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Sample records for noradrenaline represses ppar

  1. Noradrenaline represses PPAR (peroxisome-proliferator-activated receptor) gamma2 gene expression in brown adipocytes: intracellular signalling and effects on PPARgamma2 and PPARgamma1 protein levels

    DEFF Research Database (Denmark)

    Lindgren, Eva M; Nielsen, Ronni; Petrovic, Natasa

    2004-01-01

    PPAR (peroxisome-proliferator-activated receptor) gamma is expressed in brown and white adipose tissues and is involved in the control of differentiation and proliferation. Noradrenaline stimulates brown pre-adipocyte proliferation and brown adipocyte differentiation. The aim of the present study...

  2. PPARs

    DEFF Research Database (Denmark)

    Poulsen, Lars la Cour; Siersbæk, Majken; Mandrup, Susanne

    2012-01-01

    The peroxisome proliferator activated receptors (PPARs) are nuclear receptors that play key roles in the regulation of lipid metabolism, inflammation, cellular growth, and differentiation. The receptors bind and are activated by a broad range of fatty acids and fatty acid derivatives...

  3. PPARs: history and advances.

    Science.gov (United States)

    Youssef, Jihan; Badr, Mostafa Z

    2013-01-01

    Peroxisome proliferator-activated receptors (PPARs) are members of the steroid hormone receptor superfamily, discovered in 1990. To date, three PPAR subtypes have been identified; PPARα, PPAR β/δ, and PPARγ. These receptors share a high degree of homology but differ in tissue distribution and ligand specificity. PPARs have been implicated in the etiology as well as treatment of several important diseases and pathological conditions such as diabetes, inflammation, senescence-related diseases, regulation of fertility, and various types of cancer. Consequently, significant efforts to discover novel PPAR roles and delineate molecular mechanisms involved in their activation and repression as well as develop safer and more effective PPAR modulators, as therapeutic agents to treat a myriad of diseases and conditions, are underway. This volume of Methods in Molecular Biology contains details of experimental protocols used in researching these receptors.

  4. PPAR-γ ligands repress TGFβ-induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis.

    Directory of Open Access Journals (Sweden)

    Ajit A Kulkarni

    Full Text Available Transforming growth factor beta (TGFβ induced differentiation of human lung fibroblasts to myofibroblasts is a key event in the pathogenesis of pulmonary fibrosis. Although the typical TGFβ signaling pathway involves the Smad family of transcription factors, we have previously reported that peroxisome proliferator-activated receptor-γ (PPAR-γ ligands inhibit TGFβ-mediated differentiation of human lung fibroblasts to myofibroblasts via a Smad-independent pathway. TGFβ also activates the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt pathway leading to phosphorylation of Akt(S473. Here, we report that PPAR-γ ligands, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO and 15-deoxy-(12,14-15d-prostaglandin J(2 (15d-PGJ(2, inhibit human myofibroblast differentiation of normal and idiopathic pulmonary fibrotic (IPF fibroblasts, by blocking Akt phosphorylation at Ser473 by a PPAR-γ-independent mechanism. The PI3K inhibitor LY294002 and a dominant-negative inactive kinase-domain mutant of Akt both inhibited TGFβ-stimulated myofibroblast differentiation, as determined by Western blotting for α-smooth muscle actin and calponin. Prostaglandin A(1 (PGA(1, a structural analogue of 15d-PGJ(2 with an electrophilic center, also reduced TGFβ-driven phosphorylation of Akt, while CAY10410, another analogue that lacks an electrophilic center, did not; implying that the activity of 15d-PGJ(2 and CDDO is dependent on their electrophilic properties. PPAR-γ ligands inhibited TGFβ-induced Akt phosphorylation via both post-translational and post-transcriptional mechanisms. This inhibition is independent of MAPK-p38 and PTEN but is dependent on TGFβ-induced phosphorylation of FAK, a kinase that acts upstream of Akt. Thus, PPAR-γ ligands inhibit TGFβ signaling by affecting two pro-survival pathways that culminate in myofibroblast differentiation. Further studies of PPAR-γ ligands and small electrophilic molecules may lead to a new generation of

  5. Noradrenaline and Parkinson's disease

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    Claire eDelaville

    2011-05-01

    Full Text Available Parkinson’s disease (PD is characterized by the degeneration of dopamine (DA neurons in the substantia nigra pars compacta, and motor symptoms including bradykinesia, rigidity and tremor at rest. These symptoms are manifest when around 70% of striatal DA is lost. In addition to motor deficits, PD is also characterized by the manifestation of non-motor symptoms. However, depletion of DA alone in animal models has failed to simultaneously elicit both the motor and non-motor deficits of PD because the disease is a multi-system disorder that features a profound loss of other neurotransmitter systems. There is growing evidence that additional loss of noradrenaline (NA neurons of the locus coeruleus, the principal source of NA in the brain, could be involved in the clinical expression of motor as well as in non-motor deficits. In the present review, we analyzed the latest data obtained from animal models of parkinsonism and from parkinsonian patients providing evidence for the implication of NA in the pathophysiology of PD. Recent studies have shown that NA depletion alone or combined with DA depletion resulted in motor as well as in non-motor dysfunctions. In addition, by using selective agonists and antagonists of alpha receptors we, and others, have shown that α2 receptors are implicated in the control of motor activity and that α2 receptor antagonists can improve PD motor symptoms as well as L-Dopa-induced dyskinesia. Here we provide arguments that the loss of NA neurons in PD has an impact on all PD symptoms and that the association of NAergic agents to dopaminergic medication can be beneficial in the treatment of the disease.

  6. Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation.

    Science.gov (United States)

    Wang, Chenguang; Pattabiraman, Nagarajan; Zhou, Jian Nian; Fu, Maofu; Sakamaki, Toshiyuki; Albanese, Chris; Li, Zhiping; Wu, Kongming; Hulit, James; Neumeister, Peter; Novikoff, Phyllis M; Brownlee, Michael; Scherer, Philipp E; Jones, Joan G; Whitney, Kathleen D; Donehower, Lawrence A; Harris, Emily L; Rohan, Thomas; Johns, David C; Pestell, Richard G

    2003-09-01

    The cyclin D1 gene is overexpressed in human breast cancers and is required for oncogene-induced tumorigenesis. Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPAR gamma induces hepatic steatosis, and liganded PPAR gamma promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPAR gamma function, transactivation, expression, and promoter activity. PPAR gamma transactivation induced by the ligand BRL49653 was inhibited by cyclin D1 through a pRB- and cdk-independent mechanism, requiring a region predicted to form an helix-loop-helix (HLH) structure. The cyclin D1 HLH region was also required for repression of the PPAR gamma ligand-binding domain linked to a heterologous DNA binding domain. Adipocyte differentiation by PPAR gamma-specific ligands (BRL49653, troglitazone) was enhanced in cyclin D1(-/-) fibroblasts and reversed by retroviral expression of cyclin D1. Homozygous deletion of the cyclin D1 gene, enhanced expression by PPAR gamma ligands of PPAR gamma and PPAR gamma-responsive genes, and cyclin D1(-/-) mice exhibit hepatic steatosis. Finally, reduction of cyclin D1 abundance in vivo using ponasterone-inducible cyclin D1 antisense transgenic mice, increased expression of PPAR gamma in vivo. The inhibition of PPAR gamma function by cyclin D1 is a new mechanism of signal transduction cross talk between PPAR gamma ligands and mitogenic signals that induce cyclin D1.

  7. Pulmonary extraction of circulating noradrenaline in man

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Christensen, N J; Ring-Larsen, H

    1986-01-01

    Pulmonary plasma kinetics of endogenous noradrenaline (NA) and tritium labelled L-noradrenaline (3H-NA) was studied in fifteen subjects during pulmonary arterial catheterization. Plasma NA concentration in femoral artery ranged from 0.5 to 8.2 nmol l-1, mean 2.3 nmol l-1, which was not significan...

  8. Do sympathetic nerves release noradrenaline in "quanta"?

    Science.gov (United States)

    Stjärne, L

    2000-07-01

    The discovery of excitatory junction potentials (EJPs) in guinea-pig vas deferens by Burnstock and Holman (1960) showed for the first time that a sympathetic transmitter, now known to be ATP, is secreted in "quanta". As it was assumed at the time that EJPS are triggered by noradrenaline, this discovery led to attempts to use the fractional overflow of noradrenaline from sympathetically innervated tissues to assess, indirectly, the number of noradrenaline molecules in the average "quantum". The basic finding was that each pulse released 1/50000 of the tissue content of noradrenaline, when reuptake was blocked and prejunctional alpha(2)-adrenoceptors were intact. This provided the constraints, two extreme alternatives: (i) each pulse releases 0.2-3% of the content of a vesicle from all varicosities, or (ii) each pulse releases the whole content of a vesicle from 0.2 to 3% of the varicosities. New techniques have made it possible to address questions about the release probability in individual sites, or the "quantal" size, more directly. Results by optical (comparison of the labelling of SV2 and synaptotagmin, proteins in the membrane of transmitter vesicles), electrophysiological (excitatory junction currents, EJCs, at single visualized varicosities) and amperometric (the noradrenaline oxidation current at a carbon fibre electrode) methods reveal that transmitter exocytosis in varicosities is intermittent. The EJC and noradrenaline oxidation current responses (in rat arteries) to a train of single pulses were observed to be similar in intermittency and amplitude fluctuation. This suggests that they are caused by exocytosis of single or very few "quanta" of ATP and noradrenaline, respectively, equal to the contents of single vesicles, from a small population of release sites. These findings support, but do not conclusively prove the validity of the "intermittent" model of noradrenaline release. The question if noradrenaline is always secreted in packets of preset size

  9. Repressive Tolerance

    DEFF Research Database (Denmark)

    Pedersen, Morten Jarlbæk

    2016-01-01

    to an administrative culture of repressive tolerance of organised interests: authorities listen but only reacts in a very limited sense. This bears in it the risk of jeopardising the knowledge transfer from societal actors to administrative ditto thus harming the consultation institutions’ potential for strengthening...

  10. 3-Hydroxybutyrate coinfused with noradrenaline decreases resulting plasma levels of noradrenaline in Wistar rats

    OpenAIRE

    Cañas, X.; Sanchis, D.; Gómez, G.; Casanovas, J.M.; Artigas Pérez, Francesc; Fernández López, José Antonio; Remesar Betlloch, Xavier; Alemany, Marià

    1997-01-01

    Pentobarbital-anaesthetized male Wistar rats were infused with 6microgkg-1min-1 of noradrenaline. The infusion was supplemented with 8.5 mgkg-1min-1 of D-3-hydroxybutyrate (3-OHB) for 15 min in order to determine its effect on the adrenergic response of the rat. Plasma levels of noradrenaline rose to a plateau of approximately 50 nmoll-1 with infusion. In the group infused with noradrenaline alone, noradrenaline levels were maintained for 1h. Supplementation with 3-OHB induced a decrease in p...

  11. 3-Hydroxybutyrate co-infused with noradrenaline decreases resulting plasma levels of noradrenaline in Wistar rats

    OpenAIRE

    Cañas, Xavier; Sanchís, Daniel; Gómez, Gloria; Casanovas, Josep M.; Artigas, Francesc; Fernández-López, José Antonio; Remesar, Xavier; Alemany, Marià

    1997-01-01

    Pentobarbital-anaesthetized male Wistar rats were infused with 6microgkg-1min-1 of noradrenaline. The infusion was supplemented with 8.5 mgkg-1min-1 of D-3-hydroxybutyrate (3-OHB) for 15 min in order to determine its effect on the adrenergic response of the rat. Plasma levels of noradrenaline rose to a plateau of approximately 50 nmoll-1 with infusion. In the group infused with noradrenaline alone, noradrenaline levels were maintained for 1h. Supplementation with 3-OHB induced a decrease in p...

  12. PPAR{alpha} does not suppress muscle-associated gene expression in brown adipocytes but does influence expression of factors that fingerprint the brown adipocyte

    Energy Technology Data Exchange (ETDEWEB)

    Walden, Tomas B.; Petrovic, Natasa [The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm (Sweden); Nedergaard, Jan, E-mail: jan@metabol.su.se [The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm (Sweden)

    2010-06-25

    Brown adipocytes and myocytes develop from a common adipomyocyte precursor. PPAR{alpha} is a nuclear receptor important for lipid and glucose metabolism. It has been suggested that in brown adipose tissue, PPAR{alpha} represses the expression of muscle-associated genes, in this way potentially acting to determine cell fate in brown adipocytes. To further understand the possible role of PPAR{alpha} in these processes, we measured expression of muscle-associated genes in brown adipose tissue and brown adipocytes from PPAR{alpha}-ablated mice, including structural genes (Mylpf, Tpm2, Myl3 and MyHC), regulatory genes (myogenin, Myf5 and MyoD) and a myomir (miR-206). However, in our hands, the expression of these genes was not influenced by the presence or absence of PPAR{alpha}, nor by the PPAR{alpha} activator Wy-14,643. Similarly, the expression of genes common for mature brown adipocyte and myocytes (Tbx15, Meox2) were not affected. However, the brown adipocyte-specific regulatory genes Zic1, Lhx8 and Prdm16 were affected by PPAR{alpha}. Thus, it would not seem that PPAR{alpha} represses muscle-associated genes, but PPAR{alpha} may still play a role in the regulation of the bifurcation of the adipomyocyte precursor into a brown adipocyte or myocyte phenotype.

  13. Dopamine versus noradrenaline in septic shock

    Directory of Open Access Journals (Sweden)

    Bo Xu

    2011-10-01

    Full Text Available BackgroundThe ‘Surviving Sepsis’ Campaign guidelines recommend theuse of dopamine or noradrenaline as the first vasopressor inseptic shock. However, information that guides clinicians inchoosing between dopamine and noradrenaline as the firstvasopressor in patients with septic shock is limited.ObjectiveThis article presents a review of the literature regarding theuse of dopamine versus noradrenaline in patients with septicshock.ResultsTwo randomised controlled trials (RCT and two largeprospective cohort studies were analysed. RCT data showeddopamine was associated with increased arrhythmic events.One cohort study found dopamine was associated with higher30-day mortality. The other cohort study found noradrenalinewas associated with higher 28-day mortality.DiscussionData on the use of dopamine versus noradrenaline in patientswith septic shock is limited. Following the recent SOAP IIstudy, there is now strong evidence that the use of dopaminein septic shock is associated with significantly morecardiovascular adverse events, compared tonoradrenaline.ConclusionNoradrenaline should be used as the initial vasopressor inseptic shock to avoid the arrhythmic events associatedwith dopamine.

  14. [Pathophysiological relevance of peroxisome proliferators activated receptors (PPAR) to joint diseases - the pro and con of agonists].

    Science.gov (United States)

    Jouzeau, Jean-Yves; Moulin, David; Koufany, Meriem; Sebillaud, Sylvie; Bianchi, Arnaud; Netter, Patrick

    2008-01-01

    Peroxisome proliferators activated receptors (PPAR) are ligand-inducible nuclear transacting factors comprising three subtypes, PPARalpha, PPARbeta/delta and PPARgamma, which play a key role in lipids and glucose homeostasis. All PPAR subtypes have been identified in joint or inflammatory cells and their activation resulted in a transcriptional repression of pro-inflammatory cytokines (IL-1, TNFalpha), early inflammatory genes (NOS(2), COX-2, mPGES-1) or matrix metalloproteases (MMP-1, MMP-13), at least for the gamma subtype. PPAR full agonists were also shown to stimulate IL-1 receptor antagonist (IL-1Ra) production by cytokine-stimulated articular cells in a subtype-dependent manner. These anti-inflammatory and anti-catabolic properties were confirmed in animal models of joint diseases where PPAR agonists reduced synovial inflammation while preventing cartilage destruction or inflammatory bone loss, although many effects required much higher doses than needed to restore insulin sensitivity or to lower circulating lipid levels. However, these promising effects of PPAR full agonists were hampered by their ability to reduce the growth factor-dependent synthesis of extracellular matrix components or to induce chondrocyte apoptosis, by the possible contribution of immunosuppressive properties to their anti-arthritic effects, by the increased adipocyte differentiation secondary to prolonged stimulation of PPARgamma, and by a variable contribution of PPAR subtypes depending on the system. Clinical data are scarce in rheumatoid arthritis (RA) patients whereas thousands of patients worldwilde, treated with PPAR agonists for type 2 diabetes or dyslipidemia, are paradoxically prone to suffer from osteoarthritis (OA). Whereas high dosage of full agonists may expose RA patients to cardiovascular adverse effects, the proof of concept that PPAR agonists have therapeutical relevance to OA may benefit from an epidemiological follow-up of joint lesions in diabetic or

  15. Regulation of miR-200c by nuclear receptors PPAR{alpha}, LRH-1 and SHP

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    Zhang, Yuxia; Yang, Zhihong [Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132 (United States); Department of Oncological Science, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132 (United States); Whitby, Richard [Department of Chemistry, University of Southampton, Southampton, Hants SO17 1BJ (United Kingdom); Wang, Li, E-mail: l.wang@hsc.utah.edu [Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132 (United States); Department of Oncological Science, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132 (United States)

    2011-12-09

    Highlights: Black-Right-Pointing-Pointer Knockdown of PPAR{alpha} and LRH-1 abolishes miR-200c inhibition of HCC cell migration. Black-Right-Pointing-Pointer SHP represses miR-200c expression via inhibition of the activity of PPAR{alpha} and LRH-1. Black-Right-Pointing-Pointer RJW100 exhibits strong ability to downregulate ZEB1 and ZEB2 proteins. -- Abstract: We investigated regulation of miR-200c expression by nuclear receptors. Ectopic expression of miR-200c inhibited MHCC97H cell migration, which was abrogated by the synergistic effects of PPAR{alpha} and LRH-1 siRNAs. The expression of miR-200c was decreased by PPAR{alpha}/LRH-1 siRNAs and increased by SHP siRNAs, and overexpression of the receptors reversed the effects of their respective siRNAs. SHP siRNAs also drastically enhanced the ability of the LRH-1 agonist RJW100 to induce miR-200c and downregulate ZEB1 and ZEB2 proteins. Co-expression of PPAR{alpha} and LRH-1 moderately transactivated the miR-200c promoter, which was repressed by SHP co-expression. RJW100 caused strong activation of the miR-200c promoter. This is the first report to demonstrate that miR-200c expression is controlled by nuclear receptors.

  16. Control of noradrenaline release from hippocampal synaptosomes

    Energy Technology Data Exchange (ETDEWEB)

    West, D.P.; Fillenz, M.

    1981-10-01

    Potassium-evoked tritiated noradrenaline (NA) release from hippocampal synaptosomes was measured with a superfusion method. A single 2-min high-K+ pulse released 39% of the vesicular NA by a Ca2+-dependent mechanism: the Ca2+-independent release was negligible. After changing the vesicular NA store size by pretreating rats with either alpha-methyl-para-tyrosine, 500 mg/kg, or tranylcypromine, 10 mg/kg, a single K+ pulse released a constant percentage of the vesicular NA. With two K+ pulses, however, there was a reduction in the percentage of vesicular NA released in response to the second pulse.

  17. The liver-enriched transcription factor CREBH is nutritionally regulated and activated by fatty acids and PPAR{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Danno, Hirosuke; Ishii, Kiyo-aki; Nakagawa, Yoshimi; Mikami, Motoki; Yamamoto, Takashi; Yabe, Sachiko; Furusawa, Mika; Kumadaki, Shin; Watanabe, Kazuhisa; Shimizu, Hidehisa; Matsuzaka, Takashi; Kobayashi, Kazuto; Takahashi, Akimitsu; Yatoh, Shigeru; Suzuki, Hiroaki; Yamada, Nobuhiro [Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba Ibaraki 305-8575 (Japan); Shimano, Hitoshi, E-mail: hshimano@md.tsukuba.ac.jp [Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba Ibaraki 305-8575 (Japan)

    2010-01-08

    To elucidate the physiological role of CREBH, the hepatic mRNA and protein levels of CREBH were estimated in various feeding states of wild and obesity mice. In the fast state, the expression of CREBH mRNA and nuclear protein were high and profoundly suppressed by refeeding in the wild-type mice. In ob/ob mice, the refeeding suppression was impaired. The diet studies suggested that CREBH expression was activated by fatty acids. CREBH mRNA levels in the mouse primary hepatocytes were elevated by addition of the palmitate, oleate and eicosapenonate. It was also induced by PPAR{alpha} agonist and repressed by PPAR{alpha} antagonist. Luciferase reporter gene assays indicated that the CREBH promoter activity was induced by fatty acids and co-expression of PPAR{alpha}. Deletion studies identified the PPRE for PPAR{alpha} activation. Electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) assay confirmed that PPAR{alpha} directly binds to the PPRE. Activation of CREBH at fasting through fatty acids and PPAR{alpha} suggest that CREBH is involved in nutritional regulation.

  18. Noradrenaline: Central inhibitory control of blood pressure and heart rate

    NARCIS (Netherlands)

    Jong, Wybren de

    Noradrenaline injected bilaterally into the brainstem in the area of the nucleus tractus solitarii decreased systemic arterial blood pressure and heart rate of anesthetized rats. The effect of noradrenaline was prevented by a preceding injection of the α-adrenergic blocking agent phentolamine, at

  19. Noradrenaline: Central inhibitory control of blood pressure and heart rate

    NARCIS (Netherlands)

    Jong, Wybren de

    1974-01-01

    Noradrenaline injected bilaterally into the brainstem in the area of the nucleus tractus solitarii decreased systemic arterial blood pressure and heart rate of anesthetized rats. The effect of noradrenaline was prevented by a preceding injection of the α-adrenergic blocking agent phentolamine, at th

  20. Peroxisome proliferator-activated receptors (PPARs) and PPAR agonists: the 'future' in dermatology therapeutics?

    Science.gov (United States)

    Gupta, Mrinal; Mahajan, Vikram K; Mehta, Karaninder S; Chauhan, Pushpinder S; Rawat, Ritu

    2015-11-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors and comprise three different isoforms namely PPARα, PPARγ, and PPARβ/δ with PPARβ/δ being the predominant subtype in human keratinocytes. After binding with specific ligands, PPARs regulate gene expression, cell growth and differentiation, apoptosis, inflammatory responses, and tumorogenesis. PPARs also modulate a wide variety of skin functions including keratinocyte proliferation, epidermal barrier formation, wound healing, melanocyte proliferation, and sebum production. Recent studies have shown the importance of PPARs in the pathogenesis of many dermatological disorders. Clinical trials have suggested possible role of PPAR agonists in the management of various dermatoses ranging from acne vulgaris, psoriasis, hirsutism, and lipodystrophy to cutaneous malignancies including melanoma. This article is intended to be a primer for dermatologists in their understanding of clinical relevance of PPARs and PPAR agonists in dermatology therapeutics.

  1. PPAR Agonists and Cardiovascular Disease in Diabetes

    Directory of Open Access Journals (Sweden)

    Anna C. Calkin

    2008-01-01

    Full Text Available Peroxisome proliferators activated receptors (PPARs are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPAR agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPAR agonists, and more recently dual PPAR/ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPAR receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.

  2. Nutrigenomic Functions of PPARs in Obesogenic Environments

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    Chung, Soonkyu; Kim, Young Jun

    2016-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that mediate the effects of several nutrients or drugs through transcriptional regulation of their target genes in obesogenic environments. This review consists of three parts. First, we summarize current knowledge regarding the role of PPARs in governing the development of white and brown/beige adipocytes from uncommitted progenitor cells. Next, we discuss the interactions of dietary bioactive molecules, such as fatty acids and phytochemicals, with PPARs for the modulation of PPAR-dependent transcriptional activities and metabolic consequences. Lastly, the effects of PPAR polymorphism on obesity and metabolic outcomes are discussed. In this review, we aim to highlight the critical role of PPARs in the modulation of adiposity and subsequent metabolic adaptation in response to dietary challenges and genetic modifications. Understanding the changes in obesogenic environments as a consequence of PPARs/nutrient interactions may help expand the field of individualized nutrition to prevent obesity and obesity-associated metabolic comorbidities. PMID:28042289

  3. A gut feeling of the PXR, PPAR and NF-kappaB connection.

    Science.gov (United States)

    Wahli, W

    2008-06-01

    Bowel diseases reveal the complex interplay of sensing and signalling pathways in maintaining healthy homeostasis of the intestine. Recent studies of the xenobiotic nuclear receptor, pregnane X receptor and the inflammatory mediator nuclear transcription factor kappaB (NF-kappaB) reveal a functional link between xenobiotic neutralization and inflammation and explain how certain xenobiotics can affect the immune response. Furthermore, another nuclear receptor, peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to produce beneficial effects in experimental inflammatory bowel diseases by repression of NF-kappaB thereby reducing inflammation, whilst its close relative PPAR beta/delta appears at a central position in signalling pathways involved in the progression of colon cancer. Recently accumulated knowledge on the action of these nuclear receptors and NF-kappaB in intestinal homeostasis may provide the rationale for the development of innovative treatment strategies with selective receptor modulators.

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

    Science.gov (United States)

    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

  5. Plasma clearance of noradrenaline does not change with age in normal subjects

    DEFF Research Database (Denmark)

    Hilsted, J; Christensen, N J; Larsen, S

    1985-01-01

    Noradrenaline kinetics (plasma concentrations, plasma clearance and appearance rates) were investigated in seven elderly healthy subjects and in six young healthy subjects. Forearm venous plasma noradrenaline concentrations were higher in the elderly subjects compared with the young subjects. Pla....... Plasma clearance of noradrenaline was identical in the two groups. The increase in plasma noradrenaline concentration, with age, probably reflects an increased sympathetic nervous activity....

  6. PPARs: Protectors or Opponents of Myocardial Function?

    Directory of Open Access Journals (Sweden)

    Christine J. Pol

    2015-01-01

    Full Text Available Over 5 million people in the United States suffer from the complications of heart failure (HF, which is a rapidly expanding health complication. Disorders that contribute to HF include ischemic cardiac disease, cardiomyopathies, and hypertension. Peroxisome proliferator-activated receptors (PPARs are members of the nuclear receptor family. There are three PPAR isoforms: PPARα, PPARγ, and PPARδ. They can be activated by endogenous ligands, such as fatty acids, as well as by pharmacologic agents. Activators of PPARs are used for treating several metabolic complications, such as diabetes and hyperlipidemia that are directly or indirectly associated with HF. However, some of these drugs have adverse effects that compromise cardiac function. This review article aims to summarize the current basic and clinical research findings of the beneficial or detrimental effects of PPAR biology on myocardial function.

  7. PPAR-gamma in the Cardiovascular System.

    Science.gov (United States)

    Duan, Sheng Zhong; Ivashchenko, Christine Y; Usher, Michael G; Mortensen, Richard M

    2008-01-01

    Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), 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-gamma 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-gamma 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-gamma 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.

  8. PPARs: Protectors or Opponents of Myocardial Function?

    Science.gov (United States)

    Pol, Christine J.; Lieu, Melissa; Drosatos, Konstantinos

    2015-01-01

    Over 5 million people in the United States suffer from the complications of heart failure (HF), which is a rapidly expanding health complication. Disorders that contribute to HF include ischemic cardiac disease, cardiomyopathies, and hypertension. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family. There are three PPAR isoforms: PPARα, PPARγ, and PPARδ. They can be activated by endogenous ligands, such as fatty acids, as well as by pharmacologic agents. Activators of PPARs are used for treating several metabolic complications, such as diabetes and hyperlipidemia that are directly or indirectly associated with HF. However, some of these drugs have adverse effects that compromise cardiac function. This review article aims to summarize the current basic and clinical research findings of the beneficial or detrimental effects of PPAR biology on myocardial function. PMID:26713088

  9. Liganded peroxisome proliferator-activated receptors (PPARs) preserve nuclear histone deacetylase 5 levels in endothelin-treated Sprague-Dawley rat cardiac myocytes.

    Science.gov (United States)

    Zhang, Haining; Shao, Zongjun; Alibin, Caroline P; Acosta, Crystal; Anderson, Hope D

    2014-01-01

    Ligand activation of peroxisome proliferator-activated receptors (PPARs) prevents cardiac myocyte hypertrophy, and we previously reported that diacylglycerol kinase zeta (DGKζ) is critically involved. DGKζ is an intracellular lipid kinase that catalyzes phosphorylation of diacylglycerol; by attenuating DAG signaling, DGKζ suppresses protein kinase C (PKC) and G-protein signaling. Here, we investigated how PPAR-DGKζ signaling blocks activation of the hypertrophic gene program. We focused on export of histone deacetylase 5 (HDAC5) from the nucleus, a key event during hypertrophy, since crosstalk occurs between PPARs and other members of the HDAC family. Using cardiac myocytes isolated from Sprague-Dawley rats, we determined that liganded PPARs disrupt endothelin-1 (ET1)-induced nuclear export of HDAC5 in a manner that is dependent on DGKζ. When DGKζ-mediated PKC inhibition was circumvented using a constitutively-active PKCε mutant, PPARs failed to block ET1-induced nuclear retention of HDAC5. Liganded PPARs also prevented (i) activation of protein kinase D (the downstream effector of PKC), (ii) HDAC5 phosphorylation at 14-3-3 protein chaperone binding sites (serines 259 and 498), and (iii) physical interaction between HDAC5 and 14-3-3, all of which are consistent with blockade of nucleo-cytoplasmic shuttling of HDAC5. Finally, the ability of PPARs to prevent neutralization of HDAC5 activity was associated with transcriptional repression of hypertrophic genes. This occurred by first, reduced MEF2 transcriptional activity and second, augmented deacetylation of histone H3 associated with hypertrophic genes expressing brain natriuretic peptide, β-myosin heavy chain, skeletal muscle α-actin, and cardiac muscle α-actin. Our findings identify spatial regulation of HDAC5 as a target for liganded PPARs, and to our knowledge, are the first to describe a mechanistic role for nuclear DGKζ in cardiac myocytes. In conclusion, these results implicate modulation of HDAC5

  10. Noradrenaline blockade specifically enhances metacognitive performance

    Science.gov (United States)

    Hauser, Tobias U; Allen, Micah; Purg, Nina; Moutoussis, Michael; Rees, Geraint; Dolan, Raymond J

    2017-01-01

    Impairments in metacognition, the ability to accurately report one’s performance, are common in patients with psychiatric disorders, where a putative neuromodulatory dysregulation provides the rationale for pharmacological interventions. Previously, we have shown how unexpected arousal modulates metacognition (Allen et al., 2016). Here, we report a double-blind, placebo-controlled, study that examined specific effects of noradrenaline and dopamine on both metacognition and perceptual decision making. Signal theoretic analysis of a global motion discrimination task with adaptive performance staircasing revealed that noradrenergic blockade (40 mg propranolol) significantly increased metacognitive performance (type-II area under the curve, AUROC2), but had no impact on perceptual decision making performance. Blockade of dopamine D2/3 receptors (400 mg amisulpride) had no effect on either metacognition or perceptual decision making. Our study is the first to show a pharmacological enhancement of metacognitive performance, in the absence of any effect on perceptual decision making. This enhancement points to a regulatory role for noradrenergic neurotransmission in perceptual metacognition. DOI: http://dx.doi.org/10.7554/eLife.24901.001 PMID:28489001

  11. Crosstalk between the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and the vitamin D receptor (VDR) in human breast cancer cells: PPAR{gamma} binds to VDR and inhibits 1{alpha},25-dihydroxyvitamin D{sub 3} mediated transactivation

    Energy Technology Data Exchange (ETDEWEB)

    Alimirah, Fatouma; Peng, Xinjian; Yuan, Liang; Mehta, Rajeshwari R. [Cancer Biology Division, IIT Research Institute, 10 West 35th Street, Chicago, IL 60616 (United States); Knethen, Andreas von [Institute of Biochemistry, Johann Wolfgang Goethe University, Frankfurt (Germany); Choubey, Divaker [Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, P.O. Box 670056, Cincinnati, OH 45267 (United States); Mehta, Rajendra G., E-mail: rmehta@iitri.org [Cancer Biology Division, IIT Research Institute, 10 West 35th Street, Chicago, IL 60616 (United States)

    2012-11-15

    Heterodimerization and cross-talk between nuclear hormone receptors often occurs. For example, estrogen receptor alpha (ER{alpha}) physically binds to peroxisome proliferator-activated receptor gamma (PPAR{gamma}) and inhibits its transcriptional activity. The interaction between PPAR{gamma} and the vitamin D receptor (VDR) however, is unknown. Here, we elucidate the molecular mechanisms linking PPAR{gamma} and VDR signaling, and for the first time we show that PPAR{gamma} physically associates with VDR in human breast cancer cells. We found that overexpression of PPAR{gamma} decreased 1{alpha},25-dihydroxyvitamin D{sub 3} (1,25D{sub 3}) mediated transcriptional activity of the vitamin D target gene, CYP24A1, by 49% and the activity of VDRE-luc, a vitamin D responsive reporter, by 75% in T47D human breast cancer cells. Deletion mutation experiments illustrated that helices 1 and 4 of PPAR{gamma}'s hinge and ligand binding domains, respectively, governed this suppressive function. Additionally, abrogation of PPAR{gamma}'s AF2 domain attenuated its repressive action on 1,25D{sub 3} transactivation, indicating that this domain is integral in inhibiting VDR signaling. PPAR{gamma} was also found to compete with VDR for their binding partner retinoid X receptor alpha (RXR{alpha}). Overexpression of RXR{alpha} blocked PPAR{gamma}'s suppressive effect on 1,25D{sub 3} action, enhancing VDR signaling. In conclusion, these observations uncover molecular mechanisms connecting the PPAR{gamma} and VDR pathways. -- Highlights: PPAR{gamma}'s role on 1{alpha},25-dihydroxyvitamin D{sub 3} transcriptional activity is examined. Black-Right-Pointing-Pointer PPAR{gamma} physically binds to VDR and inhibits 1{alpha},25-dihydroxyvitamin D{sub 3} action. Black-Right-Pointing-Pointer PPAR{gamma}'s hinge and ligand binding domains are important for this inhibitory effect. Black-Right-Pointing-Pointer PPAR{gamma} competes with VDR for the availability of their binding

  12. The PPAR alpha-humanized mouse: a model to investigate species differences in liver toxicity mediated by PPAR alpha.

    Science.gov (United States)

    Yang, Qian; Nagano, Tomokazu; Shah, Yatrik; Cheung, Connie; Ito, Shinji; Gonzalez, Frank J

    2008-01-01

    To determine the impact of the species difference between rodents and humans in response to peroxisome proliferators (PPs) mediated by peroxisome proliferator-activated receptor (PPAR)alpha, PPAR alpha-humanized transgenic mice were generated using a P1 phage artificial chromosome (PAC) genomic clone bred onto a ppar alpha-null mouse background, designated hPPAR alpha PAC. In hPPAR alpha PAC mice, the human PPAR alpha gene is expressed in tissues with high fatty acid catabolism and induced upon fasting, similar to mouse PPAR alpha in wild-type (Wt) mice. Upon treatment with the PP fenofibrate, hPPAR alpha PAC mice exhibited responses similar to Wt mice, including peroxisome proliferation, lowering of serum triglycerides, and induction of PPAR alpha target genes encoding enzymes involved in fatty acid metabolism in liver, kidney, and heart, suggesting that human PPAR alpha (hPPAR alpha) functions in the same manner as mouse PPAR alpha in regulating fatty acid metabolism and lowering serum triglycerides. However, in contrast to Wt mice, treatment of hPPAR alpha PAC mice with fenofibrate did not cause significant hepatomegaly and hepatocyte proliferation, thus indicating that the mechanisms by which PPAR alpha affects lipid metabolism are distinct from the hepatocyte proliferation response, the latter of which is only induced by mouse PPAR alpha. In addition, a differential regulation of several genes, including the oncogenic let-7C miRNA by PPs, was observed between Wt and hPPAR alpha PAC mice that may contribute to the inherent difference between mouse and human PPAR alpha in activation of hepatocellular proliferation. The hPPAR alpha PAC mouse model provides an in vivo platform to investigate the species difference mediated by PPAR alpha and an ideal model for human risk assessment PPs exposure.

  13. Unlike PPAR{gamma}, PPAR{alpha} or PPAR{beta}/{delta} activation does not promote human monocyte differentiation toward alternative macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Bouhlel, Mohamed Amine [Univ Lille Nord de France, F-59000 Lille (France); Inserm U545, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France); Brozek, John [Genfit, Loos (France); Derudas, Bruno [Univ Lille Nord de France, F-59000 Lille (France); Inserm U545, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France); Zawadzki, Christophe; Jude, Brigitte [Inserm ERI-9 and Equipe d' Accueil 2693, IFR114, Universite de Lille, Lille (France); Staels, Bart, E-mail: bart.staels@pasteur-lille.fr [Univ Lille Nord de France, F-59000 Lille (France); Inserm U545, 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 U545, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France)

    2009-08-28

    Macrophages adapt their response to micro-environmental signals. While Th1 cytokines promote pro-inflammatory M1 macrophages, Th2 cytokines promote an 'alternative' anti-inflammatory M2 macrophage phenotype. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors expressed in macrophages where they control the inflammatory response. It has been shown that PPAR{gamma} promotes the differentiation of monocytes into anti-inflammatory M2 macrophages in humans and mice, while a role for PPAR{beta}/{delta} in this process has been reported only in mice and no data are available for PPAR{alpha}. Here, we show that in contrast to PPAR{gamma}, expression of PPAR{alpha} and PPAR{beta}/{delta} overall does not correlate with the expression of M2 markers in human atherosclerotic lesions, whereas a positive correlation with genes of lipid metabolism exists. Moreover, unlike PPAR{gamma}, PPAR{alpha} or PPAR{beta}/{delta} activation does not influence human monocyte differentiation into M2 macrophages in vitro. Thus, PPAR{alpha} and PPAR{beta}/{delta} do not appear to modulate the alternative differentiation of human macrophages.

  14. Coactivators in PPAR-Regulated Gene Expression

    Directory of Open Access Journals (Sweden)

    Navin Viswakarma

    2010-01-01

    Full Text Available Peroxisome proliferator-activated receptor (PPARα, β (also known as δ, and γ function as sensors for fatty acids and fatty acid derivatives and control important metabolic pathways involved in the maintenance of energy balance. PPARs also regulate other diverse biological processes such as development, differentiation, inflammation, and neoplasia. In the nucleus, PPARs exist as heterodimers with retinoid X receptor-α bound to DNA with corepressor molecules. Upon ligand activation, PPARs undergo conformational changes that facilitate the dissociation of corepressor molecules and invoke a spatiotemporally orchestrated recruitment of transcription cofactors including coactivators and coactivator-associated proteins. While a given nuclear receptor regulates the expression of a prescribed set of target genes, coactivators are likely to influence the functioning of many regulators and thus affect the transcription of many genes. Evidence suggests that some of the coactivators such as PPAR-binding protein (PBP/PPARBP/thyroid hormone receptor-associated protein 220 (TRAP220/mediator complex subunit 1 (MED1 may exert a broader influence on the functions of several nuclear receptors and their target genes. Investigations into the role of coactivators in the function of PPARs should strengthen our understanding of the complexities of metabolic diseases associated with energy metabolism.

  15. Molecular recognition of nitrated fatty acids by PPAR[gamma

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yong; Zhang, Jifeng; Schopfer, Francisco J.; Martynowski, Dariusz; Garcia-Barrio, Minerva T.; Kovach, Amanda; Suino-Powell, Kelly; Baker, Paul R.S.; Freeman, Bruce A.; Chen, Y. Eugene; Xu, H. Eric (Pitt); (Michigan); (Van Andel); (Morehouse-MED)

    2010-03-08

    Peroxisome proliferator activated receptor-{gamma} (PPAR{gamma}) regulates metabolic homeostasis and adipocyte differentiation, and it is activated by oxidized and nitrated fatty acids. Here we report the crystal structure of the PPAR{gamma} ligand binding domain bound to nitrated linoleic acid, a potent endogenous ligand of PPAR{gamma}. Structural and functional studies of receptor-ligand interactions reveal the molecular basis of PPAR{gamma} discrimination of various naturally occurring fatty acid derivatives.

  16. CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-gamma.

    Science.gov (United States)

    Herzig, Stephan; Hedrick, Susan; Morantte, Ianessa; Koo, Seung-Hoi; Galimi, Francesco; Montminy, Marc

    2003-11-13

    Fasting triggers a series of hormonal cues that promote energy balance by inducing glucose output and lipid breakdown in the liver. In response to pancreatic glucagon and adrenal cortisol, the cAMP-responsive transcription factor CREB activates gluconeogenic and fatty acid oxidation programmes by stimulating expression of the nuclear hormone receptor coactivator PGC-1 (refs 2-5). In parallel, fasting also suppresses lipid storage and synthesis (lipogenic) pathways, but the underlying mechanism is unknown. Here we show that mice deficient in CREB activity have a fatty liver phenotype and display elevated expression of the nuclear hormone receptor PPAR-gamma, a key regulator of lipogenic genes. CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. The coordinate induction of PGC-1 and repression of PPAR-gamma by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.

  17. PPAR Signaling in Placental Development and Function.

    Science.gov (United States)

    Barak, Yaacov; Sadovsky, Yoel; Shalom-Barak, Tali

    2008-01-01

    With the major attention to the pivotal roles of PPARs in diverse aspects of energy metabolism, the essential functions of PPARgamma and PPARbeta/delta in placental development came as a surprise and were often considered a nuisance en route to their genetic analysis. However, these findings provided an opportune entrée into placental biology. Genetic and pharmacological studies, primarily of knockout animal models and cell culture, uncovered networks of PPARgamma and PPARdelta, their heterodimeric RXR partners, associated transcriptional coactivators, and target genes, that regulate various aspects of placental development and function. These studies furnish both specific information about trophoblasts and the placenta and potential hints about the functions of PPARs in other tissues and cell types. They reveal that the remarkable versatility of PPARs extends beyond the orchestration of metabolism to the regulation of cellular differentiation, tissue development, and trophoblast-specific functions. This information and its implications are the subject of this review.

  18. In vivo activation of PPAR target genes by RXR homodimers

    NARCIS (Netherlands)

    IJpenberg, A.; Tan, N.S.; Gelman, L.; Kersten, A.H.

    2004-01-01

    The ability of a retinoid X receptor (RXR) to heterodimerize with many nuclear receptors, including LXR, PPAR, NGF1B and RAR, underscores its pivotal role within the nuclear receptor superfamily. Among these heterodimers, PPAR: RXR is considered an important signalling mediator of both PPAR ligands,

  19. Extensive mapping of PPAR binding to genomic DNA

    DEFF Research Database (Denmark)

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

    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...

  20. Histamine H3 receptor-mediated inhibition of noradrenaline release in the human brain.

    Science.gov (United States)

    Schlicker, E; Werthwein, S; Zentner, J

    1999-01-01

    Stimulation-evoked 3H-noradrenaline release in human cerebrocortical slices was inhibited by histamine (in a manner sensitive to clobenpropit) and by imetit, suggesting H3 receptor-mediated inhibition of noradrenaline release in human brain.

  1. 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

  2. Lack of CB1 receptors increases noradrenaline release in vas deferens without affecting atrial noradrenaline release or cortical acetylcholine release

    OpenAIRE

    Schlicker, Eberhard; Redmer, Agnes; Werner, André; Kathmann, Markus

    2003-01-01

    We studied whether cannabinoid CB1 receptor gene disruption (to yield CB1−/− mice) affects the electrically evoked tritium overflow from vas deferens and atrial pieces preincubated with [3H]-noradrenaline (NA) (‘noradrenaline release') and from cerebral cortex slices preincubated with [3H]-choline (‘acetylcholine release').NA release was higher by 37% in vas deferens from CB1−/− mice than in vas deferens from CB1+/+ mice. The cannabinoid receptor agonist WIN 55,212-2 inhibited, and the CB1 re...

  3. PPAR Agonists and Cardiovascular Disease in Diabetes.

    Science.gov (United States)

    Calkin, Anna C; Thomas, Merlin C

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARalpha agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARgamma agonists, and more recently dual PPARalpha/gamma coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARgamma receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.

  4. PPAR Agonists and Cardiovascular Disease in Diabetes

    Science.gov (United States)

    Calkin, Anna C.; Thomas, Merlin C.

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARα agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARγ agonists, and more recently dual PPARα/γ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARγ receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease. PMID:18288280

  5. Serotonin and noradrenaline reuptake inhibitors improve micturition control in mice.

    Directory of Open Access Journals (Sweden)

    Marco Redaelli

    Full Text Available Poor micturition control may cause profound distress, because proper voiding is mandatory for an active social life. Micturition results from the subtle interplay of central and peripheral components. It involves the coordination of autonomic and neuromuscular activity at the brainstem level, under the executive control of the prefrontal cortex. We tested the hypothesis that administration of molecules acting as reuptake inhibitors of serotonin, noradrenaline or both may exert a strong effect on the control of urine release, in a mouse model of overactive bladder. Mice were injected with cyclophosphamide (40 mg/kg, to increase micturition acts. Mice were then given one of four molecules: the serotonin reuptake inhibitor imipramine, its metabolite desipramine that acts on noradrenaline reuptake, the serotonin and noradrenaline reuptake inhibitor duloxetine or its active metabolite 4-hydroxy-duloxetine. Cyclophosphamide increased urine release without inducing overt toxicity or inflammation, except for increase in urothelium thickness. All the antidepressants were able to decrease the cyclophosphamide effects, as apparent from longer latency to the first micturition act, decreased number of urine spots and volume of released urine. These results suggest that serotonin and noradrenaline reuptake inhibitors exert a strong and effective modulatory effect on the control of urine release and prompt to additional studies on their central effects on brain areas involved in the social and behavioral control of micturition.

  6. Racism and Surplus Repression.

    Science.gov (United States)

    Johnson, Howard

    1983-01-01

    Explores the relationship between Herbert Marcuse's theory of "surplus repression" and Freud's theory of the "unconscious" with respect to latent, hidden, covert, or subliminal aspects of racism in the United States. Argues that unconscious racism, manifested in evasion/avoidance, acting out/projection, and attempted justification, perpetuates…

  7. Financial Liberalization Or Repression?

    OpenAIRE

    Ang, James

    2009-01-01

    While financial liberalization has always been advocated in developing countries, experiences with it do not always produce desirable outcomes. In order to evaluate the costs and benefits associated with financial liberalization and repression, this study highlights that the overall effectiveness of the reform programs depends on the relative strength of each financial sector policy implemented. Using India as a case study, the results indicate that interest rate controls, statutory liquidity...

  8. PPAR modulators and PPAR pan agonists for metabolic diseases: the next generation of drugs targeting peroxisome proliferator-activated receptors?

    Science.gov (United States)

    Feldman, P L; Lambert, M H; Henke, B R

    2008-01-01

    The Peroxisome Proliferator-Activated Receptors-PPAR alpha, PPAR gamma, and PPAR delta--are members of the nuclear receptor gene family that have emerged as therapeutic targets for the development of drugs to treat human metabolic diseases. The discovery of high affinity, subtype-selective agonists for each of the three PPAR subtypes has allowed elucidation of the pharmacology of these receptors and development of first-generation therapeutic agents for the treatment of diabetes and dyslipidemia. However, despite proven therapeutic benefits of selective PPAR agonists, safety concerns and dose-limiting side effects have been observed, and a number of late-stage development failures have been reported. Scientists have continued to explore ligand-based activation of PPARs in hopes of developing safer and more effective drugs. This review highlights recent efforts on two newer approaches, the simultaneous activation of all three PPAR receptors with a single ligand (PPAR pan agonists) and the selective modulation of a single PPAR receptor in a cell or tissue specific manner (selective PPAR modulator or SPPARM) in order to induce a subset of target genes and affect a restricted number of metabolic pathways.

  9. PPAR GAMMA AGONISTS: AN EFFECTIVE STRATEGY FOR CANCER TREATMENT

    Directory of Open Access Journals (Sweden)

    Divya G.S

    2013-10-01

    Full Text Available PPAR-γ regulates cellular differentiation, development and metabolism. They play these essential roles by functioning as transcription factors regulating the expression of genes. The PPARs mainly are of three types α, β and γ. The PPAR-γ expressed in three forms γ1, γ2 and γ3 present in different tissues. When PPAR binds its ligand, transcription of target gene is increased or decreased. Tzds were able to induce cell differentiation and apoptosis or inhibit cell proliferation both in vitro and in vivo. However, widespread use of thiazolidinediones (TZDs, the clinically used synthetic PPAR gamma agonists, has been limited by adverse effects. So in this review we are suggesting some new molecules other than thiazolidine diones which can act as potential anticancer agents, after explaining the mechanism of action of PPAR-γ agonists as anticancer agents especially thiazolidinediones.

  10. Extensive mapping of PPAR binding to genomic DNA

    DEFF Research Database (Denmark)

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

    The peroxisome proliferator-activated receptor (PPAR) transcription factors a, d and g are members of the nuclear hormone receptor super family. The PPARs bind regulatory DNA elements (PPREs) as heterodimers with the retinoid X receptor (RXR) and thereby induce transcription in response to ligand...... activation. The PPARs are important regulators of transcription in response to metabolic signalling, but have diverse metabolic functions. Thus, PPARg is a lipogenic transcription factor, whereas PPARa and -d induce lipid oxidation. In vivo, the PPARs are required for regulation of diverse metabolic...... 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...

  11. Hepatic PPARs: their role in liver physiology, fibrosis and treatment.

    Science.gov (United States)

    Zardi, E M; Navarini, L; Sambataro, G; Piccinni, P; Sambataro, F M; Spina, C; Dobrina, A

    2013-01-01

    Complex molecular and cellular mechanisms are involved in the pathway of liver fibrosis. Activation and transformation of hepatic stellate cells (HSCs) are considered the two main reasons for the cause and development of liver fibrosis. The peroxisome proliferator-activated receptors (PPARs) belonging to the family of ligand-activated transcription factors play a key role in liver homeostasis, regulating adipogenesis and inhibiting fibrogenesis in HSCs. Normal transcriptional function of PPARs contributes to maintain HSCs in quiescent phase. A reduced expression of PPARs in HSCs greatly induces a progression of liver fibrosis and an increased production of collagen. Here, we discuss role and function of PPARs and we take into consideration molecular factors able to reduce PPARs activity in HSCs. Finally, although further validations are needed, we illustrate novel strategies available from in vitro and animal studies on how some PPARs-agonists have been proved effective as antifibrotic substances in liver disease.

  12. 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.

  13. Effect of Noradrenaline on the Virulence Properties of Campylobacter Species

    Directory of Open Access Journals (Sweden)

    Sree V. Aroori

    2014-01-01

    Full Text Available Campylobacter species cause a spectrum of illnesses in humans. The type of illness and the outcome is dependent on the virulence of the infecting pathogen strain and host immune status. Acute stress can seriously compromise host immunity and increase susceptibility to infection. Noradrenaline (NA is a stress hormone. Several studies have shown that it stimulated growth and increased the pathogenicity of organisms including E. coli and Campylobacter jejuni. However, the effect of NA on other Campylobacter species is unknown. We have examined the effect of NA on growth rate, motility, invasion of T84 epithelial cells, and colonisation of chickens by diverse Campylobacter species. Campylobacter cultures grown with NA had reduced lag phases, increased growth rates, and higher final optical densities than controls. The motility of Campylobacter was also significantly increased in the presence of noradrenaline. Some of the Campylobacter strains tested also showed increased invasion of T84 epithelial cells, greater breakdown of tight junctions, and an enhanced potential to colonise chickens. Our results show that noradrenaline-induced enhancement of virulence of Campylobacter can influence the outcome of infection.

  14. PPAR-γ: Therapeutic Potential for Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Paul D. Drew

    2008-01-01

    Full Text Available The role of peroxisome proliferator-activated receptors (PPARs in altering lipid and glucose metabolism is well established. More recent studies indicate that PPARs also play critical roles in controlling immune responses. We and others have previously demonstrated that PPAR-γ agonists modulate the development of experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS. This review will discuss the cellular and molecular mechanisms by which these agonists are believed to modulate disease. The therapeutic potential of PPAR-γ agonists in the treatment of multiple sclerosis will also be considered.

  15. Tritium excretion after intravenous administration of tritium labelled adrenaline and noradrenaline and digital vascular reactivity to adrenaline and noradrenaline in normotensive and labile hypertensive subjects.

    Science.gov (United States)

    De Guia, D; Mendlowitz, M; Vlachakis, N D; Gitlow, S E; Nissenbaum, M

    1980-01-01

    1. The 24-h urinary excretion of tritium after tritiated adrenaline administration and digital vascular reactivity to exogenously administered adrenaline and noradrenaline were measured in ten normotensive and in twenty-eight labile essential hypertensive subjects. Tritiated noradrenaline excretion and apparent noradrenaline secretion rate were also measured in ten and eleven of these subjects, respectively. 2. Despite overlapping, the mean 24-h tritium excretion after 3H-adrenaline administration as well as reactivity to adrenaline were significantly greater in the hypertensive than in the normotensive subjects, whether or not they had increased responsiveness to noradrenaline. Significant correlation, however, was observed between tritium excretion of adrenaline and reactivity to adrenaline in both labile hypertensive and normotensive subjects. These measurements were also both significantly correlated with percentage variability in systolic and diastolic blood pressure in the labile hypertensive subjects. 3. No significant correlation was observed between adrenaline as against noradrenaline measurements, whether physiological or biochemical, in either hypertensive or normotensive subjects.

  16. Wild Type and PPAR KO Dataset

    Science.gov (United States)

    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, 2016 paper.This dataset is associated with the following publication:Das, K., C. Wood, M. Lin, A.A. Starkov, C. Lau, K.B. Wallace, C. Corton, and B. Abbott. Perfluoroalky acids-induced liver steatosis: Effects on genes controlling lipid homeostasis. TOXICOLOGY. Elsevier Science Ltd, New York, NY, USA, 378: 32-52, (2017).

  17. Noradrenaline and isoproterenol kinetics in diabetic patients with and without autonomic neuropathy

    DEFF Research Database (Denmark)

    Dejgaard, Anders; Hilsted, J; Christensen, N J

    1986-01-01

    Noradrenaline and isoproterenol kinetics using intravenous infusion of L-3H-NA and of 3H-isoproterenol were investigated in eight Type 1 (insulin-dependent) diabetic patients without neuropathy and in eight Type 1 diabetic patients with autonomic neuropathy matched for age, sex and duration...... of diabetes. Resting plasma noradrenaline and adrenaline concentrations were reduced in patients with autonomic failure (p less than 0.05). The metabolic clearance rate of noradrenaline was similar in both groups of patients, and the appearance rate of noradrenaline in plasma was reduced in patients...

  18. PPAR Genomics and Pharmacogenomics: Implications for Cardiovascular Disease

    Directory of Open Access Journals (Sweden)

    Sharon Cresci

    2008-03-01

    Full Text Available The peroxisome proliferator-activated receptors (PPARs consist of three related transcription factors that serve to regulate a number of cellular processes that are central to cardiovascular health and disease. Numerous pharmacologic studies have assessed the effects of specific PPAR agonists in clinical trials and have provided insight into the clinical effects of these genes while genetic studies have demonstrated clinical associations between PPAR polymorphisms and abnormal cardiovascular phenotypes. With the abundance of data available from these studies as a background, PPAR pharmacogenetics has become a promising and rapidly advancing field. This review focuses on summarizing the current state of understanding of PPAR genetics and pharmacogenetics and the important implications for the individualization of therapy for patients with cardiovascular diseases.

  19. Blocking the peroxisome proliferator-activated receptor (PPAR): an overview.

    Science.gov (United States)

    Ammazzalorso, Alessandra; De Filippis, Barbara; Giampietro, Letizia; Amoroso, Rosa

    2013-10-01

    Peroxisome proliferator-activated receptors (PPARs) have been studied extensively over the last few decades and have been assessed as molecular targets for the development of drugs against metabolic disorders. A rapid increase in understanding of the physiology and pharmacology of these receptors has occurred, together with the identification of novel chemical structures that are able to activate the various PPAR subtypes. More recent evidence suggests that moderate activation of these receptors could be favorable in pathological situations due to a decrease in the side effects brought about by PPAR agonists. PPAR partial agonists and antagonists are interesting tools that are currently used to better elucidate the biological processes modulated by this family of nuclear receptors. Herein we present an overview of the various molecular structures that are able to block each of the PPAR subtypes, with a focus on promising therapeutic applications. Copyright © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Financial repression and fiscal policy

    NARCIS (Netherlands)

    Gupta, KL; Lensink, R

    1997-01-01

    This paper develops a simulation model to assess the consequences of government's trying to raise revenues through financial repression in developing countries. The measures of financial repression studied are (1) government borrowing from the banking sector to finance its budget deficit (2) governm

  1. 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.

  2. Tapentadol increases levels of noradrenaline in the rat spinal cord as measured by in vivo microdialysis

    NARCIS (Netherlands)

    Tzschentke, Thomas M; Folgering, Joost H A; Flik, Gunnar; De Vry, Jean

    2012-01-01

    Spinal noradrenaline is thought to play an important role in descending pain inhibitory pathways and the modulation of nociceptive information at the spinal level. Tapentadol is a μ-opioid receptor (MOR) agonist and noradrenaline reuptake inhibitor (NRI). We showed previously that tapentadol, in con

  3. The content of PPAR, LXR, and RXR and the PPAR DNA-binding activity in macrophages over the course of inflammation in mice.

    Science.gov (United States)

    Dushkin, M I; Khoshchenko, O M; Chasovsky, M A; Pivovarova, E N

    2009-03-01

    The content of peroxisome proliferation activating proteins PPAR-alpha and PPAR-gamma, liver X receptors (LXR), and retinoid X receptors (RXR) and activity of PPAR-alpha, PPAR-gamma, and PPAR-delta binding to DNA response elements in C57Bl/6 mouse macrophages were studied during different phases of aseptic inflammation, induced by intraperitoneal injection of 50 mg/kg zymosan A. The DNA-binding activities of PPAR-alpha and PPAR-gamma and the levels of PPAR-alpha, PPAR-gamma, LXR, and RXR in peritoneal macrophages dropped on days 1 and 3 after zymosan injection. On days 7 and 14 the DNA-binding activity of PPAR-gamma and content of PPAR-gamma and LXR-beta protein increased in comparison with the control, while the DNA-binding activity and content of PPAR-alpha in the cells remained low. Recovery of RXR protein content in macrophages was observed only on day 14 after zymosan injection.

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

    DEFF Research Database (Denmark)

    Grøntved, Lars; Nielsen, Ronni; Stunnenberg, Henk

      The three PPAR subtypes alpha, beta/delta and gamma are very important transcriptional regulators of glucose and lipid metabolism. Even though the different PPAR subtypes activate genes through similar DR-1 conserved DNA motifs (PPREs), activation of the PPARs in vivo leads to opposite...... physiological scenarios. PPARa and PPARd are transcriptional regulators of fatty acid oxidation and ketogenesis, whereas PPAR? controls genes involved in lipid storage. Consequently, there must be PPAR subtype specific molecular determinants that secure PPAR selective recognition and activation of target...... promoters in a given cell type. In vitro experiments suggest that the different PPAR subtypes might have dissimilar binding preference for some PPAR target sites and may also have different affinity for some transcriptional co-factors. However the molecular mechanisms behind PPAR subtype specific activation...

  5. Fasting Upregulates PPAR Target Genes in Brain and Influences Pituitary Hormone Expression in a PPAR Dependent Manner

    Directory of Open Access Journals (Sweden)

    Bettina König

    2009-01-01

    PPAR target genes implicated in -oxidation of fatty acids (acyl-CoA oxidase, carnitine palmitoyltransferase-1, medium chain acyl-CoA dehydrogenase and ketogenesis (mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in pituitary gland and partially also in frontal cortex and diencephalon compared to nonfasted animals. These data strongly indicate that fasting activates PPAR in brain and pituitary gland. Furthermore, pituitary prolactin and luteinizing hormone- mRNA concentrations were increased upon fasting in wild-type mice but not in mice lacking PPAR. For proopiomelanocortin and thyrotropin-, genotype-specific differences in pituitary mRNA concentrations were observed. Thus, PPAR seems to be involved in transcriptional regulation of pituitary hormones.

  6. Regulation of Macrophage Functions by PPAR-α, PPAR-γ, and LXRs in Mice and Men

    National Research Council Canada - National Science Library

    Rigamonti, Elena; Chinetti-Gbaguidi, Giulia; Staels, Bart

    2008-01-01

    Peroxisome proliferator-activated receptors (PPARs) and (liver X receptors) LXRs are ligand-activated transcription factors that control lipid and glucose metabolism, as well as the inflammatory response...

  7. Modulation of noradrenaline release in rat isolated stomach by prostanoids, but not by histaminergic mechanisms.

    Science.gov (United States)

    Racké, K; Berrino, L; Möhlig, A; Jäger, R; Griepenkerl, I; Bräutigam, M; Reimann, A

    1995-12-01

    Several gastric functions are modulated by the sympathetic nervous system, but local mechanisms involved in the control of noradrenaline release are largely unknown. Overflow of endogenous noradrenaline was studied from isolated rat stomach incubated in Ussing chambers allowing the separate determination of mucosal and serosal overflow. Spontaneous noradrenaline overflow was similar at the mucosal and serosal side, but electrical field stimulation caused a frequency-dependent increase in noradrenaline overflow selectively at the serosal side. Evoked noradrenaline overflow was blocked by tetrodotoxin, not affected by indometacin and markedly enhanced (by about 250%) by yohimbine. In the presence of indometacin and yohimbine, sulprostone (an agonist at EP1/EP3 receptors) and misoprostol (an agonist at EP2/EP3 receptors) reduced the noradrenaline overflow evoked by stimulation at 3 Hz maximally by about 80% (EC50: 6 nmol/l and 11 nmol/l, respectively). The EP1 receptor selective antagonist AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) did not antagonize the inhibition by sulprostone. Noradrenaline overflow evoked by stimulation at 1 Hz and 3 Hz was increased by scopolamine by about 50% and almost completely inhibited by oxotremorine. Neither, histamine nor the H3 receptor selective agonist (R)-alpha-methyl-histamine, nor the H1, H2 and H3 selective receptor antagonists mepyramine, cimetidine and thioperamide significantly affected noradrenaline overflow evoked by stimulation at 1 Hz or 3 Hz. In conclusion, impulse-induced noradrenaline release in the rat stomach is controlled by multiple presynaptic mechanisms involving alpha 2-adrenergic autoreceptors, EP3 prostanoid and muscarine heteroreceptors, whereas histaminergic mechanisms do not appear to be significant.

  8. Characteristics of chloride currents activated by noradrenaline in rabbit ear artery cells.

    Science.gov (United States)

    Amédée, T; Large, W A; Wang, Q

    1990-09-01

    1. Responses to noradrenaline were studied in isolated rabbit ear artery cells with the nystatin method of whole-cell patch-clamp recording. With this technique it was possible to obtain reproducible responses to noradrenaline which was not possible with traditional whole-cell recording. 2. With NaCl as the major constituent of the bathing solution (potassium-free pipette and external solutions) the reversal potential (Er) of the noradrenaline-evoked current was about 0 mV. When external chloride was replaced by thiocyanate, iodide, nitrate and bromide, Er was shifted to more negative potentials which indicates that a chloride conductance increase contributes to the current activated by noradrenaline. 3. When sodium was substituted by Tris, N-methyl-D-glucamine, choline or barium, Er of the noradrenaline-evoked current did not alter. This result suggests that a cation conductance is not implicated in the response to noradrenaline recorded with the nystatin method of whole-cell recording. 4. The chloride current activated by noradrenaline was blocked by the selective alpha 1-adrenoceptor antagonist prazosin but was not affected by the alpha 2-adrenoceptor antagonist yohimbine. 5. When cells were exposed to zero calcium bathing solutions the amplitude of the current elicited by noradrenaline was unaffected when measured within 1-2 min in zero calcium conditions. Continued exposure to 0 Ca + 1 mM-EGTA solution reversibly abolished the chloride current to noradrenaline. 6. In the presence of caffeine, which releases Ca2+ from internal stores and itself induced an inward current (at a holding potential of -50 mV), noradrenaline did not elicit a current. These data suggest that the chloride current evoked by noradrenaline results from an increase in intracellular concentration of calcium derived from internal stores. 7. The chloride channel blocking agents 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS; 0.5 mM) and furosemide (0.5 mM) produced partial

  9. Attempt to separate the fluorescence spectra of adrenaline and noradrenaline using chemometrics

    DEFF Research Database (Denmark)

    Nikolajsen, Rikke P; Hansen, Åse Marie; Bro, R

    2000-01-01

    An investigation was conducted on whether the fluorescence spectra of the very similar catecholamines adrenaline and noradrenaline could be separated using chemometric methods. The fluorescence landscapes (several excitation and emission spectra were measured) of two data sets with respectively 16...... regression (Unfold-PLSR) on the larger data set and parallel factor analysis (PARAFAC) of the six samples of the smaller set showed that there was no difference between the fluorescence landscapes of adrenaline and noradrenaline. It can be concluded that chemometric separation of adrenaline and noradrenaline...

  10. A Novel Splicing Variant of Peroxisome Proliferator-Activated Receptor-γ (Pparγ1sv) Cooperatively Regulates Adipocyte Differentiation with Pparγ2

    OpenAIRE

    Yasuhiro Takenaka; Ikuo Inoue; Takanari Nakano; Yuichi Shinoda; Masaaki Ikeda; Takuya Awata; Shigehiro Katayama

    2013-01-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate expression of a number of genes associated with the cellular differentiation and development. Here, we show the abundant and ubiquitous expression of a newly identified splicing variant of mouse Pparγ (Pparγ1sv) that encodes PPARγ1 protein, and its importance in adipogenesis. The novel splicing variant has a unique 5'-UTR sequence, relative to those of Pparγ1 and Pparγ2 mRNAs, indicating the presence of a ...

  11. Glucose repression in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Kayikci, Omur; Nielsen, Jens

    2015-01-01

    Glucose is the primary source of energy for the budding yeast Saccharomyces cerevisiae. Although yeast cells can utilize a wide range of carbon sources, presence of glucose suppresses molecular activities involved in the use of alternate carbon sources as well as it represses respiration and gluc......Glucose is the primary source of energy for the budding yeast Saccharomyces cerevisiae. Although yeast cells can utilize a wide range of carbon sources, presence of glucose suppresses molecular activities involved in the use of alternate carbon sources as well as it represses respiration...... and gluconeogenesis. This dominant effect of glucose on yeast carbon metabolism is coordinated by several signaling and metabolic interactions that mainly regulate transcriptional activity but are also effective at post-transcriptional and post-translational levels. This review describes effects of glucose repression...

  12. The unified theory of repression.

    Science.gov (United States)

    Erdelyi, Matthew Hugh

    2006-10-01

    Repression has become an empirical fact that is at once obvious and problematic. Fragmented clinical and laboratory traditions and disputed terminology have resulted in a Babel of misunderstandings in which false distinctions are imposed (e.g., between repression and suppression) and necessary distinctions not drawn (e.g., between the mechanism and the use to which it is put, defense being just one). "Repression" was introduced by Herbart to designate the (nondefensive) inhibition of ideas by other ideas in their struggle for consciousness. Freud adapted repression to the defensive inhibition of "unbearable" mental contents. Substantial experimental literatures on attentional biases, thought avoidance, interference, and intentional forgetting exist, the oldest prototype being the work of Ebbinghaus, who showed that intentional avoidance of memories results in their progressive forgetting over time. It has now become clear, as clinicians had claimed, that the inaccessible materials are often available and emerge indirectly (e.g., procedurally, implicitly). It is also now established that the Ebbinghaus retention function can be partly reversed, with resulting increases of conscious memory over time (hypermnesia). Freud's clinical experience revealed early on that exclusion from consciousness was effected not just by simple repression (inhibition) but also by a variety of distorting techniques, some deployed to degrade latent contents (denial), all eventually subsumed under the rubric of defense mechanisms ("repression in the widest sense"). Freudian and Bartlettian distortions are essentially the same, even in name, except for motive (cognitive vs. emotional), and experimentally induced false memories and other "memory illusions" are laboratory analogs of self-induced distortions.

  13. Interaction between irbesartan, peroxisome proliferator-activated receptor (PPAR-γ), and adiponectin in the regulation of blood pressure and renal function in spontaneously hypertensive rats.

    Science.gov (United States)

    Afzal, S; Sattar, M A; Johns, Edward J; Abdulla, Mohammed H; Akhtar, Safia; Hashmi, Fayyaz; Abdullah, Nor Azizan

    2016-12-01

    Adiponectin exerts vasodilatory effects. Irbesartan, an angiotensin receptor blocker, possesses partial peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activity and increases circulating adiponectin. This study explored the effect of irbesartan alone and in combination with adiponectin on blood pressure, renal hemodynamic excretory function, and vasoactive responses to angiotensin II and adrenergic agonists in spontaneously hypertensive rat (SHR). Irbesartan was given orally (30 mg/kg/day) for 28 days and adiponectin intraperitoneally (2.5 μg/kg/day) for last 7 days. Groups of SHR received either irbesartan or adiponectin or in combination. A group of Wistar Kyoto rats (WKY) served as controls. Metabolic data and plasma samples were taken on days 0, 21, and 28. In acute studies, the renal vasoconstrictor actions of angiotensin II (ANGII), noradrenaline (NA), phenylephrine (PE), and methoxamine (ME) were determined. SHR control rats had a higher mean blood pressure than the WKY (132 ± 7 vs. 98 ± 2 mmHg), lower plasma and urinary adiponectin, creatinine clearance, urine flow rate and sodium excretion, and oxidative stress markers compared to WKY (all P adiponectin blunted responses to all vasoconstrictors (all P < 0.05). Combined treatment in SHR further decreased the renal vascular responses to ANGII. These findings suggest that an interactive relationship may exist between PPAR-γ, alpha adrenoceptors, and ANGII in the renal vasculature of the SHR.

  14. Synergism between PPAR-α and PPAR-γ Agonists in Metabolic Syndrome%PPAR-α/γ激动剂在代谢综合征中的协同作用

    Institute of Scientific and Technical Information of China (English)

    贺玲; 李俊明

    2012-01-01

    The metabolic syndrome is a group of insulin resistance risk factors, including abdominal obesity, hypertension, abnormal blood glucose and lipid and other metabolic diseases that increase the risk of cardiovascular disease. Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor super family of ligand-activated transcription factors. Research shows, PPARs have two major subtypes; PPAR-α and PPAR-γ. Its agonists can improve insulin resistance, hypertension, and obesity. This article discusses the synergism between PPAR-α and PPAR-γ agonists in metabolic syndrome.%代谢综合征是一组以胰岛素抵抗为核心,包括腹型肥胖、高血压、血糖异常、血脂紊乱等多种代谢异常的疾病.过氧化物酶体增殖物激活受体(PPARs)是一种配体激活的核转录因子,属于细胞核受体超家族成员.研究显示,PPARs的两个重要亚型PPAR-α和PPAR-γ,其激动剂均能改善胰岛素抵抗、高血压、肥胖等.现就PPAR-α/γ激动剂在代谢综合征的协同作用重点讨论.

  15. Effect of neostigmine on the hippocampal noradrenaline release : role of cholinergic receptors

    NARCIS (Netherlands)

    Kiss, JP; Vizi, ES; Westerink, BHC

    1999-01-01

    THE effect of the cholinesterase inhibitor neostigmine on hippocampal noradrenaline (NA) release was studied using in vivo microdialysis. Local application of neostigmine significantly increased the release of NA. The effect was potentiated by coperfusion of the nicotinic antagonist mecamylamine but

  16. Guanfacine in essential hypertension: Effect on blood pressure, plasma noradrenaline concentration and plasma renin activity

    OpenAIRE

    Schoeppe, W.; Brecht, H. M.

    1980-01-01

    1 The acute and chronic effects of guanfacine on blood pressure, plasma noradrenaline concentration and plasma renin activity were investigated in 23 patients (15 males, 8 females) with essential hypertension (WHO grade I-II).

  17. Peroxisome proliferator-activated receptor (PPAR) alpha and PPAR beta/delta, but not PPAR gamma, modulate the expression of genes involved in cardiac lipid metabolism

    NARCIS (Netherlands)

    Gilde, AJ; van der Lee, KAJM; Willemsen, PHM; Chinetti, G; van der Leij, FR; van der Vusse, GJ; Staels, B; van Bilsen, M

    2003-01-01

    Long-chain fatty acids ( FA) coordinately induce the expression of a panel of genes involved in cellular FA metabolism in cardiac muscle cells, thereby promoting their own metabolism. These effects are likely to be mediated by peroxisome proliferator-activated receptors (PPARs). Whereas the

  18. Review of the expression of peroxisome proliferator-activated receptors alpha (PPAR alpha), beta (PPAR beta), and gamma (PPAR gamma) in rodent and human development.

    Science.gov (United States)

    Abbott, Barbara D

    2009-06-01

    The peroxisome proliferator-activated receptors (PPAR) belong to the nuclear hormone receptor superfamily and there are three primary subtypes, PPARalpha, beta, and gamma. These receptors regulate important physiological processes that impact lipid homeostasis, inflammation, adipogenesis, reproduction, wound healing, and carcinogenesis. These nuclear receptors have important roles in reproduction and development and their expression may influence the responses of an embryo exposed to PPAR agonists. PPARs are relevant to the study of the biological effects of the perfluorinated alkyl acids as these compounds, including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), activate PPARalpha. Exposure of the rodent to PFOA or PFOS during gestation results in neonatal deaths, developmental delay and growth deficits. Studies in PPARalpha knockout mice demonstrate that the developmental effects of PFOA, but not PFOS, depend on expression of PPARalpha. This review provides an overview of PPARalpha, beta, and gamma protein and mRNA expression during mouse, rat, and human development. The review presents the results from many published studies and the information is organized by organ system and collated to show patterns of expression at comparable developmental stages for human, mouse, and rat. The features of the PPAR nuclear receptor family are introduced and what is known or inferred about their roles in development is discussed relative to insights from genetically modified mice and studies in the adult.

  19. Effect of niflumic acid on noradrenaline-induced contractions of the rat aorta.

    OpenAIRE

    D.N. Criddle; de Moura,R.S.; Greenwood, I A; Large, W. A.

    1996-01-01

    1. The effects of niflumic acid, an inhibitor of calcium-activated chloride channels, were compared with the actions of the calcium channel antagonist nifedipine on noradrenaline-evoked contractions in isolated preparations of the rat aorta. 2. The cumulative concentration-effect curve to noradrenaline (NA) was depressed by both nifedipine and niflumic acid in a reversible and concentration-dependent manner. The degree of inhibition of the maximal contractile response to NA (1 microM) produce...

  20. PPAR agonists as therapeutics for CNS trauma and neurological diseases

    Science.gov (United States)

    Mandrekar-Colucci, Shweta; Sauerbeck, Andrew; Popovich, Phillip G.; McTigue, Dana M.

    2013-01-01

    Traumatic injury or disease of the spinal cord and brain elicits multiple cellular and biochemical reactions that together cause or are associated with neuropathology. Specifically, injury or disease elicits acute infiltration and activation of immune cells, death of neurons and glia, mitochondrial dysfunction, and the secretion of substrates that inhibit axon regeneration. In some diseases, inflammation is chronic or non-resolving. Ligands that target PPARs (peroxisome proliferator-activated receptors), a group of ligand-activated transcription factors, are promising therapeutics for neurologic disease and CNS injury because their activation affects many, if not all, of these interrelated pathologic mechanisms. PPAR activation can simultaneously weaken or reprogram the immune response, stimulate metabolic and mitochondrial function, promote axon growth and induce progenitor cells to differentiate into myelinating oligodendrocytes. PPAR activation has beneficial effects in many pre-clinical models of neurodegenerative diseases and CNS injury; however, the mechanisms through which PPARs exert these effects have yet to be fully elucidated. In this review we discuss current literature supporting the role of PPAR activation as a therapeutic target for treating traumatic injury and degenerative diseases of the CNS. PMID:24215544

  1. Modulation of keratinocyte gene expression and differentiation by PPAR-selective ligands and tetradecylthioacetic acid

    DEFF Research Database (Denmark)

    Westergaard, M; Henningsen, J; Svendsen, M L

    2001-01-01

    Peroxisome proliferator-activated receptors (PPARs) are pleiotropic regulators of growth and differentiation of many cell types. We have performed a comprehensive analysis of the expression of PPARs, transcriptional cofactors, and marker genes during differentiation of normal human keratinocytes ...

  2. Functional characterization of the PPAR targets ANGPTL4 and HILPDA in lipid metabolism

    NARCIS (Netherlands)

    Mattijssen, F.B.J.

    2014-01-01

      The peroxisomal proliferator activator receptors (PPARs) are ligand-activated transcription factors that play important roles in the regulation of lipid metabolism. Three PPAR isoforms have been identified: PPARα, PPARβ/δ, and PPARγ. Each isoform has specific functions

  3. Rule of Repression in Chile.

    Science.gov (United States)

    American Indian Journal, 1979

    1979-01-01

    This report on the current condition of the Mapuche Indians of Chile is edited from a document on the "Situation of Human Rights in Chile" and details the repressive and inhumane treatment of the largest indigenous ethnic minority in the country. (Author/RTS)

  4. Molecular Mechanisms and Genome-Wide Aspects of PPAR Subtype Specific Transactivation

    DEFF Research Database (Denmark)

    Bugge, Anne Skovsø; Mandrup, Susanne

    2010-01-01

    The peroxisome proliferator-activated receptors (PPARs) are central regulators of fat metabolism, energy homeostasis, proliferation, and inflammation. The three PPAR subtypes, PPARα, β/δ, and γ activate overlapping but also very different target gene programs. This review summarizes the insights...... into PPAR subtype-specific transactivation provided by genome-wide studies and discusses the recent advances in the understanding of the molecular mechanisms underlying PPAR subtype specificity with special focus on the regulatory role of AF-1....

  5. PPAR and Liver Injury in HIV-Infected Patients

    Directory of Open Access Journals (Sweden)

    Maud Lemoine

    2009-01-01

    Full Text Available Due to the introduction of active HIV antiretroviral treatment, AIDS-related morbidity and mortality have markedly decreased and liver diseases are now a major cause of morbidity and mortality in HIV-infected patients. Chronic liver injury encompasses a wide spectrum of diseases due to HCV and HBV coinfection, drug-related toxicity, and NASH. HIV-infected patients who are receiving treatment present with a high prevalence of metabolic complications and lipodystrophy. Those patients are at high risk of nonalcoholic fatty liver disease, the liver feature of the metabolic syndrome. This review will focus on (1 the liver injuries in HIV-infected patients; (2 both the current experimental and human data regarding PPAR and liver diseases; (3 the interactions between HIV and PPAR; (4 the potential use of PPAR agonists for the management of HIV-related liver diseases.

  6. [Peroxisome proliferator-activated receptors (PPAR). Antiproliferative properties].

    Science.gov (United States)

    Hojka, Anna; Rapak, Andrzej

    2011-06-21

    Peroxisome proliferator-activated receptors (PPAR) are transcription factors that belong to the hormone nuclear receptor superfamily. Their main role is control of fatty acid metabolism and to maintain glucose homeostasis. Isotype γ of PPAR can also be implicated in proliferation and cellular differentiation of both normal and cancer cells. Compounds that are PPARγ ligands have a negative influence on cancer cells and can induce apoptosis, inhibit proliferation or induce cellular differentiation of these cells. This review summarizes general information about PPAR and focuses on anticancer activities of PPARγ ligands and their use in combined therapy. Combination treatment using PPARγ ligands and other agents, especially retinoids and specific kinase inhibitors, may be an effective strategy for chemoprevention and treatment of some cancers.

  7. VLDL hydrolysis by LPL activates PPAR-alpha through generation of unbound fatty acids.

    Science.gov (United States)

    Ruby, Maxwell A; Goldenson, Benjamin; Orasanu, Gabriela; Johnston, Thomas P; Plutzky, Jorge; Krauss, Ronald M

    2010-08-01

    Recent evidence suggests that lipoproteins serve as circulating reservoirs of peroxisomal proliferator activated receptor (PPAR) ligands that are accessible through lipolysis. The present study was conducted to determine the biochemical basis of PPAR-alpha activation by lipolysis products and their contribution to PPAR-alpha function in vivo. PPAR-alpha activation was measured in bovine aortic endothelial cells following treatment with human plasma, VLDL lipolysis products, or oleic acid. While plasma failed to activate PPAR-alpha, oleic acid performed similarly to VLDL lipolysis products. Therefore, fatty acids are likely to be the PPAR-alpha ligands generated by VLDL lipolysis. Indeed, unbound fatty acid concentration determined PPAR-alpha activation regardless of fatty acid source, with PPAR-alpha activation occurring only at unbound fatty acid concentrations that are unachievable under physiological conditions without lipase action. In mice, a synthetic lipase inhibitor (poloxamer-407) attenuated fasting-induced changes in expression of PPAR-alpha target genes. Apolipoprotein CIII (apoCIII), an endogenous inhibitor of lipoprotein and hepatic lipase, regulated access to the lipoprotein pool of PPAR-alpha ligands, because addition of exogenous apoCIII inhibited, and removal of endogenous apoCIII potentiated, lipolytic PPAR-alpha activation. These data suggest that the PPAR-alpha response is generated by unbound fatty acids released locally by lipase activity and not by circulating plasma fatty acids.

  8. Polymorphisms in NF-kappa B, PXR, LXR, PPAR gamma and risk of inflammatory bowel disease

    DEFF Research Database (Denmark)

    Andersen, Vibeke; Christensen, Jane; Ernst, Anja

    2011-01-01

    AIM: To investigate the contribution of polymorphisms in nuclear receptors to risk of inflammatory bowel disease (IBD). METHODS: Genotypes of nuclear factor (NF)-kappa B (NFKB1) NF kappa B -94ins/del (rs28362491); peroxisome proliferator-activated receptor (PPAR)-gamma (PPAR gamma) PPAR gamma Pro12...

  9. Genome-wide analysis of PPAR Alpha activation in murine small intestine

    NARCIS (Netherlands)

    Bünger, M.; Bosch, van den H.M.; Meijde, van der J.; Kersten, A.H.; Hooiveld, G.J.E.J.; Müller, M.R.

    2007-01-01

    The peroxisome proliferator-activated receptor alpha (PPAR) is a fatty acid-activated transcription factor that governs a variety of biological processes. Little is known about the role of PPAR in the small intestine. Since this organ is frequently exposed to high levels of PPAR ligands via the

  10. Atherosclerosis and cardiovascular risk reduction with PPAR agonists.

    Science.gov (United States)

    Kuusisto, Johanna; Andrulionyte, Laura; Laakso, Markku

    2007-10-01

    Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors belonging to the nuclear receptor superfamily. Three isoforms, PPARalpha, PPARgamma, and PPARdelta, which are encoded by separate genes, have been identified. The PPARs act as gene regulators of various metabolic pathways in energy and lipid metabolism, glucose homeostasis, adipogenesis, and inflammation. Two key classes of synthetic compounds, fibrates and thiazolidinediones (glitazones), activate PPARalpha and PPARgamma, respectively. Both of these drugs have several properties that prevent atherosclerosis in the vascular wall and reduce the levels of risk factors for cardiovascular disease. However, clinical trials have not produced convincing evidence that cardiovascular disease is prevented with the use of PPARalpha and PPARgamma agonists.

  11. (/sup 3/H)desipramine binding to rat brain tissue: binding to both noradrenaline uptake sites and sites not related to noradrenaline neurons

    Energy Technology Data Exchange (ETDEWEB)

    Baeckstroem, I.T.Ro.; Ross, S.B.; Marcusson, J.O.

    1989-04-01

    The pharmacological and biochemical characteristics of (3H)desipramine binding to rat brain tissue were investigated. Competition studies with noradrenaline, nisoxetine, nortriptyline, and desipramine suggested the presence of more than one (3H)desipramine binding site. Most of the noradrenaline-sensitive binding represented a high-affinity site, and this site appeared to be the same as the high-affinity site of nisoxetine-sensitive binding. The (3H)desipramine binding sites were abolished by protease treatment, a result suggesting that the binding sites are protein in nature. When specific binding was defined by 0.1 microM nisoxetine, the binding was saturable and fitted a single-site binding model with a binding affinity of approximately 1 nM. This binding fraction was abolished by lesioning of the noradrenaline neurons with the noradrenaline neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). In contrast, when 10 microM nisoxetine was used to define the specific binding, the binding was not saturable over the nanomolar range, but the binding fitted a two-site binding model with KD values of 0.5 and greater than 100 nM for the high- and low-affinity components, respectively. The high-affinity site was abolished after DSP4 lesioning, whereas the low-affinity site remained. The binding capacity (Bmax) for binding defined by 0.1 microM nisoxetine varied between brain regions, with very low density in the striatum (Bmax not possible to determine), 60-90 fmol/mg of protein in cortical areas and cerebellum, and 120 fmol/mg of protein in the hypothalamus. The binding capacities of these high-affinity sites correlated significantly with the regional distribution of (3H)noradrenaline uptake but not with 5-(3H)hydroxytryptamine uptake.

  12. Impact of Interaction Between PPAR Alpha and PPAR Gamma on Breast Cancer Risk in the Chinese Han Population.

    Science.gov (United States)

    Lianggeng, Xiong; Baiwu, Liang; Maoshu, Bai; Jiming, Liu; Youshan, Li

    2017-08-01

    Several studies have been conducted to investigate the association of the peroxisome proliferator-activated receptor (PPAR) alpha (PPAR A) and PPAR gamma (PPAR G) polymorphism and breast cancer (BC) risk, but the results were inconsistent, and, until now, no study focused on the impact of gene-gene interactions between PPAR A and PPAR G on BC risk; thus, the aim of this study was to investigate the impact of interaction between PPAR A and PPAR G on BC risk in the Chinese Han population. A total of 862 participants with a mean age of 63.0 ± 15.7 years were selected, including 432 patients with BC and 430 controls. A logistic regression model was used to examine the association between single-nucleotide polymorphisms and BC risk. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Generalized multifactor dimensionality reduction was employed to analyze the gene-gene interaction. Logistic regression analysis showed that BC risk was significantly higher in carriers of G allele of rs1800206 polymorphism than those with CC (CG + GG vs. CC) (adjusted OR, 1.50; 95% CI, 1.20-1.93). In addition, we found that BC risk was also significantly higher in carriers of the G allele of the rs1805192 polymorphism than those with the CC genotype (CG + GG vs. CC) (adjusted OR, 1.78; 95% CI, 1.34-2.26). There was a significant gene-gene interaction between rs1805192 and rs1800206. Overall, the 2-locus models had a cross-validation consistency of 10 of 10, and had a testing accuracy of 60.11%. Patients with CG or GG of rs1805192 and CG or GG of rs1800206 genotype have the highest BC risk, compared with patients with CC of rs1805192 and CC of rs1800206 genotype (OR, 2.59; 95% CI, 1.70-3.48, after covariates adjustment for gender, age, age at menarche, number of children, body mass index, and waist circumference). The minor allele of rs1800206 and rs1805192 and its interaction were associated with increased BC risk. Copyright © 2016 Elsevier Inc. All rights

  13. The Current Knowledge of the Role of PPAR in Hepatic Ischemia-Reperfusion Injury

    Science.gov (United States)

    Elias-Miró, M.; Jiménez-Castro, M. B.; Mendes-Braz, M.; Casillas-Ramírez, A.; Peralta, C.

    2012-01-01

    Strategies to improve the viability of steatotic livers could reduce the risk of dysfunction after surgery and increase the number of organs suitable for transplantation. Peroxisome proliferator-activated receptors (PPARs) are major regulators of lipid metabolism and inflammation. In this paper, we review the PPAR signaling pathways and present some of their lesser-known functions in liver regeneration. Potential therapies based on PPAR regulation will be discussed. The data suggest that further investigations are required to elucidate whether PPAR could be a potential therapeutic target in liver surgery and to determine the most effective therapies that selectively regulate PPAR with minor side effects. PMID:22675337

  14. Dual and pan-peroxisome proliferator-activated receptors (PPAR co-agonism: the bezafibrate lessons

    Directory of Open Access Journals (Sweden)

    Tenenbaum Alexander

    2005-09-01

    Full Text Available Abstract There are three peroxisome proliferator-activated receptors (PPARs subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. The new generation of dual-action PPARs – the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar are on deck in late-stage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar. The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan – (alpha, beta/delta, gamma PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients

  15. Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons

    Science.gov (United States)

    Tenenbaum, Alexander; Motro, Michael; Fisman, Enrique Z

    2005-01-01

    There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. The new generation of dual-action PPARs – the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) are on deck in late-stage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar). The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan – (alpha, beta/delta, gamma) PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding) as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients with features of

  16. Network analysis identifies a putative role for the PPAR and type 1 interferon pathways in glucocorticoid actions in asthmatics

    Directory of Open Access Journals (Sweden)

    Diez Diego

    2012-06-01

    focused studies can be designed. In this case, results suggested a mechanism whereby GCs repress TLR-mediated interferon production via upregulation of the PPAR signaling pathway. These results highlight the role of interferons in asthma and their potential as targets of future therapeutic efforts.

  17. Characterization of nicotinic receptors involved in the release of noradrenaline from the hippocampus

    Energy Technology Data Exchange (ETDEWEB)

    Vizi, E.S. [Institute of Experimental Medicine, Hungarian Academy of Sciences, P.O. Box 67, H-1450 Budapest (Hungary); Lajtha, A. [Center of Neurochemistry, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY (United States); Balla, A. [Institute of Experimental Medicine, Hungarian Academy of Sciences, P.O. Box 67, H-1450 Budapest (Hungary); Sershen, H. [Center of Neurochemistry, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY (United States)

    1997-01-06

    The pharmacological features of putative nicotinic acetylcholine receptor sites involved in the release of [{sup 3}H]noradrenaline were assessed in rat hippocampus. The effect of nicotinic agonists to induce [{sup 3}H]noradrenaline release was examined in superfused slices. The nicotinic agonists (-)-epibatidine, (+)-anatoxin-a, dimethylphenylpiperazinium, (-)-nicotine and (-)-lobeline released [{sup 3}H]noradrenaline. The dose-response curves to nicotinic agonists were bell shaped, and indicated that their functional efficacies and potency vary across agonists. Maximal efficacy was seen with dimethylphenylpiperazinium and lobeline (E{sub max} values two to three times higher than other agonists). The rank order of potency for the agonists to release [{sup 3}H]noradrenaline was (-)-epibatidine (+)-anatoxin-a dimethylphenylpiperazinium cytisine nicotine (-)-lobeline. The nicotinic acetylcholine receptor antagonists [n-bungarotoxin (+)-tubocurarine hexamethonium>>{alpha}-bungarotoxin=dihydro-{beta}-erythroidine] and tetrodotoxin antagonized the effect of dimethylphenylpiperazinium to release [{sup 3}H]noradrenaline. The results, based on these pharmacological profiles, suggest the possible involvement of nicotinic acetylcholine receptor {alpha}3 and {beta}2 nicotinic acetylcholine receptor subunits in the control of [{sup 3}H]noradrenaline release from hippocampal slices. The absence of effect of {alpha}-bungarotoxin and {alpha}-conotoxin-IMI excludes the possible involvement of nicotinic acetylcholine receptors containing the {alpha}7 subunit. The release of [{sup 3}H]noradrenaline by dimethylphenylpiperazinium was Ca{sup 2+} dependent. Nifedipine failed to prevent the dimethylphenylpiperazinium-induced release of [{sup 3}H]noradrenaline, but Cd{sup 2+}, {omega}-conotoxin and Ca{sup 2+}-free conditions significantly reduced the dimethylphenylpiperazinium-induced release, suggesting that N-type voltage-sensitive Ca{sup 2+} channels are involved in the nicotinic

  18. 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

  19. The Roles of PPARs in the Fetal Origins of Metabolic Health and Disease

    Directory of Open Access Journals (Sweden)

    William D. Rees

    2008-01-01

    Full Text Available Beyond the short-term effects on fertility, there is increasing evidence that obesity or the consumption of an inappropriate diet by the mother during pregnancy adversely affects the long-term health of her offspring. PPAR and RXR isotypes are widely expressed in reproductive tissues and in the developing fetus. Through their interactions with fatty acids, they may mediate adaptive responses to the changes in the maternal diet. In the maturing follicle, PPAR-γ has an important role in the granulosa cells that surround the maturing oocyte. After fertilisation, PPAR-γ and PPAR-β/δ are essential regulators of placentation and the subsequent development of key metabolic tissues such as skeletal muscle and adipose cells. Activation of PPAR-γ and PPAR-β/δ during fetal development has the potential to modify the growth and development of these tissues. PPAR-α is expressed at low levels in the fetal liver, however, this expression may be important, as changes in the methylation of DNA in its promoter region are reported to take place during this period of development. This epigenetic modification then programmes subsequent expression. These findings suggest that two separate PPAR-dependent mechanisms may be involved in the fetal adaptations to the maternal diet, one, mediated by PPAR-γ and PPAR-β/δ, regulating cell growth and differentiation; and another adapting long-term lipid metabolism via epigenetic changes in PPAR-α to optimise postnatal survival.

  20. [The role of peroxisome proliferator-activated receptors (PPAR) in carcinogenesis].

    Science.gov (United States)

    Knapp, Paweł; Jarzabek, Katarzyna; Błachnio, Agnieszka; Zbroch, Tomasz

    2006-08-01

    Peroxisome proliferators-activated receptors are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. The PPAR subfamily consists of three members: PPAR-alpha, PPAR-sigma (NUC-1 or beta) and PPAR-gamma. PPARs regulate gene expression by binding, as heterodimers with retinoid X receptors (RXR), to specific response elements (PPREs) in the promoter regions of target genes. The prostaglandin 12 especially, all arachidonic acid metabolites and polyunsaturated fatty acids are naturally occuring PPAR ligands. Synthetic PPAR ligands are thiazolidinediones (TZDs--rosiglitazone, pioglitazone, troglitazone). Activation of nuclear hormone receptors has been identified as an approach to induce differentiation and inhibit proliferation of cancer lines. The anti-proliferative, pro-differentiation effects of PPAR activators (TZDs) suggest that these compounds might be useful in slowing the proliferation of un-differentiated tumour cells. TZDs inhibit proliferation of human breast, prostate and colon cancers, both in vitro and in tumours derived from these cells implanted into rodents. Furthermore, recent studies show that PPAR-gamma ligands are potent inhibitors of angiogenesis, a process essential for solid-tumour growth and metastasis. In conclusion, the evidence to date suggests that activation of PPAR should suppress tumour growth and development. This represents an exciting novel therapeutic application of TZDs. In present paper, structural features of PPARs, their gene transcription mechanisms and recent developments in the discovery of their biological functions are reviewed.

  1. Unimpaired thermogenic response to noradrenaline in genetic (ob/ob) and hypothalamic (MSG) obese mice.

    Science.gov (United States)

    Duloo, A G; Miller, D S

    1984-04-01

    The thermogenic response to noradrenaline administration was investigated at 25 degrees C in two models of obese mice (genetic ob/ob obesity of the ' QEC ' strain and monosodium-glutamate-induced obesity) and in their respective lean littermates. Subcutaneous injections of a low dose of noradrenaline (100 micrograms/kg body wt.) elevated metabolic rate by about 30% in both obese models but not in their respective lean counterparts. In contrast, the increase in metabolic rate after injections of a high dose of noradrenaline (600 micrograms/kg body wt.) was of a similar magnitude in both lean and obese animals: metabolic rate was increased by 70-80%. These results indicate that the overall whole body thermogenic capacity is unimpaired at room temperature in this ' QEC ' strain of ob/ob mice and in the hypothalamic damaged obese mice. Obesity in these models is therefore not associated with a reduced ability to respond to noradrenaline but could rather be due to a failure to release noradrenaline.

  2. Impact of targeted PPAR gamma disruption on bone remodeling

    Science.gov (United States)

    Peroxisome proliferator-activated receptor gamma (PPAR gamma), known as the master regulator of adipogenesis, has been regarded as a promising target for new anti-osteoporosis therapy due to its role in regulating bone marrow mesenchymal stem/progenitor cell (BMSC) lineage commitment. However, the p...

  3. ACBP - a PPAR and SREBP modulated housekeeping gene

    DEFF Research Database (Denmark)

    Neess, Ditte; Kiilerich, Pia; Sandberg, Maria B

    2006-01-01

    by members of the PPAR and SREBP families. In adipocytes, PPARgamma is in part responsible for the induction during adipocyte differentiation, but other transcription factors appear to play a role as well. In hepatocytes, SREBP-1c is the main regulator of ACBP in response to changes in insulin levels during...

  4. PPAR gamma and the global map of adipogenesis and beyond

    DEFF Research Database (Denmark)

    Lefterova, M. I.; Haakonsson, A. K.; Lazar, M. A.;

    2014-01-01

    Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors (TFs) and function as a master regulator of adipocyte differentiation and metabolism. We review recent breakthroughs in the understanding of...

  5. 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.

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

    DEFF Research Database (Denmark)

    Grøntved, Lars; Nielsen, Ronni; Stunnenberg, Henk

    physiological scenarios. PPARa and PPARd are transcriptional regulators of fatty acid oxidation and ketogenesis, whereas PPAR? controls genes involved in lipid storage. Consequently, there must be PPAR subtype specific molecular determinants that secure PPAR selective recognition and activation of target...... promoters in a given cell type. In vitro experiments suggest that the different PPAR subtypes might have dissimilar binding preference for some PPAR target sites and may also have different affinity for some transcriptional co-factors. However the molecular mechanisms behind PPAR subtype specific activation...... 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...

  7. Healing the diabetic heart: modulation of cardiometabolic syndrome through peroxisome proliferator activated receptors (PPARs).

    Science.gov (United States)

    Huang, Tom Hsun-Wei; Roufogalis, Basil D

    2012-06-01

    Cardiometabolic syndrome is a mixture of interrelated risk factors predisposing individuals to elevated risk of atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Nuclear receptors, specifically peroxisome proliferator-activated receptors (PPARs), were identified to play a pivotal role in the regulation of metabolic homeostasis. However, with rosiglitazone currently under intense scrutiny great concerns have arisen regarding the safety of the thiazolidinedione PPAR-γ agonist family as a whole. This review discusses the current concern with PPAR-γ agonists by exploring if PPARs can still be considered worth pursuing as a viable target for cardiovascular diseases. We examine current research focusing on identifying ligands that are dual and pan-PPAR agonists, selective PPAR-γ modulators, PPAR-β/δ agonists and that are of natural origin.

  8. 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

  9. Response Surface Modelling of Noradrenaline Production in Hairy Root Culture of Purslane (Portulaca oleracea L.

    Directory of Open Access Journals (Sweden)

    Mehdi Ghorbani

    2015-03-01

    Full Text Available Common purslane (Portulaca oleracea L. is an annual plant as one of the natural sources for noradrenaline hormone. In this research, hairy root culture of purslane was established by using Agrobacterium rhizogenes strain ATCC 15834. In the following, Box-Behnken model of response surface methodology (RSM was employed to optimize B5 medium for the growth of P. oleracea L. hairy root line. According to the results, modelling and optimization conditions, including sucrose, CaCl2.H2O, H2PO4 and NO3-/NH4+ concentrations on maximum dry weight (0.155 g and noradrenaline content (0.36 mg.g-1 DW was predicted. These optimal conditions predicted by RSM were confirmed the enhancement of noradrenaline production as an application potential for production by hairy root cultures.

  10. Soy peptide ingestion augments the synthesis and metabolism of noradrenaline in the mouse brain.

    Science.gov (United States)

    Imai, Haruka; Moriyasu, Kazuki; Nakahata, Akane; Maebuchi, Motohiro; Ichinose, Takashi; Furuya, Shigeki

    2017-05-01

    To examine whether edible peptide intake affects neurotransmitter metabolism in the brain, we evaluated the effect of peptides derived from soy proteins or fish collagen on free amino acids and monoamines in the mouse brain. Ingestion of soy peptides led to markedly higher levels of tyrosine, a catecholamine precursor, in the serum, and cerebral cortex compared to those following ingestion of vehicle alone or collagen peptides. Soy peptide ingestion also effectively increased 3-methoxy-4-hydroxyphenylethyleneglycol and normetanephrine, the principal metabolites of noradrenaline, in the cerebral cortex, hippocampus, and brainstem, whereas collagen peptides did not exert such effects. Further, soy peptide ingestion led to a significant increase in noradrenaline itself in the brainstem, where noradrenergic neurons are present. Noradrenergic turnover was also markedly stimulated in these regions after soy peptide ingestion. These in vivo observations suggest that soy peptide ingestion can maintain and promote the synthesis and metabolism of noradrenaline in the brain.

  11. Interactions between noradrenaline and corticosteroids in the brain: from electrical activity to cognitive performance

    Directory of Open Access Journals (Sweden)

    Harmen J Krugers

    2012-04-01

    Full Text Available One of the core reactions in response to a stressful situation is the activation of the hypothalamus–pituitary–adrenal (HPA axis which increases the release of glucocorticoid hormones from the adrenal glands. In concert with other neuro-modulators, such as (noradrenaline, these hormones enable and promote cognitive adaptation to stressful events. Recent studies have demonstrated that glucocorticoid hormones and noradrenaline, via their receptors, can both rapidly and persistently regulate the function of excitatory synapses which are critical for storage of information. Here we will review how glucocorticoids and noradrenaline alone and in synergy dynamically tune these synapses in the hippocampus and amygdala, and discuss how these hormones interact to promote behavioral adaptation to stressful situations.

  12. 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.

  13. Intrathecal DSP4 selectively depletes spinal noradrenaline and attenuates morphine analgesia.

    Science.gov (United States)

    Zhong, F X; Ji, X Q; Tsou, K

    1985-10-22

    The noradrenergic neurotoxin DSP4 was injected intrathecally into the lumbar spinal subarachnoid space of the rat. After 10 days, dose-response curves for tail-flick inhibition were determined for both intraperitoneal and intraventricular injections of morphine. In rats pretreated with DSP4, the analgesic effect of morphine given either intraventricularly or intraperitoneally was significantly attenuated. The noradrenaline and 5-hydroxytryptamine contents in the brain-stem and the spinal cord were also measured. Intrathecal DSP4 depleted noradrenaline in the spinal cord but not in the brain-stem. Neither brain-stem or spinal cord 5-hydroxytryptamine was affected by DSP4.

  14. Chronic noradrenaline increases renal expression of NHE-3, NBC-1, BSC-1 and aquaporin-2.

    Science.gov (United States)

    Sonalker, Prajakta A; Tofovic, Stevan P; Bastacky, Sheldon I; Jackson, Edwin K

    2008-05-01

    1. Because chronic activation of the renal sympathetic nervous system promotes sodium and water retention, it is conceivable that long-term exposure of the kidney to the sympathetic neurotransmitter noradrenaline upregulates the expression of key renal epithelial transport systems. 2. To test this hypothesis, we used immunoblotting of renal cortical and medullary tissue to investigate the abundance of major transport systems expressed along the renal tubule in response to long-term (15 days) infusions of noradrenaline (600 ng/min) in rats. 3. Mean arterial blood pressure and heart rate were significantly elevated in rats receiving chronic infusions of noradrenaline (128 +/- 10 mmHg and 492 +/- 16 b.p.m., respectively) compared with animals treated with saline only (89 +/- 3 mmHg and 376 +/- 14 b.p.m., respectively). 4. Chronic infusions of noradrenaline also increased the protein abundance of the cortical Na(+)/H(+) exchanger isoform 3 (NHE-3; 2.5-fold; P = 0.0142), the cortical sodium-bicarbonate cotransporter NBC-1 (2.5-fold; P = 0.0067), the bumetanide-sensitive sodium-potassium-chloride cotransporter BSC-1/NKCC2 in the inner stripe of outer medulla (threefold; P = 0.0020) and aquaporin-2 in the inner medulla (twofold; P = 0.0039). 5. In contrast, noradrenaline did not significantly affect expression of the thiazide-sensitive Na(+)-Cl(-) cotransporter in the cortex, Na(+)/K(+)-ATPase-alpha(1) in the cortex and inner stripe of the outer or inner medulla, the inwardly rectifying K(+) channel (ROMK-1) in the inner stripe of the outer medulla or aquaporin-1 in the cortex or inner medulla. Noradrenaline did significantly, but modestly (less than twofold), increase aquaporin-1 in the inner stripe of the outer medulla. 6. We conclude that noradrenaline-induced increases in the expression of NHE-3, NBC-1, BSC-1 and aquaporin-2 are likely to play an important role in the regulation of salt and water transport by noradrenaline in the kidney and may explain, at least in

  15. 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.

  16. Cutaneous noradrenaline measured by microdialysis in complex regional pain syndrome during whole-body cooling and heating

    DEFF Research Database (Denmark)

    Terkelsen, Astrid Juhl; Gierthmühlen, Janne; Petersen, Lars J.

    2013-01-01

    noradrenaline, vasoconstriction, and reduction in skin temperature. The main findings were that the noradrenaline response did not differ between patients and controls or between the CRPS hand and the contralateral unaffected hand, suggesting that the evoked noradrenaline release from the cutaneous sympathetic......Complex regional pain syndrome (CRPS) is characterised by autonomic, sensory, and motor disturbances. The underlying mechanisms of the autonomic changes in CPRS are unknown. However, it has been postulated that sympathetic inhibition in the acute phase with locally reduced levels of noradrenaline...... and in healthy volunteers. Seven patients and nine controls completed whole-body cooling (sympathetic activation) and heating (sympathetic inhibition) induced by a whole-body thermal suit with simultaneous measurement of the skin temperature, skin blood flow, and release of dermal noradrenaline. CRPS pain...

  17. PPARs and Mitochondrial Metabolism: From NAFLD to HCC

    Science.gov (United States)

    Galli, Andrea

    2016-01-01

    Metabolic related diseases, such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD), are widespread threats which bring about a significant burden of deaths worldwide, mainly due to cardiovascular events and cancer. The pathogenesis of these diseases is extremely complex, multifactorial, and only partially understood. As the main metabolic organ, the liver is central to maintain whole body energetic homeostasis. At the cellular level, mitochondria are the metabolic hub connecting and integrating all the main biochemical, hormonal, and inflammatory signaling pathways to fulfill the energetic and biosynthetic demand of the cell. In the liver, mitochondria metabolism needs to cope with the energetic regulation of the whole body. The nuclear receptors PPARs orchestrate lipid and glucose metabolism and are involved in a variety of diseases, from metabolic disorders to cancer. In this review, focus is placed on the roles of PPARs in the regulation of liver mitochondrial metabolism in physiology and pathology, from NAFLD to HCC.

  18. SIRT2 suppresses adipocyte differentiation by deacetylating FOX01 and enhancing FOXO1's repressive interaction with PPAR gamma

    Science.gov (United States)

    Sirtuin family of proteins possesses NAD-dependent deacetylase and ADP ribosyltransferase activities. They are found to respond to nutrient deprivation and profoundly regulate metabolic functions. We have previously reported that caloric restriction increases the expression of one of the seven mamma...

  19. PPARgene: A Database of Experimentally Verified and Computationally Predicted PPAR Target Genes.

    Science.gov (United States)

    Fang, Li; Zhang, Man; Li, Yanhui; Liu, Yan; Cui, Qinghua; Wang, Nanping

    2016-01-01

    The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear receptor superfamily. Upon ligand binding, PPARs activate target gene transcription and regulate a variety of important physiological processes such as lipid metabolism, inflammation, and wound healing. Here, we describe the first database of PPAR target genes, PPARgene. Among the 225 experimentally verified PPAR target genes, 83 are for PPARα, 83 are for PPARβ/δ, and 104 are for PPARγ. Detailed information including tissue types, species, and reference PubMed IDs was also provided. In addition, we developed a machine learning method to predict novel PPAR target genes by integrating in silico PPAR-responsive element (PPRE) analysis with high throughput gene expression data. Fivefold cross validation showed that the performance of this prediction method was significantly improved compared to the in silico PPRE analysis method. The prediction tool is also implemented in the PPARgene database.

  20. The role of stress and noradrenaline in prepulse inhibition, a rodent study : implications for schizophrenia

    NARCIS (Netherlands)

    Sontag, Thomas Alexander

    2003-01-01

    In this study we investigated the role of stress and noradrenaline in schizophrenia. Among others schizophrenic patients display reductions in prepulse inhibition. Since this behavioural response can be measured in both humans and animals it opens the possibility to use rats in schizophrenia researc

  1. Whole body and regional clearances of noradrenaline and adrenaline in man

    DEFF Research Database (Denmark)

    Christensen, N J; Galbo, H; Gjerris, Anne Cathrine Roslev;

    1984-01-01

    The whole body clearance of noradrenaline (NA) was measured in seven patients pre- and postoperatively. L-3H-NA was infused intravenously for 90 min and steady-state concentrations of L-3H-NA were measured in both arterial and peripheral venous blood. Preoperatively, in the resting supine position...

  2. The Dynamic cerebral autoregulatory adaptive response to noradrenaline is attenuated during systemic inflammation in humans

    DEFF Research Database (Denmark)

    Berg, Ronan M G; Plovsing, Ronni R; Bailey, Damian M;

    2015-01-01

    CA following lipopolysaccharide (LPS) infusion, a human-experimental model of the systemic inflammatory response during early sepsis. The dCA in eight healthy males was examined prior to and during an intended noradrenaline-induced MAP increase of approximately 30 mmHg. This was performed at baseline...... neuroprotective effect by enhancing dCA in patients with early sepsis....

  3. Whole body and regional clearances of noradrenaline and adrenaline in man

    DEFF Research Database (Denmark)

    Christensen, N J; Galbo, H; Gjerris, Anne Cathrine Roslev

    1984-01-01

    The whole body clearance of noradrenaline (NA) was measured in seven patients pre- and postoperatively. L-3H-NA was infused intravenously for 90 min and steady-state concentrations of L-3H-NA were measured in both arterial and peripheral venous blood. Preoperatively, in the resting supine position...

  4. ATTENUATION OF HALOPERIDOL-INDUCED CATALEPSY BY NORADRENALINE AND L-THREO-DOPS

    NARCIS (Netherlands)

    VERHAGENKAMERBEEK, WDJ; HAZEMEIJER, [No Value; KORF, J; LAKKE, JPWF

    1993-01-01

    In addition to impaired dopaminergic neurotransmission a dysfunctional noradrenergic system has been demonstrated in Parkinson's disease. L-threo-3,4-dihydroxyphenylserine (DOPS), a synthetic precursor of noradrenaline (NA), appears to be effective in the treatment of some akinetic symptoms in parki

  5. CO-RELEASED ADRENALINE MARKEDLY FACILITATES NORADRENALINE OVERFLOW THROUGH PREJUNCTIONAL BETA(2)-ADRENOCEPTORS DURING SWIMMING EXERCISE

    NARCIS (Netherlands)

    COPPES, RP; SMIT, J; BENTHEM, L; VANDERLEEST, J; ZAAGSMA, J

    1995-01-01

    The effect of intravenously applied (-)adrenaline, taken up by and released from sympathetic nerves, on swimming exercise-induced noradrenaline overflow in permanently cannulated adrenal demedullated rats was studied. Adrenaline (100 ng/min) was infused for 2 h, during which a plasma concentration o

  6. Microdialysis reveals dynamics of coupling between noradrenaline release and melatonin secretion in conscious rats

    NARCIS (Netherlands)

    Drijfhout, W.J; van der Linde, A.G; de Vries, J.B; Grol, Cor; Westerink, B.H.C.

    1996-01-01

    The coupling between noradrenergic innervation of the pineal gland and melatonin production was investigated. Previously, the development of a microdialysis; technique was described which made it possible to study the noradrenaline (NA) input as well as the melatonin output with high time resolution

  7. Interactions between noradrenaline and corticosteroids in the brain: from electrical activity to cognitive performance.

    NARCIS (Netherlands)

    Krugers, H.J.; Karst, H.; Joëls, M.

    2012-01-01

    One of the core reactions in response to a stressful situation is the activation of the hypothalamus-pituitary-adrenal axis which increases the release of glucocorticoid hormones from the adrenal glands. In concert with other neuro-modulators, such as (nor)adrenaline, these hormones enable and promo

  8. Role of alpha adrenoceptors in the nucleus accumbens in the control of accumbal noradrenaline efflux: a microdialysis study with freely moving rats.

    NARCIS (Netherlands)

    Aono, Y.; Saigusa, T.; Watanabe, S.; Iwakami, T.; Mizoguchi, N.; Ikeda, H.; Ishige, K.; Tomiyama, K.; Oi, Y.; Ueda, K.; Rausch, W.D.; Waddington, J.L.; Ito, Y.; Koshikawa, N.; Cools, A.R.

    2007-01-01

    Microdialysis technique was used to study the effects of the locally applied alpha adrenoceptor agonist phenylephrine and antagonist phentolamine on the basal noradrenaline efflux as well as on the noradrenaline uptake inhibitor desipramine-elicited noradrenaline efflux in the nucleus accumbens (NAc

  9. Dual effect of DMPP on the resting release of noradrenaline from rat hippocampal slices.

    Science.gov (United States)

    Kiss, J P; Windisch, K; Balla, A; Sershen, H; Lajtha, A

    1997-01-01

    The effect of the nicotinic receptor agonist dimethylphenylpiperazinium iodide (DMPP) on the resting release of [3H]noradrenaline from superfused hippocampal slices was studied in rat. Continuous administration of DMPP at a concentration range of 1-100 microM increased the [3H]noradrenaline release in a dose-dependent manner. The response to DMPP was characterized by an immediate steep increase (peak response) followed by a sudden decline to a lower level that was constant with time (tall response) and still was significantly higher than the spontaneous release. Further analysis revealed that the release of noradrenaline in response to DMPP consists of two components. While nicotinic receptor antagonists (mecamylamine 10 microM, pancuronium 10 microM, pipecuronium 10 microM), the nonselective Ca-antagonist Cd2+ (125 microM) and tetrodotoxin (TTX, 1 microM) completely abolished the peak response (phase I), they had no effect on the tall response (phase II). Ca(2+)-free medium containing 1 mM EGTA also blocked phase I but in contrast with other drugs enhanced phase II. The release during phase I is subject to presynaptic feedback modulation, since the alpha 2-adrenoceptor agonist xylazine (3 microM) inhibited the DMPP-evoked stimulation of [3H]noradrenaline release, that inhibition was antagonized by a selective alpha 2-adrenoceptor antagonist, (+/-)-[7,8-(methylenedioxy)-14-alpha-hydroxyalloberbane hydrochloride [(+/-)-CH-38083] (2 microM). (+/-)-CH-38083 (2 microM) alone significantly enhanced the DMPP-evoked increase of [3H]noradrenaline release. Phase II was not effected by alpha 2-adrenergic drugs. Whereas the noradrenaline uptake blockers despramine (DMI, 1-10 microM), nisoxetine (1-10 microM), and nomifensine (10 microM) inhibited both phases, nomifensine at a concentration of 1 microM selectively blocked only phase II. Our data indicate that DMPP has a dual effect on the hippocampal noradrenaline release: phase I is a transient, nicotinic receptor

  10. RNAi and heterochromatin repress centromeric meiotic recombination

    DEFF Research Database (Denmark)

    Ellermeier, Chad; Higuchi, Emily C; Phadnis, Naina

    2010-01-01

    to genetic disabilities, including birth defects. The basis by which centromeric meiotic recombination is repressed has been largely unknown. We report here that, in fission yeast, RNAi functions and Clr4-Rik1 (histone H3 lysine 9 methyltransferase) are required for repression of centromeric recombination...

  11. Histamine H3 receptor-mediated inhibition of noradrenaline release in pig retina discs.

    Science.gov (United States)

    Schlicker, E; Schunack, W; Göthert, M

    1990-11-01

    Discs of pig retina were preincubated with 3H-noradrenaline, 3H-dopamine or 3H-serotonin and then superfused. Electrical field stimulation increased the outflow of tritium from discs preincubated with 3H-noradrenaline or 3H-dopamine, but no from discs preincubated with 3H-serotonin. The tritium content at the end of superfusion was similar in discs preincubated with 3H-noradrenaline or 3H-dopamine but about tenfold lower in discs preincubated with 3H-serotonin. The tritium content in discs preincubated with 3H-noradrenaline was markedly reduced when desipramine was present during preincubation but was not affected by selective inhibitors of dopamine and serotonin uptake. The tritium content in discs preincubated with 3H-dopamine and 3H-serotonin, in contrast, was reduced or tended to be reduced by a selective dopamine and serotonin uptake inhibitor, respectively. The electrically evoked overflow of tritium from discs preincubated with 3H-noradrenaline was abolished by tetrodotoxin or omission of Ca2+. In discs superfused with desipramine, the electrically evoked overflow was enhanced by phentolamine but not affected by histamine. When both desipramine and phentolamine were present in the superfusion medium, histamine inhibited the evoked overflow (pIC15 6.85). This effect was mimicked by the histamine H3 receptor agonist R-(-)-alpha-methylhistamine as well as by its S-(+)-enantiomer (pIC15 7.85 and 5.30, respectively) but not by the H1 receptor agonist 2-(2-thiazolyl)ethylamine and the H2 receptor agonist dimaprit (each 10 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

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

    Science.gov (United States)

    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.

  13. 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

  14. 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.

  15. PPAR-γ – a possible drug target for complicated pregnancies

    Science.gov (United States)

    McCarthy, Fergus P; Delany, Aoife C; Kenny, Louise C; Walsh, Sarah K

    2013-01-01

    Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors expressed in trophoblasts, which regulate both cell differentiation and proliferation. In recent years, evidence has linked PPARs to playing an integral role in pregnancy; specifically, PPAR-β and PPAR-γ have been shown to play an integral role in placentation, with PPAR-γ additionally serving to regulate trophoblast differentiation. Recent evidence has shown that PPAR-γ expression is altered in many complications of pregnancy such as intrauterine growth restriction (IUGR), preterm birth, pre-clampsia and gestational diabetes. Thus, at present, accumulating evidence from the literature suggests both a pivotal role for PPAR-γ in the progression of a healthy pregnancy and the possibility that PPAR-γ may act as a therapeutic target in complicated pregnancies. This review aims to provide a succinct and comprehensive assessment of the role of PPAR-γ in normal pregnancy and pregnancy complications, and finally its potential as a therapeutic target in the treatment and/or prevention of adverse pregnancy outcomes. PMID:23186152

  16. Expression of peroxisome proliferator-activated receptor (PPAR) in human prostate cancer.

    Science.gov (United States)

    Segawa, Yoshihiro; Yoshimura, Rikio; Hase, Taro; Nakatani, Tatsuya; Wada, Seiji; Kawahito, Yutaka; Kishimoto, Taketoshi; Sano, Hajime

    2002-05-01

    Recent studies have demonstrated that peroxisome proliferator activator-receptors (PPAR)-gamma is expressed in some cancer cells such as breast, lung, and gastric cancer, and its ligand induces growth arrest of these cancer cells through apoptosis. However, the expression and localization of PPARs in prostate have not been examined. In this study, PPARs expression was investigated in human prostate cancer (PC), prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and normal prostate (NP) tissues. Tumor specimens were obtained from 156 patients with PC, 15 with PIN, 20 with BPH, and 12 patients with NP tissues. The expressions were investigated by RT-PCR and immunohistochemical methods. Immunoreactive PPAR-alpha and -beta were significantly apparent in PC tissues. Marked expressions of PPAR-alpha and -beta were also detected in PIN, BPH, and NP groups. However, very weak or no expression of immunoreactive PPAR-gamma was found in BPH and NP cases. In contrast, we found significant expression of immunoreactive PPAR-gamma in cancer cells in PC group and in PIN group. Our results demonstrated that PPAR-gamma is induced in PC, and suggest that PPAR-gamma ligands may mediate its own potent antiproliferative effect against PC cells through differentiation. Copyright 2002 Wiley-Liss, Inc.

  17. Gene Expression Profiling in Wild-Type and PPAR-Null Mice Exposed to Perfluorooctane Sulfonate Reveals PPAR-Independent Effects

    Directory of Open Access Journals (Sweden)

    Mitchell B. Rosen

    2010-01-01

    Full Text Available Perfluorooctane sulfonate (PFOS is a perfluoroalkyl acid (PFAA and a persistent environmental contaminant found in the tissues of humans and wildlife. Although blood levels of PFOS have begun to decline, health concerns remain because of the long half-life of PFOS in humans. Like other PFAAs, such as, perfluorooctanoic acid (PFOA, PFOS is an activator of peroxisome proliferator-activated receptor-alpha (PPAR and exhibits hepatocarcinogenic potential in rodents. PFOS is also a developmental toxicant in rodents where, unlike PFOA, its mode of action is independent of PPAR. Wild-type (WT and PPAR-null (Null mice were dosed with 0, 3, or 10 mg/kg/day PFOS for 7 days. Animals were euthanized, livers weighed, and liver samples collected for histology and preparation of total RNA. Gene profiling was conducted using Affymetrix 430_2 microarrays. In WT mice, PFOS induced changes that were characteristic of PPAR transactivation including regulation of genes associated with lipid metabolism, peroxisome biogenesis, proteasome activation, and inflammation. PPAR-independent changes were indicated in both WT and Null mice by altered expression of genes related to lipid metabolism, inflammation, and xenobiotic metabolism. Such results are similar to studies done with PFOA and are consistent with modest activation of the constitutive androstane receptor (CAR, and possibly PPAR and/or PPAR/. Unique treatment-related effects were also found in Null mice including altered expression of genes associated with ribosome biogenesis, oxidative phosphorylation, and cholesterol biosynthesis. Of interest was up-regulation of Cyp7a1, a gene which is under the control of various transcription regulators. Hence, in addition to its ability to modestly activate PPAR, PFOS induces a variety of PPAR-independent effects as well.

  18. A parametric study of the effects of the noradrenaline neurotoxin DSP4 on avoidance acquisition and noradrenaline neurones in the CNS of the rat.

    OpenAIRE

    Archer, T.; G Jonsson; Ross, S. B.

    1984-01-01

    The effects of various doses of DSP4 on two-way active avoidance acquisition in rats and on central noradrenaline neurones were compared. Doses of DSP4 from 3 mg kg-1 i.p. and upwards injected one week before the onset of the avoidance trials significantly impaired two-way avoidance learning. The learning impairment caused by DSP4 (50 mg kg-1 i.p.) lasted for at least 10 weeks. Desipramine (20 mg kg-1) injected either 30 or 60 min before DSP4 (50 mg kg-1) antagonized the active avoidance impa...

  19. PPAR-γ Regulates Trophoblast Differentiation in the BeWo Cell Model

    Directory of Open Access Journals (Sweden)

    Khrystyna Levytska

    2014-01-01

    Full Text Available Common pregnancy complications, such as severe preeclampsia and intrauterine growth restriction, disrupt pregnancy progression and impair maternal and fetal wellbeing. Placentas from such pregnancies exhibit lesions principally within the syncytiotrophoblast (SCT, a layer in direct contact with maternal blood. In humans and mice, glial cell missing-1 (GCM-1 promotes differentiation of underlying cytotrophoblast cells into the outer SCT layer. GCM-1 may be regulated by the transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ; in mice, PPAR-γ promotes labyrinthine trophoblast differentiation via Gcm-1, and, as we previously demonstrated, PPAR-γ activation ameliorates disease features in rat model of preeclampsia. Here, we aimed to characterize the baseline activity of PPAR-γ in the human choriocarcinoma BeWo cell line that mimics SCT formation in vitro and modulate PPAR-γ activity to study its effects on cell proliferation versus differentiation. We report a novel negative autoregulatory mechanism between PPAR-γ activity and expression and show that blocking PPAR-γ activity induces cell proliferation at the expense of differentiation, while these remain unaltered following treatment with the agonist rosiglitazone. Gaining a deeper understanding of the role and activity of PPAR-γ in placental physiology will offer new avenues for the development of secondary prevention and/or treatment options for placentally-mediated pregnancy complications.

  20. PPARs in the central nervous system: roles in neurodegeneration and neuroinflammation.

    Science.gov (United States)

    Zolezzi, Juan M; Santos, Manuel J; Bastías-Candia, Sussy; Pinto, Claudio; Godoy, Juan A; Inestrosa, Nibaldo C

    2017-02-20

    Over 25 years have passed since peroxisome proliferators-activated receptors (PPARs), were first described. Like other members of the nuclear receptors superfamily, PPARs have been defined as critical sensors and master regulators of cellular metabolism. Recognized as ligand-activated transcription factors, they are involved in lipid, glucose and amino acid metabolism, taking part in different cellular processes, including cellular differentiation and apoptosis, inflammatory modulation and attenuation of acute and chronic neurological damage in vivo and in vitro. Interestingly, PPAR activation can simultaneously reprogram the immune response, stimulate metabolic and mitochondrial functions, promote axonal growth, induce progenitor cells to differentiate into myelinating oligodendrocytes, and improve brain clearance of toxic molecules such as β-amyloid peptide. Although the molecular mechanisms and cross-talk with different molecular pathways are still the focus of intense research, PPARs are considered potential therapeutic targets for several neuropathological conditions, including degenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. This review considers recent advances regarding PPARs, as well as new PPAR agonists. We focus on the mechanisms behind the neuroprotective effects exerted by PPARs and summarise the roles of PPARs in different pathologies of the central nervous system, especially those associated with degenerative and inflammatory mechanisms.

  1. PPARs in Liver Diseases and Cancer: Epigenetic Regulation by MicroRNAs

    Directory of Open Access Journals (Sweden)

    Marion Peyrou

    2012-01-01

    Full Text Available Peroxisome-proliferator-activated receptors (PPARs are ligand-activated nuclear receptors that exert in the liver a transcriptional activity regulating a whole spectrum of physiological functions, including cholesterol and bile acid homeostasis, lipid/glucose metabolism, inflammatory responses, regenerative mechanisms, and cell differentiation/proliferation. Dysregulations of the expression, or activity, of specific PPAR isoforms in the liver are therefore believed to represent critical mechanisms contributing to the development of hepatic metabolic diseases, disorders induced by hepatic viral infections, and hepatocellular adenoma and carcinoma. In this regard, specific PPAR agonists have proven to be useful to treat these metabolic diseases, but for cancer therapies, the use of PPAR agonists is still debated. Interestingly, in addition to previously described mechanisms regulating PPARs expression and activity, microRNAs are emerging as new important regulators of PPAR expression and activity in pathophysiological conditions and therefore may represent future therapeutic targets to treat hepatic metabolic disorders and cancers. Here, we reviewed the current knowledge about the general roles of the different PPAR isoforms in common chronic metabolic and infectious liver diseases, as well as in the development of hepatic cancers. Recent works highlighting the regulation of PPARs by microRNAs in both physiological and pathological situations with a focus on the liver are also discussed.

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

    NARCIS (Netherlands)

    el Azzouzi, H.|info:eu-repo/dai/nl/304072796

    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

  3. PPARs: Nuclear Receptors Controlled by, and Controlling, Nutrient Handling through Nuclear and Cytosolic Signaling

    Directory of Open Access Journals (Sweden)

    Maria Moreno

    2010-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs, which are known to regulate lipid homeostasis, are tightly controlled by nutrient availability, and they control nutrient handling. In this paper, we focus on how nutrients control the expression and action of PPARs and how cellular signaling events regulate the action of PPARs in metabolically active tissues (e.g., liver, skeletal muscle, heart, and white adipose tissue. We address the structure and function of the PPARs, and their interaction with other nuclear receptors, including PPAR cross-talk. We further discuss the roles played by different kinase pathways, including the extracellular signal-regulated kinases/mitogen-activated protein kinase (ERK MAPK, AMP-activated protein kinase (AMPK, Akt/protein kinase B (Akt/PKB, and the NAD+-regulated protein deacetylase SIRT1, serving to control the activity of the PPARs themselves as well as that of a key nutrient-related PPAR coactivator, PPARγ coactivator-1α (PGC-1α. We also highlight how currently applied nutrigenomic strategies will increase our understanding on how nutrients regulate metabolic homeostasis through PPAR signaling.

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

    NARCIS (Netherlands)

    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 car

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

    African Journals Online (AJOL)

    Erah

    2011-11-03

    Nov 3, 2011 ... PPAR-γ ligand) on the PPAR-γ expression and on the IL-6 and IL-8 production in ..... DNA synthesis in breast cancer-derived cell ... gamma activation in human lung epithelial cells. J Biol. Chem 2002; 277: 33153-33163. 9.

  6. Distinct effects of the serotonin-noradrenaline reuptake inhibitors milnacipran and venlafaxine on rat pineal monoamines.

    Science.gov (United States)

    Muneoka, Katsumasa; Kuwagata, Makiko; Ogawa, Tetsuo; Shioda, Seiji

    2015-06-17

    Monoamine systems are involved in the pathology and therapeutic mechanism of depression. The pineal gland contains large amounts of serotonin as a precursor for melatonin, and its activity is controlled by noradrenergic sympathetic nerves. Pineal diurnal activity and its release of melatonin are relevant to aberrant states observed in depression. We investigated the effects on pineal monoamines of serotonin-noradrenaline reuptake inhibitors, which are widely used antidepressants. Four days of milnacipran treatment led to an increase in noradrenaline and serotonin levels, whereas 4 days of venlafaxine treatment reduced 5-hydroxyindoleacetic acid levels; both agents induced an increase in dopamine levels. Our data suggest that milnacipran increases levels of the precursor for melatonin synthesis by facilitating the noradrenergic regulation of pineal activity and that venlafaxine inhibits serotonin reuptake into noradrenergic terminals on the pineal gland.

  7. Cardiovascular, metabolic, and hormonal responses to noradrenaline in diabetic patients with autonomic neuropathy

    DEFF Research Database (Denmark)

    Dejgaard, Anders; Andersen, P; Hvidberg, A

    1996-01-01

    Denervation hypersensitivity is a well-known phenomenon in patients with autonomic failure. In diabetic autonomic neuropathy hypersensitivity to beta-adrenergic stimulation has been demonstrated. We infused noradrenaline, mainly an alpha-adrenoceptor agonist, in three escalating doses (0.5, 2.......5, and 5 micrograms min-1) in three age and sex matched groups of eight subjects: healthy volunteers, diabetic patients with and without autonomic neuropathy. During steady state in each infusion period we measured heart rate, blood pressure, cardiac output, hepato-splanchnic blood flow, vascular...... resistance, glucose kinetics, metabolites (beta-hydroxybuturate, glycerol, and lactate), and glucoregulatory hormones (noradrenaline, adrenaline, growth hormone, pancreatic polypeptide, cortisol, and insulin). Systolic and mean blood pressure increased in all groups but diabetic patients with autonomic...

  8. Delphinidin immobilized on silver nanoparticles for the simultaneous determination of ascorbic acid, noradrenalin, uric acid, and tryptophan

    Directory of Open Access Journals (Sweden)

    Navid Nasirizadeh

    2016-04-01

    Full Text Available In the present study, the fabrication of a new modified electrode for electrocatalytic oxidation of noradrenalin, based on the delphinidin immobilized on silver nanoparticles modified glassy carbon electrode. Cyclic voltammetry was used to investigate the redox properties of this modified electrode. The surface charge transfer rate constant (ks and the charge transfer coefficient (α for the electron transfer between the glassy carbon electrode and the immobilized delphinidin were calculated. The differential pulse voltammetry exhibited two linear dynamic ranges and a detection limit of 0.40μM for noradrenalin determination. Moreover, the present electrode could separate the oxidation peak potentials of ascorbic acid, noradrenalin, uric acid, and tryptophan in a mixture. The usefulness of this nanosensor was also investigated for the determination of ascorbic acid, noradrenalin, and uric acid in pharmaceutical and biological fluid samples with satisfactory results.

  9. 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 in

  10. Impaired noradrenaline homeostasis in rats with painful diabetic neuropathy as a target of duloxetine analgesia

    OpenAIRE

    Kinoshita, Jun; Takahashi, Yukari; Watabe, Ayako M.; Utsunomiya, Kazunori; Kato, Fusao

    2013-01-01

    Background Painful diabetic neuropathy (PDN) is a serious complication of diabetes mellitus that affects a large number of patients in many countries. The molecular mechanisms underlying the exaggerated nociception in PDN have not been established. Recently, duloxetine (DLX), a serotonin and noradrenaline re-uptake inhibitor, has been recommended as one of the first-line treatments of PDN in the United States Food and Drug Administration, the European Medicines Agency and the Japanese Guideli...

  11. Noradrenaline blocks potassium conductance in rat dentate granule cells in vitro.

    Science.gov (United States)

    Haas, H L; Rose, G M

    1987-07-22

    The actions of noradrenaline and the beta-adrenergic agonist, isoproterenol, were studied on the dentate gyrus in hippocampal slices from rats using extra- and intracellular recording. These agents facilitated field EPSPs (excitatory postsynaptic potentials) and population spikes evoked by perforant path stimulation. Intracellular recording revealed an attenuation of the long lasting afterhyperpolarization (AHP) and the accommodation of cell discharge in response to depolarizing current injection. It is suggested that beta-receptor activation blocks a calcium-dependent potassium current.

  12. Cholinergic basal forebrain structures are involved in the mediation of the arousal effect of noradrenaline.

    Science.gov (United States)

    Lelkes, Zoltán; Porkka-Heiskanen, Tarja; Stenberg, Dag

    2013-12-01

    Cholinergic basal forebrain structures are implicated in cortical arousal and regulation of the sleep-wake cycle. Cholinergic neurones are innervated by noradrenergic terminals, noradrenaline excites them via alpha-1 receptors and microinjection of noradrenaline into the basal forebrain enhances wakefulness. However, it is not known to what extent the cholinergic versus non-cholinergic basal forebrain projection neurones contribute to the arousing effects of noradrenaline. To elucidate the roles of cholinergic basal forebrain structures we administered methoxamine, an alpha-1-adrenergic agonist into the basal forebrain, in intact animals and again after selective destruction of the basal forebrain cholinergic cells by 192 IgG-saporin. In eight male Han-Wistar rats implanted with electroencephalogram/electromyogram electrodes, a microdialysis probe targeted into the basal forebrain was perfused with artificial cerebrospinal fluid for 6 h on a baseline day, and with cerebrospinal fluid in the first and with methoxamine in the second 3-h period of the subsequent day. The sleep-wake activity was recorded for 24 h on both days. Saporin was then injected into the basal forebrain and 2 weeks later the same experimental schedule (with cerebrospinal fluid and methoxamine) was repeated. In the intact animals, methoxamine exhibited a robust arousing effect and non-rapid eye movement (NREM) and REM sleep was suppressed. Lesioning of the basal forebrain cholinergic neurones abolished almost completely the NREM sleep-suppressing effect of methoxamine, whereas the REM sleep-suppressing effect remained intact. Thus, the basal forebrain cholinergic neurones mediate, at least in part, cortical arousal and non-REM sleep-suppression, but they are not involved in the REM sleep-suppressing effects of noradrenaline. © 2013 European Sleep Research Society.

  13. Synthesis of PPAR-γ Activators Inspired by the Marine Natural Product, Paecilocin A

    Directory of Open Access Journals (Sweden)

    Bin Xiao

    2014-02-01

    Full Text Available A series of N-substituted phthalimide derivatives were synthesized based on a pharmacophore study of paecilocin A (a natural PPAR-γ agonist and synthetic leads. The introduction of hydrophilic and hydrophobic groups to the phthalimide skeleton yielded compounds 3–14. Compound 7 showed significant PPAR-γ activation in a luciferase assay using rat liver Ac2F cells. Docking simulations showed that a free hydroxyl group on the phthalimide head and a suitable hydrophilic tail, including a phenyl linker, were beneficial for PPAR-γ activation. Compound 7 and rosiglitazone concentration-dependently activated PPAR-γ with EC50 values of 0.67 μM and 0.028 μM, respectively. These phthalimide derivatives could be further investigated as a new class of PPAR-γ ligands.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  15. The PPAR-Platelet Connection: Modulators of Inflammation and Potential Cardiovascular Effects.

    Science.gov (United States)

    Spinelli, S L; O'Brien, J J; Bancos, S; Lehmann, G M; Springer, D L; Blumberg, N; Francis, C W; Taubman, M B; Phipps, R P

    2008-01-01

    Historically, platelets were viewed as simple anucleate cells responsible for initiating thrombosis and maintaining hemostasis, but clearly they are also key mediators of inflammation and immune cell activation. An emerging body of evidence links platelet function and thrombosis to vascular inflammation. peroxisome proliferator-activated receptors (PPARs) play a major role in modulating inflammation and, interestingly, PPARs (PPARbeta/delta and PPARgamma) were recently identified in platelets. Additionally, PPAR agonists attenuate platelet activation; an important discovery for two reasons. First, activated platelets are formidable antagonists that initiate and prolong a cascade of events that contribute to cardiovascular disease (CVD) progression. Dampening platelet release of proinflammatory mediators, including CD40 ligand (CD40L, CD154), is essential to hinder this cascade. Second, understanding the biologic importance of platelet PPARs and the mechanism(s) by which PPARs regulate platelet activation will be imperative in designing therapeutic strategies lacking the deleterious or unwanted side effects of current treatment options.

  16. Regional haemodynamic effects of noradrenaline injected into the hypothalamic paraventricular nuclei of conscious, unrestrained rats: possible mechanisms of action.

    Science.gov (United States)

    Bachelard, H; Harland, D; Gardiner, S M; Kemp, P A; Bennett, T

    1992-01-01

    The cardiovascular effects of noradrenaline bilaterally injected into the hypothalamic paraventricular nuclei were investigated in conscious, unrestrained Long-Evans rats and homozygous, vasopressin-deficient Brattleboro rats, chronically instrumented with pulsed Doppler probes for measurement of regional haemodynamics. In Long-Evans rats, incremental doses of noradrenaline (0.01-10 nmol) caused dose-related increases in blood pressure and a substantial, dose-related, superior mesenteric vasoconstriction. These changes were accompanied by bradycardia and reductions in renal and hind-quarter vascular conductances. In Brattleboro rats, noradrenaline (10 nmol) had no effect on blood pressure, heart rate, or renal or superior mesenteric vascular conductances. However, there was a slight vasodilatation in the vascular bed of the hindquarters. In Long-Evans rats, intravenous pretreatment with phentolamine had no effect on the bradycardia but partly inhibited the pressor response to noradrenaline injected into the paraventricular nuclei. These effects were associated with a smaller superior mesenteric vasoconstriction and an abolition of the vasoconstriction in the hindquarters. Combined intravenous pretreatment with phentolamine and propranolol had no effect on the heart rate or pressor responses to noradrenaline injected into the paraventricular nuclei, but reduced the superior mesenteric vasoconstriction, potentiated the vasoconstriction in the hindquarters and eliminated the renal vasoconstriction. These results suggest that, in untreated Long-Evans rats, alpha-adrenoceptor-mediated constriction in the mesenteric vascular bed and beta-adrenoceptor-mediated dilatation in the vascular bed of the hindquarters have important influences on the pressor response to noradrenaline injected into the paraventricular nuclei. In the presence of the vasopressin V1-receptor antagonist, d(CH2)5[Tyr(Et)]DAVP, the pressor and heart rate responses to noradrenaline injected into the

  17. Oral clonidine premedication exacerbates hypotension following tourniquet deflation by inhibiting noradrenaline release.

    Science.gov (United States)

    Maruyama, Koichi; Takeda, Shinhiro; Hongo, Takashi; Kobayashi, Noriyuki; Kim, Chol; Ogawa, Ryo

    2004-02-01

    Clonidine premedication prevents tourniquet pain and reduces sympathetic nerve activity. We evaluated hemodynamic changes and catecholamine release following tourniquet deflation during spinal anesthesia in patients who received oral clonidine premedication. The final analysis included 24 otherwise healthy patients undergoing lower-limb surgery randomly assigned to two groups: those receiving approximately 5 micrograms/kg of oral clonidine 1 hr before anesthesia (clonidine group, n = 12), and those receiving no premedication (control group, n = 12). After lumbar anesthesia, a tourniquet was applied for approximately 60 minutes to each patient. Electrocardiogram, arterial blood pressure, and consumption of butorphanol for tourniquet pain were monitored. Blood samples were obtained at different times to measure serum concentration of catecholamine. In the clonidine group, mean blood pressure decreased from 87 +/- 7 mmHg at baseline to 65 +/- 10 mmHg after tourniquet deflation (P clonidine group was significantly lower than in the control group. After receiving clonidine premedication, the plasma noradrenaline concentrations in the clonidine group were significantly lower than those in the control group. Noradrenaline concentration increased in the control group from 162.3 +/- 89.2 pg/mL before tourniquet deflation to 199.3 +/- 95.7 pg/mL afterward (P clonidine group. We conclude that oral clonidine premedication exacerbated the reduction in mean blood pressure following tourniquet deflation by inhibiting noradrenaline release.

  18. Dopamine and noradrenaline are unrelated to renalase, heart rate, and blood pressure in heart transplant recipients.

    Science.gov (United States)

    Wasilewski, G; Przybyłowski, P; Janik, L; Nowak, E; Sadowski, J; Małyszko, J

    2014-10-01

    Renalase may degrade catecholamines and regulate sympathetic tone and blood pressure. The aim of this study was to assess dopamine, norepinephrine, and renalase in 80 heart transplant recipients and 22 healthy volunteers and their correlations with heart rate, blood pressure control, type of hypotensive therapy, and renal function. Renalase, dopamine, and norepinephrine were studied by using commercially available assays. Renalase levels were higher in heart transplant recipients compared with healthy volunteers, and noradrenaline levels were lower in the studied cohort patients than in the healthy volunteers. Noradrenaline was correlated with white blood cell count (r = -0.21, P blood cell count (r = -0.22, P heart rate, blood pressure, kidney function, or New York Heart Association class. Noradrenaline was significantly higher in patients with elevated diastolic blood pressure (>90 mm Hg) compared with those with normal diastolic blood pressure (P heart transplant patients were related to kidney function but not linked to the sympathetic nervous system activity in this study population. In heart transplant recipients, these findings might suggest that sympathetic denervation and the modulation of β-receptors persist.

  19. Noradrenalin and dopamine receptors both control cAMP-PKA signaling throughout the cerebral cortex

    Directory of Open Access Journals (Sweden)

    Shinobu eNomura

    2014-08-01

    Full Text Available Noradrenergic fibers innervate the entire cerebral cortex, whereas the cortical distribution ofdopaminergic fibers is more restricted. However, the relative functional impact ofnoradrenalin and dopamine receptors in various cortical regions is largely unknown. Using aspecific genetic label, we first confirmed that noradrenergic fibers innervate the entire cortexwhereas dopaminergic fibers were present in all layers of restricted medial and lateral areasbut only in deep layers of other areas. Imaging of a genetically-encoded sensor revealed thatnoradrenalin and dopamine widely activate PKA in cortical pyramidal neurons of frontal,parietal and occipital regions with scarce dopaminergic fibers. Responses to noradrenalin hadhigher amplitude, velocity and occurred at more than 10 fold lower dose than those elicited bydopamine, whose amplitude and velocity increased along the antero-posterior axis. Thepharmacology of these responses was consistent with the involvement of Gs-coupled beta1adrenergic and D1/D5 dopaminergic receptors, but the inhibition of both noradrenalin anddopamine responses by beta adrenergic antagonists was suggestive of the existence of beta1-D1/D5 heteromeric receptors. Responses also involved Gi-coupled alpha2 adrenergic and D2-like dopaminergic receptors that markedly reduced their amplitude and velocity andcontributed to their cell-to-cell heterogeneity. Our results reveal that noradrenalin anddopamine receptors both control cAMP-PKA signaling throughout the cerebral cortex withmoderate regional and laminar differences. These receptors can thus mediate widespreadeffects of both catecholamines, which are reportedly co-released by cortical noradrenergicfibers beyond the territory of dopaminergic fibers.

  20. Paring down on Descartes: a review of brain noradrenaline and sympathetic nervous function.

    Science.gov (United States)

    Lambert, G W

    2001-12-01

    1. The conceptual framework of mind-body interaction can be traced back to the seminal observations of the French philosopher and mathematician René Descartes (1596-1650). Descartes succeeded in eliminating the soul's apparent physiological role and established the brain as the body's control centre. 2. While the pivotal role played by the central nervous system (CNS) in the maintenance of physiological and psychological health has long been recognized, the development of methods designed for the direct examination of human CNS processes has only recently come to fruition. 3. There exists a substantial body of evidence derived from clinical and experimental studies indicating that CNS monoaminergic cell groups, in particular those using noradrenaline as their neurotransmitter, participate in the excitatory regulation of the sympathetic nervous system and the development and maintenance of the hypertensive state. 4. In essential hypertension, particularly in younger patients, there occurs an activation of sympathetic nervous outflows to the kidneys, heart and skeletal muscle. The existence of a correlation between subcortical brain noradrenaline turnover and total body noradrenaline spillover to plasma, resting blood pressure and heart rate provides further support for the observation that elevated subcortical noradrenergic activity subserves a sympathoexcitatory role in the regulation of sympathetic preganglionic neurons of the thorocolumbar cord.

  1. Role of noradrenaline in wake promotion effect of orexin-A on alcohol coma in rats

    Directory of Open Access Journals (Sweden)

    Tian-hao WANG

    2013-02-01

    Full Text Available Objective  To study whether or not noradrenaline system participates in the process of orexin-A wake-promoting from alcohol coma. Methods  Twenty-four adult female SPF SD rats were divided into four groups, 6 each, and the model of alcohol coma was reproduced. Experimental rats were then divided randomly into rats receiving injection of artificial cerebrospinal fluid (ACSF, control group, orexin-A (orexin-A group, noradrenaline α1 receptor antagonists--prazosin (prazosin group, or prazosin + orexin-A (prazosin-orexin-A group into the lateral ventricle. The depth of coma was evaluated by the duration of loss of righting reflex (LORR and δ wave in electrocorticogram (ECoG. Results  The duration of LORR was significantly longer and the ratio of δ wave higher in the prazosin-treated rats than those in control group (P0.05. But the values were significantly different from those in the orexin-A group (P<0.01. Conclusion  Noradrenaline system may participate in the wake-promoting process of alcohol coma by orexin-A.

  2. Translational repression by PUF proteins in vitro.

    Science.gov (United States)

    Chritton, Jacqueline J; Wickens, Marvin

    2010-06-01

    PUF (Pumilio and FBF) proteins provide a paradigm for mRNA regulatory proteins. They interact with specific sequences in the 3' untranslated regions (UTRs) of target mRNAs and cause changes in RNA stability or translational activity. Here we describe an in vitro translation assay that reconstitutes the translational repression activity of canonical PUF proteins. In this system, recombinant PUF proteins were added to yeast cell lysates to repress reporter mRNAs bearing the 3'UTRs of specific target mRNAs. PUF proteins from Saccharomyces cerevisiae and Caenorhabditis elegans were active in the assay and were specific by multiple criteria. Puf5p, a yeast PUF protein, repressed translation of four target RNAs. Repression mediated by the HO 3'UTR was particularly efficient, due to a specific sequence in that 3'UTR. The sequence lies downstream from the PUF binding site and does not affect PUF protein binding. PUF-mediated repression was sensitive to the distance between the ORF and the regulatory elements in the 3'UTR: excessive distance decreased repression activity. Our data demonstrate that PUF proteins function in vitro across species, that different mRNA targets are regulated differentially, and that specific ancillary sequences distinguish one yeast mRNA target from another. We suggest a model in which PUF proteins can control translation termination or elongation.

  3. O-GlcNAc modification of PPAR{gamma} reduces its transcriptional activity

    Energy Technology Data Exchange (ETDEWEB)

    Ji, Suena; Park, Sang Yoon [Department of Biology, Yonsei University, Seoul 120-749 (Korea, Republic of); Roth, Juergen [Department of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul 120-749 (Korea, Republic of); Kim, Hoe Suk, E-mail: hoeskim@snu.ac.kr [Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul 110-744 (Korea, Republic of); Cho, Jin Won, E-mail: chojw311@yonsei.ac.kr [Department of Biology, Yonsei University, Seoul 120-749 (Korea, Republic of); Department of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2012-01-27

    Highlights: Black-Right-Pointing-Pointer We found that PPAR{gamma} is modified by O-GlcNAc in 3T3-L1 adipocytes. Black-Right-Pointing-Pointer The Thr54 of PPAR{gamma}1 is the major O-GlcNAc site. Black-Right-Pointing-Pointer Transcriptional activity of PPAR{gamma}1 was decreased on treatment with the OGA inhibitor. -- Abstract: The peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), a member of the nuclear receptor superfamily, is a key regulator of adipogenesis and is important for the homeostasis of the adipose tissue. The {beta}-O-linked N-acetylglucosamine (O-GlcNAc) modification, a posttranslational modification on various nuclear and cytoplasmic proteins, is involved in the regulation of protein function. Here, we report that PPAR{gamma} is modified by O-GlcNAc in 3T3-L1 adipocytes. Mass spectrometric analysis and mutant studies revealed that the threonine 54 of the N-terminal AF-1 domain of PPAR{gamma} is the major O-GlcNAc site. Transcriptional activity of wild type PPAR{gamma} was decreased 30% by treatment with the specific O-GlcNAcase (OGA) inhibitor, but the T54A mutant of PPAR{gamma} did not respond to inhibitor treatment. In 3T3-L1 cells, an increase in O-GlcNAc modification by OGA inhibitor reduced PPAR{gamma} transcriptional activity and terminal adipocyte differentiation. Our results suggest that the O-GlcNAc state of PPAR{gamma} influences its transcriptional activity and is involved in adipocyte differentiation.

  4. Chemotherapeutic drugs induce PPAR-gamma expression and show sequence-specific synergy with PPAR-gamma ligands in inhibition of non-small cell lung cancer.

    Science.gov (United States)

    Reddy, Raju C; Srirangam, Anjaiah; Reddy, Kaunteya; Chen, Jun; Gangireddy, Srinivasareddy; Kalemkerian, Gregory P; Standiford, Theodore J; Keshamouni, Venkateshwar G

    2008-06-01

    Preclinical studies have shown that peroxisome proliferator-activated receptor gamma (PPAR-gamma) ligands can exert antitumor effects against non-small cell lung cancer (NSCLC) and a variety of other cancers. In this study, we investigate the potential use of a PPAR-gamma ligand, troglitazone (Tro), in combination with either of two chemotherapeutic agents, cisplatin (Cis) or paclitaxel (Pac), for the treatment of NSCLC. In vitro, treatment of NSCLC cell lines with Tro potentiated Cis- or Pac-induced growth inhibition. The potentiation of growth inhibition was observed only when Cis or Pac treatment was followed by Tro and not vice versa, demonstrating a sequence-specific effect. Median effect analysis revealed a synergistic interaction between Tro and Cis in the inhibition of NSCLC cell growth and confirmed the sequence-specific effect. We also found that Cis or Pac up-regulated the expression of PPAR-gamma protein, accounting for the observed sequence-specific synergy. Similarly, experiments performed using a NSCLC xenograft model demonstrated enhanced effectiveness of combined treatment with Cis and PPAR-gamma ligands, Tro or pioglitazone. Tumors from Cis-treated mice also demonstrated enhanced PPAR-gamma expression. Together, our data demonstrate a novel sequence-specific synergy between PPAR-gamma ligands and chemotherapeutic agents for lung cancer treatment.

  5. Chemotherapeutic Drugs Induce PPAR-γ Expression and Show Sequence-Specific Synergy with PPAR-γ Ligands in Inhibition of Non-Small Cell Lung Cancer1

    Science.gov (United States)

    Reddy, Raju C; Srirangam, Anjaiah; Reddy, Kaunteya; Chen, Jun; Gangireddy, Srinivasareddy; Kalemkerian, Gregory P; Standiford, Theodore J; Keshamouni, Venkateshwar G

    2008-01-01

    Preclinical studies have shown that peroxisome proliferator-activated receptor γ (PPAR-γ) ligands can exert antitumor effects against non-small cell lung cancer (NSCLC) and a variety of other cancers. In this study, we investigate the potential use of a PPAR-γ ligand, troglitazone (Tro), in combination with either of two chemotherapeutic agents, cisplatin (Cis) or paclitaxel (Pac), for the treatment of NSCLC. In vitro, treatment of NSCLC cell lines with Tro potentiated Cis- or Pac-induced growth inhibition. The potentiation of growth inhibition was observed only when Cis or Pac treatment was followed by Tro and not vice versa, demonstrating a sequence-specific effect. Median effect analysis revealed a synergistic interaction between Tro and Cis in the inhibition of NSCLC cell growth and confirmed the sequence-specific effect. We also found that Cis or Pac up-regulated the expression of PPAR-γ protein, accounting for the observed sequence-specific synergy. Similarly, experiments performed using a NSCLC xenograft model demonstrated enhanced effectiveness of combined treatment with Cis and PPAR-γ ligands, Tro or pioglitazone. Tumors from Cis-treated mice also demonstrated enhanced PPAR-γ expression. Together, our data demonstrate a novel sequence-specific synergy between PPAR-γ ligands and chemotherapeutic agents for lung cancer treatment. PMID:18516296

  6. A monovalent ion-selective cation current activated by noradrenaline in smooth muscle cells of rabbit ear artery.

    Science.gov (United States)

    Wang, Q; Hogg, R C; Large, W A

    1993-04-01

    Membrane currents were recorded with the perforated-patch method with a low-chloride (35 mM) pipette solution in isolated smooth muscle cells of the rabbit ear artery. At a holding potential of -50 mV in potassium-free conditions spontaneous inward single-channel currents were observed and noradrenaline evoked a noisy inward current, which appeared to be comprised of the spontaneous currents. The reversal potential (Vr) of the spontaneous channel and noradrenaline-induced current was not affected in anion-substitution experiments but Vr was altered when external Na+ was replaced with choline or TRIS. The relationship between clamp potential and spontaneous single-channel current amplitude was linear and the mean unitary conductance was 28 pS. Caffeine, which releases calcium from the sarcoplasmic reticulum, and the calcium ionophore ionomycin activated the cation current and also blocked the response to noradrenaline. Spontaneous channel current activity and the noradrenaline-induced current were blocked when external NaCl was replaced with 89 mM CaCl2. The response to noradrenaline was blocked by prazosin but was not affected by yohimbine and therefore the response is mediated by alpha 1-adrenoceptors. It is concluded that in rabbit ear artery smooth muscle cells there is a calcium-activated cation channel of 28 pS conductance, which is relatively impermeable to calcium but can be activated by noradrenaline.

  7. Cannabinoids: A New Group of Agonists of PPARs

    Directory of Open Access Journals (Sweden)

    Yan Sun

    2007-11-01

    Full Text Available Cannabinoids have been used medicinally and recreationally for thousands of years and their effects were proposed to occur mainly via activation of the G-protein-coupled receptor CB1/CB2 (cannabinoid receptor 1/2. Discovery of potent synthetic analogs of the natural cannabinoids as clinically useful drugs is the sustained aim of cannabinoid research. This demands that these new compounds be free of the psychotropic effects that connected with the recreational use of cannabinoids. In preclinical studies cannabinoids displayed many of the characteristics of nonsteroidal anti-inflammatory drugs (NSAIDs and it seems to be free of unwanted side effects. An increasing number of therapeutic actions of cannabinoid are being reported that do not appear to be mediated by either CB1 or CB2, and recently nuclear receptor superfamily PPARs (peroxisome-proliferator-activated receptors have been suggested as the target of certain cannabinoids. This review summarizes the evidence for cannabinoid activation on PPARs and possible associated remedial potentials.

  8. PPAR-γ agonist stabilizes KLF4 protein via activating Akt signaling and reducing KLF4 ubiquitination

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Yan; Zheng, Bin; Zhang, Xin-hua; He, Ming; Guo, Zong-wei; Wen, Jin-kun, E-mail: wjk@hebmu.edu.cn

    2014-01-10

    Highlights: •PPAR-γ increases KLF4 protein level but does not influence KLF4 gene transcription. •The increase of KLF4 protein levels induced by pioglitazone is PPAR-γ-dependent. •Pioglitazone stabilizes KLF4 protein via activating Akt signaling and reducing KLF4 ubiquitination. -- Abstract: Peroxisome proliferator activated receptor γ (PPAR-γ) plays important roles in cell cycle regulation, differentiation and apoptosis. Krüppel-like factor 4 (KLF4) modulates vascular smooth muscle cell (VSMC) phenotype. Both KLF4 and PPAR-γ are involved in VSMC proliferation and differentiation. However, the actual relationship between KLF4 and PPAR-γ in VSMCs is not clear. In this study, we found that PPAR-γ agonist pioglitazone increases KLF4 protein levels but does not influence KLF4 gene transcription. PPAR-γ overexpression increases, while PPAR-γ knockdown reduces KLF4 expression, suggesting that the increase in KLF4 protein levels induced by pioglitazone is PPAR-γ-dependent. Further study showed that pioglitazone enhances KLF4 protein stability through reducing KLF4 ubiquitination. Furthermore, we demonstrated that stabilization of KLF4 by pioglitazone was related to the activation of Akt signaling pathway. Taken together, we revealed that PPAR-γ agonist pioglitazone stabilizes KLF4 protein via activating Akt signaling and reducing KLF4 ubiquitination, providing further insights into PPAR-γ and KLF4 in regulating each other’s expression in VSMCs.

  9. 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.

  10. Environmental Enrichment Attenuated Sevoflurane-Induced Neurotoxicity through the PPAR-γ Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Yupeng Zhao

    2015-01-01

    Full Text Available Sevoflurane is the most widely used inhaled anesthetic. Environmental enrichment (EE can reverse sevoflurane-induced learning and memory impairment in young mice. However, the mechanism by which EE elicits this effect is unclear. The peroxisome proliferator-activated receptor (PPAR regulatory pathway plays a critical role in the regulation of inflammation in central nervous system diseases. In this study, we investigated whether EE attenuates sevoflurane-induced learning and memory disability via the PPAR signaling pathway. Six-day-old mice were treated with 3% sevoflurane for 2 hours daily from postnatal day 6 (P6 to P8. Then, the mice were treated with EE. The effects of sevoflurane on learning and memory function, PPAR-γ expression in the brain, and the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and 5-bromodeoxyuridine-positive cells in the hippocampus were determined. Sevoflurane induced neuronal apoptosis and neurogenesis inhibition, which may impair learning and memory in young mice. Furthermore, sevoflurane downregulated PPAR-γ expression. Both EE and the PPAR-γ agonist, rosiglitazone, attenuated sevoflurane-induced neuronal apoptosis, neurogenesis inhibition, and learning and memory impairment. Our findings suggest that EE ameliorated sevoflurane-induced neurotoxicity and learning and memory impairment through the PPAR-γ signaling pathway. PPAR-γ may be a potential therapeutic target for preventing or treating sevoflurane-induced neurotoxicity.

  11. PPAR-, Microglial Cells, and Ocular Inflammation: New Venues for Potential Therapeutic Approaches

    Directory of Open Access Journals (Sweden)

    Fiorella Malchiodi-Albedi

    2008-01-01

    Full Text Available The last decade has witnessed an increasing interest for the role played by the peroxisome proliferator-activated receptor- (PPAR- in controlling inflammation in peripheral organs as well as in the brain. Activation of PPAR- has been shown to control the response of microglial cells, the main macrophage population found in brain parenchyma, and limit the inflammation. The anti-inflammatory capacity of PPAR- agonists has led to the hypothesis that PPAR- might be targeted to modulate degenerative brain diseases in which inflammation has been increasingly recognized as a significant component. Recent experimental evidence suggests that PPAR- agonists could be exploited to treat ocular diseases such as diabetic retinopathy, age-related macular degeneration, autoimmune uveitis, and optic neuritis where inflammation has relevant role. Additional PPAR- agonist beneficial effects could involve amelioration of retinal microcirculation and inhibition of neovascularization. However, PPAR- activation could, in some instances, aggravate the ocular pathology, for example, by increasing the synthesis of vascular endothelial growth factor, a proangiogenic factor that could trigger a vicious circle and further deteriorate retinal perfusion. The development of new in vivo and in vitro models to study ocular inflammation and how to modulate for the eye benefit will be instrumental for the search of effective therapies.

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

    Science.gov (United States)

    Tain, You-Lin; Hsu, Chien-Ning; Chan, Julie Y. H.

    2015-01-01

    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. PMID:26712739

  13. Zinc finger protein 407 overexpression upregulates PPAR target gene expression and improves glucose homeostasis in mice.

    Science.gov (United States)

    Charrier, Alyssa; Wang, Li; Stephenson, Erin J; Ghanta, Siddharth V; Ko, Chih-Wei; Croniger, Colleen M; Bridges, Dave; Buchner, David A

    2016-11-01

    The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors is central to the pathophysiology and treatment of metabolic disease through the receptors' ability to regulate the expression of genes involved in glucose homeostasis, adipogenesis, and lipid metabolism. However, the mechanism by which PPAR is regulated remains incompletely understood. We generated a transgenic mouse strain (ZFP-TG) that overexpressed Zfp407 primarily in muscle and heart. Transcriptome analysis by RNA-Seq identified 1,300 differentially expressed genes in the muscle of ZFP-TG mice, among which PPAR target genes were significantly enriched. Among the physiologically important PPARγ target genes, Glucose transporter (Glut)-4 mRNA and protein levels were increased in heart and muscle. The increase in Glut4 and other transcriptional effects of Zfp407 overexpression together decreased body weight and lowered plasma glucose, insulin, and HOMA-IR scores relative to control littermates. When placed on high-fat diet, ZFP-TG mice remained more glucose tolerant than their wild-type counterparts. Cell-based assays demonstrated that Zfp407 synergistically increased the transcriptional activity of all PPAR subtypes, PPARα, PPARγ, and PPARδ. The increased PPAR activity was not associated with increased PPAR mRNA or protein levels, suggesting that Zfp407 posttranslationally regulates PPAR activity. Collectively, these results demonstrate that Zfp407 overexpression improved glucose homeostasis. Thus, Zfp407 represents a new drug target for treating metabolic disease. Copyright © 2016 the American Physiological Society.

  14. The role of PPAR-γ in the immunity modulation%PPAR-γ在免疫中的调节作用

    Institute of Scientific and Technical Information of China (English)

    王文涓

    2008-01-01

    Peroxisome proliferator-activated-receptor gamma(PPAR-γ)is a member of the nuclear receptor superfamily of ligand-dependent transcription factors,PPAR-γ plays an important role in the progress of the glucose and lipid metabolism and sustains the immunity homeostasis.As the research is going on,it was found that PPAR-γ involves in the differentiation and proliferation of a lot of cells especially the immune cells,inducing apoptosis,adjusting the release of cytokines.These actions played an important role in the immunoregulation of many diseases,such as autoimmune disease,inflammation,tumor,hypersensitivity,transplantation and so on.According to these data,we made a review about PPAR-γ in immune modulation.%过氧化物酶体增殖激活受体γ(PPAR-γ)是核激素受体PPAR的一种亚型,PPAR-γ在糖脂合成与代谢以及免疫内环境稳定中发挥重要作用.随着对PPAR-γ研究日益深入,人们发现其与细胞分化、凋亡、免疫细胞增殖和细胞因子分泌调控均密切相关,在自身免疫性疾病、炎症反应、超敏反应、移植免疫及先天性免疫中发挥重要的作用.

  15. Alzheimer Disease: Crosstalk between the Canonical Wnt/Beta-Catenin Pathway and PPARs Alpha and Gamma

    Science.gov (United States)

    Vallée, Alexandre; Lecarpentier, Yves

    2016-01-01

    The molecular mechanisms underlying the pathophysiology of Alzheimer's disease (AD) are still not fully understood. In AD, Wnt/beta-catenin signaling has been shown to be downregulated while the peroxisome proliferator-activated receptor (PPAR) gamma (mARN and protein) is upregulated. Certain neurodegenerative diseases share the same Wnt/beta-catenin/PPAR gamma profile, such as bipolar disorder and schizophrenia. Conversely, other NDs share an opposite profile, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, and Friedreich's ataxia. AD is characterized by the deposition of extracellular Abeta plaques and the formation of intracellular neurofibrillary tangles in the central nervous system (CNS). Activation of Wnt signaling or inhibition of both glycogen synthase kinase-3beta and Dickkopf 1, two key negative regulators of the canonical Wnt pathway, are able to protect against Abeta neurotoxicity and to ameliorate cognitive performance in AD patients. Although PPAR gamma is upregulated in AD patients, and despite the fact that it has been shown that the PPAR gamma and Wnt/beta catenin pathway systems work in an opposite manner, PPAR gamma agonists diminish learning and memory deficits, decrease Abeta activation of microglia, and prevent hippocampal and cortical neurons from dying. These beneficial effects observed in AD transgenic mice and patients might be partially due to the anti-inflammatory properties of PPAR gamma agonists. Moreover, activation of PPAR alpha upregulates transcription of the alpha-secretase gene and represents a new therapeutic treatment for AD. This review focuses largely on the behavior of two opposing pathways in AD, namely Wnt/beta-catenin signaling and PPAR gamma. It is hoped that this approach may help to develop novel AD therapeutic strategies integrating PPAR alpha signaling.

  16. Alzheimer disease: crosstalk between the canonical Wnt/beta-catenin pathway and PPARs alpha and gamma

    Directory of Open Access Journals (Sweden)

    Alexandre VALLEE

    2016-10-01

    Full Text Available The molecular mechanisms underlying the pathophysiology of Alzheimer's disease (AD are still not fully understood. In AD, Wnt/beta-catenin signaling has been shown to be downregulated while the peroxisome proliferator-activated receptor (PPAR gamma (mARN and protein is upregulated. Certain neurodegenerative diseases share the same Wnt/beta-catenin/PPAR gamma profile, such as bipolar disorder and schizophrenia. Conversely, other NDs share an opposite profile, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis and Friedreich's ataxia. AD is characterized by the deposition of extracellular Abeta plaques and the formation of intracellular neurofibrillary tangles in the central nervous system . Activation of Wnt signaling or inhibition of both glycogen synthase kinase-3beta and Dickkopf 1, two key negative regulators of the canonical Wnt pathway, are able to protect against Abeta neurotoxicity and to ameliorate cognitive performance in AD patients. Although PPAR gamma is upregulated in AD patients, and despite the fact that it has been shown that the PPAR gamma and Wnt/beta catenin pathway systems work in an opposite manner, PPAR gamma agonists diminish learning and memory deficits, decrease Abeta activation of microglia, and prevent hippocampal and cortical neurons from dying. These beneficial effects observed in AD transgenic mice and patients might be partially due to the anti-inflammatory properties of PPAR gamma agonists. Moreover, activation of PPAR alpha upregulates transcription of the alpha-secretase gene and represents a new therapeutic treatment for AD. This review focuses largely on the behavior of two opposing pathways in AD, namely Wnt/beta-catenin signaling and PPAR gamma. It is hoped that this approach may help to develop novel AD therapeutic strategies integrating PPAR alpha signaling.

  17. Identification of putative PPAR response elements in and around the murine UCP3 gene

    DEFF Research Database (Denmark)

    Siersbæk, Majken

    in thermogenesis in unerring, the physiological functions of UCP2 and UCP3 are at present not fully understood. Synthetic agonists for the peroxisome proliferator-activated receptors (PPARs) as well as fatty acids have been shown to increase murine UCP2 and UCP3 mRNA expression but response elements and mechanisms...... differentiation. Results from sequencing of chromatin immunoprecipitated (ChIP) material from 3T3-L1 adipocytes revealed three PPAR and retinoid X receptor (RXR) binding sites in and around the murine UCP3 gene. The recruitment of PPAR and RXR to the three potential PPREs was determined by ChIP combined...

  18. Sensitive bioassay for detection of PPAR{alpha} potentially hazardous ligands with gold nanoparticle probe

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Wei; Wan, Yan-Jian [Minister of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province 430030 (China); Wang, Xianliang [Division of Environmental Pollution and Human Health, Chinese Research Academy of Environmental Sciences, Beijing 100012 (China); Li, Yuan-yuan; Yang, Wen-Jie; Wang, Chun-Xiang [Minister of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province 430030 (China); Xu, Shun-qing, E-mail: shunqing@mails.tjmu.edu.cn [Minister of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province 430030 (China)

    2011-09-15

    Highlights: {yields} We develop a sensitive and high throughput method to screen PPAR{alpha} ligands. {yields} This method is based on the ligand-receptor interaction on microplate. {yields} The sensitivity is increased through sliver enhancement on captured gold nanoparticle probes. {yields} There is a significant correlation between the bioassay and LC-MS for water spiked samples. - Abstract: There are so many kinds of peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) ligands with hazardous effect for human health in the environment, such as certain herbicides, plasticizers and drugs. Among these agonists, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and mono-(2-ethylhexyl) phthalate (MEHP) are mostly investigated due to their persistence and accumulation in environment and their potential toxicity via PPAR{alpha}. This investigation aims at developing a bioassay method to detect PPAR{alpha} ligands based on the ligand-receptor interaction on microplate. PPAR{alpha}, which formed heterodimers with retinoid X receptor-{alpha} (RXR{alpha}), were activated by PPAR{alpha} ligands to form ligands-PPAR{alpha}-RXR{alpha} complexes. Then the complexes were transferred into a microplate and captured via monoclonal anti-PPAR{alpha} antibody. The PPAR{alpha} responsive elements (PPRE) modified-gold nanoparticle probes were captured by the ligand-PPAR{alpha}-RXR{alpha} complexes immobilized on the microplate, and then could be quantified through measuring the optical density after silver enhancement. The results showed that PFOS was quantified with a linear range from 100 pM to 1 {mu}M and the detection limit was 10 pM. In addition to PFOS, PFOA and MEHP were also quantified within a proper range through the proposed bioassay. This bioassay was compared with that of liquid chromatography tandem-mass spectrometry (LC-MS) for water spiked samples with a significant correlation (r = 0.9893). This study provides a high-throughput detection

  19. Mitosis-associated repression in development.

    Science.gov (United States)

    Esposito, Emilia; Lim, Bomyi; Guessous, Ghita; Falahati, Hanieh; Levine, Michael

    2016-07-01

    Transcriptional repression is a pervasive feature of animal development. Here, we employ live-imaging methods to visualize the Snail repressor, which establishes the boundary between the presumptive mesoderm and neurogenic ectoderm of early Drosophila embryos. Snail target enhancers were attached to an MS2 reporter gene, permitting detection of nascent transcripts in living embryos. The transgenes exhibit initially broad patterns of transcription but are refined by repression in the mesoderm following mitosis. These observations reveal a correlation between mitotic silencing and Snail repression. We propose that mitosis and other inherent discontinuities in transcription boost the activities of sequence-specific repressors, such as Snail. © 2016 Esposito et al.; Published by Cold Spring Harbor Laboratory Press.

  20. Adrenomedullin receptor is found exclusively in noradrenaline-secreting cells of the rat adrenal medulla.

    Science.gov (United States)

    Renshaw, D; Thomson, L M; Michael, G J; Carroll, M; Kapas, S; Hinson, J P

    2000-04-01

    Adrenomedullin, originally identified in the adrenal medulla, has binding sites in the adrenal gland; however, its role in the adrenal medulla is unclear. This study was designed to characterise adrenomedullin binding sites in the rat adrenal medulla, using ligand binding studies, immunocytochemistry, and mRNA analysis. A single population of specific adrenomedullin receptors was identified in adrenal medullary homogenates. 125I-Adrenomedullin was displaced only by adrenomedullin1-50 and not by calcitonin gene-related peptide or amylin at concentrations up to 100 nmol/L. The receptor K(D) was 3.64 nmol/L with a receptor density of 570 fmol/mg of protein. Analysis of mRNA revealed that the genes encoding both the putative adrenomedullin receptors, termed calcitonin receptor-like receptor (CRLR) and L1, were expressed in the rat adrenal medulla. Dual-colour indirect-labelled immunofluorescence was used to localise phenylethanolamine N-methyltransferase (PNMT) and the adrenomedullin receptor in the same section. PNMT is the enzyme that converts noradrenaline to adrenaline and is not expressed in noradrenaline-secreting cells. These studies revealed that both CRLR and L1 were expressed only in cells that did not express PNMT, suggesting that adrenomedullin receptors are only found in noradrenaline-secreting cells. Further evidence to support this conclusion was provided by the demonstration of colocalisation of adrenomedullin receptors with dopamine beta-hydroxylase, confirming the presence of the receptors in medullary chromaffin cells. Taken together, these data suggest that adrenomedullin acts through a specific adrenomedullin receptor in the rat adrenal medulla. RT-PCR and northern blot analysis revealed greater abundance of mRNA for L1 than for CRLR, possibly suggesting that L1 may be the major adrenomedullin receptor expressed in this tissue. As it has been reported that adrenomedullin is synthesised predominantly by adrenaline-secreting cells, it appears likely

  1. PPAR- γ agonist in treatment of diabetes: cardiovascular safety considerations.

    Science.gov (United States)

    Abbas, Aamer; Blandon, Jimena; Rude, Jennifer; Elfar, Ahmed; Mukherjee, Debabrata

    2012-06-01

    The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors, which contain a type II zinc finger DNA binding motif and a hydrophobic ligand binding pocket. These receptors are thought to play an important role in metabolic diseases such as obesity, insulin resistance, and coronary artery disease. Three subtypes of PPAR receptors have been described: PPARα, PPARδ/β, and PPARγ. PPARα is found in the liver, muscle, kidney, and heart. In the liver, its role is to up-regulate genes involved in fatty acid uptake, binding, β-oxidation and electron transport, and oxidative phosphorylation in subcutaneous fat but not in skeletal muscle. PPARδ/β is expressed in many tissues but markedly in brain, adipose tissue, and skin. PPARγ has high expression in fat, low expression in the liver, and very low expression in the muscle. The thiazolidinediones (TZD) are synthetic ligands of PPARγ. By activating a number of genes in tissues, PPARγ increases glucose and lipid uptake, increases glucose oxidation, decreases free fatty acid concentration, and decreases insulin resistance. Although, there is a rationale for the use of TZDs in patients with type 2 diabetes mellitus, clinical studies have produced conflicting data. While currently used TZDs are clearly associated with heart failure (HF) worsening; with regards to cardiovascular outcomes, pioglitazone seems to be related to a trend toward reduction in cardiovascular morbidity and mortality, whereas rosiglitazone may actually increase risk of cardiovascular events. We review the existing literature on TZDs and discuss role and cardiovascular safety of these agents for the contemporary treatment of diabetes. Other side effects of these agents i.e. increase in osteoporosis and possible risk of bladder cancer is also discussed.

  2. Barrier and uptake mechanisms in the cerebrovascular response to noradrenaline. [/sup 133/Xe tracer technique, baboons

    Energy Technology Data Exchange (ETDEWEB)

    McCalden, T.A.; Eidelman, B.H.; Mendelow, A.D.

    1977-10-01

    Cerebral blood flow (CBF) was measured in 20 baboons by the intra-arterial xenon-133 injection method. The CBF responses to intra-arterial infusions of noradrenaline (NA) were determined. These responses were normally found to be vasodilator and mediated by beta adrenoreceptors. After infusion of substances blocking extraneuronal uptake of NA or opening of the blood-brain barrier, this vasodilation was either abolished or converted to an alpha-receptor mediated vasoconstriction. This suggests that normally the cerebral circulation is protected against noradrenergic vasoconstriction by mechanisms reducing the concentration of NA in the tunica media to below threshold for alpha-adrenoreceptor stimulation.

  3. Functional adaptation of the human β-cells after frequent exposure to noradrenaline

    DEFF Research Database (Denmark)

    Dela, Flemming

    2015-01-01

    KEY POINTS: Trained people produce less insulin than untrained; there is an adaptation of the insulin-producing cells to the trained state. The mechanism behind this adaptation is not known, but some sort of memory must be introduced into the insulin-producing cells. Here it is shown...... in noradrenaline is most likely the stimulus that introduces a memory in the insulin-producing cells. ABSTRACT: Physical training decreases glucose- and arginine-stimulated insulin secretion. The mechanism by which the pancreatic β-cells adapt to the training status of the individual is not known. We hypothesized...... the adaptation of the β-cells seen in trained people....

  4. [Noradrenaline and plasticity of the visual cortex of the kitten: a reexamination].

    Science.gov (United States)

    Adrien, J; Buisseret, P; Fregnac, Y; Gary-Bobo, E; Imbert, M; Tassin, J P; Trotter, Y

    1982-12-06

    We have undertaken a study of the role of the noradrenergic system in the functional modifications, observed in the primary visual cortex of the Kitten, following monocular deprivation. The lids of one eye were sutured in 5 week old Kittens for a period of 1 or 2 weeks. Noradrenergic depletion was obtained by 6-OHDA injection, either intraventricular or localized in the coeruleus complex. Our results indicate that disappearance of noradrenaline in area 17 does not prevent the loss of binocularity of cortical cells, but appears to limit ocular dominance shifts at a stage equivalent to that observed in the intact Kitten after 6 days of monocular deprivation.

  5. 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

  6. 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

  7. Fine tuning of PPAR ligands for type 2 diabetes and metabolic syndrome.

    Science.gov (United States)

    Ramachandran, Uma; Kumar, Rakesh; Mittal, Amit

    2006-05-01

    Type 2 diabetes mellitus (T2DM) is highly prevalent chronic disease. Recently, many biological targets are discovered for treatment of this disease. The identification of the nuclear hormone receptor peroxisome proliferator activated receptors (PPAR) and their subtypes alpha, gamma and delta or beta as targets for controlling lipid, glucose and energy homeostasis has proved to be exciting. As hyperlipidaemia, obesity and insulin resistance are independent risk factors for coronary heart disease and macrovascular complications of diabetes; new agents that increase insulin sensitivity as well as decrease hyperlipidaemia by distinct yet complementary mechanism are being studied as they may provide improved therapy for T2DM and related disorders. In this article, we review highly potent PPARgamma agonists, PPARalpha/gamma dual agonists, PPAR pan agonists, alternative PPAR ligands like partial agonists or selective PPAR modulators (SPPARMs) and antagonists from a chemist point of view.

  8. PPAR agonists stimulate adipogenesis at the expense of osteoblast differentiation while inhibiting osteoclast formation and activity.

    Science.gov (United States)

    Patel, Jessal J; Butters, Oliver R; Arnett, Timothy R

    2014-06-01

    Drugs used in the treatment of type 2 diabetes and cardiovascular disease, specifically peroxisome proliferator-activated receptor (PPAR) agonists, have been reported to affect bone cell function and fracture risk. In this study, we assessed the direct effects of PPAR-γ agonists (rosiglitazone and troglitazone), used in the treatment of diabetes, and a PPAR-α agonist (fenofibrate), used to treat hyperlipidaemia, on the function of primary osteoblasts and osteoclasts. Formation of 'trabecular' bone structures by rat calvarial osteoblasts was reduced by up to 85% in cultures treated with rosiglitazone and by 45% in troglitazone-treated or fenofibrate-treated cultures; at the same time, lipid droplet formation was increased by 40-70%. The expression of key osteogenic markers was similarly downregulated in cultures treated with PPAR agonists, whereas adipogenesis markers were upregulated. Formation of osteoclasts in cultures derived from mouse marrow diminished with fenofibrate treatment, whereas both glitazones reduced resorptive activity without affecting osteoclast number. Metformin, although not a PPAR agonist, is also commonly used in the treatment of type 2 diabetes. Here, metformin was found to have no effect on bone cell function. Taken together, these data suggest that PPAR-γ agonists may enhance bone loss via increased adipogenesis at the expense of osteoblast formation. In contrast, PPAR-α agonists may prevent bone loss. Given that the prevalence of diabetes and cardiovascular disease is expected to rise significantly, greater attention may need to be paid to the effects of PPAR agonists on bone homeostasis. Copyright © 2014 John Wiley & Sons, Ltd.

  9. Repression-Sensitization and Health Behavior.

    Science.gov (United States)

    Gayton, William F.; And Others

    1978-01-01

    Examined relationship between repression-sensitization (R-S) and visits to prison infirmary for males during a one-year period. Main effect for R-S dimension was significant for total number of visits, number of medically justified visits, and number of medically unjustified visits. Sensitizers had significantly more visits than repressors.…

  10. The great repression: chromatin and cryptic transcription.

    Science.gov (United States)

    Hennig, Bianca P; Fischer, Tamás

    2013-01-01

    The eukaryotic chromatin structure is essential in correctly defining transcription units. Impairing this structure can activate cryptic promoters, and lead to the accumulation of aberrant RNA transcripts. Here we discuss critical pathways that are responsible for the repression of cryptic transcription and the maintenance of genome integrity.

  11. Political Repression in U.S. History

    NARCIS (Netherlands)

    van Minnen, C.A.

    2009-01-01

    The authors of the essays in this book amass considerable historical evidence illustrating various forms of political repression and its relationship with democracy in the United States, from the late-eighteenth century to the present. They discuss efforts, made mostly but not only by government age

  12. Repression-Sensitization and Health Behavior.

    Science.gov (United States)

    Gayton, William F.; And Others

    1978-01-01

    Examined relationship between repression-sensitization (R-S) and visits to prison infirmary for males during a one-year period. Main effect for R-S dimension was significant for total number of visits, number of medically justified visits, and number of medically unjustified visits. Sensitizers had significantly more visits than repressors.…

  13. Cancer, acute stress disorder, and repressive coping

    DEFF Research Database (Denmark)

    Pedersen, Anette Fischer; Zachariae, Robert

    2010-01-01

    Reaction Questionnaire, and repressive coping was assessed by a combination of scores from the Marlowe-Crowne Social Desirability Scale, and the Bendig version of the Taylor Manifest Anxiety Scale. Significantly fewer patients classified as "repressors" were diagnosed with ASD compared to patients...

  14. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  16. APOE dependent-association of PPAR-γ genetic variants with Alzheimer's disease risk.

    Science.gov (United States)

    Combarros, Onofre; Rodríguez-Rodríguez, Eloy; Mateo, Ignacio; Vázquez-Higuera, José Luis; Infante, Jon; Berciano, José; Sánchez-Juan, Pascual

    2011-03-01

    The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-inducible transcription factor that suppresses microglial inflammatory responses and inhibits amyloid beta (Aβ) production through promoting cholesterol efflux from glial cells. PPAR-γ agonists have been advanced as a new disease altering approach to Alzheimer's disease (AD), with rosiglitazone therapy having improved cognition in those AD patients that did not possess an Apolipoprotein E (APOE) ε4 allele. The current study was designed to explore the effect of interactions between PPAR-γ and APOE gene polymorphisms on the AD risk. We examined genetic variations of PPAR-γ by genotyping 7 haplotype tagging SNPs (htSNPs) (rs10510412, rs17793951, rs1801282, rs4135263, rs1151999, rs709149, and rs709154) in a group of 352 Spanish late-onset AD cases and 438 controls. The PPAR-γ TCCA haplotype derived from SNPs in introns 4 (rs4135263), 5 (rs1151999), and 6 (rs709149 and rs709154) showed a strong protective effect against AD in APOE ε4 allele noncarriers (p=0.001, permutation p=0.006, Bonferroni corrected p=0.021), with a frequency of 39% in cases and 50% in controls. Our data suggest that PPAR-γ genetic variants may modify the risk of AD in an APOE ε4 allele-dependent fashion.

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

    Science.gov (United States)

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

    2017-02-19

    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. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD.

    Science.gov (United States)

    Gross, Barbara; Pawlak, Michal; Lefebvre, Philippe; Staels, Bart

    2017-01-01

    Obesity is a worldwide epidemic that predisposes individuals to cardiometabolic complications, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), which are all related to inappropriate ectopic lipid deposition. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are highly needed. The peroxisome proliferator-activated receptors (PPARs) modulate several biological processes that are perturbed in obesity, including inflammation, lipid and glucose metabolism and overall energy homeostasis. Here, we review how PPARs regulate the functions of adipose tissues, such as adipogenesis, lipid storage and adaptive thermogenesis, under healthy and pathological conditions. We also discuss the clinical use and mechanism of PPAR agonists in the treatment of obesity comorbidities such as dyslipidaemia, T2DM and NAFLD. First generation PPAR agonists, primarily those acting on PPARγ, are associated with adverse effects that outweigh their clinical benefits, which led to the discontinuation of their development. An improved understanding of the physiological roles of PPARs might, therefore, enable the development of safe, new PPAR agonists with improved therapeutic potential.

  19. [Simultaneous determination of adrenaline, noradrenaline, cortisone and cortisol in plasma with HPLC/MS/MS].

    Science.gov (United States)

    Yong, Li; Wang, Yu; Zou, Xiao-Li; Zhu, Lan; Xie, Hui-Ru; Li, Long-Jiang

    2014-01-01

    To develop a method for simultaneous determination of adrenaline, noradrenaline, cortisone and cortisol in plasma using HPLC/MS/MS. Sample proteins were precipitated with acetonitrile and the sample solution was injected into HPLC/MS/MS after centrifugation at 15,000 r/min for 5 min. Electrospray ionization (ESI) and the positive ion detection were applied with a multiple reaction monitoring (MRM) mode for quantitative analyses. Under the optimal conditions, good linearity (r > 0.999) was observed in the range of 0.02-200.00 ng/mL of target compounds. The detection limit reached 4.13 pg/mL, 4.64 pg/mL, 4.29 pg/mL and 4.52 pg/mL for adrenaline, noradrenaline, cortisone and cortisol respectively. The inter-day and intra-day precisions ranged from 1.19%-5.42% and 2.16%-6.04% respectively. Satisfied results were achieved using human plasma samples, with a spiked recovery in the range of 80.0%-109.0% and a relative standard deviation of 3.93%-7.57%. The proposed method is quick, sensitive and suitable for batch analyses of plasma samples.

  20. GPR40/FFAR1 deficient mice increase noradrenaline levels in the brain and exhibit abnormal behavior

    Directory of Open Access Journals (Sweden)

    Fuka Aizawa

    2016-12-01

    Full Text Available The free fatty acid receptor 1 (GPR40/FFAR1 is a G protein-coupled receptor, which is activated by long chain fatty acids. We have previously demonstrated that activation of brain GPR40/FFAR1 exerts an antinociceptive effect that is mediated by the modulation of the descending pain control system. However, it is unclear whether brain GPR40/FFAR1 contributes to emotional function. In this study, we investigated the involvement of GPR40/FFAR1 in emotional behavior using GPR40/FFAR1 deficient (knockout, KO mice. The emotional behavior in wild and KO male mice was evaluated at 9–10 weeks of age by the elevated plus-maze test, open field test, social interaction test, and sucrose preference test. Brain monoamines levels were measured using LC–MS/MS. The elevated plus-maze test and open field tests revealed that the KO mice reduced anxiety-like behavior. There were no differences in locomotor activity or social behavior between the wild and KO mice. In the sucrose preference test, the KO mice showed reduction in sucrose preference and intake. The level of noradrenaline was higher in the hippocampus, medulla oblongata, hypothalamus and midbrain of KO mice. Therefore, these results suggest that brain GPR40/FFAR1 is associated with anxiety- and depression-related behavior regulated by the increment of noradrenaline in the brain.

  1. Cell death is induced by ciglitazone, a peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonist, independently of PPAR{gamma} in human glioma cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Myoung Woo; Kim, Dae Seong; Kim, Hye Ryung; Kim, Hye Jin; Yang, Jin Mo; Ryu, Somi; Noh, Yoo Hun; Lee, Soo Hyun; Son, Meong Hi; Jung, Hye Lim; Yoo, Keon Hee [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Koo, Hong Hoe, E-mail: hhkoo@skku.edu [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Sung, Ki Woong, E-mail: kwsped@skku.edu [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Greater than 30 {mu}M ciglitazone induces cell death in glioma cells. Black-Right-Pointing-Pointer Cell death by ciglitazone is independent of PPAR{gamma} in glioma cells. Black-Right-Pointing-Pointer CGZ induces cell death by the loss of MMP via decreased Akt. -- Abstract: Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) regulates multiple signaling pathways, and its agonists induce apoptosis in various cancer cells. However, their role in cell death is unclear. In this study, the relationship between ciglitazone (CGZ) and PPAR{gamma} in CGZ-induced cell death was examined. At concentrations of greater than 30 {mu}M, CGZ, a synthetic PPAR{gamma} agonist, activated caspase-3 and induced apoptosis in T98G cells. Treatment of T98G cells with less than 30 {mu}M CGZ effectively induced cell death after pretreatment with 30 {mu}M of the PPAR{gamma} antagonist GW9662, although GW9662 alone did not induce cell death. This cell death was also observed when cells were co-treated with CGZ and GW9662, but was not observed when cells were treated with CGZ prior to GW9662. In cells in which PPAR{gamma} was down-regulated cells by siRNA, lower concentrations of CGZ (<30 {mu}M) were sufficient to induce cell death, although higher concentrations of CGZ ( Greater-Than-Or-Slanted-Equal-To 30 {mu}M) were required to induce cell death in control T98G cells, indicating that CGZ effectively induces cell death in T98G cells independently of PPAR{gamma}. Treatment with GW9662 followed by CGZ resulted in a down-regulation of Akt activity and the loss of mitochondrial membrane potential (MMP), which was accompanied by a decrease in Bcl-2 expression and an increase in Bid cleavage. These data suggest that CGZ is capable of inducing apoptotic cell death independently of PPAR{gamma} in glioma cells, by down-regulating Akt activity and inducing MMP collapse.

  2. N-3 PUFA supplementation triggers PPAR-α activation and PPAR-α/NF-κB interaction: anti-inflammatory implications in liver ischemia-reperfusion injury.

    Directory of Open Access Journals (Sweden)

    Jessica Zúñiga

    Full Text Available Dietary supplementation with the n-3 polyunsaturated fatty acids (n-3 PUFA eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA to rats preconditions the liver against ischemia-reperfusion (IR injury, with reduction of the enhanced nuclear factor-κB (NF-κB functionality occurring in the early phase of IR injury, and recovery of IR-induced pro-inflammatory cytokine response. The aim of the present study was to test the hypothesis that liver preconditioning by n-3 PUFA is exerted through peroxisone proliferator-activated receptor α (PPAR-α activation and interference with NF-κB activation. For this purpose we evaluated the formation of PPAR-α/NF-κBp65 complexes in relation to changes in PPAR-α activation, IκB-α phosphorylation and serum levels and expression of interleukin (IL-1β and tumor necrosis factor (TNF-α in a model of hepatic IR-injury (1 h of ischemia and 20 h of reperfusion or sham laparotomy (controls in male Sprague Dawley rats. Animals were previously supplemented for 7 days with encapsulated fish oil (General Nutrition Corp., Pittsburg, PA or isovolumetric amounts of saline (controls. Normalization of IR-altered parameters of liver injury (serum transaminases and liver morphology was achieved by dietary n-3 PUFA supplementation. EPA and DHA suppression of the early IR-induced NF-κB activation was paralleled by generation of PPAR-α/NF-κBp65 complexes, in concomitance with normalization of the IR-induced IκB-α phosphorylation. PPAR-α activation by n-3 PUFA was evidenced by enhancement in the expression of the PPAR-α-regulated Acyl-CoA oxidase (Acox and Carnitine-Palmitoyl-CoA transferase I (CPT-I genes. Consistent with these findings, normalization of IR-induced expression and serum levels of NF-κB-controlled cytokines IL-lβ and TNF-α was observed at 20 h of reperfusion. Taken together, these findings point to an antagonistic effect of PPAR-α on NF-κB-controlled transcription of pro-inflammatory mediators

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

    Directory of Open Access Journals (Sweden)

    Massimo Bionaz

    2013-01-01

    Full Text Available 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 PPAR 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.

  4. 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....... DiBP and rosiglitazone additionally reduced fetal plasma insulin levels. In mates, DiBP reduced anogenital testosterone production and testicular expression of Insl-3 and genes related to steroidogenesis. distance, PPAR alpha mRNA levels were reduced by DiBP at GD 19 in testis and liver. In females...

  5. Human muscle sympathetic nerve activity and plasma noradrenaline kinetics in space

    Science.gov (United States)

    Ertl, Andrew C.; Diedrich, Andre; Biaggioni, Italo; Levine, Benjamin D.; Robertson, Rose Marie; Cox, James F.; Zuckerman, Julie H.; Pawelczyk, James A.; Ray, Chester A.; Buckey, Jay C Jr; Lane, Lynda D.; Shiavi, Richard; Gaffney, F. Andrew; Costa, Fernando; Holt, Carol; Blomqvist, C. Gunnar; Eckberg, Dwain L.; Baisch, Friedhelm J.; Robertson, David

    2002-01-01

    Astronauts returning from space have reduced red blood cell masses, hypovolaemia and orthostatic intolerance, marked by greater cardio-acceleration during standing than before spaceflight, and in some, orthostatic hypotension and presyncope. Adaptation of the sympathetic nervous system occurring during spaceflight may be responsible for these postflight alterations. We tested the hypotheses that exposure to microgravity reduces sympathetic neural outflow and impairs sympathetic neural responses to orthostatic stress. We measured heart rate, photoplethysmographic finger arterial pressure, peroneal nerve muscle sympathetic activity and plasma noradrenaline spillover and clearance, in male astronauts before, during (flight day 12 or 13) and after the 16 day Neurolab space shuttle mission. Measurements were made during supine rest and orthostatic stress, as simulated on Earth and in space by 7 min periods of 15 and 30 mmHg lower body suction. Mean (+/- S.E.M.) heart rates before lower body suction were similar pre-flight and in flight. Heart rate responses to -30 mmHg were greater in flight (from 56 +/- 4 to 72 +/- 4 beats min(-1)) than pre-flight (from 56 +/- 4 at rest to 62 +/- 4 beats min(-1), P < 0.05). Noradrenaline spillover and clearance were increased from pre-flight levels during baseline periods and during lower body suction, both in flight (n = 3) and on post-flight days 1 or 2 (n = 5, P < 0.05). In-flight baseline sympathetic nerve activity was increased above pre-flight levels (by 10-33 %) in the same three subjects in whom noradrenaline spillover and clearance were increased. The sympathetic response to 30 mmHg lower body suction was at pre-flight levels or higher in each subject (35 pre-flight vs. 40 bursts min(-1) in flight). No astronaut experienced presyncope during lower body suction in space (or during upright tilt following the Neurolab mission). We conclude that in space, baseline sympathetic neural outflow is increased moderately and sympathetic

  6. Isorhamnetin represses adipogenesis in 3T3-L1 cells.

    Science.gov (United States)

    Lee, Jongsung; Jung, Eunsun; Lee, Jienny; Kim, Saebom; Huh, Sungran; Kim, Youngsoo; Kim, Yongwoo; Byun, Sang Yo; Kim, Yeong-Shik; Park, Deokhoon

    2009-02-01

    Adipocyte dysfunction is strongly associated with the development of obesity, which is a major risk factor for many disorders including diabetes, hypertension, and heart disease. It is generally accepted that the regulation of adipogenesis or adipokines expression prevents obesity. In this study, we show that isorhamnetin inhibits adipocyte differentiation, as evidenced by reduced triglyceride (TG) accumulation and glycerol-3-phosphate dehydrogenase (GPDH) activity. At the molecular level, the mRNA expression levels of peroxidase proliferator-activated receptor-gamma (PPAR-gamma) and CCAAT/enhancer-binding protein-alpha (C/EBP-alpha), which are the major adipogenic transcription factors, were markedly reduced by isorhamnetin. However, the mRNA levels of C/EBP-beta and -delta, the upstream regulators of PPAR-gamma and C/EBP-alpha, were not reduced by isorhamnetin. Moreover, the mRNA levels of PPAR-gamma target genes such as lipoprotein lipase (LPL), CD36, aP2, and liver X receptor-alpha (LXR-alpha) were downregulated by isorhamnetin. We also showed that isorhamnetin inhibits the expression and secretion of adiponectin, and the results of adiponectin promoter assays suggest the inhibition of PPAR-gamma expression as a possible mechanism underlying the isorhamnetin-mediated effects. Taken together, these results indicate that isorhamnetin inhibits adipogenesis through downregulation of PPAR-gamma and C/EBP-alpha.

  7. Recovery of (/sup 3/H)noradrenaline from different metabolic compartments of rat brain with respect to the role of catechol-O-methyltransferase

    Energy Technology Data Exchange (ETDEWEB)

    Koester, G.; Goede, E.; Breuer, H.

    1984-03-01

    Rats were treated with reserpine, desmethyl-imipramine, or carrier, either alone or in combination with tropolone. Either 10 min (t1) or 1 h (t2) after intraventricular injection of (/sup 3/H)noradrenaline, they were decapitated. The total /sup 3/H activity and the recovery of (/sup 3/H)noradrenaline were determined in tissue extracts from various brain regions. Maximum total /sup 3/H activity was measured at t1 in all tropolone-treated rats; the mean sum of these results served as an estimate of the initial tissue concentration of (/sup 3/H)noradrenaline. At t1, 40-50% of the sum of (/sup 3/H)noradrenaline and its metabolites was recovered unchanged in normal rats; reserpine and DMI reduced the recovery to 18-27%. In all groups, the decline of (/sup 3/H)noradrenaline was retarded after t1. Inhibition of catechol-O-methyltransferase by tropolone caused consistently elevated (/sup 3/H)noradrenaline levels, but did not affect the metabolic rate after t1 when compared with similarly pretreated, but tropolone-free rats. Thus, if catechol-O-methyltransferase was inhibited during the injection of (/sup 3/H)noradrenaline, a higher percentage of the amine had been taken up into spaces with a slow noradrenaline turnover. The maximum increase was seen when the neuronal uptake1 was inhibited by desmethylimipramine. This supported the hypothesis that an additional extraneuronal space exists, in addition to the known intraneuronal and extraneuronal compartments, which has a slow noradrenaline turnover. The tropolone effect on the noradrenaline recovery possibly shows that there might be a saturable ''methylating system,'' similar to that described for the periphery, in which catechol-O-methyltransferase is linked to the extraneuronal uptake.

  8. Peroxisome Proliferator Activator Receptor (PPAR-γ Ligand, but Not PPAR-α, Ameliorates Cyclophosphamide-Induced Oxidative Stress and Inflammation in Rat Liver

    Directory of Open Access Journals (Sweden)

    Azza A. K. El-Sheikh

    2014-01-01

    Full Text Available Hepatoprotective potential of peroxisome proliferator activator receptor (PPAR-α and -γ agonists, fenofibrate (FEN, and pioglitazone (PIO, respectively, against cyclophosphamide (CP-induced toxicity has been investigated in rat. FEN and PIO (150 and 10 mg/kg/day, resp. were given orally for 4 weeks. In separate groups, CP (150 mg/kg, i.p. was injected as a single dose 5 days before the end of experiment, with or without either PPAR agonist. CP induced hepatotoxicity, as it caused histopathological alterations, with increased serum alanine and aspartate transaminases, total bilirubin, albumin, alkaline phosphatase and lactate dehydrogenase. CP caused hepatic oxidative stress, indicated by decrease in tissue reduced glutathione, with increase in malondialdehyde and nitric oxide levels. CP also caused decrease in hepatic antioxidant enzyme levels, including catalase, superoxide dismutase, glutathione peroxidase, and glutathione S-transferase. Furthermore, CP increased serum and hepatic levels of the inflammatory marker tumor necrosis factor (TNF-α, evaluated using ELISA. Preadministration of PIO, but not FEN, prior to CP challenge improved hepatic function and histology, and significantly reversed oxidative and inflammatory parameters. In conclusion, activation of PPAR-γ, but not PPAR-α, conferred protection against CP-induced hepatotoxicity, via activation of antioxidant and anti-inflammatory mechanisms, and may serve as supplement during CP chemotherapy.

  9. Association of PPAR gene polymorphisms with osteoarthritis in a southeast Chinese population

    Indian Academy of Sciences (India)

    Ding Zheru; Fu Peiliang; Wu Yuli; Wu Haishan; Qian Qirong; Li Xiaohua; Zhao Hui; Wang Bo; Fu Qiwei

    2014-12-01

    Primary osteoarthritis (OA) is a leading cause of disability in developed countries. Currently no satisfactory treatment to stop disease progression exists. Recent studies suggest that activation of the transcription factor peroxisome proliferator-activated receptor gamma (PPAR) is an interesting therapeutic target for this disease. PPAR is a transcription factor important for adipogenesis and adipocyte differentiation. Agonists of PPAR inhibit inflammation and reduce generation of cartilage degradation products both in vitro and in vivo, and reduce the development/progression of cartilage lesions in OA animal models. However, there are no studies to assess the role of PPAR in OA susceptibility of human peripheral joints in a Chinese population. We conducted a case–control study in a southeast Chinese population to determine the association of PPAR gene polymorphisms (rs1801282, rs12629751, rs2292101, rs4135275 and rs1175543) with OA. One-hundred knee OA cases and 100 controls were studied. Statistically significant differences were detected in genotype and allele frequencies between OA and control groups in this population. For knee OA, the highest risk was associated with the variant allele T of the single-nucleotide polymorphism rs12629751 (odds ratio (OR): 0.341, 95% confidence interval (CI):0.173–0.673, $P = 0.002$), and allele T of SNP rs12629751 (chi-square: 9.546, $P = 0.002$) could be considered as a risk factor of knee OA. Therefore, PPAR mutation could be associated with the incidence of OA in a Chinese population. There is a significant association between the PPAR polymorphism rs12629751 and susceptibility to knee OA in a southeast Chinese population.

  10. Interference of pollutants with PPARs: endocrine disruption meets metabolism.

    Science.gov (United States)

    Casals-Casas, C; Feige, J N; Desvergne, B

    2008-12-01

    The concept of endocrine disruption emerged over a decade ago with the observation that several natural or industrial compounds can interfere with estrogen and androgen signaling, and thereby affect both male and female reproductive functions. Since then, many endocrine-disrupting chemicals (EDCs) have been identified and the concept has been broadened to receptors regulating other aspects of endocrine pathways. In that context, interference of EDCs with receptors regulating metabolism has been proposed as a factor that could contribute to metabolic diseases such as obesity and diabetes. We review recent studies showing that several pollutants, including phthalates and organotins, interfere with PPAR (peroxisome proliferator-activated receptors) nuclear receptors and may thereby affect metabolic homeostasis. Particular emphasis is given on the mechanisms of action of these compounds. However, unlike what has been suspected, we provide evidence from mouse models suggesting that in utero exposure to the phthalate ester di-ethyl-hexyl-phthalate most likely does not predispose to obesity. Collectively, these studies define a subclass of EDCs that perturb metabolic signaling and that we propose to define as metabolic disruptors.

  11. Nuclear AXIN2 represses MYC gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Rennoll, Sherri A.; Konsavage, Wesley M.; Yochum, Gregory S., E-mail: gsy3@psu.edu

    2014-01-03

    Highlights: •AXIN2 localizes to cytoplasmic and nuclear compartments in colorectal cancer cells. •Nuclear AXIN2 represses the activity of Wnt-responsive luciferase reporters. •β-Catenin bridges AXIN2 to TCF transcription factors. •AXIN2 binds the MYC promoter and represses MYC gene expression. -- Abstract: The β-catenin transcriptional coactivator is the key mediator of the canonical Wnt signaling pathway. In the absence of Wnt, β-catenin associates with a cytosolic and multi-protein destruction complex where it is phosphorylated and targeted for proteasomal degradation. In the presence of Wnt, the destruction complex is inactivated and β-catenin translocates into the nucleus. In the nucleus, β-catenin binds T-cell factor (TCF) transcription factors to activate expression of c-MYC (MYC) and Axis inhibition protein 2 (AXIN2). AXIN2 is a member of the destruction complex and, thus, serves in a negative feedback loop to control Wnt/β-catenin signaling. AXIN2 is also present in the nucleus, but its function within this compartment is unknown. Here, we demonstrate that AXIN2 localizes to the nuclei of epithelial cells within normal and colonic tumor tissues as well as colorectal cancer cell lines. In the nucleus, AXIN2 represses expression of Wnt/β-catenin-responsive luciferase reporters and forms a complex with β-catenin and TCF. We demonstrate that AXIN2 co-occupies β-catenin/TCF complexes at the MYC promoter region. When constitutively localized to the nucleus, AXIN2 alters the chromatin structure at the MYC promoter and directly represses MYC gene expression. These findings suggest that nuclear AXIN2 functions as a rheostat to control MYC expression in response to Wnt/β-catenin signaling.

  12. Transthyretin represses neovascularization in diabetic retinopathy

    Science.gov (United States)

    Shao, Jun

    2016-01-01

    Purpose The apoptosis of human umbilical vein endothelial cells has been reportedly induced by the protein transthyretin (TTR). In human ocular tissue, TTR is generally considered to be secreted mainly by retinal pigment epithelial cells (hRPECs); however, whether TTR affects the development of neovascularization in diabetic retinopathy (DR) remains unclear. Methods Natural and simulated DR media were used to culture human retinal microvascular endothelial cells (hRECs). Hyperglycemia was simulated by increasing the glucose concentration from 5.5 mM up to 25 mM, while hypoxia was induced with 200 µM CoCl2. To understand the effects of TTR on hRECs, cell proliferation was investigated under natural and DR conditions. Overexpression of TTR, an in vitro wound-healing assay, and a tube formation assay were employed to study the repression of TTR on hRECs. Real-time fluorescence quantitative PCR (qRT-PCR) was used to study the mRNA levels of DR-related genes, such as Tie2, VEGFR1, VEGFR2, Angpt1, and Angpt2. Results The proliferation of hRECs was significantly decreased in the simulated hyperglycemic and hypoxic DR environments. The cells were further repressed by added exogenous or endogenous TTR only under hyperglycemic conditions. The in vitro migration and tube formation processes of the hRECs were inhibited with TTR; furthermore, in the hyperglycemia and hyperglycemia/hypoxia environments, the levels of Tie2 and Angpt1 mRNA were enhanced with exogenous TTR, while those of VEGFR1, VEGFR2, and Angpt1 were repressed. Conclusions In hyperglycemia, the proliferation, migration, and neovascularization of hRECs were significantly inhibited by TTR. The key genes for DR neovascularization, including Tie2, VEGFR1, VEGFR2, Angpt1, and Angpt2, were regulated by TTR. Under DR conditions, TTR significantly represses neovascularization by inhibiting the proliferation, migration and tube formation of hRECs. PMID:27746673

  13. Polycomb repressive complex 1 controls uterine decidualization

    OpenAIRE

    Fenghua Bian; Fei Gao; Kartashov, Andrey V.; Jegga, Anil G; Artem Barski; Das, Sanjoy K.

    2016-01-01

    Uterine stromal cell decidualization is an essential part of the reproductive process. Decidual tissue development requires a highly regulated control of the extracellular tissue remodeling; however the mechanism of this regulation remains unknown. Through systematic expression studies, we detected that Cbx4/2, Rybp, and Ring1B [components of polycomb repressive complex 1 (PRC1)] are predominantly utilized in antimesometrial decidualization with polyploidy. Immunofluorescence analyses reveale...

  14. [Peroxisome proliferator-activated receptors (PPAR) in pathophysiology of the circulatory system and prospective use of agonists of these receptors in therapy].

    Science.gov (United States)

    Bełtowski, Jerzy; Wójcicka, Grazyna; Jamroz, Anna

    2003-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors which regulate the expression of target genes. Three types of PPAR have been identified: PPAR alpha, PPAR beta/delta and PPAR gamma. The known endogenous PPAR ligands are polyunsaturated fatty acids and eicosanoids, such as 15-deoxy-delta 12,14-prostaglandin J2 and leukotriene B4. Two classes of drugs, fibrates and thiazolidinediones, bind to PPAR alpha and PPAR gamma, respectively. PPARs are involved in the regulation of the lipid metabolism and adipogenesis but are also expressed in the vasculature. PPARs activators inhibit inflammatory reactions within the vascular wall, inhibit vascular smooth muscle cells migration and proliferation and affect foam cells formation by changing the expression of scavenger receptors. PPAR agonists lower blood pressure and improve endothelial function in different animal models of hypertension as well as in humans. PPAR gamma ligands inhibit the development of atherosclerosis in LDL receptor deficient and apolipoprotein E deficient mice and in diabetic humans. PPAR gamma agonists have also been shown to attenuate myocardial hypertrophy and protect against ischemia-reperfuion injury.

  15. Adrenaline but not noradrenaline is a determinant of exercise-induced lipid mobilization in human subcutaneous adipose tissue

    DEFF Research Database (Denmark)

    Glisezinski, I. de; Larrouy, D.; Bajzova, M.

    2009-01-01

    The relative contribution of noradrenaline (norepinephrine) and adrenaline (epinephrine) in the control of lipid mobilization in subcutaneous adipose tissue (SCAT) during exercise was evaluated in men treated with a somatostatin analogue, octreotide. Eight lean and eight obese young men matched...... specifically to SCAT and exercise only or if conclusions could be extended to all forms of lipolysis in humans Udgivelsesdato: 2009/7/1...

  16. The noradrenaline-dopamine interaction in the rat medial prefrontal cortex studied by multi-probe microdialysis

    NARCIS (Netherlands)

    Kawahara, H; Kawahara, Y; Westerink, BHC

    2001-01-01

    Multi-probe microdialysis was used to investigate the interaction between the release of noradrenaline and dopamine in the medial prefrontal cortex. Retrograde microdialysis was used to stimulate or inhibit the activity of the locus coeruleus for a restricted period of time, and the response of extr

  17. Autoradiographic localization of 5-hydroxytryptamine and noradrenaline in the central nervous system of Lithobius forficatus L. (Myriapoda; Chilopoda)

    NARCIS (Netherlands)

    Descamps, Michel; Joly, Robert; Jamault-Navarro, Catherine

    1985-01-01

    Using the ability of selective uptake by the neurons of their own secreted amines, two 3H labeled neurotransmitters were used: 5-hydroxytryptamine (5 HT, serotonin) and noradrenaline (NA). Autoradiographic study was conducted on semithin and on ultrathin sections. In the brain, 3H-5 HT labeling is o

  18. Antipsychotic drugs classified by their effects on the release of dopamine and noradrenaline in the prefrontal cortex and striatum

    NARCIS (Netherlands)

    Westerink, B.H.C.; Kawahara, Y; de Boer, P; Geels, C; de Vries, J.B; Wikström, H.V; van Kalkeren, A; van Vliet, B; Kruse, C.H; Long, S.K

    2001-01-01

    Dose-effect curves were established for the effects of the antipsychotic drugs haloperidol, clozapine, olanzapine, risperidone and ziprasidone on extracellular levels of dopamine and noradrenaline in the medial prefrontal cortex, and of dopamine in the striatum. Haloperidol was more effective in sti

  19. Circadian rhythm in plasma noradrenaline of healthy sleep-deprived subjects.

    Science.gov (United States)

    Candito, M; Pringuey, D; Jacomet, Y; Souêtre, E; Salvati, E; Ardisson, J L; Chambon, P; Darcourt, G

    1992-12-01

    Under normal sleep-wake conditions, noradrenaline (NA) secretions in supine subjects exhibit a weak circadian variation with a peak that occurs around noon; the sleep span is characterized by reduced NA secretion. Some investigators have reported that the circadian NA rhythm is completely obliterated during sleep deprivation. In our laboratory, plasma NA was assayed every hour for 24 h in nine healthy men 20-23 years of age. All men were deprived of sleep and were required to eat and walk around every hour to prevent sleep. However, subjects remained supine for 20 min before blood samples were collected to eliminate the effect of activity. Persistence of a slight decrease in the night concentration in several subjects, despite sleep deprivation, suggests that NA secretion may be influenced by a biological clock whose activity becomes visible when the influence of posture is removed.

  20. Noradrenaline spillover during exercise in active versus resting skeletal muscle in man

    DEFF Research Database (Denmark)

    Savard, G; Strange, S; Kiens, Bente

    1987-01-01

    Increases in plasma noradrenaline (NA) concentration occur during moderate to heavy exercise in man. This study was undertaken to examine the spillover of NA from both resting and contracting skeletal muscle during exercise. Six male subjects performed one-legged knee-extension so that all...... in the exercising leg than in the resting leg both during 50% and 100% leg exercise. These results suggest that contracting skeletal muscle may contribute to a larger extent than resting skeletal muscle to increasing the level of plasma NA during exercise. Contractile activity may influence the NA spillover from...... measurements could be made both in the exercising and in the resting leg. Subjects exercised for 10 min at each of 50% and 100% of the peak performance capacity of the leg. Leg blood flow was measured by thermodilution and blood samples were drawn for the determination of plasma NA and adrenaline, first...

  1. Nocturnal secretion of growth hormone, noradrenaline, cortisol and insulin in cluster headache remission.

    Science.gov (United States)

    Meyer, E L; Marcus, C; Waldenlind, E

    2007-08-01

    We have previously shown decreased, nocturnal lipolysis in both phases of cluster headache (CH). Lipolysis is stimulated by noradrenaline (NA), growth hormone (GH) and cortisol, and inhibited by insulin, hormones which are directly or indirectly regulated by the hypothalamus. Our aim was to investigate the nocturnal secretion of NA, GH, cortisol and insulin in nine CH patients in remission and 10 healthy controls. Nocturnal venous blood samples were collected in hourly intervals for analysis of NA, cortisol and insulin and in 30-min intervals for GH. We found a reduced increase in GH between 24.00 h and 01.00 h (anova, P insulin did not differ significantly between the groups. The altered nocturnal GH pattern that was seen in CH patients in remission might in part explain the altered nocturnal lipolysis previously found and further indicate a permanent hypothalamic disturbance in CH.

  2. Atropine-sensitive, tetrodotoxin-resistant contraction induced by noradrenaline in isolated cat rectum.

    Directory of Open Access Journals (Sweden)

    Neya,Toshiaki

    1985-02-01

    Full Text Available Effects of noradrenaline (NA on the isolated rectal circular muscle of the cats were studied in comparison with the effects on the internal anal sphincter (IAS. NA (10(-8-10(-7 g/ml caused tonic contraction in four of 15 strips of the rectum taken from 15 animals, and in all 15 strips of the IAS. Phenylephrine also induced rectal and IAS contraction. Rectal contraction induced by NA was resistant to phentolamine, yohimbine, propranolol, hexamethonium and tetrodotoxin, but blocked by atropine. IAS contraction induced by NA was resistant to propranolol, atropine, hexamethonium and tetrodotoxin, but blocked by phentolamine and yohimbine. It is suggested that an atropine-sensitive excitatory adrenergic mechanism other than the excitatory alpha-adrenergic mechanism exists in the rectal circular muscle.

  3. Role of glycogenolysis in memory and learning: regulation by noradrenaline, serotonin and ATP

    Directory of Open Access Journals (Sweden)

    Marie Elizabeth Gibbs

    2016-01-01

    Full Text Available This paper reviews the role played by glycogen breakdown (glycogenolysis and glycogen re-synthesis in memory processing in two different chick brain regions, (1 the hippocampus and (2 the avian equivalent of the mammalian cortex, the intermediate medial mesopallium (IMM. Memory processing is regulated by the neuromodulators noradrenaline and serotonin soon after training and glycogen breakdown and re-synthesis are involved. In day-old domestic chicks, memory formation is dependent on the breakdown of glycogen (glycogenolysis at three specific times during the first 60 min after learning (around 2.5, 30 and 55 min. The chicks learn to discriminate in a single trial between beads of two colours and tastes. Inhibition of glycogen breakdown by the inhibitor of glycogen phosphorylase 1,4-dideoxy-1,4-imino-D-arabinitol (DAB given at specific times prior to the formation of long-term memory prevents memory forming. Noradrenergic stimulation of cultured chicken astrocytes by a selective β2-adrenergic (AR agonist reduces glycogen levels and we believe that in vivo this triggers memory consolidation at the second stage of glycogenolysis. Serotonin acting at 5-HT2B receptors acts on the first stage, but not on the second. We have shown that noradrenaline, acting via post-synaptic α2-ARs, is also responsible for the synthesis of glycogen and our experiments suggest that there is a readily accessible labile pool of glycogen in astrocytes which is depleted within 10 min if glycogen synthesis is inhibited. Endogenous ATP promotion of memory consolidation at 2.5 and 30 min is also dependent on glycogen breakdown. ATP acts at P2Y1 receptors and the action of thrombin suggests that it causes the release of internal calcium ([Ca2+]i] in astrocytes. Glutamate and GABA, the primary neurotransmitters in the brain, cannot be synthesized in neurons de novo. Neurons rely on astrocytic glutamate synthesis, requiring glycogenolysis.

  4. ATP and noradrenaline activate CREB in astrocytes via noncanonical Ca(2+) and cyclic AMP independent pathways.

    Science.gov (United States)

    Carriba, Paulina; Pardo, Luis; Parra-Damas, Arnaldo; Lichtenstein, Mathieu P; Saura, Carlos A; Pujol, Aurora; Masgrau, Roser; Galea, Elena

    2012-09-01

    In neurons, it is well established that CREB contributes to learning and memory by orchestrating the translation of experience into the activity-dependent (i.e., driven by neurotransmitters) transcription of plasticity-related genes. The activity-dependent CREB-triggered transcription requires the concerted action of cyclic AMP/protein kinase A and Ca(2+) /calcineurin via the CREB-regulated transcription co-activator (CRTC). It is not known, however, whether a comparable molecular sequence occurs in astrocytes, despite the unquestionable contribution of these cells to brain plasticity. Here we sought to determine whether and how ATP and noradrenaline cause CREB-dependent transcription in rat cortical astrocyte cultures. Both transmitters induced CREB phosphorylation (Western Blots), CREB-dependent transcription (CRE-luciferase reporter assays), and the transcription of Bdnf, a canonical regulator of synaptic plasticity (quantitative RT-PCR). We indentified a Ca(2+) and diacylglycerol-independent protein kinase C at the uppermost position of the cascade leading to CREB-dependent transcription. Notably, CREB-dependent transcription was partially dependent on ERK1/2 and CRTC, but independent of cyclic AMP/protein kinase A or Ca(2+) /calcineurin. We conclude that ATP and noradrenaline activate CREB-dependent transcription in cortical astrocytes via an atypical protein kinase C. It is of relevance that the signaling involved be starkly different to the one described in neurons since there is no convergence of Ca(2+) and cyclic AMP-dependent pathways on CRTC, which, moreover, exerts a modulatory rather than a central role. Our data thus point to the existence of an alternative, non-neuronal, glia-based role of CREB in plasticity.

  5. Histamine H3A receptor-mediated inhibition of noradrenaline release in the mouse brain cortex.

    Science.gov (United States)

    Schlicker, E; Behling, A; Lümmen, G; Göthert, M

    1992-04-01

    Mouse brain cortex slices preincubated with 3H-noradrenaline were superfused with physiological salt solution containing desipramine plus a drug with alpha 2-adrenoceptor antagonist properties, and the effects of histamine receptor ligands on the electrically (0.3 Hz) evoked tritium overflow were studied. The evoked overflow (from slices superfused with phentolamine) was inhibited by histamine (pIC35 6.53), the H3 receptor agonist R-(-)-alpha-methylhistamine (7.47) and its S-(+)-enantiomer (5.82) but not influenced by the H1 receptor agonist 2-(2-thiazolyl)-ethylamine 3.2 mumol/l and the H2 receptor agonist dimaprit 10 mumol/l. The inhibitory effect of histamine was not affected by the H1 receptor antagonist dimetindene 1 mumol/l and the H2 receptor antagonist ranitidine 10 mumol/l. The concentration-response curve of histamine (determined in the presence of rauwolscine) was shifted to the right by the H3 receptor antagonists thioperamide (apparent pA2 8.67), impromidine (7.30) and burimamide (6.82) as well as by dimaprit (6.16). The pA2 values of the four drugs were compared with their affinities for H3A and H3B binding sites in rat brain membranes (West et al. 1990 Mol Pharmacol 38:610); a significant correlation was obtained for the H3A, but not for the H3B sites. The results suggest that noradrenaline release in the mouse brain cortex is inhibited by histamine via H3A receptors and that dimaprit is an H3 receptor antagonist of moderate potency.

  6. Chicks incubated in hypomagnetic field need more exogenous noradrenaline for memory consolidation

    Science.gov (United States)

    Xiao, Ying; Wang, Qian; Xu, Mu-Ling; Jiang, Jin-Chang; Li, Bing

    2009-07-01

    The geomagnetic field (GMF) is one of the essential characteristics of the terrestrial environment but does not apply in outer space. The elimination of GMF may interfere with the normal activities of life in many aspects. Previous behavioral experiments have found that long-term memory is impaired in chicks incubated in a near-zero magnetic environment (i.e. hypomagnetic field or HMF). The present study was designed to evaluate the possible involvement of noradrenergic change in the functional abnormality observed before. A HMF space was produced by nullifying the natural GMF with three pairs of Helmholtz coils. The one-trial passive avoidance learning paradigm was performed on day-old chicks incubated in either the HMF space or the natural GMF. Exogenous noradrenaline was administered by intracerebral injections and the effect on memory consolidation was compared between the two categories of subjects. In the behavioral paradigm, the HMF chicks had a higher elimination rate than the GMF chicks and displayed a significant reduction in overall responsiveness. The administration of moderate doses (0.1-0.5 nmol/hemisphere) of noradrenaline led to fairly good memory retention in GMF chicks but had little effect on HMF chicks. However, long-term memory of HMF chicks could be elevated to the normal level by much higher doses (1.0-1.75 nmol/hem) of the drug. These results suggest that prolonged exposure to HMF may induce disorders in the noradrenergic system in the brain and indicate a potentiality of counteracting the ill-effect of GMF deprivation with appropriate pharmacological manipulation.

  7. Caffeine and central noradrenaline: effects on mood, cognitive performance, eye movements and cardiovascular function.

    Science.gov (United States)

    Smith, Andrew; Brice, Carolyn; Nash, Jon; Rich, Neil; Nutt, David J

    2003-09-01

    There have been numerous studies on the effects of caffeine on behaviour and cardiovascular function. It is now important to clarify the mechanisms that underlie such effects, and the main objective of the present study was to investigate whether changes in central noradrenaline underlie some of the behavioural and cardiovascular effects of caffeine. This was examined using a clonidine challenge paradigm. Twenty-four healthy volunteers were assigned to one of four conditions: (i) clonidine/caffeine; (ii) clonidine/placebo; (iii) placebo/caffeine: (iv) placebo/placebo. Baseline measurements of mood, cognitive performance, saccadic eye movements and cardiovascular function were recorded. Subsequently, volunteers were given either clonidine (200 microg) or placebo and consumed coffee containing caffeine (1.5 mg/kg) or placebo. The test battery was then repeated 30 min, 150 min and 270 min later. A second cup of coffee (with the same amount of caffeine as the first) was consumed 120 min after the first cup. The results showed that clonidine reduced alertness, impaired many aspects of performance and slowed saccadic eye movements; caffeine removed many of these impairments. Both clonidine and caffeine influenced blood pressure (clonidine reduced it, caffeine raised it) but the effects appeared to be independent, suggesting that separate mechanisms were involved. In addition, there were some behavioural effects of caffeine that were independent of the clonidine effect (e.g. effects on speed of encoding of new information) and these may reflect other neurotransmitter systems (e.g cholinergic effects). Overall, the results suggest that caffeine counteracts reductions in the turnover of central noradrenaline. This mechanism may underlie the beneficial effects of caffeine seen in low alertness states.

  8. Effect of niflumic acid on noradrenaline-induced contractions of the rat aorta.

    Science.gov (United States)

    Criddle, D N; de Moura, R S; Greenwood, I A; Large, W A

    1996-06-01

    1. The effects of niflumic acid, an inhibitor of calcium-activated chloride channels, were compared with the actions of the calcium channel antagonist nifedipine on noradrenaline-evoked contractions in isolated preparations of the rat aorta. 2. The cumulative concentration-effect curve to noradrenaline (NA) was depressed by both nifedipine and niflumic acid in a reversible and concentration-dependent manner. The degree of inhibition of the maximal contractile response to NA (1 microM) produced by 10 microM niflumic acid (38%) was similar to the effect of 1 microM nifedipine (39%). 3. Contractions to brief applications (30 s) of 1 microM NA were inhibited by 55% and 62% respectively by 10 microM niflumic acid and 1 microM nifedipine. 4. In the presence of 0.1 microM nifedipine, niflumic acid (10 microM) produced no further inhibition of the NA-evoked contractions. Thus, the actions of niflumic acid and nifedipine were not additive. 5. In Ca-free conditions the transient contraction induced by 1 microM NA was not inhibited by niflumic acid (10 microM) and therefore this agent does not reduce the amount of calcium released from the intracellular store or reduce the sensitivity of the contractile apparatus to calcium. 6. Niflumic acid 10 microM did not inhibit the contractions produced by KCl (up to 120 mM) which were totally blocked by nifedipine. Contractions induced by 25 mM KCl were completely inhibited by 1 microM levcromakalim but were unaffected by niflumic acid. 7. It was concluded that niflumic acid produces selective inhibition of a component of NA-evoked contraction which is probably mediated by voltage-gated calcium channels. These data are consistent with a model in which NA stimulates a calcium-activated chloride conductance which leads to the opening of voltage-gated calcium channels to produce contraction.

  9. Role of Glycogenolysis in Memory and Learning: Regulation by Noradrenaline, Serotonin and ATP.

    Science.gov (United States)

    Gibbs, Marie E

    2015-01-01

    This paper reviews the role played by glycogen breakdown (glycogenolysis) and glycogen re-synthesis in memory processing in two different chick brain regions, (1) the hippocampus and (2) the avian equivalent of the mammalian cortex, the intermediate medial mesopallium (IMM). Memory processing is regulated by the neuromodulators noradrenaline and serotonin soon after training glycogen breakdown and re-synthesis. In day-old domestic chicks, memory formation is dependent on the breakdown of glycogen (glycogenolysis) at three specific times during the first 60 min after learning (around 2.5, 30, and 55 min). The chicks learn to discriminate in a single trial between beads of two colors and tastes. Inhibition of glycogen breakdown by the inhibitor of glycogen phosphorylase 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) given at specific times prior to the formation of long-term memory prevents memory forming. Noradrenergic stimulation of cultured chicken astrocytes by a selective β2-adrenergic (AR) agonist reduces glycogen levels and we believe that in vivo this triggers memory consolidation at the second stage of glycogenolysis. Serotonin acting at 5-HT2B receptors acts on the first stage, but not on the second. We have shown that noradrenaline, acting via post-synaptic α2-ARs, is also responsible for the synthesis of glycogen and our experiments suggest that there is a readily accessible labile pool of glycogen in astrocytes which is depleted within 10 min if glycogen synthesis is inhibited. Endogenous ATP promotion of memory consolidation at 2.5 and 30 min is also dependent on glycogen breakdown. ATP acts at P2Y1 receptors and the action of thrombin suggests that it causes the release of internal calcium ([Ca(2+)]i) in astrocytes. Glutamate and GABA, the primary neurotransmitters in the brain, cannot be synthesized in neurons de novo and neurons rely on astrocytic glutamate synthesis, requiring glycogenolysis.

  10. High concentrations of KCl release noradrenaline from noradrenergic neurons in the rat anococcygeus muscle

    Directory of Open Access Journals (Sweden)

    C.B.L. Araujo

    2003-01-01

    Full Text Available The aim of the present study was to investigate the effects of high concentrations of KCl in releasing noradrenaline from sympathetic nerves and its actions on postsynaptic alpha-adrenoceptors. We measured the isotonic contractions induced by KCl in the isolated rat anococcygeus muscle under different experimental conditions. The contractile responses induced by KCl were inhibited by alpha-adrenoceptor antagonists in 2.5 mM Ca2+ solution. Prazosin reduced the maximum effect from 100 to 53.9 ± 10.2% (P<0.05 while the pD2 values were not changed. The contractile responses induced by KCl were abolished by prazosin in Ca2+-free solution (P<0.05. Treatment of the rats with reserpine reduced the maximum effect induced by KCl as compared to the contractile responses induced by acetylcholine from 339.5 ± 157.8 to 167.3 ± 65.5% (P<0.05, and increased the pD2 from 1.57 ± 0.01 to 1.65 ± 0.006 (P<0.05, but abolished the inhibitory effect of prazosin (P<0.05. In contrast, L-NAME increased the contractile responses induced by 120 mM KCl by 6.2 ± 2.3% (P<0.05, indicating that KCl could stimulate the neurons that release nitric oxide, an inhibitory component of the contractile response induced by KCl. Our results indicate that high concentrations of KCl induce the release of noradrenaline from noradrenergic neurons, which interacts with alpha1-adrenoceptors in smooth muscle cells, producing a contractile response in 2.5 mM Ca2+ (100% and in Ca2+-free solution, part of which is due to a direct effect of KCl on the rat anococcygeus muscle.

  11. PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal.

    Science.gov (United States)

    Lee, Hsiang-Ying; Gao, Xiaofei; Barrasa, M Inmaculada; Li, Hu; Elmes, Russell R; Peters, Luanne L; Lodish, Harvey F

    2015-06-25

    Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor α (PPAR-α) by the PPAR-α agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-α agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-α alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-α co-occupies many chromatin sites with GR; when activated by PPAR-α agonists, additional PPAR-α is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-α agonists in stimulating self-renewal of early erythroid

  12. 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.

  13. Adrenergic drugs modify the level of noradrenaline in the insular cortex and alter extinction of conditioned taste aversion in rats.

    Science.gov (United States)

    Fresquet, Nadine; Angst, Marie-Josée; Schleef, Carmen; Gobaille, Serge; Sandner, Guy

    2007-03-12

    We compared the effect of conditioned taste aversion in rats by measuring the amount of sucrose that they drunk after conditioning, which differed according to whether rats had drunk the sucrose freely (SD: self drinking) during the conditioning session, or had been forced to drink it (IO: intra-oral administration through a chronically implanted cannula). The SD procedure delayed the extinction of conditioned taste aversion. Enhanced arousal, alertness, awareness or attention in the SD condition may have strengthened the memory of the taste. Brain noradrenergic networks are involved in such processes. We administered two noradrenergic drugs that produce opposite effects on noradrenaline release in the brain, methoxy-idazoxan, RX821002 (1mg/kg, i.p.), and guanfacine (0.12mg/kg, i.p.). We evaluated their effect (i) on the level of noradrenaline in the gustatory cortex using microdialysis, (ii) on glycaemia that is an essential factor of taste learning and (iii) on the comparative SD versus IO conditioned taste aversion protocol mentioned above. Injecting RX821001 increased the level of noradrenaline in the gustatory cortex up to two-fold of the baseline. This effect lasted 1h. The same dose of RX821002 did not elicit any alteration of glycaemia. It enhanced extinction of conditioned taste aversion in the SD group of rats. Injecting 0.12mg/kg of guanfacine produced the opposite effect. The noradrenaline level of the gustatory cortex decreased, but only down to 20% of the baseline. This decrease lasted 2h. Guanfacine increased glycaemia. Extinction of conditioned taste aversion was only marginally decreased by guanfacine in the SD group of rats. These results fit with Aston-Jones' point of view that the role of the noradrenergic coeruleo-cortical system may be to enhance arousal, alertness, awareness or attention to an event by a transient increase of cortical noradrenaline.

  14. PPAR{gamma} transcriptionally regulates the expression of insulin-degrading enzyme in primary neurons

    Energy Technology Data Exchange (ETDEWEB)

    Du, Jing; Zhang, Lang; Liu, Shubo; Zhang, Chi [Protein Science Key Laboratory of the Ministry of Education, Department of Biological Sciences and Biotechnology, School of Medicine, Tsinghua University, Beijing 100084 (China); Huang, Xiuqing; Li, Jian [The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730 (China); Zhao, Nanming [Protein Science Key Laboratory of the Ministry of Education, Department of Biological Sciences and Biotechnology, School of Medicine, Tsinghua University, Beijing 100084 (China); Wang, Zhao, E-mail: zwang@tsinghua.edu.cn [Protein Science Key Laboratory of the Ministry of Education, Department of Biological Sciences and Biotechnology, School of Medicine, Tsinghua University, Beijing 100084 (China)

    2009-06-12

    Insulin-degrading enzyme (IDE) is a protease that has been demonstrated to play a key role in degrading both A{beta} and insulin and deficient in IDE function is associated with Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2) pathology. However, little is known about the cellular and molecular regulation of IDE expression. Here we show IDE levels are markedly decreased in DM2 patients and positively correlated with the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) levels. Further studies show that PPAR{gamma} plays an important role in regulating IDE expression in rat primary neurons through binding to a functional peroxisome proliferator-response element (PPRE) in IDE promoter and promoting IDE gene transcription. Finally, we demonstrate that PPAR{gamma} participates in the insulin-induced IDE expression in neurons. These results suggest that PPAR{gamma} transcriptionally induces IDE expression which provides a novel mechanism for the use of PPAR{gamma} agonists in both DM2 and AD therapies.

  15. Roles of PPAR transcription factors in the energetic metabolic switch occurring during adult neurogenesis.

    Science.gov (United States)

    Di Giacomo, E; Benedetti, E; Cristiano, L; Antonosante, A; d'Angelo, M; Fidoamore, A; Barone, D; Moreno, S; Ippoliti, R; Cerù, M P; Giordano, A; Cimini, A

    2017-01-02

    PPARs are a class of ligand-activated transcription factors belonging to the superfamily of receptors for steroid and thyroid hormones, retinoids and vitamin D that control the expression of a large number of genes involved in lipid and carbohydrate metabolism and in the regulation of cell proliferation, differentiation and death. The role of PPARs in the CNS has been primarily associated with lipid and glucose metabolism; however, these receptors are also implicated in neural cell differentiation and death, as well as neuronal maturation. Although it has been demonstrated that PPARs play important roles in determining NSCs fate, less is known about their function in regulating NSCs metabolism during differentiation. In order to identify the metabolic events, controlled by PPARs, occurring during neuronal precursor differentiation, the glucose and lipid metabolism was followed in a recognized model of neuronal differentiation in vitro, the SH-SY5Y neuroblastoma cell line. Moreover, PPARs distribution were also followed in situ in adult mouse brains. The concept of adult neurogenesis becomes relevant especially in view of those disorders in which a loss of neurons is described, such as Alzheimer disease, Parkinson disease, brain injuries and other neurological disorders. Elucidating the crucial steps in energetic metabolism and the involvement of PPARγ in NSC neuronal fate (lineage) may be useful for the future design of preventive and/or therapeutic interventions.

  16. Studies on PPAR α and γ participating in progression of liver fibrosis by regulating ACSL1

    Directory of Open Access Journals (Sweden)

    XIN Xuan

    2014-08-01

    Full Text Available During the development and procession of liver fibrosis, peroxisome proliferator-activated receptor (PPAR α and γ are in charge of the regulation of lipid metabolism, fatty acid metabolism, anti-liver fibrosis, etc., and are closely related to fat metabolism-related enzymes. As a key enzyme in fat metabolism, acyl-CoA synthetase long-chain family member 1 (ACSL1 is involved in lipid synthesis and catabolism and then causes lipid deposition and inflammation in the liver, so it directly or indirectly promotes hepatic fibrosis. The biological functions and roles of PPAR α and γ and ACSL1 are reviewed; the action mechanisms of PPAR α and γ in the transcriptional regulation of ACSL1 are briefly described; the regulatory effects of PPAR α and γ on ACSL1 and their effects on the progression of hepatic fibrosis are analyzed from the aspects of liver lipid metabolism and hepatic stellate cell activation. It is pointed out that in the liver PPAR α and γ are directly or indirectly involved in the progression of hepatic fibrosis by regulating ACSL1.

  17. Identification of putative PPAR response elements in and around the murine UCP3 gene

    DEFF Research Database (Denmark)

    Siersbæk, Majken

    in thermogenesis in unerring, the physiological functions of UCP2 and UCP3 are at present not fully understood. Synthetic agonists for the peroxisome proliferator-activated receptors (PPARs) as well as fatty acids have been shown to increase murine UCP2 and UCP3 mRNA expression but response elements and mechanisms...... are not yet characterized. The aim of this study was to investigate the transcriptional regulation of UCP3 by the PPARs. Results: The PPAR agonists increase UCP2 and UCP3 mRNA expression in skeletal muscle cells (C2C12). In addition, UCP2 and UCP3 mRNA expression is upregulated during 3T3-L1 adipocyte...... differentiation. Results from sequencing of chromatin immunoprecipitated (ChIP) material from 3T3-L1 adipocytes revealed three PPAR and retinoid X receptor (RXR) binding sites in and around the murine UCP3 gene. The recruitment of PPAR and RXR to the three potential PPREs was determined by ChIP combined...

  18. Expressions of GSK-3beta, Beta-Catenin and PPAR-Gamma in Medulloblastoma

    Institute of Scientific and Technical Information of China (English)

    Xiong Zhang; Lu Si; Yu Li; Can Mi

    2009-01-01

    Objective: To investigate the expressions of GSK-3beta, Beta-catenin and PPAR-gamma, and their relationship in medulloblastoma, and to explore their value in clinic application.Methods: Immunohistochemical staining with SP method was conducted to determine the expressions of GSK-3beta, Beta-catenin and PPAR-gamma in 48 cases of medulloblastoma and 10 normal cerebellar tissues.Results: The rate of abnormal expressions of beta-catenin and PPAR-gamma in MB was higher than that in normal. Conversely, GSK-3beta in MB was lower than that in the normal (P<0.05). Furthermore, in medulloblastoma, beta-catenin and GSK-3beta showed a negative correlation, PPAR-gamma and beta-catenin had a positive correlation.Conclusion: Abnormal expression of beta-catenin plays a crucial role in the development of medulloblastoma. Meanwhile, PPAR-gamma and GSK-3beta which are tightly related with beta-catenin are both involved in the genesis and development of medulloblastoma.

  19. Therapeutic modulators of peroxisome proliferator-activated receptors (PPAR): a patent review (2008-present).

    Science.gov (United States)

    Lamers, Christina; Schubert-Zsilavecz, Manfred; Merk, Daniel

    2012-07-01

    Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. The three known subtypes PPARα, PPARγ and PPARδ have different tissue distribution and play a key role as regulators of glucose and lipid homeostasis as well as in cell proliferation, differentiation and inflammatory responses. They have gained a lot of interest as pharmaceutical targets over the last years and with the antidiabetic thiazolidindiones (TZDs) and the hypolipidemic fibrates, two classes of drugs had entered the market. Early observations of severe adverse events changed the situation in the recent past. Herein the authors summarize recent (2008-present) patent applications concerning PPAR ligands claimed for the use in metabolic disorders as well as patents indicating new applications for modulators of the PPAR subtypes. Looking at the recent patent activity regarding novel compounds, there have not been real innovations. As major applications for therapeutic PPAR ligands cancer therapy, skin-related disorders and systemic anti-inflammatory therapies might arise in the mid-term future. The known PPAR targeting drugs might see a repurposing for novel indications.

  20. Hydroxyeicosapentaenoic acids from the Pacific krill show high ligand activities for PPARs.

    Science.gov (United States)

    Yamada, Hidetoshi; Oshiro, Eriko; Kikuchi, Sayaka; Hakozaki, Mayuka; Takahashi, Hideyuki; Kimura, Ken-Ichi

    2014-05-01

    PPARs regulate the expression of genes for energy metabolism in a ligand-dependent manner. PPARs can influence fatty acid oxidation, the level of circulating triglycerides, glucose uptake and insulin sensitivity. Here, we demonstrate that 5-hydroxyeicosapentaenoic acid (HEPE), 8-HEPE, 9-HEPE, 12-HEPE and 18-HEPE (hydroxylation products of EPA) obtained from methanol extracts of Pacific krill (Euphausia pacifica) can act as PPAR ligands. Two of these products, 8-HEPE and 9-HEPE, enhanced the transcription levels of GAL4-PPARs to a significantly greater extent than 5-HEPE, 12-HEPE, 18-HEPE, EPA, and EPA ethyl-ester. 8-HEPE also activated significantly higher transcription of GAL4-PPARα, GAL4-PPARγ, and GAL4-PPARδ than EPA at concentrations greater than 4, 64, and 64 μM, respectively. We also demonstrated that 8-HEPE increased the expression levels of genes regulated by PPARs in FaO, 3T3-F442A, and C2C12 cells. Furthermore, 8-HEPE enhanced adipogenesis and glucose uptake. By contrast, at the same concentrations, EPA showed weak or little effect, indicating that 8-HEPE was the more potent inducer of physiological effects.

  1. DEPENDENCE OF PPAR LIGAND-INDUCED MAPK SIGNALING ON EPIDERMAL GROWTH FACTOR RECEPTOR TRANSACTIVATION HEPARIN-BINDING EGF CLEAVAGE MEDIATES ZINC-INDUCED EGF RECEPTOR PHOSPHORYLATION

    Science.gov (United States)

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that function as ligand-activated transcription factors regulating lipid metabolism and homeostasis. In addition to their ability to regulate PPAR-mediated gene transcription, PPARalpha and gamma li...

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

    Science.gov (United States)

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

    2011-01-01

    Abstract 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. PMID:20477906

  3. Isoflavones and PPAR Signaling: A Critical Target in Cardiovascular, Metastatic, and Metabolic Disease

    Directory of Open Access Journals (Sweden)

    Rakesh P. Patel

    2010-01-01

    Full Text Available Isoflavone intake through foods and dietary supplements has both health advocates and critics. The latter come from a concern about the estrogenic effects of isoflavones in certain species. However, careful removal of isoflavones and other estrogens from the diet of rodents leads to the metabolic syndrome. These results suggest that isoflavones have other mechanisms of action, potentially those involving regulation of fatty acid metabolism via the nuclear receptors PPARα and PPARγ. The goal of this paper was to examine the evidence for isoflavone/PPAR signaling and to identify diseases in which such signaling would have an important impact. It is therefore of note that investigators using a chemical structure approach to discover PPAR ligands identified isoflavones as the best structures in the library of compounds that they tested. Future studies will involve careful identification of the underlying mechanisms whereby isoflavones have their action via PPAR signaling.

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    weekly, and plasma concentrations of adiponectin, leptin, insulin, glucose, triacylglycerols, total cholesterol, as well as of markers of inflammation and oxidative stress were measured (12h fasted) at the end of the feeding period. Adiponectin and peroxisome-proliferator-activated-receptor (PPAR......)-gamma mRNA were measured in adipose tissue (WAT) by real-time RT-PCR. PPAR-gamma transactivation was investigated by means of a reporter gene assay. HF feeding resulted in elevated fasted plasma glucose concentrations, while HFQ did not differ from LF feeding. In the HFQ group plasma concentrations...... 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...

  5. Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode

    Science.gov (United States)

    Capelli, Davide; Cerchia, Carmen; Montanari, Roberta; Loiodice, Fulvio; Tortorella, Paolo; Laghezza, Antonio; Cervoni, Laura; Pochetti, Giorgio; Lavecchia, Antonio

    2016-10-01

    The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARγ full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a structure-based virtual screening approach that let us identify a novel PPAR pan-agonist with a very attractive activity profile and its crystal structure in the complex with PPARα and PPARγ, respectively. In PPARα this ligand occupies a new pocket whose filling is allowed by the ligand-induced switching of the F273 side chain from a closed to an open conformation. The comparison between this pocket and the corresponding cavity in PPARγ provides a rationale for the different activation of the ligand towards PPARα and PPARγ, suggesting a novel basis for ligand design.

  6. PPAR-gamma in overcoming kinase resistance in chronic myeloid leukemia.

    Science.gov (United States)

    Yousefi, B; Shafiei-Irannejad, V; Azimi, A; Samadi, N; Zarghami, N

    2016-07-31

    Peroxisome proliferator-activated receptor gamma (PPARγ) plays key roles in regulating cellular differentiation, proliferation and apoptosis pathways. As such, they are considered promising targets for anticancer drug development, especially for breast cancer, multiple myeloma and hematologic malignancies. Chronic myeloid leukemia (CML) is a myeloproliferative disorder arising from an oncogenic Bcr-Abl tyrosine kinase. Inhibitors of this oncogene by small molecules such as imatinib are effective only in 75% of the patient's population. One of the potential strategies to overcome this resistance is to devise combination therapy protocols with other therapeutic agents including PPAR ligands. Since PPAR ligands are potentially interesting in different hematologic malignancies, this article will review the potential of PPAR ligands for use in CML treatment.

  7. Positive regulation of the peroxisomal beta-oxidation pathway by fatty acids through activation of peroxisome proliferator-activan>ated receptors (PPAR).

    Science.gov (United States)

    Dreyer, C; Keller, H; Mahfoudi, A; Laudet, V; Krey, G; Wahli, W

    1993-01-01

    Peroxisome proliferators regulate the transcription of genes by activating ligand-dependent transcription factors, which, due to their structure and function, can be assigned to the superfamily of nuclear hormone receptors. Three such peroxisome proliferator-activan>ated receptors (PPAR alpha, beta, and gamma) have been cloned in Xenopus laevis. Their mRNAs are expressed differentially; xPPAR alpha and beta but not xPPAR gamma are expressed in oocytes and embryos. In the adult, expression of xPPAR alpha and beta appears to be ubiquitous, and xPPAR gamma is mainly observed in adipose tissue and kidney. Immunocytochemical analysis revealed that PPARs are nuclear proteins, and that their cytoplasmic-nuclear translocation is independent of exogenous activators. A target gene of PPARs is the gene encoding acyl-CoA oxidase (ACO), which catalyzes the rate-limiting step in the peroxisomal beta-oxidation of fatty acids. A peroxisome proliferator response element (PPRE), to which PPARs bind, has been identified within the promoter of the ACO gene. Besides the known xenobiotic activators of PPARs, such as hypolipidemic drugs, natural activators have been identified. Polyunsaturated fatty acids at physiological concentrations are efficient activators of PPARs, and 5,8,11,14-eicosatetraynoic acid (ETYA), which is the alkyne homolog of arachidonic acid, is the most potent activator of xPPAR alpha described to date. Taken together, our data suggest that PPARs have an important role in lipid metabolism.

  8. 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, E-mail: yiqingwangbiopaper@163.com [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.

  9. PPAR agonists for the treatment of cardiovascular disease in patients with diabetes.

    Science.gov (United States)

    Wilding, J P H

    2012-11-01

    Diabetes is a complex disease defined by hyperglycaemia; however, strong associations with abdominal obesity, hypertension and dyslipidaemia contribute to the high risk of cardiovascular disease. Although aggressive glycaemic control reduces microvascular complications, the evidence for macrovascular complications is less certain. The theoretical benefits of the mode of action of peroxisome proliferator-activated receptor (PPAR) agonists are clear. In clinical practice, PPAR-α agonists such as fibrates improve dyslipidaemia, while PPAR-γ agonists such as thiazolidinediones improve insulin resistance and diabetes control. However, although these agents are traditionally classed according to their target, they have different and sometimes conflicting clinical benefit and adverse event profiles. It is speculated that this is because of differing properties and specificities for the PPAR receptors (each of which targets specific genes). This is most obvious in the impact on cardiovascular outcomes--in clinical trials pioglitazone appeared to reduce cardiovascular events, whereas rosiglitazone potentially increased the risk of myocardial infarction. The development of a dual PPAR-α/γ agonist may prove beneficial in effectively managing glycaemic control and improving dyslipidaemia in patients with type 2 diabetes. Yet, development of agents such as muraglitazar and tesaglitazar has been hindered by various serious adverse events. Aleglitazar, a balanced dual PPAR-α/γ agonist, is currently the most advanced in clinical development and has shown promising results in phase II clinical trials with beneficial effects on glucose and lipid variables. A phase III study, ALECARDIO, is ongoing and will establish whether improvements in laboratory test profiles translate into an improvement in cardiovascular outcomes.

  10. Presynaptic. cap alpha. -adrenoceptors and opiate receptors: inhibition of (/sup 3/H)noradrenaline release from rat cerebral cortex slices by different mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Schoffelmeer, A.N.M.; Mulder, A.H. (Vrije Univ., Amsterdam (Netherlands))

    1982-04-23

    The inhibitory effects of morphine and Cd/sup 2 +/ on electrically evoked (/sup 3/H)noradrenaline release from superfused brain slices were unaffected when release was enhanced by increasing the pulse duration, while the inhibitory effect of noradrenaline and the enhancing effect of phentolamine were diminished. A similar enhancement of (/sup 3/H)noradrenaline release by 4-aminopyridine reduced the modulatory effects of all drugs examined. Therefore there seem to be different mechanisms for the effect of presynaptic ..cap alpha..-adrenoceptors and opiate receptors on the availability of Ca/sup 2 +/ for the stimulus-secretion coupling process in noradrenergic nerve terminals.

  11. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the action of gamma linolenic acid in breast cancer cells.

    Science.gov (United States)

    Jiang, W G; Redfern, A; Bryce, R P; Mansel, R E

    2000-02-01

    Gamma linolenic acid (GLA) is a polyunsaturated fatty acid, which induces cytotoxicity and regulates cell adhesion in cancer cells. The molecular mechanism of these actions is not clear. We have shown that GLA acts via peroxisome proliferator activated receptors (PPARs), by stimulating their phosphorylation and translocation to the nucleus. Removing PPAR gamma with antisense oligos abolished the effect of GLA on the expression of adhesion molecules and tumour suppressor genes, whereas removal of PPAR alpha had no effect. Tissues from patients with breast cancer showed a reduction of expression of both PPARs in cancer tissues, as compared with normal. Thus, PPAR gamma serves as the receptor for GLA in the regulation of gene expression in breast cancer cells.

  12. Expression of PPAR-γ and effect of its ligand in prostate cancer tissues%前列腺癌组织PPAR-γ及其配体表达和作用机制的研究

    Institute of Scientific and Technical Information of China (English)

    祝海; 翁博文; 徐珞; 于小玲; 侯四川; 孙小庆; 朱磊一; 綦海燕

    2012-01-01

    OHIECTTVE; To investigate the protein expression of PPAR-y in prostate cancer and the inhibitory effect of its ligand TGZ on the growth of human prostate cancer cell. METHODS; Expression of PPAR-y was detected in adult prostate,hyperplastic and cancerous tissues by immunohistochemistry. PC-3 cells treated by various concentration of TGZ were assessed. The expression of PPAR-y was detected by immunohistochemistry,antiproliferation was obtained by MTT assay and the analysis of apoptosis was detected by flow cytometer. RESULTS; Expression of PPAR-y in prostate rancer tissues was significantly higher than that in hyperplastic prostates and adult prostates. Expression of PPAR-y was closely related to cell differentiation and TNM stages of prostate cancer. Irnmunohislochemistry showed thai PPAR-y was expressed in PC-3 cell line and the expression of PPAR-y showed an urr regulation trend in dose-dependenl manner when TGZ was used in different concentrations to exert their anti-proliferative activity. Mil assay demonstrated that TGZ had a potent inhibitory effect on the growth of PC-3 cells with a dose-dependent and time-dependent manner. Flow cytometer showed that TGZ induced apoptosis in dose-dependent manner. CONCLUSIONS; PPAR-y is closely associated with clinieopathological characteristics of prostate cancer. The growth inhibitory and apoptosis effect of TGZ is mediated through PPAR-y signaling pathway in prostate cancer cells in vitro .suggesting that PPAR-y might be a novel therapeutic target for prostate cancer.%目的:研究人前列腺癌组织及前列腺癌细胞中PPAR-γ的表达及其配体曲格列酮对前列腺癌细胞生长的影响,探讨曲格列酮抑制前列腺癌的机制.方法:免疫组化法检测成人前列腺组织、前列腺增生组织和前列腺癌组织PPAR-γ蛋白表达.不同浓度的曲格列酮处理人前列腺癌PC-3细胞,采用MTT法观察细胞增殖抑制作用;Annexin V/PI法流式细胞仪检测细胞凋亡;免疫组

  13. Bending the rules of transcriptional repression: tightly looped DNA directly represses T7 RNA polymerase.

    Science.gov (United States)

    Lionberger, Troy A; Meyhöfer, Edgar

    2010-08-09

    From supercoiled DNA to the tight loops of DNA formed by some gene repressors, DNA in cells is often highly bent. Despite evidence that transcription by RNA polymerase (RNAP) is affected in systems where DNA is deformed significantly, the mechanistic details underlying the relationship between polymerase function and mechanically stressed DNA remain unclear. Seeking to gain additional insight into the regulatory consequences of highly bent DNA, we hypothesize that tightly looping DNA is alone sufficient to repress transcription. To test this hypothesis, we have developed an assay to quantify transcription elongation by bacteriophage T7 RNAP on small, circular DNA templates approximately 100 bp in size. From these highly bent transcription templates, we observe that the elongation velocity and processivity can be repressed by at least two orders of magnitude. Further, we show that minicircle templates sustaining variable levels of twist yield only moderate differences in repression efficiency. We therefore conclude that the bending mechanics within the minicircle templates dominate the observed repression. Our results support a model in which RNAP function is highly dependent on the bending mechanics of DNA and are suggestive of a direct, regulatory role played by the template itself in regulatory systems where DNA is known to be highly bent. 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  14. Translational repression contributes greater noise to gene expression than transcriptional repression.

    Science.gov (United States)

    Komorowski, Michał; Miekisz, Jacek; Kierzek, Andrzej M

    2009-01-01

    Stochastic effects in gene expression may result in different physiological states of individual cells, with consequences for pathogen survival and artificial gene network design. We studied the contributions of a regulatory factor to gene expression noise in four basic mechanisms of negative gene expression control: 1), transcriptional regulation by a protein repressor, 2), translational repression by a protein; 3), transcriptional repression by RNA; and 4), RNA interference with the translation. We investigated a general model of a two-gene network, using the chemical master equation and a moment generating function approach. We compared the expression noise of genes with the same effective transcription and translation initiation rates resulting from the action of different repressors, whereas previous studies compared the noise of genes with the same mean expression level but different initiation rates. Our results show that translational repression results in a higher noise than repression on the promoter level, and that this relationship does not depend on quantitative parameter values. We also show that regulation of protein degradation contributes more noise than regulated degradation of mRNA. These are unexpected results, because previous investigations suggested that translational regulation is more accurate. The relative magnitude of the noise introduced by protein and RNA repressors depends on the protein and mRNA degradation rates, and we derived expressions for the threshold below which the noise introduced by a protein repressor is higher than the noise introduced by an RNA repressor.

  15. BEND3 mediates transcriptional repression and heterochromatin organization.

    Science.gov (United States)

    Khan, Abid; Prasanth, Supriya G

    2015-01-01

    Transcription repression plays a central role in gene regulation. Transcription repressors utilize diverse strategies to mediate transcriptional repression. We have recently demonstrated that BEND3 (BANP, E5R and Nac1 domain) protein represses rDNA transcription by stabilizing a NoRC component. We discuss the role of BEND3 as a global regulator of gene expression and propose a model whereby BEND3 associates with chromatin remodeling complexes to modulate gene expression and heterochromatin organization.

  16. Mechanism of catabolite repression of tryptophanase synthesis in Escherichia coli.

    Science.gov (United States)

    Isaacs, H; Chao, D; Yanofsky, C; Saier, M H

    1994-08-01

    Repression of tryptophanase (tryptophan indole-lyase) by glucose and its non-metabolizable analogue methyl alpha-glucoside has been studied employing a series of isogenic strains of Escherichia coli lacking cyclic AMP phosphodiesterase and altered for two of the proteins of the phosphoenolpyruvate:sugar phosphotransferase system (PTS), Enzyme I and Enzyme IIAGlc. Basal activity of tryptophanase was depressed mildly by inclusion of glucose in the growth medium, but inducible tryptophanase synthesis was subject to strong glucose repression in the parental strain, which exhibited normal PTS enzyme activities. Methyl alpha-glucoside was without effect in this strain. Loss of Enzyme I decreased sensitivity to repression by glucose but enhanced sensitivity to repression by methyl alpha-glucoside. Loss of Enzyme IIAGlc activity largely abolished repression by methyl alpha-glucoside but had a less severe effect on glucose repression. The repressive effects of both sugars were fully reversed by inclusion of cyclic AMP in the growth medium. Tryptophan uptake under the same conditions was inhibited weakly by glucose and more strongly by methyl alpha-glucoside in the parental strain. Inhibition by both sugars was alleviated by partial loss of Enzyme I. Inhibition by methyl alpha-glucoside appeared to be largely due to energy competition and was not responsible for repression of tryptophanase synthesis. Measurement of net production of cyclic AMP as well as intracellular concentrations of cyclic AMP revealed a good correlation with intensity of repression. The results suggest that while basal tryptophanase synthesis is relatively insensitive to catabolite repression, inducible synthesis is subject to strong repression by two distinct mechanisms, one dependent on enzyme IIAGlc of the PTS and the other independent of this protein. Both mechanisms are attributable to depressed rates of cyclic AMP synthesis. No evidence for a cyclic-AMP-independent mechanism of catabolite

  17. ATRX represses alternative lengthening of telomeres.

    Science.gov (United States)

    Napier, Christine E; Huschtscha, Lily I; Harvey, Adam; Bower, Kylie; Noble, Jane R; Hendrickson, Eric A; Reddel, Roger R

    2015-06-30

    The unlimited proliferation of cancer cells requires a mechanism to prevent telomere shortening. Alternative Lengthening of Telomeres (ALT) is an homologous recombination-mediated mechanism of telomere elongation used in tumors, including osteosarcomas, soft tissue sarcoma subtypes, and glial brain tumors. Mutations in the ATRX/DAXX chromatin remodeling complex have been reported in tumors and cell lines that use the ALT mechanism, suggesting that ATRX may be an ALT repressor. We show here that knockout or knockdown of ATRX in mortal cells or immortal telomerase-positive cells is insufficient to activate ALT. Notably, however, in SV40-transformed mortal fibroblasts ATRX loss results in either a significant increase in the proportion of cell lines activating ALT (instead of telomerase) or in a significant decrease in the time prior to ALT activation. These data indicate that loss of ATRX function cooperates with one or more as-yet unidentified genetic or epigenetic alterations to activate ALT. Moreover, transient ATRX expression in ALT-positive/ATRX-negative cells represses ALT activity. These data provide the first direct, functional evidence that ATRX represses ALT.

  18. Adrenaline but not noradrenaline is a determinant of exercise-induced lipid mobilization in human subcutaneous adipose tissue

    DEFF Research Database (Denmark)

    de Glisezinski, I; Larrouy, D; Bajzova, M

    2009-01-01

    The relative contribution of noradrenaline (norepinephrine) and adrenaline (epinephrine) in the control of lipid mobilization in subcutaneous adipose tissue (SCAT) during exercise was evaluated in men treated with a somatostatin analogue, octreotide. Eight lean and eight obese young men matched...... of octreotide suppressed plasma insulin and growth hormone levels at rest and during exercise. It blocked the exercise-induced increase in plasma adrenaline while that of noradrenaline was unchanged. Plasma natriuretic peptides (NPs) level was higher at rest and during exercise under octreotide infusion in lean...... contributing to exercise-induced lipolysis in SCAT. Moreover, it is the combined action of insulin suppression and NPs release which explains the lipolytic response which remains under octreotide after full local blockade of fat cell adrenergic receptors. For the moment, it is unknown if results apply...

  19. Optical dynamic imaging of the regional blood flow in the rat mesentery under the effect of noradrenalin

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    The regional blood flow in the rat mesentery under the effect of noradrenalin is monitored using the laser speckle imaging method. The results show that at the third minute of application of noradrenalin, the blood flow begins to decrease, and the venule blood flow decreases more rapidly than that in the arteriole. Five minutes later blood flow in part of blood vessels begins to resume and the blood flow in the arteriole recovers more quickly than that in the venule. These suggest that laser speckle imaging can obtain the temporal-spatial characteristic of blood flow in mesentery without the need of scanning. It provides a new approach for investigating the change of regional blood flow in the mesentery in microcirculation studies.

  20. Effect of noradrenaline on tail arteries of SHR and WKY under perfusion at constant flow and constant pressure

    DEFF Research Database (Denmark)

    Matchkov, Vladimir; Tarasova, Olga S; Timin, Eugeny N;

    1997-01-01

    pressure. Two series of experiments were performed. In the first series, vessels were perfused/superfused with Krebs-Henseleit solution. In the second one a modified salt solution was used, in which NaCl was totally replaced by an equimolar amount of KCI. Under constant flow conditions noradrenaline evoked......, vasoconstriction at constant pressure in SHR became more pronounced than that in WKY. We suggest that there is greater wall thickness:lumen diameter ratio in SHR vessels and thus different contribution of distension-activated myogenic response is of primary importance for the data obtained....... a more prominent resistance increase in SHR compared with WKY independently of the composition of solution (normal or high-K+) used. At constant pressure perfusion with normal solution, the vasoconstrictor response to noradrenaline was more prominent in WKY. Under application of high-K+ solution...

  1. Prenatal malnutrition-induced functional alterations in callosal connections and in interhemispheric asymmetry in rats are prevented by reduction of noradrenaline synthesis during gestation

    National Research Council Canada - National Science Library

    Soto-Moyano, R; Alarcon, S; Hernández, A; Pérez, H; Ruiz, S; Carreño, P; Kusch, C; Belmar, J

    1998-01-01

    ... and synaptic elimination. This suggests that some of the functional disturbances in brain induced by prenatal malnutrition could be due at least in part to increased noradrenaline activity that may enhance regressive events...

  2. The effects of cocaine and diphenhydramine upon the reactivity of rat vas deferens to supramaximal doses of noradrenaline and of other agonists: the mode of action of cocaine.

    Science.gov (United States)

    Pennefather, J N

    1976-02-01

    The effects of cocaine on responses to supramaximal concentrations of agonists have been studied in preparations of rat vas deferens. Cocaine 10 muM decreased the mean time to peak and increased the mean magnitude of responses to noradrenaline but not to supramaximal field stimulation of sympathetic fibres, to high potassium or to methoxamine. Diphenydramine 10 muM affected responses to noradrenaline similarly. It is proposed that the prejunctional action of cocaine and of diphenhydramine to reduce the rate of neuronal uptake of noradrenaline may provide a sufficient explanation for the enhanced reactivity of the vas deferens to noradrenaline, as this would allow an increased rate of rise of amine concentration at the receptors. Cocaine also enhanced the reactivity of the vas deferens to acetylcholine. The basis of this enhancement by cocaine of the reactivity of the vas deferens to acetylcholine remains to be established, but clearly is not mediated postjunctionally since responses to carbachol were not similarly affected.

  3. Serotonin, Dopamine and Noradrenaline Adjust Actions of Myelinated Afferents via Modulation of Presynaptic Inhibition in the Mouse Spinal Cord

    OpenAIRE

    García-Ramírez, David L.; Calvo, Jorge R.; Shawn Hochman; Jorge N Quevedo

    2014-01-01

    Gain control of primary afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including primary afferent depolarization (PAD). PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (5HT), dopamine (DA) and noradrenaline...

  4. Implication of ionotropic glutamate receptors in the release of noradrenaline in hippocampal CA1 and CA3 subregions under oxygen and glucose deprivation.

    Science.gov (United States)

    Milusheva, E A; Baranyi, M

    2003-11-01

    A strong linkage between adrenergic and glutamatergic systems exists in the CNS but it is still unclear whether the excessive release of noradrenaline under ischemic conditions is modulated by excitatory amino acids. We studied the effect of selective glutamate receptor antagonists on the release of [3H]noradrenaline evoked by glucose and oxygen deprivation in hippocampal CA1, CA3 and dentate gyrus subregions. The release of glutamate, aspartate and GABA was measured by HPLC. Omission of oxygen and glucose increased the release of [3H]noradrenaline as well as the release of amino acids. Maximum effect on noradrenaline release was observed in CA1 region. The relative increase of the release after 30 min energy deprivation (R(2)) versus the basal release under normal conditions (R(1)), i.e. the R(2)/R(1) ratio was 7.1+/-1.0, 3.87+/-0.4 and 3.26+/-0.27 for CA1, CA3 and dentate gyrus, respectively. The [3H]noradrenaline outflow in response to glucose and oxygen deprivation was abolished at low temperature, but not by Ca(2+) removal, suggesting a cytoplasmic release process. In CA1 and CA3 [3H]noradrenaline release was significantly attenuated by MK-801, an NMDA receptor antagonist. The AMPA receptor antagonist GYKI-53784 had no effect in CA3, but partly reduced noradrenaline release in CA1. Our results suggest that ionotropic glutamate receptors seem to be implicated in the massive cytoplasmic release of noradrenaline in CA1 what may contribute to its selective vulnerability.

  5. Effects of noradrenaline on the cell-surface glucose transporters in cultured brown adipocytes: novel mechanism for selective activation of GLUT1 glucose transporters.

    Science.gov (United States)

    Shimizu, Y; Satoh, S; Yano, H; Minokoshi, Y; Cushman, S W; Shimazu, T

    1998-01-01

    Glucose transport into rat brown adipocytes has been shown to be stimulated directly by the sympathetic neurotransmitter, noradrenaline, without a significant increase in the protein content of either GLUT1 or GLUT4 glucose transporter in the plasma membrane [Shimizu, Kielar, Minokoshi and Shimazu (1996) Biochem. J. 314, 485-490]. In the present study, we labelled the exofacial glucose-binding sites of GLUT1 and GLUT4 with a membrane-impermeant photoaffinity reagent, 2-N-[4-(1-azitrifluoroethyl)benzoyl]-[2-3H]1,3-bis- (D-mannos-4-yloxy)-2-propylamine (ATB-[3H]BMPA), to determine which isoform is responsible for the noradrenaline-induced increase in glucose transport into intact brown adipocytes in culture. Insulin stimulated the rate of hexose transport by increasing ATB-[3H]BMPA-labelled cell-surface GLUT4. In contrast, the noradrenaline-induced increase in glucose transport was not accompanied by an increased ATB-[3H]BMPA labelling of GLUT4, nor with an increased amount of GLUT4 in the plasma membrane fraction as assessed by Western blotting, indicating that noradrenaline does not promote the translocation of GLUT4. However, noradrenaline induced an increase in photoaffinity labelling of cell-surface GLUT1 without an apparent increase in the immunoreactive GLUT1 protein in the plasma membrane. This is suggestive of an increased affinity of GLUT1 for the ligand. In fact, the Ki value of non-radioactive ATB-BMPA for 2-deoxy-D-glucose uptake was significantly decreased after treatment of the cells with noradrenaline. The increased photoaffinity labelling of GLUT1 and increased glucose transport caused by noradrenaline were inhibited by a cAMP antagonist, cAMP-S Rp-isomer. These results demonstrate that noradrenaline stimulates glucose transport in brown adipocytes by enhancing the functional activity of GLUT1 through a cAMP-dependent mechanism. PMID:9461536

  6. Noradrenaline-induced increases in calcium and tension in skeletal muscle conductance and resistance arteries from rats with post-infarction heart failure.

    Science.gov (United States)

    Trautner, Simon; Amtorp, Ole; Boesgaard, Soren; Andersen, Claus B; Galbo, Henrik; Haunsoe, Stig; Sheykhzade, Majid

    2006-05-10

    We tested the hypothesis that arterial reactivity to noradrenaline is augmented in congestive heart failure (CHF), which could contribute to the deleterious changes in peripheral vascular resistance and compliance in this condition. From male Wistar rats with post-infarction CHF and sham-operated rats, skeletal muscle conductance and resistance arteries (mean lumen diameters: 514 and 186 microm) were isolated and mounted on wire myographs, and wall tension was recorded in response to cumulative application of acetylcholine and noradrenaline to the vessel segments. In a subset of experiments, wall tension and cytosolic free calcium ion concentration [Ca(2+)](i) were recorded simultaneously during noradrenaline application, using wire myography and the FURA-2 technique. No significant differences were found in the arterial baseline levels of [Ca(2+)](i) or tension between CHF and sham rats. In the resistance arteries of CHF rats, the noradrenaline-induced increases in [Ca(2+)](i) were significantly enhanced (P=0.003). Despite the augmented [Ca(2+)](i) levels, the tension responses to noradrenaline were unaltered in these arteries. In the conductance arteries, there were no significant differences in noradrenaline-induced [Ca(2+)](i) or tension responses between CHF and control rats. CHF did not alter vascular morphology or change vascular relaxations to acetylcholine in either type of artery. In conclusion, these results do not support the contention that arterial reactivity to noradrenaline is augmented in the skeletal muscle vascular bed in CHF. On the contrary, the unchanged contractile responsiveness in the resistance arteries despite the enhanced levels of [Ca(2+)](i) during noradrenaline application suggests that the contractile function of these vessels is compromised in CHF. Neither vascular remodeling, endothelial dysfunction nor changes in baseline vascular tone could be demonstrated in the skeletal muscle vascular bed of this animal model of heart failure.

  7. Noradrenaline and adrenaline concentrations in various vascular beds in patients with cirrhosis. Relation to haemodynamics

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Christensen, N J; Ring-Larsen, H

    1981-01-01

    Plasma noradrenaline (NA) and adrenaline (A) concentrations were related to various haemodynamic parameters in fifteen patients with cirrhosis. In supine position at rest plasma NA and A in peripheral venous blood were significantly higher in patients with cirrhosis than in normal subjects. Mean...... plasma NA averaged 0.66 and 0.21 ng/ml, respectively (P less than 0.01). The corresponding values for plasma A were 0.14 and 0.05 ng/ml (P less than 0.03). Splanchnic arterial-hepatic venous extraction ratio of NA in patients with cirrhosis averaged 0.46 (P less than 0.01). The right kidney released NA.......001) and to heart rate (r = 0.61, P less than 0.02), but inversely correlated to plasma volume (r = 0.83, P less than 0.01) in cirrhotic patients. Arterial blood pressure was reduced in these patients compared to controls (P less than 0.02), but not significantly correlated to plasma NA. The increased plasma NA...

  8. Central noradrenaline transporter availability in highly obese, non-depressed individuals

    Energy Technology Data Exchange (ETDEWEB)

    Hesse, Swen; Sabri, Osama [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Leipzig University Medical Centre, Integrated Treatment and Research Centre (IFB) Adiposity Diseases, Leipzig (Germany); Becker, Georg-Alexander; Bresch, Anke; Luthardt, Julia; Patt, Marianne; Meyer, Philipp M. [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Rullmann, Michael [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Leipzig University Medical Centre, Integrated Treatment and Research Centre (IFB) Adiposity Diseases, Leipzig (Germany); Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig (Germany); Hankir, Mohammed K.; Zientek, Franziska; Reissig, Georg; Fenske, Wiebke K. [Leipzig University Medical Centre, Integrated Treatment and Research Centre (IFB) Adiposity Diseases, Leipzig (Germany); Arelin, Katrin [Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig (Germany); University of Leipzig, Day Clinic for Cognitive Neurology, Leipzig (Germany); Lobsien, Donald [University of Leipzig, Department of Neuroradiology, Leipzig (Germany); Mueller, Ulrich [University of Cambridge, Department of Psychiatry and Behavioural and Clinical Neuroscience Institute, Cambridge (United Kingdom); Baldofski, S.; Hilbert, Anja [Leipzig University Medical Centre, Integrated Treatment and Research Centre (IFB) Adiposity Diseases, Leipzig (Germany); University of Leipzig, Department of Medical Psychology and Medical Sociology, Leipzig (Germany); Blueher, Matthias [University of Leipzig, Department of Internal Medicine, Leipzig (Germany); Fasshauer, Mathias; Stumvoll, Michael [Leipzig University Medical Centre, Integrated Treatment and Research Centre (IFB) Adiposity Diseases, Leipzig (Germany); University of Leipzig, Department of Internal Medicine, Leipzig (Germany); Ding, Yu-Shin [New York University School of Medicine, Departments of Radiology and Psychiatry, New York, NY (United States)

    2017-06-15

    The brain noradrenaline (NA) system plays an important role in the central nervous control of energy balance and is thus implicated in the pathogenesis of obesity. The specific processes modulated by this neurotransmitter which lead to obesity and overeating are still a matter of debate. We tested the hypothesis that in vivo NA transporter (NAT) availability is changed in obesity by using positron emission tomography (PET) and S,S-[{sup 11}C]O-methylreboxetine (MRB) in twenty subjects comprising ten highly obese (body mass index BMI > 35 kg/m{sup 2}), metabolically healthy, non-depressed individuals and ten non-obese (BMI < 30 kg/m{sup 2}) healthy controls. Overall, we found no significant differences in binding potential (BP{sub ND}) values between obese and non-obese individuals in the investigated brain regions, including the NAT-rich thalamus (0.40 ± 0.14 vs. 0.41 ± 0.18; p = 0.84) though additional discriminant analysis correctly identified individual group affiliation based on regional BP{sub ND} in all but one (control) case. Furthermore, inter-regional correlation analyses indicated different BP{sub ND} patterns between both groups but this did not survive testing for multiple comparions. Our data do not find an overall involvement of NAT changes in human obesity. However, preliminary secondary findings of distinct regional and associative patterns warrant further investigation. (orig.)

  9. Intravenous tryptophan administration attenuates cortisol secretion induced by intracerebroventricular injection of noradrenaline.

    Science.gov (United States)

    Sutoh, Madoka; Kasuya, Etsuko; Yayou, Ken-ichi; Ohtani, Fumihiro; Kobayashi, Yosuke

    2016-02-01

    This study was conducted to investigate the possibility of suppression of stress-induced cortisol (CORT) secretion by tryptophan (TRP) administration and to better understand its regulatory mechanisms by using a noradrenaline (NA) injection into the third ventricle (3V) as a stress model in cattle. A total of 25 Holstein steers with a cannula in the 3V were used. First, the increase in CORT secretion was observed following a NA injection into the 3V in a dose-dependent manner, verifying the appropriateness of this treatment as a stress model of CORT secretion (Experiment 1). The effect of prior-administration of TRP into peripheral blood with a dose that has been demonstrated to increase brain 5-hydroxytryptamine levels on the elevation of plasma CORT induced by NA or corticotropin-releasing hormone (CRH) was then examined (Experiment 2). The prior administration of TRP suppressed NA-induced, but not CRH-induced, CORT elevation. These results suggest that an increase in TRP absorption into peripheral blood could suppress the stress-induced CORT secretion in cattle via the attenuation of the stimulatory effect of NA on the hypothalamic CRH release.

  10. Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioural, and neurotoxic effects of methamphetamine

    Science.gov (United States)

    Weinshenker, David; Ferrucci, Michela; Busceti, Carla L.; Biagioni, Francesca; Lazzeri, Gloria; Liles, L. Cameron; Lenzi, Paola; Murri, Luigi; Paparelli, Antonio; Fornai, Francesco

    2008-01-01

    N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus (LC), the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP-4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine β-hydroxylase; DBH). We found that genetic deletion of DBH (DBH −/− mice) and acute treatment of wild-type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP-4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured by in vivo microdialysis of DA and 2,3-dihydroxybenzoic acid), and behavioural stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioural, and neurotoxic effects of METH. PMID:18042179

  11. Uptake of [3H]-nicotine and [3H]-noradrenaline by cultured chromaffin cells.

    Science.gov (United States)

    Ceña, V.; García, A. G.; Montiel, C.; Sánchez-García, P.

    1984-01-01

    Three day-old cultured bovine adrenal chromaffin cells incubated at room temperature with Krebs-HEPES solution containing different concentrations of [3H]-nicotine, took up and retained increasing amounts of the drug by a mechanism that did not saturate. Concentrations of cold nicotine as high as 100 microM did not alter the amount of [3H]-nicotine retained by cells. Imipramine, cocaine, tetracaine or mecamylamine, at concentrations (10 microM) that blocked the catecholamine secretory effects of nicotine completely, did not modify the uptake of [3H]-nicotine. Both imipramine and cocaine drastically inhibited [3H]-noradrenaline uptake by cells in a concentration-dependent manner (IC50S of 0.08 and 1 microM, respectively). These data indicate that the secretory effects of nicotine are not coupled to its previous uptake into cells, and are evidence in favour of a site of action for nicotine located in or at the surface of the chromaffin cell membrane. PMID:6704577

  12. Activation of gastric afferents increases noradrenaline release in the paraventricular nucleus and plasma oxytocin level.

    Science.gov (United States)

    Ueta, Y; Kannan, H; Higuchi, T; Negoro, H; Yamaguchi, K; Yamashita, H

    2000-01-14

    Effects of electrical stimulation of the gastric vagal nerves on plasma levels of oxytocin (OXT) and arginine vasopressin (AVP) were examined in rats anesthetized with urethane. Electrical stimulation of the gastric vagal nerves increased the plasma levels of OXT, but not AVP. The concentrations of extracellular noradrenaline (NA) in the paraventricular nucleus (PVN) were measured by in vivo microdialysis in rats anesthetized with urethane. Electrical stimulation of the gastric vagal nerves evoked an increase followed by a slight decrease in the concentrations of NA. The responses of spontaneous firing magnocellular neurosecretory neurons in the PVN to both electrical stimulation of the gastric vagal nerves and intravenous (i.v.) administration of CCK-8 were examined. Most of the putative OXT-secreting cells recorded were excited by both electrical stimulation of gastric vagal nerves and i.v. administration of CCK-8. These results suggest that gastric vagal afferents activate the central noradrenergic system from the brainstem to the PVN and secretion of OXT.

  13. Genesis and Maintenance of Attentional Biases: The Role of the Locus Coeruleus-Noradrenaline System

    Directory of Open Access Journals (Sweden)

    Mana R. Ehlers

    2017-01-01

    Full Text Available Emotionally arousing events are typically better remembered than mundane ones, in part because emotionally relevant aspects of our environment are prioritized in attention. Such biased attentional tuning is itself the result of associative processes through which we learn affective and motivational relevance of cues. We propose that the locus coeruleus-noradrenaline (LC-NA system plays an important role in the genesis of attentional biases through associative learning processes as well as their maintenance. We further propose that individual differences in and disruptions of the LC-NA system underlie the development of maladaptive biases linked to psychopathology. We provide support for the proposed role of the LC-NA system by first reviewing work on attentional biases in development and its link to psychopathology in relation to alterations and individual differences in NA availability. We focus on pharmacological manipulations to demonstrate the effect of a disrupted system as well as the ADRA2b polymorphism as a tool to investigate naturally occurring differences in NA availability. We next review associative learning processes that—modulated by the LC-NA system—result in such implicit attentional biases. Further, we demonstrate how NA may influence aversive and appetitive conditioning linked to anxiety disorders as well as addiction and depression.

  14. SAGA complex components and acetate repression in Aspergillus nidulans.

    Science.gov (United States)

    Georgakopoulos, Paraskevi; Lockington, Robin A; Kelly, Joan M

    2012-11-01

    Alongside the well-established carbon catabolite repression by glucose and other sugars, acetate causes repression in Aspergillus nidulans. Mutations in creA, encoding the transcriptional repressor involved in glucose repression, also affect acetate repression, but mutations in creB or creC, encoding components of a deubiquitination system, do not. To understand the effects of acetate, we used a mutational screen that was similar to screens that uncovered mutations in creA, creB, and creC, except that glucose was replaced by acetate to identify mutations that were affected for repression by acetate but not by glucose. We uncovered mutations in acdX, homologous to the yeast SAGA component gene SPT8, which in growth tests showed derepression for acetate repression but not for glucose repression. We also made mutations in sptC, homologous to the yeast SAGA component gene SPT3, which showed a similar phenotype. We found that acetate repression is complex, and analysis of facA mutations (lacking acetyl CoA synthetase) indicates that acetate metabolism is required for repression of some systems (proline metabolism) but not for others (acetamide metabolism). Although plate tests indicated that acdX- and sptC-null mutations led to derepressed alcohol dehydrogenase activity, reverse-transcription quantitative real-time polymerase chain reaction showed no derepression of alcA or aldA but rather elevated induced levels. Our results indicate that acetate repression is due to repression via CreA together with metabolic changes rather than due to an independent regulatory control mechanism.

  15. On the mechanism of noradrenaline-induced prostaglandin E2-Synthesis in primary cell cultures from rabbit splenic pulpa.

    Science.gov (United States)

    Brückner-Schmidt, R; Jackisch, R; Hertting, G

    1981-10-01

    The role of Ca2+ and phospholipase A2 in alpha-adrenoceptor mediated stimulation of prostaglandin (PG)E2-release was investigated in primary cell cultures of rabbit splenic pulpa. Noradrenaline enhanced PGE2-release only in the presence of extracellular Ca2+. In contrast, PGE2-release induced by arachidonic acid was unchanged when Ca2+ was omitted. In the presence of Ca2+, the ionophore A 23187 increased PGE2-release concentration-dependently. During incubation in Ca2+-free medium, the ionophore was ineffective. Inhibitors of phospholipase A2 (mepacrine, p-bromophenacyl bromide) abolished the noradrenaline-induced PGE2-release and reduced the effect of A 23187; the stimulation of PGE2-release by arachidonic acid was not affected. Addition of exogenous phospholipase A2 enhances release of PGE2. From these results we suggest that noradrenaline-induced PGE2-release in rabbit splenic fibroblasts via alpha-adrenoceptors involves the following steps: influx of Ca2+, activation of a Ca2+-dependent phospholipase and liberation of arachidonic acid which is transformed into PGs.

  16. Noradrenaline acting on alpha1-adrenoceptor mediates REM sleep deprivation-induced increased membrane potential in rat brain synaptosomes.

    Science.gov (United States)

    Das, Gitanjali; Mallick, Birendra Nath

    2008-01-01

    We hypothesized that one of the functions of REM sleep is to maintain brain excitability and therefore, REM sleep deprivation is likely to modulate neuronal transmembrane potential; however, so far there was no direct evidence to support the claim. In this study a cationic dye, 3,3'-diethylthiacarbocyanine iodide was used to estimate the potential in synaptosomal samples prepared from control and REM sleep deprived rat brains. The activity of Na-K-ATPase that maintains the transmembrane potential was also estimated in the same sample. Further, the roles of noradrenaline and alpha1-adrenoceptor in mediating the responses were studied both in vivo as well as in vitro. Rats were REM sleep deprived for 4 days by the classical flower-pot method; large platform and recovery controls were carried out in addition to free-moving control. The fluorescence intensity increased in samples prepared from REM sleep deprived rat brain as compared to control, which reflected synaptosomal depolarization after deprivation. The Na-K-ATPase activity also increased in the same deprived sample. Furthermore, both the effects were mediated by noradrenaline acting on alpha1-adrenoceptors in the brain. This is the first direct evidence showing that REM sleep deprivation indeed increased neuronal depolarization, which is the likely cause for increased brain excitability, thus supporting our hypothesis and the effect was mediated by noradrenaline acting through the alpha1-adrenoceptor.

  17. Effect of subarachnoid hemorrhage on contractile responses and noradrenaline release evoked in cat cerebral arteries by histamine

    Energy Technology Data Exchange (ETDEWEB)

    Lobato, R.D.; Marin, J.; Salaices, M.; Rico, M.L.; Sanchez, C.F.

    1981-10-01

    This study analyzes the changes induced by subarachnoid hemorrhage (SAH) on the contractile responses and the noradrenaline release evoked in cat cerebral arteries by histamine. The dose-dependent vasoconstriction induced by histamine on the cerebral arteries of normal cats was significantly reduced by diphenhydramine and phentolamine. When SAH was produced 3 and 7 days before the experiment, the histamine-induced vasoconstriction also decreased. Thereafter, a tendency to normalization in the contractile vascular responses was observed such that in 15 days after the hemorrhage it was not significantly different from that found in controls animals. The decrease in the contractile responses to histamine provoked by SAH was similar to that seen after pretreatment with intracisternal injections of 6-hydroxydopamine. The amount of radioactivity released by histamine following preincubation with /sup 3/H-noradrenaline from the cerebral arteries of cats exposed to SAH 3, 7, and 15 days before the experiment was significantly reduced when compared with controls. Moreover, the basal level of tritium release and the radioactivity retained at the end of the experiment were also decreased after SAH. Results indicate histamine releases noradrenaline from cat cerebral arteries, and SAH produce a transient denervation of the perivascular adrenergic nerve endings, which explained by the impairment of the indirect adrenergic mechanism involved in the overall contractile response elicited by this amine in cerebral arteries. Histamine does not seem to play a significant role in the production of the cerebral vasospasm occurring after SAH.

  18. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets

    Science.gov (United States)

    Domínguez-Avila, J. Abraham; González-Aguilar, Gustavo A.; Alvarez-Parrilla, Emilio; de la Rosa, Laura A.

    2016-01-01

    Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity. PMID:27367676

  19. Relation between the hypertriglyceridemic waist and the gene polymorphism of PPARs

    Institute of Scientific and Technical Information of China (English)

    朱秋荣

    2013-01-01

    Objective To analyze the correlation between the 3subtypes of PPAR genes (PPARα,PPARβ,and PPARγ) and the hypertriglyceridemic waist (HTGW) ,and to study whether there is an interaction in the 10 single nucleotide polymorphisms (SNPs) of the above 3 subtypes in causing HTGW.Methods Eight hundred and

  20. Do PPAR-Gamma Agonists Have a Future in Parkinson's Disease Therapy?

    Directory of Open Access Journals (Sweden)

    Anna R. Carta

    2011-01-01

    Full Text Available Thiazolidinediones (TZDs are peroxisome proliferator-activated receptor (PPAR-γ agonists commonly used as insulin-sensitizing drugs for the treatment of type 2 diabetes. In the last decade, PPAR-γ agonists have received increasing attention for their neuroprotective properties displayed in a variety of neurodegenerative diseases, including Parkinson's disease (PD, likely related to the anti-infammatory activity of these compounds. Recent studies indicate that neuroinflammation, specifically reactive microglia, plays important roles in PD pathogenesis. Moreover, after the discovery of infiltrating activated Limphocytes in the substantia nigra (SN of PD patients, most recent research supports a role of immune-mediated mechanisms in the pathological process leading to chronic neuroinflammation and dopaminergic degeneration. PPAR-γ are highly expressed in cells of both central and peripheral immune systems, playing a pivotal role in microglial activation as well as in monocytes and T cells differentiation, in which they act as key regulators of immune responses. Here, we review preclinical evidences of PPAR-γ-induced neuroprotection in experimental PD models and highlight relative anti-inflammatory mechanisms involving either central or peripheral immunomodulatory activity. Specific targeting of immune functions contributing to neuroinflammation either directly (central or indirectly (peripheral may represent a novel therapeutic approach for disease modifying therapies in PD.

  1. PPAR-γ inhibits IL-13-induced collagen production in mouse airway fibroblasts.

    Science.gov (United States)

    Lu, Jiamei; Liu, Lu; Zhu, Yanting; Zhang, Yonghong; Wu, Yuanyuan; Wang, Guizuo; Zhang, Dexin; Xu, Jing; Xie, Xinming; Ke, Rui; Han, Dong; Li, Shaojun; Feng, Wei; Xie, Mei; Liu, Yun; Fang, Ping; Shi, Hongyang; He, Ping; Liu, Yuan; Sun, Xiuzhen; Li, Manxiang

    2014-08-15

    Interleukin-13 (IL-13) plays an important role in extracellular matrix production of airway remodeling in asthma. Activation of PPAR-γ has been shown to inhibit the occurrence of airway fibrosis in asthma, yet it remains unknown whether the effect of PPAR-γ on suppression of airway fibrosis is associated with the inhibition of IL-13 signaling. In the present study, primary cultured airway fibroblasts were stimulated with IL-13, and JAK inhibitor, PDGF receptor blocker and MEK inhibitor were applied to investigate the involvement of these pathways in IL-13-induced collagen production. Our results demonstrate that IL-13 dose- and time-dependently induced collagen production in primary cultured mouse airway fibroblasts; this effect was blocked by inhibition of JAK/STAT6 signal pathway. IL-13 also stimulated JAK/STAT6-dependent PDGF production, elevation of PDGF in turn activated ERK1/2 MAPK and caused collagen production. Activation of PPAR-γ by rosiglitazone reduced IL-13-induced collagen expression by suppression of STAT6-driven PDGF production. Our results indicate that activation of JAK/STAT6 signal and subsequent PDGF generation and ERK1/2 MAPK activation mediate IL-13-induced collagen production in airway fibroblasts. This study suggests that activation of PPAR-γ might be a novel strategy for the treatment of asthma partially by inhibition of airway fibrosis.

  2. 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,...

  3. 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.

  4. PPAR-γ与消化系肿瘤的研究进展

    Institute of Scientific and Technical Information of China (English)

    刘莹(综述); 林瑶光(审校)

    2006-01-01

    过氧化物酶增殖物激活受体(peroxisome proliferators—acti—vated recepors,PPAR)是一类配体依赖的序列特异的核转录因子,属Ⅱ核基因受体超家族中的一员。PPAR可分为独立基因编码的PPAR-α、PPAR—β和PPAR-γ 3种亚型,该3种亚型在结构和功能上均有差异,其中PPAR-γ具有多种生物学效应,最近的研究报道,PPAR-γ在调控肿瘤细胞的生长、分化及凋亡等方面起重要的转录调节作用,从而成为新的肿瘤治疗靶点。

  5. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets

    Directory of Open Access Journals (Sweden)

    J. Abraham Domínguez-Avila

    2016-06-01

    Full Text Available Peroxisome proliferator-activated receptors (PPAR are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity.

  6. PPAR-α as a Key Nutritional and Environmental Sensor for Metabolic Adaptation12

    Science.gov (United States)

    Contreras, Alejandra V.; Torres, Nimbe; Tovar, Armando R.

    2013-01-01

    Peroxisome proliferator-activated receptors (PPARs) are transcription factors that belong to the superfamily of nuclear hormone receptors and regulate the expression of several genes involved in metabolic processes that are potentially linked to the development of some diseases such as hyperlipidemia, diabetes, and obesity. One type of PPAR, PPAR-α, is a transcription factor that regulates the metabolism of lipids, carbohydrates, and amino acids and is activated by ligands such as polyunsaturated fatty acids and drugs used to treat dyslipidemias. There is evidence that genetic variants within the PPARα gene have been associated with a risk of the development of dyslipidemia and cardiovascular disease by influencing fasting and postprandial lipid concentrations; the gene variants have also been associated with an acceleration of the progression of type 2 diabetes. The interactions between genetic PPARα variants and the response to dietary factors will help to identify individuals or populations who can benefit from specific dietary recommendations. Interestingly, certain nutritional conditions, such as the prolonged consumption of a protein-restricted diet, can produce long-lasting effects on PPARα gene expression through modifications in the methylation of a specific locus surrounding the PPARα gene. Thus, this review underlines our current knowledge about the important role of PPAR-α as a mediator of the metabolic response to nutritional and environmental factors. PMID:23858092

  7. Stimulation of prostaglandin E2-synthesis by noradrenaline in primary cell cultures from rabbit splenic pulpa is mediated by atypical alpha-adrenoceptors.

    Science.gov (United States)

    Brückner-Schmidt, R; Jackisch, R; Hertting, G

    1981-02-01

    In primary cell cultures originating from rabbit splenic pulpa the effects of various adrenoceptor agonists on prostaglandin (PG)-synthesis were studied. The cells - microscopically identified as fibroblasts - released PGs into the medium: especially PGE2 besides small amounts of PGF2alpha and PGD2. Noradrenaline increased dose-dependently the amount of PGs released into the medium. Besides noradrenaline, only the catecholamines adrenaline and alpha-methylnoradrenaline strongly activated PG-synthesis. Other alpha-adrenoceptor agonists like the phenylethylamine and imidazoline derivatives were only weak agonists or completely ineffective. All adrenoceptor agonists without intrinsic activity in these cells antagonized the noradrenaline effect on PG-synthesis, the imidazolines being more potent antagonists than the phenylethylamines. The beta-adrenoceptor agonist isoprenaline stimulated PG-synthesis at high concentration only. The effects of both noradrenaline and isoprenaline were inhibited by low concentrations of phentolamine phenoxybenzamine, but not by propranolol. The preferential alpha2-adrenoceptor antagonists yohimbine and rauwolscine were about 50 times more potent in blocking the noradrenaline effect on PG-synthesis than the more alpha1-specific antagonist corynanthine. However, prazosin, another alpha1-adrenoceptor antagonist, was about equipotent with yohimbine. It is concluded that noradrenaline elicits PG-synthesis in rabbit splenic fibroblasts via alpha-adrenoceptor stimulation. The alpha-adrenoceptor involved has properties which are different from those reported so far for alpha1- or alpha2-adrenoceptors.

  8. Nitrogen Catabolite Repression in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Hofman-Bang, H Jacob Peider

    1999-01-01

    In Saccharomyces cerevisiae the expression of all known nitrogen catabolite pathways are regulated by four regulators known as Gln3, Gat1, Da180, and Deh1. This is known as nitrogen catabolite repression (NCR). They bind to motifs in the promoter region to the consensus sequence S' GATAA 3'. Gln3...... and Gat1 act positively on gene expression whereas :Da180 and Deh1 act negatively. Expression of nitrogen catabolite pathway genes known to be regulated by these four regulators are glutamine, glutamate, proline, urea, arginine, GABA, and allantoine. In addition, the expression of the genes encoding...... thereby providing a nitrogen source to the cell.In this review, all known promoter sequences related to expression of nitrogen catabolite pathways are discussed as well as other regulatory proteins. Overview of metabolic pathways and promoters are presented....

  9. Carbon catabolite repression in Thermoanaerobacterium saccharolyticum

    Directory of Open Access Journals (Sweden)

    Tsakraklides Vasiliki

    2012-11-01

    Full Text Available Abstract Background The thermophilic anaerobe Thermoanaerobacterium saccharolyticum is capable of directly fermenting xylan and the biomass-derived sugars glucose, cellobiose, xylose, mannose, galactose and arabinose. It has been metabolically engineered and developed as a biocatalyst for the production of ethanol. Results We report the initial characterization of the carbon catabolite repression system in this organism. We find that sugar metabolism in T. saccharolyticum is regulated by histidine-containing protein HPr. We describe a mutation in HPr, His15Asp, that leads to derepression of less-favored carbon source utilization. Conclusion Co-utilization of sugars can be achieved by mutation of HPr in T. saccharolyticum. Further manipulation of CCR in this organism will be instrumental in achieving complete and rapid conversion of all available sugars to ethanol.

  10. Nuclear receptors of the peroxisome proliferator-activated receptor (PPAR) family in gestational diabetes: from animal models to clinical trials.

    Science.gov (United States)

    Arck, Petra; Toth, Bettina; Pestka, Aurelia; Jeschke, Udo

    2010-08-01

    Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance and affects 2%-8% of all pregnancies. Among other complications, GDM can lead to the development of type 2 diabetes mellitus (DM 2) in both mother and child. Peroxisome proliferator-activated receptors (PPARs) are major regulators of glucose and lipid metabolism. Furthermore, PPARs are mediators of inflammation and angiogenesis and are involved in the maternal adaptational dynamics during pregnancy to serve the requirements of the growing fetus. PPARs were originally named for their ability to induce hepatic peroxisome proliferation in mice in response to xenobiotic stimuli. The expression of three PPAR isoforms, alpha, beta/delta, and gamma, have been described. Each of them is encoded by different genes; however, they share 60%-80% homology in their ligand-binding and DNA-binding domains. PPARs are involved in trophoblast differentiation, invasion, metabolism, and parturition and are expressed in invasive extravillous trophoblast and villous trophoblast cells. Nuclear receptors, to which PPARs belong, are promising targets for disease-specific treatment strategies because they act as transcription factors controlling cellular processes at the level of gene expression and may produce selective alterations in downstream gene expression. To date, PPAR agonists are therapeutically used in patients with DM 2 and in patients with reproductive disorders such as polycystic ovary syndrome. Because of safety concerns and limited data, PPAR agonists are not yet included in GDM-related treatment strategies. Our objective herein is to review newly emerging generations of selective PPAR modulators and panagonists, which may have potent therapeutic implications in the context of GDM.

  11. Kinetically-defined component actions in gene repression.

    Directory of Open Access Journals (Sweden)

    Carson C Chow

    2015-03-01

    Full Text Available Gene repression by transcription factors, and glucocorticoid receptors (GR in particular, is a critical, but poorly understood, physiological response. Among the many unresolved questions is the difference between GR regulated induction and repression, and whether transcription cofactor action is the same in both. Because activity classifications based on changes in gene product level are mechanistically uninformative, we present a theory for gene repression in which the mechanisms of factor action are defined kinetically and are consistent for both gene repression and induction. The theory is generally applicable and amenable to predictions if the dose-response curve for gene repression is non-cooperative with a unit Hill coefficient, which is observed for GR-regulated repression of AP1LUC reporter induction by phorbol myristate acetate. The theory predicts the mechanism of GR and cofactors, and where they act with respect to each other, based on how each cofactor alters the plots of various kinetic parameters vs. cofactor. We show that the kinetically-defined mechanism of action of each of four factors (reporter gene, p160 coactivator TIF2, and two pharmaceuticals [NU6027 and phenanthroline] is the same in GR-regulated repression and induction. What differs is the position of GR action. This insight should simplify clinical efforts to differentially modulate factor actions in gene induction vs. gene repression.

  12. Polycomb complexes act redundantly to repress genomic repeats and genes

    DEFF Research Database (Denmark)

    Leeb, Martin; Pasini, Diego; Novatchkova, Maria

    2010-01-01

    Polycomb complexes establish chromatin modifications for maintaining gene repression and are essential for embryonic development in mice. Here we use pluripotent embryonic stem (ES) cells to demonstrate an unexpected redundancy between Polycomb-repressive complex 1 (PRC1) and PRC2 during the form...

  13. Chronic Inhibition of PPAR-γ Signaling Induces Endothelial Dysfunction In The Juvenile Lamb

    Science.gov (United States)

    Sharma, Shruti; Barton, Jubilee; Rafikov, Ruslan; Aggarwal, Saurabh; Kuo, Hsuan-Chang; Oishi, Peter E.; Datar, Sanjeev A.; Fineman, Jeffrey R; Black, Stephen M.

    2013-01-01

    We have recently shown that the development of endothelial dysfunction in lambs with increased pulmonary blood flow (PBF) correlates with a decrease in peroxisome proliferator activated receptor-γ (PPAR-γ) signaling. Thus, in this study we determined if the loss of PPAR-γ signaling is necessary and sufficient to induce endothelial dysfunction by exposing lambs with normal PBF to the PPAR-γ antagonist, GW9662. Two-weeks of exposure to GW9662 significantly decreased both PPAR-γ protein and activity. In addition, although eNOS protein and nitric oxide metabolites (NOx) were significantly increased, endothelial dependent pulmonary vasodilation in response to acetylcholine was attenuated, indicative of endothelial dysfunction. To elucidate whether downstream mediators of vasodilation were impaired we examined soluble guanylate cyclase (sGC)- α and β subunit protein, cGMP levels, and phosphodiesterase 5 (PDE5) protein and activity, but we found no significant changes. However, we found that peroxynitrite levels were significantly increased in GW9662-treated lambs and this correlated with a significant increase in protein kinase G-1α (PKG-1α) nitration and a reduction in PKG activity. Peroxynitrite is formed by the interaction of NO with superoxide and we found that there was a significant increase in superoxide generation in GW9662-treated lambs. Further, we identified dysfunctional mitochondria as the primary source of the increased superoxide. Finally, we found that the mitochondrial dysfunction was due to a disruption in carnitine metabolism. We conclude that loss of PPAR-γ signaling is sufficient to induce endothelial dysfunction confirming its important role in maintaining a healthy vasculature. PMID:23257346

  14. PPAR-gamma ligands modulate effects of LPS in stimulated rat synovial fibroblasts.

    Science.gov (United States)

    Simonin, Marie-Agnès; Bordji, Karim; Boyault, Sandrine; Bianchi, Arnaud; Gouze, Elvire; Bécuwe, Philippe; Dauça, Michel; Netter, Patrick; Terlain, Bernard

    2002-01-01

    This work demonstrated the constitutive expression of peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-alpha in rat synovial fibroblasts at both mRNA and protein levels. A decrease in PPAR-gamma expression induced by 10 microg/ml lipopolysaccharide (LPS) was observed, whereas PPAR-alpha mRNA expression was not modified. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) dose-dependently decreased LPS-induced cyclooxygenase (COX)-2 (-80%) and inducible nitric oxide synthase (iNOS) mRNA expression (-80%), whereas troglitazone (10 microM) only inhibited iNOS mRNA expression (-50%). 15d-PGJ(2) decreased LPS-induced interleukin (IL)-1 beta (-25%) and tumor necrosis factor (TNF)-alpha (-40%) expression. Interestingly, troglitazone strongly decreased TNF-alpha expression (-50%) but had no significant effect on IL-1 beta expression. 15d-PGJ(2) was able to inhibit DNA-binding activity of both nuclear factor (NF)-kappa B and AP-1. Troglitazone had no effect on NF-kappa B activation and was shown to increase LPS-induced AP-1 activation. 15d-PGJ(2) and troglitazone modulated the expression of LPS-induced iNOS, COX-2, and proinflammatory cytokines differently. Indeed, troglitazone seems to specifically target TNF-alpha and iNOS pathways. These results offer new insights in regard to the anti-inflammatory potential of the PPAR-gamma ligands and underline different mechanisms of action of 15d-PGJ(2) and troglitazone in synovial fibroblasts.

  15. Association between PPAR-γ2 Pro12Ala polymorphism and obesity: a meta-analysis.

    Science.gov (United States)

    Yao, Ying-Shui; Li, Jie; Jin, Yue-Long; Chen, Yan; He, Lian-Ping

    2015-06-01

    The peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) gene has been reported in the pathogeny of obesity. However, the results have been inconsistent. The purpose of this meta-analysis was to acquire a more accurate assessment of the association between PPAR-γ2 Pro12Ala polymorphism and obesity. PubMed, Wan Fang (Chinese) databases, Chinese Biomedical Medical databases, and Chinese National Knowledge Infrastructure were searched to identify eligible studies. Finally, 25 studies (6491 cases and 8242 controls) were enrolled in this meta-analysis. The effect summary odds ratio (OR) with 95 % confidence interval (CI) was applied. Random-effects or fixed-effects model was performed based on the heterogeneity. STATA 12.0 was applied for this meta-analysis. The combined results showed that PPAR-γ Pro12Ala polymorphism was associated with the obesity risk (Ala vs. Pro: OR = 1.55, 95 % CI 1.34-1.80; Pro/Ala vs. Pro/Pro: OR = 1.54, 95 % CI 1.31-1.82; Ala/Ala + Pro/Ala vs. Pro/Pro: OR = 1.61, 95 % CI 1.36-1.90). Subgroup analysis by ethnicity showed that there were significant associations between PPAR-γ Pro12Ala polymorphism and obesity risk in Caucasians, Asians, and Mixed population. Subgroup analysis by obesity's cutoff points showed that the associations were found among the patients with the cutoff point of BMI ≥24 and BMI ≥30 but not among the patients with the cutoff point of BMI ≥95th percentile. These results suggested that PPAR-γ Pro12Ala polymorphism might be a risk factor for obesity susceptibility.

  16. In vitro screening of inhibition of PPAR-γ activity as a first step in identification of potential breast carcinogens

    DEFF Research Database (Denmark)

    Kopp, Tine Iskov; Lundqvist, J.; Petersen, R. K.

    2015-01-01

    Alcohol consumption and increased estrogen levels are major risk factors for breast cancer, and peroxisome proliferator-activated receptor γ (PPAR-γ) plays an important role in alcohol-induced breast cancer. PPAR-γ activity is inhibited by ethanol, leading to increased aromatase activity...... and estrogen biosynthesis ultimately leading to breast cancer. If other organic solvents inhibit PPAR-γ activity, they should also lead to increased oestrogen biosynthesis and thus be potential breast carcinogens. Ten commonly used hydrophilic organic solvents were first tested in a cell-based screening assay...

  17. Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta

    National Research Council Canada - National Science Library

    Muoio, Deborah M; MacLean, Paul S; Lang, David B; Li, Shi; Houmard, Joseph A; Way, James M; Winegar, Deborah A; Corton, J Christopher; Dohm, G Lynis; Kraus, William E

    2002-01-01

    Ablation of peroxisome proliferator activated receptor (PPAR) alpha, a lipid-activated transcription factor that regulates expression of beta-oxidative genes, results in profound metabolic abnormalities in liver and heart...

  18. Effects of Noradrenaline and Potassium Chloride on peripheral vessels in one experimental model of heart failure

    Directory of Open Access Journals (Sweden)

    Mohammadi Naghadeh M

    2000-11-01

    Full Text Available We investigated contraction to noradrenaline (NA and KC1 and sensitivity of NA at the level of larger vessels (thoracic aorta and vena cava; left renal artery and left renal vein; lateral saphenous artery and lateral saphenous vein and finally central ear artery and marginal ear vein in a model devised to mimic heart failure. The model presented here is the rabbit coronary ligation model in which myocardial infarction was produced ligation model in which myocardial infarction was produced in male New Zeeland white myocardial infarction was produced in male New Zeeland white rabbits (2.6 kg-3.0 Kg by ligation of the marginal branch of the left descending coronary artery. The development of chronic heart failure was allowed to proceed over eight weeks. Animals were killed by overdose with pentobarbitone sodium (IV injection. Arteries and veins were carefully removed with as little connective tissue as possible and placed in cold physiological salt solution (PSS. The arterial and venous rings were mounted in 10 ml isolated organ baths, bathed in Kerbs maintained at 37 °c with 95% O2 plus 5% CO2. The rings were then placed under different resting tensions. After initial application of tension, tissues were left to equilibrate for a 60 min period. Then all tissues were exposed to cumulative concentration of NA (1nM-300µM. Following complete washout, the preparations were left for 45 minutes to re-equilibrate. Then all preparations were contracted with KCl (Krebs solution, sodium free and high KCl, 125 mM and allowed to contract for 5-10 min. Following complete washout with normal Krebs an additional 30 minutes equilibration period was allowed. Then cumulative concentration-response curves (CCRS to NA obtained by increasing the concentration-response curves (CCRC to NA obtained by increasing the concentration of the agonist in half-log increments. In contraction responses to NA aorta, ear artery and ear vein were the most sensitive preparations (pD2

  19. Copper Induces Vasorelaxation and Antagonizes Noradrenaline -Induced Vasoconstriction in Rat Mesenteric Artery

    Directory of Open Access Journals (Sweden)

    Yu-Chun Wang

    2013-11-01

    Full Text Available Background/Aims: Copper is an essential trace element for normal cellular function and contributes to critical physiological or pathological processes. The aim of the study was to investigate the effects of copper on vascular tone of rat mesenteric artery and compare the effects of copper on noradrenaline (NA and high K+ induced vasoconstriction. Methods: The rat mesenteric arteries were isolated and the vessel tone was measured by using multi wire myograph system in vitro. Blood pressure of carotid artery in rabbits was measured by using physiological data acquisition and analysis system in vivo. Results: Copper dose-dependently blunted NA-induced vasoconstriction of rat mesenteric artery. Copper-induced vasorelaxation was inhibited when the vessels were pretreated with NG-nitro-L-arginine methyl ester (L-NAME. Copper did not blunt high K+-induced vasoconstriction. Copper preincubation inhibited NA-evoked vasoconstriction and the inhibition was not affected by the presence of L-NAME. Copper preincubation showed no effect on high K+-evoked vasoconstriction. Copper chelator diethyldithiocarbamate trihydrate (DTC antagonized the vasoactivity induced by copper in rat mesenteric artery. In vivo experiments showed that copper injection (iv significantly decreased blood pressure of rabbits and NA or DTC injection (iv did not rescue the copper-induced hypotension and animal death. Conclusion: Copper blunted NA but not high K+-induced vasoconstriction of rat mesenteric artery. The acute effect of copper on NA-induced vasoconstriction was depended on nitric oxide (NO, but the effect of copper pretreatment on NA-induced vasoconstriction was independed on NO, suggesting that copper affected NA-induced vasoconstriction by two distinct mechanisms.

  20. Learning-induced reversal of the effect of noradrenalin on the postburst AHP.

    Science.gov (United States)

    Brosh, Inbar; Rosenblum, Kobi; Barkai, Edi

    2006-10-01

    Pyramidal neurons in the piriform cortex from olfactory-discrimination-trained rats have reduced postburst afterhyperpolarization (AHP), for 3 days after learning, and are thus more excitable during this period. Such AHP reduction is caused by decreased conductance of one or more of the calcium-dependent potassium currents, I(AHP) and sI(AHP), that mediate the medium and slow AHPs. In this study, we examined which potassium current is reduced by learning and how the effect of noradrenalin (NE) on neuronal excitability is modified by such reduction. The small conductance (SK) channels inhibitor, apamin, that selectively blocks I(A)(HP), reduced the AHP in neurons from trained, naïve, and pseudotrained rats to a similar extent, thus maintaining the difference in AHP amplitude between neurons from trained rats and controls. In addition, the protein expression level of the SK1, SK2, and SK3 channels was also similar in all groups. NE, which was shown to enhance I(AHP) while suppressing (S)I(AHP), reduced the AHP in neurons from controls but enhanced the AHP in neurons from trained rats. Our data show that learning-induced enhancement of neuronal excitability is not the result of reduction in the I(AHP) current. Thus it is probably mediated by reduction in conductance of the other calcium-dependent potassium current, sI(AHP). Consequently, the effect of NE on neuronal excitability is reversed. We propose that the change in the effect of NE after learning may act to counterbalance learning-induced hyperexcitability and preserve the piriform cortex ability to subserve olfactory learning.

  1. Inhibition of noradrenaline release in the rat brain cortex via presynaptic H3 receptors.

    Science.gov (United States)

    Schlicker, E; Fink, K; Hinterthaner, M; Göthert, M

    1989-12-01

    The effects of histamine and related drugs on the evoked tritium overflow from superfused rat brain cortex slices preincubated with 3H-noradrenaline were determined. Tritium overflow was stimulated electrically (3 Hz; slices superfused with normal physiological salt solution) or by introduction of CaCl2 1.3 mmol/l (slices superfused with Ca2(+)-free medium containing K+ 20 mmol/l). Histamine slightly decreased the electrically evoked 3H overflow in slices superfused in the presence of desipramine. The degree of inhibition obtained with histamine was doubled when both desipramine and phentolamine were present in the superfusion medium (pIC15 6.46). Under the latter condition, the evoked overflow was inhibited by the H3 receptor agonist R-(-)-alpha-methylhistamine and its S-(+) enantiomer (pIC15 7.36 and 5.09, respectively), but was not affected by the H2 receptor agonist dimaprit and the H1 receptor agonist 2-thiazolylethylamine (both at up to 32 mumols/l). The concentration-response curve of histamine was shifted to the right by the H3 receptor antagonists thioperamide, impromidine and burimamide (apparent pA2 8.37, 6.86 and 7.05, respectively), by the H2 receptor antagonist ranitidine (apparent pA2 4.27) and was not affected by the H1 receptor antagonist dimetindene (32 mumols/l). The inhibitory effect of R-(-)-alpha-methylhistamine on the evoked overflow was also counteracted by thioperamide. Given alone, none of the five histamine receptor antagonists affected the evoked overflow. In the absence of desipramine plus phentolamine, impromidine and burimamide facilitated the electrically evoked 3H overflow whereas thioperamide had no effect. The facilitatory effects of impromidine and burimamide were abolished by phentolamine, but not affected by desipramine.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Quantified distribution of the noradrenaline innervation in the hippocampus of adult rat

    Energy Technology Data Exchange (ETDEWEB)

    Oleskevich, S.; Descarries, L.; Lacaille, J.C. (Universite de Montreal, Quebec (Canada))

    1989-11-01

    A recently developed radioautographic technique, based on the uptake labeling of monoamine terminals in vitro, was used to quantify the noradrenaline (NA) innervation in adult rat hippocampus. After incubation of brain slices with 1 microM 3H-NA, the NA varicosities were visualized as small aggregates of silver grains, in light microscope radioautographs prepared at 3 equidistant horizontal levels across the ventral 2/3 of the hippocampus. Using a computer-assisted image analyzer, counts were obtained from the subiculum (SUB), 3 sectors of Ammon's horn (CA1, CA3-a, CA3-b) and 3 sectors of the dentate gyrus (DG-medial blade, crest, and lateral blade), every lamina being sampled in each region. After a double correction for duration of radioautographic exposure and section thickness, and following measurement of varicosity diameter in electron microscope radioautographs, it was possible to express these results in number of terminals per volumetric unit of tissue. It was thus found that the overall density of hippocampal NA innervation averages 2.1 million varicosities/mm3 of tissue, a value almost twice as high as that in cerebral cortex. This innervation is 20% denser ventrally than dorsally and is heterogeneous both in terms of regional and laminar distribution. SUB and DG are more strongly innervated than Ammon's horn, wherein CA1 has the lowest overall density. In SUB and CA1, there is a clear predilection of NA varicosities for the stratum moleculare. In CA3, there is a narrow band of even stronger innervation in the stratum radiatum, near the apical border of the stratum pyramidale, contrasting with a 3 times lower density in this cell layer and the stratum oriens. In DG, the NA innervation is again the weakest in the cell body layer and exhibits an almost 3-fold greater density in the polymorph layer, the highest of all hippocampus.

  3. Effects of acetylcholine and noradrenalin on action potentials of isolated rabbit sinoatrial and atrial myocytes

    Directory of Open Access Journals (Sweden)

    Arie O. Verkerk

    2012-05-01

    Full Text Available The autonomic nervous system controls heart rate and contractility through sympathetic and parasympathetic inputs to the cardiac tissue, with acetylcholine (ACh and noradrenalin (NA as the chemical transmitters. In recent years, it has become clear that specific Regulators of G protein Signalling proteins (RGS proteins suppress muscarinic sensitivity and parasympathetic tone, identifying RGS proteins as intriguing potential therapeutic targets. In the present study, we have identified the effects of 1 µM ACh and 1 µM NA on the intrinsic action potentials of sinotrial (SA nodal and atrial myocytes. Single cells were enzymatically isolated from the SA node or from the left atrium of rabbit hearts. Action potentials were recorded using the amphotericin-perforated patch-clamp technique in the absence and presence of ACh, NA or a combination of both. In SA nodal myocytes, ACh increased cycle length and decreased diastolic depolarization rate, whereas NA decreased cycle length and increased diastolic depolarization rate. Both ACh and NA increased maximum upstroke velocity. Furthermore, ACh hyperpolarized the maximum diastolic potential. In atrial myocytes stimulated at 2 Hz, both ACh and NA hyperpolarized the maximum diastolic potential, increased the action potential amplitude, and increased the maximum upstroke velocity. Action potential duration at 50 and 90% repolarization was decreased by ACh, but increased by NA. The effects of both ACh and NA on action potential duration showed a dose dependence in the range of 1–1,000 nM, while a clear-cut frequency dependence in the range of 1–4 Hz was absent. Intermediate results were obtained in the combined presence of ACh and NA in both SA nodal and atrial myocytes. Our data uncover the extent to which SA nodal and atrial action potentials are intrinsically dependent on ACh, NA or a combination of both and may thus guide further experiments with RGS proteins.

  4. Noradrenaline-induced changes in intracellular Ca(2+) and tension in mesenteric arteries from diabetic rats.

    Science.gov (United States)

    Chow, W L; Zhang, L; MacLeod, K M

    2001-09-01

    1. The purpose of this investigation was to determine whether enhanced contractile responses to noradrenaline (NA) of mesenteric arteries from rats with chronic streptozotocin-induced diabetes are associated with increases in mean cytosolic [Ca(2+)]i. 2. [Ca(2+)]i was measured with fura 2-AM, and was monitored simultaneously with tension in perfused endothelium-denuded mesenteric arterial rings from 12 - 14 week diabetic rats and age- and gender-matched control rats. 3. Basal [Ca(2+)]i (expressed as R(n), the normalized fura 2 ratio) was not significantly different in arteries from control and diabetic rats. Similarly, no differences between control and diabetic arteries in the tension or [Ca(2+)]i responses to 80 mM KCl in the presence of phentolamine were detected. 4. The rate of tension development, peak tension and integrated tension in response to 30 microM NA were all significantly greater in diabetic than control arteries. However, this was not associated with enhancement of the corresponding [Ca(2+)]i responses in the diabetic arteries. 5. Peak contractile responses to perfusion with both 0.3 and 3 microM NA, but peak [Ca(2+)]i only in response to 0.3 microM NA, were significantly greater in diabetic than control arteries. 6. NA (30 microM) produced a greater increase in both peak tension and [Ca(2+)]i in diabetic than control arteries perfused with Ca(2+)-free solution containing 1 mM EGTA. Neither the rate nor the magnitude of NA-induced Ca(2+) influx appeared to be altered in the diabetic arteries. 7. The enhanced sustained contractile response of diabetic arteries to NA appears to be dissociated from increases in [Ca(2+)]i, and may be due to other factors, such as an increase in the Ca(2+) sensitivity of the contractile proteins.

  5. Daily variations in the influence of noradrenaline on preferred ambient temperature of the Siberian hamster.

    Science.gov (United States)

    Jefimow, Małgorzata; Wojciechowski, Michał; Tegowska, Eugenia

    2003-04-01

    Daily variations in sensitivity to noradrenaline (NA) and the activation of nonshivering thermogenesis (NST) are important for survival under a potentially wide range of environmental conditions. However, little is known regarding the ability of the Siberian hamster and other species to activate NST in the day and night when they may be subjected to marked variations in environmental temperature. In this study, the effects of acclimation temperature and time of day on the behavioral thermoregulatory response to NA injections in Siberian hamsters (Phodopus sungorus) was investigated. Hamsters were acclimated for 4 weeks to 23 degrees C and a L:D 12:12 h photoperiod. After acclimation, preferred ambient temperatures (PT(a)) in saline- and NA-injected animals were measured continuously in the temperature gradient system. NA (0.6 mg/kg; s.c.) was given every 4 h while PT(a) was monitored. After NA injections there was a rapid drop in PT(a), decreasing to approximately 15 degrees C within 10-20 min after each NA injection. Following 4 weeks of acclimation to 10 degrees C and a L:D 8:16 h photoperiod, the same hamsters were re-tested in the temperature gradient system. Cold acclimation led to an accentuation in the behavioral response with a decrease in PT(a) of approximately 10 degrees C. The maximal decrease in preferred ambient temperatures was recorded during the light phase of the day and during the second part of the night. Lowering of PT(a) after NA allows for rapid dissipation of the heat from NST. Overall, the behavioral response reflects the daily changes in brown adipose tissue sensitivity to NA and thus capacity for NST.

  6. Viral-genetic tracing of the input-output organization of a central noradrenaline circuit.

    Science.gov (United States)

    Schwarz, Lindsay A; Miyamichi, Kazunari; Gao, Xiaojing J; Beier, Kevin T; Weissbourd, Brandon; DeLoach, Katherine E; Ren, Jing; Ibanes, Sandy; Malenka, Robert C; Kremer, Eric J; Luo, Liqun

    2015-08-01

    Deciphering how neural circuits are anatomically organized with regard to input and output is instrumental in understanding how the brain processes information. For example, locus coeruleus noradrenaline (also known as norepinephrine) (LC-NE) neurons receive input from and send output to broad regions of the brain and spinal cord, and regulate diverse functions including arousal, attention, mood and sensory gating. However, it is unclear how LC-NE neurons divide up their brain-wide projection patterns and whether different LC-NE neurons receive differential input. Here we developed a set of viral-genetic tools to quantitatively analyse the input-output relationship of neural circuits, and applied these tools to dissect the LC-NE circuit in mice. Rabies-virus-based input mapping indicated that LC-NE neurons receive convergent synaptic input from many regions previously identified as sending axons to the locus coeruleus, as well as from newly identified presynaptic partners, including cerebellar Purkinje cells. The 'tracing the relationship between input and output' method (or TRIO method) enables trans-synaptic input tracing from specific subsets of neurons based on their projection and cell type. We found that LC-NE neurons projecting to diverse output regions receive mostly similar input. Projection-based viral labelling revealed that LC-NE neurons projecting to one output region also project to all brain regions we examined. Thus, the LC-NE circuit overall integrates information from, and broadcasts to, many brain regions, consistent with its primary role in regulating brain states. At the same time, we uncovered several levels of specificity in certain LC-NE sub-circuits. These tools for mapping output architecture and input-output relationship are applicable to other neuronal circuits and organisms. More broadly, our viral-genetic approaches provide an efficient intersectional means to target neuronal populations based on cell type and projection pattern.

  7. Volume Transmission in Central Dopamine and Noradrenaline Neurons and Its Astroglial Targets.

    Science.gov (United States)

    Fuxe, Kjell; Agnati, Luigi F; Marcoli, Manuela; Borroto-Escuela, Dasiel O

    2015-12-01

    Already in the 1960s the architecture and pharmacology of the brainstem dopamine (DA) and noradrenaline (NA) neurons with formation of vast numbers of DA and NA terminal plexa of the central nervous system (CNS) indicated that they may not only communicate via synaptic transmission. In the 1980s the theory of volume transmission (VT) was introduced as a major communication together with synaptic transmission in the CNS. VT is an extracellular and cerebrospinal fluid transmission of chemical signals like transmitters, modulators etc. moving along energy gradients making diffusion and flow of VT signals possible. VT interacts with synaptic transmission mainly through direct receptor-receptor interactions in synaptic and extrasynaptic heteroreceptor complexes and their signaling cascades. The DA and NA neurons are specialized for extrasynaptic VT at the soma-dendrtitic and terminal level. The catecholamines released target multiple DA and adrenergic subtypes on nerve cells, astroglia and microglia which are the major cell components of the trophic units building up the neural-glial networks of the CNS. DA and NA VT can modulate not only the strength of synaptic transmission but also the VT signaling of the astroglia and microglia of high relevance for neuron-glia interactions. The catecholamine VT targeting astroglia can modulate the fundamental functions of astroglia observed in neuroenergetics, in the Glymphatic system, in the central renin-angiotensin system and in the production of long-distance calcium waves. Also the astrocytic and microglial DA and adrenergic receptor subtypes mediating DA and NA VT can be significant drug targets in neurological and psychiatric disease.

  8. The expression and significance of PPAR-γ in hypertrophic scar fibroblasts%PPAR-γ在增生性瘢痕成纤维细胞中的表达及意义

    Institute of Scientific and Technical Information of China (English)

    潘姝; 李叶扬; 戴丽冰; 黄粤

    2009-01-01

    Objective To investigate the expression of peroxisome proliferator -activated receptor gamma(PPAR-γ) in human hypertrophic scar fibroblasts and normal skin fibroblasts. Methods The expression of PeAR -γ gamma were examined by immtmocytochemistry in 3 cases of hypertrophic scar and normal skin. Results Immunocytochemistry showed that PPAR -γ was expressed in both hypertrophic scar and normal skin fibroblasts. The level of PeAR -γ protein in hypertrophic scar fibroblasts significantly decreased. Conclusion The expression of PeAR -γ is lower in human hy-pertrophic scar fibroblasts than that in normal skin fibroblasts. Activating PPAR -γ may be a novel approach for the treat-ment of hypertrophic scar.%目的 探讨核转录因子过氧化物酶体增殖物激活受体-γ(PPAR-γ)在增生性瘢痕成纤维细胞中的表达状况及其意义.方法 应用免疫细胞化学检测3例增生性瘢痕和正常皮肤成纤维细胞中PPAR-γ的表达.结果 免疫细胞化学显示PPAR-γ蛋白在增生性瘢痕和正常皮肤成纤维细胞中均有表达,但是在增生性瘢痕中表达较正常皮肤低.结论 核内受体PPAR-γ在增生性瘢痕成纤维细胞中呈下调表达,提示激活PPAR-γ可能是增生性瘢痕治疗的一种新方法.

  9. Expression of PPAR-γ in patients with chronic rhinosinusitis without or with nasal polyps%PPAR-γ在CRSsNP鼻窦黏膜和CRSwNP鼻息肉中表达差异性研究

    Institute of Scientific and Technical Information of China (English)

    彭先兵; 孔维佳; 王彦君

    2014-01-01

    目的:探讨过氧化物酶体增殖物激活受体-γ(PPAR-γ)在慢性鼻-鼻窦炎不伴鼻息肉(chronic rhinosinusitis without nasal polyps,CRSsNP)患者鼻窦黏膜和慢性鼻-鼻窦炎伴鼻息肉(chronic rhinosinusitis with nasal polyps,CRSwNP)患者鼻息肉中的表达差异及临床意义.方法:应用实时定量PCR技术和免疫组织化学技术检测PPAR-γ在CRSsNP鼻窦黏膜、CRSwNP鼻息肉及正常下鼻甲中的表达.结果:①PPAR-γ在CRSsNP鼻窦黏膜、CRSwNP鼻息肉及正常下鼻甲中均有表达;②PPAR-γ的mRNA和蛋白水平在CRSsNP鼻窦黏膜及CRSwNP鼻息肉中的表达较正常下鼻甲组织下降,差异均有统计学意义(P<0.05);③PPAR γ的mRNA和蛋白水平在CRSsNP鼻窦黏膜和CRSwNP鼻息肉中的表达无显著性差异.结论:PPAR-γ在人的鼻腔黏膜中有表达,同时在CRSsNP鼻窦黏膜及CRSwNP鼻息肉中的表达下降.PPAR-γ可能与CRSsNP及CRSwNP炎症长期存在有关,提示激活PPAR-γ可能为慢性鼻-鼻窦炎治疗提供一种新的方法.

  10. A semi-quantitative RT-PCR method to measure the in vivo effect of dietary conjugated linoleic acid on porcine muscle PPAR gene expression

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    Meadus W.J.

    2003-01-01

    Full Text Available Conjugated linoleic acid (CLA can activate (in vitro the nuclear transcription factors known as the peroxisome proliferators activated receptors (PPAR. CLA was fed at 11 g CLA/kg of feed for 45d to castrated male pigs (barrows to better understand long term effects of PPAR activation in vivo. The barrows fed CLA had lean muscle increased by 3.5% and overall fat reduced by 9.2% but intramuscular fat (IMF % was increased by 14% (P < 0.05. To measure the effect of long term feeding of CLA on porcine muscle gene expression, a semi-quantitative RT-PCR method was developed using cDNA normalized against the housekeeping genes cyclophilin and &bgr;-actin. This method does not require radioactivity or expensive PCR instruments with real-time fluorescent detection. PPAR&ggr; and the PPAR responsive gene AFABP but not PPAR&agr; were significantly increased (P < 0.05 in the CLA fed pig’s muscle. PPAR&agr; and PPAR&ggr; were also quantitatively tested for large differences in gene expression by western blot analysis but no significant difference was detected at this level. Although large differences in gene expression of the PPAR transcriptional factors could not be confirmed by western blotting techniques. The increased expression of AFABP gene, which is responsive to PPAR transcriptional factors, confirmed that dietary CLA can induce a detectable increase in basal PPAR transcriptional activity in the live animal.

  11. Interactions between PPAR Gamma and the Canonical Wnt/Beta-Catenin Pathway in Type 2 Diabetes and Colon Cancer

    Science.gov (United States)

    Claes, Victor

    2017-01-01

    In both colon cancer and type 2 diabetes, metabolic changes induced by upregulation of the Wnt/beta-catenin signaling and downregulation of peroxisome proliferator-activated receptor gamma (PPAR gamma) may help account for the frequent association of these two diseases. In both diseases, PPAR gamma is downregulated while the canonical Wnt/beta-catenin pathway is upregulated. In colon cancer, upregulation of the canonical Wnt system induces activation of pyruvate dehydrogenase kinase and deactivation of the pyruvate dehydrogenase complex. As a result, a large part of cytosolic pyruvate is converted into lactate through activation of lactate dehydrogenase. Lactate is extruded out of the cell by means of activation of monocarboxylate lactate transporter-1. This phenomenon is called Warburg effect. PPAR gamma agonists induce beta-catenin inhibition, while inhibition of the canonical Wnt/beta-catenin pathway activates PPAR gamma.

  12. PPARs与TLR-NF-κB信号通路%PPARs and TLR-NF-κB signaling pathway

    Institute of Scientific and Technical Information of China (English)

    耿彦婷; 张军平; 徐士欣; 吕仕超

    2012-01-01

    Peroxisome proliferator — activated receptors (PPARs) influence Toll — like receptors (TLRs) —nuclear receptor — κB ( NF — κB) signaling pathway through diverse mechanisms to negalively regulate TLR — NF — κB signaling — mediated inflammalion and immune responses under para — inflammation condition. However, in pathological stales, the balance between inhibition and promotion of inflammation, which is regulated by PPARs and TLR — NF — κB signaling pathway, respectively, has been broken down, resulting in inflammatory cascade and eventually causing chronic non — infectious inflammatory diseases, such as atherosclerosis, ulcerative colitis and rheumatoid arthritis. This review mainly focuses on the interaction between PPARs and TLR — NF — κB signaling pathway either in para — inflammatory status or pathological state, which highlights the importance of PPARs in the process of inflammation and immune responses and provides new interfering targets for the treatment of the diseases like coronary atherosclerotic heart disease.

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

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    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

  14. Perspective: repression of competition and the evolution of cooperation.

    Science.gov (United States)

    Frank, Steven A

    2003-04-01

    Repression of competition within groups joins kin selection as the second major force in the history of life shaping the evolution of cooperation. When opportunities for competition against neighbors are limited within groups, individuals can increase their own success only by enhancing the efficiency and productivity of their group. Thus, characters that repress competition within groups promote cooperation and enhance group success. Leigh first expressed this idea in the context of fair meiosis, in which each chromosome has an equal chance of transmission via gametes. Randomized success means that each part of the genome can increase its own success only by enhancing the total number of progeny and thus increasing the success of the group. Alexander used this insight about repression of competition in fair meiosis to develop his theories for the evolution of human sociality. Alexander argued that human social structures spread when they repress competition within groups and promote successful group-against-group competition. Buss introduced a new example with his suggestion that metazoan success depended on repression of competition between cellular lineages. Maynard Smith synthesized different lines of thought on repression of competition. In this paper, I develop simple mathematical models to illustrate the main processes by which repression of competition evolves. With the concepts made clear, I then explain the history of the idea. I finish by summarizing many new developments in this subject and the most promising lines for future study.

  15. Keratinocyte differentiation and upregulation of ceramide synthesis induced by an oat lipid extract via the activation of PPAR pathways.

    Science.gov (United States)

    Chon, Su-Hyoun; Tannahill, Ruth; Yao, Xiang; Southall, Michael D; Pappas, Apostolos

    2015-04-01

    Activation of peroxisome proliferator-activated receptors (PPARs) has been shown to have an important role in skin barrier function by regulating differentiation and lipid synthesis in keratinocytes. Oat (Avena sativa) has long been used as a soothing agent to relieve skin irritations, and the clinical benefits of topical oat formulations have been proven; however, the mechanistic understanding of oat's mode of action remains unknown. We investigated whether an oat lipid extract could activate PPARs and subsequently increase epidermal lipid synthesis and differentiation markers. Primary human epidermal keratinocytes and transformed cell lines were treated with PPAR agonists and oat lipid extracts to investigate the PPAR agonism. PPAR target genes and epidermal differentiation markers were analysed using quantitative real-time PCR and HPTLC analysis. Oat lipid extract demonstrated robust dual agonism for PPARα and PPARβ/δ, and increased direct PPAR target gene induction in primary human keratinocytes. In addition, oat oil treatment increased both receptor expression and, consistent with the literature on PPARs, oat oil treatment resulted in a significant upregulation of differentiation genes (involucrin, SPRRs and transglutaminase 1) and ceramide processing genes (β-glucocerebrosidase, sphingomyelinases 3 and ABCA12). Further, oat oil treatment in keratinocytes significantly increased ceramide levels (70%), suggesting a functional translation of PPAR activation by oat oil in keratinocytes. Taken together, these results demonstrate that oat lipids possess robust dual agonistic activities for PPARα and PPARβ/δ, increase their gene expression and induce differentiation and ceramide synthesis in keratinocytes, which can collectively improve skin barrier function. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. PPAR-γ Activation Inhibits Angiogenesis by Blocking ELR+CXC Chemokine Production in Non-small Cell Lung Cancer

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    Venkateshwar G. Keshamouni

    2005-03-01

    Full Text Available Activation of peroxisome proliferator-activated receptor-γ (PPAR-γ results in inhibition of tumor growth in various types of cancers, but the mechanism(s by which PPAR-γ induces growth arrest has not been completely defined. In a recent study, we demonstrated that treatment of A549 (human non small cell lung cancer cell line tumor-bearing SCID mice with PPAR-γ ligands troglitazone (Tro and pioglitazone significantly inhibits primary tumor growth. In this study, immunohistochemical analysis of Tro-treated and Pio-treated tumors with factor VIII antibody revealed a significant reduction in blood vessel density compared to tumors in control animals, suggesting inhibition of angiogenesis. Further analysis showed that treatment of A549 cells in vitro with Tro or transient transfection of A549 cells with constitutively active PPAR-γ (VP16-PPAR-γ construct blocked the production of the angiogenic ELR +CXC chemokines IL-8 (CXCL8, ENA-78 (CXCL5, Gro-α (CXCL1. Similarly, an inhibitor of NF-ΚB activation (PDTC also blocked CXCL8, CXCL5, CXCL1 production, consistent with their NF-ΚB-dependent regulation. Conditioned media from A549 cells induce human microvascular endothelial cell (HMVEC chemotaxis. However, conditioned media from Tro-treated A549 cells induced significantly less HMVEC chemotaxis compared to untreated A549 cells. Furthermore, PPAR-γ activation inhibited NF-ΚB transcriptional activity, as assessed by TransAM reporter gene assay. Collectively, our data suggest that PPAR-γ ligands can inhibit tumor-associated angiogenesis by blocking the production of ELR+CXC chemokines, which is mediated through antagonizing NF-ΚB activation. These antiangiogenic effects likely contribute to the inhibition of primary tumor growth by PPAR-γ ligands.

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

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    Luis Carlos Mejía Rivera

    2001-01-01

    Full Text Available 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; todavía existen muchos interrogantes acerca de su relación con el metabolismo de los carbohidratos pero su uso en el manejo de la diabetes mellitus tipo 2 cada vez gana más importancia. Por otro lado, los antiinflamatorios no esteroideos se relacionan de alguna manera con las funciones de los PPARδ; hasta el momento se ha logrado establecer una relación molecular y epidemiológica de estos fármacos y receptores con el cáncer de colon. 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, δand γthese receptors are involved in the regulation of diferent metabolic processes, being the group of receptors more intensely studied. PPARαare 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

  18. Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice.

    Science.gov (United States)

    Memon, R A; Tecott, L H; Nonogaki, K; Beigneux, A; Moser, A H; Grunfeld, C; Feingold, K R

    2000-11-01

    Peroxisome proliferator-activated receptors (PPARs) are transcription factors that play an important role in the regulation of genes involved in lipid utilization and storage, lipoprotein metabolism, adipocyte differentiation, and insulin action. The three isoforms of the PPAR family, i.e. alpha, delta, and gamma, have distinct tissue distribution patterns. PPAR-alpha is predominantly present in the liver, and PPAR-gamma in adipose tissue, whereas PPAR-delta is ubiquitously expressed. A recent study reported increased PPAR-gamma messenger RNA (mRNA) expression in the liver in ob/ob mice; however, it is not known whether increased PPAR-gamma expression in the liver has any functional consequences. The expression of PPAR-alpha and -delta in the liver in obesity has not been determined. We have now examined the mRNA levels of PPAR-alpha, -delta, and -gamma in three murine models of obesity, namely, ob/ob (leptin-deficient), db/db (leptin-receptor deficient), and serotonin 5-HT2c receptor (5-HT2cR) mutant mice. 5-HT2cR mutant mice develop a late-onset obesity that is associated with higher plasma leptin levels. Our results show that PPAR-alpha mRNA levels in the liver are increased by 2- to 3-fold in all three obese models, whereas hepatic PPAR-gamma mRNA levels are increased by 7- to 9-fold in ob/ob and db/db mice and by 2-fold in obese 5-HT2cR mutant mice. PPAR-delta mRNA expression is not altered in ob/ob or db/db mice. To determine whether increased PPAR-gamma expression in the liver has any functional consequences, we examined the effect of troglitazone treatment on the hepatic mRNA levels of several PPAR-gamma-responsive adipose tissue-specific genes that have either no detectable or very low basal expression in the liver. The treatment of lean control mice with troglitazone significantly increased the expression of adipocyte fatty acid-binding protein (aP2) and fatty acid translocase (FAT/CD36) in the liver. This troglitazone-induced increase in the expression

  19. Expression profiling of peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues using tissue microarray.

    Science.gov (United States)

    Higashiyama, Hiroyuki; Billin, Andrew N; Okamoto, Yuji; Kinoshita, Mine; Asano, Satoshi

    2007-05-01

    Peroxisome proliferator-activated receptor-delta (PPAR-delta) is known as a transcription factor involved in the regulation of fatty acid oxidation and mitochondrial biogenesis in several tissues, such as skeletal muscle, liver and adipose tissues. In this study, to elucidate systemic physiological functions of PPAR-delta, we examined the tissue distribution and localization of PPAR-delta in adult mouse tissues using tissue microarray (TMA)-based immunohistochemistry. PPAR-delta positive signals were observed on variety of tissues/cells in multiple systems including cardiovascular, urinary, respiratory, digestive, endocrine, nervous, hematopoietic, immune, musculoskeletal, sensory and reproductive organ systems. In these organs, PPAR-delta immunoreactivity was generally localized on the nucleus, although cytoplasmic localization was observed on several cell types including neurons in the nervous system and cells of the islet of Langerhans. These expression profiling data implicate various physiological roles of PPAR-delta in multiple organ systems. TMA-based immunohistochemistry enables to profile comprehensive protein localization and distribution in a high-throughput manner.

  20. 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.

  1. Peroxisome proliferator-activated receptors (PPARs) and ovarian function – implications for regulating steroidogenesis, differentiation, and tissue remodeling

    Science.gov (United States)

    Komar, Carolyn M

    2005-01-01

    The peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors involved in varied and diverse processes such as steroidogenesis, angiogenesis, tissue remodeling, cell cycle, apoptosis, and lipid metabolism. These processes are critical for normal ovarian function, and all three PPAR family members – alpha, delta, and gamma, are expressed in the ovary. Most notably, the expression of PPARgamma is limited primarily to granulosa cells in developing follicles, and is regulated by luteinizing hormone (LH). Although much has been learned about the PPARs since their initial discovery, very little is known regarding their function in ovarian tissue. This review highlights what is known about the roles of PPARs in ovarian cells, and discusses potential mechanisms by which PPARs could influence ovarian function. Because PPARs are activated by drugs currently in clinical use (fibrates and thiazolidinediones), it is important to understand their role in the ovary, and how manipulation of their activity may impact ovarian physiology as well as ovarian pathology. PMID:16131403

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

    Science.gov (United States)

    Ortuño Sahagún, D; Márquez-Aguirre, A L; Quintero-Fabián, S; López-Roa, R I; Rojas-Mayorquín, A E

    2012-01-01

    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.

  3. Phenolics from Glycyrrhiza glabra roots and their PPAR-gamma ligand-binding activity.

    Science.gov (United States)

    Kuroda, Minpei; Mimaki, Yoshihiro; Honda, Shinichi; Tanaka, Hozumi; Yokota, Shinichi; Mae, Tatsumasa

    2010-01-15

    Bioassay-guided fractionation of the EtOH extract of licorice (Glycyrrhiza glabra roots), using a GAL-4-PPAR-gamma chimera assay method, resulted in the isolation of 39 phenolics, including 10 new compounds (1-10). The structures of the new compounds were determined by analysis of their spectroscopic data. Among the isolated compounds, 5'-formylglabridin (5), (2R,3R)-3,4',7-trihydroxy-3'-prenylflavane (7), echinatin, (3R)-2',3',7-trihydroxy-4'-methoxyisoflavan, kanzonol X, kanzonol W, shinpterocarpin, licoflavanone A, glabrol, shinflavanone, gancaonin L, and glabrone all exhibited significant PPAR-gamma ligand-binding activity. The activity of these compounds at a sample concentration of 10microg/mL was three times more potent than that of 0.5microM troglitazone.

  4. Regulation of Sulfotransferase and UDP-Glucuronosyltransferase Gene Expression by the PPARs

    Directory of Open Access Journals (Sweden)

    Melissa Runge-Morris

    2009-01-01

    Full Text Available During phase II metabolism, a substrate is rendered more hydrophilic through the covalent attachment of an endogenous molecule. The cytosolic sulfotransferase (SULT and UDP-glucuronosyltransferase (UGT families of enzymes account for the majority of phase II metabolism in humans and animals. In general, phase II metabolism is considered to be a detoxication process, as sulfate and glucuronide conjugates are more amenable to excretion and elimination than are the parent substrates. However, certain products of phase II metabolism (e.g., unstable sulfate conjugates are genotoxic. Members of the nuclear receptor superfamily are particularly important regulators of SULT and UGT gene transcription. In metabolically active tissues, increasing evidence supports a major role for lipid-sensing transcription factors, such as peroxisome proliferator-activated receptors (PPARs, in the regulation of rodent and human SULT and UGT gene expression. This review summarizes current information regarding the regulation of these two major classes of phase II metabolizing enzyme by PPARs.

  5. 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.

  6. Peroxisome Proliferator-Activated Receptor (PPAR): Balance for Survival in Parasitic Infections

    Science.gov (United States)

    Chan, Marion M.; Evans, Kyle W.; Moore, Andrea R.; Fong, Dunne

    2010-01-01

    Parasitic infections induce a magnitude of host responses. At the opposite ends of the spectrum are those that ensure the host's needs to eliminate the invaders and to minimize damage to its own tissues. This review analyzes how parasites would manipulate immunity by activating the immunosuppressive nuclear factor, peroxisome proliferator-activated receptors (PPARs) with type 2 cytokines and free fatty acids from arachidonic acid metabolism. PPARs limit the action of type 1 immunity, in which classically activated macrophages act through the production of proinflammatory signals, to spare the parasites. They also favor the development of alternately activated macrophages which control inflammation so the host would not be destroyed. Possibly, the nuclear factors hold a pivotal role in the establishment of chronic infection by delicately balancing the pro- and anti-inflammatory signaling mechanisms and their ligands may be used as combination therapeutics to limit host pathology. PMID:20169106

  7. Effects of denervation on the sensitizing effect to noradrenaline induced by morphine in the vas deferens of mice treated chronically with morphine.

    Science.gov (United States)

    Contreras, E; Tamayo, L; Gaete, S; Juica, S

    1982-08-01

    The acute administration of morphine to the isolated vas deferens from mice chronically exposed to this analgesic, induced a facilitatory effect on the responses of the muscle to exogenous noradrenaline. It has been suggested that this sensitizing property of morphine might reflect a dependence-like state of the vas deferens. In the present paper, the capability of met- and leu-enkephalin to substitute for morphine was studied, as well as the influence of innervation on the apparent dependence state. The contractile responses to noradrenaline and to acetylcholine were increased after the administration of morphine to the bath containing a denervated vas deferences, prepared from chronically morphinized mice. Morphine administration facilitated noradrenaline- but not acetylcholine-induced contractile effects in vas deferens isolated from mice which had been chronically treated with either morphine or morphine plus guanethidine. The presence of met- or leu-enkephalin in the isolated vas deferens from chronically morphinized mice (either intact, denervated or treated with guanethidine) failed to sensitize contractile responses to noradrenaline or acetylcholine. It is concluded that (a) the sensitizing effect induced by morphine in the vas deferens from mice chronically treated with morphine is specific for the adrenergic neurotransmitter; (b) the effect of morphine is not mimicked by opiate peptides; and (c) denervation of the vas deferens of mice treated chronically with morphine does not suppress the noradrenaline-sensitizing property of morphine.

  8. Adrenaline but not noradrenaline is a determinant of exercise-induced lipid mobilization in human subcutaneous adipose tissue.

    Science.gov (United States)

    de Glisezinski, I; Larrouy, D; Bajzova, M; Koppo, K; Polak, J; Berlan, M; Bulow, J; Langin, D; Marques, M A; Crampes, F; Lafontan, M; Stich, V

    2009-07-01

    The relative contribution of noradrenaline (norepinephrine) and adrenaline (epinephrine) in the control of lipid mobilization in subcutaneous adipose tissue (SCAT) during exercise was evaluated in men treated with a somatostatin analogue, octreotide. Eight lean and eight obese young men matched for age and physical fitness performed 60 min exercise bouts at 50% of their maximal oxygen consumption on two occasions: (1) during i.v. infusion of octreotide, and (2) during placebo infusion. Lipolysis and local blood flow changes in SCAT were evaluated using in situ microdialysis. Infusion of octreotide suppressed plasma insulin and growth hormone levels at rest and during exercise. It blocked the exercise-induced increase in plasma adrenaline while that of noradrenaline was unchanged. Plasma natriuretic peptides (NPs) level was higher at rest and during exercise under octreotide infusion in lean men. Under placebo, no difference was found in the exercise-induced increase in glycerol between the probe perfused with Ringer solution alone and that with phentolamine (an alpha-adrenergic receptor antagonist) in lean subjects while a greater increase in glycerol was observed in the obese subjects. Under placebo, propranolol infusion in the probe containing phentolamine reduced by about 45% exercise-induced glycerol release; this effect was fully suppressed under octreotide infusion while noradrenaline was still elevated and exercise-induced lipid mobilization maintained in both lean and obese individuals. In conclusion, blockade of beta-adrenergic receptors during exercise performed during infusion of octreotide (blocking the exercise-induced rise in adrenaline but not that of noradrenaline) does not alter the exercise-induced lipolysis. This suggests that adrenaline is the main adrenergic agent contributing to exercise-induced lipolysis in SCAT. Moreover, it is the combined action of insulin suppression and NPs release which explains the lipolytic response which remains

  9. Influence of dopamine as noradrenaline precursor on the secretory function of the bovine corpus luteum in vitro.

    OpenAIRE

    Kotwica, J.; Skarzynski, D.; Bogacki, M.; Miszkiel, G.

    1996-01-01

    1. Dopamine is assumed to affect the ovary function after its conversion into noradrenaline (NA). 2. To study this bovine luteal slices from 11-14 days of the oestrous cycle were preincubated for 24 h to recover beta-receptors and next they were incubated for 1, 2 or 4 h with (a) different doses of dopamine; (b) dopamine together with a beta-antagonist (propranolol) or with a dopamine receptor blocker (droperidol); (c) dopamine with a dopamine-beta-hydroxylase inhibitor. 3. Dopamine stimulate...

  10. Development of Novel Nonagonist PPAR-Gamma Ligands for Lung Cancer Treatment

    Science.gov (United States)

    2016-08-01

    provides insight into the groups of patients for whom this combination therapy may benefit . We continue to make progress on the other aims of this grant...identify a core gene set that is indicative of the inhibition of the phosphorylation of PPAR gamma in the setting of carboplatin treatment. Using gene...these two genotypes upon treatment with carboplatin is consistent with the idea that S273 phophorylation is a critical event in response to carboplatin

  11. Sesame oil attenuates nutritional fibrosing steatohepatitis by modulating matrix metalloproteinases-2, 9 and PPAR-γ.

    Science.gov (United States)

    Periasamy, Srinivasan; Hsu, Dur-Zong; Chang, Po-Cheng; Liu, Ming-Yie

    2014-03-01

    Sesame oil is a nutrient-rich antioxidant popular in alternative medicine. It contains sesamin, sesamol, and sesamolin, all of which contribute to its improved liver function in various animal model studies. However, its effect on nutritional fibrosing steatohepatitis is unclear. We investigated therapeutic sesame oil on matrix metalloproteinases-2, 9 (MMP-2, 9) in nutritional fibrosing steatohepatitic mice. C57BL/6 J mice were fed with methionine-choline deficient (MCD) diet for 35 days to induce fibrosing steatohepatitis. Sesame oil was treated from 29-35th day. Body weight, steatosis, aspartate transaminase, alanine transaminase, peroxisome proliferator-activated receptor (PPAR)-γ, α-smooth muscle actin (α-SMA), MMP-2, 9, and tissue inhibitor of matrix metalloproteinases (TIMP)-1 were assessed after 35 days. All tested parameters except TIMP-1 and PPAR-γ were higher in MCD fed mice than in normal control mice. Mice fed with MCD diet for 4 weeks showed severe liver injury with steatosis, necrotic-inflammation, and fibrosis. In sesame-oil (4 ml)-treated mice, all tested parameters except TIMP-1, α-SMA, and PPAR-γ were significantly attenuated compared with MCD fed mice. Sesame oil inhibited MMP-2, 9 activities, but up-regulated TIMP-1 expression in MCD fed mice. In addition, a histological analysis of liver tissue samples showed that sesame oil provided significant protection against fibrosis. We conclude that therapeutic sesame oil protects against fibrosing steatohepatitis by inhibiting MMP-2, 9 activities, up-regulating TIMP-1 expression, and PPAR-γ. © 2014.

  12. Sympathetic activity in the rat: effects of anaesthesia on noradrenaline kinetics.

    Science.gov (United States)

    Maignan, E; Dong, W X; Legrand, M; Safar, M; Cuche, J L

    2000-04-12

    Noradrenaline (NA) kinetics represent an effective tool for evaluating the activity of the sympathetic system: thus plasma NA concentration, spillover rate (SOR) and metabolic clearance rate (MC) were measured in the rat. The dilution technique was adapted and validated: pithing that caused mechanical destruction of the spinal cord was shown to reduce drastically NA-SOR and plasma NA concentration with no effect on NA-MC. NA-SOR and plasma NA concentration were restored within their normal limits when 2.5 Hz electrical stimulation of the sympathetic roots was superimposed. Normal values of NA kinetics in non-anaesthetised normotensive 12-week-old rats are reported: NA-SOR=196.1+/-26.4 ng/kg/min, NA-MC=413.9+/-38.8 ml/kg/min and plasma NA=486+/-52 pg/ml. NA kinetic was investigated in response to anaesthesia, known to depress excitable tissues of the central nervous system and expected to depress the activity of the sympathetic system. When NA-SOR was significantly reduced during anaesthesia with either sodium pentobarbital or chloralose, plasma NA concentration was not changed because NA-MC was also reduced. Thus, plasma NA concentration can be a misleading marker of the sympathetic activity. The response of the sympathetic activity to four different anaesthetic agents is shown to be heterogeneous, ranging from inhibition to stimulation. Sodium pentobarbital anaesthesia was associated with a statistically significant reduction of both NA-SOR (105.6+/-14.1 ng/kg/min, P<0. 01) and NA-MC (239.3+/-18.7 ml/kg/min, P<0.001) while plasma NA was not changed (438+/-47 pg/ml). Chloralose reduced NA-SOR (101.6+/-20. 1 ng/kg/min, P<0.05) while ketamine did not (150.6+/-35.5 ng/kg/min, n.s.): both compounds reduced NA-MC (257.9+/-27.8 ml/kg/min, P<0.01 and 265.8+/-34.3 ml/kg/min, P<0.05, respectively). Diethyl ether was shown to increase both NA-SOR (472.2+/-111 ng/kg/min, P<0.05) and plasma NA concentration (1589+/-436 pg/ml, P<0.01), while NA-MC remained unchanged. Thus, any

  13. Multiple repressive mechanisms in the hippocampus during memory formation.

    Science.gov (United States)

    Cho, Jun; Yu, Nam-Kyung; Choi, Jun-Hyeok; Sim, Su-Eon; Kang, SukJae Joshua; Kwak, Chuljung; Lee, Seung-Woo; Kim, Ji-il; Choi, Dong Il; Kim, V Narry; Kaang, Bong-Kiun

    2015-10-02

    Memory stabilization after learning requires translational and transcriptional regulations in the brain, yet the temporal molecular changes that occur after learning have not been explored at the genomic scale. We used ribosome profiling and RNA sequencing to quantify the translational status and transcript levels in the mouse hippocampus after contextual fear conditioning. We revealed three types of repressive regulations: translational suppression of ribosomal protein-coding genes in the hippocampus, learning-induced early translational repression of specific genes, and late persistent suppression of a subset of genes via inhibition of estrogen receptor 1 (ESR1/ERα) signaling. In behavioral analyses, overexpressing Nrsn1, one of the newly identified genes undergoing rapid translational repression, or activating ESR1 in the hippocampus impaired memory formation. Collectively, this study unveils the yet-unappreciated importance of gene repression mechanisms for memory formation. Copyright © 2015, American Association for the Advancement of Science.

  14. Targeted Transcriptional Repression in Bacteria Using CRISPR Interference (CRISPRi).

    Science.gov (United States)

    Hawkins, John S; Wong, Spencer; Peters, Jason M; Almeida, Ricardo; Qi, Lei S

    2015-01-01

    Clustered regularly interspersed short palindromic repeats (CRISPR) interference (CRISPRi) is a powerful technology for sequence-specifically repressing gene expression in bacterial cells. CRISPRi requires only a single protein and a custom-designed guide RNA for specific gene targeting. In Escherichia coli, CRISPRi repression efficiency is high (~300-fold), and there are no observable off-target effects. The method can be scaled up as a general strategy for the repression of many genes simultaneously using multiple designed guide RNAs. Here we provide a protocol for efficient guide RNA design, cloning, and assay of the CRISPRi system in E. coli. In principle, this protocol can be used to construct CRISPRi systems for gene repression in other species of bacteria.

  15. 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.

  16. Molecular docking studies on potential PPAR-γ agonist from Rhizophora apiculata

    Directory of Open Access Journals (Sweden)

    Gurudeeban Selvaraj

    2014-08-01

    Full Text Available Peroxisome proliferator-activated receptor gamma (PPARγ agonists are beneficial in the management of diabetes by increasing insulin sensitivity and inhibiting hepatic gluconeogenesis. The aim of the present study was to isolate and evaluate PPAR-γ agonist property of phytocompounds from Rhizophora apiculata using in silico approach. 30 g powdered leaves of R. apiculata extracted through acid-base method and subjected to GC-MS analysis. GC-MS results identified 18 phytocompounds, among those major peaks were 1-adamantyl-p-methylbenzalimine, clivorin, 4-butyl pyridine, 1-oxide, acetamide and p-aminodiethylaniline. In silico analysis of major compounds on human PPAR-γ protein was determined by AutoDock 4.0. Compared to thiazolidinediones, R. apiculata derived ligands acts as a potential agonist with binding energy -4.41, -5.29, -5.28 and -4.27 kcal/mol respectively. The molecular interaction of ligands was at residues of TYR473, ILE326, ARG288, HIS323 and ARG 288 to activate the action of PPAR-γ protein.

  17. Effects of PPAR-γ agonist treatment on LPS-induced mastitis in rats.

    Science.gov (United States)

    Mingfeng, Ding; Xiaodong, Ming; Yue, Liu; Taikui, Piao; Lei, Xiao; Ming, Liu

    2014-12-01

    PPAR-γ, a member of the nuclear receptor superfamily, plays an important role in lipid metabolism and inflammation. The aim of this study was to investigate the preventive effects of synthetic PPAR-γ agonist rosiglitazone on lipopolysaccharide (LPS)-induced mastitis in rats. The mouse model of mastitis was induced by the injection of LPS through the duct of the mammary gland. Rosiglitazone was injected 1 h before the induction of LPS intraperitoneally. The results showed that rosiglitazone attenuated the infiltration of inflammatory cells, the activity of myeloperoxidase (MPO), and the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in a dose-dependent manner. Additionally, Western blotting showed that rosiglitazone inhibited the phosphorylation of IκB-α and NF-κB p65. These results indicated that rosiglitazone has a protective effect on mastitis, and the anti-inflammatory mechanism of rosiglitazone on LPS-induced mastitis in rats may be due to its ability to inhibit NF-κB signaling pathways. PPAR-γ may be a potential therapeutic target against mastitis.

  18. Protection against myocardial ischaemia/reperfusion injury by PPAR-alpha activation is related to production of nitric oxide and endothelin-1

    DEFF Research Database (Denmark)

    Bulhak, A A; Sjöquist, P-O; Xu, C-B;

    2006-01-01

    BACKGROUND: Ligands of peroxisome proliferator-activated receptor alpha (PPAR-alpha) have been shown to reduce ischaemia/reperfusion injury. The mechanisms behind this effect are not well known. We hypothesized that activation of PPAR-alpha exerts cardioprotection via a mechanism related to nitri....... CONCLUSION: The results suggest that the PPAR-alpha activation protects the rat myocardium against ischaemia/ reperfusion injury via a mechanism related to production of NO, and possibly ET-1....

  19. Repressive coping and alexithymia in idiopathic environmental intolerance

    DEFF Research Database (Denmark)

    Skovbjerg, Sine; Zachariae, Robert; Rasmussen, Alice;

    2010-01-01

    To examine if the non-expression of negative emotions (i.e., repressive coping) and differences in the ability to process and regulate emotions (i.e., alexithymia) is associated with idiopathic environmental intolerance (IEI).......To examine if the non-expression of negative emotions (i.e., repressive coping) and differences in the ability to process and regulate emotions (i.e., alexithymia) is associated with idiopathic environmental intolerance (IEI)....

  20. Anti-inflammatory effect of simvastatin in an experimental model of spinal cord trauma: involvement of PPAR

    Directory of Open Access Journals (Sweden)

    Esposito Emanuela

    2012-04-01

    Full Text Available Abstract Background Statins such as simvastatin are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA reductase used in the prevention of cardiovascular disease. In addition to their cholesterol-lowering activities, statins exert pleiotropic anti-inflammatory effects, which might contribute to their beneficial effects on lipid-unrelated inflammatory diseases. Recently it has been demonstrated that the peroxisome proliferator-activated receptor (PPAR-α mediates anti-inflammatory effects of simvastatin in vivo models of acute inflammation. Moreover, previous results suggest that PPAR-α plays a role in control of secondary inflammatory process associated with spinal cord injury (SCI. Methods With the aim to characterize the role of PPAR-α in simvastatin activity, we tested the efficacy of simvastatin (10 mg/kg dissolved in saline i.p. 1 h and 6 h after the trauma in an experimental model of SCI induced in mice by extradural compression of the spinal cord (T6-T7 level using an aneurysm clip with a closing force of 24 g via a four-level T5-T8 laminectomy, and comparing mice lacking PPAR-α (PPAR-α KO with wild type (WT mice. In order to elucidate whether the effects of simvastatin are due to activation of the PPAR-α, we also investigated the effect of a PPAR-α antagonist, GW6471 (1 mg/kg administered i.p. 30 min prior treatment with simvastatin on the protective effects of on simvastatin. Results Results indicate that simvastatin activity is weakened in PPAR-α KO mice, as compared to WT controls. In particular, simvastatin was less effective in PPAR-α KO, compared to WT mice, as evaluated by inhibition of the degree of spinal cord inflammation, neutrophil infiltration, nitrotyrosine formation, pro-inflammmatory cytokine expression, nuclear factor (NF-κB activation, inducible nitric-oxide synthase (iNOS expression, and apoptosis. In addition we demonstrated that GW6471 significantly antagonized the effect of the statin and thus

  1. PPAR-γ在人前列腺癌组织及裸鼠移植瘤中的表达%Expression of PPAR-γin prostate cancer and xenograft tumor in nude mice

    Institute of Scientific and Technical Information of China (English)

    祝海; 綦海燕; 刘之俊; 候四川; 徐珞

    2011-01-01

    目的 研究PPAR-γ在人前列腺癌组织及裸鼠移植瘤中的表达,分析PPAR-γ的表达与前列腺癌临床病理特征之间的关系,探讨曲格列酮抑制前列腺癌的作用.方法 采用免疫组化法检测成人前列腺组织、前列腺增生组织、前列腺癌组织及裸鼠移植瘤PPAP-γ蛋白表达,并通过图像分析测定各组的平均吸光度值.建立人前列腺癌细胞的裸鼠移植瘤模型,观察曲格列酮对移植瘤生长的抑制作用.结果 PPAR-γ在前列腺癌组织中的表达高于成人前列腺组织与前列腺增生组织.PPAR-γ的表达与细胞分化程度、TNM分期有密切关系.与对照组相比,曲格列酮可明显抑制前列腺癌裸鼠移植瘤生长速度.肿瘤体积、重量明显减少;PPAR-γ蛋白表达增加.结论 PPAR-γ表达与前列腺癌的临床病理特征密切相关.曲格列酮对前列腺癌的抑制作用是通过PPAR-γ受体激活发挥其抗肿瘤作用.

  2. Organic acid mediated repression of sugar utilization in rhizobia.

    Science.gov (United States)

    Iyer, Bhagya; Rajput, Mahendrapal Singh; Jog, Rahul; Joshi, Ekta; Bharwad, Krishna; Rajkumar, Shalini

    2016-11-01

    Rhizobia are a class of symbiotic diazotrophic bacteria which utilize C4 acids in preference to sugars and the sugar utilization is repressed as long as C4 acids are present. This can be manifested as a diauxie when rhizobia are grown in the presence of a sugar and a C4 acid together. Succinate, a C4 acid is known to repress utilization of sugars, sugar alcohols, hydrocarbons, etc by a mechanism termed as Succinate Mediated Catabolite Repression (SMCR). Mechanism of catabolite repression determines the hierarchy of carbon source utilization in bacteria. Though the mechanism of catabolite repression has been well studied in model organisms like E. coli, B. subtilis and Pseudomonas sp., mechanism of SMCR in rhizobia has not been well elucidated. C4 acid uptake is important for effective symbioses while mutation in the sugar transport and utilization genes does not affect symbioses. Deletion of hpr and sma0113 resulted in the partial relief of SMCR of utilization of galactosides like lactose, raffinose and maltose in the presence of succinate. However, no such regulators governing SMCR of glucoside utilization have been identified till date. Though rhizobia can utilize multitude of sugars, high affinity transporters for many sugars are yet to be identified. Identifying high affinity sugar transporters and studying the mechanism of catabolite repression in rhizobia is important to understand the level of regulation of SMCR and the key regulators involved in SMCR.

  3. Peroxisome proliferator-activated receptor (PPAR)β/δ, a possible nexus of PPARα- and PPARγ-dependent molecular pathways in neurodegenerative diseases: Review and novel hypotheses.

    Science.gov (United States)

    Aleshin, Stepan; Strokin, Mikhail; Sergeeva, Marina; Reiser, Georg

    2013-10-01

    Peroxisome proliferator-activated receptors (PPARα, -β/δ and -γ) are lipid-activated transcription factors. Synthetic PPARα and PPARγ ligands have neuroprotective properties. Recently, PPARβ/δ activation emerged as the focus of a novel approach for the treatment of a wide range of neurodegenerative diseases. To fill the gap of knowledge about the role of PPARβ/δ in brain, new hypotheses about PPARβ/δ involvement in neuropathological processes are requested. In this paper, we describe a novel hypothesis, claiming the existence of tight interactions between the three PPAR isotypes, which we designate the "PPAR triad". We propose that PPARβ/δ has a central control of the PPAR triad. The majority of studies analyze the regulation only by one of the PPAR isotypes. A few reports describe the mutual regulation of expression levels of all three PPAR isotypes by PPAR agonists. Analysis of these studies where pairwise interactions of PPARs were described allows us to support the existence of the PPAR triad with central role for PPARβ/δ. In the present review, we propose the hypothesis that in a wide range of brain disorders, PPARβ/δ plays a central role between PPARα and PPARγ. Finally, we prove the advantages of the PPAR triad concept by describing hypotheses of PPARβ/δ involvement in the regulation of myelination, glutamate-induced neurotoxicity, and signaling pathways of reactive oxygen species/NO/Ca(2+). Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Association between PRO12ALA polymorphism of the PPAR-γ2 gene and type 2 diabetes mellitus in Iranian patients

    OpenAIRE

    Azadeh Motavallian; Sasan Andalib; Golnaz Vaseghi; Hamid Mirmohammad-Sadeghi; Masoud Amini

    2013-01-01

    Background: Peroxisome proliferator-activated receptor (PPARs) have been identified as ligand-activated transcription factors that belong to the nuclear receptor superfamily. It has been shown that an association exists between Proline 12 alanine (Pro12Ala) polymorphism of PPAR-GAMMA2 (PPAR-γ2) gene and increased risk of type 2 diabetes mellitus (T2DM) in different populations. Therefore, the present study was designed to investigate the association between Pro12Ala polymorphism of PPAR-γ2 ge...

  5. Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-Repressive Complex 2

    DEFF Research Database (Denmark)

    Pasini, Diego; Hansen, Klaus H; Christensen, Jesper;

    2008-01-01

    Polycomb group (PcG) proteins regulate important cellular processes such as embryogenesis, cell proliferation, and stem cell self-renewal through the transcriptional repression of genes determining cell fate decisions. The Polycomb-Repressive Complex 2 (PRC2) is highly conserved during evolution......, and its intrinsic histone H3 Lys 27 (K27) trimethylation (me3) activity is essential for PcG-mediated transcriptional repression. Here, we show a functional interplay between the PRC2 complex and the H3K4me3 demethylase Rbp2 (Jarid1a) in mouse embryonic stem (ES) cells. By genome-wide location analysis we...... found that Rbp2 is associated with a large number of PcG target genes in mouse ES cells. We show that the PRC2 complex recruits Rbp2 to its target genes, and that this interaction is required for PRC2-mediated repressive activity during ES cell differentiation. Taken together, these results demonstrate...

  6. Effects of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) on alpha2-adrenoceptors which regulate the synthesis and release of noradrenaline in the rat brain.

    Science.gov (United States)

    Prieto, M; Giralt, M T

    2001-03-01

    N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) induces a degeneration of noradrenergic axons originating in the locus coeruleus. The sensitivity of alpha2-adrenoceptors which regulate the synthesis and release of noradrenaline was investigated in three brain regions which receive an unequal innervation from locus coeruleus, 21 days after DSP4 (50 mg/kg) administration. After giving treated rats a dopa decarboxylase inhibitor, the in vivo tyrosine hydroxylase activity and the tissue concentrations of noradrenaline were also evaluated. Relevant reductions of noradrenaline levels were found in hippocampus and parietal cortex (91% and 77.5%, respectively; PDSP4 (10+/-5% vs 57+/-3% in the control group, PDSP4 for noradrenergic terminals arising from locus coeruleus and suggest a more severe lesioning of the hippocampus than the parietal cortex.

  7. Noradrenaline-induced increases in calcium and tension in skeletal muscle conductance and resistance arteries from rats with post-infarction heart failure

    DEFF Research Database (Denmark)

    Trautner, Simon; Amtorp, Ole; Boesgaard, Soren

    2006-01-01

    We tested the hypothesis that arterial reactivity to noradrenaline is augmented in congestive heart failure (CHF), which could contribute to the deleterious changes in peripheral vascular resistance and compliance in this condition. From male Wistar rats with post-infarction CHF and sham-operated......, endothelial dysfunction nor changes in baseline vascular tone could be demonstrated in the skeletal muscle vascular bed of this animal model of heart failure.......We tested the hypothesis that arterial reactivity to noradrenaline is augmented in congestive heart failure (CHF), which could contribute to the deleterious changes in peripheral vascular resistance and compliance in this condition. From male Wistar rats with post-infarction CHF and sham......-operated rats, skeletal muscle conductance and resistance arteries (mean lumen diameters: 514 and 186 microm) were isolated and mounted on wire myographs, and wall tension was recorded in response to cumulative application of acetylcholine and noradrenaline to the vessel segments. In a subset of experiments...

  8. Inhibition of noradrenaline release from the sympathetic nerves of the human saphenous vein by presynaptic histamine H3 receptors.

    Science.gov (United States)

    Molderings, G J; Weissenborn, G; Schlicker, E; Likungu, J; Göthert, M

    1992-07-01

    The human saphenous vein was used to examine whether presynaptic histamine receptors can modulate noradrenaline release and, if so, to determine their pharmacological characteristics. Strips of this blood vessel were incubated with [3H]noradrenaline and subsequently superfused with physiological salt solution containing desipramine and corticosterone. Electrically (2 Hz) evoked 3H overflow was inhibited by histamine and the H3 receptor agonist R-(-)-alpha-methylhistamine. Histamine-induced inhibition of electrically evoked tritium overflow was not affected by alpha 2-adrenoceptor blockade by rauwolscine. S-(+)-alpha-methylhistamine (up to 10 mumol/l) as well as the histamine H1 and H2 receptor agonists 2-(2-thiazolyl)ethylamine (up to 3 mumol/l) and dimaprit (up to 30 mumol/l), respectively, were ineffective. The selective histamine H3 receptor antagonist thioperamide abolished the inhibitory effect of histamine. The histamine H2 and H1 receptor antagonists ranitidine and pheniramine, respectively, did not affect the histamine-induced inhibition of evoked tritium overflow. The present results are compatible with the suggestion that the sympathetic nerves of the human saphenous vein are endowed with inhibitory presynaptic histamine receptors of the H3 class.

  9. Possible participation of histamine H3 receptors in the modulation of noradrenaline release from rat spinal cord slices.

    Science.gov (United States)

    Celuch, S M

    1995-12-12

    Rat spinal cord slices prelabelled with [3H]noradrenaline were superfused with a medium containing 1 mu M desipramine plus 0.3 mu M phentolamine. Histamine (0.01-10 mu M) and the selective histamine H3 receptor agonist R-(-)-alpha-methylhistamine (0.001-10 mu M) caused a concentration-dependent decrease in the release of radioactivity evoked by electrical field stimulation (0.8 Hz, 20 mA, 2 min). The inhibitory effect of histamine was not modified by either pyrilamine (1 mu M) or ranitidine (10 mu M), but it was antagonized by burimamide (1 mu M). The inhibitory action of histamine (1 mu M) was attenuated by pertussis toxin (3 mu g/ml) and was abolished by N-ethylmaleimide (30 mu M). Neither forskolin (10 mu M) nor rolipram (100 mu M), nor the combination of both drugs, modified the inhibitory effect of histamine. Histamine (1 mu M) did not modify the overflow of tritium induced by electrical stimulation in the absence of phentolamine. The present results suggest that in the rat spinal cord the release of noradrenaline elicited by electrical stimulation is negatively modulated by histamine, probably through the activation of histamine H3 receptors. This modulatory mechanism is likely to involve the participation of regulatory Go/Gi proteins.

  10. The influence of steroids on noradrenaline-mediated contractile reactivity of the superficial nasal and facial veins in cycling gilts.

    Science.gov (United States)

    Grzegorzewski, W J; Muszak, J; Wasowska, B; Jan, B; Stefańczyk-Krzymowska, S

    2012-01-01

    The nasal venous blood may be directed through the facial vein into the systemic circulation or through the frontal vein into the venous cavernous sinus of the perihypophyseal vascular complex, where hormones and pheromones permeate from the venous blood into the arterial blood supplying the brain and hypophysis. The present study was designed to determine the effect of noradrenaline (NA) on the tension of the nasal, frontal and facial veins of cycling gilts, and influence of ovarian steroid hormones on NA-mediated contractile reactivity. Additionally, the enzyme dopamine-beta-hydroxylase catalysing the conversion of dopamine to noradrenaline (DbetaH) was immunolocalized in these vessels. Among three studied veins, the frontal proximal vein, that fulfill a key role in the supply of the nasal venous blood into the venous cavernous sinus, reacted to NA most strongly (P tension of the frontal proximal vein during the periestrous period (P superficial nasal and facial veins of gilts in both studied stages of the estrous cycle. We suggest that the reactivity of the superficial veins of the nose and face to NA combined with the previously demonstrated reactivity of these veins to steroid ovarian hormones and male steroid pheromones may regulate the access of priming pheromone androstenol (resorebed in the nasal cavity) to the brain of gilts during periestrous period via humoral local destination transfer.

  11. μ-Opioid receptor activation and noradrenaline transport inhibition by tapentadol in rat single locus coeruleus neurons.

    Science.gov (United States)

    Sadeghi, Mahsa; Tzschentke, Thomas M; Christie, MacDonald J

    2015-01-01

    Tapentadol is a novel analgesic that combines moderate μ-opioid receptor agonism and noradrenaline reuptake inhibition in a single molecule. Both mechanisms of action are involved in producing analgesia; however, the potency and efficacy of tapentadol in individual neurons has not been characterized. Whole-cell patch-clamp recordings of G-protein-coupled inwardly rectifying K(+) (KIR 3.x) currents were made from rat locus coeruleus neurons in brain slices to investigate the potency and relative efficacy of tapentadol and compare its intrinsic activity with other clinically used opioids. Tapentadol showed agonist activity at μ receptors and was approximately six times less potent than morphine with respect to KIR 3.x current modulation. The intrinsic activity of tapentadol was lower than [Met]enkephalin, morphine and oxycodone, but higher than buprenorphine and pentazocine. Tapentadol inhibited the noradrenaline transporter (NAT) with potency similar to that at μ receptors. The interaction between these two mechanisms of action was additive in individual LC neurons. Tapentadol displays similar potency for both µ receptor activation and NAT inhibition in functioning neurons. The intrinsic activity of tapentadol at the μ receptor lies between that of buprenorphine and oxycodone, potentially explaining the favourable profile of side effects, related to μ receptors. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2013 The British Pharmacological Society.

  12. Sympathetic control of skeletal muscle function: possible co-operation between noradrenaline and neuropeptide Y in rabbit jaw muscles.

    Science.gov (United States)

    Grassi, C; Deriu, F; Roatta, S; Santarelli, R; Azzena, G B; Passatore, M

    1996-07-19

    Stimulation of the cervical sympathetic nerve at 10/s increases by 12.9 +/- 0.7% peak tension of maximal twitches in the directly stimulated jaw muscles and markedly depresses (41.6 +/- 1.3%) the tonic vibration reflex (TVR) elicited in the same muscles by vibration of the mandible. Both effects are not significantly influenced by administration of beta-adrenoceptor antagonists. When both alpha- and beta-adrenergic receptors are blocked, sympathetic stimulation induces a very small increase in twitch tension (3.8 +/- 0.7%), while no detectable change in the TVR is observed. Close arterial injection of alpha 1-adrenoceptor agonist phenylephrine mimics the effects induced by sympathetic stimulation on twitch tension and TVR, dose-dependently. The noradrenaline co-transmitter neuropeptide Y also produces a long-lasting, dose-dependent increase in the twitch tension which is unaffected by blockade of adrenergic receptors as well as of the neuromuscular junctions. Contribution of neuropeptide Y to the sympathetically-induced reduction of the stretch reflex is not clearly demonstrated. These data suggest that co-operation between noradrenaline and neuropeptide Y may be effective in determining sympathetic modulation of skeletal muscle function.

  13. Influence of dopamine as noradrenaline precursor on the secretory function of the bovine corpus luteum in vitro.

    Science.gov (United States)

    Kotwica, J.; Skarzynski, D.; Bogacki, M.; Miszkiel, G.

    1996-01-01

    1. Dopamine is assumed to affect the ovary function after its conversion into noradrenaline (NA). 2. To study this bovine luteal slices from 11-14 days of the oestrous cycle were preincubated for 24 h to recover beta-receptors and next they were incubated for 1, 2 or 4 h with (a) different doses of dopamine; (b) dopamine together with a beta-antagonist (propranolol) or with a dopamine receptor blocker (droperidol); (c) dopamine with a dopamine-beta-hydroxylase inhibitor. 3. Dopamine stimulated the luteal content of oxytocin (OT) and progesterone. This effect was inhibited by propanolol but not by droperidol. 4. Dopamine added to the medium was followed by an increase of noradrenaline there. This rise was dose and time-dependent. 5. The dopamine-beta-hydroxylase inhibitor, inhibited the stimulating effect of dopamine on luteal progesterone and OT content. 6. Bovine corpus luteum can synthesize de novo NA from dopamine as a precursor. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:8842430

  14. Noradrenaline increases intracellular glutathione in human astrocytoma U-251 MG cells by inducing glutamate-cysteine ligase protein via β3-adrenoceptor stimulation.

    Science.gov (United States)

    Yoshioka, Yasuhiro; Kadoi, Hisatsugu; Yamamuro, Akiko; Ishimaru, Yuki; Maeda, Sadaaki

    2016-02-05

    Glutathione (GSH) plays a critical role in protecting cells from oxidative damage. Since neurons rely on the supply of GSH from astrocytes to maintain optimal intracellular GSH concentrations, the GSH concentration of astrocytes is important for the survival of neighboring neurons against oxidative stress. The neurotransmitter noradrenaline is known to modulate the functions of astrocytes and has been suggested to have neuroprotective properties in neurodegenerative diseases. To elucidate the mechanisms underlying the neuroprotective properties of noradrenaline, in this study, we investigated the effect of noradrenaline on the concentrations of intracellular GSH in human U-251 malignant glioma (MG; astrocytoma) cells. Treatment of the cells with noradrenaline for 24h concentration-dependently increased their intracellular GSH concentration. This increase was inhibited by a non-selective β-adrenoceptor antagonist propranolol and by a selective β3-adrenoceptor antagonist SR59230A, but not by a non-selective α-adrenoceptor antagonist phenoxybenzamine, or by a selective β1-adrenoceptor antagonist atenolol or by a selective β2-adrenoceptor antagonist butoxamine. In addition, the selective β3-adrenoceptor agonist CL316243 increased the intracellular GSH in U-251 MG cells. Treatment of the cells with noradrenaline (10μM) for 24h increased the protein level of the catalytic subunit of glutamate-cysteine ligase (GCLc), the rate-limiting enzyme of GSH synthesis; and this increase was inhibited by SR59230A. These results thus suggest that noradrenaline increased the GSH concentration in astrocytes by inducing GCLc protein in them via β3-adrenoceptor stimulation.

  15. PPAR-γ regulates carnitine homeostasis and mitochondrial function in a lamb model of increased pulmonary blood flow.

    Directory of Open Access Journals (Sweden)

    Shruti Sharma

    Full Text Available OBJECTIVE: Carnitine homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow (Shunt. Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in PPAR-γ expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-γ signaling and carnitine dysfunction, and whether the PPAR-γ agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs. METHODS AND RESULTS: siRNA-mediated PPAR-γ knockdown significantly reduced carnitine palmitoyltransferases 1 and 2 (CPT1 and 2 and carnitine acetyltransferase (CrAT protein levels. This decrease in carnitine regulatory proteins resulted in a disruption in carnitine homeostasis and induced mitochondrial dysfunction, as determined by a reduction in cellular ATP levels. In turn, the decrease in cellular ATP attenuated NO signaling through a reduction in eNOS/Hsp90 interactions and enhanced eNOS uncoupling. In vivo, rosiglitazone treatment preserved carnitine homeostasis and attenuated the development of mitochondrial dysfunction in Shunt lambs maintaining ATP levels. This in turn preserved eNOS/Hsp90 interactions and NO signaling. CONCLUSION: Our study indicates that PPAR-γ signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo. Further, it identifies a new mechanism by which PPAR-γ regulates NO signaling through Hsp90. Thus, PPAR-γ agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow.

  16. [Noradrenaline and the enzymes of its synthesis and breakdown in the rat hypothalamus after a flight on the Kosmos-936 biosatellite].

    Science.gov (United States)

    Torda, T; Kvetnansky, R; Tigranian, R A; Chulman, J; Genin, A M

    1981-01-01

    In the hypothalamus of the weightless and centrifuged rats flown for 18.5 days on board the biosatellite Cosmos-936 the noradrenaline concentration and activity of the enzymes involved in the catecholamine synthesis and degradation were measured. It was found that under the space flight influence the noradrenaline concentration and tyrosine hydroxylase, dopamine-beta-hydroxylase and monoamine oxidase activities remained unaltered. These findings indicate that a prolonged exposure to weightlessness was not a stressogenic agent that could activate the adrenergic system in the rat hypothalamus.

  17. Effect of the dihydropyridine Bay K 8644 on the release of [3H]-noradrenaline from the rat isolated vas deferens.

    OpenAIRE

    Ceña, V; García, A.G.; Khoyi, M. A.; Salaices, M.; Sanchez-García, P.

    1985-01-01

    The effects of Bay K 8644 on the release of [3H]-noradrenaline evoked by potassium, electrical stimulation or tyramine from the rat isolated vas deferens labelled with [3H]-noradrenaline were investigated. Bay K 8644 (1 microM) by itself did not affect the spontaneous release of tritium from the rat isolated vas deferens. However, it increased the calcium-dependent release of tritium elicited by both high potassium (59 mM) and electrical field stimulation. The exposure of rat vas deferens to ...

  18. 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...

  19. 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...

  20. Glycogen content regulates peroxisome proliferator activated receptor-∂ (PPAR-∂ activity in rat skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Andrew Philp

    Full Text Available Performing exercise in a glycogen depleted state increases skeletal muscle lipid utilization and the transcription of genes regulating mitochondrial β-oxidation. Potential candidates for glycogen-mediated metabolic adaptation are the peroxisome proliferator activated receptor (PPAR coactivator-1α (PGC-1α and the transcription factor/nuclear receptor PPAR-∂. It was therefore the aim of the present study to examine whether acute exercise with or without glycogen manipulation affects PGC-1α and PPAR-∂ function in rodent skeletal muscle. Twenty female Wistar rats were randomly assigned to 5 experimental groups (n = 4: control [CON]; normal glycogen control [NG-C]; normal glycogen exercise [NG-E]; low glycogen control [LG-C]; and low glycogen exercise [LG-E]. Gastrocnemius (GTN muscles were collected immediately following exercise and analyzed for glycogen content, PPAR-∂ activity via chromatin immunoprecipitation (ChIP assays, AMPK α1/α2 kinase activity, and the localization of AMPK and PGC-1α. Exercise reduced muscle glycogen by 47 and 75% relative to CON in the NG-E and LG-E groups, respectively. Exercise that started with low glycogen (LG-E finished with higher AMPK-α2 activity (147%, p<0.05, nuclear AMPK-α2 and PGC-1α, but no difference in AMPK-α1 activity compared to CON. In addition, PPAR-∂ binding to the CPT1 promoter was significantly increased only in the LG-E group. Finally, cell reporter studies in contracting C2C12 myotubes indicated that PPAR-∂ activity following contraction is sensitive to glucose availability, providing mechanistic insight into the association between PPAR-∂ and glycogen content/substrate availability. The present study is the first to examine PPAR-∂ activity in skeletal muscle in response to an acute bout of endurance exercise. Our data would suggest that a factor associated with muscle contraction and/or glycogen depletion activates PPAR-∂ and initiates AMPK translocation in skeletal

  1. Role of the peroxisome proliferator-activated receptors (PPAR)-α, β/δ and γ triad in regulation of reactive oxygen species signaling in brain.

    Science.gov (United States)

    Aleshin, Stepan; Reiser, Georg

    2013-12-01

    Overwhelming evidence shows that oxidative stress is a major cause in development of brain disorders. Low activity of the reactive oxygen species (ROS)-degrading system as well as high levels of oxidative damage markers have been observed in brain tissue of patients with neurodegenerative and other brain diseases to a larger extent than in healthy individuals. Many studies aimed to develop effective and safe antioxidant strategies for the therapy or prevention of brain diseases. Nevertheless, it became clear that rigorous suppression of ROS is deleterious for normal cell functioning. Thus, approaches that can regulate the ROS levels over a wide range, from inhibition to induction, will be a powerful tool for neuroprotection. A most prominent target for such ROS management is the family of peroxisome proliferator-activated receptors (PPARs). All three members (PPAR-α, -β/δ and -γ) of this nuclear receptor subfamily form a tightly connected triad. For individual PPAR isoforms, neuroprotective properties have been well proven. Their involvement in regulation of ROS production and degradation underlies the therapeutic effects. Nevertheless, the current paradigms of the involvement of PPAR in neuroprotective therapy ignore such interconnections of PPARs and aim at antioxidant effects of individual PPAR isoforms, but do not take into account the necessity of careful regulation of ROS levels. The present review (i) summarizes the data, which support the concept of the PPAR triad in brain, (ii) demonstrates that usage of the PPAR triad allows the regulation of PPAR-dependent genes over a wide range, from inhibition to upregulation, and (iii) summarizes the known data concerning the PPAR triad involvement in regulation of ROS. Our report opens new directions in the field of PPAR/ROS-related neuroscience research.

  2. Involvement of PPAR gamma and E-cadherin/beta-catenin pathway in the antiproliferative effect of conjugated linoleic acid in MCF-7 cells.

    Science.gov (United States)

    Bocca, Claudia; Bozzo, Francesca; Francica, Simona; Colombatto, Sebastiano; Miglietta, Antonella

    2007-07-15

    Conjugated linoleic acid (CLA) is a naturally occurring fatty acid, which has been shown to exert beneficial effects against breast carcinogenesis. It has been reported that CLA could modulate cellular proliferation and differentiation through the activation of peroxisome proliferator-activated receptors (PPARs). Among different PPAR isotypes, PPAR gamma is involved in growth inhibition of transformed cells. Ligands of PPAR gamma are considered as potential anticancer drugs, so CLA was tested for its ability to induce PPAR gamma expression in MCF-7 breast cancer cells. The effects of CLA and of a specific synthetic PPAR gamma antagonist were evaluated on cell growth as well as on parameters responsible for cell growth regulation. We demonstrated here that CLA stimulated the expression of PPAR gamma to levels up to control and caused PPAR gamma translocation into the nucleus. Furthermore, the overexpression of PPAR gamma positively correlates with the inhibition of cell proliferation and with the modulation of ERK signaling induced by CLA; in all cases the administration of the antagonist reverted CLA effects. The PPAR-signaling pathway is connected with the beta-catenin/E-cadherin pathway, thus we evaluated CLA effects on the expression and cellular distribution of these proteins, which are involved in cell adhesion and responsible for invasive behavior. The treatment with CLA determined the up-regulation and the redistribution of beta-catenin and E-cadherin and the antagonist reverted only the effect on beta-catenin. These studies indicate that CLA regulates PPAR gamma expression by selectively acting as an agonist and may influence cell-cell adhesion and invasiveness of MCF-7 cells. (c) 2007 Wiley-Liss, Inc.

  3. Glycogen content regulates peroxisome proliferator activated receptor-∂ (PPAR-∂) activity in rat skeletal muscle.

    Science.gov (United States)

    Philp, Andrew; MacKenzie, Matthew G; Belew, Micah Y; Towler, Mhairi C; Corstorphine, Alan; Papalamprou, Angela; Hardie, D Grahame; Baar, Keith

    2013-01-01

    Performing exercise in a glycogen depleted state increases skeletal muscle lipid utilization and the transcription of genes regulating mitochondrial β-oxidation. Potential candidates for glycogen-mediated metabolic adaptation are the peroxisome proliferator activated receptor (PPAR) coactivator-1α (PGC-1α) and the transcription factor/nuclear receptor PPAR-∂. It was therefore the aim of the present study to examine whether acute exercise with or without glycogen manipulation affects PGC-1α and PPAR-∂ function in rodent skeletal muscle. Twenty female Wistar rats were randomly assigned to 5 experimental groups (n = 4): control [CON]; normal glycogen control [NG-C]; normal glycogen exercise [NG-E]; low glycogen control [LG-C]; and low glycogen exercise [LG-E]). Gastrocnemius (GTN) muscles were collected immediately following exercise and analyzed for glycogen content, PPAR-∂ activity via chromatin immunoprecipitation (ChIP) assays, AMPK α1/α2 kinase activity, and the localization of AMPK and PGC-1α. Exercise reduced muscle glycogen by 47 and 75% relative to CON in the NG-E and LG-E groups, respectively. Exercise that started with low glycogen (LG-E) finished with higher AMPK-α2 activity (147%, pexercise. Our data would suggest that a factor associated with muscle contraction and/or glycogen depletion activates PPAR-∂ and initiates AMPK translocation in skeletal muscle in response to exercise.

  4. 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 inve......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......-steroidal anti-inflammatory medicine. Methods: A case-cohort study including 1031 ACS cases and a sub-cohort of 1703 persons was nested within the population-based prospective study Diet, Cancer and Health of 57,053 individuals. Results: Homozygous male variant allele carriers of PPAR gamma 2 Pro(12)Ala were...

  5. 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.

  6. Synthetic and natural Peroxisome Proliferator-Activated Receptor (PPAR) agonists as candidates for the therapy of the metabolic syndrome.

    Science.gov (United States)

    Tan, Chek Kun; Zhuang, Yan; Wahli, Walter

    2017-03-01

    Peroxisome proliferator-activated receptors (PPARs) are the molecular targets of hypolipidemic and insulin-sensitizing drugs and implicated in a multitude of processes that fine-tune the functions of all organs in vertebrates. As transcription factors they sense endogenous and exogenous lipid signaling molecules and convert these signals into intricate gene responses that impact health and disease. The PPARs act as modulators of cellular, organ, and systemic processes, such as lipid and carbohydrate metabolism, making them valuable for understanding body homeostasis influenced by nutrition and exercise. Areas covered: This review concentrates on synthetic and natural PPAR ligands and how they have helped reveal many aspects of the transcriptional control of complex processes important in health. Expert opinion: The three PPARs have complementary roles in the fine-tuning of most fundamental body functions, especially energy metabolism. Understanding their inter-relatedness using ligands that simultaneously modulate the activity of more than one of these receptors is a major goal. This approach may provide essential knowledge for the development of dual or pan-PPAR agonists or antagonists as potential new health-promoting agents and for nutritional approaches to prevent metabolic diseases.

  7. Genotyping of peroxisome proliferator-activated receptor gamma (PPAR-γ) polymorphism (Pro12Ala) in Iranian population.

    Science.gov (United States)

    Namvaran, Fatemeh; Rahimi-Moghaddam, Parvaneh; Azarpira, Negar

    2011-03-01

    The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear hormone receptor. It is predominantly expressed in adipose tissue and as a receptor for thiazolidinediones, it has drawn attentions towards itself as a key molecule to trigger pathways involving in some diseases such as cancers, type 2 diabetes, inflammations and osteoporosis. A proline changed to alanine in codon 12 of PPAR-γ gene (Pro12Ala) has been known to be responsible for decreased risk of type 2 diabetes. The aim of the present study is to investigate the frequency of Pro12Ala polymorphism in PPAR-γ in healthy Iranian population to compare with other populations. Understanding this polymorphism may help us in better diagnosis, prevention, and therapeutic approaches toward a better management of diseases such as type 2 diabetes and osteoporosis. 128 healthy volunteers were enrolled in this study. To determine single nucleotide polymorphisms (SNPs), we did real time polymerase chain reaction (RT-PCR), using TaqMan allelic discrimination assays. Genotype frequencies for PPAR-γ gene Pro12Ala (rs1801282) polymorphism were 0.86 for CC, 0.14 for CG, 0.00 for GG while allelic frequencies were 0.93 and 0.0.07 for C and G, respectively. There are statistical differences between the distribution of the PPAR-γ-2 Pro12Ala polymorphism in other populations and Iranian population.

  8. CRISPR Technology for Genome Activation and Repression in Mammalian Cells.

    Science.gov (United States)

    Du, Dan; Qi, Lei S

    2016-01-04

    Targeted modulation of transcription is necessary for understanding complex gene networks and has great potential for medical and industrial applications. CRISPR is emerging as a powerful system for targeted genome activation and repression, in addition to its use in genome editing. This protocol describes how to design, construct, and experimentally validate the function of sequence-specific single guide RNAs (sgRNAs) for sequence-specific repression (CRISPRi) or activation (CRISPRa) of transcription in mammalian cells. In this technology, the CRISPR-associated protein Cas9 is catalytically deactivated (dCas9) to provide a general platform for RNA-guided DNA targeting of any locus in the genome. Fusion of dCas9 to effector domains with distinct regulatory functions enables stable and efficient transcriptional repression or activation in mammalian cells. Delivery of multiple sgRNAs further enables activation or repression of multiple genes. By using scaffold RNAs (scRNAs), different effectors can be recruited to different genes for simultaneous activation of some and repression of others. The CRISPRi and CRISPRa methods provide powerful tools for sequence-specific control of gene expression on a genome-wide scale to aid understanding gene functions and for engineering genetic regulatory systems.

  9. Percept-genetic signs of repression in histrionic personality disorder.

    Science.gov (United States)

    Rubino, I A; Saya, A; Pezzarossa, B

    1992-04-01

    Several types of perceptual distortions of two anxiety-arousing visual stimuli are coded as repression in the Defense Mechanism Test, a tachistoscopic, percept-genetic technique. Given the well-established correspondence between hysteria and repression, the study included a clinical validation of these variants of repression against the diagnosis of histrionic personality disorder. 41 subjects with evidence of this disorder on the Millon Clinical Multiaxial Inventory-II were compared with 41 nonhistrionic controls. Significantly more histrionics were coded for the type of repression in which the threatening figure is transformed into a harmless object (code 1:42), while animal- and statue-repressions, when combined (codes 1:1 and 1:2), were significantly more characteristic of the nonhistrionic group. As an unpredicted finding, significantly more histrionic subjects employed defensive strategies, currently coded as reaction formations (code 4:). Histrionic subjects without concomitant compulsive features were coded more frequently for introaggression (code 6:) compared both with nonhistrionic controls and with histrionic-compulsive subjects. The findings are discussed within the context of the available percept-genetic literature. It is suggested that the Defense Mechanism Test may be further employed to objectify and investigate the defense mechanisms of the DSM-III-R disorders.

  10. Ethical issues in the search for repressed memories.

    Science.gov (United States)

    Merskey, H

    1996-01-01

    Currently, concepts of repression and dissociation are in flux. It has been pointed out that there is no scientific evidence for the occurrence of repression and that the whole notion is anecdotal. Dissociation, which is offered as an alternative to repression, cannot logically be held to operate without a motive force, as Freud argued, or a weakness of the organism, as Janet proposed. The concepts have been applied particularly to the idea that early childhood experience could be repressed but recovered many years later. This claim is at variance with established knowledge concerning human memory. Practices of subtle and overt suggestion, employed in recovered-memory treatments, give rise to a false-memory syndrome in which individuals, who have undergone various levels of suggestion, accuse their parents and others of childhood sexual abuse. The common phenomenon of childhood sexual abuse is contaminated by many cases that may be regarded on strong grounds as being false and have been retracted in more than 1,000 instances. Repressed-memory (RM) treatment is also at variance with traditional psychotherapy, which does not encourage confrontation on the basis of uncorroborated information; moreover, many cases of RM therapy seem to result in deterioration. Unlike traditional psychotherapy, some RM practitioners strongly encourage patients to hate individuals in their family circle. The consequences of these developments, the need for informed consent, and the development of legislative initiatives to challenge RM therapy are noted. The impact of these therapies and proposed legislation upon regular psychotherapy and psychiatry is outlined.

  11. Association of PPAR Alpha Intron 7 G/C, PPAR Gamma 2 Pro12Ala, and C161T Polymorphisms with Serum Fetuin-A Concentrations.

    Science.gov (United States)

    Márkus, Bernadett; Vörös, Krisztián; Supák, Dorina; Melczer, Zsolt; Cseh, Károly; Kalabay, László

    2017-01-01

    Both peroxisome activator proteins (PPARs) and fetuin-A play a role in lipid and glucose metabolism. We investigated whether PPARα intron 7 G2468/C and PPARγ2 Pro12Ala and PPARγ exon 6 C161T polymorphisms are associated with serum fetuin-A concentrations. The PPARα intron 7 G/C polymorphism was studied in cohort 1 (79 reference individuals, 165 postinfarction patients). The two PPARγ polymorphisms were investigated in cohort 2 (162 reference individuals, 165 postinfarction patients). Fetuin-A levels and PPAR polymorphisms were determined by radial immunodiffusion and polymerase chain reaction-restriction fragment length polymorphism techniques. The C allele variant of PPARα intron 7 G2467C was associated with higher fetuin-A levels (p = 0.018). Postinfarction status (p = 0.001), PPARα intron 7 GG/GC/CC genotypes (p = 0.032), and the C allele (p = 0.021) were the strongest determinants of fetuin-A concentration in a multiple regression model. Higher fetuin-A levels were associated with the Pro variant of PPARγ2 (p = 0.047). Postinfarction status (p = 0.041) and BMI (p < 0.001) but not PPARγ2 Pro were the strongest determinants of fetuin-A concentrations. PPARγ exon 6 C161T genotypes were not associated with fetuin-A levels. Fetuin-A was determined mainly by the PPARα intron 7C allele and postinfarction status in cohort 1 and the BMI and postinfarction in cohort 2. The PPARα intron 7C and PPARγ2 Pro variants are associated with fetuin-A levels.

  12. THE DEVELOPMENT OF AN IN VITRO ASSAY FOR EVALUATING THE BINDING OF PERFLUOROALKYL ACIDS (PFAAS) TO THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARS)

    Science.gov (United States)

    The purpose of this work was to evaluate the binding of PFAAs to PPAR receptors and determine the potential for activation or antagonism of the pathway during embryonic development. Activation of mouse and human PPAR isoforms by perfluorooctanoic acid (PFOA) and perfluorooctanes...

  13. PPARα Promotes Cancer Cell Glut1 Transcription Repression.

    Science.gov (United States)

    You, Mengli; Jin, Jianhua; Liu, Qian; Xu, QingGang; Shi, Juanjuan; Hou, Yongzhong

    2017-06-01

    Abundant nutrient availability including glucose and amino acids plays an important role in maintaining cancer cell energetic and biosynthetic pathways. As a nuclear receptor, peroxisome-proliferator-activated receptor α (PPARα) regulates inflammation and cancer progression, however, it is still unclear the interaction of PPARα with the cancer cell glucose metabolism. Here we found that PPARα reduced Glut1 (Glucose transporter 1) protein and gene levels in HCT-116, SW480, HeLa, and MCF-7 cancer cell lines. In contrast, silenced PPARα reversed this event. Further analysis shows that PPARα directly targeted the consensus PPRE motif of Glut1 promoter region resulting in Glut1 transcription repression. PPARα-mediated Glut1 transcription repression led to decreased influx of glucose in cancer cells. These findings revealed a novel mechanism of PPARα-mediated cancer cell Glut1 transcription repression. J. Cell. Biochem. 118: 1556-1562, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  14. Suppression and repression: A theoretical discussion illustrated by a movie

    Directory of Open Access Journals (Sweden)

    Maria Lucia de Souza Campos Paiva

    2012-02-01

    Full Text Available The first translations of Freud's work into Portuguese have presented problems because they were not translated from the German language. More than a hundred years after the beginning of Psychoanalysis, there are still many discussions on Freud's metapsychology and a considerable difficulty in obtaining a consensus on the translation of some concepts. This paper refers back to Freud's concepts of primal repression, repression and suppression. In order to discuss such concepts, we have made use of a film, co-produced by Germans and Argentineans, which is named "The Song in me" (Das Lied in mir, released to the public in 2011 and directed by Florian Micoud Cossen. Through this motion picture, the following of Freud's concepts are analyzed, and the differentiation between them is discussed: suppression and repression, as well as the importance of their precise translation.

  15. 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.

  16. Plasma cortisol and noradrenalin concentrations in pigs: automated sampling of freely moving pigs housed in PigTurn versus manually sampled and restrained pigs

    Science.gov (United States)

    Minimizing the effects of restraint and human interaction on the endocrine physiology of animals is essential for collection of accurate physiological measurements. Our objective was to compare stress-induced cortisol (CORT) and noradrenalin (NorA) responses in automated versus manual blood sampling...

  17. Responses to noradrenaline of tail arteries in hypertensive, hypotensive and normotensive rats under different regimens of perfusion: role of the myogenic response

    DEFF Research Database (Denmark)

    Matchkov, Vladimir; Vlasova, Maria A; Tarasova, Olga S;

    1998-01-01

    The vasoconstrictor effects of noradrenaline were studied in spontaneously hypertensive rats (SHR) compared with Wistar Kyoto rats (WKY), and in Wistar rats with regional hypotension (WH) compared to control Wistar rats (WC). The abdominal aorta was ligated in WH distal to the renal arteries...... thickness causing different degrees of activation of the myogenic response to distension....

  18. Ca(2+) sensitisation of force production by noradrenaline in femoral conductance and resistance arteries from rats with postinfarction congestive heart failure

    DEFF Research Database (Denmark)

    Trautner, Simon; Amtorp, Ole; Boesgaard, Soren

    2006-01-01

    In this study we tested the hypothesis that arterial myofilament Ca(2+) sensitivity and/or the Ca(2+) sensitising effect of noradrenaline (NA) is enhanced in post-infarction congestive heart failure (CHF), which could contribute to the high peripheral vascular resistance in this condition. Femora...

  19. Metabolism of (/sup 3/H)noradrenaline in different compartments of rat brain with respect to the role of catechol-O-methyltransferase

    Energy Technology Data Exchange (ETDEWEB)

    Koester, G.; Goede, E.; Breuer, H.

    1984-03-01

    Rats were pretreated with either reserpine or desmethylimipramine, either alone or in combination with tropolone. At either 10 min or 1 h after the intraventricular injection of (/sup 3/H)noradrenaline, in several brain regions the complete metabolic patterns were determined: normetanephrine; the glycol metabolites (methylated and nonmethylated) and their sulfate conjugates; and the acidic metabolites (methylated and non-methylated). A reserpine-induced increase in the turnover of (/sup 3/H)noradrenaline caused a transient increase of the catechol glycol followed by elevated levels of the two glycol sulfates. The stimulated (/sup 3/H)noradrenaline turnover if achieved by desmethylimipramine caused a transient increase of normetanephrine and initially lowered values of catechol glycols (both free and sulfated), which were followed by elevated levels. Drug-pretreated rats compensated for the inhibition of catechol-O-methyl-transferase by tropolone in different ways: Reserpine caused an early increase of the catechol glycol beyond the measurements in other treatment groups, whereas desmethylimipramine increased the nonmethylated carboxylic acid and glycol sulfates rather slowly to levels beyond those of other groups. The results support the existence of two compartments with a fast metabolism (an intraneuronal monoamine oxidase compartment and an extraneuronal catechol-O-methyltransferase compartment). In addition, there seems to exist another extra-neuronal space with a slow, monoamine oxidase-dependent noradrenaline turnover.

  20. Histaminergic H1 and H2 Receptors Mediate the Effects of Propofol on the Noradrenalin-Inhibited Neurons in Rat Ventrolateral Preoptic Nucleus.

    Science.gov (United States)

    Liu, Yang; Zhang, Yu; Qian, Kun; Zhang, Lin; Yu, Tian

    2017-02-09

    The ventrolateral preoptic nucleus is a sleep-promoting nucleus located in the basal forebrain. A commonly used intravenous anesthetic, propofol, had been reported to induce sleep spindles and augment the firing rate of neurons in ventrolateral preoptic nucleus, but the underlining mechanism is yet to be known. By using patch clamp recording on neuron in acute brain slice, present study tested if histaminergic H1 and H2 receptors play a role in the effect of propofol on the noradrenalin-inhibited neurons in ventrolateral preoptic nucleus. We found that the firing rate of noradrenalin-inhibited neurons were significantly augmented by propofol; the frequency of inhibitory postsynaptic currents of noradrenalin-inhibited neuron were evidently attenuated by propofol; such inhibition effect was suppressed by histamine; and both triprolidine (antagonist for H1 histamine receptor) and ranitidine (antagonist for H2 histamine receptor) were able to increase the inhibition rate of propofol in presence of histamine. Present study demonstrated that propofol-induced inhibition of inhibitory postsynaptic currents on noradrenalin-inhibited neurons were mediated by histaminergic H1 and H2 receptors.

  1. 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

  2. Increased Contractile Response to Noradrenaline Induced By Factors Associated with the Metabolic Syndrome in Cultured Small Mesenteric Arteries

    DEFF Research Database (Denmark)

    Blædel, Martin; Sams, Anette; Boonen, Harrie C M

    2016-01-01

    UNLABELLED: This study investigated the effect of the metabolic syndrome associated risk factors hyperglycemia (glucose [Glc]), hyperinsulinemia (insulin [Ins]) and low-grade inflammation (tumor necrosis factor α [TNFα]) on the vasomotor responses of resistance arteries. Isolated small mesenteric...... arteries from 3-month-old Sprague-Dawley rats, were suspended for 21-23 h in tissue cultures containing either elevated Glc (30 mmol/l), Ins (100 nmol/l), TNFα (100 ng/ml) or combinations thereof. After incubation, the vascular response to noradrenaline (NA), phenylephrine, isoprenaline and NA...... in the presence of propranolol (10 µmol/l) was measured by wire myography. RESULTS: Arteries exposed only to combinations of the risk factors showed a significant 1.6-fold increase in the contractile NA sensitivity, which suggests that complex combinations of metabolic risk factors might lead to changes...

  3. Quantitative gene expression of somatostatin receptors and noradrenaline transporter underlying scintigraphic results in patients with neuroendocrine tumors

    DEFF Research Database (Denmark)

    Binderup, Tina; Knigge, Ulrich; Mellon Mogensen, Anne

    2008-01-01

    AIM: To measure, by a quantitative approach, the gene expression underlying the results of somatostatin receptor (sst) scintigraphy ((111)In-DTPA-octreotide) and noradrenaline transporter (NAT) scintigraphy ((123)I-MIBG) in patients with neuroendocrine (NE) tumors. METHODS: The gene expression...... of somatostatin receptors 1-5 (sst) and NAT was measured quantitatively by real-time PCR in a group of patients with NE tumors (n = 14) and compared to a group of patients with colorectal adenocarcinomas (n = 15). If available, scintigraphic results were compared with gene expression results (9 octreotide and 3...... in gene expression of sst(2) corresponded with scintigraphic results. Our data support that sst(2) is the best target for visualization of NE tumors, whereas NAT is only a useful target in a subpopulation of NE tumors. Comparison of scintigraphic results with quantitative gene expression may be used...

  4. Complexes of osmium, uranium, molybdenum, and tungsten with the catechol amines adrenaline, noradrenaline, dopamine, dopa, and isoproterenol

    Energy Technology Data Exchange (ETDEWEB)

    El-Hendawy, A.M.; Griffith, W.P.; Pumphrey, C.A.

    1988-07-01

    New complexes of the form trans-(OsO/sub 2/L/sub 2/)/sup 2-/ and UO/sub 2/Lcenter dotnH/sub 2/O (H/sub 2/L = adrenaline (H/sub 2/ad), noradrenaline (H/sub 2/nad), dopamine (H/sub 2/dpm), dopa (H/sub 2/dp), and isoproterenol (H/sub 2/prot)) are reported, as are cis(MO/sub 2/L/sub 2/)/sup 2-/(L = nad, dp, prot for M = Mo or W, and ad for M = W), (MO/sub 2/(Hdpm)/sub 2/) (M = Mo or W), and (Mo/sub 2/O/sub 5/(Had)/sub 2/). The structures of these species are discussed on the basis of their Raman, infrared, /sup 1/H and /sup 13/C n.m.r. spectra.

  5. Inhibitory action of niflumic acid on noradrenaline- and 5-hydroxytryptamine-induced pressor responses in the isolated mesenteric vascular bed of the rat.

    Science.gov (United States)

    Criddle, D N; de Moura, R S; Greenwood, I A; Large, W A

    1997-03-01

    1. The effects of niflumic acid, an inhibitor of calcium-activated chloride currents, were compared with the actions of the calcium channel blocker nifedipine on noradrenaline- and 5-hydroxytryptamine (5-HT)-induced pressor responses of the rat perfused isolated mesenteric vascular bed. 2. Bolus injections of noradrenaline (1 and 10 nmol) increased the perfusion pressure in a dose-dependent manner. Nifedipine (1 microM) inhibited the increase in pressure produced by 1 nmol noradrenaline by 31 +/- 5%. Niflumic acid (10 and 30 microM) also inhibited the noradrenaline-induced increase in perfusion pressure and 30 microM niflumic acid reduced the pressor response to 1 nmol noradrenaline by 34 +/- 6%. 3. The increases in perfusion elicited by 5-HT (0.3 and 3 nmol) were reduced by niflumic acid (10 and 30 microM) in a concentration-dependent manner and 30 microM niflumic acid inhibited responses to 0.3 and 3 nmol 5-HT by, respectively, 49 +/- 8% and 50 +/- 7%. Nifedipine (1 microM) decreased the pressor response to 3 nmol 5-HT by 44 +/- 9%. 4. In the presence of a combination of 30 microM niflumic acid and 1 microM nifedipine the inhibition of the pressor effects of noradrenaline (10 nmol) and 5-HT (3 nmol) was not significantly greater than with niflumic acid (30 microM) alone. Thus the effects of niflumic acid and nifedipine were not additive. 5. In Ca-free conditions the transient contractions induced by 5-HT (3 nmol) were not reduced by 30 microM niflumic acid, suggesting that this agent does not inhibit calcium release from the intracellular store or the binding of 5-HT to its receptor. 6. Niflumic acid 30 microM did not inhibit the pressor responses induced by KCl (20 and 60 mumol) which were markedly reduced by 1 microM nifedipine. In addition, 1 microM levcromakalim decreased pressor responses produced by 20 mumol KCl. These data suggest that niflumic acid does not block directly calcium channels or activate potassium channels. 7. It is concluded that niflumic

  6. Synthesis and evaluation of a bromine-76-labeled PPAR{gamma} antagonist 2-bromo-5-nitro-N-phenylbenzamide

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hsiaoju [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Finck, Brian N. [Department of Internal Medicine, Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis. MO 63110 (United States); Jones, Lynne A. [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Welch, Michael J. [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Mach, Robert H. [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States)]. E-mail: rhmach@mir.wustl.edu

    2006-10-15

    Peroxisome proliferator activated-receptor gamma (PPAR{gamma}) binds to peroxisome receptor response elements with its heterodimeric partner, retinoid X receptor, and regulates downstream gene expression. PPAR{gamma} transcriptionally modulates fat metabolism, and receptor agonists have been developed to treat type II diabetes. PPAR{gamma} is also overexpressed in some tumor cell lines and primary tumors, including breast and prostate tumors. Two PPAR{gamma} antagonists, 2-chloro-5-nitro-N-phenylbenzamide (GW9662) and 2-chloro-5-nitro-N-pyridin-4-yl-benzamide (T0070907), represent good lead compounds for radiotracer development. In the current study, four additional halogen substituted analogs were synthesized and evaluated in a whole cell screening assay for PPAR{gamma} binding activity. Two bromine-containing analogs having EC{sub 5} values <5 nM were chosen for bromine-76 radiolabeling. Bromine-76-labeled 2-bromo-5-nitro-N-phenyl-benzamide was selected for subsequent in vitro and in vivo studies due to its superior radiolabeling yield ({approx}70%) and the well-characterized pharmacological properties of its analog GW9662. An in vitro stability study showed that 40% of the compound remained intact in plasma and about 25% in whole blood after 30 min. Biodistribution studies in MDA-MB-435 human breast tumor-bearing nude mice were carried out at 5 min, 30 min, 2 h and 24 h post injection of the radiotracer. Although in vivo metabolite studies demonstrated rapid compound degradation, at least 10% of the parent compound was delivered to the tumor. We are currently exploring second generation analogs of these lead compounds for the development of radiolabeled antagonists of the PPAR{gamma} receptor.

  7. 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.

  8. Political Repressions in USSR (Against Speculations, Perversion and Mystifications)

    OpenAIRE

    2012-01-01

    In the article the great numbers of political repressions, which were exaggerated by authors: R.A. Medvedev, A.I. Solzhenitsyn, O.G. Shatunovskoy, A.V. Antonov-Ovseenko in 80-90s are criticized. The author characterizes figures given in tens and even in hundreds of millions of victims as a statistical charlatanism.After checking up the KGB archives, and documents of division responsible for NKVD-MVD special settlements, the author spills the light on real numbers of political repressions in U...

  9. Chromatin Repressive Complexes in Stem Cells, Development, and Cancer

    DEFF Research Database (Denmark)

    Laugesen, Anne; Helin, Kristian

    2014-01-01

    of the polycomb repressive complexes, PRC1 and PRC2, and the HDAC1- and HDAC2-containing complexes, NuRD, Sin3, and CoREST, in stem cells, development, and cancer, as well as the ongoing efforts to develop therapies targeting these complexes in human cancer. Furthermore, we discuss the role of repressive......The chromatin environment is essential for the correct specification and preservation of cell identity through modulation and maintenance of transcription patterns. Many chromatin regulators are required for development, stem cell maintenance, and differentiation. Here, we review the roles...... complexes in modulating thresholds for gene activation and their importance for specification and maintenance of cell fate....

  10. Mechanisms of transcriptional repression by histone lysine methylation

    DEFF Research Database (Denmark)

    Hublitz, Philip; Albert, Mareike; Peters, Antoine H F M

    2009-01-01

    . In this report, we review the recent literature to deduce mechanisms underlying Polycomb and H3K9 methylation mediated repression, and describe the functional interplay with activating H3K4 methylation. We summarize recent data that indicate a close relationship between GC density of promoter sequences......, transcription factor binding and the antagonizing activities of distinct epigenetic regulators such as histone methyltransferases (HMTs) and histone demethylases (HDMs). Subsequently, we compare chromatin signatures associated with different types of transcriptional outcomes from stable repression to highly...... dynamic regulated genes, strongly suggesting that the interplay of different epigenetic pathways is essential in defining specific types of heritable chromatin and associated transcriptional states....

  11. Nitrogen catabolite repression of asparaginase II in Saccharomyces cerevisiae.

    OpenAIRE

    Dunlop, P C; Meyer, G M; Roon, R J

    1980-01-01

    The biosynthesis of asparaginase II in Saccharomyces cerevisiae is subject to strong catabolite repression by a variety of nitrogen compounds. In the present study, asparaginase II synthesis was examined in a wild-type yeast strain and in strains carrying gdhA, gdhCR, or gdhCS mutations. The following effects were observed: (i) In the wild-type strain, the biosynthesis of asparaginase II was strongly repressed when either 10 mM ammonium sulfate or various amino acids (10 mM) served as the sou...

  12. Extremadura: Behind the material traces of Franco’s repression

    OpenAIRE

    Muñoz Encinar, Laura; Chaves Palacios, Julián

    2014-01-01

    After the failed coup d’état of July 17th, 1936 and after the start of the Spanish Civil War that followed it, rebels carried out a repressive strategy based on the execution of thousands of people as a key tool of social control. The socialization of fear and terror through humiliation, killing and disappearance would become the main strategy employed throughout the war and the post-war period. In this context, perpetrators would exercise repressive practices on victims and their bodies. As ...

  13. Chronic sleep restriction induces long-lasting changes in adenosine and noradrenaline receptor density in the rat brain

    Science.gov (United States)

    WEISSHAUPT, ANGELA; WEDEKIND, FRANZISKA; KROLL, TINA; MCCARLEY, ROBERT W.

    2015-01-01

    SUMMARY Although chronic sleep restriction frequently produces long-lasting behavioural and physiological impairments in humans, the underlying neural mechanisms are unknown. Here we used a rat model of chronic sleep restriction to investigate the role of brain adenosine and noradrenaline systems, known to regulate sleep and wakefulness, respectively. The density of adenosine A1 and A2a receptors and β-adrenergic receptors before, during and following 5 days of sleep restriction was assessed with autoradiography. Rats (n = 48) were sleep-deprived for 18 h day–1 for 5 consecutive days (SR1–SR5), followed by 3 unrestricted recovery sleep days (R1–R3). Brains were collected at the beginning of the light period, which was immediately after the end of sleep deprivation on sleep restriction days. Chronic sleep restriction increased adenosine A1 receptor density significantly in nine of the 13 brain areas analysed with elevations also observed on R3 (+18 to +32%). In contrast, chronic sleep restriction reduced adenosine A2a receptor density significantly in one of the three brain areas analysed (olfactory tubercle which declined 26–31% from SR1 to R1). A decrease in b-adrenergic receptors density was seen in substantia innominata and ventral pallidum which remained reduced on R3, but no changes were found in the anterior cingulate cortex. These data suggest that chronic sleep restriction can induce long-term changes in the brain adenosine and noradrenaline receptors, which may underlie the long-lasting neurocognitive impairments observed in chronic sleep restriction. PMID:25900125

  14. Protocol for a randomised controlled trial of VAsopressin versus Noradrenaline as Initial therapy in Septic sHock (VANISH).

    Science.gov (United States)

    Gordon, Anthony C; Mason, Alexina J; Perkins, Gavin D; Ashby, Deborah; Brett, Stephen J

    2014-07-03

    Vasopressin is an alternative vasopressor in the management of septic shock. It spares catecholamine use but whether it improves outcome remains uncertain. Current evidence suggests that it may be most effective if used early and possibly in conjunction with corticosteroids. This trial will compare vasopressin to noradrenaline as initial vasopressor in the management of adult septic shock and investigate whether there is an interaction of vasopressin with corticosteroids. This is a multicentre, factorial (2×2), randomised, double-blind, placebo-controlled trial. 412 patients will be recruited from multiple UK intensive care units and randomised to receive vasopressin (0-0.06 U/min) or noradrenaline (0-12 µg/min) as a continuous intravenous infusion as initial vasopressor therapy. If maximum infusion rates of this first study drug are reached, the patient will be treated with either hydrocortisone (initially 50 mg intravenous bolus six-hourly) or placebo, before additional open-label catecholamine vasopressors are prescribed. The primary outcome of the trial will be the difference in renal failure-free days between treatment groups. Secondary outcomes include need for renal replacement therapy, survival rates, other organ failures and resource utilisation. The trial protocol and information sheets have received a favourable opinion from the Oxford A Research Ethics Committee (12/SC/0014). There is an independent Data Monitoring and Ethics Committee and independent membership of the Trial Steering Committee including patient and public involvement. The trial results will be published in peer-reviewed journals and presented at national and international scientific meetings. ISRCTN 20769191 and EudraCT 2011-005363-24. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  15. Effects of chronic and acute oestrogen treatment on the developing noradrenaline-containing nerves of the rat uterus.

    Science.gov (United States)

    Brauer, M M; Corbacho, A M; Burnstock, G

    1995-12-01

    The developing noradrenaline-containing (NA-C) sympathetic nerves of the rat uterus were analyzed following acute and chronic treatment with oestrogen. Histochemical methods were used in association with nerve density measurements and biochemical assays. For comparative purposes, noradrenaline (NA) levels were measured in the urinary bladder and right auricle following chronic oestrogen treatment. Acute treatment was performed by s.c. administration of a single dose of 40 micrograms oestradiol cypionate on the 25th day of age. Chronic treatment consisted of four doses of 10 micrograms oestradiol on days 10, 15, 20 and 25 of postnatal development. Both acute- and chronic-treated animals were killed at 28 days of age. The main biochemical findings were the following: (a) both acute and chronic oestrogen treatment increased the weight of the uterine horn, parametrial tissue and uterine cervix; (b) in the uterine horn, the total content of NA was reduced following both oestrogen treatments. However, the degree of reduction was greater after chronic treatment; (c) in the parametrial tissue, the NA levels were reduced only after chronic treatment; (d) in the cervix, the NA total content was increased after both treatments; (e) in the urinary bladder, there was a parallel increase between organ growth and NA content following chronic oestrogen treatment; (e) in the auricle neither the tissue weight nor the total content of NA were changed by chronic estrogen treatment. Histochemical studies showed that: (a) acute treatment with one single dose of oestradiol, provoked a marked reduction in the density of NA-C nerves associated with the myometrial and parametrial smooth muscle, without affecting the innervation of blood vessels; (b) following chronic treatment, the only fibers we were able to recognize were those associated with blood vessels. These fibers were thinner and less intensely fluorescent than in controls. Results are interpreted considering the differential

  16. The effects of compound stimulus extinction and inhibition of noradrenaline reuptake on the renewal of alcohol seeking

    Science.gov (United States)

    Furlong, T M; Pan, M J; Corbit, L H

    2015-01-01

    Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli can reduce their impact on relapse; however, the expression of extinction can be disrupted when testing occurs outside the context where extinction learning took place, an effect termed renewal. Behavioral and pharmacological methods have recently been shown to augment extinction learning; yet, it is not known whether the improved expression of extinction following these treatments remains context-dependent. Here we examined whether two methods, compound–stimulus extinction and treatment with the noradrenaline reuptake inhibitor atomoxetine, would reduce the vulnerability of extinction to a change in context. Following alcohol self-administration, responding was extinguished in a distinct context. After initial extinction, further extinction was given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg kg−1; Experiment 2). A stimulus extinguished as part of a compound elicited less responding than a stimulus receiving equal extinction alone regardless of whether animals were tested in the training or extinction context; however, reliable renewal was not observed in this paradigm. Importantly, atomoxetine enhanced extinction relative to controls even in the presence of a reliable renewal effect. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Importantly, both methods improve extinction even when the context is changed between extinction training and test, and thus could be utilized to enhance the outcome of extinction-based treatments for alcohol-use disorders. PMID:26327688

  17. A Reexamination of the PPAR-α Activation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants

    Science.gov (United States)

    Guyton, Kathryn Z.; Chiu, Weihsueh A.; Bateson, Thomas F.; Jinot, Jennifer; Scott, Cheryl Siegel; Brown, Rebecca C.; Caldwell, Jane C.

    2009-01-01

    Background Diverse environmental contaminants, including the plasticizer di(2-ethylhexyl)phthalate (DEHP), are hepatocarcinogenic peroxisome proliferators in rodents. Peroxisome proliferator–activated receptor-α (PPAR-α) activation and its sequelae have been proposed to constitute a mode of action (MOA) for hepatocarcinogenesis by such agents as a sole causative factor. Further, based on a hypothesized lower sensitivity of humans to this MOA, prior reviews have concluded that rodent hepatocarcinogenesis by PPAR-α agonists is irrelevant to human carcinogenic risk. Data synthesis Herein, we review recent studies that experimentally challenge the PPAR-α activation MOA hypothesis, providing evidence that DEHP is hepatocarcinogenic in PPAR-α–null mice and that the MOA but not hepatocarcinogenesis is evoked by PPAR-α activation in a transgenic mouse model. We further examine whether relative potency for PPAR-α activation or other steps in the MOA correlates with tumorigenic potency. In addition, for most PPAR-α agonists of environmental concern, available data are insufficient to characterize relative human sensitivity to this rodent MOA or to induction of hepatocarcinogenesis. Conclusions Our review and analyses raise questions about the hypothesized PPAR-α activation MOA as a sole explanation for rodent hepatocarcinogenesis by PPAR-α agonists and therefore its utility as a primary basis for assessing human carcinogenic risk from the diverse compounds that activate PPAR-α. These findings have broad implications for how MOA hypotheses are developed, tested, and applied in human health risk assessment. We discuss alternatives to the current approaches to these key aspects of mechanistic data evaluation. PMID:20049115

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

    Science.gov (United States)

    Lecarpentier, Yves; Claes, Victor; Duthoit, Guillaume; Hébert, Jean-Louis

    2014-01-01

    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, hypertension, diabetes

  19. Downregulation of peroxisome proliferator-activated receptors (PPARs in nasal polyposis

    Directory of Open Access Journals (Sweden)

    Adner Mikael

    2005-11-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptor (PPAR α, βδ and γ are nuclear receptors activated by fatty acid metabolites. An anti-inflammatory role for these receptors in airway inflammation has been suggested. Methods Nasal biopsies were obtained from 10 healthy volunteers and 10 patients with symptomatic allergic rhinitis. Nasal polyps were obtained from 22 patients, before and after 4 weeks of local steroid treatment (fluticasone. Real-time RT-PCR was used for mRNA quantification and immunohistochemistry for protein localization and quantification. Results mRNA expression of PPARα, PPARβδ, PPARγ was found in all specimens. No differences in the expression of PPARs were obtained in nasal biopsies from patients with allergic rhinitis and healthy volunteers. Nasal polyps exhibited lower levels of PPARα and PPARγ than normal nasal mucosa and these levels were, for PPARγ, further reduced following steroid treatment. PPARγ immunoreactivity was detected in the epithelium, but also found in smooth muscle of blood vessels, glandular acini and inflammatory cells. Quantitative evaluation of the epithelial immunostaining revealed no differences between nasal biopsies from patients with allergic rhinitis and healthy volunteers. In polyps, the PPARγ immunoreactivity was lower than in nasal mucosa and further decreased after steroid treatment. Conclusion The down-regulation of PPARγ, in nasal polyposis but not in turbinates during symptomatic seasonal rhinitis, suggests that PPARγ might be of importance in long standing inflammations.

  20. PPAR-α Agonist Fenofibrate Decreased RANTES Levels in Type 2 Diabetes Patients with Hypertriglyceridemia.

    Science.gov (United States)

    Feng, Xiaomeng; Gao, Xia; Jia, Yumei; Zhang, Heng; Xu, Yuan; Wang, Guang

    2016-03-05

    BACKGROUND Regulated upon activation, normal T cells expressed and secreted (RANTES) is associated with inflammation and atherosclerosis. We investigated the effect of fenofibrate, a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, on RANTES in type 2 diabetes mellitus (T2DM) patients with hypertriglyceridemia. MATERIAL AND METHODS This study evaluated cross-sectional and interventional studies of 25 T2DM patients with hypertriglyceridemia (group A) and 32 controls (group B). Group A was treated with fenofibrate (200 mg/day) for 8 weeks. Serum RANTES and clinical characteristics were examined. RESULTS Serum RANTES was significantly higher in group A compared with group B (59.04±16.74 vs. 38.57±12.98 ng/ml, Phypertriglyceridemia (β=11.496, P=0.002) were independently related to high serum RANTES levels. After 8 weeks of fenofibrate treatment, serum RANTES significantly decreased in group A compared with baseline (52.75±17.41 vs. 59.04±16.74 ng/ml, P=0.018). CONCLUSIONS Fenofibrate decreased serum RANTES levels in T2DM patients with hypertriglyceridemia, indicating that PPAR-a agonists may play an important role in inhibiting inflammatory responses.

  1. Cardioprotective effect of the PPAR ligand tetradecylthioacetic acid in type 2 diabetic mice.

    Science.gov (United States)

    Khalid, Ahmed M; Hafstad, Anne Dragøy; Larsen, Terje S; Severson, David L; Boardman, Neoma; Hagve, Martin; Berge, Rolf K; Aasum, Ellen

    2011-06-01

    Tetradecylthioacetic acid (TTA) is a novel peroxisome proliferator-activated receptor (PPAR) ligand with marked hypolipidemic and insulin-sensitizing effects in obese models. TTA has recently been shown to attenuate dyslipidemia in patients with type 2 diabetes, corroborating the potential for TTA in antidiabetic therapy. In a recent study on normal mice, we showed that TTA increased myocardial fatty acid (FA) oxidation, which was associated with decreased cardiac efficiency and impaired postischemic functional recovery. The aim of the present study was, therefore, to elucidate the effects of TTA treatment (0.5%, 8 days) on cardiac metabolism and function in a hyperlipidemic type 2 diabetic model. We found that TTA treatment increased myocardial FA oxidation, not only in nondiabetic (db/+) mice but also in diabetic (db/db) mice, despite a clear lipid-lowering effect. Although TTA had deleterious effects in hearts from nondiabetic mice (decreased efficiency and impaired mitochondrial respiratory capacity), these effects were not observed in db/db hearts. In db/db hearts, TTA improved ischemic tolerance, an effect that is most likely related to the antioxidant property of TTA. The present study strongly advocates the need for investigation of the cardiac effects of PPAR ligands used in antidiabetic/hypolipidemic therapy, because of their pleiotropic properties.

  2. Metabolic syndrome and type 2 diabetes mellitus: focus on peroxisome proliferator activated receptors (PPAR

    Directory of Open Access Journals (Sweden)

    Fisman Enrique Z

    2003-03-01

    Full Text Available Abstract The metabolic syndrome is a highly prevalent clinical entity. The recent Adult Treatment Panel (ATP III guidelines have called specific attention to the importance of targeting the cardiovascular risk factors of the metabolic syndrome as a method of risk reduction therapy. The main factors characteristic of this syndrome are abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance (with or without glucose intolerance, prothrombotic and proinflammatory states. An insulin resistance following nuclear peroxisome proliferator activated receptors (PPAR deactivation (mainly obesity-related is the key phase of metabolic syndrome initiation. Afterwards, there are 2 principal pathways of metabolic syndrome development: 1 with preserved pancreatic beta cells function and insulin hypersecretion which can compensate for insulin resistance. This pathway leads mainly to the macrovascular complications of metabolic syndrome; 2 with massive damage of pancreatic beta cells leading to progressively decrease of insulin secretion and to hyperglycemia (e.g. overt type 2 diabetes. This pathway leads to both microvascular and macrovascular complications. We suggest that a PPAR-based appraisal of metabolic syndrome and type 2 diabetes may improve our understanding of these diseases and set a basis for a comprehensive approach in their treatment.

  3. Financial repression, money growth, and seignorage: The Polish experience

    NARCIS (Netherlands)

    Aarle, B. van; Budina, N.

    1997-01-01

    Financial Repression, Money Growth and Seignorage: The Polish Experience. — A small analytical framework is developed to analyze the relation between reserve requirements, base money growth and seignorage revenues. From the analysis, the authors can derive of steady-state seignorage revenues as a

  4. PICKLE acts during germination to repress expression of embryonic traits

    Science.gov (United States)

    Li, Hui-Chun; Chuang, King; Henderson, James T.; Rider, Stanley Dean; Bai, Yinglin; Zhang, Heng; Fountain, Matthew; Gerber, Jacob; Ogas, Joe

    2008-01-01

    SUMMARY PICKLE (PKL) codes for a CHD3 chromatin remodeling factor that plays multiple roles in Arabidopsis growth and development. Previous analysis of the expression of genes that exhibit PKL-dependent regulation suggested that PKL acts during germination to repress expression of embryonic traits. In this study, we examined the expression of PKL protein to investigate when and where PKL acts to regulate development. A PKL:eGFP translational fusion is preferentially localized in the nucleus of cells, consistent with the proposed role for PKL as a chromatin remodeling factor. A steroid-inducible version of PKL - a fusion of PKL to the glucocorticoid receptor (PKL:GR) - was used to examine when PKL acts to repress expression of embryonic traits. We found that activation of PKL:GR during germination was sufficient to repress expression of embryonic traits in the primary roots of pkl seedlings whereas activation of PKL:GR after germination had little effect. In contrast, we observed that PKL is required continuously after germination to repress expression of PHERES1, a type I MADS box gene that is normally expressed during early embryogenesis in wild-type plants. Thus PKL acts at multiple points during development to regulate patterns of gene expression in Arabidopsis. PMID:16359393

  5. Financial repression, money growth, and seignorage: The Polish experience

    NARCIS (Netherlands)

    Aarle, B. van; Budina, N.

    1997-01-01

    Financial Repression, Money Growth and Seignorage: The Polish Experience. — A small analytical framework is developed to analyze the relation between reserve requirements, base money growth and seignorage revenues. From the analysis, the authors can derive of steady-state seignorage revenues as a fu

  6. miRNA-dependent translational repression in the Drosophila ovary.

    Directory of Open Access Journals (Sweden)

    John Reich

    Full Text Available BACKGROUND: The Drosophila ovary is a tissue rich in post-transcriptional regulation of gene expression. Many of the regulatory factors are proteins identified via genetic screens. The more recent discovery of microRNAs, which in other animals and tissues appear to regulate translation of a large fraction of all mRNAs, raised the possibility that they too might act during oogenesis. However, there has been no direct demonstration of microRNA-dependent translational repression in the ovary. METHODOLOGY/PRINCIPAL FINDINGS: Here, quantitative analyses of transcript and protein levels of transgenes with or without synthetic miR-312 binding sites show that the binding sites do confer translational repression. This effect is dependent on the ability of the cells to produce microRNAs. By comparison with microRNA-dependent translational repression in other cell types, the regulated mRNAs and the protein factors that mediate repression were expected to be enriched in sponge bodies, subcellular structures with extensive similarities to the P bodies found in other cells. However, no such enrichment was observed. CONCLUSIONS/SIGNIFICANCE: Our results reveal the variety of post-transcriptional regulatory mechanisms that operate in the Drosophila ovary, and have implications for the mechanisms of miRNA-dependent translational control used in the ovary.

  7. Financial repression, money growth, and seignorage: The Polish experience

    NARCIS (Netherlands)

    Aarle, B. van; Budina, N.

    1997-01-01

    Financial Repression, Money Growth and Seignorage: The Polish Experience. — A small analytical framework is developed to analyze the relation between reserve requirements, base money growth and seignorage revenues. From the analysis, the authors can derive of steady-state seignorage revenues as a fu

  8. Intellectual Performance as a Function of Repression and Menstrual Cycle.

    Science.gov (United States)

    Englander-Golden, Paula; And Others

    Performance on complex (Space Relations and Verbal Reasoning) and simple (Digit Symbol) tests was investigated as a function of Byrne's Repression-Sensitization (RS) dimension, phase of menstrual cycle and premenstrual-menstrual (PM) symptomatology in a group of females not taking oral contraceptives. Two control groups, consisting of males and…

  9. Onset of carbon catabolite repression in Aspergillus nidulans

    NARCIS (Netherlands)

    Flipphi, M.; Vondervoort, van de P.J.I.; Ruijter, G.J.G.; Visser, J.; Arst Jr., H.N.; Felenbok, B.

    2003-01-01

    The role of hexose phosphorylating enzymes in the signaling of carbon catabolite repression was investigated in the filamentous fungus Aspergillus nidulans. A D-fructose non-utilizing, hexokinase-deficient (hxkA1, formerly designated frA1) strain was utilized to obtain new mutants lacking either glu

  10. PPARs Mediate the Regulation of Energy Metabolism By Long-Chain Fatty Acids%PPARs 在长链脂肪酸调控能量代谢中的作用

    Institute of Scientific and Technical Information of China (English)

    姚艳; 王宗保; 唐朝克

    2016-01-01

    过氧化物酶体增殖物激活受体α(PPARα)主要在肝脏中表达,饥饿时能诱导β-氧化与生酮作用相关基因和成纤维化生长因子21(FGF21)表达,这在肝脏的饥饿代谢适应中起重要作用。饥饿与耐力训练时,骨骼肌中,过氧化物酶体增殖物激活受体δ(PPARδ)能诱导长链脂肪酸(LCFAs)氧化基因、叉头转录因子(FOXO1)及 PPARδ共激活物α1(PGC1α)表达,其中,FOXO1和 PGC1α能调控糖代谢与线粒体生物发生。脂肪细胞中,PPARγ能介导 LCFAs 调控能量代谢,活化的PPARγ能诱导与 LCFAs 转化为甘油三酯形式储存相关的基因表达。脂联素,PPARγ的另一靶基因,能维持脂肪细胞的胰岛素敏感性。本文就 PPARs 在 LCFAs 调控能量代谢中的作用做一综述。%PPAR-alpha expressed primarily in liver is essential for metabolic adaptation to starvation by inducing genes for beta-oxidation and ketogenesis to increase the utility of LCFAs and fibroblast growth factor 21.PPAR-delta induces genes for LCFA oxidation during fasting and endurance exercise in skeletal muscle.PPAR-delta also regulates glucose metabolism and mitochondrial biogenesis by inducing FOXO1 and PGC1-alpha.PPAR-gamma can induces the pathways to store LCFAs as triglycerides in adipocytes . Adiponectin,another important target of PPAR-gamma may maintain insulin sensitivity between adipo-cytes.The present review summarize that PPARs mediate the regulation of energy metabolism by long-chain fatty acids.

  11. The Protective Effect of Apigenin on Myocardial Injury in Diabetic Rats mediating Activation of the PPAR-γ Pathway

    Directory of Open Access Journals (Sweden)

    Umesh B. Mahajan

    2017-04-01

    Full Text Available We substantiated the role of peroxisome proliferator-activated receptor-γ (PPAR-γ activation in the protective effect of apigenin against the myocardial infarction (MI in diabetic rats. Diabetes was induced by intraperitoneal administration of a single dose of streptozotocin (55 mg/kg. The study groups included diabetic rats receiving vehicle, apigenin (75 mg/kg/day, orally, GW9662 (1 mg/kg/day, intraperitoneally, and a combination of apigenin and GW9662 for 14 days. The MI was induced in all the study groups except the diabetic control group by subcutaneous injection of 100 mg/kg/day of isoproterenol on the two terminal days. The diabetes and isoproterenol-induced MI was evident as a reduction in the maximal positive and negative rate of developed left ventricular pressure and an increase in the left ventricular end-diastolic pressure. The activities of creatine kinase on myocardial bundle (CK-MB and lactate dehydrogenase (LDH were also reduced. Apigenin treatment prevented the hemodynamic perturbations, restored the left ventricular function and reinstated a balanced redox status. It protected rats against an MI by attenuating myonecrosis, edema, cell death, and oxidative stress. GW9662, a PPAR-γ antagonist reversed the myocardial protection conferred by apigenin. Further, an increase in the PPAR-γ expression in the myocardium of the rats receiving apigenin reinforces the role of PPAR-γ pathway activation in the cardioprotective effects of apigenin.

  12. ADDP and PS-PPh3: an efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists

    Directory of Open Access Journals (Sweden)

    Wilhite David M

    2006-10-01

    Full Text Available Abstract A series of pyridine ether PPAR agonists were synthesized through an ADDP and PS-PPh3 modified Mitsunobu protocol, which eliminated significant by-product formation. This method proved to be versatile, efficient and amenable to parallel synthesis.

  13. 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.…

  14. Synthesis and evaluation of novel [alpha]-heteroaryl-phenylpropanoic acid derivatives as PPAR[alpha/gamma] dual agonists

    Energy Technology Data Exchange (ETDEWEB)

    Casimiro-Garcia, Agustin; Bigge, Christopher F.; Davis, Jo Ann; Padalino, Teresa; Pulaski, James; Ohren, Jeffrey F.; McConnell, Patrick; Kane, Christopher D.; Royer, Lori J.; Stevens, Kimberly A.; Auerbach, Bruce; Collard, Wendy; McGregor, Christine; Song, Kun; Pfizer

    2010-09-27

    The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the {alpha}-position and their evaluation for binding and activation of PPAR{alpha} and PPAR{gamma} are presented in this report. Among the new compounds, (S)-3-{l_brace}4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl{r_brace}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPAR{alpha}/{gamma} dual agonist (EC{sub 50} = 0.013 and 0.061 {micro}M, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies.

  15. 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 biol

  16. 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

  17. 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

  18. Mangiferin Inhibits IL-1β-Induced Inflammatory Response by Activating PPAR-γ in Human Osteoarthritis Chondrocytes.

    Science.gov (United States)

    Qu, Yanlong; Zhou, Li; Wang, Chunlei

    2017-02-01

    Inflammation has been reported to play critical roles in the development of osteoarthritis. In the present study, we investigated whether mangiferin (MFN) had anti-inflammatory effects in IL-1β-stimulated human osteoarthritis chondrocytes. The cells were treated with various concentrations of MFN in the presence or absence of IL-1β. The production of MMP-1, MMP-3, PGE2, and NO was measured in this study. The expression of NF-kB and PPAR-γ was detected by western blot analysis. MFN inhibited IL-1β-induced inflammatory mediators PGE2 and NO production. MFN also inhibited IL-1β-induced MMP1 and MMP3 production. IL-1β-induced NF-kB activation was significantly inhibited by MFN. In addition, MFN was found to up-regulate the expression of PPAR-γ in human osteoarthritis chondrocytes. PPAR-γ inhibitor GW9662 significantly reversed the anti-inflammatory effects of MFN. These results suggest that MFN inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes by activating PPAR-γ.

  19. 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.

  20. 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.…

  1. 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.

  2. 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 RATIONALE: 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. OBJECTIVES: 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. MATERIALS AND METHODS: 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. FINDINGS: 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. CONCLUSIONS: Greater prenatal PAH exposure was associated with increased weight, fat mass, adipose gene expression and epigenetic changes in progeny.

  3. The Pro12Ala polymorphism of the PPAR-gamma gene is not associated with the polycystic ovary syndrome.

    Science.gov (United States)

    Xita, Nectaria; Lazaros, Leandros; Georgiou, Ioannis; Tsatsoulis, Agathocles

    2009-01-01

    Insulin resistance is a key factor in the pathogenesis of polycystic ovary syndrome (PCOS). Peroxisome proliferator-activated- receptor-gamma (PPAR-gamma) has been implicated in insulin resistance and adiposity. The aim of the study was to investigate the possible involvement of the Pro12Ala polymorphism of the PPAR-gamma gene in the pathogenesis of PCOS. We studied 180 women with PCOS and 140 healthy controls. Body mass index (BMI) was recorded. Blood samples were drawn after overnight fasting and serum glucose, insulin, lipid and hormonal profiles were determined. The fasting glucose/insulin ratio and HOMA index were calculated. Moreover, 100 women with PCOS underwent a 75g oral glucose tolerance test and the area under the curve for insulin and glucose was estimated. DNA was extracted from peripheral blood leucocytes and the Pro12Ala polymorphism was genotyped. The PPAR-gamma genotypes were found to be in the Hardy-Weinberg equilibrium in both study groups. No difference was found in the distribution of the Pro12Ala polymorphism between PCOS and controls. Insulin resistance indices and lipid and hormonal profile were not different among the various genotypes of the Pro12Ala polymorphism. The Pro12Ala polymorphism of the PPAR-gamma gene is not involved in the pathogenesis or the phenotypic expression of PCOS.

  4. 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.

  5. 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.

  6. The Pro12Ala polymorphism in the PPAR-γ2 gene is not associated to obesity and type 2 diabetes mellitus in a Cameroonian population.

    Science.gov (United States)

    Mato, Edith Pascale M; Pokam-Fosso, Priscille Eunice; Atogho-Tiedeu, Barbara; Noubiap, Jean Jacques N; Evehe, Marie-Solange; Djokam-Dadjeu, Rosine; Donfack, Olivier Sontsa; Ngwa, Elvis Ndonwi; Guewo-Fokeng, Magellan; Mbacham, Wilfred F; Sobngwi, Eugene; Mbanya, Jean Claude

    2016-01-01

    Peroxisome proliferator-activated receptor gamma 2 (PPAR-γ2) is a transcription factor with a key role in adipocyte differentiation, lipid storage and glucose homeostasis. The Ala allele of the common Pro12Ala polymorphism in the isoform PPAR-γ2 is at the center of many controversies because in some populations, it has been observed to be associated with T2DM or obesity but, not in others. The aim of this study was to investigate the association of Pro12Ala polymorphism in the PPAR-γ2 gene with susceptibility to obesity or T2DM in a Cameroonian population. This case-control study included 62 obese, 60 T2DM patients and 120 controls (60 non obese and 60 patients without T2DM), all unrelated and of Cameroonian origin. PPAR-γ2 was examined by genotyping for Pro12Ala using the Restriction Fragment Length Polymorphism - Polymerase Chain Reaction (PCR - RFLP). A portion of the 270 base pair bands of the PPAR-γ2 gene was successfully amplified. The Ala12 variant was totally absent from the study population, all participants being homozygote Pro/Pro. PPAR-γ2 Pro12Ala gene polymorphism may not be associated with obesity and T2DM. These results suggest that, PPAR-γ2 is unlikely a major gene for obesity or T2DM in the study population.

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

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    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.

  8. 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.

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

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    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.

  10. PPAR-α and PPARGC1A gene variants have strong effects on aerobic performance of Turkish elite endurance athletes.

    Science.gov (United States)

    Tural, Ercan; Kara, Nurten; Agaoglu, Seydi Ahmet; Elbistan, Mehmet; Tasmektepligil, Mehmet Yalcin; Imamoglu, Osman

    2014-09-01

    The aim of this study was to investigate the effect of PPAR-α intron 7G>C and PPARGC1A gene Gly482Ser polymorphisms on aerobic performance of elite level endurance athletes. This study was carried out on 170 individuals (60 elite level endurance athletes and 110 sedentary controls). Aerobic performance of athletes and sedentary control groups were defined by maximal oxygen uptake capacity. DNA was isolated from peripheral blood using GeneJet Genomic DNA Purification kit. Genotyping of the PPAR-α intron 7G>C and PPARGC1A Gly482Ser polymorphisms was performed using PCR-RFLP methods, and statistical evaluations were carried out using SPSS 15.0. Mean age of athletes were 21.38 ± 2.83 (18-29) and control mean age were 25.92 ± 4.88 (18-35). Mean maximal oxygen consumption of athletes were 42.14 ± 7.6 ml/(kg min) and controls were 34.33 ± 5.43 ml/(kg min). We found statistically significant differences between the athlete and control groups with respect to both PPAR-α and PPARGC1A genotype distributions (p = 0.006, performance test parameters, we found a statistically significant association between velocity, time and maximal oxygen consumption and PPAR-α and PPARGC1A genotypes (p C and PPARGC1A Gly482Ser gene polymorphisms in elite level endurance athletes. Our results suggest that PPAR-α and PPARGC1A genes have strong effect on aerobic performance of elit level athletes.

  11. PPAR-γ2 and PTPRD gene polymorphisms influence type 2 diabetes patients' response to pioglitazone in China

    Institute of Scientific and Technical Information of China (English)

    Qi PEI; Zhao-qian LIU; Qiong HUANG; Guo-ping YANG; Ying-chun ZHAO; Ji-ye YIN; Min SONG; Yi ZHENG; Zhao-hui MO; Hong-hao ZHOU

    2013-01-01

    Aim: To investigate the influence of peroxisome proliferator-activated receptor y2 (PPAR-Y2) gene polymorphism rs1801282 and protein tyrosine phosphatase receptor type D (PTPRD) gene polymorphism rs17584499 on the occurrence of type 2 diabetes and pioglitazone efficacy in a Chinese Han population.Methods: One hundred ninety seven type 2 diabetes patients and 212 healthy controls were enrolled.Among them,67 type 2 diabetes patients were administered pioglitazone (30 mg/d,po) for 3 months.All the subjects were genotyped for genetic variants in PPAR-γ2 and PTPRD using MALDI-TOF mass spectrometry.Fasting plasma glucose,postprandial plasma glucose,glycated hemoglobin,serum triglyceride,total cholesterol,low-density and high-density lipoprotein-cholesterol were determined.Results: The PPAR-y2 gene rs1801282 polymorphism was significantly associated with type 2 diabetes susceptibility (OR=0.515,95% CI 0.268-0.990) and the PTPRD gene rs17584499 polymorphism was also significantly associated with type 2 diabetes (OR=1.984,95% Cl 1.135-3.469) in a dominant model adjusted for age,gender and BMI.After pioglitazone treatment for 3 months,the type 2 diabetes patients with PPAR-γ2 rs1801282 CG genotypes significantly showed higher differential values of postprandial plasma glucose and serum triglyceride compared with those with rs1801282 CC genotype.The patients with PTPRD rs17584499 CT+TT genotypes showed significantly lower differential value of postprandial plasma glucose compared to those with rs17584499 CC genotype.Conclusion: Diabetes risk alleles in PPAR-y2 (rs1801282) and PTPRD (rs17584499) are associated with pioglitazone therapeutic efficacy.

  12. PROBLEM OF CRIMINAL REPRESSION, APPLIED OUTSIDE OF CRIMINAL LIABILITY

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    Vitaly Stepashin

    2017-01-01

    Full Text Available УДК 343.2A new institute of repressive measures applied outside the criminal liability in criminal law (including as a condition for exemption from criminal liability is forming now in Russian legislation. The author concludes that the provisions of the criminal law on monetary compensation and a court fine should be deleted because of the following reasons. 1 By their nature, and monetary compensation and a court fine, not being a formal punishment (and, therefore, a form of realization of criminal responsibility is a monetary penalty, i.e., penalty-punishment. Moreover, the rules of court fine destination identical rules of criminal sentencing. 2 Quantitatively court fine may exceed the minimum limits of criminal punish-ment in the form of fines. The dimensions of monetary compensation in the order of hours. Pt. 2, Art. 76.1 of the Criminal Code and at all close to the maximum values of fine-punishment. 3 Exemption from criminal liability requires states to refrain from prosecuting the person alleged to have committed a crime, which means that the nonuse of criminal repression. Regulatory standards analyzed, on the other hand, require mandatory use of repression, ie, virtually no exemption from criminal liability does not occur at all. 4 The use of a quasi-penalty in the form of monetary compensation and court fines are not an exemption from criminal responsibility, but on the contrary, the use of criminal repression (of responsibility, and in a simplified manner. 5 Contrary to the requirements of the Constitution and the Criminal Code of criminal repression is applied to persons whose guilt has not been established in the commission of a crime. Thus, in criminal law introduced a presumption of guilt. 6 Customization repression (in fact – of criminal responsibility in the application of the judicial penalty is substantially limited, and the application of monetary compensation is excluded at all, contrary to the requirement that the rough

  13. The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys

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    Swanson Christine R

    2011-08-01

    Full Text Available Abstract Background Activation of the peroxisome proliferator-activated receptor gamma (PPAR-γ has been proposed as a possible neuroprotective strategy to slow down the progression of early Parkinson's disease (PD. Here we report preclinical data on the use of the PPAR-γ agonist pioglitazone (Actos®; Takeda Pharmaceuticals Ltd. in a paradigm resembling early PD in nonhuman primates. Methods Rhesus monkeys that were trained to perform a battery of behavioral tests received a single intracarotid arterial injection of 20 ml of saline containing 3 mg of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP. Twenty-four hours later the monkeys were assessed using a clinical rating scale, matched accordingly to disability, randomly assigned to one of three groups [placebo (n = 5, 2.5 (n = 6 or 5 (n = 5 mg/kg of pioglitazone] and their treatments started. Three months after daily oral dosing, the animals were necropsied. Results We observed significant improvements in clinical rating score (P = 0.02 in the animals treated with 5 mg/kg compared to placebo. Behavioral recovery was associated with preservation of nigrostriatal dopaminergic markers, observed as higher tyrosine hydroxylase (TH putaminal optical density (P = 0.011, higher stereological cell counts of TH-ir (P = 0.02 and vesicular monoamine transporter-2 (VMAT-2-ir nigral neurons (P = 0.006. Stereological cell counts of Nissl stained nigral neurons confirmed neuroprotection (P = 0.017. Pioglitazone-treated monkeys also showed a dose-dependent modulation of CD68-ir inflammatory cells, that was significantly decreased for 5 mg/kg treated animals compared to placebo (P = 0.018. A separate experiment to assess CSF penetration of pioglitazone revealed that 5 mg/kg p.o. induced consistently higher levels than 2.5 mg/kg and 7.5 mg/kg. p.o. Conclusions Our results indicate that oral administration of pioglitazone is neuroprotective when administered early after inducing a

  14. Nutrición molecular, papel del sistema PPAR en el metabolismo lipídico y su importancia en obesidad y diabetes mellitus: regulation of lipid metabolism by peroxisome proliferator activated receptors (PPAR). Their relatioship to obesity and diabetes mellitus

    OpenAIRE

    Uauy D,Ricardo; Martínez A,Jessica I.; Rojas B,Cecilia V.

    2000-01-01

    PPARs are transcription factors belonging to the super family of hormonal receptors. Their activity is regulated by fibrates, thiazolidinediones, certain anti inflammatory drugs and fatty acid derivatives, present in food. PPAR isoforms play a central role in lipid homeostasis, regulating anabolic (PPARg) and catabolic (PPARa) pathways of lipid metabolism. Additionally, these receptors participate in glucose homeostasis, influence cellular proliferation and differentiation and participate in ...

  15. Molecular cloning, characterization and expression analysis of PPAR gamma in the orange-spotted grouper (Epinephelus coioides) after the Vibrio alginolyticus challenge.

    Science.gov (United States)

    Luo, Shengwei; Huang, Youhua; Xie, Fuxing; Huang, Xiaohong; Liu, Yuan; Wang, Weina; Qin, Qiwei

    2015-04-01

    PPAR gamma was a key nuclear receptor, playing an important role in the immune defense and the anti-inflammatory mechanism. In this study, the full-length PPAR gamma (EcPPAR gamma) was obtained, containing a 5'UTR of 133 bp, an ORF of 1602 bp and a 3'UTR of 26 bp besides the poly (A) tail. The EcPPAR gamma gene encoded a protein of 533 amino acids with an estimated molecular mass of 60.02 KDa and a predicted isoelectric point (pI) of 6.26. The deduced amino acid sequence showed that EcPPAR gamma consisted of the conserved residues and the domains known to be critical for the PPAR gamma function. The quantitative real-time PCR analysis revealed that EcPPAR gamma transcript was expressed in all the examined tissue, while the strong expression was observed in intestine, followed by the expression in liver, gill, spleen heart, kidney and muscle. Vibrio challenge could stimulate the inflammatory response in grouper and induce a sharp increase of pro-inflammatory cytokines expression, lipid peroxidation and DNA damage, while the up-regulation of vibrio-induced inflammation could also increase the non-specific immune defense. The groupers challenged with Vibrio alginolyticus showed a sharp increase of EcPPAR gamma transcript in immune tissues. Subcellular localization analysis revealed that EcPPAR gamma was distributed in the nucleus. Furthermore, overexpression of EcPPAR gamma could down-regulated the expression of IL1b, IL6, TNF1 and TNF2. In addition, the administration of PPAR gamma antagonist, GW9662, could up-regulate the expression of pro-inflammatory genes, including IL1b, IL6, TNF1 and TNF2. Together, these results indicated that EcPPAR gamma serving as a negative regulator of pro-inflammatory cytokines may play an important role in the immune defense against vibrio-induced inflammation in grouper.

  16. PPAR{gamma} activates ABCA1 gene transcription but reduces the level of ABCA1 protein in HepG2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Mogilenko, Denis A., E-mail: denis@iem.sp.ru [Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg (Russian Federation); Department of Embryology, St. Petersburg State University, 199034 St. Petersburg (Russian Federation); Shavva, Vladimir S. [Department of Embryology, St. Petersburg State University, 199034 St. Petersburg (Russian Federation); Dizhe, Ella B. [Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg (Russian Federation); Orlov, Sergey V., E-mail: serge@iem.sp.ru [Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg (Russian Federation); Department of Embryology, St. Petersburg State University, 199034 St. Petersburg (Russian Federation); Perevozchikov, Andrej P., E-mail: app@iem.sp.ru [Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg (Russian Federation); Department of Embryology, St. Petersburg State University, 199034 St. Petersburg (Russian Federation)

    2010-11-19

    Research highlights: {yields} PPAR{gamma} activates ABCA1 gene expression but decreases ABCA1 protein content in human hepatoma cell line HepG2. {yields} Treatment of HepG2 cells with PPAR{gamma} agonist GW1929 leads to dissociation of LXR{beta} from ABCA1-LXR{beta} complex. {yields} Inhibition of protein kinases MEK1/2 abolishes PPAR{gamma}-mediated dissociation of LXR{beta} from ABCA1/LXR{beta} complex. {yields} Activation of PPAR{gamma} leads to increasing of the level of LXR{beta} associated with LXRE within ABCA1 gene promoter. -- Abstract: Synthesis of ABCA1 protein in liver is necessary for high-density lipoproteins (HDL) formation in mammals. Nuclear receptor PPAR{gamma} is known as activator of ABCA1 expression, but details of PPAR{gamma}-mediated regulation of ABCA1 at both transcriptional and post-transcriptional levels in hepatocytes have not still been well elucidated. In this study we have shown, that PPAR{gamma} activates ABCA1 gene transcription in human hepatoma cells HepG2 through increasing of LXR{beta} binding with promoter region of ABCA1 gene. Treatment of HepG2 cells with PPAR{gamma} agonist GW1929 leads to dissociation of LXR{beta} from ABCA1/LXR{beta} complex and to nuclear translocation of this nuclear receptor resulting in reduction of ABCA1 protein level 24 h after treatment. Inhibition of protein kinases MEK1/2 abolishes PPAR{gamma}-mediated dissociation of LXR{beta} from ABCA1/LXR{beta} complex, but does not block PPAR{gamma}-dependent down-regulation of ABCA1 protein in HepG2 cells. These data suggest that PPAR{gamma} may be important for regulation of the level of hepatic ABCA1 protein and indicate the new interplays between PPAR{gamma}, LXR{beta} and MEK1/2 in regulation of ABCA1 mRNA and protein expression.

  17. Political Repressions in USSR (Against Speculations, Perversion and Mystifications

    Directory of Open Access Journals (Sweden)

    Viktor N. Zemskov

    2012-12-01

    Full Text Available In the article the great numbers of political repressions, which were exaggerated by authors: R.A. Medvedev, A.I. Solzhenitsyn, O.G. Shatunovskoy, A.V. Antonov-Ovseenko in 80-90s are criticized. The author characterizes figures given in tens and even in hundreds of millions of victims as a statistical charlatanism.After checking up the KGB archives, and documents of division responsible for NKVD-MVD special settlements, the author spills the light on real numbers of political repressions in USSR. In his view, the total number of political victims does not exceed 2, 6 million people. This number implies over 800 thousand of death sentenced for political reasons, around 600 thousand political prisoners who died in labor camps, and about 1, 2 million people died in exile (including ‘Kulak Exile’ and during transportation (deported ethnic groups and others.

  18. An Updated GA Signaling 'Relief of Repression' Regulatory Model

    Institute of Scientific and Technical Information of China (English)

    Xiu-Hua Gao; Sen-Lin Xiao; Qin-Fang Yao; Yu-Juan Wang; Xiang-Dong Fu

    2011-01-01

    Gibberellic acid (GA)regulates many aspects of plant growth and development. The DELLA proteins act to restrain plant growth, and GA relieves this repression by promoting their degradation via the 26S proteasome pathway.The elucidation of the crystalline structure of the GA soluble receptor GID1 protein represents an important breakthrough for understanding the way in which GA is perceived and how it induces the destabilization of the DELLA proteins. Recent advances have revealed that the DELLA proteins are involved in protein-protein interactions within various environmental and hormone signaling pathways. In this review, we highlight our current understanding of the 'relief of repression" model that aims to explain the role of GA and the function of the DELLA proteins, incorporating the many aspects of cross-talk shown to exist in the control of plant development and the response to stress.

  19. N-methyl-D-aspartate (NMDA)-stimulated noradrenaline (NA) release in rat brain cortex is modulated by presynaptic H3-receptors.

    Science.gov (United States)

    Fink, K; Schlicker, E; Göthert, M

    1994-02-01

    In superfused rat brain cortex slices and synaptosomes preincubated with [3H]noradrenaline the effect of agonists or antagonists at presynaptic H3 receptors on NMDA-evoked [3H]noradrenaline release was investigated. In experiments on slices, histamine and the preferential H3 receptor agonist R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow (IC20 values 0.27 mumol/l or 0.032 mumol/l, respectively); S-(+)-alpha-methylhistamine (up to 10 mumol/l) as well as the selective H1 receptor agonist (2-(2-thiazolyl)ethylamine and the selective H2 receptor agonist dimaprit (each up to 10 mumol/l) were ineffective. The H3 receptor antagonist thioperamide abolished the inhibitory effect of histamine whereas the preferential H1 receptor antagonist dimetindene and the preferential H2 receptor antagonist ranitidine were ineffective. In experiments on synaptosomes, histamine and R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow, whereas 2-(2-thiazolyl)ethylamine or dimaprit had no effect. The inhibitory effect of histamine was abolished by thioperamide. When tritium overflow was stimulated by NMDA in the presence of omega-conotoxin GVIA (which by itself decreased the response to NMDA by about 55%), R-(-)-alpha-methylhistamine did not inhibit NMDA-evoked overflow. It is concluded that NMDA-evoked noradrenaline release in the cerebral cortex can be modulated by inhibitory H3 receptors. NMDA receptors and H3 receptors are both located presynaptically and may interact at the same noradrenergic varicosity. An unimpaired function of the N-type voltage-sensitive calcium channel probably is a prerequisite for the inhibition of NMDA-evoked noradrenaline release by H3 receptor stimulation.

  20. Effects of inorganic cations on K+-, 5-hydroxytryptamine- and noradrenaline-induced contractions of the isolated rat jugular vein and aorta

    NARCIS (Netherlands)

    Gouw, M.A.M.; Wilffert, B.; Van Zwieten, P.A.

    1990-01-01

    We investigated the inhibitory effects of 1 mM of the inorganic cations, La3+, Cd2+, Mn2+, Ni2+and Co2+on contractions induced by K+(100 mM) and 5-hydroxytryptamine (5-HT, 10-5M) in the isolated rat jugular vein and on contractions induced by K+(100 mM), 5-HT (10-5) and noradrenaline (NA, 10-5M) in

  1. Hypofunction of prefrontal cortex NMDA receptors does not change stress-induced release of dopamine and noradrenaline in amygdala but disrupts aversive memory.

    Science.gov (United States)

    Del Arco, Alberto; Ronzoni, Giacomo; Mora, Francisco

    2015-07-01

    A dysfunction of prefrontal cortex has been associated with the exacerbated response to stress observed in schizophrenic patients and high-risk individuals to develop psychosis. The hypofunction of NMDA glutamatergic receptors induced by NMDA antagonists produces cortico-limbic hyperactivity, and this is used as an experimental model to resemble behavioural abnormalities observed in schizophrenia. The aim of the present study was to investigate whether injections of NMDA antagonists into the medial prefrontal cortex of the rat change (1) the increases of dopamine, noradrenaline and corticosterone concentrations produced by acute stress in amygdala, and (2) the acquisition of aversive memory related to a stressful event. Male Wistar rats were implanted with guide cannulae to perform microdialysis and bilateral microinjections (0.5 μl/side) of the NMDA antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phophonic acid (CPP) (25 and 100 ng). Prefrontal injections were performed 60 min before restraint stress in microdialysis experiments, or training (footshock; 0.6 mA, 2 s) in inhibitory avoidance test. Retention latency was evaluated 24 h after training as an index of aversive memory. Acute stress increased amygdala dialysate concentrations of dopamine (160% of baseline), noradrenaline (145% of baseline) and corticosterone (170% of baseline). Prefrontal injections of CPP did not change the increases of dopamine, noradrenaline or corticosterone produced by stress. In contrast, CPP significantly reduced the retention latency in the inhibitory avoidance test. These results suggest that the hypofunction of prefrontal NMDA receptors does not change the sensitivity to acute stress of dopamine and noradrenaline projections to amygdala but impairs the acquisition of aversive memory.

  2. PPAR{delta} is a fatty acid sensor, which enhances mitochondrial oxidation in insulin

    DEFF Research Database (Denmark)

    Ravnskjaer, Kim; Frigerio, Francesca; Boergesen, Michael;

    2010-01-01

    against adverse effects on GSIS associated with prolonged fatty acid exposure. The presented results indicate that the nuclear receptor PPARdelta is a fatty acid sensor that adapts beta-cell mitochondrial function to long-term changes in unsaturated fatty acid levels. As maintenance of mitochondrial...... is the PPAR subtype expressed at the highest level in insulinoma cells and rat pancreatic islets. Furthermore, PPARdelta displays high transcriptional activity and acts in pronounced synergy with RXR. Interestingly, unsaturated fatty acids mimic the effects of synthetic PPARdelta agonists. Using sh......RNA-mediated knockdown we demonstrate that the ability of unsaturated fatty acids to stimulate fatty acid metabolism is dependent on PPARdelta. Activation of PPARdelta increases the fatty acid oxidation potential in INS-1E beta-cells, enhances glucose-stimulated insulin secretion (GSIS) from islets, and protects GSIS...

  3. The Role of PPARs in the Endothelium: Implications for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Karen E. Swales

    2008-11-01

    Full Text Available The growth and metastasis of cancers intimately involve the vasculature and in particular the endothelial cell layer. Tumours require new blood vessel formation via angiogenesis to support growth. In addition, inflammation, coagulation, and platelet activation are common signals in the growth and metastasis of tumour cells. The endothelium plays a central role in the homeostatic control of inflammatory cell recruitment, regulating platelet activation and coagulation pathways. PPARα, -β/δ, and -γ are all expressed in endothelial cells. This review will discuss the roles of PPARs in endothelial cells in relation to angiogenesis, inflammation, coagulation, and platelet control pathways. In particular, we will discuss the recent evidence that supports the hypothesis that PPARα and PPARγ are antiangiogenic receptors, while PPARβ/δ is proangiogenic.

  4. [PPARs: physiological functions and pharmacological roles of agonists in human diseases. Note II].

    Science.gov (United States)

    Filip-Ciubotaru, Florina; Manciuc, Carmen; Grigore, Cecilia; Foia, Liliana

    2012-01-01

    Increasing attention paid to the main family of peroxisome proliferator activated receptors--PPARs is generated, on one hand by the multiple functions of its members in numerous metabolically active tissues, and on the other hand by the therapeutic benefits expresed by some specific ligands that are used in certain metabolic diseases treatment plan. PPARalpha stimulates the beta-oxidative degradation of fatty acids and controls plasma lipid transport through the mediated action upon the triglycerides and fatty acids metabolism and by modulation of biosynthesis and catabolism of bile acids in the liver. PPARgamma promotes adipocytes differentiation and fat storage. PPARbeta/delta is involved in control and management of adipogenesis. While PPARalpha mediates the hypolipemiant actions of fibrates, PPARgamma is the receptor for thiazolidinediones (glitazones) reccomended in type 2 diabetes treatment; by binding to PPARgamma, glitazones modulates transcription of genes involved in lipid and carbohydrate metabolism.

  5. Repressive coping and alexithymia in idiopathic environmental intolerance

    Science.gov (United States)

    Zachariae, Robert; Rasmussen, Alice; Johansen, Jeanne Duus; Elberling, Jesper

    2010-01-01

    Objective To examine if the non-expression of negative emotions (i.e., repressive coping) and differences in the ability to process and regulate emotions (i.e., alexithymia) is associated with idiopathic environmental intolerance (IEI). Methods The study included participants who had previously participated in a general population-based study and reported symptoms of environmental intolerance (n = 787) and patients with IEI (n = 237). The participants completed questionnaires assessing IEI, namely, a measure of repressive coping combining scores on the Marlowe–Crowne Social Desirability Scale (MCSDS) and the Taylor Manifest Anxiety Scale (TMAS), the Toronto Alexithymia Scale (TAS-20), and a negative affectivity scale (NAS). Multiple, hierarchical linear regression analyses were conducted using IEI variables as the dependent variables. Results The TMAS and MCSDS scores were independently associated with the IEI variables, but there was no evidence of a role of the repressive coping construct. While the total alexithymia score was unrelated to IEI, the TAS-20 subscale of difficulties identifying feelings (DIF) was independently associated with symptoms attributed to IEI. Negative affectivity was a strong independent predictor of the IEI variables and a mediator of the association between DIF and IEI. Conclusion Our results provide no evidence for a role of repressive coping in IEI, and our hypothesis of an association with alexithymia was only partly supported. In contrast, strong associations between IEI and negative emotional reactions, defensiveness and difficulties identifying feelings were found, suggesting a need for exploring the influence of these emotional reactions in IEI. PMID:21432559

  6. Repression and reactivation of lithium efflux from erythrocytes.

    Science.gov (United States)

    Goodnick, P J; Meltzer, H L; Dunner, D L; Fieve, R R

    1979-10-01

    Efflux of lithium from human erythrocytes was studied in patients before, during, and after discontinuation of administration of lithium carbonate. Onset of lithium-induced repression of efflux took approximately 10 days and was significantly shorter in patients who had had lithium therapy previously. Reactivation took a longer period of time--approximately 2 week--and was found to be related to duration of lithium therapy. Theoretical pathways of lithium flow through membranes are discussed.

  7. Repressive effects of resveratrol on androgen receptor transcriptional activity.

    Directory of Open Access Journals (Sweden)

    Wen-feng Shi

    Full Text Available BACKGROUND: The chemopreventive effects of resveratrol (RSV on prostate cancer have been well established; the androgen receptor (AR plays pivotal roles in prostatic tumorigenesis. However, the exact underlying molecular mechanisms about the effects of RSV on AR have not been fully elucidated. A model system is needed to determine whether and how RSV represses AR transcriptional activity. METHODOLOGY: The AR cDNA was first cloned into the retroviral vector pOZ-N and then integrated into the genome of AR-negative HeLa cells to generate the AR(+ cells. The constitutively expressed AR was characterized by monitoring hormone-stimulated nuclear translocation, DNA binding, and transcriptional activation, with the AR(- cells serving as controls. AR(+ cells were treated with RSV, and both AR protein levels and AR transcriptional activity were measured simultaneously. Chromatin immunoprecipitation (ChIP assays were used to detect the effects of RSV on the recruitment of AR to its cognate element (ARE. RESULTS: AR in the AR (+ stable cell line functions in a manner similar to that of endogenously expressed AR. Using this model system we clearly demonstrated that RSV represses AR transcriptional activity independently of any effects on AR protein levels. However, neither the hormone-mediated nucleus translocation nor the AR/ARE interaction was affected by RSV treatment. CONCLUSION: We demonstrated unambiguously that RSV regulates AR target gene expression, at least in part, by repressing AR transcriptional activity. Repressive effects of RSV on AR activity result from mechanisms other than the affects of AR nuclear translocation or DNA binding.

  8. Impact of the PPAR gamma-2 gene polymorphisms on the metabolic state of postmenopausal women

    Indian Academy of Sciences (India)

    BOGNA GRYGIEL-GÓRNIAK; MARIA MOSOR; JUSTYNA MARCINKOWSKA; JULIUSZ PRZYSŁAWSKI; JERZY NOWAK

    2016-09-01

    The relationship Pro12Ala (rs1801282) and C1431T (rs3856806) polymorphisms of PPAR gamma-2 with glucose and lipid metabolism is not clear after menopause. We investigated the impact of the Pro12Ala and C1431T silentsubstitution in the 6th exon in PPAR gamma-2 gene on nutritional and metabolic status in 271 postmenopausal women(122 lean and 149 obese). The general linear model (GLM) approach to the two-way analysis of variance (ANOVA) was used to infer the interactions between the analysed genotypes. The frequency of the Pro-T haplotype was higher in obese than in lean women ($p\\lt 0.0349$). In the analysed GLM models according to obesity status, the C1431C genotypewas related to a lower glucose concentration ($\\beta=-0.2103$) in lean women, and to higher folliculotropic hormone FSH levels ($\\beta=0.1985$) and lower waist circumferences ($\\beta=-0.1511$) in obese women. The influence of C1431C waspresent regardless of the occurrence of the Pro12Ala polymorphism. The co-existence of the C1431C and Pro12Progenotypes was related to lower values for triceps skinfold thickness compared those for the T1241/X and Ala12/X polymorphisms ($\\beta=-0.1425$). The presence of C1431C decreased the differences between triceps values that weredetermined by Pro or Ala allele. In conclusion, C1431T polymorphism seems to have a more essential influence onanthropometric and biochemical parameters than is the case with Pro12Ala polymorphism.

  9. Cognitive decline and the PPAR-γ Pro12Ala genotype: variation by sex and ethnicity.

    Science.gov (United States)

    A West, Nancy; Baxter, Judith; L Bryant, Lucinda; L Nelson, Tracy

    2017-01-06

    We investigated the association between the peroxisome proliferator-activated receptor (PPAR)-gamma Pro12Ala polymorphism and cognitive decline in older adults. Participants from a population-based cohort of older Hispanic and non-Hispanic white adults (n = 492) were administered the Mini Mental State Examination (MMSE), a multi-domain cognitive screening tool, and the Behavioral Dyscontrol Scale (BDS), a measure of executive cognitive function, at baseline and at follow-up, an average of 22 months later. Multiple linear regression was used to investigate the association between the two cognitive test scores and the Pro12Ala polymorphism. At baseline, presence of the Ala12 allele was not significantly associated with MMSE score (P = 0.62) nor with BDS score (P = 0.85). Heterogeneity was present for cognitive decline as measured by the MMSE among ethnic, sex and Ala12 allele status (P = 0.04 for three-way interaction term). Stratification by the cross-classification of sex and ethnicity revealed significantly greater declines in MMSE score among male Hispanic carriers of the Ala12 allele compared to male Hispanic non-carriers (decline = 4.0 versus 1.6 points; P = 0.02). A significant difference in decline between Ala12 carriers and non-carriers was not present among the other sex/ethnic groups. Carriers of the PPAR-γ Ala12 allele showed greater cognitive decline compared to non-carriers as detected by the MMSE but the risk varied across sex and ethnic groups. Male Ala12 carriers of Hispanic origin may be a high-risk group for cognitive decline.

  10. Noradrenaline as a putative neurotransmitter mediating hypotension—induced FOs—like immunoreactivity in the supraoptic nucleus of the rat

    Institute of Scientific and Technical Information of China (English)

    SHENEH; XIASUN

    1995-01-01

    Hemorrhage or hypotension induces extensive Fos-like immunoreactivity in the magnocellular neurosecretory cells in the supraoptic nucleus of the hypothalamus in rat,especially in the vasopressin neurons.The present study was to explore the neurotransmitter mediating this effect,Microinfusion of the alpha-adrenergic blocker into the supraoptic nucleus reduced the hypotension-induced FOs.whereas beta-antagonist did not affect it significantly.Alaha1-and alpha2-antagonist,prazosin and yohimbine,both reduced the Fos-Positive cell counts.However,the effective dosage of yohimbine was much larger,Alpha1-agonist,methoxamine,induced abundant Fos-like immunoreactivity in the vasopressin cells in this nucleus,while beta-and alpha2-agonist did not elicit such effect.Administration of the noradrenergic re-uptake inhibitor desipramine,to this nucleus to locally accumulate the spontaneously released noradrenaline from the nerve terminals also induced Fos expression,mostly in the vasopressin cells.

  11. Analysis of microdialysate monoamines, including noradrenaline, dopamine and serotonin, using capillary ultra-high performance liquid chromatography and electrochemical detection.

    Science.gov (United States)

    Ferry, Barbara; Gifu, Elena-Patricia; Sandu, Ioana; Denoroy, Luc; Parrot, Sandrine

    2014-03-01

    Electrochemical methods are very often used to detect catecholamine and indolamine neurotransmitters separated by conventional reverse-phase high performance liquid chromatography (HPLC). The present paper presents the development of a chromatographic method to detect monoamines present in low-volume brain dialysis samples using a capillary column filled with sub-2μm particles. Several parameters (repeatability, linearity, accuracy, limit of detection) for this new ultrahigh performance liquid chromatography (UHPLC) method with electrochemical detection were examined after optimization of the analytical conditions. Noradrenaline, adrenaline, serotonin, dopamine and its metabolite 3-methoxytyramine were separated in 1μL of injected sample volume; they were detected above concentrations of 0.5-1nmol/L, with 2.1-9.5% accuracy and intra-assay repeatability equal to or less than 6%. The final method was applied to very low volume dialysates from rat brain containing monoamine traces. The study demonstrates that capillary UHPLC with electrochemical detection is suitable for monitoring dialysate monoamines collected at high sampling rate.

  12. Tetrahydro-beta-carbolines and corresponding tryptamines: In vitro inhibition of serotonin, dopamine and noradrenaline uptake in rat brain synaptosomes.

    Science.gov (United States)

    Komulainen, H; Tuomisto, J; Airaksinen, M M; Kari, I; Peura, P; Pollari, L

    1980-04-01

    The structure activity relationships of tryptolines and some other beta-carbolines and tryptamines as inhibitors of serotonin (5-HT), dopamine (DA) and noradrenaline (NA) uptake were studied in rat brain synaptosomes. All beta-carbolines inhibited to higher degree the uptake of 5-HT than that of DA or NA(IC50's 5-100 times lower). The most potent tryptoline derivative was 6-hydroxy-tetrahydro-beta-carboline (5-hydroxytryptoline, 6-OH-THBC) with an IC50 of 5.0 x 10(-7) M at a 5-HT concentration of 10(-7) M. 6-Methoxy-tetrahydro-beta-carboline (5-methoxytryptoline) was slightly weaker; the inhibition of 5-HT uptake and DA uptake being competitive. Also tetrahydro-beta-carboline (tryptoline) was more potent than its 1-methylderivative, tetrahydroharmane (methtryptoline) or norharmane (beta-carboline). All of them were, however, weaker inhibitors of 5-HT uptake than the freely rotating indoleamines N-methyl-tryptamine (N-Me-T) or 5-HT itself. N-Me-T and 5-HT were also more potent inhibitors of DA and NA uptake than most of the beta-carbolines, DA uptake, however, was inhibited better by 6-OH-THBC than by 5-HT or N-ME-T. Tetrahydro-beta-carbolines may inhibit 5-HT uptake also in vivo but is unlikely that catecholamine uptake is affected.

  13. Simultaneous Determination of Epinephrine, Noradrenaline and Dopamine in Human Serum Samples by High Performance Liquid Chromatography with Chemiluminescence Detection

    Institute of Scientific and Technical Information of China (English)

    CHEN, Fu-Nan; ZHANG, Ying-Xue; ZHANG, Zhu-Jun

    2007-01-01

    A simple, rapid and accurate high performance liquid chromatographic (HPLC) technique coupled with chemiluminescence (CL) detection was developed for the simultaneous determination of epinephrine (E),noradrenaline (NA) and dopamine (DA). It was based on the analyte enhancement effect on the CL reaction between luminol and potassium ferricyanide. The effects of various parameters, such as potassium ferricyanide concentration, luminol concentration, pH value and component of the mobile phase on chromatographic behaviors of the analytes (E, NA and DA) were investigated. The separation was carried out on C18 column using the mobile tions, E, NA and DA showed good linear relationships in the range of 1×10-8-5×10-6, 5.0×10-9-1.0× 10-6 and 5.0×10-9-1.0×10-6 g/mL respectively. The detection limits for E, NA and DA were 4.0×10-9, 1.0×10-9 and 8.0×10-10 g/mL. The proposed method has been applied successfully to the analysis of E, NA and DA in human serum samples.

  14. Pupillometric evidence for the locus coeruleus-noradrenaline system facilitating attentional processing of action-triggered visual stimuli.

    Science.gov (United States)

    Kihara, Ken; Takeuchi, Tatsuto; Yoshimoto, Sanae; Kondo, Hirohito M; Kawahara, Jun I

    2015-01-01

    It has been argued that attentional processing of visual stimuli is facilitated by a voluntary action that triggers the stimulus onset. However, the relationship between action-induced facilitation of attention and the neural substrates has not been well established. The present study investigated whether the locus coeruleus-noradrenaline (LC-NA) system is involved in this facilitation effect. A rapid serial visual presentation paradigm was used to assess the dynamics of transient attention in humans. Participants were instructed to change a digit stream to a letter stream by pressing a button and specifying successive targets of four letters. Pupil dilation was measured as an index of LC-NA function. Accuracy of target identification was better when the temporal delay between participants' key press and target onset was 800 ms than when targets appeared just after the key press or when targets appeared without key press. Accuracy of target identification was positively correlated with both the peak amplitude of pupil dilation and the pupil size at the time of the key press. These results indicate that target identification in the visual task is closely linked to pupil dilation. We conclude that the LC-NA system plays an important role in the facilitation of transient attention driven by voluntary action.

  15. Fluxes of lactate into, from, and among gap junction-coupled astrocytes and their interaction with noradrenaline

    Directory of Open Access Journals (Sweden)

    Leif eHertz

    2014-09-01

    Full Text Available Lactate is a versatile metabolite with important roles in modulation of brain glucose utilization rate (CMRglc, diagnosis of brain-injured patients, redox- and receptor-mediated signaling, memory, and alteration of gene transcription. Neurons and astrocytes release and accumulate lactate using equilibrative monocarboxylate transporters that carry out net transmembrane transport of lactate only until intra- and extracellular levels reach equilibrium. Astrocytes have much faster lactate uptake than neurons and shuttle more lactate among gap junction-coupled astrocytes than to nearby neurons. Lactate diffusion within syncytia can provide precursors for oxidative metabolism and glutamate synthesis and facilitate its release from endfeet to perivascular space to stimulate blood flow. Lactate efflux from brain during activation underlies the large underestimation of CMRglc with labeled glucose and fall in CMRO2/CMRglc ratio. Receptor-mediated effects of lactate on locus coeruleus neurons include noradrenaline release in cerebral cortex and c-AMP-mediated stimulation of astrocytic gap junctional coupling, thereby enhancing its dispersal and release from brain. Lactate transport is essential for its multifunctional roles.

  16. Voltametric Behavior of Noradrenaline at 2-Mercaptoethanol Self-Assembled Monolayer Modified Gold Electrode and its Analytical Application

    Directory of Open Access Journals (Sweden)

    ShengFu Wang

    2003-02-01

    Full Text Available 2-Mercaptoethanol self-assembled monolayer (ME/Au SAMs was prepared on a gold electrode. The ME/Au SAMs was characterized by using ATR-FTIR and dynamic contact angle measurements. The electrochemical behaviors of noradrenaline (NE on the ME/Au SAMs were studied in BR buffer solution. The modified electrode accelerated electron transfer rate of the redox of NE and showed an excellent eletrocatalytic activity. The diffusion coefficient (D of NE was obtained to be 4.3×10-8 cm2 s-1. The catalytic current increased linearly with the concentration of NE in the range of 2.0×10-6 -1.0×10-3 M by square wave voltammetry response. The modified electrode could eliminate the interference of ascorbic acid (AA at 40-fold concentration of NE and could be satisfactorily used for the determination of NE in the drug injection.

  17. Pupillometric evidence for the locus coeruleus-noradrenaline system facilitating attentional processing of action-triggered visual stimuli

    Directory of Open Access Journals (Sweden)

    Ken eKihara

    2015-06-01

    Full Text Available It has been argued that attentional processing of visual stimuli is facilitated by a voluntary action that triggers the stimulus onset. However, the relationship between action-induced facilitation of attention and the neural substrates has not been well established. The present study investigated whether the locus coeruleus-noradrenaline (LC-NA system is involved in this facilitation effect. A rapid serial visual presentation paradigm was used to assess the dynamics of transient attention in humans. Participants were instructed to change a digit stream to a letter stream by pressing a button and specifying successive targets of four letters. Pupil dilation was measured as an index of LC-NA function. Accuracy of target identification was better when the temporal delay between participants' key press and target onset was 800 ms than when targets appeared just after the key press or when targets appeared without key press. Accuracy of target identification was positively correlated with both the peak amplitude of pupil dilation and the pupil size at the time of the key press. These results indicate that target identification in the visual task is closely linked to pupil dilation. We conclude that the LC-NA system plays an important role in the facilitation of transient attention driven by voluntary action.

  18. Cerebral hemorrhage increases plasma concentrations of noradrenalin and creatine kinase MB fraction with induction of cardiomyocyte damage in rats.

    Science.gov (United States)

    Liang, Xiao-Min; Chen, Jia; Zhang, Tao; Liu, Juan; Jiang, Xiao-Jiang; Xu, Zhi-Qiang

    2014-12-01

    The incidence of cardiac damage is high during acute cerebral hemorrhage. The animal data on the relationship between cerebral apoplexy and cardiac damage are lacking. Thus, the aim of the study was to evaluate the effects of cerebral hemorrhage on plasma concentrations of monoamine transmitter noradrenalin (NA), creatine kinase muscle and brain (CK-MB) isoenzyme fraction, and cardiomyocyte changes in the rat model. In this study, 140 Wistar rats were randomly and equally divided into experimental and control groups, and collagenase was injected into the right caudate nucleus to induce cerebral hemorrhage in the experimental group. Plasma NA was analyzed using high-performance liquid chromatography with electrochemical detection and serum CK-MB was measured by enzyme reaction rate method. We found that both NA and CK-MB were elevated (p MB concentrations reached peak levels at 24 h which were found to be 3.52 ± 0.06 μg/L and 5.47 ± 0.49 μkat/L, respectively. Thereafter, NA and CK-MB concentrations decreased gradually. Plasma NA declined to the preoperative level (1.66 ± 0.03 μg/L) at 72 h, while CK-MB level (2.71 ± 0.17 μkat/L) was found to be still higher than its preoperative level. It was, therefore, concluded that plasma NA might be involved in the induction and development of cardiomyocytes damage during cerebral hemorrhage.

  19. Repression and activation by multiprotein complexes that alter chromatin structure.

    Science.gov (United States)

    Kingston, R E; Bunker, C A; Imbalzano, A N

    1996-04-15

    Recent studies have provided strong evidence that macromolecular complexes are used in the cell to remodel chromatin structure during activation and to create an inaccessible structure during repression, Although there is not yet any rigorous demonstration that modification of chromatin structure plays a direct, causal role in either activation or repression, there is sufficient smoke to indicate the presence of a blazing inferno nearby. It is clear that complexes that remodel chromatin are tractable in vitro; hopefully this will allow the establishment of systems that provide a direct analysis of the role that remodeling might play in activation. These studies indicate that establishment of functional systems to corroborate the elegant genetic studies on repression might also be tractable. As the mechanistic effects of these complexes are sorted out, it will become important to understand how the complexes are regulated. In many of the instances discussed above, the genes whose products make up these complexes were identified in genetic screens for effects on developmental processes. This implies a regulation of the activity of these complexes in response to developmental cues and further implies that the work to fully understand these complexes will occupy a generation of scientists.

  20. Snai1 represses Nanog to promote embryonic stem cell differentiation

    Directory of Open Access Journals (Sweden)

    F. Galvagni

    2015-06-01

    Full Text Available Embryonic stem cell (ESC self-renewal and pluripotency is maintained by an external signaling pathways and intrinsic regulatory networks involving ESC-specific transcriptional complexes (mainly formed by OCT3/4, Sox2 and Nanog proteins, the Polycomb repressive complex 2 (PRC2 and DNA methylation [1–8]. Among these, Nanog represents the more ESC specific factor and its repression correlates with the loss of pluripotency and ESC differentiation [9–11]. During ESC early differentiation, many development-associated genes become upregulated and although, in general, much is known about the pluripotency self-renewal circuitry, the molecular events that lead ESCs to exit from pluripotency and begin differentiation are largely unknown. Snai1 is one the most early induced genes during ESC differentiation in vitro and in vivo [12,13]. Here we show that Snai1 is able to directly repress several stemness-associated genes including Nanog. We use a ESC stable-line expressing a inducible Snai1 protein. We here show microarray analysis of embryonic stem cells (ESC expressing Snail-ER at various time points of induction with 4-OH. Data were deposited in Gene Expression Omnibus (GEO datasets under reference GSE57854 and here: http://epigenetics.hugef-research.org/data.php.

  1. Transcriptional Repression of Catalase in Mouse Skin Tumor Progression

    Directory of Open Access Journals (Sweden)

    Kevin A. Kwei

    2004-09-01

    Full Text Available Previous studies in our laboratory have shown that the elevation of reactive oxygen species levels and the repression of the antioxidant enzyme, catalase, played a critical role in the in vitro progression of benign papilloma cells to malignant carcinoma cells. Catalase message, protein levels, and activity levels were found to be downregulated in the malignantly progressed cells. The goal of this study is to further characterize the repression of catalase in malignant progression of mouse skin tumors. To validate the in vitro observations, we examined catalase expression in tumor samples generated by the multistep chemical carcinogenesis protocol. Higher levels of catalase mRNA and protein were observed in benign papillomas versus malignant carcinomas. Nuclear run-on analysis showed that catalase repression in the cultured malignant cells was transcription-dependent. Results from luciferase reporter assays indicated that malignant cells have lower catalase promoter activities than benign papilloma cells, in part through the Wilm's tumor suppressor 1 (WT1 binding site within the proximal promoter region. The WTi protein levels were found to be inversely correlated with the observed catalase promoter activities, with higher levels observed in the malignant cells versus the benign cells. These results led us to conclude that WTi is acting as a transcription repressor in catalase gene regulation during tumor progression.

  2. Trans-inactivation: Repression in a wrong place.

    Science.gov (United States)

    Shatskikh, Aleksei S; Abramov, Yuriy A; Lavrov, Sergey A

    2016-08-19

    Trans-inactivation is the repression of genes on a normal chromosome under the influence of a rearranged homologous chromosome demonstrating the position effect variegation (PEV). This phenomenon was studied in detail on the example of brown(Dominant) allele causing the repression of wild-type brown gene on the opposite chromosome. We have investigated another trans-inactivation-inducing chromosome rearrangement, In(2)A4 inversion. In both cases, brown(Dominant) and In(2)A4, the repression seems to be the result of dragging of the euchromatic region of the normal chromosome into the heterochromatic environment. It was found that cis-inactivation (classical PEV) and trans-inactivation show different patterns of distribution along the chromosome and respond differently to PEV modifying genes. It appears that the causative mechanism of trans-inactivation is de novo heterochromatin assembly on euchromatic sequences dragged into the heterochromatic nuclear compartment. Trans-inactivation turns out to be the result of a combination of heterochromatin-induced position effect and the somatic interphase chromosome pairing that is widespread in Diptera.

  3. Nitric oxide participates in plant flowering repression by ascorbate

    Science.gov (United States)

    Senthil Kumar, Rajendran; Shen, Chin-Hui; Wu, Pei-Yin; Suresh Kumar, Subbiah; Hua, Moda Sang; Yeh, Kai-Wun

    2016-01-01

    In Oncidium, redox homeostasis involved in flowering is mainly due to ascorbic acid (AsA). Here, we discovered that Oncidium floral repression is caused by an increase in AsA-mediated NO levels, which is directed by the enzymatic activities of nitrate reductase (NaR) and nitrite reducatase (NiR). Through Solexa transcriptomic analysis of two libraries, ‘pseudobulb with inflorescent bud’ (PIB) and ‘pseudobulb with axillary bud’ (PAB), we identified differentially expressed genes related to NO metabolism. Subsequently, we showed a significant reduction of NaR enzymatic activities and NO levels during bolting and blooming stage, suggesting that NO controlled the phase transition and flowering process. Applying AsA to Oncidium PLB (protocorm-like bodies) significantly elevated the NO content and enzyme activities. Application of sodium nitroprusside (-NO donor) on Arabidopsis vtc1 mutant caused late flowering and expression level of flowering-associated genes (CO, FT and LFY) were reduced, suggesting NO signaling is vital for flowering repression. Conversely, the flowering time of noa1, an Arabidopsis NO-deficient mutant, was not altered after treatment with L-galacturonate, a precursor of AsA, suggesting AsA is required for NO-biosynthesis involved in the NO-mediated flowering-repression pathway. Altogether, Oncidium bolting is tightly regulated by AsA-mediated NO level and downregulation of transcriptional levels of NO metabolism genes. PMID:27731387

  4. Revisiting the Master-Signifier, or, Mandela and Repression.

    Science.gov (United States)

    Hook, Derek; Vanheule, Stijn

    2015-01-01

    The concept of the master-signifier has been subject to a variety of applications in Lacanian forms of political discourse theory and ideology critique. While there is much to be commended in literature of this sort, it often neglects salient issues pertaining to the role of master signifiers in the clinical domain of (individual) psychical economy. The popularity of the concept of the master (or "empty") signifier in political discourse analysis has thus proved a double-edged sword. On the one hand it demonstrates how crucial psychical processes are performed via the operations of the signifier, extending thus the Lacanian thesis that identification is the outcome of linguistic and symbolic as opposed to merely psychological processes. On the other, the use of the master signifier concept within the political realm to track discursive formations tends to distance the term from the dynamics of the unconscious and operation of repression. Accordingly, this paper revisits the master signifier concept, and does so within the socio-political domain, yet while paying particular attention to the functioning of unconscious processes of fantasy and repression. More specifically, it investigates how Nelson Mandela operates as a master signifier in contemporary South Africa, as a vital means of knitting together diverse elements of post-apartheid society, enabling the fantasy of the post-apartheid nation, and holding at bay a whole series of repressed and negated undercurrents.

  5. Revisiting the Master-Signifier, or, Mandela and Repression

    Science.gov (United States)

    Hook, Derek; Vanheule, Stijn

    2016-01-01

    The concept of the master-signifier has been subject to a variety of applications in Lacanian forms of political discourse theory and ideology critique. While there is much to be commended in literature of this sort, it often neglects salient issues pertaining to the role of master signifiers in the clinical domain of (individual) psychical economy. The popularity of the concept of the master (or “empty”) signifier in political discourse analysis has thus proved a double-edged sword. On the one hand it demonstrates how crucial psychical processes are performed via the operations of the signifier, extending thus the Lacanian thesis that identification is the outcome of linguistic and symbolic as opposed to merely psychological processes. On the other, the use of the master signifier concept within the political realm to track discursive formations tends to distance the term from the dynamics of the unconscious and operation of repression. Accordingly, this paper revisits the master signifier concept, and does so within the socio-political domain, yet while paying particular attention to the functioning of unconscious processes of fantasy and repression. More specifically, it investigates how Nelson Mandela operates as a master signifier in contemporary South Africa, as a vital means of knitting together diverse elements of post-apartheid society, enabling the fantasy of the post-apartheid nation, and holding at bay a whole series of repressed and negated undercurrents. PMID:26834664

  6. Effects of calcium and nifedipine on noradrenaline- and PGF-2 alpha-induced activity of the ampullary-isthmic junction of the human oviduct in vitro.

    Science.gov (United States)

    Forman, A; Andersson, K E; Ulmsten, U

    1983-03-01

    From 22 women undergoing hysterectomy at various stages of the menstrual cycle, strip preparations were dissected from the outer, longitudinal and the inner, circular smooth muscle layers of the ampullary-isthmic junction (AIJ). The strips were mounted in organ baths, and isometric tension was recorded. Spontaneous contractions were recorded mainly in circular muscle strips. Contractions were elicited by 127 mM-K+, 10(-6) M-noradrenaline and 10(-6) M-PGF-2 alpha. Potassium induced biphasic responses that were slightly different in the two tissues. In circular muscle strips, noradrenaline and PGF-2 alpha induced phasic contractions superimposed on a rise in tone. In longitudinal muscle specimens, the two compounds produced tonic responses. All types of mechanical activity were inhibited by removal of extracellular calcium. K+-induced responses and phasic contractions produced by noradrenaline and PGF-2 alpha could be abolished by 10(-6) M-nifedipine whereas the tonic contractions in the circular and longitudinal muscle were more resistant to the calcium antagonist. The results suggest that K+-induced responses in circular and longitudinal muscle of the human AIJ, and the phasic contractions in circular muscle, depend on calcium influx via potential-sensitive membrane channels. Receptor-operated calcium channels seem to be involved in the tonic contractions observed mainly in the longitudinal smooth muscle.

  7. Noradrenaline-induced enhancement of oscillatory local field potentials in the mouse accessory olfactory bulb does not depend on disinhibition of mitral cells.

    Science.gov (United States)

    Leszkowicz, Emilia; Khan, Selina; Ng, Stephanie; Ved, Nikita; Swallow, Daniel L; Brennan, Peter A

    2012-05-01

    The olfactory bulb differs from other brain regions by its use of bidirectional synaptic transmission at dendrodendritic reciprocal synapses. These reciprocal synapses provide tight coupling of inhibitory feedback from granule cell interneurons to mitral cell projection neurons in the accessory olfactory bulb (AOB), at the first stage of vomeronasal processing. It has been proposed that both the mGluR2 agonist DCG-IV and noradrenaline promote mate recognition memory formation by reducing GABAergic feedback on mitral cells. The resultant mitral cell disinhibition is thought to induce a long-lasting enhancement in the gain of inhibitory feedback from granule to mitral cells, which selectively gates the transmission of the learned chemosensory information. However, we found that local infusions of both noradrenaline and DCG-IV failed to disinhibit AOB neural activity in urethane-anaesthetised mice. DCG-IV infusion had similar effects to the GABA(A) agonist isoguvacine, suggesting that it increased GABAergic inhibition in the AOB rather than reducing it. Noradrenaline infusion into the AOB also failed to disinhibit mitral cells in awake mice despite inducing long-term increases in power of AOB local field potentials, similar to those observed following memory formation. These results suggest that mitral cell disinhibition is not essential for the neural changes in the AOB that underlie mate recognition memory formation in mice.

  8. [Noradrenaline and glycogen content and the activity of several enzymes of carbohydrate metabolism in normal, embryonic, and partly denervated livers and in hepatomas of the rat].

    Science.gov (United States)

    Iljin, S V; Shanigina, K I; Sydow, G; Parfhenova, N S

    1977-01-01

    The noradrenaline and glycogen contents as well as hexokinase, glucokinase and glucose-6-phosphatase activities were determined in normal, embryonic and partially denervated (bilateral dissection of the Nervus splanchnicus or Nervus vagus) rat liver and in two transplantable hepatomas. In embryonic liver and hepatomas a strong decrease or complete loss of noradrenaline and glycogen levels and glucokinase and glucose-6-phosphatase activities is demonstrable as compared to the livers of adult animals, while the hexokinase activity is enhanced. Following bilateral splanchnicotomy the glycogen content and hexokinase activity are enhanced; the glucose-6-phosphatase activity is reduced, and the liver does not contain any noradrenaline. Bilateral vagotomy causes decrease of the glycogen content, of the hexokinase and glucokinase activities and an enhancement of glucose-6-phosphatase activity. The results lend support to the idea of antagonistic action of the sympathetic and parasympathetic nervous systems upon several partial reactions of carbohydrate metabolism of liver. In addition, it can be assumed that the alterations of the carbohydrate metabolism demonstrable in hepatomas as compared to normal liver are not solely attributable to disturbance or breakdown of the nervous regulation.

  9. Role of adipocyte lipid-binding protein (ALBP) and acyl-coA binding protein (ACBP) in PPAR-mediated transactivation

    DEFF Research Database (Denmark)

    Helledie, Torben; Jørgensen, Claus; Antonius, Marianne

    2002-01-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that are activated by a number of fatty acids and fatty acid derivatives. By contrast, we have recently shown that acyl-CoA esters display PPAR antagonistic properties in vitro. We have also shown that the adipocyte....... We therefore speculated that FABPs and ACBP might regulate the availability of PPAR agonists and antagonists by affecting not only their esterification in the cytoplasm but also their transport to and availability in the nucleus. We show here that coexpression of ALBP or ACBP exerts a negative effect...... on ligand-dependent PPAR transactivation, when tetradecylthioacetic (TTA) is used as ligand but not when the thiazolidinedione BRL49653 is used as ligand. The results presented here do not support the hypothesis that ALBP facilitates the transport of the fatty acid-type ligands to the nucleus, rather ALBP...

  10. PPAR-γ and CYP46A1 genes polymorphism is associated with Primary Open Angle Glaucoma (POAG in hypertensive North Indians

    Directory of Open Access Journals (Sweden)

    Syed Tasleem Raza

    2017-04-01

    Conclusions: CYP46A1 (rs754203 gene polymorphism was associated with POAG in both hypertensive and normotensive patients whereas, only GG genotype of PPAR-γ (rs10865710 SNP shows significant association with POAG in hypertensive POAG patients.

  11. 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.

  12. Molecular effects of leptin on peroxisome proliferator activated receptor gamma (PPAR-γ) mRNA expression in rat's adipose and liver tissue.

    Science.gov (United States)

    Abbasi, A; Moghadam, A A; Kahrarian, Z; Abbsavaran, R; Yari, K; Alizadeh, E

    2017-08-15

    Leptin is a 16-kDa peptide hormone secreted by adipose tissue that participates in the regulation of energy homeostasis. The aim of this study was to determine the effect of leptin injection on mRNA expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and comparison of PPAR-γ mRNA expression in rat's adipose and liver tissue. Twenty adult male rats were divided into the following groups: Group 1asa control (n=10) that did not receive any treatment. Group 2as a treatment (n=10) that received leptin (30 µg ⁄ kg BW) intraperitoneally (ip) for two successive days. Blood samples were taken before and one day after second leptin injection for triglyceride (TG), Free Fatty Acid (FFA), HLD-cholesterol, and LDL-cholesterol measurement. Total RNA was extractedfrom the adipose tissue and liver tissues of rats.  Adipose and liver tissue cells' cDNA was synthesized to characterize the expression of PPAR-γ. Gene expression of PPAR-γ mRNA was tested by RT- PCR technique. Results show leptin decreases expression of PPAR-γ on rat. Low levels of PPAR-γ mRNA were detected in adipose and liver tissues of treatment rats in comparison to control group. In treatment group, the level of PPAR-γ mRNA in liver tissue was very lower than the adipose tissue. The levels of HDL and FFA in treatment rats were increased whereas serum levels TG, VLDL and LDL were not changed. It is concluded that leptin signal with suppressing of PPAR-γ mRNA expression in rat's adipose and liver tissues can result in lipolysis instead of lipogenesis.

  13. Comparative transcriptional network modeling of three PPAR-α/γ co-agonists reveals distinct metabolic gene signatures in primary human hepatocytes.

    Directory of Open Access Journals (Sweden)

    Renée Deehan

    Full Text Available AIMS: To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR-α/γ agonist, aleglitazar, with tesaglitazar (a dual PPAR-α/γ agonist or a combination of pioglitazone (Pio; PPAR-γ agonist and fenofibrate (Feno; PPAR-α agonist in human hepatocytes. METHODS AND RESULTS: Gene expression microarray profiles were obtained from primary human hepatocytes treated with EC(50-aligned low, medium and high concentrations of the three treatments. A systems biology approach, Causal Network Modeling, was used to model the data to infer upstream molecular mechanisms that may explain the observed changes in gene expression. Aleglitazar, tesaglitazar and Pio/Feno each induced unique transcriptional signatures, despite comparable core PPAR signaling. Although all treatments inferred qualitatively similar PPAR-α signaling, aleglitazar was inferred to have greater effects on high- and low-density lipoprotein cholesterol levels than tesaglitazar and Pio/Feno, due to a greater number of gene expression changes in pathways related to high-density and low-density lipoprotein metabolism. Distinct transcriptional and biologic signatures were also inferred for stress responses, which appeared to be less affected by aleglitazar than the comparators. In particular, Pio/Feno was inferred to increase NFE2L2 activity, a key component of the stress response pathway, while aleglitazar had no significant effect. All treatments were inferred to decrease proliferative signaling. CONCLUSIONS: Aleglitazar induces transcriptional signatures related to lipid parameters and stress responses that are unique from other dual PPAR-α/γ treatments. This may underlie observed favorable changes in lipid profiles in animal and clinical studies with aleglitazar and suggests a differentiated gene profile compared with other dual PPAR-α/γ agonist treatments.

  14. PPAR-γ and CYP46A1 genes polymorphism is associated with Primary Open Angle Glaucoma (POAG) in hypertensive North Indians

    OpenAIRE

    Syed Tasleem Raza; Saliha Rizvi; Luxmi Singh; Shania Abbas; Zeashan Haider Zaidi; Farzana Mahdi

    2017-01-01

    Background: Involvement of genetic factors like gene polymorphisms was found to contribute significantly to development and progression of Primary Open Angle Glaucoma (POAG) in the last few decades. Aim of study: The present study was carried out to investigate association of PPAR-γ (rs10865710) and CYP46A1 (rs754203) gene polymorphism with development of POAG in hypertensive North Indians. Patients and methods: Study included 328 individuals, 226 as POAG cases and 102 controls. PPAR-γ ...

  15. Effect of Buyanghuanwu Decoction on PPAR-γ Expression in Diabetic Rats%补阳还五汤对糖尿病大鼠主动脉PPAR-γ表达的影响

    Institute of Scientific and Technical Information of China (English)

    李阳; 徐洁; 王芳; 郭伟; 谭燚; 付金凤

    2012-01-01

    Objective:To investigate the effects of Buyanghuanwu Decoction on blood glucose,blood fat and PPAR-r expression in diabetic rats. Methods: Male Wistar rats were randomly divided into the normal group and the model group. The model group was given intravenous injection of streptozotocin (STZ) solution (30mg/kg) to make DM rats. The DM rats were randomly divided into DM model group (DM group),The metformin group(MF group), the Buyanghuanwu Decoction high-does group (BH group) and the Buyanghuanwu Decoction low-does group(BL group). These groups were respectively given the distilled water,the metformin with 0.75g/kg·d and the Buyanghuanwu Decoction with 22.5g/kg·d or 5.4g/kg·d. The normal group was given equal citrate buffer. The treatment was lasted for 6 weeks to measure the changes in blood glucose, blood fat and the expression of PPAR-r. Results: Buyanghuanwu Decoction significantly reduced BG,TC,TG levels and increased the expression of PPAR-r in the aortic sinus. Conclusion: Buyanghuanwu Decoction can prevent diabetes vascular complications by regulation of glycolipid metabolism and increase PPAR-r expression.%目的 观察补阳还五汤对糖尿病大鼠血脂及主动脉中过氧化物酶体增殖物激活受体(PPAR)-γ表达的影响.方法 Wistar雄性大鼠随机分为正常对照组和造模组.造模组大鼠尾静脉注射链脲佐菌素(STZ)溶液(30mg/kg);将造模成功的糖尿病大鼠随机分为糖尿病模型组(DM组)、二甲双胍组(MF组)、补阳还五汤高剂量组(BH组)、补阳还五汤低剂量组(BL组),分别给予灌服等容积蒸馏水、二甲双胍混悬液0.75g/(kg·d)、高剂量补阳还五汤22.5g/(kg·d)、低剂量补阳还五汤5.4g/(kg·d).正常对照组给予注射等量枸橼酸缓冲液.连续给药6周后,检测糖尿病大鼠灌胃后血糖(BG)、胆固醇(TC)、甘油三酯(TG)及免疫荧光染色测定主动脉PPAR-γ表达.结果 BH组能降低BG、TC、TG的水平,并能明显增加糖尿病大鼠主动脉PPAR

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

    Science.gov (United States)

    Laganà, Antonio Simone; Vitale, Salvatore Giovanni; Nigro, Angela; Sofo, Vincenza; Salmeri, Francesca Maria; Rossetti, Paola; Rapisarda, Agnese Maria Chiara; La Vignera, Sandro; Condorelli, Rosita Angela; Rizzo, Gianluca; Buscema, Massimo

    2016-01-01

    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. PMID:27347932

  17. Two Isomeric C16 Oxo-Fatty Acids from the Diatom Chaetoceros karianus Show Dual Agonist Activity towards Human Peroxisome Proliferator-Activated Receptors (PPARs α/γ

    Directory of Open Access Journals (Sweden)

    Angel Moldes-Anaya

    2017-05-01

    Full Text Available The peroxisome proliferator-activated receptors (PPARs function as ligand-activated transcription factors that convert signals in the form of lipids to physiological responses through the activation of metabolic target genes. Due to their key roles in lipid and carbohydrate metabolism, the PPARs are important drug targets. However, for several of the PPAR drugs currently in use, adverse side effects have been reported. In an effort to identify compounds from marine organisms that may serve as molecular scaffolds for the development of novel and safer PPAR-targeting drugs, we performed a bioassay-guided screening of organic extracts made from organisms supplied by the Norwegian Biobank of Arctic Marine Organisms (Marbank. Among several interesting hits, we identified two poorly described isomeric oxo-fatty acids from the microalgae Chaetoceros karianus for which we provide the first evidence that they might display dual specificity towards human PPARα and PPARγ. Principal component analysis showed that C. karianus stood out from other Chaetoceros species, both with respect to the metabolic profile and the PPAR activity. The isolation of these compounds holds the potential of uncovering a PPAR pharmacophore with tunable activity and specificity.

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

    Science.gov (United States)

    Laganà, Antonio Simone; Vitale, Salvatore Giovanni; Nigro, Angela; Sofo, Vincenza; Salmeri, Francesca Maria; Rossetti, Paola; Rapisarda, Agnese Maria Chiara; La Vignera, Sandro; Condorelli, Rosita Angela; Rizzo, Gianluca; Buscema, Massimo

    2016-06-24

    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; Narrative review aimed to synthesize cutting-edge evidence retrieved from searches of computerized databases; 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; 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.

  19. 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.

  20. Various Terpenoids Derived from Herbal and Dietary Plants Function as PPAR Modulators and Regulate Carbohydrate and Lipid Metabolism

    Directory of Open Access Journals (Sweden)

    Tsuyoshi Goto

    2010-01-01

    Full Text Available Several herbal plants improve medical conditions. Such plants contain many bioactive phytochemicals. Terpenoids (also called “isoprenoids” constitute one of the largest families of natural products accounting for more than 40,000 individual compounds of both primary and secondary metabolisms. In particular, terpenoids are contained in many herbal plants, and several terpenoids have been shown to be available for pharmaceutical applications, for example, artemisinin and taxol as malaria and cancer medicines, respectively. Various terpenoids are contained in many plants for not only herbal use but also dietary use. In this paper, we describe several bioactive terpenoids contained in herbal or dietary plants, which can modulate the activities of ligand-dependent transcription factors, namely, peroxisome proliferator-activated receptors (PPARs. Because PPARs are dietary lipid sensors that control energy homeostasis, daily eating of these terpenoids might be useful for the management for obesity-induced metabolic disorders, such as type 2 diabetes, hyperlipidemia, insulin resistance, and cardiovascular diseases.

  1. PPAR-gamma ligands and amino acid deprivation promote apoptosis of melanoma, prostate, and breast cancer cells.

    Science.gov (United States)

    Núñez, Nomelí P; Liu, Huaitian; Meadows, Gary G

    2006-05-08

    The PPAR-gamma ligands, 15-deoxy-Delta(12,14)-prostaglandin J(2) and ciglitazone, and the PPAR-alpha ligand, WY-14643, were examined for their effects on proliferation and apoptosis of A375 melanoma, DU145 and PC3 prostate cancer, and MB-MDA-231 breast cancer. While 15-deoxy-Delta(12,14)-prostaglandin J(2) inhibited proliferation of A375 melanoma, ciglitazone was inactive against this and the other cell lines. Restriction of specific amino acids known to inhibit proliferation and induce apoptosis sensitized all cell lines to ciglitazone, and the combined effects were greater than the individual effects of either treatment. WY-14643 alone or in combination with amino acid deprivation was inactive. Normal fibroblasts were resistant to the treatments.

  2. Quantified regional and laminar distribution of the noradrenaline innervation in the anterior half of the adult rat cerebral cortex

    Energy Technology Data Exchange (ETDEWEB)

    Audet, M.A.; Doucet, G.; Oleskevich, S.; Descarries, L.

    1988-08-15

    The regional and laminar distribution of the noradrenaline (NA) innervation in the adult rat cerebral cortex was quantified in radioautographs of semithin sections from whole hemisphere slices incubated with tritiated catecholamines and a monoamine oxidase inhibitor. Uptake-labeled axonal varicosities (aggregates of silver grains) were counted with the help of a computerized image analyzer in seven cytoarchitectonic areas of the rostral half of the cortex: Cg3, rostral AID, Cg2, Fr1, Par1, caudal AID, and Pir (prepiriform) according to Zilles's nomenclature. Both dopamine (DA) and NA terminals were detected after incubation with (3H)DA and citalopram or with (3H)NA alone. In the presence of desipramine (DMI), DA terminals alone were demonstrated; the number of NA terminals was then obtained by subtraction from counts in adjacent slices incubated with or without DMI. These counts suggested that DA and NA varicosities were fully visualized only after labeling with their respective tritiated amine. Similar numbers of labeled NA varicosities as inferred after (3H)NA incubation with or without DMI were observed after (3H)NA incubation in the presence of benztropine (BZ). This indicated that NA terminals were then maximally detected to the exclusion of the DA ones, and the latter approach was adopted for the acquisition of normative data. Since the average diameter of the labeled NA varicosities was known from earlier measurements in electron microscope radioautographs, the initial counts of labeled sites/mm2 of histological section could be expressed as numbers of varicosities/mm3 of tissue following a double correction for incomplete detection at the chosen duration of radioautographic exposure and section thickness.

  3. Tph2 gene deletion enhances amphetamine-induced hypermotility: effect of 5-HT restoration and role of striatal noradrenaline release.

    Science.gov (United States)

    Carli, Mirjana; Kostoula, Chrysaugi; Sacchetti, Giuseppina; Mainolfi, Pierangela; Anastasia, Alessia; Villani, Claudia; Invernizzi, Roberto William

    2015-11-01

    Variants of tryptophan hydroxylase-2 (Tph2), the gene encoding enzyme responsible for the synthesis of brain serotonin (5-HT), have been associated with neuropsychiatric disorders, substance abuse and addiction. This study assessed the effect of Tph2 gene deletion on motor behavior and found that motor activity induced by 2.5 and 5 mg/kg amphetamine was enhanced in Tph2(-/-) mice. Using the in vivo microdialysis technique we found that the ability of amphetamine to stimulate noradrenaline (NA) release in the striatum was reduced by about 50% in Tph2(-/-) mice while the release of dopamine (DA) was not affected. Tph2 deletion did not affect the release of NA and DA in the prefrontal cortex. The role of endogenous 5-HT in enhancing the effect of amphetamine was confirmed showing that treatment with the 5-HT precursor 5-hydroxytryptophan (10 mg/kg) restored tissue and extracellular levels of brain 5-HT and the effects of amphetamine on striatal NA release and motor activity in Tph2(-/-) mice. Treatment with the NA precursor dihydroxyphenylserine (400 mg/kg) was sufficient to restore the effect of amphetamine on striatal NA release and motor activity in Tph2(-/-) mice. These findings indicate that amphetamine-induced hyperactivity is attenuated by endogenous 5-HT through the inhibition of striatal NA release. Tph2(-/-) mice may be a useful preclinical model to assess the role of 5-HT-dependent mechanisms in the action of psychostimulants. Acute sensitivity to the motor effects of amphetamine has been associated to increased risk of psychostimulant abuse. Here, we show that deletion of Tph2, the gene responsible for brain 5-HT synthesis, enhances the motor effect of amphetamine in mice through the inhibition of striatal NA release. This suggests that Tph2(-/-) mice is a useful preclinical model to assess the role of 5-HT-dependent mechanisms in psychostimulants action. Tph2, tryptophan hydroxylase-2.

  4. Serotonin, Dopamine and Noradrenaline Adjust Actions of Myelinated Afferents via Modulation of Presynaptic Inhibition in the Mouse Spinal Cord

    Science.gov (United States)

    García-Ramírez, David L.; Calvo, Jorge R.; Hochman, Shawn; Quevedo, Jorge N.

    2014-01-01

    Gain control of primary afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including primary afferent depolarization (PAD). PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (5HT), dopamine (DA) and noradrenaline (NA) on afferent transmission and PAD. Responses were evoked by stimulation of myelinated hindlimb cutaneous and muscle afferents in the isolated neonatal mouse spinal cord. Monosynaptic responses were examined in the deep dorsal horn either as population excitatory synaptic responses (recorded as extracellular field potentials; EFPs) or intracellular excitatory postsynaptic currents (EPSCs). The magnitude of PAD generated intraspinally was estimated from electrotonically back-propagating dorsal root potentials (DRPs) recorded on lumbar dorsal roots. 5HT depressed the DRP by 76%. Monosynaptic actions were similarly depressed by 5HT (EFPs 54%; EPSCs 75%) but with a slower time course. This suggests that depression of monosynaptic EFPs and DRPs occurs by independent mechanisms. DA and NA had similar depressant actions on DRPs but weaker effects on EFPs. IC50 values for DRP depression were 0.6, 0.8 and 1.0 µM for 5HT, DA and NA, respectively. Depression of DRPs by monoamines was nearly-identical in both muscle and cutaneous afferent-evoked responses, supporting a global modulation of the multimodal afferents stimulated. 5HT, DA and NA produced no change in the compound antidromic potentials evoked by intraspinal microstimulation indicating that depression of the DRP is unrelated to direct changes in the excitability of intraspinal afferent fibers, but due to metabotropic receptor activation. In summary, both myelinated afferent-evoked DRPs and monosynaptic transmission in the

  5. An electrophysiological analysis of the effects of noradrenaline and alpha-receptor antagonists on neuromuscular transmission in mammalian muscular arteries.

    Science.gov (United States)

    Holman, M E; Surprenant, A

    1980-01-01

    1 The effects of exogenously applied noradrenaline (NA) and alpha-adrenoceptor antagonists on the mechanical and intracellularly recorded responses to perivascular nerve stimulation were examined in the rabbit ear artery, rabbit saphenous artery and rat tail artery. 2 Excitatory junction potentials (e.j.ps) and action potentials recorded from these smooth muscles were not blocked or depressed by phentolamine, phenoxybenzamine, prazosin, or labetolol in concentrations as high as 10 microgram/ml. Phentolamine (1 to 10 microgram/ml) depressed neurally-evoked contractions of the ear and saphenous, but not the tail artery, and also depressed the contractions produced by direct muscle stimulation in the ear and saphenous arteries. Prazosin and labetolol (0.1 to 10 microgram/ml) had no effect on the neurally evoked contractile response in any of the arteries examined. 3 The amplitude of the steady-state e.j.p. during repetitive stimulation at 0.45 to 2 Hz was increased by phentolamine or phenoxybenzamine but not by prazosin or labetolol. Phentolamine and phenoxybenzamine also increased the amplitude of the e.j.p. evoked by a single stimulus in the majority of the preparations. 4 Concentrations of NA greater than or equal to 1 microgram/ml depolarized the smooth muscle while concentrations greater than or equal to 0.5 microgram/ml depressed the amplitude of the e.j.ps recorded from these arteries. alpha-Antagonists did not suppress either the NA-induced membrane depolarization or depression of e.j.ps. 5 These observations call into question the physiological relevance of both pre- and postsynaptic alpha-receptors in regard to adrenergic neuromuscular transmission in muscular arteries.

  6. Serotonin, dopamine and noradrenaline adjust actions of myelinated afferents via modulation of presynaptic inhibition in the mouse spinal cord.

    Directory of Open Access Journals (Sweden)

    David L García-Ramírez

    Full Text Available Gain control of primary afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including primary afferent depolarization (PAD. PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (5HT, dopamine (DA and noradrenaline (NA on afferent transmission and PAD. Responses were evoked by stimulation of myelinated hindlimb cutaneous and muscle afferents in the isolated neonatal mouse spinal cord. Monosynaptic responses were examined in the deep dorsal horn either as population excitatory synaptic responses (recorded as extracellular field potentials; EFPs or intracellular excitatory postsynaptic currents (EPSCs. The magnitude of PAD generated intraspinally was estimated from electrotonically back-propagating dorsal root potentials (DRPs recorded on lumbar dorsal roots. 5HT depressed the DRP by 76%. Monosynaptic actions were similarly depressed by 5HT (EFPs 54%; EPSCs 75% but with a slower time course. This suggests that depression of monosynaptic EFPs and DRPs occurs by independent mechanisms. DA and NA had similar depressant actions on DRPs but weaker effects on EFPs. IC50 values for DRP depression were 0.6, 0.8 and 1.0 µM for 5HT, DA and NA, respectively. Depression of DRPs by monoamines was nearly-identical in both muscle and cutaneous afferent-evoked responses, supporting a global modulation of the multimodal afferents stimulated. 5HT, DA and NA produced no change in the compound antidromic potentials evoked by intraspinal microstimulation indicating that depression of the DRP is unrelated to direct changes in the excitability of intraspinal afferent fibers, but due to metabotropic receptor activation. In summary, both myelinated afferent-evoked DRPs and monosynaptic

  7. Activation of PPAR-γ reduces HPA axis activity in diabetic rats by up-regulating PI3K expression.

    Science.gov (United States)

    Torres, Rafael Carvalho; Magalhães, Nathalia Santos; E Silva, Patrícia M R; Martins, Marco A; Carvalho, Vinicius F

    2016-10-01

    Increased hypothalamus-pituitary-adrenal axis (HPA) activity in diabetes is strongly associated with several morbidities noted in patients with the disease. We previously demonstrated that hyperactivity of HPA axis under diabetic conditions is associated with up-regulation of adrenocorticotrophic hormone (ACTH) receptors (MC2R) in adrenal and down-regulation of glucocorticoid receptors (GR and MR) in pituitary. This study investigates the role of peroxisome proliferator-activated receptor (PPAR)-γ in HPA axis hyperactivity in diabetic rats. Diabetes was induced by intravenous injection of alloxan into fasted rats. The PPAR-γ agonist rosiglitazone and/or PI3K inhibitor wortmannin were administered daily for 18 consecutive days, starting 3days after diabetes induction. Plasma ACTH and corticosterone were evaluated by radioimmunoassay, while intensities of MC2R, proopiomelanocortin (POMC), GR, MR, PI3K p110α and PPAR-γ were assessed using immunohistochemistry. Rosiglitazone treatment inhibited adrenal hypertrophy and hypercorticoidism observed in diabetic rats. Rosiglitazone also significantly reversed the diabetes-induced increase in the MC2R expression in adrenal cortex. We noted that rosiglitazone reduced the number of corticotroph cells and inhibited both anterior pituitary POMC expression and plasma ACTH levels. Furthermore, rosiglitazone treatment was unable to restore the reduced expression of GR and MR in the anterior pituitary of diabetic rats. Rosiglitazone increased the number of PPAR-γ(+) cells and expression of PI3K p110α in both anterior pituitary and adrenal cortex of diabetic rats. In addition, wortmannin blocked the ability of rosiglitazone to restore corticotroph cell numbers, adrenal hypertrophy and plasma corticosterone levels in diabetic rats. In conclusion, our findings revealed that rosiglitazone down-regulates HPA axis hyperactivity in diabetic rats via a mechanism dependent on PI3K activation in pituitary and adrenal glands.

  8. 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.

  9. CDK inhibitors-induced SSAT expression requires NF?B and PPAR? inMCF-7 breast cancer cells

    OpenAIRE

    Obakan, Pinar; YILDIRIM, ŞEYMA; ÖZTÜRK, MERT BURAK; BERRAK, ÖZGE; GÜRKAN, AJDA ÇOKER; ARISAN, ELİF DAMLA; ÜNSAL, ZEYNEP NARÇİN

    2015-01-01

    The cyclin-dependent kinase (CDK) inhibitors purvalanol and roscovitine are therapeutic agents that control cell proliferation through regulating cell-cycle machinery. They also affect polyamine (PA) metabolism, which is activated in malignant tissues. Therefore, PA catabolism became a remarkable target in cancer therapies. Induction of the PA catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT) is under the control of transcription factors such as NF?B and PPARγ. Th...

  10. Repression of death consciousness and the psychedelic trip

    Directory of Open Access Journals (Sweden)

    Varsha Dutta

    2012-01-01

    Full Text Available Death is our most repressed consciousness, it inheres our condition as the primordial fear. Perhaps it was necessary that this angst be repressed in man or he would be hurled against the dark forces of nature. Modern ethos was built on this edifice, where the ′denial of death′ while ′embracing one′s symbolic immortality′ would be worshipped, so this ideology simply overturned and repressed looking into the morass of the inevitable when it finally announced itself. Once this slowly pieced its way into all of life, ′death′ would soon become a terminology in medicine too and assert its position, by giving a push to those directly dealing with the dying to shy away from its emotional and spiritual affliction. The need to put off death and prolong one′s life would become ever more urgent. Research using psychedelics on the terminally ill which had begun in the 1950s and 1960s would coerce into another realm and alter the face of medicine; but the aggression with which it forced itself in the 1960s would soon be politically maimed, and what remained would be sporadic outpours that trickled its way from European labs and underground boot camps. Now, with the curtain rising, the question has etched itself again, about the use of psychedelic drugs in medicine, particularly psychedelic psychotherapy with the terminally ill. This study is an attempt to philosophically explore death anxiety from its existential context and how something that is innate in our condition cannot be therapeutically cured. Psychedelic use was immutably linked with ancient cultures and only recently has it seen its scientific revival, from which a scientific culture grew around psychedelic therapy. How much of what was threaded in the ritual and spiritual mores can be extricated and be interpreted in our own mechanized language of medicine is the question that nudges many.

  11. Repression of death consciousness and the psychedelic trip.

    Science.gov (United States)

    Dutta, Varsha

    2012-01-01

    Death is our most repressed consciousness, it inheres our condition as the primordial fear. Perhaps it was necessary that this angst be repressed in man or he would be hurled against the dark forces of nature. Modern ethos was built on this edifice, where the 'denial of death' while 'embracing one's symbolic immortality' would be worshipped, so this ideology simply overturned and repressed looking into the morass of the inevitable when it finally announced itself. Once this slowly pieced its way into all of life, 'death' would soon become a terminology in medicine too and assert its position, by giving a push to those directly dealing with the dying to shy away from its emotional and spiritual affliction. The need to put off death and prolong one's life would become ever more urgent. Research using psychedelics on the terminally ill which had begun in the 1950s and 1960s would coerce into another realm and alter the face of medicine; but the aggression with which it forced itself in the 1960s would soon be politically maimed, and what remained would be sporadic outpours that trickled its way from European labs and underground boot camps. Now, with the curtain rising, the question has etched itself again, about the use of psychedelic drugs in medicine, particularly psychedelic psychotherapy with the terminally ill. This study is an attempt to philosophically explore death anxiety from its existential context and how something that is innate in our condition cannot be therapeutically cured. Psychedelic use was immutably linked with ancient cultures and only recently has it seen its scientific revival, from which a scientific culture grew around psychedelic therapy. How much of what was threaded in the ritual and spiritual mores can be extricated and be interpreted in our own mechanized language of medicine is the question that nudges many.

  12. Metformin and low dose radiation modulates cisplatin-induced oxidative injury in rat via PPAR-γ and MAPK pathways.

    Science.gov (United States)

    Mansour, Heba H; El Kiki, Shereen M; Galal, Shereen M

    2017-02-15

    Cisplatin (CIS) is a chemotherapeutic agent used for therapy of many tumors and has been limited by its toxicity. The aim of this study was to investigate the role of Peroxisome proliferator-activated receptor-gamma (PPAR-γ), mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B(NFkB) in the pathogenesis of hepatic damage induced by CIS, and investigated the modulatory effect of metformin (MET) and/or low dose gamma radiation (LDR) on CIS-induced hepatotoxicity in rats. CIS(7.5 mg/kg, i.p.) hepatotoxicity was evidenced by alteration of serum hepatic indices (ALT and AST) accompanied with decreased hepatic PPAR-γ, superoxide dismutase (SOD) activities and reduced glutathione (GSH) content, whereas the levels of malondialdehyde (MDA), total nitrate/nitrite (NOx) and NFkB significantly increased as well as MAPK activity compared with the control, MET and LDR groups. Furthermore, CIS induces apoptosis as indicated by an elevation of hepatic caspase-3. Treatment with MET (150 mg/kg, orally for 14 days) and/or LDR (0.5 Gy), prior to CIS alleviates CIS-induced hepatic damage by mitigating oxidative/ nitrosative stress and PPAR-γ activity reduction, hepatic caspase-3 elevation, and inhibition of NFκB, and MAPK activity levels.

  13. Regulation of FADS2 transcription by SREBP-1 and PPAR-α influences LC-PUFA biosynthesis in fish

    Science.gov (United States)

    Dong, Xiaojing; Tan, Peng; Cai, Zuonan; Xu, Hanlin; Li, Jingqi; Ren, Wei; Xu, Houguo; Zuo, Rantao; Zhou, Jianfeng; Mai, Kangsen; Ai, Qinghui

    2017-01-01

    The present study was conducted to explore the mechanisms leading to differences among fishes in the ability to biosynthesize long-chain polyunsaturated fatty acids (LC-PUFAs). Replacement of fish oil with vegetable oil caused varied degrees of increase in 18-carbon fatty acid content and decrease in n-3 LC-PUFA content in the muscle and liver of rainbow trout (Oncorhynchus mykiss), Japanese seabass (Lateolabrax japonicus) and large yellow croaker (Larimichthys crocea), suggesting that these fishes have differing abilities to biosynthesize LC-PUFAs. Fish oil replacement also led to significantly up-regulated expression of FADS2 and SREBP-1 but different responses of the two PPAR-α homologues in the livers of these three fishes. An in vitro experiment indicated that the basic transcription activity of the FADS2 promoter was significantly higher in rainbow trout than in Japanese seabass or large yellow croaker, which was consistent with their LC-PUFA biosynthetic abilities. In addition, SREBP-1 and PPAR-α up-regulated FADS2 promoter activity. These regulatory effects varied considerably between SREBP-1 and PPAR-α, as well as among the three fishes. Taken together, the differences in regulatory activities of the two transcription factors targeting FADS2 may be responsible for the different LC-PUFA biosynthetic abilities in these three fishes that have adapted to different ambient salinity. PMID:28067297

  14. 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.

  15. The In Vitro and In Vivo Anti-Inflammatory Effects of a Phthalimide PPAR-γ Agonist.

    Science.gov (United States)

    Su, Mingzhi; Cao, Jiafu; Huang, Jin; Liu, Sen; Im, Dong Soon; Yoo, Jin-Wook; Jung, Jee H

    2017-01-04

    Previously, the authors found that 4-hydroxy-2-(4-hydroxyphenethyl) isoindoline-1,3-dione (PD1) (a phthalimide analogue) bound to and activated peroxisome proliferator-activated receptor-γ (PPAR-γ). Since PPAR-γ suppresses inflammatory responses, the present study was undertaken to investigate the anti-inflammatory effects of PD1. In lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages, PD1 suppressed the inductions of pro-inflammatory factors, including inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase 2 (COX-2), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Concomitantly, PD1 enhanced the expressions of anti-inflammatory factors, such as arginase-1 and interleukin-10 (IL-10), and suppressed LPS-evoked nuclear factor kappa B (NF-κB) p65 subunit phosphorylation in macrophages. In addition, PPAR-γ activated by PD1 was intensively translocated to the nucleus. These observations suggest that the anti-inflammatory mechanism of PD1 involves inhibition of the NF-κB pathway. In a subsequent in vivo animal experiment conducted using a carrageenan-induced acute inflammatory rat paw edema model, intraperitoneal injection of PD1 significantly reduced paw swelling. Histological analysis of rat paw tissue sections revealed less infiltration of immune cells in PD1-pretreated animals. These findings suggest that PD1 be viewed as a lead compound for the development of novel anti-inflammatory therapeutics.

  16. Hepatic ATGL mediates PPAR-α signaling and fatty acid channeling through an L-FABP independent mechanism.

    Science.gov (United States)

    Ong, Kuok Teong; Mashek, Mara T; Davidson, Nicholas O; Mashek, Douglas G

    2014-05-01

    Adipose TG lipase (ATGL) catalyzes the rate-limiting step in TG hydrolysis in most tissues. We have shown that hepatic ATGL preferentially channels hydrolyzed FAs to β-oxidation and induces PPAR-α signaling. Previous studies have suggested that liver FA binding protein (L-FABP) transports FAs from lipid droplets to the nucleus for ligand delivery and to the mitochondria for β-oxidation. To determine if L-FABP is involved in ATGL-mediated FA channeling, we used adenovirus-mediated suppression or overexpression of hepatic ATGL in either WT or L-FABP KO mice. Hepatic ATGL knockdown increased liver weight and TG content of overnight fasted mice regardless of genotype. L-FABP deletion did not impair the effects of ATGL overexpression on the oxidation of hydrolyzed FAs in primary hepatocyte cultures or on serum β-hydroxybutyrate concentrations in vivo. Moreover, L-FABP deletion did not influence the effects of ATGL knockdown or overexpression on PPAR-α target gene expression. Taken together, we conclude that L-FABP is not required to channel ATGL-hydrolyzed FAs to mitochondria for β-oxidation or the nucleus for PPAR-α regulation.