17. Vasoactive receptors in abdominal blood vessels of the dogfish shark, Squalus acanthias.

    Science.gov (United States)

    Evans, D H

    2001-01-01

    Previous studies have demonstrated that the ventral aorta of the dogfish shark, Squalus acanthias, responds to a variety of cell-signaling agents. To investigate the generality of vasoactive receptors in the shark vasculature, in particular a conductance artery (anterior mesenteric) and vein (posterior intestinal), I measured the effect of acetylcholine, endothelin, nitric oxide, natriuretic peptides, and prostaglandins on tension in isolated rings from these vessels. Both vessels responded to these agents, and responses to receptor-specific ligands for endothelin and natriuretic peptide receptors suggest that B-type endothelin receptors are expressed in both vessels and that the artery expresses both A- and B-type natriuretic peptide receptors; however, the vein (like the ventral aorta) expresses only the B-type natriuretic peptide receptor. My data suggest that a suite of signaling systems is ubiquitous in both arteries and veins in at least this elasmobranch species. Their role in hemodynamics and osmoregulation (perfusion of gill and rectal gland) remains to be determined.

  18. Inhibition of Nitric Oxide and Prostaglandin E 2 Expression by ...

    African Journals Online (AJOL)

    Inhibition of Nitric Oxide and Prostaglandin E 2 Expression by Methanol Extract of Polyopes affinis in Lipopolysaccharide-stimulated BV2 Microglial Cells through Suppression of Akt-dependent NF-kB Activity and MAPK Pathway.

  19. Enzymatic synthesis of tritium-labelled prostaglandin D2 and its conversion to other prostaglandins

    International Nuclear Information System (INIS)

    Shram, S.I.; Lazurkina, T.Yu.; Shevchenko, V.P.; Nagaev, I.Yu.; Myasoedov, N.F.

    1994-01-01

    The one-stage enzymatic synthesis of tritium-labelled prostaglandin D 2 from labelled arachidonic acid was performed by using the enzyme system PGH-synthetase/PGH-PGD-isomerase. By enzymatic and chemical transformation of [ 3 H]PGD 2 the following compounds were obtained: 15-keto-13,14-dihydro-[ 3 H]PGD 2 , 9α,11β-[ 3 H]PGF 2 , 9-deoxy-Δ 9 -[ 3 H]-PGD 2 ([ 3 H]PGJ 2 ) and Δ 12 -13,14-dihydro-[ 3 H]PGJ 2 . It was found that L-selectride is a more effective reducing agent than sodium borohydride in the synthesis of 9α, 11β-[ 3 H]PGF 2 . (Author)

  20. Improvement in the quality of hematopoietic prostaglandin D synthase crystals in a microgravity environment

    International Nuclear Information System (INIS)

    Tanaka, Hiroaki; Tsurumura, Toshiharu; Aritake, Kosuke; Furubayashi, Naoki; Takahashi, Sachiko; Yamanaka, Mari; Hirota, Erika; Sano, Satoshi; Sato, Masaru; Kobayashi, Tomoyuki; Tanaka, Tetsuo; Inaka, Koji; Urade, Yoshihiro

    2011-01-01

    Crystals of hematopoietic prostaglandin D synthase grown in microgravity show improved quality. Human hematopoietic prostaglandin synthase, one of the better therapeutic target enzymes for allergy and inflammation, was crystallized with 22 inhibitors and in three inhibitor-free conditions in microgravity. Most of the space-grown crystals showed better X-ray diffraction patterns than the terrestrially grown ones, indicating the advantage of a microgravity environment on protein crystallization, especially in the case of this protein