Inhibition of hypoxia inducible factor-1alpha by dihydroxyphenylethanol, a product from olive oil, blocks microsomal prostaglandin-E synthase-1/vascular endothelial growth factor expression and reduces tumor angiogenesis.

Science.gov (United States)

Terzuoli, Erika; Donnini, Sandra; Giachetti, Antonio; Iñiguez, Miguel A; Fresno, Manuel; Melillo, Giovanni; Ziche, Marina

2010-08-15

2-(3,4-dihydroxyphenil)-ethanol (DPE), a polyphenol present in olive oil, has been found to attenuate the growth of colon cancer cells, an effect presumably related to its anti-inflammatory activity. To further explore the effects of DPE on angiogenesis and tumor growth we investigated the in vivo efficacy of DPE in a HT-29 xenograft model and in vitro activities in colon cancer cells exposed to interleukin-1beta (IL-1beta) and prostaglandin E-2 (PGE-2). DPE (10 mg/kg/day for 14 days) inhibited tumor growth, reducing vessel lumina and blood perfusion to tumor, and diminished expression of hypoxia inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), and microsomal prostaglandin-E synthase-1 (mPGEs-1). In vitro, DPE (100 mumol/L) neither affected cell proliferation nor induced apoptosis in HT-29 and WiDr cells. DPE prevented the IL-1beta-mediated increase of mPGEs-1 expression and PGE-2 generation, as it did the silencing of HIF-1alpha. Moreover, DPE blocked mPGEs-1-dependent expression of VEGF and inhibited endothelial sprouting induced by tumor cells in a coculture system. PGE-2 triggers a feed-forward loop involving HIF-1alpha, which impinges on mPGEs-1 and VEGF expression, events prevented by DPE via extracellular signal-related kinase 1/2. The reduction of PGE-2 and VEGF levels, caused by DPE, was invariably associated with a marked decrease in HIF-1alpha expression and activity, independent of proteasome activity, indicating that the DPE effects on tumor growth and angiogenesis are dependent on the inhibition of HIF-1alpha translation. We show that the in vivo DPE antitumor effect is associated with anti-inflammatory and antiangiogenic activities resulting from the downregulation of the HIF-1alpha/mPGEs-1/VEGF axis.

Dominant role of prostaglandin E2 EP4 receptor in furosemide-induced salt-losing tubulopathy: a model for hyperprostaglandin E syndrome/antenatal Bartter syndrome

DEFF Research Database (Denmark)

Nüsing, Rolf M; Treude, Antje; Weissenberger, Christian

2005-01-01

Increased formation of prostaglandin E2 (PGE2) is a key part of hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS), a renal disease characterized by NaCl wasting, water loss, and hyperreninism. Inhibition of PGE2 formation by cyclo-oxygenase inhibitors significantly lowers patient...

Do stress responses promote leukemia progression? An animal study suggesting a role for epinephrine and prostaglandin-E2 through reduced NK activity.

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Shelly Inbar

2011-04-01

Full Text Available In leukemia patients, stress and anxiety were suggested to predict poorer prognosis. Oncological patients experience ample physiological and psychological stress, potentially leading to increased secretion of stress factors, including epinephrine, corticosteroids, and prostaglandins. Here we tested whether environmental stress and these stress factors impact survival of leukemia-challenged rats, and studied mediating mechanisms. F344 rats were administered with a miniscule dose of 60 CRNK-16 leukemia cells, and were subjected to intermittent forced swim stress or to administration of physiologically relevant doses of epinephrine, prostaglandin-E(2 or corticosterone. Stress and each stress factor, and/or their combinations, doubled mortality rates when acutely applied simultaneously with, or two or six days after tumor challenge. Acute administration of the β-adrenergic blocker nadolol diminished the effects of environmental stress, without affecting baseline survival rates. Prolonged β-adrenergic blockade or COX inhibition (using etodolac also increased baseline survival rates, possibly by blocking tumor-related or normal levels of catecholamines and prostaglandins. Searching for mediating mechanisms, we found that each of the stress factors transiently suppressed NK activity against CRNK-16 and YAC-1 lines on a per NK basis. In contrast, the direct effects of stress factors on CRNK-16 proliferation, vitality, and VEGF secretion could not explain or even contradicted the in vivo survival findings. Overall, it seems that environmental stress, epinephrine, and prostaglandins promote leukemia progression in rats, potentially through suppressing cell mediated immunity. Thus, patients with hematological malignancies, which often exhibit diminished NK activity, may benefit from extended β-blockade and COX inhibition.

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

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

2009-12-01

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

Curcumin induces apoptosis and inhibits prostaglandin E(2) production in synovial fibroblasts of patients with rheumatoid arthritis.

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Park, Cheol; Moon, Dong-Oh; Choi, Il-Whan; Choi, Byung Tae; Nam, Taek-Jeong; Rhu, Chung-Ho; Kwon, Taeg Kyu; Lee, Won Ho; Kim, Gi-Young; Choi, Yung Hyun

2007-09-01

Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterized by hyperplasia of the synovial fibroblasts, which is partly the result of decreased apoptosis. This study investigated the mechanisms through which curcumin, a polyphenolic compound from the rhizome of Curcuma longa, exerts its anti-proliferative action in the synovial fibroblasts obtained from patients with RA. Exposure of the synovial fibroblasts to curcumin resulted in growth inhibition and the induction of apoptosis, as measured by MTT assay, fluorescent microscopy and Annexin-V-based assay. RT-PCR and immunoblotting showed that treating the cells with curcumin resulted in the down-regulation of anti-apoptotic Bcl-2 and the X-linked inhibitor of the apoptosis protein as well as the up-regulation of pro-apoptotic Bax expression in a concentration-dependent manner. Curcumin-induced apoptosis was also associated with the proteolytic activation of caspase-3 and caspase-9, and the concomitant degradation of poly(ADP-ribose) polymerase protein. Furthermore, curcumin decreased the expression levels of the cyclooxygenase (COX)-2 mRNA and protein without causing significant changes in the COX-1 levels, which was correlated with the inhibition of prostaglandin E(2) synthesis. These results show that curcumin might help identify a new therapeutic pathway against hyperplasia of the synovial fibroblasts in RA.

Prostaglandin E2 release from dermis regulates sodium permeability of frog skin epithelium

DEFF Research Database (Denmark)

Rytved, Klaus A.; Brodin, Birger; Nielsen, Robert

1995-01-01

Arachidonic acid, cAMP, epithelium, frog skin, intracellular calcium, prostaglandin E*U2, sodium transport, tight epithelium.......Arachidonic acid, cAMP, epithelium, frog skin, intracellular calcium, prostaglandin E*U2, sodium transport, tight epithelium....

Solute concentration affects bradykinin-mediated increases in renal prostaglandin E2

International Nuclear Information System (INIS)

Zenser, T.V.; Davis, E.S.; Rapp, N.S.; Davis, B.B.

1981-01-01

The effects of solute concentration on the bradykinin-mediated increase in inner medullary slice prostaglandin E2 (PGE2) synthesis were investigated. PG content was determined by specific RIA. Bradykinin stimulation was prevented by the addition of the following solutes to Krebs buffer: 1.0 M urea, 0.5 or 1.0 M NaCl, 0.5 or 1.0 M mannitol, 1.0 M urea plus 0.5 M NaCl, or 1.0 M mannitol plus 0.5 M NaCl. By contrast, basal PGE2 synthesis was increased by 1.0 M mannitol or by 1.0 M mannitol plus 0.5 M NaCl, but decreased by 1.0 M urea. Urea elicited a concentration-dependent, reversible inhibition of bradykinin stimulation, with 0.01 M urea being the lowest effective concentration. By contrast, basal PGE2 synthesis was only reduced at a urea concentration greater than 0.6 M. Arachidonic acid-mediated increases in both PGE2 and PGF2 alpha synthesis were not prevented by 1.0 M urea. The latter suggests that neither PG endoperoxide synthetase nor PG endoperoxide E isomerase are inhibited by urea. The data indicate that different hypertonic solutions have different effects on basal PG production, but all inhibit bradykinin stimulation

NO2 inhalation promotes Alzheimer’s disease-like progression: cyclooxygenase-2-derived prostaglandin E2 modulation and monoacylglycerol lipase inhibition-targeted medication

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Yan, Wei; Yun, Yang; Ku, Tingting; Li, Guangke; Sang, Nan

2016-03-01

Air pollution has been reported to be associated with increased risks of cognitive impairment and neurodegenerative diseases. Because NO2 is a typical primary air pollutant and an important contributor to secondary aerosols, NO2-induced neuronal functional abnormalities have attracted greater attention, but the available experimental evidence, modulating mechanisms, and targeting medications remain ambiguous. In this study, we exposed C57BL/6J and APP/PS1 mice to dynamic NO2 inhalation and found for the first time that NO2 inhalation caused deterioration of spatial learning and memory, aggravated amyloid β42 (Aβ42) accumulation, and promoted pathological abnormalities and cognitive defects related to Alzheimer’s disease (AD). The microarray and bioinformation data showed that the cyclooxygenase-2 (COX-2)-mediated arachidonic acid (AA) metabolism of prostaglandin E2 (PGE2) played a key role in modulating this aggravation. Furthermore, increasing endocannabinoid 2-arachidonoylglycerol (2-AG) by inhibiting monoacylglycerol lipase (MAGL) prevented PGE2 production, neuroinflammation-associated Aβ42 accumulation, and neurodegeneration, indicating a therapeutic target for relieving cognitive impairment caused by NO2 exposure.

The Kallikrein-Kinin System in Bartter's Syndrome and Its Response to Prostaglandin Synthetase Inhibition

Science.gov (United States)

Vinci, Joseph M.; Gill, John R.; Bowden, Robert E.; Pisano, John J.; Izzo, Joseph L.; Radfar, Nazam; Taylor, Addison A.; Zusman, Randall M.; Bartter, Frederic C.; Keiser, Harry R.

1978-01-01

The kallikrein-kinin system was characterized in seven patients with Bartter's syndrome on constant metabolic regimens before, during, and after treatment with prostaglandin synthetase inhibitors. Patients with Bartter's syndrome had high values for plasma bradykinin, plasma renin activity (PRA), urinary kallikrein, urinary immunoreactive prostaglandin E excretion, and urinary aldosterone; urinary kinins were subnormal and plasma prekallikrein was normal. Treatment with indomethacin or ibuprofen which decreased urinary immunoreactive prostaglandin E excretion by 67%, decreased mean PRA (patients recumbent) from 17.3±5.3 (S.E.M.) ng/ml per h to 3.3±1.1 ng/ml per h, mean plasma bradykinin (patients recumbent) from 15.4±4.4 ng/ml to 3.9±0.9 ng/ml, mean urinary kallikrein excretion from 24.8±3.2 tosyl-arginine-methyl ester units (TU)/day to 12.4±2.0 TU/day, but increased mean urinary kinin excretion from 3.8±1.3 μg/day to 8.5±2.5 μg/day. Plasma prekallikrein remained unchanged at 1.4 TU/ml. Thus, with prostaglandin synthetase inhibition, values for urinary kallikrein and kinin and plasma bradykinin returned to normal pari passu with changes in PRA, in aldosterone, and in prostaglandin E. The results suggest that, in Bartter's syndrome, prostaglandins mediate the low urinary kinins and the high plasma bradykinin, and that urinary kallikrein, which is aldosterone dependent, does not control kinin excretion. The high plasma bradykinin may be a cause of the pressor hyporesponsiveness to angiotensin II which characterizes the syndrome. PMID:96139

Selective inhibition of prostaglandin E2 receptors EP2 and EP4 inhibits adhesion of human endometriotic epithelial and stromal cells through suppression of integrin-mediated mechanisms.

Science.gov (United States)

Lee, JeHoon; Banu, Sakhila K; Burghardt, Robert C; Starzinski-Powitz, Anna; Arosh, Joe A

2013-03-01

Endometriosis is a chronic gynecological disease of reproductive age women characterized by the presence of functional endometrial tissues outside the uterine cavity. Interactions between the endometriotic cells and the peritoneal extracellular matrix proteins (ECM) are crucial mechanisms that allow adhesion of the endometriotic cells into peritoneal mesothelia. Prostaglandin E2 (PGE2) plays an important role in the pathogenesis of endometriosis. In previous studies, we have reported that selective inhibition of PGE2 receptors PTGER2 and PTGER4 decreases survival and invasion of human endometriotic epithelial and stromal cells through multiple mechanisms. Results of the present study indicates that selective inhibition of PTGER2- and PTGER4-mediated PGE2 signaling 1) decreases the expression and/or activity of specific integrin receptor subunits Itgb1 (beta1) and Itgb3 (beta3) but not Itgb5 (beta5), Itga1 (alpha1), Itga2 (alpha2), Itga5 (alpha5), and Itgav (alphav); 2) decreases integrin-signaling components focal adhesion kinase or protein kinase 2 (PTK2) and talin proteins; 3) inhibits interactions between Itgb1/Itgb3 subunits, PTK2, and talin and PTGER2/PTGER4 proteins through beta-arrestin-1 and Src kinase protein complex in human endometriotic epithelial cells 12Z and stromal cells 22B; and 4) decreases adhesion of 12Z and 22B cells to ECM collagen I, collagen IV, fibronectin, and vitronectin in a substrate-specific manner. These novel findings provide an important molecular framework for further evaluation of selective inhibition of PTGER2 and PTGER4 as potential nonsteroidal therapy to expand the spectrum of currently available treatment options for endometriosis in child-bearing age women.

Inhibition of prostaglandin synthesis after metabolism of menadione by cultured porcine endothelial cells

International Nuclear Information System (INIS)

Barchowsky, A.; Tabrizi, K.; Kent, R.S.; Whorton, A.R.

1989-01-01

We have examined the effects of menadione on porcine aortic endothelial cell prostaglandin synthesis. Addition of 1-20 microM menadione caused a dose- and time-dependent inhibition of stimulated prostaglandin synthesis with an IC50 of 5 microM at 15 min. Concentrations greater than 100 microM menadione were necessary to increase 51 Cr release from prelabeled cells. Recovery of enzyme inactivated by menadione required a 6-h incubation in 1% serum. In a microsomal preparation, menadione was shown to have no direct effect on conversion of arachidonic acid to prostaglandins. In intact cells menadione caused only a 40% inhibition of the conversion of PGH2 to prostacyclin. Enzymes involved in the incorporation and the release of arachidonic acid were not affected by menadione (20 microM, 15 min). Menadione undergoes oxidation/reduction reactions in intact cells leading to partial reduction of oxygen-forming, reactive oxygen species. In our cells menadione was found to increase KCN-resistant oxygen consumption. Further, an increased accumulation of H 2 O 2 was observed with a time course consistent with menadione-induced inhibition of prostaglandin synthesis. We conclude that menadione at sublethal doses caused inhibition of prostaglandin synthesis. The mechanism involves inactivation of PGH2 synthase by a reactive species resulting from metabolism of menadione by endothelial cells

Regulation of prostaglandin E2 synthesis after brain irradiation

International Nuclear Information System (INIS)

Moore, Amy H.; Olschowka, John A.; Williams, Jacqueline P.; Okunieff, Paul; O'Banion, M. Kerry

2005-01-01

Purpose: A local tissue reaction, termed neuroinflammation, occurs after irradiation of brain tissue. Previous work suggested that cyclooxygenase (COX)-2 activity was important for changes in gene expression associated with neuroinflammation as well as increased prostaglandin E 2 (PGE 2 ) levels seen after radiation treatment. Methods and materials: To begin to determine the contributions of other enzymes involved in PGE 2 production, we examined protein levels of COX-1 and COX-2 as well as 2 PGE synthases (membrane and cytosolic PGES) 4 h after 35 Gy single dose irradiation to the brains of C3HeN mice. We also evaluated the effects of specific COX inhibitors on PGE 2 production and PGES expression. Results: As expected, COX-2 expression increased after radiation exposure. Brain irradiation also increased tissue protein levels for both PGES isoforms. Specific COX-2 inhibition with NS398 lowered brain PGE 2 levels by about 60%. Surprisingly, COX-1 inhibition with SC560 completely prevented the elevation of PGE 2 seen after irradiation. Interestingly, NS398 reduced the membrane-associated PGES isoform, whereas SC560 treatment lowered cytosolic isoform levels below those seen in unirradiated controls. Conclusions: Taken together, these data indicate that both cyclooxygenases contribute to PGE 2 production in irradiated brain and reveal dependence of PGES isoforms expression on specific cyclooxygenase activities

Prostaglandin-E2 Mediated Increase in Calcium and Phosphate Excretion in a Mouse Model of Distal Nephron Salt Wasting.

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Manoocher Soleimani

Full Text Available Contribution of salt wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (pendrin/NCC-dKO mice display severe salt wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion. Confirmatory studies revealed decreases in the expression levels of sodium phosphate transporter-2 isoforms a and c, increases in the expression of cytochrome p450 family 4a isotypes 12 a and b, as well as prostaglandin E synthase 1, and cyclooxygenases 1 and 2. Pendrin/NCC-dKO animals also had a significant increase in urinary prostaglandin E2 (PGE-2 and renal content of 20-hydroxyeicosatetraenoic acid (20-HETE levels. Pendrin/NCC-dKO animals exhibit reduced expression levels of the sodium/potassium/2chloride co-transporter 2 (NKCC2 in their medullary thick ascending limb. Further assessment of the renal expression of NKCC2 isoforms by quantitative real time PCR (qRT-PCR reveled that compared to WT mice, the expression of NKCC2 isotype F was significantly reduced in pendrin/NCC-dKO mice. Provision of a high salt diet to rectify volume depletion or inhibition of PGE-2 synthesis by indomethacin, but not inhibition of 20-HETE generation by HET0016, significantly improved hypercalciuria and salt wasting in pendrin/NCC dKO mice. Both high salt diet and indomethacin treatment also corrected the alterations in NKCC2 isotype expression in pendrin/NCC-dKO mice. We propose that severe salt wasting and volume depletion, irrespective of the primary originating nephron segment, can secondarily impair the reabsorption of salt and calcium in the thick ascending limb of Henle and/or proximal tubule, and reabsorption of

R-Flurbiprofen Traps Prostaglandins within Cells by Inhibition of Multidrug Resistance-Associated Protein-4

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Ivonne Wobst

2016-12-01

Full Text Available R-flurbiprofen is the non-COX-inhibiting enantiomer of flurbiprofen and is not converted to S-flurbiprofen in human cells. Nevertheless, it reduces extracellular prostaglandin E2 (PGE2 in cancer or immune cell cultures and human extracellular fluid. Here, we show that R-flurbiprofen acts through a dual mechanism: (i it inhibits the translocation of cPLA2α to the plasma membrane and thereby curtails the availability of arachidonic acid and (ii R-flurbiprofen traps PGE2 inside of the cells by inhibiting multidrug resistance–associated protein 4 (MRP4, ABCC4, which acts as an outward transporter for prostaglandins. Consequently, the effects of R-flurbiprofen were mimicked by RNAi-mediated knockdown of MRP4. Our data show a novel mechanism by which R-flurbiprofen reduces extracellular PGs at physiological concentrations, particularly in cancers with high levels of MRP4, but the mechanism may also contribute to its anti-inflammatory and immune-modulating properties and suggests that it reduces PGs in a site- and context-dependent manner.

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

International Nuclear Information System (INIS)

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

1985-01-01

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

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

Energy Technology Data Exchange (ETDEWEB)

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

1985-12-15

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

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

Science.gov (United States)

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

2012-01-01

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

Stimulation of prostaglandin E2 production by phorbol esters and epidermal growth factor in porcine thyroid cells

International Nuclear Information System (INIS)

Kasai, K.; Hiraiwa, M.; Emoto, T.; Akimoto, K.; Takaoka, T.; Shimoda, S.I.

1987-01-01

Effects of phorbol esters and epidermal growth factor (EGF) on prostaglandin E 2 production by cultured porcine thyroid cells were examined. Both phorbol 12-myristate 13-acetate (PMA) and EGF stimulated prostaglandin E 2 production by the cells in dose related fashion. PMA stimulated prostaglandin E 2 production over fifty-fold with the dose of 10 -7 M compared with control. EGF (10 -7 M) also stimulated it about ten-fold. The ED 50 values of PMA and EGF were respectively around 1 x 10 -9 M and 5 x 10 -10 M. Thyroid stimulating hormone (TSH), however, did not stimulate prostaglandin E 2 production from 1 to 24-h incubation. The release of radioactivity from [ 3 H]-arachidonic acid prelabeled cells was also stimulated by PMA and EGF, but not by TSH. These results indicate that both PMA and EGF are potent stimulators of prostaglandin E 2 production, associated with the activity to stimulate arachidonic acid release in porcine thyroid cells. 36 references, 2 figures, 1 table

Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats

Science.gov (United States)

Rojas, Asheebo; Ganesh, Thota; Manji, Zahra; O’neill, Theon; Dingledine, Raymond

2016-01-01

Survivors of exposure to an organophosphorus nerve agent may develop a number of complications including long-term cognitive deficits (Miyaki et al., 2005; Nishiwaki et al., 2001). We recently demonstrated that inhibition of the prostaglandin E2 receptor, EP2, attenuates neuroinflammation and neurodegeneration caused by status epilepticus (SE) induced by the soman analog, diisopropylfluorophosphate (DFP), which manifest within hours to days of the initial insult. Here, we tested the hypothesis that DFP exposure leads to a loss of cognitive function in rats that is blocked by early, transient EP2 inhibition. Adult male Sprague-Dawley rats were administered vehicle or the competitive EP2 antagonist, TG6-10-1, (ip) at various times relative to DFP-induced SE. DFP administration resulted in prolonged seizure activity as demonstrated by cortical electroencephalography (EEG). A single intraperitoneal injection of TG6-10-1 or vehicle 1 h prior to DFP did not alter the development of seizures, the latency to SE or the duration of SE. Rats administered six injections of TG6-10-1 starting 90 min after the onset of DFP-induced SE could discriminate between a novel and familiar object 6–12 weeks after SE, unlike vehicle treated rats which showed no preference for the novel object. By contrast, behavioral changes in the light-dark box and open field assays were not affected by TG6-10-1. Delayed mortality after DFP was also unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor may prevent SE-induced memory impairment in rats caused by exposure to a high dose of DFP. PMID:27477533

Prostaglandin E 2 (PgE 2 ) Inhibition By Crude Extracts Of Selected ...

African Journals Online (AJOL)

This study was undertaken to assess anti-inflammatory activity of crude extracts of Cassine transvaalensis Burtt-Davy, Clerodendrum uncinatum Schinz and Commiphora glandulosa Schinz using COX inhibition assay. Water extract of C. transvaalensis root bark (125mg/ml) exhibited a (90%) PGE2 inhibition in ...

Prevotella intermedia induces prostaglandin E2 via multiple signaling pathways.

Science.gov (United States)

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

2011-01-01

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

Effects of prostaglandin E/sub 1/ on the metabolism in rat parathyroid gland in vitro

Energy Technology Data Exchange (ETDEWEB)

Licata, A A [Rochester Univ., NY (USA). School of Medicine and Dentistry; Au, W Y [Arkansas Univ., Little Rock (USA); Vera, J; Bartter, F C [National Institutes of Health, Bethesda, MD (USA)

1979-01-04

Some effects of prostaglandin E/sub 1/ on the metabolism of rat parathyroid glands have been investigated using a culture system containing basal Eagle's medium supplemented with 5-10% heat-inactivated rat serum. Rat parathyroid glands incorporate (/sup 3/H)fucose and /sup 14/C-labeled amino acids into cellular glycoproteins and secrete some of these into the culture medium. Gel filtration chromatography separates these glycoproteins into three classes, the smallest of which (peak 3) is secreted with immunoreactive parathyroid hormone. In cultures of 48 h, prostaglandin E/sub 1/ (1 ..mu..g/ml) specifically inhibits the secretion of peak 3 and of parathyroid hormone but has no effect on the incorporation of (/sup 3/H)-fucose, /sup 14/C-labeled amino acids, or (/sup 3/H)uridine into parathyroid glands. Cytochalasin B inhibits the secretion of parathyroid hormone and the incorporation of isotopic fucose and amino acids. Cortisol stimulates incorporation of (/sup 3/H)fucose and the secretion of parathyroid hormone even in the presence of inhibitory doses of prostaglandin E/sub 1/. It is concluded that, in organ culture, prostaglandin E/sub 1/ inhibits the secretion of parathyroid hormone and of a specific glycoprotein the function of which may be related to the secretion of the hormone.

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

International Nuclear Information System (INIS)

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

1979-01-01

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

Problems connected with the production of highly specific antisera against prostaglandin E2 (PGE2) and prostaglandin A2 (PGA2) for radioimmunoassay

International Nuclear Information System (INIS)

Kopp, H.G.; Vetter, W.; Siegenthaler, W.

1978-01-01

To obtain sensitive and specific antisera against PGE 2 and PGA 2 these substances were coupled to thyroglobulin (Tg). Coupling reactions were performed by using either a hydroxy-succinimide-ester as intermediate step leading to a complex carrying 170mol PGE 2 per mol Tg (''PGE 2 -OSU-Tg'') and 240mol PGA 2 per mol Tg (''PGA 2 -OSU-Tg''), or N, N'-carbonyl-diimidazole resulting in ''PGE 2 -CDI-Tg'' (400mol PGE 2 per mol Tg) and ''PGA 2 -CDI-Tg'' (600mol PGA 2 per mol Tg). Two tracer systems ( 3 H-prostaglandin and 125 I-histamine-prostaglandin) were used for analysis of antibody activity. The PGE 2 -CDI-Tg and PGA 2 -CDI-Tg complexes were both poor immunogens in rabbits. The PGE 2 -OSU-Tg and PGA 2 -OSU-Tg conjugates were injected in rabbits and in guinea-pigs. These two compounds resulted in very high antibody titres in both animal species. However, in guinea-pigs a markedly higher antibody sensitivity and antibody specificity were observed than in rabbits. Our results indicate that the guinea-pig may be the animal of choice for immunization against prostaglandins. Antibody specificity of guinea-pig antisera may be high enough to measure the concentration of PGE 2 and PGA 2 in the presence of other prostaglandins or prostaglandin metabolites. (author)

Problems connected with the production of highly specific antisera against prostaglandin E2 (PGE2) and prostaglandin A2 (PGA2) for radioimmunoassay

International Nuclear Information System (INIS)

Kopp, H.G.; Vetter, W.; Siegenthaler, W.

1977-01-01

To obtain sensitive and specific antisera against PGE 2 and PGA 2 these substances were coupled to thyroglobulin (Tg). Coupling reactions were either performed by using a hydroxysuccinimideester as intermediate step leading to a complex carrying 170 mol PGE 2 per mol Tg ('PGE 2 -OSU-Tg') and 240 mol PGA 2 per mol Tg ('PGA 2 -OSU-Tg') or alternatively by using N,N'-carbonyl-diimidazole resulting in 'PGE 2 -CDI-Tg' (400 mol PGE 2 per mol Tg) and 'PGA 2 -CDI-Tg' (600 mol PGA 2 per mol Tg). Two tracer systems ( 3 H-prostaglandin, 125 I-histamine-prostaglandin) were used for analysis of antibody activity. Both PGE 2 - and PGA 2 -CDI-Tg complexes were poor immunogens in rabbits. The PGE 2 - and PGA 2 -OSU-Tg conjugates were injected both in rabbits and in guinea pigs. These two compounds resulted in very high antibody titers in both animal species. However, in guinea pigs markedly higher antibody sensitivity and antibody specificity were observed than in rabbits. Our results indicate that the guinea pig may be the animal of choice for immunization against prostaglandins. Antibody specificity of guinea pig antisera may be perhaps high enough to measure the concentration of PGE 2 and PGA 2 in the presence of other prostaglandins or prostaglandin metabolites. (orig.) [de

The Effect of Thyroid Hormone, Prostaglandin E2, and Calcium Gluconate on Orthodontic Tooth Movement and Root Resorption in Rats.

Science.gov (United States)

Seifi, Massoud; Hamedi, Roya; Khavandegar, Zohre

2015-03-01

A major objective of investigators is to clarify the role of metabolites in achievement of maximum tooth movement with minimal root damage during orthodontic tooth movement (OTM). The aim of this study was to determine the effect of administration of thyroid hormone, prostaglandin E2, and calcium on orthodontic tooth movement and root resorption in rats. Sixty four male Wistar rats were randomly divided into 8 groups of eight rats each: 1- 20µg/kg thyroxine was injected in traperitoneally after installation of the orthodontic appliance.  2- 0.1 ml of 1 mg/ml prostaglandin E2 was injected submucosally.  3- 10% (200 mg/kg) calcium gluconate was injected.  4- Prostaglandin E2 was injected submucosally and 10% calcium was injected intraperitoneally.  5- Thyroxine was injected intraperitoneally and prostaglandin E2 was injected submucosally.  6- 20µg/kg thyroxine with calcium was injected. 7- Prostaglandin E2 was injected submucosally with calcium and thyroxine.  8- Distilled water was used in control group. The orthodontic appliances comprised of a NiTi closed coil were posteriorly connected to the right first molar and anteriorly to the upper right incisor. OTM was measured with a feeler gauge. The mid-mesial root of the first molar and the adjacent tissues were histologically evaluated. The Data were analyzed by one-way ANOVA and Student-Newman-Keuls test. The highest mean OTM was observed in the thyroxine and prostaglandin E2 group (Mean±SD = 0.7375±0.1359 mm) that was significantly different (proot resorption was observed between the prostaglandin E2 (0.0192±0.0198 mm(2)) and the other groups. It seems that the combination of thyroxine and prostaglandin E2, with a synergistic effect, would decrease the root resorption and increase the rate of orthodontic tooth movement in rats.

Reversal by prostaglandin E2 infusion of the effects of indomethacin on the excretion of nitrogenous compounds in the rat.

OpenAIRE

Rowe, D. J.; Gedeon, G.

1983-01-01

Rats were treated with Indomethacin (Indo; 2 mg/kg/d) with or without concomitant infusion of prostaglandin (PG)E2 (100 micrograms/d) to investigate the effects of inhibition of PG synthesis and PG replacement on the urinary excretion of total nitrogenous compounds, urea and creatinine and on the plasma concentration of urea and creatinine. The results indicated: (1) Indo significantly reduced the urine excretion of nitrogen, urea and creatinine within 48 hours of drug administration. (2) Thi...

Screening and identification of dietary oils and unsaturated fatty acids in inhibiting inflammatory prostaglandin E2 signaling in fat stromal cells

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Ruan Diana

2012-08-01

Full Text Available Abstract Background The molecular mechanisms of dietary oils (such as fish oil and unsaturated fatty acids, which are widely used by the public for anti-inflammation and vascular protection, have not been settled yet. In this study, prostaglandin E2 (PGE2-mediated calcium signaling was used to screen dietary oils and eight unsaturated fatty acids for identification of their anti-inflammatory mechanisms. Isolated fat/stromal cells expressing endogenous PGE2 receptors and an HEK293 cell line specifically expressing the recombinant human PGE2 receptor subtype-1 (EP1 were cultured and used in live cell calcium signaling assays. The different dietary oils and unsaturated fatty acids were used to affect cell signaling under the specific stimulation of a pathological amount of inflammatory PGE2. Results It was identified that fish oil best inhibited the PGE2 signaling in the primary cultured stromal cells. Second, docosahexaenoic acid (DHA, found in abundance in fish oil, was identified as a key factor of inhibition of PGE2 signaling. Eicosapentaenoic acid (EPA, another major fatty acid found in fish oil and tested in this study was found to have small effect on EP1 signaling. The study suggested one of the four PGE2 subtype receptors, EP1 as the key target for the fish oil and DHA target. These findings were further confirmed by using the recombinant EP1 expressed in HEK293 cells as a target. Conclusion This study demonstrated the new mechanism behind the positive effects of dietary fish oils in inhibiting inflammation originates from the rich concentration of DHA, which can directly inhibit the inflammatory EP1-mediated PGE2 receptor signaling, and that the inflammatory response stimulated by PGE2 in the fat stromal cells, which directly related to metabolic diseases, could be down regulated by fish oil and DHA. These findings also provided direct evidence to support the use of dietary oils and unsaturated fatty acids for protection against heart

Involvement of prostaglandins F/sub 2α/ and E1 with rabbit endometrium

International Nuclear Information System (INIS)

Orlicky, D.J.

1985-01-01

Several growth factors and hormones are thought to play a role in the growth control of endometrial cells. The authors have shown that prostaglandin F/sub 2→/ (PGF/sub 2α/) is a growth factor for primary cultures of rabbit endometrium cultured in chemically-defined serum-free medium and that prostaglandin E 1 (PGE 1 ) antagonizes the PGF/sub 2→/ induction of growth. Both [ 3 H]PGF/sub 2α/ and [ 3 H]PGE 1 bind in a time and temperature dependent, dissociable, saturable and specific manner. The binding of [ 3 H]PGF/sub 2α/ and [ 3 H]PGE 1 can be both down and up regulated and is enzyme sensitive. PGE 1 stimulates intracellular cAMP synthesis and accumulation in a time and concentration dependent manner. PGF/sub 2α/ probably exerts its effects through an amiloride-sensitive intermediate. Both PGF/sub 2α/ and PGE 1 are constitutively synthesized by these primary cultures, and they have shown this synthesis to be both drug and hormone sensitive. They hypothesize that it is the ratio, rather than the absolute quantities, of PGF/sub 2α/ and PGE 1 which is of more importance in the regulation of endometrial cell growth. Furthermore, they believe this regulation of endometrial growth plays a role in control of proliferation during the decidual response and that a derangement in the ratio of these prostaglandins may lead to either infertility or hyperplasia. The ability of these cultures to synthesize prostaglandins in a hormonally regulatable manner may be of importance in the study of dysmenorrhea and uterine cramping as caused by the myometrial contracting prostaglandin, PGF/sub 2α/

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

DEFF Research Database (Denmark)

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

1995-01-01

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

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

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Xiaowei Wang

2016-08-01

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

In vitro prostaglandin E2 stimulation of 45Ca mobilization from chick bone

International Nuclear Information System (INIS)

Satterlee, D.G.; Amborski, G.F.; McIntyre, M.D.; Parker, M.S.; Jacobs-Perry, L.A.

1984-01-01

The ability of prostaglandin E2 (PGE2) to mobilize 45 Ca from chick embryo long bones was assayed in an in vitro bone culture system. Concentrations of PGE2 tested ranged from 10(-9) to 10(-5) M. The PGE2 was effective in stimulating release of 45 Ca from prelabelled bones at all concentrations tested except at 10(-9) M. In addition, stimulation of 45 Ca release could be produced daily for 4 consecutive days of PGE2 culture-pulsing at what appeared to be the optimal PGE2 concentration, 10(-7) M. The authors conclude, as in mammals, PGE2 is a potent stimulator of calcium mobilization from avian bone. The potential involvement of prostaglandins in eggshell formation is discussed

Effect of Intravasclar Influsion of Endogenous Pyrogen or Prostaglandin E2 on Neuronal Activity of Rat's Hypothalamus

OpenAIRE

Sakata, Yoshiyuki; Watanabe, Tatsuo; Morimoto, Akio; Murakami, Naotoshi

1989-01-01

We investigated the effects of intracarotid infusion of prostaglandin E2 or intravenous infusion of an endogenous pyrogen on the neuronal activity of the neuronal activity of the preoptic and anterior hypothalamic (PO/AH) region in rats. The present results suggest that thermore sponsive neurons of the PO/AH region respond well to intravascular application of prostaglandin E2 or the endogenous pyrogen, compared with thermally insensive neurons. Intravenous infusion of the endogenous pyrogen a...

Prostaglandin E2 Exerts Multiple Regulatory Actions on Human Obese Adipose Tissue Remodeling, Inflammation, Adaptive Thermogenesis and Lipolysis.

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Verónica García-Alonso

Full Text Available Obesity induces white adipose tissue (WAT dysfunction characterized by unremitting inflammation and fibrosis, impaired adaptive thermogenesis and increased lipolysis. Prostaglandins (PGs are powerful lipid mediators that influence the homeostasis of several organs and tissues. The aim of the current study was to explore the regulatory actions of PGs in human omental WAT collected from obese patients undergoing laparoscopic bariatric surgery. In addition to adipocyte hypertrophy, obese WAT showed remarkable inflammation and total and pericellular fibrosis. In this tissue, a unique molecular signature characterized by altered expression of genes involved in inflammation, fibrosis and WAT browning was identified by microarray analysis. Targeted LC-MS/MS lipidomic analysis identified increased PGE2 levels in obese fat in the context of a remarkable COX-2 induction and in the absence of changes in the expression of terminal prostaglandin E synthases (i.e. mPGES-1, mPGES-2 and cPGES. IPA analysis established PGE2 as a common top regulator of the fibrogenic/inflammatory process present in this tissue. Exogenous addition of PGE2 significantly reduced the expression of fibrogenic genes in human WAT explants and significantly down-regulated Col1α1, Col1α2 and αSMA in differentiated 3T3 adipocytes exposed to TGF-β. In addition, PGE2 inhibited the expression of inflammatory genes (i.e. IL-6 and MCP-1 in WAT explants as well as in adipocytes challenged with LPS. PGE2 anti-inflammatory actions were confirmed by microarray analysis of human pre-adipocytes incubated with this prostanoid. Moreover, PGE2 induced expression of brown markers (UCP1 and PRDM16 in WAT and adipocytes, but not in pre-adipocytes, suggesting that PGE2 might induce the trans-differentiation of adipocytes towards beige/brite cells. Finally, PGE2 inhibited isoproterenol-induced adipocyte lipolysis. Taken together, these findings identify PGE2 as a regulator of the complex network of

Direct analysis of prostaglandin-E2 and -D2 produced in an inflammatory cell reaction and its application for activity screening and potency evaluation using turbulent flow chromatography liquid chromatography-high resolution mass spectrometry.

Science.gov (United States)

Shin, Jeong-Sook; Peng, Lei; Kang, Kyungsu; Choi, Yongsoo

2016-09-09

Direct analysis of prostaglandin-E2 (PGE2) and -D2 (PGD2) produced from a RAW264.7 cell-based reaction was performed by liquid chromatography high-resolution mass spectrometry (LC-HRMS), which was online coupled with turbulent flow chromatography (TFC). The capability of this method to accurately measure PG levels in cell reaction medium containing cytokines or proteins as a reaction byproduct was cross-validated by two conventional methods. Two methods, including an LC-HRMS method after liquid-liquid extraction (LLE) of the sample and a commercial PGE2 enzyme-linked immunosorbent assay (ELISA), showed PGE2 and/or PGD2 levels almost similar to those obtained by TFC LC-HRMS over the reaction time after LPS stimulation. After the cross-validation, significant analytical throughputs, allowing simultaneous screening and potency evaluation of 80 natural products including 60 phytochemicals and 20 natural product extracts for the inhibition of the PGD2 produced in the cell-based inflammatory reaction, were achieved using the TFC LC-HRMS method developed. Among the 60 phytochemicals screened, licochalcone A and formononetin inhibited PGD2 production the most with IC50 values of 126 and 151nM, respectively. For a reference activity, indomethacin and diclofenac were used, measuring IC50 values of 0.64 and 0.21nM, respectively. This method also found a butanol extract of Akebia quinata Decne (AQ) stem as a promising natural product for PGD2 inhibition. Direct and accurate analysis of PGs in the inflammatory cell reaction using the TFC LC-HRMS method developed enables the high-throughput screening and potency evaluation of as many as 320 samples in less than 48h without changing a TFC column. Copyright © 2016 Elsevier B.V. All rights reserved.

Influence of prostaglandins E2 and F/sub 2α/ on the zinc transport across rat mid-intestine in vitro

International Nuclear Information System (INIS)

Song, M.K.; Adham, N.F.; Lee, D.B.N.; Carmack, C.R.

1986-01-01

Effects of physiological (5.0 μM) and pharmacological (50 μM) doses of prostaglandins (PG) E 2 and F/sub 2α/ on the zinc transport rate across rat jejunum mounted on a Ussing Chamber were determined. Zinc transport rate from mucosal to serosal direction was 4.82 +/- 0.81 n moles/hr/cm 2 whereas the opposite direction was 18.71 +/- 0.96 n moles/hr/cm 2 . When 5.0 μM or 50 μM PGE 2 or PGF/sub 2α/ were added into Ringers-Krebs bicarbonate solution containing 3 mM L-histidine and 0.5 mM 65 Zn Cl 2 to the mucosal side of mucosa, no significant difference in 65 Zn transport rate was observed compared to controls. However, 5.0 μM PGF/sub 2α/ and 50 μM PGE 2 significantly inhibited zinc transport from mucosal to serosal direction. When PGs were added to the opposite side of mucosa, only 5.0 μM PGs significantly inhibited zinc transport from serosal to mucosal direction. Results suggest that PGs act on the inhibition of zinc transport across the basolateral membrane of columnar absorbing cells and that 50 μM PGE 2 was the most powerful inhibitor

9-Hydroxyprostaglandin dehydrogenase in rat kidney cortex converts prostaglandin I2 into 15-keto-13,14-dihydro 6-ketoprostaglandin E1.

Science.gov (United States)

Pace-Asciak, C R; Domazet, Z

1984-11-14

15-Keto-13,14-dihydro 6-ketoprostaglandin E1 was positively identified by gas chromatography-mass spectrometry with negative-ion chemical ionisation detection from samples of rat kidney high-speed supernatant incubated with prostaglandin I2 in the presence of NAD+. A decreased formation of this product was observed when NAD+ was substituted with NADP+ and none was observed in the absence of nucleotide or substrate prostaglandin I2. Experiments with [9 beta-3H]prostaglandin I2 showed a time- and concentration-dependent loss of tritium which appeared as tritiated water, typical of reaction of [9 beta-3H]prostaglandin substrates with the enzyme, 9-hydroxyprostaglandin dehydrogenase. Time-course measurements of the appearance of tritiated water showed similar rates with 6-keto[9 beta-3H]prostaglandin F1 alpha and 15-keto-13,14-dihydro 6-keto[9 beta-3H]prostaglandin F1 alpha as substrates. These experiments suggest that the transformation of prostaglandin I2 and 6-ketoprostaglandin F1 alpha into the 15-keto-13,14-dihydro 6-ketoprostaglandin E1 catabolite occurs in this in vitro preparation via the corresponding 15-keto-13,14-dihydro catabolite of 6-ketoprostaglandin F1 alpha.

A novel selective prostaglandin E2 synthesis inhibitor relieves pyrexia and arthritis in Guinea pigs inflammatory models

Directory of Open Access Journals (Sweden)

Ryusuke Sugita

2016-02-01

Full Text Available Prostaglandin E2 (PGE2, one of the terminal products in the cyclooxygenase pathway, plays an important role in various inflammatory responses. To determine whether selective inhibition of PGE2 may relieve these inflammatory symptoms, we synthesized a selective PGE2 synthesis inhibitor, compound A [1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl-N-[(1S,2R-2-(hydroxymethylcyclohexyl]piperidine-4-carboxamide], then investigated the effects on pyrexia, arthritis and inflammatory pain in guinea pigs. In LPS-stimulated guinea pig macrophages, compound A selectively inhibited inducible PGE2 biosynthesis in a dose-dependent manner whereas enhanced the formation of thromboxane B2 (TXB2. Compound A suppressed yeast-evoked PGE2 production selectively and enhanced the production of TXB2 and 6-keto PGF1α in vivo. In addition, compound A relieved yeast-induced pyrexia and also suppressed paw swelling in an adjuvant-induced arthritis model. The effect on gastrointestinal (GI ulcer formation was also evaluated and compound A showed a lower GI adverse effect than indomethacin. However, compound A failed to relieve yeast-induced thermal hyperalgesia. These results suggest that selective inhibition of PGE2 synthesis may have anti-pyretic and anti-inflammatory properties without GI side effect, but lack the analgesic efficacy.

Comparative study of labour induced by oral prostaglandin E2 and intravenous syntocinon.

Science.gov (United States)

Murray, C P; Clinch, J

1975-03-22

The use of prostaglandin E2 for the induction of labor with intact membranes is described and its effectiveness is compared to intravenous syntocinon. 40 primigravida and 60 multigravid patients with previous medical and obstetrical histories were studied. The patients were numbered as they entered the trial, with the odd numbers in each group being given oral prostaglandin and the even numbers intravenous syntocinon. In no case was the pregnancy less than 38 weeks maturity. No patient was in labor prior to being given either drug. Prostaglandin E2 (PGE2) was supplied in ampoules containing 5 milligrams in 0.5 milliliter of ethanol. This was added to 49.5 milliliters of sterile water to produce a concentration of the drug of 0.1 milligrams per ml. The syntocinon infusion was prepared by putting 20 units of syntocinon into 1 liter of 5% dextrose in water to produce a solution concentration of 20 mu/ml. The accepted criteria for diagnosing established labor for both groups of patients was the presence of uterine contractions occurring once every 3 minutes, associated with progressive dilatation of the cervix. For both groups of patients it was decided that cervical dilatation should be at least 6 cm within 18 hours of the infusion starting. Using this criterion there was only 1 failure, occurring in the 1st primigravid patient given PGE2, the labor in this instance being completed with intravenous syntocinon. A further 8 patients failed to complete the trial as they had to be delivered by cesarian section. Syntocin was considerably more efficient than PGE2 in inducing labor in the remaining 91 patients particularly in primigravida. This was the case whether judged by the length of labor or by the induction delivery interval. Toco-dynamometric studies showed that the contractions produced by prostaglandin more closely resembled those of normal labor and were less painful.

R-Flurbiprofen Traps Prostaglandins within Cells by Inhibition of Multidrug Resistance-Associated Protein-4.

Science.gov (United States)

Wobst, Ivonne; Ebert, Lisa; Birod, Kerstin; Wegner, Marthe-Susanna; Hoffmann, Marika; Thomas, Dominique; Angioni, Carlo; Parnham, Michael J; Steinhilber, Dieter; Tegeder, Irmgard; Geisslinger, Gerd; Grösch, Sabine

2016-12-30

R -flurbiprofen is the non-COX-inhibiting enantiomer of flurbiprofen and is not converted to S -flurbiprofen in human cells. Nevertheless, it reduces extracellular prostaglandin E₂ (PGE₂) in cancer or immune cell cultures and human extracellular fluid. Here, we show that R -flurbiprofen acts through a dual mechanism: (i) it inhibits the translocation of cPLA 2α to the plasma membrane and thereby curtails the availability of arachidonic acid and (ii) R -flurbiprofen traps PGE₂ inside of the cells by inhibiting multidrug resistance-associated protein 4 (MRP4, ABCC4), which acts as an outward transporter for prostaglandins. Consequently, the effects of R -flurbiprofen were mimicked by RNAi-mediated knockdown of MRP4. Our data show a novel mechanism by which R -flurbiprofen reduces extracellular PGs at physiological concentrations, particularly in cancers with high levels of MRP4, but the mechanism may also contribute to its anti-inflammatory and immune-modulating properties and suggests that it reduces PGs in a site- and context-dependent manner.

Design of group IIA secreted/synovial phospholipase A(2 inhibitors: an oxadiazolone derivative suppresses chondrocyte prostaglandin E(2 secretion.

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Jean-Edouard Ombetta

Full Text Available Group IIA secreted/synovial phospholipase A(2 (GIIAPLA(2 is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E(2 (PGE(2, the main eicosanoid contributing to pain and inflammation in rheumatic diseases. We designed, by molecular modeling, 7 novel analogs of 3-{4-[5(indol-1-ylpentoxy]benzyl}-4H-1,2,4-oxadiazol-5-one, denoted C1, an inhibitor of the GIIAPLA(2 enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA(2, along with their chemical synthesis and results from PLA(2 inhibition tests. Modeling predicted some derivatives to display greater GIIAPLA(2 affinities than did C1, and such predictions were confirmed by in vitro PLA(2 enzymatic tests. Compound C8, endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA(2 inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1beta-stimulated PGE(2 secretion in these cells. Interestingly, it did not modify the COX-1 to COX-2 ratio. C8 is therefore a potential candidate for anti-inflammatory therapy in joints.

Aspirin inhibits interleukin 1-induced prostaglandin H synthase expression in cultured endothelial cells

International Nuclear Information System (INIS)

Wu, K.K.; Sanduja, R.; Tsai, A.L.; Ferhanoglu, B.; Loose-Mitchell, D.S.

1991-01-01

Prostaglandin H (PGH) synthase is a key enzyme in the biosynthesis of prostaglandins, thromboxane, and prostacyclin. In cultured human umbilical vein endothelial cells, interleukin 1 (IL-1) is known to induce the synthesis of this enzyme, thereby raising the level of PGH synthase protein severalfold over the basal level. Pretreatment with aspirin at low concentrations inhibited more than 60% of the enzyme mass and also the cyclooxygenase activity in IL-1-induced cells with only minimal effects on the basal level of the synthase enzyme in cells without IL-1. Sodium salicylate exhibited a similar inhibitory action whereas indomethacin had no apparent effect. Similarly low levels of aspirin inhibited the increased L-[ 35 S]methionine incorporation into PGH synthase that was induced by IL0-1 and also suppressed expression of the 2.7-kilobase PGH synthase mRNA. These results suggest that in cultured endothelial cells a potent inhibition of eicosanoid biosynthetic capacity can be effected by aspirin or salicylate at the level of PGH synthase gene expression. The aspirin effect may well be due to degradation of salicylate

Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

DEFF Research Database (Denmark)

Kristensen, David M.; Skalkam, Maria L.; Audouze, Karine Marie Laure

2011-01-01

Background: Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine disrupting compounds (EDCs) share a high...... suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades....

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

Czech Academy of Sciences Publication Activity Database

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

2016-01-01

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

A role of prostaglandin E/sub2/ in radiation-induced hyperthermia

International Nuclear Information System (INIS)

Cernak, I.; Stanimirovic, D.; Simovic, M.; Ivanovic, L.; Markovic, M.; Savic, J.

1989-01-01

Radiation-induced (6.7 Gy X-ray) changes in body temperature were investigated in rats exposed to: whole body irradiation pretreatment with indomethacin (5 mg/kg b.w.) 30 min before whole body irradiation and irradiation of the body with protected head. Content of prostaglandin E 2 (PGE 3 ) was measured in the rat brain hypothalamic regions and compared to correspondent body temperature. Hypothalamic PGE 2 content strongly correlated with body temperature (r=0.79, p 2 in the hypothalamus is presumed as a putative mediator of radiation-induced changes in body temperature. (author). 8 refs.; 2 figs.; 1 tab

Involvement of prostaglandins F/sub 2. cap alpha. / and E/sub 1/ with rabbit endometrium

Energy Technology Data Exchange (ETDEWEB)

Orlicky, D.J.

1985-01-01

Several growth factors and hormones are thought to play a role in the growth control of endometrial cells. The authors have shown that prostaglandin F/sub 2..-->../ (PGF/sub 2..cap alpha../) is a growth factor for primary cultures of rabbit endometrium cultured in chemically-defined serum-free medium and that prostaglandin E/sub 1/ (PGE/sub 1/) antagonizes the PGF/sub 2..-->../ induction of growth. Both (/sup 3/H)PGF/sub 2..cap alpha../ and (/sup 3/H)PGE/sub 1/ bind in a time and temperature dependent, dissociable, saturable and specific manner. The binding of (/sup 3/H)PGF/sub 2..cap alpha../ and (/sup 3/H)PGE/sub 1/ can be both down and up regulated and is enzyme sensitive. PGE /sub 1/ stimulates intracellular cAMP synthesis and accumulation in a time and concentration dependent manner. PGF/sub 2..cap alpha../ probably exerts its effects through an amiloride-sensitive intermediate. Both PGF/sub 2..cap alpha../ and PGE/sub 1/ are constitutively synthesized by these primary cultures, and they have shown this synthesis to be both drug and hormone sensitive. They hypothesize that it is the ratio, rather than the absolute quantities, of PGF/sub 2..cap alpha../ and PGE/sub 1/ which is of more importance in the regulation of endometrial cell growth. Furthermore, they believe this regulation of endometrial growth plays a role in control of proliferation during the decidual response and that a derangement in the ratio of these prostaglandins may lead to either infertility or hyperplasia. The ability of these cultures to synthesize prostaglandins in a hormonally regulatable manner may be of importance in the study of dysmenorrhea and uterine cramping as caused by the myometrial contracting prostaglandin, PGF/sub 2..cap alpha../.

N-Acetylcysteine enhances the action of anti-inflammatory drugs as suppressors of prostaglandin production in monocytes

Directory of Open Access Journals (Sweden)

Erica Hoffer

2002-01-01

Full Text Available The anti-inflammatory effect of non-steroidal anti-inflammatory drugs (NSAIDs is associated with inhibition of cyclooxygenase (COX, the rate-limiting enzyme responsible for the synthesis of prostaglandins. Since oxygen free radicals can act as second cellular messengers, especially to modulate the metabolism of arachidonic acid and the prostaglandin tract, it seems plausible that antioxidants might affect the production of prostaglandin by activated cells. This research is focused on the effect of the antioxidant N-acetylcysteine (NAC on the inhibition of prostaglandin E2 formation in activated monocytes by specific and non-specific COX inhibitors. We found that lipopolysaccharide-induced prostaglandin E2 formation was significantly reduced by rofecoxib and by diclofenac, two NSAIDs. Addition of NAC to each of these drugs enhanced the effect of the NSAIDs. These results suggest that one might expect either a potentiation of the anti-inflammatory effect of COX inhibitors by their simultaneous administration with NAC, or obtaining the same anti-inflammatory at lower drug levels.

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

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Dey, Indranil; Chadee, Kris

2008-11-01

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

Utilization of a single antiserum for the direct radioimmunoassay of prostaglandins E and F in semen and prostaglandin F in amniotic fluid

International Nuclear Information System (INIS)

Clarke, A.H.; Ing, R.M.Y.; Jones, W.R.; Llewellyn-Jones, D.; Shutt, D.A.

1974-01-01

Antibodies to both prostaglandin F (PGF) and prostaglandin E (PGE) were raised in rabbits after they were immunized with prostaglandin F/sub 2a/ conjugated to bovine serum albumin (PGF/sub 2a/--BSA). The antisera were group specific although the antibodies to the F group of prostaglandins showed greater specificity than those to the E group. The antisera were sufficiently specific however to allow the direct radioimmunoassay of PGF and PGE in human semen and PGF in amniotic fluid during induced abortion. Specificity of the direct radioimmunoassay was checked by chromatographic separation of the prostaglandins prior to analysis. Estimation of the prostaglandins in the semen of 30 men attending the infertility clinic showed that 19 of the men had normal semen levels of PGE and PGF of 68 +- 7 (SE) and 6.0 +- 0.6 μg/ml respectively, as compared with data on normal fertile males, whilst the other 11 men had lower levels of 16 +- 2 (SE) and 0.8 +- 0.1 μg/ml respectively. Application of the method to amniotic fluid showed that the PGF concentration in amniotic fluid during the induction of abortion with extra-ovular saline increased from less than 0.6 ng/ml to 6.4 ng/ml when the induction-abortion intervals ranged from 6 to 48 hours. (U.S.)

Intracrine prostaglandin E2 pro-tumoral actions in prostate epithelial cells originate from non-canonical pathways.

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Madrigal-Martínez, Antonio; Fernández-Martínez, Ana B; Lucio Cazaña, Francisco J

2018-04-01

Prostaglandin E 2 (PGE 2 ) increases cell proliferation and stimulates migratory and angiogenic abilities in prostate cancer cells. However, the effects of PGE 2 on non-transformed prostate epithelial cells are unknown, despite the fact that PGE 2 overproduction has been found in benign hyperplastic prostates. In the present work we studied the effects of PGE 2 in immortalized, non-malignant prostate epithelial RWPE-1 cells and found that PGE 2 increased cell proliferation, cell migration, and production of vascular endothelial growth factor-A, and activated in vitro angiogenesis. These actions involved a non-canonic intracrine mechanism in which the actual effector was intracellular PGE 2 (iPGE 2 ) instead of extracellular PGE 2 : inhibition of the prostaglandin uptake transporter (PGT) or antagonism of EP receptors prevented the effects of PGE 2 , which indicated that PGE 2 activity depended on its carrier-mediated translocation from the outside to the inside of cells and that EP receptors located intracellularly (iEP) mediated the effects of PGE 2 . iPGE 2 acted through transactivation of epidermal growth factor-receptor (EGFR) by iEP, leading to increased expression and activity of hypoxia-inducible factor-1α (HIF-1α). Interestingly, iPGE 2 also mediates the effects of PGE 2 on prostate cancer PC3 cells through the axis iPGE 2 -iEP receptors-EGFR-HIF-1α. Thus, this axis might be responsible for the growth-stimulating effects of PGE 2 on prostate epithelial cells, thereby contributing to prostate proliferative diseases associated with chronic inflammation. Since this PGT-dependent non-canonic intracrine mechanism of PGE 2 action operates in both benign and malignant prostate epithelial cells, PGT inhibitors should be tested as a novel therapeutic modality to treat prostate proliferative disease. © 2017 Wiley Periodicals, Inc.

Inhibition of prostaglandin synthesis after metabolism of menadione by cultured porcine endothelial cells.

OpenAIRE

Barchowsky, A; Tabrizi, K; Kent, R S; Whorton, A R

1989-01-01

We have examined the effects of menadione on porcine aortic endothelial cell prostaglandin synthesis. Addition of 1-20 microM menadione caused a dose- and time-dependent inhibition of stimulated prostaglandin synthesis with an IC50 of 5 microM at 15 min. Concentrations greater than 100 microM menadione were necessary to increase 51Cr release from prelabeled cells. Recovery of enzyme inactivated by menadione required a 6-h incubation in 1% serum. In a microsomal preparation, menadione was show...

Opposing effects of nitric oxide and prostaglandin inhibition on muscle mitochondrial VO2 during exercise

DEFF Research Database (Denmark)

Boushel, Robert C; Fuentes, Teresa; Hellsten, Ylva

2012-01-01

Nitric oxide (NO) and prostaglandins (PG) together play a role in regulation blood flow during exercise. NO also regulates mitochondrial oxygen consumption through competitive binding to cytochrome c oxidase. Indomethacin both uncouples and inhibits the electron transport chain in a concentration......-dependent manner, and thus inhibition of NO and PG may regulate both muscle oxygen delivery and utilization. The purpose of this study was to examine the independent and combined effects of NO and PG blockade (L-NMMA and indomethacin respectively) on mitochondrial respiration in human muscle following knee...... extension (KE) exercise. Mitochondrial respiration was measured ex-vivo by high resolution respirometry in saponin-permeabilized fibers following 6 min KE in control (CON, n=8), arterial infusion of LNMMA (n=4) and Indo (n=4) followed by combined inhibition of NO and PG (L-NMMA + Indo, n=8). ADP...

Close teamwork between Nrf2 and peroxiredoxins 1 and 6 for the regulation of prostaglandin D2 and E2 production in macrophages in acute inflammation.

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Ishii, Tetsuro

2015-11-01

Inflammation is a complex biological self-defense reaction triggered by tissue damage or infection by pathogens. Acute inflammation is regulated by the time- and cell type-dependent production of cytokines and small signaling molecules including reactive oxygen species and prostaglandins. Recent studies have unveiled the important role of the transcription factor Nrf2 in the regulation of prostaglandin production through transcriptional regulation of peroxiredoxins 1 and 6 (Prx1 and Prx6) and lipocalin-type prostaglandin D synthase (L-PGDS). Prx1 and Prx6 are multifunctional proteins important for cell protection against oxidative stress, but also work together to facilitate production of prostaglandins E2 and D2 (PGE2 and PGD2). Prx1 secreted from cells under mild oxidative stress binds Toll-like receptor 4 and induces NF-κB activation, important for the expression of cyclooxygenase-2 and microsomal PGE synthase-1 (mPGES-1) expression. The activated MAPKs p38 and ERK phosphorylate Prx6, leading to NADPH oxidase-2 activation, which contributes to production of PGD2 by hematopoietic prostaglandin D synthase (H-PGDS). PGD2 and its end product 15-deoxy-∆(12,14)-prostaglandin J2 (15d-PGJ2) activate Nrf2 thereby forming a positive feedback loop for further production of PGD2 by L-PGDS. Maintenance of cellular glutathione levels is an important role of Nrf2 not only for cell protection but also for the synthesis of prostaglandins, as mPGES-1 and H-PGDS require glutathione for their activities. This review is aimed at describing the functions of Prx1 and Prx6 in the regulation of PGD2 and PGE2 production in acute inflammation in macrophages and the importance of 15d-PGJ2 as an intrinsic Nrf2 activator. Copyright © 2015 Elsevier Inc. All rights reserved.

Selective inhibition of prostaglandin E2 receptors EP2 and EP4 induces apoptosis of human endometriotic cells through suppression of ERK1/2, AKT, NFkappaB, and beta-catenin pathways and activation of intrinsic apoptotic mechanisms.

Science.gov (United States)

Banu, Sakhila K; Lee, JeHoon; Speights, V O; Starzinski-Powitz, Anna; Arosh, Joe A

2009-08-01

Endometriosis is a benign chronic gynecological disease of reproductive-age women characterized by the presence of functional endometrial tissues outside the uterine cavity. It is an estrogen-dependent disease. Current treatment modalities to inhibit biosynthesis and actions of estrogen compromise menstruation, pregnancy, and the reproductive health of women and fail to prevent reoccurrence of disease. There is a critical need to identify new specific signaling modules for non-estrogen-targeted therapies for endometriosis. In our previous study, we reported that selective inhibition of cyclooxygenase-2 prevented survival, migration, and invasion of human endometriotic epithelial and stromal cells, which was due to decreased prostaglandin E(2) (PGE(2)) production. In this study, we determined mechanisms through which PGE(2) promoted survival of human endometriotic cells. Results of the present study indicate that 1) PGE(2) promotes survival of human endometriotic cells through EP2 and EP4 receptors by activating ERK1/2, AKT, nuclear factor-kappaB, and beta-catenin signaling pathways; 2) selective inhibition of EP2 and EP4 suppresses these cell survival pathways and augments interactions between proapoptotic proteins (Bax and Bad) and antiapoptotic proteins (Bcl-2/Bcl-XL), facilitates the release of cytochrome c, and thus activates caspase-3/poly (ADP-ribose) polymerase-mediated intrinsic apoptotic pathways; and 3) these PGE(2) signaling components are more abundantly expressed in ectopic endometriosis tissues compared with eutopic endometrial tissues during the menstrual cycle in women. These novel findings may provide an important molecular framework for further evaluation of selective inhibition of EP2 and EP4 as potential therapy, including nonestrogen target, to expand the spectrum of currently available treatment options for endometriosis in women.

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

International Nuclear Information System (INIS)

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

2004-01-01

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

Effect of forskolin and prostaglandin E1 on stimulus secretion coupling in cultured bovine adrenal chromaffin cells.

Science.gov (United States)

Marriott, D; Adams, M; Boarder, M R

1988-02-01

Treatment of adrenal chromaffin cells with forskolin (0.1-10 microM) stimulated cyclic AMP levels, reduced the maximal stimulation of release of noradrenaline by nicotine, and increased release in response to elevated external potassium and the calcium ionophore A23187. The presence of the phosphodiesterase inhibitor Ro 20-17-24 with forskolin potentiated both the stimulation of cyclic AMP and the inhibition of nicotine-induced noradrenaline release. Dibutyryl cyclic AMP, and the elevation of cyclic AMP with prostaglandin E1, also attenuated nicotine-stimulated release. However, when the stimulation of intracellular cyclic AMP production by prostaglandin E1 was potentiated by low levels of forskolin, there was not a concomitant potentiation of effect on noradrenaline release. Dideoxyforskolin, an analogue of forskolin which does not stimulate adenylate cyclase, inhibited both potassium- and nicotine-stimulated release, probably by a mechanism unrelated to the action of forskolin in these experiments. Using Fura-2 to estimate free intracellular calcium levels, both forskolin and dideoxyforskolin (at 10 microM) reduced the calcium transient in response to nicotine. These results support a model in which elevation of cyclic AMP inhibits the activation of nicotinic receptors, but augments stimulus secretion coupling downstream of calcium entry. The data, however, do not indicate a simple relationship between total intracellular cyclic AMP levels and the attenuation of nicotinic stimulation of release.

Inhibition of hematopoietic prostaglandin D2 synthase (H-PGDS) by an alkaloid extract from Combretum molle.

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Moyo, Rejoice; Chimponda, Theresa; Mukanganyama, Stanley

2014-07-05

Hematopoietic prostaglandin D2 synthase (H-PGDS, GST Sigma) is a member of the glutathione S-transferase super family of enzymes that catalyses the conjugation of electrophilic substances with reduced glutathione. The enzyme catalyses the conversion of PGH2 to PGD2 which mediates inflammatory responses. The inhibition of H-PGDS is of importance in alleviating damage to tissues due to unwarranted synthesis of PGD2. Combretum molle has been used in African ethno medicinal practices and has been shown to reduce fever and pain. The effect of C. molle alkaloid extract on H-PGDS was thus, investigated. H-PGDS was expressed in Escherichia coli XL1-Blue cells and purified using nickel immobilized metal affinity chromatography. The effect of C. molle alkaloid extract on H-PGDS activity was determined with 1-chloro-2, 4-dinitrobenzene (CDNB) as substrate. The effect of C. molle alkaloid extract with time on H-PGDS was determined. The mechanism of inhibition was then investigated using CDNB and glutathione (GSH) as substrates. A specific activity of 24 μmol/mg/min was obtained after H-PGDS had been purified. The alkaloid extract exhibited a 70% inhibition on H-PGDS with an IC50 of 13.7 μg/ml. C. molle alkaloid extract showed an uncompetitive inhibition of H-PGDS with Ki = 41 μg/ml towards GSH, and non-competitive inhibition towards CDNB with Ki = 7.7 μg/ml and Ki' = 9.2 μg/ml. The data shows that C. molle alkaloid extract is a potent inhibitor of H-PGDS. This study thus supports the traditional use of the plant for inflammation.

Prostaglandin E1 and prostaglandin F2 alpha in exudate in nickel allergy

DEFF Research Database (Denmark)

Lerche, A; Bisgaard, H; Kassis, V

1989-01-01

Ten nickel-allergic patients and 5 healthy control subjects participated in a study of the kinetics of the flux and concentration of migrated leukocytes and extracellular PGE1 and PGF2 alpha during a 48 h period, using a skin chamber technique. The patients were provided with two skin chambers, one...... with and one without nickel challenge. A higher flux of leukocytes, PGE1 and PGF2 alpha was observed during the second day of allergen exposure, while the concentrations probably due to dilution were unchanged or diminished, indicating an unspecific role of the prostaglandins during the contact allergic...

Prostaglandin E2 facilitates neurite outgrowth in a motor neuron-like cell line, NSC-34

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Hiroshi Nango

2017-10-01

Full Text Available Prostaglandin E2 (PGE2 exerts various biological effects by binding to E-prostanoid receptors (EP1-4. Although recent studies have shown that PGE2 induces cell differentiation in some neuronal cells such as mouse DRG neurons and sensory neuron-like ND7/23 cells, it is unclear whether PGE2 plays a role in differentiation of motor neurons. In the present study, we investigated the mechanism of PGE2-induced differentiation of motor neurons using NSC-34, a mouse motor neuron-like cell line. Exposure of undifferentiated NSC-34 cells to PGE2 and butaprost, an EP2-selective agonist, resulted in a reduction of MTT reduction activity without increase the number of propidium iodide-positive cells and in an increase in the number of neurite-bearing cells. Sulprostone, an EP1/3 agonist, also significantly lowered MTT reduction activity by 20%; however, no increase in the number of neurite-bearing cells was observed within the concentration range tested. PGE2-induced neurite outgrowth was attenuated significantly in the presence of PF-0441848, an EP2-selective antagonist. Treatment of these cells with dibutyryl-cAMP increased the number of neurite-bearing cells with no effect on cell proliferation. These results suggest that PGE2 promotes neurite outgrowth and suppresses cell proliferation by activating the EP2 subtype, and that the cAMP-signaling pathway is involved in PGE2-induced differentiation of NSC-34 cells. Keywords: Prostaglandin E2, E-prostanoid receptors, Motor neuron, Neurite outgrowth, cAMP

Prostaglandin E2 released from activated microglia enhances astrocyte proliferation in vitro

International Nuclear Information System (INIS)

Zhang Dan; Hu Xiaoming; Qian Li; Wilson, Belinda; Lee, Christopher; Flood, Patrick; Langenbach, Robert; Hong, J.-S.

2009-01-01

Microglial activation has been implicated in many astrogliosis-related pathological conditions including astroglioma; however, the detailed mechanism is not clear. In this study, we used primary enriched microglia and astrocyte cultures to determine the role of microglial prostaglandin E 2 (PGE 2 ) in the proliferation of astrocytes. The proliferation of astrocytes was measured by BrdU incorporation. The level of PGE 2 was measured by ELISA method. Pharmacological inhibition or genetic ablation of COX-2 in microglia were also applied in this study. We found that proliferation of astrocytes increased following lipopolysaccharide (LPS) treatment in the presence of microglia. Furthermore, increased proliferation of astrocytes was observed in the presence of conditioned media from LPS-treated microglia. The potential involvement of microglial PGE 2 in enhanced astrocyte proliferation was suggested by the findings that PGE 2 production and COX-2 expression in microglia were increased by LPS treatment. In addition, activated microglia-induced increases in astrocyte proliferation were blocked by the PGE 2 antagonist AH6809, COX-2 selective inhibitor DuP-697 or by genetic knockout of microglial COX-2. These findings were further supported by the finding that addition of PGE 2 to the media significantly induced astrocyte proliferation. These results indicate that microglial PGE 2 plays an important role in astrocyte proliferation, identifying PGE 2 as a key neuroinflammatory molecule that triggers the pathological response related to uncontrollable astrocyte proliferation. These findings are important in elucidating the role of activated microglia and PGE 2 in astrocyte proliferation and in suggesting a potential avenue in the use of anti-inflammatory agents for the therapy of astroglioma.

A comparison of oral misoprostol and vaginal prostaglandin e2 tablets for induction of labour at term

International Nuclear Information System (INIS)

Munzar, Z.

2015-01-01

To compare the efficacy and safety of oral misoprostol with prostaglandin E2 vaginal tablets for ripening of cervix and induction of labour at term. Study Design: A non blinded, randomised, controlled trial. Place and Duration of Study: Department of Obstetrics and Gynaecology, Pakistan Air Force Hospital, Air Headquarters Islamabad from July 2005 to January 2006. Patients and Methods: Hundred pregnant women with a singleton live pregnancy, at term (37-42 weeks) with cephalic presentation were selected for induction of labour for various indications having a Bishop's score of < or =5. These women were randomly allocated to receive either 100 micro gm of misoprostol rally repeated four hourly to a maximum of four doses or a 3mg PGE2 tablet vaginally repeated six hourly to a maximum of two doses. Main outcomes measured: Cervical score before and after oral misoprostol and prostaglandin E2 vaginal tablets, vaginal birth within 24 hours of first prostaglandin dose, no of patients having failed induction, caesarean sections (all), caesarean section for fetal distress and uterine hyperstimulation with associated changes in fetal heart rate. Results: Over the period of one year 100 women were recruited for the study, 50 to the misoprostol group and 50 to the vaginal prostaglandin E2 group. There was no significant differences between the two treatment groups in the primary outcomes: improvement in bishops score in both the groups, no of patients with failed induction in both the groups misoprostol 2/50 (4%) v PGE2 3/50 (6%) , vaginal birth achieved in 24 hours (misoprostol 27/50 (54%) v PGE2 29/50 (58%), caesarean sections 14/50 (28%) v 12/50(24%) caesarean section for fetal distress 4/50((8%) v 5/50(9%); uterine hyperstimulation with fetal heart rate changes 2/50 ((4%) v none in the PGE2 group.). Neonatal outcomes were not significantly different in the two groups. Conclusion: Oral misoprostol in strength of 100 micro gm has similar efficacy to vaginal PGE2 tablets

Prostaglandin E2/leukotriene B4 balance induced by Lutzomyia longipalpis saliva favors Leishmania infantum infection.

Science.gov (United States)

Araújo-Santos, Théo; Prates, Deboraci Brito; França-Costa, Jaqueline; Luz, Nívea F; Andrade, Bruno B; Miranda, José Carlos; Brodskyn, Claudia I; Barral, Aldina; Bozza, Patrícia T; Borges, Valéria Matos

2014-12-20

Eicosanoids and sand fly saliva have a critical role in the Leishmania infection. Here, we evaluated the effect of Lutzomyia longipalpis salivary gland sonicate (SGS) on neutrophil and monocyte recruitment and activation of eicosanoid production in a murine model of inflammation. C57BL/6 mice were inoculated intraperitonealy with Lutzomyia longipalpis SGS or Leishmania infantum or both, followed by analyses of cell recruitment, parasite load and eicosanoid production. Intraperitoneal injection of Lutzomyia longipalpis SGS together with Leishmania infantum induced an early increased parasite viability in monocytes and neutrophils. L. longipalpis SGS increased prostaglandin E2 (PGE2), but reduced leukotriene B4 (LTB4) production ex vivo in peritoneal leukocytes. In addition, the pharmacological inhibition of cyclooxygenase 2 (COX-2) with NS-398 decreased parasite viability inside macrophages during Leishmania infection in the presence of L. longipalpis SGS arguing that PGE2 production is associated with diminished parasite killing. These findings indicate that L. longipalpis SGS is a critical factor driving immune evasion of Leishmania through modulation of PGE2/LTB4 axis, which may represent an important mechanism on establishment of the infection.

Influence of prostaglandin analogues on epithelial cell proliferation and xenograft growth.

Science.gov (United States)

Tutton, P J; Barkla, D H

1980-01-01

The influence of two prostaglandin (PG) analogues, 16,16-dimethyl PG E2 and 16,16-dimethyl PG F2 alpha and of the cyclo-oxygenase inhibitor, flurbiprofen, on epithelial cell proliferation was assessed using a stathmokinetic technique. The epithelia examined were those of the jejunal crypts, the colonic crypts and that of dimethylhydrazine-induced adenocarcinomas of rat colon. The influence of the two prostaglandin analogues, and of flurbiprofen, on the growth of a human colorectal tumour propagated as xenografts in immune-deprived mice was also assessed. The PG E2 analogue transiently inhibited xenograft growth, but was without effect on the mitotic rate in the rat tissues. The PG F2 alpha analogue was also found to inhibit xenograft growth but, unlike the PG E2 analogue, it was found to be a strong inhibitor of cell proliferation in rat colonic tumours, and an accelerator of proliferation in jejunal-crypt cells. The only statistically significant effect of flurbiprofen was to accelerate cell division in the rat colonic tumours.

Expanded adipose-derived stem cells suppress mixed lymphocyte reaction by secretion of prostaglandin E2.

Science.gov (United States)

Cui, Lei; Yin, Shuo; Liu, Wei; Li, Ningli; Zhang, Wenjie; Cao, Yilin

2007-06-01

Multipotent mesenchymal stem cells (MSCs) in adult tissue are known to be less immunogenic and immunosuppressive. Previous study showed that primary cultures of human adipose-derived stem cells (ADSCs) shared their immunomodulatory properties with other MSCs. However, whether passaged human ADSCs can retain their immunomodulatory effect after in vitro expansion remains unknown. In addition, the mechanism of ADSC-mediated immunomodulatory effect remains to be elucidated. This study aimed to investigate these issues by using passaged human ADSCs as an in vitro study model. Flow cytometry showed that passaged ADSCs expressed human leukocyte antigen (HLA) class I but not class II molecules, which could be induced to express to a high level with interferon-gamma (IFN-gamma) treatment. The study found that passaged ADSCs could not elicit lymphocyte proliferation after co-culturing with them, even after IFN-gamma treatment. In addition, either IFN-gamma-treated or non-treated ADSCs could inhibit phytohemagglutinin (PHA)-stimulated lymphocyte proliferation. Moreover, passaged ADSCs could serve as the third-party cells to inhibited two-way mixed lymphocyte reaction (MLR). Further study using a transwell system also showed that this type of immunosuppressive effect was not cell-cell contact dependent. In defining possible soluble factors, we found that passaged ADSCs significantly increased their secretion of prostaglandin E2 (PGE2), but not transforming growth factor-beta (TGF-beta) and hepatocyte growth factor (HGF), when they were co-cultured with MLR. Furthermore, the result demonstrated that only PGE2 production inhibitor indomethacine, but not TGF-beta- and HGF-neutralizing antibodies, could significantly counteract ADSC-mediated suppression on allogeneic lymphocyte proliferation. These results indicated that in vitro expanded ADSCs retain low immunogenicity and immunosuppressive effect, and PGE2 might be the major soluble factor involved in the in vitro inhibition of

Expression of microsomal prostaglandin E synthase-1 in intestinal type gastric adenocarcinoma and in gastric cancer cell lines

NARCIS (Netherlands)

van Rees, Bastiaan P.; Sivula, Anna; Thorén, Staffan; Yokozaki, Hiroshi; Jakobsson, Per-Johan; Offerhaus, G. Johan A.; Ristimäki, Ari

2003-01-01

Gastrointestinal carcinomas synthesize elevated levels of prostaglandin E(2) (PGE(2)), which has been mechanistically linked to carcinogenesis. Recently, microsomal prostaglandin E synthase-1 (mPGES-1) was cloned, which seems to be inducible and linked to cyclooxygenase-2 (Cox-2) in the biosynthesis

Prostaglandin E and the local immune response in chronic periodontal disease

International Nuclear Information System (INIS)

Loening, T.; Albers, H.-K.; Lisboa, B.P.; Burkhardt, A.; Caselitz, J.

1980-01-01

The local immune reaction of progressive chronic periodontal disease may be particularly influenced by macrophages and macrophage-derived factors. Among these substances the prostaglandins and lysosomal enzymes may play an important pathogenetic role. Parallel immunohistochemical and radioimmunological studies were done to investigate the relatiships of the immune-competent cells and the inflammatory mediators in gingival tissues. The radioimmunological analysis revealed that prostaglandin E increases markedly in the established gingival lesions. Immunohistochemically prostaglandin E was mainly localized within macrophage-like cells. Cytoplasmic lysozyme could be detected in these cells, too. On the other hand, the B-cell response is the prominent feature in established chronic periodontal disease. However, there is apparently a disturbed B-cell reaction as indicated by the irregular IgG-subclass pattern and by the production of mainly monomeric IgA. The possible interactions of macrophages and especially B-cells via prostaglandin E-mediated mechanisms are discussed. (author)

Role of pathogen-derived cell wall carbohydrates and prostaglandin E2 in immune response and suppression of fish immunity by the oomycete Saprolegnia parasitica.

Science.gov (United States)

Belmonte, Rodrigo; Wang, Tiehui; Duncan, Gary J; Skaar, Ida; Mélida, Hugo; Bulone, Vincent; van West, Pieter; Secombes, Christopher J

2014-11-01

Saprolegnia parasitica is a freshwater oomycete that is capable of infecting several species of fin fish. Saprolegniosis, the disease caused by this microbe, has a substantial impact on Atlantic salmon aquaculture. No sustainable treatment against saprolegniosis is available, and little is known regarding the host response. In this study, we examined the immune response of Atlantic salmon to S. parasitica infection and to its cell wall carbohydrates. Saprolegnia triggers a strong inflammatory response in its host (i.e., induction of interleukin-1β1 [IL-1β1], IL-6, and tumor necrosis factor alpha), while severely suppressing the expression of genes associated with adaptive immunity in fish, through downregulation of T-helper cell cytokines, antigen presentation machinery, and immunoglobulins. Oomycete cell wall carbohydrates were recognized by fish leukocytes, triggering upregulation of genes involved in the inflammatory response, similar to what is observed during infection. Our data suggest that S. parasitica is capable of producing prostaglandin [corrected] E2 (PGE2) in vitro, a metabolite not previously shown to be produced by oomycetes, and two proteins with homology to vertebrate enzymes known to play a role in prostaglandin biosynthesis have been identified in the oomycete genome. Exogenous PGE2 was shown to increase the inflammatory response in fish leukocytes incubated with cell wall carbohydrates while suppressing genes involved in cellular immunity (gamma interferon [IFN-γ] and the IFN-γ-inducible protein [γ-IP]). Inhibition of S. parasitica zoospore germination and mycelial growth by two cyclooxygenase inhibitors (aspirin and indomethacin) also suggests that prostaglandins may be involved in oomycete development. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Prostaglandin E2 and the protein kinase A pathway mediate arachidonic acid induction of c-fos in human prostate cancer cells

Science.gov (United States)

Chen, Y.; Hughes-Fulford, M.

2000-01-01

Arachidonic acid (AA) is the precursor for prostaglandin E2 (PGE2) synthesis and increases growth of prostate cancer cells. To further elucidate the mechanisms involved in AA-induced prostate cell growth, induction of c-fos expression by AA was investigated in a human prostate cancer cell line, PC-3. c-fos mRNA was induced shortly after addition of AA, along with a remarkable increase in PGE2 production. c-fos expression and PGE2 production induced by AA was blocked by a cyclo-oxygenase inhibitor, flurbiprofen, suggesting that PGE2 mediated c-fos induction. Protein kinase A (PKA) inhibitor H-89 abolished induction of c-fos expression by AA, and partially inhibited PGE2 production. Protein kinase C (PKC) inhibitor GF109203X had no significant effect on c-fos expression or PGE2 production. Expression of prostaglandin (EP) receptors, which mediate signal transduction from PGE2 to the cells, was examined by reverse transcription polymerase chain reaction in several human prostate cell lines. EP4 and EP2, which are coupled to the PKA signalling pathway, were expressed in all cells tested. Expression of EP1, which activates the PKC pathway, was not detected. The current study showed that induction of the immediate early gene c-fos by AA is mediated by PGE2, which activates the PKA pathway via the EP2/4 receptor in the PC-3 cells.

The influence of some prostaglandins on DNA synthesis and DNA excision repair in mouse spleen cells ''in vitro''

International Nuclear Information System (INIS)

Klein, W.; Altmann, H.; Kocsis, F.; Egg, D.; Guenther, R.

1978-03-01

''In vitro'' experiments were performed on mouse spleen cells to establish possible influences of some naturally occurring prostaglandins on DNA synthesis and DNA excision repair. The prostaglandins A 1 , B 1 , E 1 , E 2 and Fsub(2α) were tested in concentrations of 10 pg, 5 ng and 2,5μg per ml cell suspension. DNA synthesis was significantly increased by PgFsub(2α) in all the three concentrations tested, while the other tested prostaglandins were essentially ineffective. DNA excision repair was significantly inhibited by PgE 1 and PgE 2 at 5 ng/ml and at 2,5 μg/ml but increased by PgFsub(2α) in the two lower concentrations. The rejoining of DNA-strand breaks after gamma-irradiation was slightly reduced by PgE 1 , PgE 2 and PgF 2 at 2,5 μg/ml. (author)

Perubahan Kadar Prostaglandin E2 (PGE2) Setelah Aplikasi Ekstrak Gambir (Uncaria Gambir ROXB) Pada Kasus Pulpitis Ireversible.

OpenAIRE

Samad, Rasmidar

2017-01-01

The dental pulp was soft tissue, reside in the cental of tooth, enclosed by, email, dentine and cementum, Inflammation of dental pulp was called pulpitis. Two groups of pulpitis, among these pulpitis, irreversible pulpitis. Design of this researc pre and post test to evaluate change the levels of prostaglandin E2 (PGE2) post application gambier (Uncaria Gambier Roxb) extract, in January-April 2016 in the Biofarmaca Laboratory Research Center Activities Faclty of Pharmacy.

Prostaglandin E2-Induced COX-2 Expressions via EP2 and EP4 Signaling Pathways in Human LoVo Colon Cancer Cells

Directory of Open Access Journals (Sweden)

Hsi-Hsien Hsu

2017-05-01

Full Text Available Metastasis is the most dangerous risk faced by patients with hereditary non-polyposis colon cancer (HNPCC. The expression of matrix metalloproteinases (MMPs has been observed in several types of human cancers and regulates the efficacy of many therapies. Here, we show that treatment with various concentrations of prostaglandin E2 (PGE2; 0, 1, 5 or 10 μM promotes the migration ability of the human LoVo colon cancer cell line. As demonstrated by mRNA and protein expression analyses, EP2 and EP4 are the major PGE2 receptors expressed on the LoVo cell membrane. The Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K/Akt cell survival pathway was upregulated by EP2 and EP4 activation. Following the activation of the PI3K/Akt pathway, β-catenin translocated into the nucleus and triggered COX2 transcription via LEF-1 and TCF-4 and its subsequent translation. COX2 expression correlated with the elevation in the migration ability of LoVo cells. The experimental evidence shows a possible mechanism by which PGE2 induces cancer cell migration and further suggests PGE2 to be a potential therapeutic target in colon cancer metastasis. On inhibition of PGE2, in order to determine the downstream pathway, the levels of PI3K/Akt pathway were suppressed and the β-catenin expression was also modulated. Inhibition of EP2 and EP4 shows that PGE2 induces protein expression of COX-2 through EP2 and EP4 receptors in LoVo colon cancer cells.

Regulation of cyclic AMP metabolism by prostaglandins in rabbit cortical collecting tubule cells

International Nuclear Information System (INIS)

Sonnenburg, W.K.

1987-01-01

In the rabbit cortical collecting tubule (RCCT), prostaglandin E 1 (PGE 1 ) and prostaglandin E 2 (PGE 2 ) at 1 nM inhibit arginine-vasopressin (AVP)-induced water reabsorption, while 100 nM PGE 1 and PGE 2 alone stimulate water reabsorption. Reported here are studies designed to investigate the molecular basis for the biphasic physiological action of PGE 1 and PGE 2 in the collecting duct. In freshly isolated RCCT cells, PGE 1 , PGE 2 , and 16,16-dimethyl-PGE 2 (DM-PGE 2 ) stimulated cAMP synthesis at concentrations ranging from 0.1 to 10 M. Other prostaglandins including the synthetic PGE 2 analogue, sulprostone, failed to stimulate cAMP synthesis. Moreover, sulprostone did not antagonize PGE 2 -stimulated cAMP formation. In contrast, PGE 2 and sulprostone at concentrations ranging from 1 to 100 nM, inhibited AVP-induced cAMP accumulation in freshly isolated RCCT cells. PGE 2 , PGE 1 , DM-PGE 2 and sulprostone at 100 nM were equally effective in inhibiting AVP-induced cAMP formation. Moreover sulprostone inhibited AVP-stimulated adenylate cyclase activity. These results suggest that PGE derivatives mediate either inhibition or activation of adenylate cyclase by stimulating different PGE receptors. To further test this concept, PGE 2 binding to freshly isolated RCCT cell membranes was characterized. Two different classes of PGE 2 binding were detected. / 3 H/PGE 2 binding to the high affinity class of sites was increased by the GTP-analogue, GTP S, while pertussis toxin pretreatment blocked the stimulatory action. In contrast, / 3 H/ PGE 2 binding to the low affinity class of sites was decreased by GTP S; this inhibitory effect was not blocked by pertussis toxin pretreatment

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

Energy Technology Data Exchange (ETDEWEB)

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

2015-01-02

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

Prostaglandin E2 Levels of Aqueous and Vitreous Humor in Ketorolac 0.4% and Nepafenac 0.1% Administered Healthy Rabbits.

Science.gov (United States)

Acar, Ugur; Acar, Damla Erginturk; Tanriverdi, Cafer; Acar, Mutlu; Ozdemir, Ozdemir; Erikci, Acelya; Ornek, Firdevs

2017-06-01

To compare the lowering effects of ketorolac 0.4% and nepafenac 0.1% on aqueous and vitreous humor prostaglandin E 2 (PGE 2 ) levels in rabbits. Ketorolac and nepafenac ophthalmic solutions were administered to the right eyes of 24 healthy rabbits after randomized division into two groups. The left eyes of these rabbits were considered as controls for the two groups. On the 4th day of the experiment, the samples were taken from the aqueous and vitreous humors of the rabbits bilaterally, and PGE 2 levels were measured by an enzyme immune assay kit. Ketorolac and nepafenac achieved a statistically significant decrease (phumor (6.58 ± 4.62 and 9.83 ± 4.55 pg/mL, respectively). Both ketorolac and nepafenac inhibited PGE 2 levels in both the aqueous and vitreous humors of rabbits. Although PGE 2 -lowering effects were similar in the aqueous humor, nepafenac seemed to be more potent than ketorolac in the vitreous humor.

The Value of Intravenous Prostaglandin E2 after Intra-uterine Death

African Journals Online (AJOL)

1974-09-21

Sep 21, 1974 ... ficantly smaller doses of prostaglandins can achieve deli- very of the fetus and an intravenous route will be the method of choice. However, in cases of rhesus iso- immunisation, where larger doses of prostaglandin are required, with correspondingly more severe side-effects, the extra-amniotic route may be ...

Prostaglandin E(2) mediates acid-induced heartburn in healthy volunteers.

Science.gov (United States)

Kondo, Takashi; Oshima, Tadayuki; Tomita, Toshihiko; Fukui, Hirokazu; Watari, Jiro; Okada, Hiroki; Kikuchi, Shojiro; Sasako, Mitsuru; Matsumoto, Takayuki; Knowles, Charles H; Miwa, Hiroto

2013-03-15

Prostaglandin E(2) (PGE(2)) plays a major role in pain processing and hypersensitivity. This study investigated whether PGE(2) levels are increased in the esophageal mucosa after acid infusion and whether increases in PGE(2) are associated with heartburn. Furthermore, expression of the PGE(2) receptor EP1 was investigated in human esophageal mucosa. Fourteen healthy male volunteers were randomized to 30-min lower esophageal acid (1% HCl) or saline perfusion. Before and after acid perfusion, endoscopic biopsies were taken from the distal esophagus. PGE(2) concentration (pg/mg protein) and EP1 mRNA and protein in biopsy samples were measured by ELISA, RT-PCR, and Western blotting. Symptom status of heartburn was evaluated with a validated categorical rating scale with a higher values corresponding to increasing intensity. PGE(2) levels in the esophageal mucosa significantly increased after acid infusion (before vs. after acid infusion: 23.2 ± 8.6 vs. 68.6 ± 18.3, P heartburn in the acid-infusion group was also significantly greater compared with saline (saline vs. acid infusion: 54.3 ± 13.1 vs. 178.5 ± 22.8, P heartburn.

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

LENUS (Irish Health Repository)

O'Callaghan, G

2012-02-03

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

Effects of drugs inhibiting prostaglandin or leukotriene biosynthesis on postirradiation haematopoiesis in mouse

International Nuclear Information System (INIS)

Kozubik, A.; Hofmanova, J.; Pospisil, M.; Netikova, J.; Hola, J.; Lojek, A.

1994-01-01

Two non-steroidal anti-inflammatory drugs, i.e. indomethacin (INDO), an inhibitor of prostaglandin production, and esculetin (ESCUL), an inhibitor of leukotriene production, were tested for their ability to modify haematopoiesis in three experimental systems: (a) in vitro clonal proliferation of marrow GM-CFC from the irradiated mouse was found to be augmented by addition of INDO at a low concentration, and inhibited by ESCUL in a dose-dependent manner; (b) in the lethally irradiated and bone marrow-transplanted mice treated with the drugs in the postirradiation period, stimulatory effects of INDO on CFU-S and GM-CFC populations and an inhibitory effect of ESCUL on GM-CFC were observed; and (c) when the drugs were administered i.p. to mice 1 h before 5-Gy irradiation, INDO enhanced the postirradiation recovery of haematopoietic indices such the numbers of CFU-S, GM-CFC, peripheral blood granuloctyes, and nucleated bone marrow cells, while ESCUL had no effect or even inhibited the recovery of these indices. (author)

Effects of drugs inhibiting prostaglandin or leukotriene biosynthesis on postirradiation haematopoiesis in mouse

Energy Technology Data Exchange (ETDEWEB)

Kozubik, A.; Hofmanova, J.; Pospisil, M.; Netikova, J.; Hola, J.; Lojek, A. (Ceskoslovenska Akademie Ved, Brno (Czech Republic). Biofysikalni Ustav)

1994-03-01

Two non-steroidal anti-inflammatory drugs, i.e. indomethacin (INDO), an inhibitor of prostaglandin production, and esculetin (ESCUL), an inhibitor of leukotriene production, were tested for their ability to modify haematopoiesis in three experimental systems: (a) in vitro clonal proliferation of marrow GM-CFC from the irradiated mouse was found to be augmented by addition of INDO at a low concentration, and inhibited by ESCUL in a dose-dependent manner; (b) in the lethally irradiated and bone marrow-transplanted mice treated with the drugs in the postirradiation period, stimulatory effects of INDO on CFU-S and GM-CFC populations and an inhibitory effect of ESCUL on GM-CFC were observed; and (c) when the drugs were administered i.p. to mice 1 h before 5-Gy irradiation, INDO enhanced the postirradiation recovery of haematopoietic indices such the numbers of CFU-S, GM-CFC, peripheral blood granuloctyes, and nucleated bone marrow cells, while ESCUL had no effect or even inhibited the recovery of these indices. (author).

Prostaglandin A1 metabolism and inhibition of cyclic AMP extrusion by avian erythrocytes

International Nuclear Information System (INIS)

Heasley, L.E.; Brunton, L.L.

1985-01-01

Prostaglandins (PG) inhibit active cyclic AMP export from pigeon red cells, PGA1 and PGA2 most potently. To probe the mechanism of this action of PGA1, the authors have studied the interaction of [ 3 H]PGA1 with suspensions of pigeon red cells. The interaction of PGA1 with pigeon red cells is a multistep process of uptake, metabolism, and secretion. [ 3 H] PGA1 rapidly enters red cells and is promptly metabolized to a compound(s) that remains in the aqueous layer after ethylacetate extraction. The glutathione-depleting agent, diamide, inhibits formation of the PGA1 metabolite. The red cells secrete the polar metabolite of PGA1 by a saturable mechanism that lowered temperatures inhibit. Because uptake and metabolism progress with much greater rates than metabolite secretion, red cells transiently concentrate the polar compound intracellularly. Onset and reversal of inhibition of cyclic AMP export by PGA1 coincide with accumulation and secretion of PGA1 metabolite, suggesting that the polar metabolite acts at an intracellular site to inhibit cyclic AMP efflux

Increased renal sodium absorption by inhibition of prostaglandin synthesis during fasting in healthy man. A possible role of the epithelial sodium channels

Directory of Open Access Journals (Sweden)

Graffe Carolina C

2010-10-01

Full Text Available Abstract Background Treatment with prostaglandin inhibitors can reduce renal function and impair renal water and sodium excretion. We tested the hypotheses that a reduction in prostaglandin synthesis by ibuprofen treatment during fasting decreased renal water and sodium excretion by increased absorption of water and sodium via the aquaporin2 water channels and the epithelial sodium channels. Methods The effect of ibuprofen, 600 mg thrice daily, was measured during fasting in a randomized, placebo-controlled, double-blinded crossover study of 17 healthy humans. The subjects received a standardized diet on day 1, fasted at day 2, and received an IV infusion of 3% NaCl on day 3. The effect variables were urinary excretions of aquaporin2 (u-AQP2, the beta-fraction of the epithelial sodium channel (u-ENaCbeta, cyclic-AMP (u-cAMP, prostaglandin E2 (u-PGE2. Free water clearance (CH2O, fractional excretion of sodium (FENa, and plasma concentrations of vasopressin, angiotensin II, aldosterone, atrial-, and brain natriuretic peptide. Results Ibuprofen decreased u-AQP2, u-PGE2, and FENa at all parts of the study. During the same time, ibuprofen significantly increased u-ENaCbeta. Ibuprofen did not change the response in p-AVP, u-c-AMP, urinary output, and free water clearance during any of these periods. Atrial-and brain natriuretic peptide were higher. Conclusion During inhibition of prostaglandin synthesis, urinary sodium excretion decreased in parallel with an increase in sodium absorption and increase in u-ENaCbeta. U-AQP2 decreased indicating that water transport via AQP2 fell. The vasopressin-c-AMP-axis did not mediate this effect, but it may be a consequence of the changes in the natriuretic peptide system and/or the angiotensin-aldosterone system Trial Registration Clinical Trials Identifier: NCT00281762

Decreased production of interleukin-6 and prostaglandin E2 associated with inhibition of delta-5 desaturation of omega6 fatty acids in mice fed safflower oil diets supplemented with sesamol.

Science.gov (United States)

Chavali, S R; Forse, R A

1999-12-01

The differences in the immune responses in mice fed sesame oil diets and those fed sesamin may be attributed to the presence of other lignans in the non-fat portion of the oil. The fatty acid composition (mean +/- SD mol. %) of liver membrane phospholipids and the levels of endotoxin-induced prostaglandin (PG) E2, interleukin (IL)-6, IL-10, IL-12 and tumor necrosis factor (TNF)-alpha were determined in mice fed diets supplemented with 5% safflower oil (SO) in the absence or presence of 1% sesamol. The levels of dihomo-gamma-linolenic acid (20:3omega6) were markedly higher (P<0.025) in the livers from mice fed sesamol supplemented SO diets (1.6 +/- 0.1) compared to the controls (1.4 +/- 0.1). These data suggest that sesamol or its metabolite could inhibit the in vivo delta-5 desaturation of omega6 fatty acids. Further, in animals fed sesamol supplemented SO diets, the levels of PGE2 (228 +/- 41 pg/ml) were markedly lower (P<0.01) compared to those fed SO diet alone (1355 +/- 188 pg/ml). Concomitantly, the concentrations of IL-6 were also lower (P<0.01) in mice fed sesamol diet (63 +/- 11 ng/ml) compared to the controls (143 +/- 22 ng/ml). A marked reduction in the levels of PGE2 in animals fed sesamol diets suggests that sesamol or its metabolite could inhibit the activity of cyclooxygenase enzyme.

Inhibition of Nitric Oxide and Prostaglandin E2 Expression by ...

African Journals Online (AJOL)

HP

ZL, Wu CJ. Inhibition of lipopolysaccharide (LPS)- induced inflammatory responses by Sargassum hemiphyllum sulfated polysaccharide extract in. RAW 264.7 macrophage cells. J Agric Food Chem. 2011; 59: 2062–2068. 19. Baldwin AS (Jr). The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol.

Effect of human milk prostaglandins and lactoferrin on respiratory syncytial virus and rotavirus.

Science.gov (United States)

Grover, M; Giouzeppos, O; Schnagl, R D; May, J T

1997-03-01

The effect of lactoferrin and prostaglandins E and F2 alpha on the growth of rotavirus and respiratory syncytial virus in cell culture was investigated. Lactoferrin inhibited the growth of respiratory syncytial virus at a concentration tenfold lower than that normally present in human milk. The prostaglandins had no effect on either virus growth, even at a concentration of 100-fold more than that found in human milk. Lactoferrin may have some antiviral properties in human milk in addition to its known antibacterial functions.

Tartrazine and the prostaglandin system.

Science.gov (United States)

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

1979-04-01

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

Does prostaglandin D2 hold the cure to male pattern baldness?

Science.gov (United States)

Nieves, Ashley; Garza, Luis A

2014-04-01

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

Increased jejunal prostaglandin E2 concentrations in patients with acute cholera

NARCIS (Netherlands)

Speelman, P.; Rabbani, G. H.; Bukhave, K.; Rask-Madsen, J.

1985-01-01

Supraphysiologic doses of prostaglandins (PGs) mimic the effect of cholera toxin and cAMP in the small intestine, but not all observations are explicable in terms of the theory that links PGs to cAMP. Because no data exist on endogenous PGs in human cholera we measured PGE2 concentrations in jejunal

Dissociation of bradykinin-induced prostaglandin formation from phosphatidylinositol turnover in Swiss 3T3 fibroblasts: evidence for G protein regulation of phospholipase A2

International Nuclear Information System (INIS)

Burch, R.M.; Axelrod, J.

1987-01-01

In Swiss 3T3 fibroblasts bradykinin stimulated inositol phosphate (InsP) formation and prostaglandin E 2 (PGE 2 ) synthesis. The EC 50 values for stimulation of PGE 2 synthesis and InsP formation by bradykinin were similar, 200 pM and 275 pM, respectively. Guanosine-5'-[γ-thio]triphosphate stimulated PGE 2 synthesis and InsP formation, and guanosine-5'-[β-thio]diphosphate inhibited both PGE 2 synthesis and InsP formation stimulated by bradykinin. Neither bradykinin-stimulated PGE 2 synthesis nor InsP formation was sensitive to pertussis toxin. Phorbol ester, dexamethasone, and cycloheximide distinguished between bradykinin-stimulated PGE 2 synthesis and InsP formation. Phorbol 12-myristate 13-acetate enhanced bradykinin-stimulated PGE 2 synthesis but inhibited bradykinin-stimulated InsP formation. Pretreatment of cells with dexamethasone for 24 hr inhibited bradykinin-stimulated PGE 2 synthesis but was without effect on bradykinin-stimulated InsP formation. Cycloheximide inhibited on bradykinin-stimulated InsP formation. When bradykinin was added to cells prelabeled with [ 3 H] choline, the phospholipase A 2 products lysophosphatidylcholine and glycerophosphocholine were generated. The data suggest that bradykinin receptors are coupled by GTP-binding proteins to both phospholipase C and phospholipase A 2 and that phospholipase A 2 is the enzyme that catalyzes release of arachidonate for prostaglandin synthesis

Prostaglandins in Cancer Cell Adhesion, Migration, and Invasion

Directory of Open Access Journals (Sweden)

David G. Menter

2012-01-01

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

Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury

Science.gov (United States)

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

2014-01-01

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

Effects of indomethacin, NS-398 (a selective prostaglandin H synthase-2 inhibitor) and protein synthesis inhibitors on prostaglandin production by the guinea-pig placenta.

Science.gov (United States)

Aitken, H; Poyser, N L

2001-01-01

The outputs of PGF(2 alpha), PGE2 and 6-keto-PGF(1 alpha)were similar from the day 22 guinea-pig placenta and sub-placenta in culture, except for PGE2 output from the sub-placenta which was lower. Between days 22 and 29 of pregnancy, the outputs of PGF(2 alpha), PGE2 and 6-keto-PGF(1 alpha)during the initial 2 h culture period increased 6.9-, 1.1- and 3.2-fold, respectively, from the placenta, and 2.1-, 1.4- and 2.2-fold, respectively, from the sub-placenta. Therefore, there was a relatively specific increase in PGF(2 alpha)production by the guinea-pig placenta between days 22 and 29 of pregnancy. The output of PGFM from the cultured placenta also increased between days 22 and 29, indicating that the increase in PGF(2 alpha)output was due to increased synthesis rather than to decreased metabolism. By comparing the amounts of prostaglandins produced by tissue homogenates during a 1 h incubation period, it appears that there is approximately a 2-fold increase in the amount of prostaglandin H synthase (PGHS) present in the guinea-pig placenta between days 22 and 29. NS-398 (a specific inhibitor of PGHS-2) and indomethacin (an inhibitor of both PGHS-1 and PGHS-2) both inhibited prostaglandin production by homogenates of day 22 and day 29 placenta. Indomethacin was more effective than NS-398, except for their actions on PGF(2 alpha)production by the day 29 placenta where indomethacin and NS-398 were equiactive. Indomethacin and NS-398 were both very effective at inhibiting the outputs of PGF(2 alpha), PGE2 and 6-keto-PGF(1 alpha)from the day 22 and day 29 placenta and sub-placenta in culture, indicating that prostaglandin production by the guinea-pig placenta and sub-placenta in culture is largely dependent upon the activity of PGHS-2. The high production of PGF(2 alpha)by the day 29 placenta is not dependent on the continual synthesis of fresh protein(s), as inhibitors of protein synthesis did not reduce PGF(2 alpha)output from the day 29 guinea-pig placenta in culture

Prostaglandin E2 stimulates the expression of cumulus expansion-related genes in pigs: the role of protein kinase B

Czech Academy of Sciences Publication Activity Database

Blaha, Milan; Procházka, Radek; Adámková, K.; Nevoral, J.; Němcová, Lucie

2017-01-01

Roč. 130, č. 2 (2017), s. 38-46 ISSN 1098-8823 R&D Projects: GA MZe(CZ) QJ1510138; GA MŠk EF15_003/0000460 Institutional support: RVO:67985904 Keywords : cumulus * oocyte * prostaglandin E2 * protein kinase B Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Reproductive biology (medical aspects to be 3) Impact factor: 2.640, year: 2016

Polysubstituted 4,6-bis(hetero)arylpyrimidines as dual inhibitors of nitric oxide and prostaglandin E-2 production

Czech Academy of Sciences Publication Activity Database

Kolman, Viktor; Jansa, Petr; Kalčic, Filip; Janeba, Zlatko; Zídek, Zdeněk

2017-01-01

Roč. 67, Jul 1 (2017), s. 53-57 ISSN 1089-8603 R&D Projects: GA TA ČR(CZ) TE01020028 Institutional support: RVO:61388963 ; RVO:68378041 Keywords : pyrimidine derivatives * nitric oxide * prostaglandin E-2 * dual inhibitors * anti-inflammatory properties Subject RIV: CE - Biochemistry; CC - Organic Chemistry (UEM-P) OBOR OECD: Biochemistry and molecular biology; Organic chemistry (UEM-P) Impact factor: 4.181, year: 2016

Impact of FDA-Approved Drugs on the Prostaglandin Transporter OATP2A1/SLCO2A1.

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Kamo, Shunsuke; Nakanishi, Takeo; Aotani, Rika; Nakamura, Yoshinobu; Gose, Tomoka; Tamai, Ikumi

2017-09-01

To understand interaction of drugs with the prostaglandin transporter OATP2A1/SLCO2A1 that regulates disposition of prostaglandins, we explored the impact of 636 drugs in an FDA-approved drug library on 6-carboxyfluorescein (6-CF) uptake by OATP2A1-expressing HEK293 cells (HEK/2A1). Fifty-one and 10 drugs were found to inhibit and enhance 6-CF uptake by more than 50%, respectively. Effect of the 51 drugs on 6-CF uptake was positively correlated with that on PGE 2 uptake (r = 0.64, p < 0.001). Among those, 5 drugs not structurally related to prostaglandins, suramin, pranlukast, zafirlukast, olmesartan medoxomil, and losartan potassium, exhibited more than 90% PGE 2 uptake inhibition. Inhibitory affinity of suramin to OATP2A1 was the highest (IC 50,2A1 of 0.17 μM), and its IC 50 values to MRP4-mediated PGE 2 transport (IC 50,MRP4 ) and PGE 2 synthesis in human U-937 cells treated with phorbol 12-myristate 13-acetate (IC 50,Syn ) were 73.6 and 336.7 times higher than IC 50,2A1 , respectively. Moreover, structure-activity relationship study in 29 nonsteroidal anti-inflammatory drugs contained in the library displayed inhibitory activities of anthranilic acid derivatives, but enhancing effects of propionic acid derivatives. These results demonstrate that suramin is a potent selective inhibitor of OATP2A1, providing a comprehensive information about drugs in clinical use that interact with OATP2A1. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Prostaglandins and prostaglandin receptor antagonism in migraine

DEFF Research Database (Denmark)

Antonova, Maria

2013-01-01

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

Topical Prostaglandin E Analog Restores Defective Dendritic Cell–Mediated Th17 Host Defense Against Methicillin-Resistant Staphylococcus Aureus in the Skin of Diabetic Mice

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Dejani, Naiara N.; Brandt, Stephanie L.; Piñeros, Annie; Glosson-Byers, Nicole L.; Wang, Sue; Son, Young Min; Medeiros, Alexandra I.; Serezani, C. Henrique

2016-01-01

People with diabetes are more prone to Staphylococcus aureus skin infection than healthy individuals. Control of S. aureus infection depends on dendritic cell (DC)–induced T-helper 17 (Th17)–mediated neutrophil recruitment and bacterial clearance. DC ingestion of infected apoptotic cells (IACs) drive prostaglandin E2 (PGE2) secretion to generate Th17 cells. We speculated that hyperglycemia inhibits skin DC migration to the lymph nodes and impairs the Th17 differentiation that accounts for poo...

Effects of endogenous pyrogen and prostaglandin E2 on hypothalamic neurons in rat brain slices.

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Watanabe, T; Morimoto, A; Murakami, N

1987-06-01

We investigated the effects of endogenous pyrogen and prostaglandin E2 (PGE2) on the preoptic and anterior hypothalamic (POAH) neurons using brain slice preparations from the rat. Partially purified endogenous pyrogen did not change the activities of most of the neurons in the POAH region when applied locally through a micropipette attached to the recording electrode in proximity to the neurons. This indicates that partially purified endogenous pyrogen does not act directly on the neuronal activity in the POAH region. The partially purified endogenous pyrogen, applied into a culture chamber containing a brain slice, facilitated the activities in 24% of the total neurons tested, regardless of the thermal specificity of the neurons. Moreover, PGE2 added to the culture chamber facilitated 48% of the warm-responsive, 33% of the cold-responsive, and 29% of the thermally insensitive neurons. The direction of change in neuronal activity induced by partially purified endogenous pyrogen appears to be almost the same as that induced by PGE2 when these substances were applied by perfusion to the same neuron in the culture chamber. These results suggest that partially purified pyrogen applied to the perfusate of the culture chamber stimulates some constituents of brain tissue to synthesize and release prostaglandin, which in turn affects the neuronal activity of the POAH region.

Gingival inflammation assessed by histology, 3H-estrone metabolism and prostaglandin E2 levels

International Nuclear Information System (INIS)

Holmes, L.G.; ElAttar, T.M.A.

1977-01-01

Gingival samples were histologically evaluated and placed in two groups, 7 samples each. Group 1 was normal gingiva with no or very few inflammatory cells and group 2 was inflamed gingiva with moderately dense accumulation of imflammatory cells in isolated areas, and sparse distribution in other areas. One hundred to three hundred mg gingival tissue samples were separately homogenized in 7 ml of 0.1 M potasssium phosphate buffer (pH 7.4) and incubated with 1.51 x 10 -4 μM of 3 H-estrone in the presence of NADPH at 37 deg for three hours. Organic solvent extracts of the homogenates were separated by silica gel thin layer chromatography and the radioactivity incorporated in estrone (E 1 ) and estradiol-17 β (E 2 ) zones was extracted with methanol and measured by liquid scintillation spectrometry. The rate conversion of (E 1 ) to (E 2 ) in normal and inflamed gingiva was 4.4 and 8.3 x 10 -7 μM/g/min respectively. Prostaglandin E 2 in 3 normal and 2 inflamed gingival samples were 37.8 and 448.7 pmole/g respectively. The significant increase in the biosynthesis of (E 2 ) and PGE 2 in inflamed as compared with normal gingiva could be a systemic factor in aggravating gingival inflammation due to the hyperemic effects of these hormones. (author)

Do prostaglandins affect cellular radiosensitivity in vitro

International Nuclear Information System (INIS)

Millar, B.C.; Jinks, S.

1984-01-01

The authors were unable to detect any change in the in vitro radiation response of mouse fibrosarcoma cells, HSDM 1 C 1 , which secrete 2 μg PGE 2 /mg cell protein/24 h, in the presence of the prostaglandin biosynthesis inhibitor flurbiprofen. Furthermore, addition of exogenous PGE 1 or PGA 2 to cultures of Chinese hamster cells was similarly without effect on radiation response. Although a high concentration of PGA 2 inhibited the growth of Chinese hamster cells in vitro this effect disappeared upon removal of the prostaglandin. The implications of these results for radiotherapy are discussed. (author)

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

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

2014-01-01

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

Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength.

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Ho, Andrew T V; Palla, Adelaida R; Blake, Matthew R; Yucel, Nora D; Wang, Yu Xin; Magnusson, Klas E G; Holbrook, Colin A; Kraft, Peggy E; Delp, Scott L; Blau, Helen M

2017-06-27

Skeletal muscles harbor quiescent muscle-specific stem cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targets MuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromises muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1 Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes muscle repair and strength. Through such gain- or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent.

Pyometra in Bitches Induces Elevated Plasma Endotoxin and Prostaglandin F2α Metabolite Levels

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Hagman R

2006-03-01

Full Text Available Endotoxemia in bitches with pyometra can cause severe systemic effects directly or via the release of inflammatory mediators. Plasma endotoxin concentrations were measured in ten bitches suffering from pyometra with moderately to severely deteriorated general condition, and in nine bitches admitted to surgery for non-infectious reasons. Endotoxin samples were taken on five occasions before, during and after surgery. In addition, urine and uterine bacteriology was performed and hematological, blood biochemical parameters, prostaglandin F2α metabolite 15-ketodihydro-PGF2α (PG-metabolite, progesterone and oestradiol (E2-17β levels were analysed. The results confirm significantly increased plasma levels of endotoxin in bitches with pyometra and support previous reports of endotoxin involvement in the pathogenesis of the disease. Plasma concentrations of PG-metabolite were elevated in pyometra bitches and provide a good indicator of endotoxin release since the concentrations were significantly correlated to the endotoxin levels and many other hematological and chemistry parameters. The γ-globulin serum protein electrophoresis fraction and analysis of PG-metabolite can be valuable in the diagnosis of endotoxin involvement if a reliable, rapid and cost-effective test for PG-metabolite analysis becomes readily available in the future. Treatment inhibiting prostaglandin biosynthesis and related compounds could be beneficial for bitches suffering from pyometra.

n3 and n6 polyunsaturated fatty acids differentially modulate prostaglandin E secretion but not markers of lipogenesis in adipocytes

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Saxton Arnold M

2009-01-01

Full Text Available Abstract A dramatic rise in the incidence of obesity in the U.S. has accelerated the search for interventions that may impact this epidemic. One recently recognized target for such intervention is adipose tissue, which secretes a variety of bioactive substances including prostaglandins. Prostaglandin E2 (PGE2 has been shown to decrease lipolysis in adipocytes, but limited studies have explored alternative mechanisms by which PGE2 might impact obesity, such as adipogenesis or lipogenesis. Studies conducted on ApcMin/+ mice indicated that selective inhibition of the cyclooxygenase (COX-2 enzyme led to significant reductions in fatty acid synthase (FAS activity in adipose tissue suggesting lipogenic effects of PGE2. To further investigate whether these lipid mediators directly regulate lipogenesis, we used 3T3-L1 adipocytes to determine the impact of eicosapentaenoic acid (EPA and celecoxib on PGE2 formation and FAS used as a lipogenic marker. Both arachidonic acid (AA and EPA dose-dependently increased PGE secretion from adipocytes. AA was expectedly more potent and exhibiting at 150 uM dose a 5-fold increase in PGE2 secretion over EPA. Despite higher secretion of PGE by EPA and AA compared to control, neither PUFA significantly altered FAS activity. By contrast both AA and EPA significantly decreased FAS mRNA levels. Addition of celecoxib, a selective COX-2 inhibitor, significantly decreased PGE2 secretion (p 2 and celecoxib further decreased the FAS activity compared to PGE2 alone or untreated controls. In conclusion, EPA-mediated inhibition of AA metabolism did not significantly alter FAS activity while both AA and EPA significantly decreased FAS mRNA expression. COX-2 inhibition significantly decreased PGE2 production resulting in a decrease in FAS activity and expression that was not reversed with the addition of exogenous PGE2, suggesting an additional mechanism that is independent of COX-2.

Attenuation of prostaglandin E2 elimination across the mouse blood-brain barrier in lipopolysaccharide-induced inflammation and additive inhibitory effect of cefmetazole

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Akanuma Shin-ichi

2011-10-01

Full Text Available Abstract Background Peripheral administration of lipopolysaccharide (LPS induces inflammation and increases cerebral prostaglandin E2 (PGE2 concentration. PGE2 is eliminated from brain across the blood-brain barrier (BBB in mice, and this process is inhibited by intracerebral or intravenous pre-administration of anti-inflammatory drugs and antibiotics such as cefmetazole and cefazolin that inhibit multidrug resistance-associated protein 4 (Mrp4/Abcc4-mediated PGE2 transport. The purpose of this study was to examine the effect of LPS-induced inflammation on PGE2 elimination from brain, and whether antibiotics further inhibit PGE2 elimination in LPS-treated mice. Methods [3H]PGE2 elimination across the BBB of intraperitoneally LPS-treated mice was assessed by the brain efflux index (BEI method. Transporter protein amounts in brain capillaries were quantified by liquid chromatography-tandem mass spectrometry. Results The apparent elimination rate of [3H]PGE2 from brain was lower by 87%, in LPS-treated mice compared with saline-treated mice. The Mrp4 protein amount was unchanged in brain capillaries of LPS-treated mice compared with saline-treated mice, while the protein amounts of organic anion transporter 3 (Oat3/Slc22a8 and organic anion transporting polypeptide 1a4 (Oatp1a4/Slco1a4 were decreased by 26% and 39%, respectively. Either intracerebral or intravenous pre-administration of cefmetazole further inhibited PGE2 elimination in LPS-treated mice. However, intracerebral or intravenous pre-administration of cefazolin had little effect on PGE2 elimination in LPS-treated mice, or in LPS-untreated mice given Oat3 and Oatp1a4 inhibitors. These results indicate that peripheral administration of cefmetazole inhibits PGE2 elimination across the BBB in LPS-treated mice. Conclusion PGE2 elimination across the BBB is attenuated in an LPS-induced mouse model of inflammation. Peripheral administration of cefmetazole further inhibits PGE2 elimination in LPS

Multiple roles of the prostaglandin D2 signaling pathway in reproduction.

Science.gov (United States)

Rossitto, Moïra; Ujjan, Safdar; Poulat, Francis; Boizet-Bonhoure, Brigitte

2015-01-01

Prostaglandins signaling molecules are involved in numerous physiological processes. They are produced by several enzyme-limited reactions upon fatty acids, which are catalyzed by two cyclooxygenases and prostaglandin synthases. In particular, the prostaglandins E2 (PGE2), D2 (PGD2), and F2 (PGF2 α) have been shown to be involved in female reproductive mechanisms. Furthermore, widespread expression of lipocalin- and hematopoietic-PGD2 synthases in the male reproductive tract supports the purported roles of PGD2 in the development of both embryonic and adult testes, sperm maturation, and spermatogenesis. In this review, we summarize the putative roles of PGD2 signaling and the roles of both PGD2 synthases in testicular formation and function. We review the data reporting the involvement of PGD2 signaling in the differentiation of Sertoli and germ cells of the embryonic testis. Furthermore, we discuss the roles of lipocalin-PGD2 synthase in steroidogenesis and spermatogenesis, in terms of lipid molecule transport and PGD2 production. Finally, we discuss the hypothesis that PGD2 signaling may be affected in certain reproductive diseases, such as infertility, cryptorchidism, and testicular cancer. © 2015 Society for Reproduction and Fertility.

Impaired neonatal macrophage phagocytosis is not explained by overproduction of prostaglandin E2

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Ballinger Megan N

2011-12-01

Full Text Available Abstract Background Neonates and young infants manifest increased susceptibility to bacterial, viral and fungal lung infections. Previous work has identified a role for eicosanoids in mediating host defense functions of macrophages. This study examines the relationship between alveolar macrophage (AM host defense and production of lipid mediators during the neonatal period compared to adult AMs. Methods AMs were harvested from young (day 7 and day 14 and adult (~10 week rats. The functionality of these cells was assessed by examining their ability to phagocytose opsonized targets, produce cytokines, eicosanoids and intracellular cAMP measured by enzyme immunoassays, and gene expression of proteins, enzymes and receptors essential for eicosanoid generation and phagocytosis measured by real time RT-PCR. Results AMs from young animals (day 7 and 14 were defective in their ability to phagocytose opsonized targets and produce tumor necrosis factor (TNF- α. In addition, young AMs produce more prostaglandin (PG E2, a suppressor of host defense, and less leukotriene (LT B4, a promoter of host defense. Young AMs express higher levels of enzymes responsible for the production of PGE2 and LTB4; however, there was no change in the expression of E prostanoid (EP receptors or LT receptors. Despite the similar EP profiles, young AMs are more responsive to PGE2 as evidenced by their increased production of the important second messenger, cyclic AMP. In addition, young AMs express higher levels of PDE3B and lower levels of PDE4C compared to adult AMs. However, even though the young AMs produced a skewed eicosanoid profile, neither the inhibition of PGE2 by aspirin nor the addition of exogenous LTB4 rescued the defective opsonized phagocytosis. Examination of a receptor responsible for mediating opsonized phagocytosis showed a significant decrease in the gene expression levels of the Fcgamma receptor in young (day 7 AMs compared to adult AMs. Conclusion These

Methanol Extract of Hydroclathrus clathratus Inhibits Production of ...

African Journals Online (AJOL)

Methanol Extract of Hydroclathrus clathratus Inhibits Production of Nitric Oxide, Prostaglandin E2 and Tumor Necrosis Factor-α in Lipopolysaccharidestimulated BV2 Microglial Cells via Inhibition of NF-κB Activity. RGPT Jayasooriya, D-O Moon, YH Chol, C-H Yoon, G-Y Kim ...

Lokal østrogen-fobehandling reducerer aborttiden ven prostaglandin E1 analog-induceret abort i 2. trimester

DEFF Research Database (Denmark)

Petersen, Lone Kjeld; Uldbjerg, N; Allen, J G

1991-01-01

Twenty-eight patients (median gestational age 17 weeks) referred for induction of second trimester abortion, were randomized to intracervical preliminary treatment by either 50 mg 17 beta-oestradiol or placebo. Abortion was then induced by 1 mg prostaglandin E1 vagitories. The preliminary treatme...

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

International Nuclear Information System (INIS)

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

1982-01-01

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

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

Science.gov (United States)

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

1999-11-05

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

Prostaglandin E2 Regulates Liver versus Pancreas Cell Fate Decisions and Endodermal Outgrowth

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Nissim, Sahar; Sherwood, Richard I.; Wucherpfennig, Julia; Saunders, Diane; Harris, James M.; Esain, Virginie; Carroll, Kelli J.; Frechette, Gregory M.; Kim, Andrew J.; Hwang, Katie L.; Cutting, Claire C.; Elledge, Susanna; North, Trista E.; Goessling, Wolfram

2014-01-01

SUMMARY The liver and pancreas arise from common endodermal progenitors. How these distinct cell fates are specified is poorly understood. Here, we describe prostaglandin E2 (PGE2) as a regulator of endodermal fate specification during development. Modulating PGE2 activity has opposing effects on liver-versus-pancreas specification in zebrafish embryos as well as mouse endodermal progenitors. The PGE2 synthetic enzyme cox2a and receptor ep2a are patterned such that cells closest to PGE2 synthesis acquire a liver fate whereas more distant cells acquire a pancreas fate. PGE2 interacts with the bmp2b pathway to regulate fate specification. At later stages of development, PGE2 acting via the ep4a receptor promotes outgrowth of both the liver and pancreas. PGE2 remains important for adult organ growth, as it modulates liver regeneration. This work provides in vivo evidence that PGE2 may act as a morphogen to regulate cell fate decisions and outgrowth of the embryonic endodermal anlagen. PMID:24530296

Urinary prostaglandin E and vasopressin excretion in essential fatty acid-deficient rats

DEFF Research Database (Denmark)

Hansen, Harald S.; Jensen, B.

1983-01-01

excretion of prostaglandin E (PGE), immunoreactive arginine vasopressin (iA VP), and kallikrein were determined. PGE was quantitated with a radioimmunoassay having 4.9% cross-reactivity with prostaglandin E (PGE). After 4 weeks on the diet, water consumption and urinary iAVP excretion increased....... Increased water consumption and increased urinary iAVP excretion seem to be early symptoms (after 4 weeks) of EFA deficiency, whereas decreased urine output and decreased urinary PGE excretion occur much later (after 10 weeks). Two energy% linolenate supplementation to a fat-free diet did not change...

Do prostaglandins affect cellular radiosensitivity in vitro

Energy Technology Data Exchange (ETDEWEB)

Millar, B.C.; Jinks, S. (Institute of Cancer Research, Sutton (UK). Surrey Branch)

1984-10-01

The authors were unable to detect any change in the in vitro radiation response of mouse fibrosarcoma cells, HSDM/sub 1/C/sub 1/, which secrete 2 ..mu..g PGE/sub 2//mg cell protein/24 h, in the presence of the prostaglandin biosynthesis inhibitor flurbiprofen. Furthermore, addition of exogenous PGE/sub 1/ or PGA/sub 2/ to cultures of Chinese hamster cells was similarly without effect on radiation response. Although a high concentration of PGA/sub 2/ inhibited the growth of Chinese hamster cells in vitro this effect disappeared upon removal of the prostaglandin. The implications of these results for radiotherapy are discussed.

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders.

Science.gov (United States)

Koeberle, Andreas; Werz, Oliver

2015-11-01

Prostaglandin (PG)E2 encompasses crucial roles in pain, fever, inflammation and diseases with inflammatory component, such as cancer, but is also essential for gastric, renal, cardiovascular and immune homeostasis. Cyclooxygenases (COX) convert arachidonic acid to the intermediate PGH2 which is isomerized to PGE2 by at least three different PGE2 synthases. Inhibitors of COX - non-steroidal anti-inflammatory drugs (NSAIDs) - are currently the only available therapeutics that target PGE2 biosynthesis. Due to adverse effects of COX inhibitors on the cardiovascular system (COX-2-selective), stomach and kidney (COX-1/2-unselective), novel pharmacological strategies are in demand. The inducible microsomal PGE2 synthase (mPGES)-1 is considered mainly responsible for the excessive PGE2 synthesis during inflammation and was suggested as promising drug target for suppressing PGE2 biosynthesis. However, 15 years after intensive research on the biology and pharmacology of mPGES-1, the therapeutic value of mPGES-1 as drug target is still vague and mPGES-1 inhibitors did not enter the market so far. This commentary will first shed light on the structure, mechanism and regulation of mPGES-1 and will then discuss its biological function and the consequence of its inhibition for the dynamic network of eicosanoids. Moreover, we (i) present current strategies for interfering with mPGES-1-mediated PGE2 synthesis, (ii) summarize bioanalytical approaches for mPGES-1 drug discovery and (iii) describe preclinical test systems for the characterization of mPGES-1 inhibitors. The pharmacological potential of selective mPGES-1 inhibitor classes as well as dual mPGES-1/5-lipoxygenase inhibitors is reviewed and pitfalls in their development, including species discrepancies and loss of in vivo activity, are discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

Prostaglandin E (dmPGE{sub 2}) action in vitro on the activity of rat liver Golgi apparatus galactosyltransferase

Energy Technology Data Exchange (ETDEWEB)

Kordowiak, A.M.; Tomecki, J.; Procyk, K.; Kapusta, P. [Uniwersytet Jagiellonski, Cracow (Poland)

1993-12-31

In vitro addition of 16,16`-dimethyl prostaglandin E{sub 2} to Golgi-rich membrane fraction in final concentration of 0.1 {mu}g/1 mg of protein increased generally the activity of galactosyltransferase in comparison with control. The percentage of phospholipids in the whole fraction was similar in both investigated groups, only the sum of phosphatidylenoamine + phosphatidic acid was significantly lower after addition of dmPGE{sub 2} than in the control (0.001 < P < 0.01). (author). 25 refs, 2 figs, 1 tab.

Model-based analysis of thromboxane B2 and prostaglandin E2 as biomarkers in the safety evaluation of naproxen

International Nuclear Information System (INIS)

Sahota, Tarjinder; Sanderson, Ian; Danhof, Meindert; Della Pasqua, Oscar

2014-01-01

The assessment of safety in traditional toxicology protocols relies on evidence arising from observed adverse events (AEs) in animals and on establishing their correlation with different measures of drug exposure (e.g., C max and AUC). Such correlations, however, ignore the role of biomarkers, which can provide further insight into the underlying pharmacological mechanisms. Here we use naproxen as a paradigm drug to explore the feasibility of a biomarker-guided approach for the prediction of AEs in humans. A standard toxicology protocol was set up for the evaluation of effects of naproxen in rat, in which four doses were tested (7.5, 15, 40 and 80 mg/kg). In addition to sparse blood sampling for the assessment of exposure, thromboxane B 2 and prostaglandin E 2 were also collected in satellite groups. Nonlinear mixed effects modelling was used to evaluate the predictive performance of the approach. A one-compartmental model with first order absorption was found to best describe the pharmacokinetics of naproxen. A nonlinear relationship between dose and bioavailability was observed which leads to a less than proportional increase in naproxen concentrations with increasing doses. The pharmacodynamics of TXB 2 and PGE 2 was described by direct inhibition models with maximum pharmacological effects achieved at doses > 7.5 mg/kg. The predicted PKPD relationship in humans was within 10-fold of the values previously published. Moreover, our results indicate that biomarkers can be used to assess interspecies differences in PKPD and extrapolated data from animals to humans. Biomarker sampling should be used systematically in general toxicity studies. - Highlights: • Prediction of a drug's safety profile from preclinical protocols remains challenging. • Pharmacokinetic measures of safe exposure (e.g., AUC) ignore the role of biomarkers. • PKPD relationships enable the evaluation of adverse events in a mechanistic manner. • Major differences exist between rats and

Changes in the Th1 : Th2 Cytokine Bias in Pregnancy and the Effects of the Anti-Inflammatory Cyclopentenone Prostaglandin 15-Deoxy-Δ12,14-Prostaglandin J2

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Lynne Sykes

2012-01-01

Full Text Available Pregnancy is a complex immunological state in which a bias towards T helper 2 (Th2 protects the fetus. Evidence suggests that proinflammatory cytokines increase the risk of poor neonatal outcome, independently of the direct effect of preterm labour. The anti-inflammatory prostaglandin 15-deoxy-Δ12,14-Prostaglandin J2 (15dPGJ2 inhibits nuclear factor Kappa B (NF-κB in amniocytes and myocytes in vitro and is a ligand for the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 receptor. Here we examine the Th1:Th2 cytokine bias in pregnancy and whether 15dPGJ2 could be used to inhibit the production of the proinflammatory cytokines through inhibition of NF-κB while simultaneously promoting Th2 interleukin 4 (IL-4 synthesis via CRTH2 in T helper cells. Peripheral blood mononuclear cells (PBMCs from women at 28 weeks, term pre-labour, term labour as well as non-pregnant female controls were cultured with 15dPGJ2 or vehicle control and stimulated with phorbol myristyl acetate (PMA/ionomycin. The percentage of CD4+ cells producing interferon gamma (IFN-γ and tumor necrosis factor alpha (TNF-α in response to PMA/ionomycin was significantly reduced in pregnancy. 15dPGJ2 reduced IFN-γ and TNF-α production in stimulated T helper cells, but did not alter IL-4 production in CRTH2+ve cells. 15dPGJ2 also reduced phospho-p65 in stimulated PBMCs. In summary, 15dPGJ2 suppresses the Th1 response of PBMCs during pregnancy and active labour whilst maintaining the Th2 response suggesting a therapeutic benefit in reducing neonatal morbidity in inflammation-induced PTL.

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

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

2013-02-15

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

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

Directory of Open Access Journals (Sweden)

Michelle M C Buckner

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

15-Deoxy-Delta-12,14-Prostaglandin J2 Inhibits Lung Inflammation and Remodeling in Distinct Murine Models of Asthma

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Diego S. Coutinho

2017-06-01

Full Text Available 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2 has been described as an anti-inflammatory lipid mediator in several in vitro and in vivo studies, but its effect on allergic pulmonary inflammation remains elusive. The aim of this study was to investigate the therapeutic potential of 15d-PGJ2 based on distinct murine models of allergic asthma triggered by either ovalbumin (OVA or house dust mite extract (HDM. Characteristics of lung inflammation, airway hyper-reactivity (AHR, mucus exacerbation, and lung remodeling in sensitized A/J mice treated or not with 15d-PGJ2 were assessed. 15d-PGJ2 treatments were carried out systemically or topically given via subcutaneous injection or intranasal instillation, respectively. Analyses were carried out 24 h after the last allergen provocation. Irrespective of the route of administration, 15d-PGJ2 significantly inhibited the peribronchial accumulation of eosinophils and neutrophils, subepithelial fibrosis and also mucus exacerbation caused by either OVA or HDM challenge. The protective effect of 15d-PGJ2 occurred in parallel with inhibition of allergen-induced AHR and lung tissue production of pro-inflammatory cytokines, such as interleukin (IL-5, IL-13, IL-17, and TNF-α. Finally, 15d-PGJ2 was found effective in inhibiting NF-κB phosphorylation upon HDM challenge as measured by Western blotting. In conclusion, our findings suggest that 15d-PGJ2 can reduce crucial features of asthma, including AHR, lung inflammation, and remodeling in distinct murine models of the disease. These effects are associated with a decrease in lung tissue generation of pro-inflammatory cytokines by a mechanism related to downregulation of NF-κB phosphorylation.

Effects of treatments for experimental bone tumor on prostaglandin E level and bone scintigrams

Energy Technology Data Exchange (ETDEWEB)

Otsuka, Nobuaki; Ito, Yasuhiko; Yoneda, Masaya; Muranaka, Akira; Nishishita, Soichi; Morita, Rikushi [Kawasaki Medical School, Kurashiki, Okayama (Japan)

1983-10-01

The role of Prostaglandin E (PgE) level was studied experimentally as follows: 1) intrahepatic implantation of VX-2, 2) intravenous injection of VX-2, 3) effect of treatments on intramedullary implanted VX-2. The levels of PgE in intrahepatic and intravenous transplantation were not higher than that of intramedullary transplantation. Mitomycin C (MMC) did not reduce the PgE level and appearance time of bone scan abnormality was the same as that of untreated animals. A combination of indomethacin and MMC caused a delay in appearance time of bone scan abnormalities.

Regulation of rat intrapulmonary arterial tone by arachidonic acid and prostaglandin E2 during hypoxia.

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Gaoliang Yan

Full Text Available Arachidonic acid (AA and its metabolites, prostaglandins (PG are known to be involved in regulation of vascular homeostasis including vascular tone and vessel wall tension, but their potential role in Hypoxic pulmonary vasoconstriction (HPV remains unclear. In this study, we examined the effects of AA and PGE2 on the hypoxic response in isolated rat intrapulmonary arteries (IPAs.We carried out the investigation on IPAs by vessel tension measurement. Isotetrandrine (20 µM significantly inhibited phase I, phase IIb and phase IIc of hypoxic vasoconstriction. Both indomethacin (100 µM and NS398 attenuated KPSS-induced vessel contraction and phase I, phase IIb and phase IIc of HPV, implying that COX-2 plays a primary role in the hypoxic response of rat IPAs. PGE2 alone caused a significant vasoconstriction in isolated rat IPAs. This constriction is mediated by EP4. Blockage of EP4 by L-161982 (1 µM significantly inhibited phase I, phase IIb and phase IIc of hypoxic vasoconstriction. However, AH6809 (3 µM, an antagonist of EP1, EP2, EP3 and DP1 receptors, exerted no effect on KPSS or hypoxia induced vessel contraction. Increase of cellular cAMP by forskolin could significantly reduce KPSS-induced vessel contraction and abolish phase I, phase II b and phase II c of HPV.Our results demonstrated a vasoconstrictive effect of PGE2 on rat IPAs and this effect is via activation of EP4. Furthermore, our results suggest that intracellular cAMP plays dual roles in regulation of vascular tone, depending on the spatial distribution of cAMP and its coupling with EP receptor and Ca(2+ channels.

Lepeophtheirus salmonis: characterization of prostaglandin E(2) in secretory products of the salmon louse by RP-HPLC and mass spectrometry.

Science.gov (United States)

Fast, M D; Ross, N W; Craft, C A; Locke, S J; MacKinnon, S L; Johnson, S C

2004-01-01

Lepeophtheirus salmonis is an ectoparasitic copepod that causes serious disease outbreaks in both wild and farmed salmonids. As the relationship between L. salmonis and its hosts is not well understood, the current investigation was undertaken to investigate whether any immunomodulatory compounds could be identified from secretions of L. salmonis. By incubating live L. salmonis adults with the neurotransmitter dopamine in seawater, we were able to obtain secretions from the parasite. These were analyzed by RP-HPLC column, as well as LC-MS. L. salmonis secretions contained a compound with the same retention time and mass of PGE(2). The identity of this compound as PGE(2) was confirmed by MS-in source dissociation. The concentrations of PGE(2) in L. salmonis secretions ranged from 0.2 to 12.3 ng/individual and varied with incubation temperature and time kept off the host. Prostaglandin E(2) is a potent vasodilator and thought to aid in parasite evasion from host immune responses. This is the first reported evidence of prostaglandin production in parasitic copepod secretions and its implications for the host-parasite relationship are discussed.

Effect of bradykinin antagonists on bradykinin-induced plasma extravasation, venoconstriction, prostaglandin E2 release, nociceptor stimulation and contraction of the iris sphincter muscle in the rabbit.

Science.gov (United States)

Griesbacher, T.; Lembeck, F.

1987-01-01

1 The inhibition of the bradykinin-induced plasma extravasation by six bradykinin (Bk) antagonists was tested on rabbit skin. All of them showed inhibitory effects without an agonistic action in the does used. B4310 (Lys-Lys-3-Hyp-5,8-Thi-7-DPhe-Bk) was the most active antagonist and was therefore used in the subsequent experiments. 2 B4310 (5-500 nM) antagonized the bradykinin-induced reduction of the venous outflow from the rabbit isolated ear in dose-dependent manner without affecting the arterial vasoconstriction induced by angiotensin II. 3 The bradykinin-induced release of prostaglandin E2 (PGE2) from the perfused rabbit ear was reduced by 63% when B4310 (800 nM) was infused before, during and after the bradykinin injection. 4 Bradykinin was injected into the ear artery of anaesthetized rabbits and the reflex hypotensive response was used as indicator of the nociception. The response was antagonized by a local infusion of B4310 (50 and 500 nM). The antagonism was dose-dependent and reversible. The parallel shift of the dose-response curve to bradykinin suggests a competitive inhibition. However, B4310 did not antagonize acetylcholine-induced nociceptor stimulation. 5 B4310 inhibited bradykinin-induced stimulation of the trigeminal nerve which results in a substance P-mediated contraction of the iris sphincter muscle. A pA2 of 7.59 was calculated. B4310 did not inhibit capsaicin-induced contractions. 6 It is concluded that B4310 inhibits specifically five different actions of bradykinin which are related to its possible pathophysiological role. PMID:3479223

Preferential binding of growth inhibitory prostaglandins by the target protein of a carcinogen

Energy Technology Data Exchange (ETDEWEB)

Khan, S.H.; Sorof, S. (Fox Chase Cancer Center, Philadelphia, PA (United States))

1990-12-01

Liver fatty acid binding protein (L-FABP) is the principal target protein of the hepatic carcinogen N-(2-fluorenyl)acetamide (2-acetylaminofluorene) in rat liver. In addition, the cyclopentenone prostaglandins (PG), PGA, PGJ{sub 2}, and {Delta}{sup 12}-PGJ{sub 2}, inhibit the growth of many cell types in vitro. This report describes the preferential binding of the growth inhibitory prostaglandins by L-FABP and the reversible inhibition of thymidine incorporation into DNA by PGA{sub 2} and {Delta}{sup 12}-PGJ{sub 2} in primary cultures of purified rat hepatocytes. As a model ligand, ({sup 3}H)PGA{sub 1} bound to L-FABP specifically, reversibly, rapidly, and with high affinity. Its dissociation constants were 134 nM (high affinity) and 3.6 {mu}M (low affinity). The high-affinity finding of ({sup 3}H)PGA{sup 1} correlated with their growth inhibitory activities reported previously and here. The in vitro actions of L-FABP are compatible with those of a specific and dissociable carrier of growth inhibitory prostaglandins in rat hepatocytes and suggest that the carcinogen may usurp the cellular machinery of the growth inhibitory prostaglandins.

The Value of Intravenous Prostaglandin E2 after Intra-uterine Death

African Journals Online (AJOL)

1974-09-21

Sep 21, 1974 ... using different routes of administration of the prosta- glandin. Given by ..... The disadvantages of intravenous prostaglandins are the systemic ... advantage of this method is that labour can be accurately monitored and the dose ...

Effects of NSAIDs on the Release of Calcitonin Gene-Related Peptide and Prostaglandin E2 from Rat Trigeminal Ganglia

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Vittorio Vellani

2017-01-01

Full Text Available Nonsteroidal anti-inflammatory drugs (NSAIDs are frequently used to treat migraine, but the mechanisms of their effects in this pathology are not fully elucidated. The trigeminal ganglia and calcitonin gene-related peptide (CGRP have been implicated in the pathophysiology of migraine. The release of CGRP and prostaglandin E2 (PGE2 from freshly isolated rat trigeminal ganglia was evaluated after oral administration of nimesulide, etoricoxib, and ketoprofen, NSAIDs with different pharmacological features. Thirty minutes after oral administration, nimesulide, 10 mg/Kg, decreased the GCRP release induced by an inflammatory soup, while the other NSAIDs were ineffective at this point in time. Two hours after oral nimesulide (5 and 10 mg/Kg and ketoprofen (10 mg/Kg, but not of etoricoxib, a significant decrease in the CGRP release was observed. All drugs reduced PGE2, although with some differences in timing and doses, and the action on CGRP does not seem to be related to PGE2 inhibition. The reduction of CGRP release from rat trigeminal ganglia after nimesulide and ketoprofen may help to explain the mechanism of action of NSAIDs in migraine. Since at 30 minutes only nimesulide was effective in reducing CGRP release, these results suggest that this NSAID may exert a particularly rapid effect in patients with migraine.

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

Energy Technology Data Exchange (ETDEWEB)

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

1982-11-01

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

Prostaglandin production by melanocytic cells and the effect of alpha-melanocyte stimulating hormone.

Science.gov (United States)

Nicolaou, Anna; Estdale, Sian E; Tsatmali, Marina; Herrero, Daniel Pascual; Thody, Anthony J

2004-07-16

Prostaglandins are potent mediators of the inflammatory response and are also involved in cancer development. In this study, we show that human melanocytes and FM55 melanoma cells express cyclooxygenase-1 and -2 (COX-1 and -2) and thus have the capability to produce prostaglandins. The FM55 cells produced predominantly PGE2 and PGF2alpha, whereas the HaCaT keratinocyte cell line produced mainly PGE2. The anti-inflammatory peptide, alpha-melanocyte stimulating hormone (alpha-MSH), reduced prostaglandin production in FM55 and HaCaT cells and reversed the effect of the pro-inflammatory cytokine TNF-alpha in the former. These results indicate that melanocytes produce prostaglandins and that alpha-MSH, by inhibiting this response, may play an important role in regulating inflammatory responses in the skin.

COX-2 and Prostaglandin EP3/EP4 Signaling Regulate the Tumor Stromal Proangiogenic Microenvironment via CXCL12-CXCR4 Chemokine Systems

Science.gov (United States)

Katoh, Hiroshi; Hosono, Kanako; Ito, Yoshiya; Suzuki, Tatsunori; Ogawa, Yasufumi; Kubo, Hidefumi; Kamata, Hiroki; Mishima, Toshiaki; Tamaki, Hideaki; Sakagami, Hiroyuki; Sugimoto, Yukihiko; Narumiya, Shuh; Watanabe, Masahiko; Majima, Masataka

2010-01-01

Bone marrow (BM)–derived hematopoietic cells, which are major components of tumor stroma, determine the tumor microenvironment and regulate tumor phenotypes. Cyclooxygenase (COX)−2 and endogenous prostaglandins are important determinants for tumor growth and tumor-associated angiogenesis; however, their contributions to stromal formation and angiogenesis remain unclear. In this study, we observed that Lewis lung carcinoma cells implanted in wild-type mice formed a tumor mass with extensive stromal formation that was markedly suppressed by COX-2 inhibition, which reduced the recruitment of BM cells. Notably, COX-2 inhibition attenuated CXCL12/CXCR4 expression as well as expression of several other chemokines. Indeed, in a Matrigel model, prostaglandin (PG) E2 enhanced stromal formation and CXCL12/CXCR4 expression. In addition, a COX-2 inhibitor suppressed stromal formation and reduced expression of CXCL12/CXCR4 and a fibroblast marker (S100A4) in a micropore chamber model. Moreover, stromal formation after tumor implantation was suppressed in EP3−/− mice and EP4−/− mice, in which stromal expression of CXCL12/CXCR4 and S100A4 was reduced. The EP3 or EP4 knockout suppressed S100A4+ fibroblasts, CXCL12+, and/or CXCR4+ stromal cells as well. Immunofluorescent analyses revealed that CXCL12+CXCR4+S100A4+ fibroblasts mainly comprised stromal cells and most of these were recruited from the BM. Additionally, either EP3- or EP4-specific agonists stimulated CXCL12 expression by fibroblasts in vitro. The present results address the novel activities of COX-2/PGE2-EP3/EP4 signaling that modulate tumor biology and show that CXCL12/CXCR4 axis may play a crucial role in tumor stromal formation and angiogenesis under the control of prostaglandins. PMID:20110411

Intravenous infusion of prostaglandin E2 for management of premature rupture of membranes.

Science.gov (United States)

Thiery, M; Parewijck, W; Martens, G

1982-01-01

In term with premature rupture of the membranes (PROM) and an unripe cervix who have no contraindications for prostaglandin (PG) administration and vaginal delivery, intravenous (I.V.) infusion of titrated PGE2 is highly effective. In healthy gravidas with dito fetus this treatment appeared perinatally safe and was well tolerated by the mother. To enhance its safety margin and procedure must be conducted under toco-cardiographic control.

Altered aortic and cremaster muscle prostaglandin synthesis in diabetic rats

International Nuclear Information System (INIS)

Myers, T.O.; Messina, E.J.; Rodrigues, A.M.; Gerritsen, M.E.

1985-01-01

Alterations in the synthesis and release of prostaglandins have been reported in humans and animal models of diabetes mellitus. In the present study synthesis and release of prostaglandins by thoracic aorta and cremaster muscle of rats with streptozotocin-induced diabetes of 8 wk duration was compared with age-matched controls. Prostaglandin synthesis was assessed by the measurement of immunoreactive prostaglandin E2 (PGE2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) release and by quantifying metabolism of exogenous [1- 14 C]arachidonic acid by thoracic aortic rings and minced cremaster muscle. These studies indicate that diminished prostacyclin (PGI2) and/or PGE2 production is not a general feature of all diabetic vascular tissues, suggesting that large and small blood vessels may not be similarly affected by diabetes in regard to the metabolism of exogenous arachidonic acid and the synthesis and release of prostaglandins. Furthermore, the vascular changes often observed in conjunction with diabetes, i.e., alterations in vascular reactivity and microangiopathy in small blood vessels and atherosclerosis of large blood vessels may be related in some way to the segmental differences observed in prostaglandin synthesis

Model-based analysis of thromboxane B{sub 2} and prostaglandin E{sub 2} as biomarkers in the safety evaluation of naproxen

Energy Technology Data Exchange (ETDEWEB)

Sahota, Tarjinder; Sanderson, Ian; Danhof, Meindert [Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden (Netherlands); Della Pasqua, Oscar [Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden (Netherlands); Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Uxbridge (United Kingdom)

2014-08-01

The assessment of safety in traditional toxicology protocols relies on evidence arising from observed adverse events (AEs) in animals and on establishing their correlation with different measures of drug exposure (e.g., C{sub max} and AUC). Such correlations, however, ignore the role of biomarkers, which can provide further insight into the underlying pharmacological mechanisms. Here we use naproxen as a paradigm drug to explore the feasibility of a biomarker-guided approach for the prediction of AEs in humans. A standard toxicology protocol was set up for the evaluation of effects of naproxen in rat, in which four doses were tested (7.5, 15, 40 and 80 mg/kg). In addition to sparse blood sampling for the assessment of exposure, thromboxane B{sub 2} and prostaglandin E{sub 2} were also collected in satellite groups. Nonlinear mixed effects modelling was used to evaluate the predictive performance of the approach. A one-compartmental model with first order absorption was found to best describe the pharmacokinetics of naproxen. A nonlinear relationship between dose and bioavailability was observed which leads to a less than proportional increase in naproxen concentrations with increasing doses. The pharmacodynamics of TXB{sub 2} and PGE{sub 2} was described by direct inhibition models with maximum pharmacological effects achieved at doses > 7.5 mg/kg. The predicted PKPD relationship in humans was within 10-fold of the values previously published. Moreover, our results indicate that biomarkers can be used to assess interspecies differences in PKPD and extrapolated data from animals to humans. Biomarker sampling should be used systematically in general toxicity studies. - Highlights: • Prediction of a drug's safety profile from preclinical protocols remains challenging. • Pharmacokinetic measures of safe exposure (e.g., AUC) ignore the role of biomarkers. • PKPD relationships enable the evaluation of adverse events in a mechanistic manner. • Major

The Correlation Between Urinary 8-Iso-Prostaglandin F2α and Hydrogen Peroxide Toward Renal Function in T2DM Patients Consuming Sulfonylurea and Combination of Metformin-Sulfonylurea.

Science.gov (United States)

Sauriasari, Rani; Wulandari, Fitri; Nurifahmi, Rahmaningtyas; Sekar, Andisyah P; Susilo, Veronika Y

2018-01-01

Renal dysfunction is a common complication in type 2 diabetes mellitus patients associated with oxidative damage which could be characterized by 8-iso-prostaglandin F2α and hydrogen peroxide level as oxidative stress markers. The aim of our study is to determine if there is a difference in 8-iso-prostaglandin F2α and hydrogen peroxide levels between sulfonylurea and combination of metformin-sulfonylurea in diabetic patients. We also wanted to determine if these oxidative stress markers correlate with the estimated Glomerular Filtration Rate (eGFR). We conducted a cross-sectional study with inclusion of 55 patients with type 2 diabetes mellitus in Dr. Sitanala Tangerang Hospital, Indonesia with purposive sampling. The value of eGFR was obtained by serum creatinine levels, while the level of 8-iso-prostaglandin F2α was measured by ELISA and urinary hydrogen peroxide using FOX-1 (Ferrous Ion Oxidation Xylenol Orange 1). There was no difference in 8-iso-prostaglandin F2α and hydrogen peroxide level between the two groups (p=0.088 and p=0.848). Moreover, there was no difference in eGFR values between the two groups, measured by Cockroft-Gault, MDRD, and CKD-EPI. 8-iso-prostaglandin F2α (n=55) was positively correlated with eGFR based on Cockroft-Gault (r=0.382; p=0.009), whereas urinary hydrogen peroxide (n=47) also generate significant positive correlation with eGFR based on the MDRD equation (r=0.326; p=0.021). Linear regression analysis showed that 8-iso-prostaglandin F2α is the most predictive factor and the only significant factor for eGFR in Cockroft-Gault, MDRD and also CKDEPI, even after controlled by gender, age, BMI, HbA1c, systole, and H2O2. The two treatments did not have any significant differences in antioxidant activity. However, an increase of urinary 8-iso-prostaglandin F2. and hydrogen peroxide which correlates with eGFR in the total sample may play a significant role in the pathophysiology of diabetic nephropathy. Copyright© Bentham Science

Eupafolin inhibits PGE2 production and COX2 expression in LPS-stimulated human dermal fibroblasts by blocking JNK/AP-1 and Nox2/p47phox pathway

International Nuclear Information System (INIS)

Tsai, Ming-Horng; Lin, Zih-Chan; Liang, Chan-Jung; Yen, Feng-Lin; Chiang, Yao-Chang; Lee, Chiang-Wen

2014-01-01

Eupafolin, a major active component found in the methanol extracts of Phyla nodiflora, has been used to treat inflammation of skin. We examined its effects on cyclooxygenase-2 (COX-2) expression in LPS-treated human dermal fibroblasts. Lipopolysaccharide (LPS) significantly increased prostaglandin-E2 (PGE2) production associated with increased COX-2 expression in Hs68 cells. This effect was blocked by eupafolin, TLR-4 antibody, antioxidants (APO and NAC), as well as inhibitors, including U0126 (ERK1/2), SB202190 (p38), SP600125 (JNK1/2), and Tanshinone IIA (AP-1). In gene regulation level, qPCR and promoter assays revealed that COX-2 expression was attenuated by eupafolin. In addition, eupafolin also ameliorated LPS-induced p47 phox activation and decreased reactive oxygen species (ROS) generation and NADPH oxidase (Nox) activity. Moreover, pretreatment with eupafolin and APO led to reduced LPS-induced phosphorylation of ERK1/2, JNK, and p38. Further, eupafolin attenuated LPS-induced increase in AP-1 transcription factor binding activity as well as the increase in the phosphorylation of c-Jun and c-Fos. In vivo studies have shown that in dermal fibroblasts of LPS treated mice, eupafolin exerted anti-inflammation effects by decreasing COX-2 protein levels. Our results reveal a novel mechanism for anti-inflammatory and anti-oxidative effects of eupafolin that involved inhibition of LPS-induced ROS generation, suppression of MAPK phosphorylation, diminished DNA binding activity of AP-1 and attenuated COX-2 expression leading to reduced production of prostaglandin E2 (PGE2). Our results demonstrate that eupafolin may be used to treat inflammatory responses associated with dermatologic diseases. - Highlights: • LPS activates the Nox2/p47 phox /JNK/AP-1 and induces COX2 expression in Hs68 cells. • Eupafolin inhibits LPS-induced COX-2 expression via Nox2/p47 phox inhibition. • Eupafolin may be used in the treatment of skin diseases involving inflammation

A biphasic response of urinary prostaglandin E2 excretion to water deprivation in conscious diabetes insipidus Brattleboro rats

DEFF Research Database (Denmark)

Kanters, J K; Holstein-Rathlou, N H; Christensen, P

1989-01-01

The effects of water deprivation on the urinary excretion rate of prostaglandin E2 (PGE2) were examined in conscious Brattleboro rats. In order to study the time course of the changes in the PGE2 excretory rate, urine was collected in 6 periods, Control: 0-1 hour (h.). 1: 3-4.5 h., 8-10 h., III: 12......-15 h., IV: 24-28 h. and V: 32-36 h. after removal of water and food. It was found that the PGE2 excretion rate changed in a biphasic pattern. During the first 2 experimental periods it increased. Thereafter it decreased towards the control value. There was an increase in PGE2 excretion with urinary...

Gastric bicarbonate secretion and release of prostaglandin E2 are increased in duodenal ulcer patients but not in Helicobacter pylori-positive healthy subjects

DEFF Research Database (Denmark)

Mertz-Nielsen, A; Hillingsø, Jens; Frøkiaer, H

1996-01-01

BACKGROUND: Duodenal ulcer (DU) patients have impaired proximal duodenal mucosal bicarbonate secretion at rest and in response to luminal acid with higher acid-stimulated mucosal release of prostaglandin (PG) E2 than healthy subjects. Our purpose was to determine whether this abnormality was pres......BACKGROUND: Duodenal ulcer (DU) patients have impaired proximal duodenal mucosal bicarbonate secretion at rest and in response to luminal acid with higher acid-stimulated mucosal release of prostaglandin (PG) E2 than healthy subjects. Our purpose was to determine whether this abnormality...... was present also in the stomach of DU patients. METHODS: Simultaneous determinations of gastric and duodenal bicarbonate secretion and luminal release of PGE2 were performed in 16 healthy volunteers (5 Helicobacter pylori-positive) and 8 inactive DU patients (all H. pylori-positive). RESULTS: In healthy...... for the abnormally high gastric secretion of bicarbonate in inactive DU patients. The defective duodenal secretion of bicarbonate observed in these patients may be a consequence of previous ulceration rather than the mere presence of H. pylori infection....

Bone changes from prostaglandin therapy

International Nuclear Information System (INIS)

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

1985-01-01

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

Eupafolin inhibits PGE2 production and COX2 expression in LPS-stimulated human dermal fibroblasts by blocking JNK/AP-1 and Nox2/p47{sup phox} pathway

Energy Technology Data Exchange (ETDEWEB)

Tsai, Ming-Horng [Department of Pediatrics, Division of Neonatology and Pediatric Hematology/Oncology, Chang Gung Memorial Hospital, Yunlin, Taiwan (China); Lin, Zih-Chan [Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Liang, Chan-Jung [Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Yen, Feng-Lin [Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Institute of Biomedical Sciences, Sun Yat-Sen University, 70 Lienhai Rd., Kaohsiung, Taiwan (China); Chiang, Yao-Chang [Center for Drug Abuse and Addiction, China Medical University Hospital, Taichung, Taiwan (China); China Medical University, Taichung, Taiwan (China); Lee, Chiang-Wen, E-mail: cwlee@gw.cgust.edu.tw [Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi, Taiwan (China); Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chia-Yi, Taiwan (China); Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan (China)

2014-09-01

Eupafolin, a major active component found in the methanol extracts of Phyla nodiflora, has been used to treat inflammation of skin. We examined its effects on cyclooxygenase-2 (COX-2) expression in LPS-treated human dermal fibroblasts. Lipopolysaccharide (LPS) significantly increased prostaglandin-E2 (PGE2) production associated with increased COX-2 expression in Hs68 cells. This effect was blocked by eupafolin, TLR-4 antibody, antioxidants (APO and NAC), as well as inhibitors, including U0126 (ERK1/2), SB202190 (p38), SP600125 (JNK1/2), and Tanshinone IIA (AP-1). In gene regulation level, qPCR and promoter assays revealed that COX-2 expression was attenuated by eupafolin. In addition, eupafolin also ameliorated LPS-induced p47 phox activation and decreased reactive oxygen species (ROS) generation and NADPH oxidase (Nox) activity. Moreover, pretreatment with eupafolin and APO led to reduced LPS-induced phosphorylation of ERK1/2, JNK, and p38. Further, eupafolin attenuated LPS-induced increase in AP-1 transcription factor binding activity as well as the increase in the phosphorylation of c-Jun and c-Fos. In vivo studies have shown that in dermal fibroblasts of LPS treated mice, eupafolin exerted anti-inflammation effects by decreasing COX-2 protein levels. Our results reveal a novel mechanism for anti-inflammatory and anti-oxidative effects of eupafolin that involved inhibition of LPS-induced ROS generation, suppression of MAPK phosphorylation, diminished DNA binding activity of AP-1 and attenuated COX-2 expression leading to reduced production of prostaglandin E2 (PGE2). Our results demonstrate that eupafolin may be used to treat inflammatory responses associated with dermatologic diseases. - Highlights: • LPS activates the Nox2/p47{sup phox}/JNK/AP-1 and induces COX2 expression in Hs68 cells. • Eupafolin inhibits LPS-induced COX-2 expression via Nox2/p47{sup phox} inhibition. • Eupafolin may be used in the treatment of skin diseases involving inflammation.

Prostaglandin E2 and thromboxane B2 release from human monocytes treated with bacterial lipopolysaccharide

International Nuclear Information System (INIS)

Nichols, F.C.; Garrison, S.W.; Davis, H.W.

1988-01-01

We investigated the capacity of counterflow-isolated human monocytes to independently synthesize thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) when stimulated with bacterial lipopolysaccharide (LPS). Independent metabolism was confirmed by establishing different specific activities (dpm/ng) of TxB2 and PGE2 released from LPS-treated cells. For metabolites released during the initial 2-hr treatment period, the specific activity of PGE2 was approximately threefold higher than that of TxB2 regardless of labeling with [3H]arachidonic acid (AA) or [14C]AA. Cells that were pulse-labeled for 2 hr with [3H]AA demonstrated a decreasing PGE2 specific activity over 24 hr, whereas the TxB2 specific activity remained unchanged. In contrast, cells continuously exposed to [14C]AA demonstrated an increasing TxB2 specific activity that approached the level of PGE2 by 24 hr. These results suggest the presence of at least 2 cyclooxygenase metabolic compartments in counterflow-isolated monocytes. Although freshly isolated monocytes have been reported to contain variable numbers of adherent platelets, additional experiments demonstrated that counterflow-isolated platelets are not capable of releasing elevated levels of TxB2 or PGE2 when treated with LPS. It is proposed from these findings that at least two subsets of monocytes exist in peripheral blood that can be distinguished on the basis of independent conversion of AA to TxB2 and PGE2

Prostaglandin E2 blocks menadione-induced apoptosis through the Ras/Raf/Erk signaling pathway in promonocytic leukemia cell lines.

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Yeo, Hyun-Seok; Shehzad, Adeeb; Lee, Young Sup

2012-04-01

Altered oxidative stress has long been observed in cancer cells, and this biochemical property of cancer cells represents a specific vulnerability that can be exploited for therapeutic benefit. The major role of an elevated oxidative stress for the efficacy of molecular targeted drugs is under investigation. Menadione is considered an attractive model for the study of oxidative stress, which can induce apoptosis in human leukemia HL-60 cell lines. Prostaglandin E(2) (PGE(2)) via its receptors not only promotes cell survival but also reverses apoptosis and promotes cancer progression. Here, we present evidence for the biological role of PGE(2) as a protective agent of oxidative stress-induced apoptosis in monocytic cells. Pretreatment of HL-60 cells with PGE(2) markedly ameliorated the menadione-induced apoptosis and inhibited the degradation of PARP and lamin B. The EP(2) receptor antagonist AH6809 abrogated the inhibitory effect of PGE(2), suggesting the role of the EP(2)/cAMP system. The PKA inhibitor H89 also reversed apoptosis and decreased the PKA activity that was elevated 10-fold by PGE(2). The treatment of HL-60 cells with NAC or zinc chloride showed a similar protective effect as with PGE(2) on menadione-treated cells. Furthermore, PGE(2) activated the Ras/Raf/MEK pathway, which in turn initiated ERK activation, and ultimately protected menadione-induced apoptosis. These results imply that PGE(2) via cell survival pathways may protect oxidative stress-induced apoptosis in monocytic cells. This study warrants further pre-clinical investigation as well as application towards leukemia clinics.

Assessing the usefulness of prostaglandin E2 (Cervidil) for transcervical artificial insemination in ewes.

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Bartlewski, Pawel M; Candappa, Ivanka B R

2015-12-01

The underlying theme of this study involved the evaluation of the dilatory effects of prostaglandin E2 on the ovine cervix and thus the assessment of its potential applicability to transcervical artificial insemination (TCAI) in ewes. A novel method of prostaglandin E2 administration (controlled slow-release vaginal inserts) was examined, and the practical implications of this approach including cervical penetrability and posttreatment pregnancy rates were evaluated. The Guelph method of TCAI was performed during the seasonal anestrus (n = 40) and the breeding season (n = 40) on multiparous Rideau Arcott × Polled Dorset ewes, with or without the pretreatment with Cervidil (for a duration of 12 hours or 24 hours before TCAI). Cervical penetration rates averaged 82.5% (66 of 80), and they varied neither (P > 0.05) between the two seasons nor between Cervidil-treated ewes and their respective controls. Cervidil priming significantly reduced the total time required for TCAI during the breeding season in comparison with controls (54 vs. 98 seconds), especially after the 24-hour exposure (38 vs. 108 seconds). The time taken to traverse the uterine cervix was negatively correlated (P ewes. Four out of 36 (11%) successfully penetrated ewes in the breeding season (three ewes allocated to the 12-hour control group and one ewe that had received Cervidil for 12 hours) became pregnant and carried the lambs to term. Vaginal mucus impedance at TCAI was significantly and positively correlated with the total time required to complete the procedure in cyclic ewes, and the negative correlation between vaginal mucus impedance and total time values at the time of controlled intravaginal drug release device removal approached to significance in anestrous ewes. The present results indicate a moderate benefit of using Cervidil for inducing cervical dilation before TCAI in ewes, mainly in the breeding season. The specific reason(s) for impaired fertility after the TCAI using

Influence of endogenous pyrogen on the cerebral prostaglandin-synthetase system.

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Ziel, R; Krupp, P

1976-11-15

The biotransformation of arachidonic acid to prostaglandins in vitro is specifically augmented by endogenous pyrogen to a degree depending on the concentration applied, providing that the microsomal fraction of the cerebral cortex is used as prostaglandin-synthetase system. This effect is inhibited by non-steroidal anti-inflammatory agents. These findings are compatible with the hypothesis that prostaglandins might act as mediators of the febrile reaction induced by endogenous pyrogen.

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

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

2009-01-01

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

A positive feedback loop between progesterone and microsomal prostaglandin E synthase-1-mediated PGE2 promotes production of both in mouse granulosa cells.

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Tamura, Kazuhiro; Naraba, Hiroaki; Hara, Takahiko; Nakamura, Kota; Yoshie, Mikihiro; Kogo, Hiroshi; Tachikawa, Eiichi

2016-03-01

Microsomal prostaglandin E synthase-1 (mPGES-1) is primarily expressed in granulosa cells (GCs) in the preovulatory follicle. Both prostaglandin E2 (PGE2) and progesterone (P4) are implicated in various reproductive functions. Here, we demonstrate that mPges-1 may be a direct downstream target gene of the P4 receptor and P4-stimulated PGE2 secretion can stimulate P4 production in a newly generated mouse GC line (GtsT). Treatment of GtsT cells with a P4 receptor agonist, norgestrel, markedly increased mPGES-1 expression detected by RT-PCR analysis. PGE2 secretion measured by an enzyme-linked immunosorbent assay was enhanced by P4 treatment. Luciferase assays revealed that the proximal promoter region of the mPges-1 gene was responsible for the effects of P4 treatment. Conversely, PGE2 treatment stimulated P4 secretion, which coordinated with mRNA expression of steroidogenic acute regulatory protein. Taken together, P4 may regulate mPGES-1 expression to increase PGE2 secretion and in turn P4 production. An autocrine loop between P4 and PGE2 might function to maintain the increased levels of both in GCs. Copyright © 2016 Elsevier Inc. All rights reserved.

Prostaglandin E2 enhances long-term repopulation but does not permanently alter inherent stem cell competitiveness.

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Hoggatt, Jonathan; Mohammad, Khalid S; Singh, Pratibha; Pelus, Louis M

2013-10-24

Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for malignant and nonmalignant hematologic diseases and metabolic disorders. Although successful, hematopoietic transplantation can be hindered by inadequate stem cell number or poor engrafting efficiency. To overcome these deficits, we and others have previously reported the HSC-enhancing ability of a short-term exposure of prostaglandin E2 (PGE2); this strategy has now progressed to phase 1 clinical trials in double cord blood transplantation. To further analyze the short- and long-term effects of HSC exposure to PGE2, we followed the repopulation kinetics of PGE2-treated hematopoietic grafts through 5 serial transplantations and compared inherent long-term competitiveness in a HSC head-to-head secondary transplantation model. Treatment with PGE2 did not result in a long-term increase in HSC competitiveness, lineage bias, or enhanced proliferative potential, demonstrating that pulse exposure to PGE2 results in transient increases in HSC homing and engraftment potential.

An evaluation of prostaglandin E2 vaginal gel use in practice.

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Taylor, S J; Peat, J K; Armour, C L

1999-08-01

The purpose of this study was to investigate the effectiveness of prostaglandin E2 vaginal gel as used in practice, rather than its efficacy as assessed in randomised, controlled, clinical trials. This product is used to ripen the cervix prior to induction of labour, sometimes making unnecessary the use of the standard treatment for induction, artificial rupture of the membranes (ARM) plus oxytocin. In this study, effectiveness of the gel was assessed in terms of changes in mode of delivery, and in particular the risk of Caesarean section. An historical control was used and the risk of Caesarean section for women induced in the 1990/91 (before the introduction of the gel) was compared with that for women induced in 1992/93 (after the introduction of the gel). Maternal characteristics which may have been different in the two groups and factors which might influence the risk of Caesarean section were controlled for statistically using logistic regression, thus reducing any bias towards one group. After adjusting for the factors which had a significant effect on the process of labour from induction to birth, it was found that the risk of Caesarean section was not significantly lower in the 1992/93-time period, when the gel was in regular use, from that in the 2 years prior to its introduction (Odds ratio 1.09, CI95% 0.88, 1.36). Following the introduction of PGE2 gel, no difference in effectiveness, as measured in terms of mode of delivery, was detected in this study of practice, which included patients with more complex obstetric problems.

Effects of a single administration of prostaglandin F2alpha, or a combination of prostaglandin F2alpha and prostaglandin E2, or placebo on fertility variables in dairy cows 3-5 weeks post partum, a randomized, double-blind clinical trial.

Science.gov (United States)

Hirsbrunner, Gaby; Burkhardt, Heinz W; Steiner, Adrian

2006-12-21

Delayed uterine involution has negative effects on the fertility of cows; use of prostaglandin F2alpha alone as a single treatment has not been shown to consistently improve fertility. Combined administration of PGF2alpha and PGE2 increased uterine pressure in healthy cows. We hypothesized, that the combination of both prostaglandins would accelerate uterine involution and have, therefore, a positive effect on fertility variables. In commercial dairy farming, the benefit of a single post partum combined prostaglandin treatment should be demonstrated. 383 cows from commercial dairy farms were included in this study. Uterine size and secretion were evaluated at treatment 21-35 days post partum and 14 days later. Cows were randomly allocated to one of three treatment groups: PGF2alpha and PGE2, PGF2alpha or placebo. For every animal participating in the study, the following reproduction variables were recorded: Interval from calving to first insemination, days open, number of artificial inseminations (AI) to conception; subsequent treatment of uterus, subsequent treatment of ovaries. Plasma progesterone level at time of treatment was used as a covariable. For continuous measurements, analysis of variance was performed. Fisher's exact test for categorical non-ordered data and exact Kruskal-Wallis test for ordered data were used; pairwise group comparisons with Bonferroni adjustment of significance level were performed. There was no significant difference among treatment groups in uterine size. Furthermore, there was no significant difference among treatments concerning days open, number of AI, and subsequent treatment of uterus and ovaries. Days from calving to first insemination tended to be shorter for cows with low progesterone level given PGF2alpha and PGE2 in combination than for the placebo-group (P = 0.024). The results of this study indicate that the administration of PGF2alpha or a combination of PGF2alpha and PGE2 21 to 35 days post partum had no beneficial

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

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Högberg Thomas

2007-02-01

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

Regional differences in prostaglandin E2 metabolism in human colorectal cancer liver metastases

International Nuclear Information System (INIS)

Young, Alastair L; Chalmers, Claire R; Hawcroft, Gillian; Perry, Sarah L; Treanor, Darren; Toogood, Giles J; Jones, Pamela F; Hull, Mark A

2013-01-01

Prostaglandin (PG) E 2 plays a critical role in colorectal cancer (CRC) progression, including epithelial-mesenchymal transition (EMT). Activity of the rate-limiting enzyme for PGE 2 catabolism (15-hydroxyprostaglandin dehydrogenase [15-PGDH]) is dependent on availability of NAD+. We tested the hypothesis that there is intra-tumoral variability in PGE 2 content, as well as in levels and activity of 15-PGDH, in human CRC liver metastases (CRCLM). To understand possible underlying mechanisms, we investigated the relationship between hypoxia, 15-PGDH and PGE 2 in human CRC cells in vitro. Tissue from the periphery and centre of 20 human CRCLM was analysed for PGE 2 levels, 15-PGDH and cyclooxygenase (COX)-2 expression, 15-PGDH activity, and NAD+/NADH levels. EMT of LIM1863 human CRC cells was induced by transforming growth factor (TGF) β. PGE 2 levels were significantly higher in the centre of CRCLM compared with peripheral tissue (P = 0.04). There were increased levels of 15-PGDH protein in the centre of CRCLM associated with reduced 15-PGDH activity and low NAD+/NADH levels. There was no significant heterogeneity in COX-2 protein expression. NAD+ availability controlled 15-PGDH activity in human CRC cells in vitro. Hypoxia induced 15-PGDH expression in human CRC cells and promoted EMT, in a similar manner to PGE 2 . Combined 15-PGDH expression and loss of membranous E-cadherin (EMT biomarker) were present in the centre of human CRCLM in vivo. There is significant intra-tumoral heterogeneity in PGE 2 content, 15-PGDH activity and NAD+ availability in human CRCLM. Tumour micro-environment (including hypoxia)-driven differences in PGE 2 metabolism should be targeted for novel treatment of advanced CRC

Penetration effect of prostaglandin E2 gel on oral mucosa of rats

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Rafinus Arifin

2012-09-01

Full Text Available Background: Several researches reported that Prostaglandin E2 (PGE2 injection on buccal mucosa combined with orthodontic pressure can faster tooth movement but has disadvantages such as high alveolar bone and root resorption furthermore pain from injection needle. PGE2 gel was made to better replace the lacks of injectable PGE2. Purpose: This research was aimed to prove that PGE 2 gel can penetrate rat’s oral mucosa effecting the appearance of PMN cells. Methods: This research was an in vivo laboratory experiment using 36 Sprague Dawley rats which were divided into 3 groups: normal group, topical PGE2 gel group after 1, 2, 4, 8 hours (4 subgroups, and topical gel without PGE2 group after 1, 2, 4, 8 hours (4 subgroups. Each group consists of 4 rats, therefore the total sample for all research groups were 36 rats. Gel with 25 µg/mL of PGE2 and gel without PGE2 were applied on oral mucosa for 2 minutes. Then, the rats were sacrificed after 1 hour, 2 hours, 4 hours, and 8 hours application. After that, the samples were prepared for histological examination with Hematoxyllin and Eosin. The picture were taken with OptiLab View and PMN cells amount were counted with light microscope, set 400 times of magnification. Results: Penetration effect of PGE2 gel on rat’s oral mucosa result in PMN inflammation cells distribution. One-way ANOVA showed no significant difference on PMN cells count in rats’ lower jaws between groups of normal and gel without PGE2. There was significant difference between groups of PGE2 gel and gel without PGE2 (p=0,001. PGE2 gel application showed PGE2 as inflammatory media, even though administered topically. Conclusion: PGE2 gel can penetrate rat’s oral mucosa, effecting PMN cells 1, 2, 4 and 8 hours after application of PGE2 gel.Latar belakang: Beberapa penelitian melaporkan bahwa injeksi (Prostaglandin E2 PGE2pada mukosa bukal yang dikombinasikan dengan tekanan ortodonti dapat mempercepat pergerakan gigi, tapi

Microsomal prostaglandin E synthase-1 in rheumatic diseases

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Marina eKorotkova

2011-01-01

Full Text Available Microsomal prostaglandin E synthase-1 (mPGES-1 is a well recognized target for the development of novel anti-inflammatory drugs that can reduce symptoms of inflammation in rheumatic diseases and other inflammatory conditions. In this review, we focus on mPGES-1 in rheumatic diseases with the aim to cover the most recent advances in the understanding of mPGES-1 in rheumatoid arthritis, osteoarthritis and inflammatory myopathies. Novel findings regarding regulation of mPGES1 cell expression as well as enzyme inhibitors are also summarized.

Acetylsalicylic Acid Daily vs Acetylsalicylic Acid Every 3 Days in Healthy Volunteers: Effect on Platelet Aggregation, Gastric Mucosa, and Prostaglandin E2 Synthesis.

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Ferreira, Plinio Minghin Freitas; Gagliano-Jucá, Thiago; Zaminelli, Tiago; Sampaio, Marinalva Ferreira; Blackler, Rory Willian; Trevisan, Miriam da Silva; Novaes Magalhães, Antônio Frederico; De Nucci, Gilberto

2016-07-01

Substantial platelet inhibition was observed 3 days after a single administration of acetylsalicylic acid 81 mg to healthy volunteers. Here we investigate prostaglandin E2 (PGE2 ) antrum concentrations and gastrointestinal symptoms in two treatment groups: one receiving losartan and acetylsalicylic acid every day and the other receiving losartan every day and acetylsalicylic acid every 3 days. Twenty-eight healthy volunteers from both sexes received either 50 mg losartan and acetylsalicylic acid 81 mg daily or 50 mg losartan and acetylsalicylic acid 81 every 3 days with placebo on the other days. Therapy was delivered for 30 days for both groups. Gastric endoscopy was performed before and after treatment period. Biopsies were collected for PGE2 quantification. Platelet function tests were carried out before and during treatment and TXB2 release on platelet rich plasma was measured. The every 3 day low-dose acetylsalicylic acid regimen produced complete inhibition of platelet aggregation compared to the daily treatment. Thromboxane B2 release was substantially abolished for both groups during treatment. There was no significant difference on the endoscopic score of both treatment groups after the 30-day treatment (P = .215). There was over 50% suppression of antrum PGE2 content on volunteers receiving acetylsalicylic acid daily (P = .0016), while for the every 3 day dose regimen there was no significant difference between pre and post-treatment antrum PGE2 dosages (P = .4193). Since PGE2 is involved in gastric healing, we understand that this new approach could be safer and as efficient as the standard daily therapy on a long-term basis. © 2015, The American College of Clinical Pharmacology.

Plasma 8-iso-Prostaglandin F2α concentrations and outcomes after acute intracerebral hemorrhage.

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Du, Quan; Yu, Wen-Hua; Dong, Xiao-Qiao; Yang, Ding-Bo; Shen, Yong-Feng; Wang, Hao; Jiang, Li; Du, Yuan-Feng; Zhang, Zu-Yong; Zhu, Qiang; Che, Zhi-Hao; Liu, Qun-Jie

2014-11-01

Higher plasma 8-iso-Prostaglandin F2α concentrations have been associated with poor outcome of severe traumatic brain injury. We further investigated the relationships between plasma 8-iso-Prostaglandin F2α concentrations and clinical outcomes in patients with acute intracerebral hemorrhage. Plasma 8-iso-Prostaglandin F2α concentrations of 128 consecutive patients and 128 sex- and gender-matched healthy subjects were measured by enzyme-linked immunosorbent assay. We assessed their relationships with disease severity and clinical outcomes including 1-week mortality, 6-month mortality and unfavorable outcome (modified Rankin Scale score>2). Plasma 8-iso-Prostaglandin F2α concentrations were substantially higher in patients than in healthy controls. Plasma 8-iso-Prostaglandin F2α concentrations were positively associated with National Institutes of Health Stroke Scale (NIHSS) scores and hematoma volume using a multivariate linear regression. It emerged as an independent predictor for clinical outcomes of patients using a forward stepwise logistic regression. ROC curves identified the predictive values of plasma 8-iso-Prostaglandin F2α concentrations, and found its predictive value was similar to NIHSS scores and hematoma volumes. However, it just numerically added the predictive values of NIHSS score and hematoma volume. Increased plasma 8-iso-Prostaglandin F2α concentrations are associated with disease severity and clinical outcome after acute intracerebral hemorrhage. Copyright © 2014 Elsevier B.V. All rights reserved.

Circadian and estral changes in the hypothalamic prostaglandin e content and [h]prostaglandin e binding in female rats.

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Bommelaer-Bayet, M C; Wisner, A; Renard, C A; Levi, F A; Dray, F

1990-04-01

Abstract Prostaglandin E(2), (PGE(2)) is involved in the luteinizing hormone-releasing hormone-stimulated luteinizing hormone surge in female rats and may act via specific membrane receptors. The following studies were performed to determine whether there were any changes in the hypothalamic PGE(2) binding and/or PGE(2) content which were specific to proestrus and not to the rest of the estrous cycle. Groups of female Wistar rats were sacrificed at 3-h intervals throughout the estrous cycle to determine both the circadian and circaestral changes in the hypothalamic PGE(2) content and [(3)H]PGE(2) binding. The hypothalamic PGE(2) content was maximal at 1700 h on each of the 4 consecutive days of the estrous cycle but was independent of the stage of the cycle. [(3)H]PGE(2) binding also displayed a circadian rhythm; the lowest binding occurred near the circadian peak of PGE(2), suggesting that the PGE(2) binding sites were occupied by endogenous PGE(2). Since such circadian rhythms were not observed in the hypothalamus of male rats, they may be under the control of ovarian steroids. Also, since PGE(2) binding and the PGE(2) content both exhibit a diurnal pattern independent of the day of the cycle, there may be changes in the PGE(2) receptor-mediated process coupled to an adenylyl cyclase which could explain the luteinizing hormone surge in proestrus.

Madecassoside Inhibits Melanin Synthesis by Blocking Ultraviolet-Induced Inflammation

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Eunsun Jung

2013-12-01

Full Text Available Madecassoside (MA, a pentacyclic triterpene isolated from Centella asitica (L., is used as a therapeutic agent in wound healing and also as an anti-inflammatory and anti-aging agent. However, the involvement of MA in skin-pigmentation has not been reported. This study was conducted to investigate the effects of MA on ultraviolet (UV-induced melanogenesis and mechanisms in a co-culture system of keratinocytes and melanocytes. MA significantly inhibited UVR-induced melanin synthesis and melanosome transfer in the co-culture system. These effects were further demonstrated by the MA-induced inhibition of protease-activated receptor-2 expression and its signaling pathway, cyclooxygenase-2, prostaglandin E2 and prostaglandin F2 alpha in keratinocytes. The clinical efficacy of MA was confirmed on artificially tanned human skin. MA significantly reduced UV-induced melanin index at 8 weeks after topical application. Overall, the study demonstrated significant benefits of MA use in the inhibition of hyperpigmentation caused by UV irradiation.

Inibidores seletivos de prostaglandina endoperóxido sintase-2 (PGHS-2: nova estratégia para o tratamento da inflamação Selective inhibitors of prostaglandin endoperoxide synthase-2 (PGHS-2: new target to the treatment for inflammatory diseases

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Adriana dos Santos Lages

1998-11-01

Full Text Available Prostaglandins (PG's, produced from arachidonic acid metabolism, are potent mediators of inflammation. Nonsteroidal anti-inflammatory (NSAIDs exert their effects by inhibition of prostaglandin endoperoxide synthase (PGHS enzyme, which catalyses the first committed step in arachidonic acid metabolism. Two isoforms of PGHS are known: PGHS-1, constitutively expressed in most tissues, and is responsible for physiological production of PG's. The second isoform, PGHS-2, is induced by cytokines, mitogens and endotoxins in inflammatory cells, and appears to be responsible for the elevated production of PG's during inflammation. With the recent discovery of the inducible PGHS (PGHS-2, the medicinal chemist now possesses a novel target for designing therapeutic agents that could provide suitable anti-inflammatory activity without the ulcerogenic and renal side effects associated with currently available NSAIDs, all of which inhibit both PGHS-1 and PGHS-2.

Effect of prostaglandin E2 injection on the structural properties of the rat patellar tendon

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Ferry Scott T

2012-01-01

Full Text Available Abstract Background Increased tendon production of the inflammatory mediator prostaglandin E2 (PGE2 has been suggested to be a potential etiologic agent in the development of tendinopathy. Repeated injection of PGE2 into tendon has been proposed as a potential animal model for studying treatments for tendinopathy. In contrast, nonsteroidal anti-inflammatory drugs (NSAIDs which inhibit PGE2 production and are commonly prescribed in treating tendinopathy have been shown to impair the healing of tendon after acute injury in animal models. The contradictory literature suggests the need to better define the functional effects of PGE2 on tendon. Our objective was to characterize the effects of PGE2 injection on the biomechanical and biochemical properties of tendon and the activity of the animals. Our hypothesis was that weekly PGE2 injection to the rat patellar tendon would lead to inferior biomechanical properties. Methods Forty rats were divided equally into four groups. Three groups were followed for 4 weeks with the following peritendinous injection procedures: No injection (control, 4 weekly injections of saline (saline, 4 weekly injections of 800 ng PGE2 (PGE2-4 wks. The fourth group received 4 weekly injections of 800 ng PGE2 initially and was followed for a total of 8 weeks. All animals were injected bilaterally. The main outcome measurements included: the structural and material properties of the patellar tendon under tensile loading to failure, tendon collagen content, and weekly animal activity scores. Results The ultimate load of PGE2-4 wks tendons at 4 weeks was significantly greater than control or saline group tendons. The stiffness and elastic modulus of the PGE2 injected tendons at 8 weeks was significantly greater than the control or saline tendons. No differences in animal activity, collagen content, or mean fibril diameter were observed between groups. Conclusions Four weekly peritendinous injections of PGE2 to the rat patellar

Prostaglandin synthesis can be inhibited locally by infusion of NSAIDS through microdialysis catheters in human skeletal muscle

DEFF Research Database (Denmark)

Mikkelsen, Ulla Ramer; Helmark, Ida Carøe; Kjaer, Michael

2008-01-01

of nonsteroidal anti-inflammatory drugs (NSAIDs). However, to study the local role of prostaglandins, the formation of prostaglandins within the tissue must be controlled. Microdialysis enables determination of local concentrations of water-soluble substances within the tissue. In the present study......, the microdialysis method was used to infuse NSAIDs locally into human skeletal muscles producing a local block of prostaglandin formation. In addition, the graded blockade at various distances from the infusion site within the muscle during rest, exercise and recovery was determined. Microdialysis was performed...... in thigh muscles (vastus lateralis muscle) in six healthy men. One of the microdialysis catheters was used to block prostaglandin synthesis by infusion of the NSAID indomethacin. Additional catheters were placed 1 and 4 cm away from the infusion and in the contralateral leg (working control). Following 2 h...

Prostaglandin levels and lysosomal enzyme activities in irradiated rats

International Nuclear Information System (INIS)

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

1980-01-01

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

Radioimmunoassay determination of urinary prostaglandins in patients with progressive systemic sclerosis

International Nuclear Information System (INIS)

Ramirez P, P.; Erbessd, M.L.; Mares, G.; Recinos, G.; Graef S, A.; Lavalle, C.

1985-01-01

The results of urinary determinations of E-2 prostaglandines by radioimmunoassay (RIA) in 24-hour urine are presented for three groups: progressive systemic sclerotic patients with normotension and with elevated or normal APR, progressive systemic sclerotic patients with hypertension and with normal or low APR, control group of normal subjects. In a recent report of progressive systemic sclerosis in patients we demonstrated changes in the urine concentratrion of APR levels, sodium excretion and in total blood volume. Based on these findings we felt the need to perform quantifications of E-2 prostaglandines (PGE-2) in 24-hour recently taken urine samples stored at 70 0 and measure the sodium amounts excreted in the urine. We concluded that urinary determination of E-2 prostaglandines was the most suitable for our study as it allowed the establishment of relationships between APR, aldosterone and metabolic sodium balance. (author)

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

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Alessandra Cambi

2013-03-01

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

Angiotensin II potentiates prostaglandin stimulation of cyclic AMP levels in intact bovine adrenal medulla cells but not adenylate cyclase in permeabilized cells.

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Boarder, M R; Plevin, R; Marriott, D B

1988-10-25

The level of cyclic AMP in primary cultures of bovine adrenal medulla cells is elevated by prostaglandin E1. Angiotensin II is commonly reported to act on receptors linked to phosphoinositide metabolism or to inhibition of adenylate cyclase. We have investigated the effect of angiotensin II on prostaglandin E1-stimulated cyclic AMP levels in these primary cultures. Rather than reducing cyclic AMP levels, we have found that angiotensin II powerfully potentiates prostaglandin E1-stimulated cyclic AMP accumulation in intact cells, both in the presence and absence of phosphodiesterase inhibitors. The 50% maximal response was similar to that for stimulation of phosphoinositide breakdown by angiotensin II in these cultures. The potentiation of stimulated cyclic AMP levels was seen, although to a smaller maximum, with the protein kinase C (Ca2+/phospholipid-dependent enzyme) activating phorbol ester tetradecanoyl phorbolacetate and with the synthetic diacylglycerol 1-oleoyl-2-acetylglycerol; pretreatment (24 h) with active phorbol ester, which would be expected to diminish protein kinase C levels, attenuated the angiotensin II potentiation of cyclic AMP. Using digitonin-permeabilized cells we showed that adenylate cyclase activity was stimulated by prostaglandin E1 with the same dose-response relationship as was cyclic AMP accumulation in intact cells, but the permeabilized cells showed no response to angiotensin II. The results are discussed with respect to the hypothesis that the angiotensin II influence on cyclic AMP levels is mediated, in part, by diacylglycerol stimulation of protein kinase C.

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

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Jenna L. Leclerc

2015-04-01

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

Stretch independent regulation of prostaglandin E(2) production within the isolated guinea-pig lamina propria.

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Nile, Christopher J; de Vente, Jan; Gillespie, James I

2010-02-01

To use an isolated preparation of the guinea-pig bladder lamina propria (LP) to investigate the effects of adenosine tri-phosphate (ATP) and nitric oxide (NO) on the release of prostaglandin E(2) (PGE(2)). The bladders of female guinea-pigs (200-400 g) were isolated and opened to expose the urothelial surface. The LP was dissected free of the underlying detrusor muscle and cut into strips from the dome to base. Strips were then incubated in Krebs buffer at 37 degrees C. Each tissue piece was then exposed to the stable ATP analogue, BzATP, and a NO donor, diethylamine-NONOate (DEANO), and the effect on PGE(2) output into the supernatant determined using the Parameter(TM) PGE(2) enzyme immunoassay kit (R & D Systems, Abingdon, UK). Experiments were repeated in the presence of purinergic receptor and cyclooxygenase (COX) enzymes, COX I and COX II, antagonists. The cellular location of COX I, COX II and neuronal NO synthase (nNOS) within the bladder LP was also determined by immunohistochemistry. PGE(2) production was significantly increased by BzATP. Antagonist studies showed the purinergic stimulation involved both P(2)X and P(2)Y receptors. The BzATP response was inhibited by the COX inhibitor indomethacin (COX I >COX II) but not by DUP 697 (COX II >COX I). Thus, BzATP stimulation occurs because of COX I stimulation. NO had no effect on PGE(2) production over the initial 10 min of an exposure. However, PGE(2) output was increased 100 min after exposure to the NO donor. In the presence of NO, the BzATP stimulation was abolished. Immunohistochemistry was used to confirm the location of COX I to the basal and inner intermediate urothelial layers and to cells within the diffuse layer of LP interstitial cells. In addition, nNOS was also located in the basal urothelial layers whilst COX II was found in the interstitial cell layers. There is complex interaction between ATP and NO to modulate PGE(2) release from the bladder LP in the un-stretched preparation. Such

Sulindac Sulfide, but Not Sulindac Sulfone, Inhibits Colorectal Cancer Growth

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Christopher S. Williams

1999-06-01

Full Text Available Sulindac sulfide, a metabolite of the nonsteroidal antiinflammatory drug (NSAID sulindac sulfoxide, is effective at reducing tumor burden in both familial adenomatous polyposis patients and in animals with colorectal cancer. Another sulindac sulfoxide metabolite, sulindac sulfone, has been reported to have antitumor properties without inhibiting cyclooxygenase activity. Here we report the effect of sulindac sulfone treatment on the growth of colorectal carcinoma cells. We observed that sulindac sulfide or sulfone treatment of HCA-7 cells led to inhibition of prostaglandin E2 production. Both sulindac sulfide and sulfone inhibited HCA-7 and HCT-116 cell growth in vitro. Sulindac sulfone had no effect on the growth of either HCA-7 or HCT-116 xenografts, whereas the sulfide derivative inhibited HCA-7 growth in vivo. Both sulindac sulfide and sulfone inhibited colon carcinoma cell growth and prostaglandin production in vitro, but sulindac sulfone had no effect on the growth of colon cancer cell xenografts in nude mice.

Areca nut extract up-regulates prostaglandin production, cyclooxygenase-2 mRNA and protein expression of human oral keratinocytes.

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Jeng, J H; Ho, Y S; Chan, C P; Wang, Y J; Hahn, L J; Lei, D; Hsu, C C; Chang, M C

2000-07-01

There are about 600 million betel quid (BQ) chewers in the world. BQ chewing is associated with increased incidence of oral cancer and submucous fibrosis. In this study, areca nut (AN) extract (200-800 microg/ml) induced the prostaglandin E(2) (PGE(2)) production by 1. 4-3.4-fold and 6-keto-PGF(1 alpha) production by 1.1-1.7-fold of gingival keratinocytes (GK), respectively, following 24 h of exposure. Exposure of GK to AN extract (>400 microg/ml) led to cell retraction and intracellular vacuoles formation. At concentrations of 800 and 1200 microg/ml, AN extract induced cell death at 21-24 and 32-52% as detected by MTT assay and cellular lactate dehydrogenase release, respectively. Interestingly, AN-induced morphological changes of GK are reversible. GK can still proliferate following exposure to AN extract. Cytotoxicity of AN extract cannot be inhibited by indomethacin (1 microM) and aspirin (50 microM), indicating that prostaglandin (PG) production is not the major factor responsible for AN cytotoxicity. PGE(2) exhibited little effect on the growth of GK at concentrations ranging from 100-1000 pg/ml. Stimulating GK production of PGs by AN extract could be due to induction of cyclooxygenase-2 (COX-2) mRNA expression and protein production. These results suggest that AN ingredients are critical in the pathogenesis of oral submucous fibrosis and oral cancer via their stimulatory effects on the PGs, COX-2 production and associated tissue inflammatory responses. AN cytotoxicity to GK is not directly mediated by COX-2 stimulation and PG production.

Effects of a single administration of prostaglandin F2alpha, or a combination of prostaglandin F2alpha and prostaglandin E2, or placebo on fertility variables in dairy cows 3–5 weeks post partum, a randomized, double-blind clinical trial

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Steiner Adrian

2006-12-01

Full Text Available Abstract Background Delayed uterine involution has negative effects on the fertility of cows; use of prostaglandin F2alpha alone as a single treatment has not been shown to consistently improve fertility. Combined administration of PGF2alpha and PGE2 increased uterine pressure in healthy cows. We hypothesized, that the combination of both prostaglandins would accelerate uterine involution and have, therefore, a positive effect on fertility variables. In commercial dairy farming, the benefit of a single post partum combined prostaglandin treatment should be demonstrated. Methods 383 cows from commercial dairy farms were included in this study. Uterine size and secretion were evaluated at treatment 21–35 days post partum and 14 days later. Cows were randomly allocated to one of three treatment groups: PGF2alpha and PGE2, PGF2alpha or placebo. For every animal participating in the study, the following reproduction variables were recorded: Interval from calving to first insemination, days open, number of artificial inseminations (AI to conception; subsequent treatment of uterus, subsequent treatment of ovaries. Plasma progesterone level at time of treatment was used as a covariable. For continuous measurements, analysis of variance was performed. Fisher's exact test for categorical non-ordered data and exact Kruskal-Wallis test for ordered data were used; pairwise group comparisons with Bonferroni adjustment of significance level were performed. Results There was no significant difference among treatment groups in uterine size. Furthermore, there was no significant difference among treatments concerning days open, number of AI, and subsequent treatment of uterus and ovaries. Days from calving to first insemination tended to be shorter for cows with low progesterone level given PGF2alpha and PGE2 in combination than for the placebo-group (P = 0.024. Conclusion The results of this study indicate that the administration of PGF2alpha or a combination

Effects of a single administration of prostaglandin F2alpha, or a combination of prostaglandin F2alpha and prostaglandin E2, or placebo on fertility variables in dairy cows 3–5 weeks post partum, a randomized, double-blind clinical trial

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Hirsbrunner, Gaby; Burkhardt, Heinz W; Steiner, Adrian

2006-01-01

Background Delayed uterine involution has negative effects on the fertility of cows; use of prostaglandin F2alpha alone as a single treatment has not been shown to consistently improve fertility. Combined administration of PGF2alpha and PGE2 increased uterine pressure in healthy cows. We hypothesized, that the combination of both prostaglandins would accelerate uterine involution and have, therefore, a positive effect on fertility variables. In commercial dairy farming, the benefit of a single post partum combined prostaglandin treatment should be demonstrated. Methods 383 cows from commercial dairy farms were included in this study. Uterine size and secretion were evaluated at treatment 21–35 days post partum and 14 days later. Cows were randomly allocated to one of three treatment groups: PGF2alpha and PGE2, PGF2alpha or placebo. For every animal participating in the study, the following reproduction variables were recorded: Interval from calving to first insemination, days open, number of artificial inseminations (AI) to conception; subsequent treatment of uterus, subsequent treatment of ovaries. Plasma progesterone level at time of treatment was used as a covariable. For continuous measurements, analysis of variance was performed. Fisher's exact test for categorical non-ordered data and exact Kruskal-Wallis test for ordered data were used; pairwise group comparisons with Bonferroni adjustment of significance level were performed. Results There was no significant difference among treatment groups in uterine size. Furthermore, there was no significant difference among treatments concerning days open, number of AI, and subsequent treatment of uterus and ovaries. Days from calving to first insemination tended to be shorter for cows with low progesterone level given PGF2alpha and PGE2 in combination than for the placebo-group (P = 0.024). Conclusion The results of this study indicate that the administration of PGF2alpha or a combination of PGF2alpha and PGE2 21 to

15-deoxy-δ12,14-prostaglandin j2 inhibits osteolytic breast cancer bone metastasis and estrogen deficiency-induced bone loss.

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Ki Rim Kim

Full Text Available Breast cancer is the major cause of cancer death in women worldwide. The most common site of metastasis is bone. Bone metastases obstruct the normal bone remodeling process and aberrantly enhance osteoclast-mediated bone resorption, which results in osteolytic lesions. 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2 is an endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARγ that has anti-inflammatory and antitumor activity at micromolar concentrations through PPARγ-dependent and/or PPARγ-independent pathways. We investigated the inhibitory activity of 15d-PGJ2 on the bone loss that is associated with breast cancer bone metastasis and estrogen deficiency caused by cancer treatment. 15d-PGJ2 dose-dependently inhibited viability, migration, invasion, and parathyroid hormone-related protein (PTHrP production in MDA-MB-231 breast cancer cells. 15d-PGJ2 suppressed receptor activator of nuclear factor kappa-B ligand (RANKL mRNA levels and normalized osteoprotegerin (OPG mRNA levels in hFOB1.19 osteoblastic cells treated with culture medium from MDA-MB-231 cells or PTHrP, which decreased the RANKL/OPG ratio. 15d-PGJ2 blocked RANKL-induced osteoclastogenesis and inhibited the formation of resorption pits by decreasing the activities of cathepsin K and matrix metalloproteinases, which are secreted by mature osteoclasts. 15d-PGJ2 exerted its effects on breast cancer and bone cells via PPARγ-independent pathways. In Balb/c nu/nu mice that received an intracardiac injection of MDA-MB-231 cells, subcutaneously injected 15d-PGJ2 substantially decreased metastatic progression, cancer cell-mediated bone destruction in femora, tibiae, and mandibles, and serum PTHrP levels. 15d-PGJ2 prevented the destruction of femoral trabecular structures in estrogen-deprived ICR mice as measured by bone morphometric parameters and serum biochemical data. Therefore, 15d-PGJ2 may be beneficial for the prevention and treatment of breast cancer

Combined inhibition of nitric oxide and prostaglandins reduces human skeletal muscle blood flow during exercise

DEFF Research Database (Denmark)

Boushel, Robert Christopher; Langberg, Henning; Gemmer, Carsten

2002-01-01

The vascular endothelium is an important mediator of tissue vasodilatation, yet the role of the specific substances, nitric oxide (NO) and prostaglandins (PG), in mediating the large increases in muscle perfusion during exercise in humans is unclear. Quadriceps microvascular blood flow......, respectively (P exercise in humans. These findings demonstrate an important synergistic role of NO and PG for skeletal muscle vasodilatation and hyperaemia during muscular contraction....... was quantified by near infrared spectroscopy and indocyanine green in six healthy humans during dynamic knee extension exercise with and without combined pharmacological inhibition of NO synthase (NOS) and PG by L-NAME and indomethacin, respectively. Microdialysis was applied to determine interstitial release...

The roles of the cyclo-oxygenases types one and two in prostaglandin synthesis in human fetal membranes at term.

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Sawdy, R J; Slater, D M; Dennes, W J; Sullivan, M H; Bennett, P R

2000-01-01

The aim of this study was to determine the relative contributions of cyclo-oxygenase (COX) types 1 and 2 to prostaglandin synthesis at term. Fetal membranes were collected from 6 pregnancies after elective caesarean section at term, prior to labour. The presence of COX-1 and COX-2 protein was determined using Western analysis. The relative contributions of the two isoforms of COX to prostaglandin synthesis were determined by incubation of fetal membrane discs with either a COX-2 selective inhibitor, SC236, or a COX-1 selective inhibitor, SC560, and measurement of prostaglandin release during 24 h using enzyme-linked immuno-sorbent assay (ELISA). Both COX-1 and COX-2 protein were demonstrated in amnion and chorion-decidua. The COX-2 selective inhibitor, SC-236, significantly reduced prostaglandin synthesis, both in its COX-2 specific and higher, non-specific concentration ranges. The COX-1 selective inhibitor, SC-560, had no effect upon prostaglandin synthesis in its COX-1 specific concentration range, but did significantly reduce prostaglandin synthesis at higher, non-selective concentrations. Fetal membranes contain both COX-1 and COX-2 at term, but only COX-2 contributes towards prostaglandin synthesis. COX-2 selective NSAI drugs will be as effective as non-selective agents in inhibition of fetal membrane prostaglandin synthesis and may represent a new strategy for tocolysis. Copyright 2000 Harcourt Publishers Ltd.

Induction of human microsomal prostaglandin E synthase 1 by activated oncogene RhoA GTPase in A549 human epithelial cancer cells

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Choi, Hye Jin [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Lee, Dong-Hyung [Department of Obstetrics and Gynecology, Medical Research Institute, Pusan National University, Busan (Korea, Republic of); Park, Seong-Hwan; Kim, Juil; Do, Kee Hun [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); An, Tae Jin; Ahn, Young Sup; Park, Chung Berm [Department of Herbal Crop Research, NIHHS, RDA, Eumseong (Korea, Republic of); Moon, Yuseok, E-mail: moon@pnu.edu [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Medical Research Institute and Research Institute for Basic Sciences, Pusan National University, Busan (Korea, Republic of)

2011-09-30

Highlights: {yields} As a target of oncogene RhoA-linked signal, a prostaglandin metabolism is assessed. {yields} RhoA activation increases PGE{sub 2} levels and its metabolic enzyme mPGES-1. {yields} RhoA-activated NF-{kappa}B and EGR-1 are positively involved in mPGES-1 induction. -- Abstract: Oncogenic RhoA GTPase has been investigated as a mediator of pro-inflammatory responses and aggressive carcinogenesis. Among the various targets of RhoA-linked signals, pro-inflammatory prostaglandin E{sub 2} (PGE{sub 2}), a major prostaglandin metabolite, was assessed in epithelial cancer cells. RhoA activation increased PGE{sub 2} levels and gene expression of the rate-limiting PGE{sub 2} producing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase 1 (mPGES-1). In particular, human mPGES-1 was induced by RhoA via transcriptional activation in control and interleukin (IL)-1{beta}-activated cancer cells. To address the involvement of potent signaling pathways in RhoA-activated mPGES-1 induction, various signaling inhibitors were screened for their effects on mPGES-1 promoter activity. RhoA activation enhanced basal and IL-1{beta}-mediated phosphorylated nuclear factor-{kappa}B and extracellular signal-regulated kinase1/2 proteins, all of which were positively involved in RhoA-induced gene expression of mPGES-1. As one potent down-stream transcription factor of ERK1/2 signals, early growth response gene 1 product also mediated RhoA-induced gene expression of mPGES-1 by enhancing transcriptional activity. Since oncogene-triggered PGE{sub 2} production is a critical modulator of epithelial tumor cells, RhoA-associated mPGES-1 represents a promising chemo-preventive or therapeutic target for epithelial inflammation and its associated cancers.

Effects of prostaglandin E2 on the electrical properties of thermally classified neurons in the ventromedial preoptic area of the rat hypothalamus

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Griffin John D

2005-02-01

Full Text Available Abstract Background Physiological and morphological evidence suggests that activation of the ventromedial preoptic area of the hypothalamus (VMPO is an essential component of an intravenous LPS-dependent fever. In response to the endogenous pyrogen prostaglandin E2 (PGE2, the majority of temperature insensitive neurons in the VMPO show an increase in firing rate, while warm sensitive neurons are inhibited. We have hypothesized that these PGE2 dependent effects on firing rate are due to changes in the inherent electrical properties of VMPO neurons, which are regulated by the activity of specific ionic currents. Results To characterize the electrical properties of VMPO neurons, whole-cell recordings were made in tissue slices from male Sprague-Dawley rats. Our results indicate that PGE2 dependent firing rate responses were not the result of changes in resting membrane potential, action potential amplitude and duration, or local synaptic input. However, PGE2 reduced the input resistance of all VMPO neurons, while increasing the excitability of temperature insensitive neurons and decreasing the excitability of warm sensitive neurons. In addition, the majority of temperature insensitive neurons responded to PGE2 with an increase in the rate of rise of the depolarizing prepotential that precedes each action potential. This response to PGE2 was reversed for warm sensitive neurons, in which the prepotential rate of rise decreased. Conclusion We would therefore suggest that PGE2 is having an effect on the ionic currents that regulate firing rate by controlling how fast membrane potential rises to threshold during the prepotential phase of the action potential.

Effects of prostaglandin E2 and cAMP elevating drugs on GM-CSF release by cultured human airway smooth muscle cells. Relevance to asthma therapy.

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Lazzeri, N; Belvisi, M G; Patel, H J; Yacoub, M H; Chung, K F; Mitchell, J A

2001-01-01

Human airway smooth muscle (HASM) cells release granulocyte macrophage-colony stimulating factor (GM-CSF) and express cyclooxygenase (COX)-2 (resulting in the release of prostaglandin [PG] E2) after stimulation with cytokines. Because COX-2 activity can regulate a number of inflammatory processes, we have assessed its effects, as well as those of agents that modulate cyclic adenosine monophosphate (cAMP), on GM-CSF release by HASM cells. Cells stimulated with a combination of proinflammatory cytokines (interleukin-1beta and tumor necrosis factor-alpha each at 10 ng/ml) for 24 h released significant amounts of PGE2 (measured by radioimmunoassay) and GM-CSF (measured by enzyme-linked immunosorbent assay). Indomethacin and other COX-1/COX-2 inhibitors caused concentration-dependent inhibitions of PGE2 concomitantly with increases in GM-CSF formation. Addition of exogenous PGE2 or the beta2-agonist fenoterol, which increase cAMP, to cytokine-treated HASM cells had no effect on GM-CSF release unless COX activity was first blocked with indomethacin. The type 4 phosphodiesterase inhibitors rolipram and SB 207499 both caused concentration-dependent reductions in GM-CSF production. Thus, when HASM cells are activated with cytokines they release PGE2, which acts as a "braking mechanism" to limit the coproduction of GM-CSF. Moreover, agents that elevate cAMP also reduce GM-CSF formation by these cells.

Opposite effects of methanandamide on lipopolysaccharide-induced prostaglandin E2 and F2α synthesis in uterine explants from pregnant mice.

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Claudia A Vercelli

Full Text Available Prostaglandins (PG are effective abortifacients and are important mediators of lipopolisaccharide (LPS-induced embryonic resorption (ER. Besides, anandamide (AEA has been described as one of the major endocannabinoids present in the uterus suggesting that it might play a role in reproduction. It has been reported that high levels of AEA are associated with pregnancy failure and that LPS increases AEA production. Also, it has been observed that AEA modulates PG production in different tissues. In this sense, we studied whether LPS-induced PG production is modulated by AEA and we also assessed the effect of this endocannabinoid on PG metabolism in an in vitro model. Uterine explants from BALB/c implantation sites were cultured in the presence of LPS plus cannabinoid receptor (CB specific antagonists and PG production was assessed. Then, we studied the effect of exogenous AEA on different steps of PG metabolic pathway. We showed that AEA is involved in LPS-induced PG biosynthesis. Also, we observed that AEA exerts opposite effects on PGE(2 and PGF(2α biosynthesis, by inhibiting PGE(2 production and increasing PGF(2α levels. We suggest that AEA could be involved in the mechanisms implicated in LPS-induced ER. A better understanding of how AEA could be affecting ER could help developing specific interventions to prevent this pathology.

Myostatin inhibits eEF2K-eEF2 by regulating AMPK to suppress protein synthesis.

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Deng, Zhao; Luo, Pei; Lai, Wen; Song, Tongxing; Peng, Jian; Wei, Hong-Kui

2017-12-09

Growth of skeletal muscle is dependent on the protein synthesis, and the rate of protein synthesis is mainly regulated in the stage of translation initiation and elongation. Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily, is a negative regulator of protein synthesis. C2C12 myotubes was incubated with 0, 0.01, 0.1, 1, 2, 3 μg/mL myostatin recombinant protein, and then we detected the rates of protein synthesis by the method of SUnSET. We found that high concentrations of myostatin (2 and 3 μg/mL) inhibited protein synthesis by blocking mTOR and eEF2K-eEF2 pathway, while low concentration of myostatin (0.01, 0.1 and 1 μg/mL) regulated eEF2K-eEF2 pathway activity to block protein synthesis without affected mTOR pathway, and myostatin inhibited eEF2K-eEF2 pathway through regulating AMPK pathway to suppress protein synthesis. It provided a new mechanism for myostatin regulating protein synthesis and treating muscle atrophy. Copyright © 2017. Published by Elsevier Inc.

H2S-induced HCO3- secretion in the rat stomach--involvement of nitric oxide, prostaglandins, and capsaicin-sensitive sensory neurons.

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Takeuchi, Koji; Ise, Fumitaka; Takahashi, Kento; Aihara, Eitaro; Hayashi, Shusaku

2015-04-30

Hydrogen sulfide (H2S) is known to be an important gaseous mediator that affects various functions under physiological and pathological conditions. We examined the effects of NaHS, a H2S donor, on HCO3(-) secretion in rat stomachs and investigated the mechanism involved in this response. Under urethane anesthesia, rat stomachs were mounted on an ex vivo chamber and perfused with saline. Acid secretion had been inhibited by omeprazole. The secretion of HCO3(-) was measured at pH 7.0 using a pH-stat method and by the addition of 10 mM HCl. NaHS (0.5-10 mM) was perfused in the stomach for 5 min. Indomethacin or L-NAME was administered s.c. before NaHS treatment, while glibenclamide (a KATP channel blocker), ONO-8711 (an EP1 antagonist), or propargylglycine (a cystathionine γ-lyase inhibitor) was given i.p. before. The mucosal perfusion of NaHS dose-dependently increased the secretion of HCO3(-), and this effect was significantly attenuated by indomethacin, L-NAME, and sensory deafferentation, but not by glibenclamide or ONO-8711. The luminal output of nitric oxide, but not the mucosal production of prostaglandin E2, was increased by the perfusion of NaHS. Mucosal acidification stimulated HCO3(-) secretion, and this response was inhibited by sensory deafferentation, indomethacin, L-NAME, and ONO-8711, but not by propargylglycine. These results suggested that H2S increased HCO3(-) secretion in the stomach, and this effect was mediated by capsaicin-sensitive afferent neurons and dependent on nitric oxide and prostaglandins, but not ATP-sensitive K(+) channels. Further study is needed to define the role of endogenous H2S in the mechanism underlying acid-induced gastric HCO3(-) secretion. Copyright © 2014 Elsevier Inc. All rights reserved.

mPGES-1-derived prostaglandin E2 stimulates Stat3 to promote podocyte apoptosis.

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Yu, Jing; Wu, Yimei; Wang, Lu; Zhang, Wen; Xu, Man; Song, Jiayu; Fu, Yu; Cui, Yiyun; Gong, Wei; Li, Shuzhen; Xia, Weiwei; Huang, Songming; Zhang, Aihua; Jia, Zhanjun

2017-11-01

We previously reported that microsomal prostaglandin E synthase-1 (mPGES-1) contributed to adriamycin (Adr)-induced podocyte apoptosis. However, the molecular mechanism remains unclear. Here we studied the role of mPGES-1/PGE2 cascade in activating Stat3 signaling and the contribution of Stat3 in PGE2- and Adr-induced podocyte apoptosis. In murine podocytes, PGE2 dose- and time-dependently increased the phosphorylation of Stat3 in line with the enhanced cell apoptosis and reduced podocyte protein podocin. In agreement with the increased Stat3 phosphorylation, Stat3-derived cytokines including IL-6, IL-17, MCP-1, and ICAM-1 were significantly upregulated following PGE2 treatment. By application of a specific Stat3 inhibitor S3I-201, PGE2-induced podocyte apoptosis was largely abolished in parallel with a blockade of podocin reduction. Next, we observed that Adr treatment also enhanced p-Stat3 and activated mPGES-1/PGE2 cascade. Blockade of Stat3 by S3I-201 significantly ameliorated Adr-induced cell apoptosis and podocin reduction. More interestingly, silencing mPGES-1 in podocytes by mPGES-1 siRNA blocked Adr-induced increments of Stat-3 phosphorylation, PGE2 production, and Stat3-derived inflammatory cytokines. Taken together, this study suggested that mPGES-1-derived PGE2 could activate Stat3 signaling to promote podocyte apoptosis. Targeting mPGES-1/PGE2/Stat3 signaling might be a potential strategy for the treatment of podocytopathy.

Effects of Camphorquinone on Cytotoxicity, Cell Cycle Regulation and Prostaglandin E2 Production of Dental Pulp Cells: Role of ROS, ATM/Chk2, MEK/ERK and Hemeoxygenase-1.

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Mei-Chi Chang

Full Text Available Camphorquinone (CQ is a popularly-used photosensitizer in composite resin restoration. In this study, the effects of CQ on cytotoxicity and inflammation-related genes and proteins expression of pulp cells were investigated. The role of reactive oxygen species (ROS, ATM/Chk2/p53 and hemeoxygenase-1 (HO-1 and MEK/ERK signaling was also evaluated. We found that ROS and free radicals may play important role in CQ toxicity. CQ (1 and 2 mM decreased the viability of pulp cells to about 70% and 50% of control, respectively. CQ also induced G2/M cell cycle arrest and apoptosis of pulp cells. The expression of type I collagen, cdc2, cyclin B, and cdc25C was inhibited, while p21, HO-1 and cyclooxygenase-2 (COX-2 were stimulated by CQ. CQ also activated ATM, Chk2, and p53 phosphorylation and GADD45α expression. Besides, exposure to CQ increased cellular ROS level and 8-isoprostane production. CQ also stimulated COX-2 expression and PGE2 production of pulp cells. The reduction of cell viability caused by CQ can be attenuated by N-acetyl-L-cysteine (NAC, catalase and superoxide dismutase (SOD, but can be promoted by Zinc protoporphyin (ZnPP. CQ stimulated ERK1/2 phosphorylation, and U0126 prevented the CQ-induced COX-2 expression and prostaglandin E2 (PGE2 production. These results indicate that CQ may cause cytotoxicity, cell cycle arrest, apoptosis, and PGE2 production of pulp cells. These events could be due to stimulation of ROS and 8-isoprostane production, ATM/Chk2/p53 signaling, HO-1, COX-2 and p21 expression, as well as the inhibition of cdc2, cdc25C and cyclin B1. These results are important for understanding the role of ROS in pathogenesis of pulp necrosis and pulpal inflammation after clinical composite resin filling.

Prostaglandin E2 and Transforming Growth Factor-β Play a Critical Role in Suppression of Allergic Airway Inflammation by Adipose-Derived Stem Cells.

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Kyu-Sup Cho

Full Text Available The role of soluble factors in the suppression of allergic airway inflammation by adipose-derived stem cells (ASCs remains to be elucidated. Moreover, the major soluble factors responsible for the immunomodulatory effects of ASCs in allergic airway diseases have not been well documented. We evaluated the effects of ASCs on allergic inflammation in asthmatic mice treated with a prostaglandin E2 (PGE2 inhibitor or transforming growth factor-β (TGF-β neutralizing antibodies.Asthmatic mice were injected intraperitoneally with a PGE2 inhibitor or TGF-β neutralizing antibodies at approximately the same time as ASCs injection and were compared with non-treated controls. In asthmatic mice, ASCs significantly reduced airway hyperresponsiveness, the number of total inflammatory cells and eosinophils in the bronchoalveolar lavage fluid (BALF, eosinophilic inflammation, goblet cell hyperplasia, and serum total and allergen-specific IgE and IgG1. ASCs significantly inhibited Th2 cytokines, such as interleukin (IL-4, IL-5, and IL-13, and enhanced the Th1 cytokine (Interferon-γ and regulatory cytokines (IL-10 and TGF-β in the BALF and lung draining lymph nodes (LLNs. ASCs engraftment caused significant increases in the regulatory T cell (Treg and IL-10+ T cell populations in LLNs. However, blocking PGE2 or TGF-β eliminated the immunosuppressive effect of ASCs in allergic airway inflammation.ASCs are capable of secreting PGE2 and TGF-β, which may play a role in inducing Treg expansion. Furthermore, treatment with a PGE2 inhibitor or TGF-β neutralizing antibodies eliminated the beneficial effect of ASCs treatment in asthmatic mice, suggesting that PGE2 and TGF-β are the major soluble factors responsible for suppressing allergic airway inflammation.

15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) mediates repression of TNF-α by decreasing levels of acetylated histone H3 and H4 at its promoter

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Engdahl, Ryan; Monroy, M. Alexandra; Daly, John M.

2007-01-01

Prostaglandin metabolite 15-Deoxy-Δ 12,14 -prostaglandin J2 (15d-PGJ2) is known to inhibit a number of pro-inflammatory cytokines as well as being a ligand for nuclear receptor PPARγ. We investigated the ability of 15d-PGJ2 to inhibit TNF-α gene expression through mechanisms that involve histone modification. Pretreatment with 15d-PGJ2 (10 μM) inhibited LPS-stimulated TNF-α mRNA in THP-1 monocytes or PMA-differentiated cells to nearly basal levels. A specific PPARγ ligand, GW1929, failed to inhibit LPS-induced TNF-α mRNA expression nor did a PPARγ antagonist, GW9662, alter the repression of TNF-α mRNA in LPS-stimulated cells pretreated with 15d-PGJ2 suggesting a PPARγ-independent inhibition of TNF-α mRNA in THP-1 cells. Transfection studies with a reporter construct and subsequent treatment with 15d-PGJ2 demonstrated a dose-dependent inhibition of the TNF-α promoter. Additional studies demonstrated that inhibition of histone deacetylases with trichostatin A (TSA) or overexpression of histone acetyltransferase CBP could overcome 15d-PGJ2-mediated repression of the TNF-α promoter, suggesting that an important mechanism whereby 15d-PGJ2 suppresses a cytokine is through factors that regulate histone modifications. To examine the endogenous TNF-α promoter, chromatin immunoprecipitations (ChIP) were performed. ChIP assays demonstrated that LPS stimulation induced an increase in histone H3 and H4 acetylation at the TNF-α promoter, which was reduced in cells pretreated with 15d-PGJ2. These results highlight the ability of acetylation and deacetylation factors to affect the TNF-α promoter and demonstrate that an additional important mechanism whereby 15d-PGJ2 mediates TNF-α transcriptional repression by altering levels of acetylated histone H3 and H4 at its promoter

Anti-inflammatory activity of 6-hydroxy-2,7-dimethoxy-1,4-henanthraquinone from tuberous roots of yam (Dioscorea batatas) through inhibition of prostaglandin D₂ and leukotriene C₄ production in mouse bone marrow-derived mast cells.

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Jin, Meihua; Lu, Yue; Yang, Ju Hye; Jo, Tae Hyung; Park, Young In; Lee, Chong-Kil; Park, Sang-Jo; Son, Kun Ho; Chang, Hyeun Wook

2011-09-01

6-Hydroxy-2,7-dimethoxy-1,4-phenanthraquinone (PAQ) isolated from the tuberous roots of Yam (Dioscorea batatas) inhibited cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) dependent prostaglandin D(2) (PGD(2)) generation in mouse bone marrow-derived mast cells in a concentration-dependent manner with IC(50) values of 0.08 μM and 0.27 μM, respectively. In the Western blotting with specific anti-COX-2 antibodies, the decrease of the quantity of PGD(2) was accompanied by a decrease in the COX-2 protein level. But PAQ did not affect COX-1 protein level. In addition, this compound inhibited 5-lipoxygenase (5-LOX) dependent production of leukotriene C(4) in a dose-dependent manner, with an IC(50) of 0.032 μM. These results demonstrate that PAQ has a dual COX-2/5-LOX inhibitory activity. This compound also inhibited the degranulation reaction in a dose-dependent manner with an IC(50) of 2.7 μM. Thus, these results suggest that PAQ may be useful in regulating mast cell-mediated inflammatory diseases.

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

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Huang Li-Yen

2007-08-01

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

Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib.

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Kirane, Amanda; Toombs, Jason E; Larsen, Jill E; Ostapoff, Katherine T; Meshaw, Kathryn R; Zaknoen, Sara; Brekken, Rolf A; Burrows, Francis J

2012-09-01

Although cyclooxygenase-2 (COX-2) inhibitors, such as the late stage development drug apricoxib, exhibit antitumor activity, their mechanisms of action have not been fully defined. In this study, we characterized the mechanisms of action of apricoxib in HT29 colorectal carcinoma. Apricoxib was weakly cytotoxic toward naive HT29 cells in vitro but inhibited tumor growth markedly in vivo. Pharmacokinetic analyses revealed that in vivo drug levels peaked at 2-4 µM and remained sufficient to completely inhibit prostaglandin E(2) production, but failed to reach concentrations cytotoxic for HT29 cells in monolayer culture. Despite this, apricoxib significantly inhibited tumor cell proliferation and induced apoptosis without affecting blood vessel density, although it did promote vascular normalization. Strikingly, apricoxib treatment induced a dose-dependent reversal of epithelial-mesenchymal transition (EMT), as shown by robust upregulation of E-cadherin and the virtual disappearance of vimentin and ZEB1 protein expression. In vitro, either anchorage-independent growth conditions or forced EMT sensitized HT29 and non-small cell lung cancer cells to apricoxib by 50-fold, suggesting that the occurrence of EMT may actually increase the dependence of colon and lung carcinoma cells on COX-2. Taken together, these data suggest that acquisition of mesenchymal characteristics sensitizes carcinoma cells to apricoxib resulting in significant single-agent antitumor activity.

The effect of watermelon frost on prostaglandin E2 (PGE2 in inflamed pulp tissue (in vitro study

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Dennis Dennis

2009-06-01

Full Text Available Background: Pulp inflammation can be marked by the increase of prostaglandin E2(PGE2 level compared to normal pulp. The increase of PGE2 may lead to vasodilatation, increase of vascular permeability, pain and bone resorption. Watermelon frost has been well known in Chinese society for pain relief and inflammation in oral cavity and teeth. Purpose: The aim of this study was to investigate that watermelon frost can be used to decrease the PGE2 level. Method: 27 samples of pulp tissues used in this in-vitro study, were extirpated from the patients’ teeth with symptomatic irreversible pulpitis referred to clinic of Conservative Dentistry, RSPGM Faculty of Dentistry, USU. Trial materials were applied to 27 samples i.e. watermelon frost as a trial material and commercial watermelon frost and eugenol to observe their effect on PGE2. PGE2 level of each material was detected through ELISA method by measuring and comparing the absorbance reading of the wells of the samples against standards with a micro plate reader at W1 = 650 nm and W2 = 490 nm. Result: The result showed the biggest effect was found in the third group (eugenol, mean 4.6933, followed by the first group (watermelon frost as a trial material, mean 18,1578 then the second group (commercial watermelon frost, mean 82,2689. OneWay ANOVA revealed that there were significant differences among all trial materials (p < 0.001 on PGE2 level. Conclusion: This study demonstrated that watermelon frost can be used to decrease the PGE2 level in inflamed pulp tissue and led to the acceptance of traditional medicine and natural products as an alternative form of dental care.

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

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

2014-01-01

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

Cyclo-oxygenase-2 mediated prostaglandin release regulates blood flow in connective tissue during mechanical loading in humans

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Langberg, H; Boushel, Robert Christopher; Skovgaard, D

2003-01-01

prior to the experiment) or COX unspecific (n = 8, indomethacin 100 mg (12 and 1 h pre-experiment) and acetyl salicylic acid 500 mg day-1 for 3 days pre-experiment). Prostaglandin E2 (PGE2) concentration was determined by microdialysis and blood flow by 133Xe washout. In C, interstitial PGE2 rose from...

New insights into the catalytic mechanism of Bombyx mori prostaglandin E synthase gained from structure–function analysis

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Yamamoto, Kohji, E-mail: yamamok@agr.kyushu-u.ac.jp [Faculty of Agriculture, Kyushu University Graduate School, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan); Suzuki, Mamoru; Higashiura, Akifumi [Institute for Protein Research, Osaka University, Suita 565-0871 (Japan); Aritake, Kosuke; Urade, Yoshihiro; Uodome, Nobuko [Department of Molecular Behavioral Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874 (Japan); Hossain, MD. Tofazzal [Faculty of Agriculture, Kyushu University Graduate School, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan); Nakagawa, Atsushi [Institute for Protein Research, Osaka University, Suita 565-0871 (Japan)

2013-11-01

Highlights: •Structure of Bombyx mori prostaglandin E synthase is determined. •Bound glutathione sulfonic acid is located at the glutathione-binding site. •Electron-sharing network is present in this protein. •This network includes Asn95, Asp96, and Arg98. •Site-directed mutagenesis reveals that the residues contribute to the catalytic activity. -- Abstract: Prostaglandin E synthase (PGES) catalyzes the isomerization of PGH{sub 2} to PGE{sub 2}. We previously reported the identification and structural characterization of Bombyx mori PGES (bmPGES), which belongs to Sigma-class glutathione transferase. Here, we extend these studies by determining the structure of bmPGES in complex with glutathione sulfonic acid (GTS) at a resolution of 1.37 Å using X-ray crystallography. GTS localized to the glutathione-binding site. We found that electron-sharing network of bmPGES includes Asn95, Asp96, and Arg98. Site-directed mutagenesis of these residues to create mutant forms of bmPGES mutants indicate that they contribute to catalytic activity. These results are, to our knowledge, the first to reveal the presence of an electron-sharing network in bmPGES.

Export of cyclic AMP by avian red cells and inhibition by prostaglandin A1

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Heasley, L.E.

1985-01-01

The mechanism by which PGA 1 inhibits cAMP export by avian red cells was studied, to provide details on the molecular mechanism of a prostaglandin action and on the process of cAMP export itself. The interaction of PGA 1 with pigeon red cells is a multi-step process of uptake, metabolism and secretion. [ 3 H]PGA rapidly enters red cells and is promptly metabolized (V/sub max/ ≥ 1 nmol/min/10 7 cells) to a compound (5) that remains in the aqueous layer after ethyl acetate extraction. Chromatographic analyses, amino acid content and fast atom bombardment mass spectrometry reveal that the polar metabolite is conjugated with glutathione (PGA 1 -GSH) at C-11 via a thioether bond and is largely (80%) reduced to the C-9 hydroxyl derivative

Oligonol supplementation attenuates body temperature and the circulating levels of prostaglandin E2 and cyclooxygenase-2 after heat stress in humans.

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Shin, Young Oh; Lee, Jeong Beom; Song, Young Ju; Min, Young Ki; Yang, Hun Mo

2013-04-01

Oligonol, a phenolic production from lychee, has been reported to exhibit anti-oxidative and anti-inflammatory effects. This study investigated the effect of Oligonol supplementation on circulating levels of prostaglandin E2 (PGE2) and cyclooxygenase (COX)-2, as well as body temperature, after heat stress in 17 healthy human male volunteers (age, 21.6±2.1 years). All experiments were performed in an automated climate chamber (26.0°C±0.5°C, relative humidity 60%±3.0%, air velocity less than 1 m/sec) between 2 and 5 p.m. Subjects ingested an Oligonol (100 mg)-containing beverage or placebo beverage before half-body immersion into hot water (42°C±0.5°C for 30 min). Tympanic and skin temperatures were measured and mean body temperatures were calculated. Serum concentrations of PGE2 and COX-2 were analyzed before, immediately after, and 60 min after immersion. Oligonol intake significantly prevented elevation of tympanic (temperature difference: 0.17°C at Post, Pbody temperatures (temperature difference: 0.18°C at Post, Pbody temperature under heat stress, and this is associated with decreases in serum levels of PGE2 and COX-2.

Thiyl radical-induced cis-trans-isomerization of arachidonic acid inhibits prostaglandin metabolism

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Kratzsch, S.; Droessler, K.; Sprinz, H.; Brede, O.

2002-01-01

Complete text of publication follows. Thiyl radicals radiolytically generated from thiophenol in methanolic solution are known to isomerise double bonds of poly-unsaturated fatty acids (PUFA). γ-irradiating of such a system containing all-cis 5,8,11,14 eicosatetraenoic acid (arachidonic acid, AA) with low doses (0.1-0.8 kGy) results in a mixture of 8 to 32% mono-trans-isomers. Here we report about the influence of mono-trans-AA on the primary steps of AA-metabolism and prostaglandin synthesis, catalysed by cyclooxygenase (COX). In the cell-free model system the reaction of COX-1 with AA was analysed by controlling the oxygen level during the enzymatic reaction. As an example, a mixture of a low quantity of mono-trans-isomerized AA (10%) and 90% all-cis-isomer exhibits a marked reduced oxygen consumption by 45%. As further proofs - the yield of reactive oxygen species (ROS) generated by the COX-coupled peroxidase reaction was detected, - and the COX-1 activity in presence of different amounts of trans-AA was characterized using a photometric assay based on the oxidation of TMPD. All these methods indicated semiquantitatively a reduced activity of COX-1, depending on the trans-isomer yield. Therefore, an inhibition of COX-1 activity by only one trans-double-bond in AA could be concluded. Furthermore, in vitro cell-line experiments were performed analysing the influence of mono-trans-isomerized AA on the activity of the cell-own COX-2. Hence, VD 3 -differentiated and LPS-stimulated monocyte-like cells were incubated with mono-trans-AA and ROS-production was detected by the chemiluminescence measurements mentioned above. Compared to the reaction with all-cis-AA we found a considerable lowered formation of ROS. Likewise, we obtained a reduced PGE 2 -expression between 15 and 40% for cells treated with 8 to 29% trans-AA. The model as well as in vivo experiments demonstrate an inhibition effect of mono-trans-AA and give rise for postulating an enzyme blocking mechanism

COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function

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Veltman, Joris D; Lambers, Margaretha EH; Nimwegen, Menno van; Hendriks, Rudi W; Hoogsteden, Henk C; Aerts, Joachim GJV; Hegmans, Joost PJJ

2010-01-01

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that accumulates in tumour-bearing hosts. These cells are induced by tumour-derived factors (e.g. prostaglandins) and have a critical role in immune suppression. MDSC suppress T and NK cell function via increased expression of arginase I and production of reactive oxygen species (ROS) and nitric oxide (NO). Immune suppression by MDSC was found to be one of the main factors for immunotherapy insufficiency. Here we investigate if the in vivo immunoregulatory function of MDSC can be reversed by inhibiting prostaglandin synthesis by specific COX-2 inhibition focussing on ROS production by MDSC subtypes. In addition, we determined if dietary celecoxib treatment leads to refinement of immunotherapeutic strategies. MDSC numbers and function were analysed during tumour progression in a murine model for mesothelioma. Mice were inoculated with mesothelioma tumour cells and treated with cyclooxygenase-2 (COX-2) inhibitor celecoxib, either as single agent or in combination with dendritic cell-based immunotherapy. We found that large numbers of infiltrating MDSC co-localise with COX-2 expression in those areas where tumour growth takes place. Celecoxib reduced prostaglandin E2 levels in vitro and in vivo. Treatment of tumour-bearing mice with dietary celecoxib prevented the local and systemic expansion of all MDSC subtypes. The function of MDSC was impaired as was noticed by reduced levels of ROS and NO and reversal of T cell tolerance; resulting in refinement of immunotherapy. We conclude that celecoxib is a powerful tool to improve dendritic cell-based immunotherapy and is associated with a reduction in the numbers and suppressive function of MDSC. These data suggest that immunotherapy approaches benefit from simultaneously blocking cyclooxygenase-2 activity

Synergistic Induction of Cyclooxygenase-2 by Transforming Growth Factor-β1 and Epidermal Growth Factor Inhibits Apoptosis in Epithelial Cells

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Debabrata Saha

1999-12-01

Full Text Available Increased expression of cyclooxygenase-2 (COX-2 expression has been observed in several human tumor types and in selected animal and cell culture models of carcinogenesis, including lung cancer. Increased expression of COX-2 and production of prostaglandins appear to provide a survival advantage to transformed cells through the inhibition of apoptosis, increased attachment to extracellular matrix, increased invasiveness, the stimulation of angiogenesis. In the present studies, we found that transforming growth factor β1 (TGF-β1 and epidermal growth factor (EGF synergistically induced the expression of COX-2 and prostaglandin E2 (PGE2 production in mink lung epithelial (Mvi Lu cells. EGF, but not PDGF or IGF-1, was able to inhibit TGF-β1-induced apoptosis in Mvi Lu cells and this effect was blocked by NS-398, a selective inhibitor of COX-2 activity, suggesting a possible role for COX-2 in the anti-apoptosic effect of EGF receptor ligands. The combination of TGF-β1 and EGF also significantly induced COX-2 expression in rat intestinal epithelial (RIE-1 cells and completely prevented sodium butyrate (NaBu-induced apoptosis. The synergistic induction of COX-2 by TGF-β1 and EGF was not observed in R1B-L17 cells, a line derived from Mvi Lu cells that lacks the TGF-β type-I receptor. AG1478, a selective inhibitor of EGF receptor tyrosine kinase activity, completely suppressed the induction of COX-2 expression by either EGF or TGF-β1+EGF. Also, PD98059, a specific inhibitor of MEK/ERK pathway, SB203580, a specific inhibitor of p38 MAPK activity, significantly inhibited the induction of COX-2 in response to combined EGF and TGF-β1. These results suggest an important collaborative interaction of TGF-β1 and EGF signaling in the induction of COX-2 and prostaglandin production in Mv1Lu cells.

Matrix metalloproteinase activity and prostaglandin E2 are elevated in the synovial fluid of meniscus tear patients.

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Liu, Betty; Goode, Adam P; Carter, Teralyn E; Utturkar, Gangadhar M; Huebner, Janet L; Taylor, Dean C; Moorman, Claude T; Garrett, William E; Kraus, Virginia B; Guilak, Farshid; DeFrate, Louis E; McNulty, Amy L

Meniscus tears are a common knee injury and are associated with the development of post-traumatic osteoarthritis (OA). The purpose of this study is to evaluate potential OA mediators in the synovial fluid and serum of meniscus tear subjects compared to those in the synovial fluid of radiographic non-OA control knees. Sixteen subjects with an isolated unilateral meniscus injury and six subjects who served as reference controls (knee Kellgren-Lawrence grade 0-1) were recruited. Twenty-one biomarkers were measured in serum from meniscus tear subjects and in synovial fluid from both groups. Meniscus tear subjects were further stratified by tear type to assess differences in biomarker levels. Synovial fluid total matrix metalloproteinase (MMP) activity and prostaglandin E2 (PGE2) were increased 25-fold and 290-fold, respectively, in meniscus tear subjects as compared to reference controls (p meniscus tear subjects (R = 0.83, p meniscus tear subjects, synovial fluid levels of MMP activity, MMP-2, MMP-3, sGAG, COMP, IL-6, and PGE2 were higher than serum levels (p meniscus tears had higher synovial fluid MMP-10 (p meniscus injury may be targets to promote meniscus repair and prevent OA development.

Enzymatic synthesis of tritium-labelled prostaglandin D2 and its conversion to other prostaglandins

International Nuclear Information System (INIS)

Shram, S.I.; Lazurkina, T.Yu.; Shevchenko, V.P.; Nagaev, I.Yu.; Myasoedov, N.F.

1994-01-01

The one-stage enzymatic synthesis of tritium-labelled prostaglandin D 2 from labelled arachidonic acid was performed by using the enzyme system PGH-synthetase/PGH-PGD-isomerase. By enzymatic and chemical transformation of [ 3 H]PGD 2 the following compounds were obtained: 15-keto-13,14-dihydro-[ 3 H]PGD 2 , 9α,11β-[ 3 H]PGF 2 , 9-deoxy-Δ 9 -[ 3 H]-PGD 2 ([ 3 H]PGJ 2 ) and Δ 12 -13,14-dihydro-[ 3 H]PGJ 2 . It was found that L-selectride is a more effective reducing agent than sodium borohydride in the synthesis of 9α, 11β-[ 3 H]PGF 2 . (Author)

Lung Myofibroblasts Are Characterized by Down-Regulated Cyclooxygenase-2 and Its Main Metabolite, Prostaglandin E2

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Gabasa, Marta; Royo, Dolores; Molina-Molina, Maria; Roca-Ferrer, Jordi; Pujols, Laura; Picado, Cesar

2013-01-01

Background Prostaglandin E2 (PGE2), the main metabolite of cyclooxygenase (COX), is a well-known anti-fibrotic agent. Moreover, myofibroblasts expressing α-smooth muscle actin (α-SMA), fibroblast expansion and epithelial-mesenchymal transition (EMT) are critical to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our aim was to investigate the expression of COX-2 and PGE2 in human lung myofibroblasts and establish whether fibroblast-myofibroblast transition (FMT) and EMT are associated with COX-2 and PGE2 down-regulation. Methods Fibroblasts obtained from IPF patients (n = 6) and patients undergoing spontaneous pneumothorax (control, n = 6) and alveolar epithelial cell line A549 were incubated with TGF-β1 and FMT and EMT markers were evaluated. COX-2 and α-SMA expression, PGE2 secretion and cell proliferation were measured after IL-1β and PGE2 incubation. Results Myofibroblasts from both control and IPF fibroblast cultures stimulated with IL-1β showed no COX-2 expression. IPF fibroblasts showed increased myofibroblast population and reduced COX-2 expression in response to IL-1β. TGF-β1 increased the number of myofibroblasts in a time-dependent manner. In contrast, TGF-β1 induced slight COX-2 expression at 4 h (without increase in myofibroblasts) and 24 h, but not at 72 h. Both IPF and control cultures incubated with TGF-β1 for 72 h showed diminished COX-2 induction, PGE2 secretion and α-SMA expression after IL-1β addition. The latter decreased proliferation in fibroblasts but not in myofibroblasts. A549 cells incubated with TGF-β1 for 72 h showed down-regulated COX-2 expression and low basal PGE2 secretion in response to IL-1β. Immuno-histochemical analysis of IPF lung tissue showed no COX-2 immuno-reactivity in myofibroblast foci. Conclusions Myofibroblasts are associated with COX-2 down-regulation and reduced PGE2 production, which could be crucial in IPF development and progression. PMID:23755232

Saliva, Serum Levels of Interleukin-21, -33 and Prostaglandin E2 in Patients with Generalised Aggressive or Chronic Periodontitis.

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Gümüş, Pınar; Nizam, Nejat; Nalbantsoy, Ayşe; Özçaka, Özgün; Buduneli, Nurcan

This cross-sectional study aims to evaluate saliva, serum levels of interleukin-21 (IL-21), IL-33, and prostaglandin E2 (PGE2) in patients with generalised chronic periodontitis or aggressive periodontitis. Before initiation of any periodontal treatment, saliva and serum samples were collected and clinical periodontal measurements were recorded from 94 participants (25 aggressive periodontitis patients, 25 chronic periodontitis patients, 44 periodontally healthy individuals). IL-21, IL-33 and PGE2 levels in serum and saliva samples were determined by ELISA. Data were tested statistically using Kruskal-Wallis, Mann-Whitney U-, and Spearman-rho rank tests. Saliva IL-33 levels were statistically significantly higher in the chronic than the aggressive group (p periodontitis groups. Saliva IL-33 levels correlated with age in the chronic periodontitis group (p periodontitis groups (p chronic and aggressive periodontitis, but the present findings support the role of these cytokines in periodontitis. Statistically significantly higher saliva IL-33 levels in the chronic periodontitis group warrant further research.

Methodologic problems in the radioimmunoassay of prostaglandin E2 and Fsub(2α) in human urine

International Nuclear Information System (INIS)

Ciabattoni, G.; Pugliese, F.; Cinotti, G.A.; Patrono, C.

1979-01-01

Validation of RIA measurement of urinary prostaglandins cannot rely upon classical criteria of specificity, such as dilution studies, since different antisera meeting such requirement may recognize a variable proportion of different compounds accompanying PGE 2 through extraction purification procedures. Validation should therefore be sought by comparison with an independent method of analysis (GC/MS) and/or characterization of the TLC behaviour of PG-LI. Storage of urine before extraction may variably affect PG concentration, as a function of temperature and time. In order to avoid variable losses, urine should be frozen immediately after voiding and kept at -20 0 C until extraction. Urinary PG excretion rate is highly variable during human menstrual cycle, with no apparent pattern. A higher degree of reproducibility was found when 2-h specimens were collected under standard conditions of hydration and immediately frozen. 2-h collections may represent a convenient method to investigate physiological and pharmacological factors controlling urinary PG excretion in healthy subjects. (Auth.)

Synthesis and Antimycobacterial and Photosynthesis-Inhibiting Evaluation of 2-[(E-2-Substituted-ethenyl]-1,3-benzoxazoles

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Ales Imramovsky

2014-01-01

Full Text Available A series of twelve 2-[(E-2-substituted-ethenyl]-1,3-benzoxazoles was designed. All the synthesized compounds were tested against three mycobacterial strains. The compounds were also evaluated for their ability to inhibit photosynthetic electron transport (PET in spinach (Spinacia oleracea L. chloroplasts. 2-[(E-2-(4-Methoxyphenylethenyl]-1,3-benzoxazole, 2-[(E-2-(2,3-dihydro-1-benzofuran-5-ylethenyl]-1,3-benzoxazole and 2-{(E-2-[4-(methylsulfanylphenyl]ethenyl}-1,3-benzoxazole showed the highest activity against M. tuberculosis, M. kansasii, and M. avium, and they demonstrated significantly higher activity against M. avium and M. kansasii than isoniazid. The PET-inhibiting activity of the most active ortho-substituted compound 2-[(E-2-(2-methoxyphenylethenyl]-1,3-benzoxazole was IC50 = 76.3 μmol/L, while the PET-inhibiting activity of para-substituted compounds was significantly lower. The site of inhibitory action of tested compounds is situated on the donor side of photosystem II. The structure-activity relationships are discussed.

Prostaglandin H synthase-mediated bioactivation of the amino acid pyrolysate product Trp P-2

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Petry, T.W.; Krauss, R.S.; Eling, T.E.

1986-08-01

We report evidence that the mutagen and carcinogen 3-amino-1-methyl-5H pyrido(4,3b)indole (Trp P-2) is a substrate for co-oxidation by prostaglandin H synthase (PHS) in ram seminal vesicle (RSV) microsomes. Trp P-2 serves as a reducing cofactor for the hydroperoxidase activity of PHS as shown by the concentration-dependent inhibition of the hydroperoxidase catalyzed incorporation of molecular oxygen into phenylbutazone. Spectral data suggest that this metabolism results in disruption of the double bond conjugation within the nucleus of the molecule. A single metabolite peak which was dependent upon arachidonic acid and substrate concentration was separated from the parent compound by h.p.l.c. following incubation with RSV microsomes. Co-oxidation of Trp P-2 produced reactive intermediates which bound covalently to microsomal protein (9 nmol/mg) and to calf thymus DNA (475 pmol/mg). Binding was inhibited by indomethacin, and supported by substitution of hydrogen peroxide for arachidonic acid. These data suggest a possible role for PHS in the in situ activation of Trp P-2 to its ultimate carcinogenic form in tissues which contain PHS.

The effects of prostaglandin E2 in growing rats - Increased metaphyseal hard tissue and cortico-endosteal bone formation

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Jee, W. S. S.; Ueno, K.; Deng, Y. P.; Woodbury, D. M.

1985-01-01

The role of in vivo prostaglandin E2 (PGE2) in bone formation is investigated. Twenty-five male Sprague-Dawley rats weighing between 223-267 g were injected subcutaneously with 0.3, 1.0, 3.0, and 6.0 mg of PGE2-kg daily for 21 days. The processing of the tibiae for observation is described. Radiographs and histomorphometric analyses are also utilized to study bone formation. Body weight, weights of soft tissues and bones morphometry are evaluated. It is observed that PGE2 depressed longitudinal bone growth, increased growth cartilage thickness, decreased degenerative cartilage cell size and cartilage cell production, and significantly increased proximal tibial metaphyseal hard tissue mass. The data reveal that periosteal bone formation is slowed down at higher doses of PGE2 and endosteal bone formation is slightly depressed less than 10 days post injection; however, here is a late increase (10 days after post injection) in endosteal bone formation and in the formation of trabecular bone in the marrow cavity of the tibial shaft. It is noted that the effects of PGE2 on bone formation are similar to the responses of weaning rats to PGE2.

In vitro anti-inflammatory activity of carvacrol: Inhibitory effect on COX-2 catalyzed prostaglandin E-2 biosynthesis

Czech Academy of Sciences Publication Activity Database

Landa, Přemysl; Kokoška, L.; Přibylová, Marie; Vaněk, Tomáš; Maršík, Petr

2009-01-01

Roč. 32, č. 1 (2009), s. 75-78 ISSN 0253-6269 R&D Projects: GA ČR GA525/08/1179; GA MŠk 1P04OC926.001 Institutional research plan: CEZ:AV0Z50380511 Keywords : Carvacrol * Cyclooxygenase * Prostaglandin Subject RIV: GM - Food Processing Impact factor: 1.159, year: 2009

Inhibition of release of inflammatory mediators in primary and cultured cells by a Chinese herbal medicine formula for allergic rhinitis

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McPhee Sarah

2007-02-01

Full Text Available Abstract Background We demonstrated that a Chinese herbal formula, which we refer to as RCM-101, developed from a traditional Chinese medicine formula, reduced nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR. The present study in primary and cultured cells was undertaken to investigate the effects of RCM-101 on the production/release of inflammatory mediators known to be involved in SAR. Methods Compound 48/80-induced histamine release was studied in rat peritoneal mast cells. Production of leukotriene B4 induced by the calcium ionophore A23187 was studied in porcine neutrophils using an HPLC assay and lipopolysaccharide-stimulated prostaglandin E2 production was studied in murine macrophage (Raw 264.7 cells by immune-enzyme assay. Expression of cyclooxygenase-1 (COX-1 and cyclooxygenase-2 (COX-2 was determined in Raw 264.7 cells, using western blotting techniques. Results RCM-101 (1–100 μg/mL produced concentration-dependent inhibition of compound 48/80-induced histamine release from rat peritoneal mast cells and of lipopolysaccharide-stimulated prostaglandin E2 release from Raw 264.7 cells. Over the range 1 – 10 μg/mL, it inhibited A23187-induced leukotriene B4 production in porcine neutrophils. In addition, RCM-101 (100 μg/mL inhibited the expression of COX-2 protein but did not affect that of COX-1. Conclusion The findings indicate that RCM-101 inhibits the release and/or synthesis of histamine, leukotriene B4 and prostaglandin E2 in cultured cells. These interactions of RCM-101 with multiple inflammatory mediators are likely to be related to its ability to reduce symptoms of allergic rhinitis.

Effects of indomethacin on plasma homovanillic acid concentration in normal subjects: a study of prostaglandin-dopamine interactions.

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Kahn, R S; Davidson, M; Kanof, P; McQueeney, R T; Singh, R R; Davis, K L

1991-01-01

In laboratory animals, prostaglandins have been shown to act as endogenous neuromodulators of central dopamine (DA) activity. To examine the interaction between prostaglandins and DA in man, the effect of a prostaglandin synthesis inhibitor, indomethacin, was studied on plasma concentrations of the DA metabolite, homovanillic acid (pHVA). Indomethacin (150 mg PO) as compared to placebo significantly elevated mean pHVA concentrations in eight normal subjects. Results of this study support the hypothesis that, as in animals, inhibition of prostaglandin synthesis increases central DA turnover in man.

Evaluation of peri-implant crevicular fluid prostaglandin E2 levels in augmented extraction sockets by different biomaterials.

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Alkan, Eylem Ayhan; Tüter, Gülay; Parlar, Ateş; Yücel, Ayşegül; Kurtiş, Bülent

2016-10-01

This study compares peri-implant crevicular fluid (PICF) prostaglandin E 2 (PGE 2 ) levels, clinical parameters and implant stability quotient (ISQ) values around implants placed in augmented extraction sockets. The sockets (24 in total) were randomly augmented using either EMD or Bio-Oss Collagen. Implant placements were performed after three months of healing. ISQ readings were evaluated at three points: at the time of surgery, at the first month and at the third month. PICF was collected for PGE 2 evaluation after the first and the third months of implant surgery. After the first month, a higher level of PICF PGE 2 was observed in the EMD group than in the Bio-Oss Collagen group, and this increase was of statistical significance; however, at the third month there was no statistically significant difference in PICF PGE 2 levels between the two groups. For implants placed in EMD sites, ISQ values were statistically higher at the third month than at the first month, while no significant differences in ISQ value were detected between the first and third months in Bio-Oss Collagen sites. The results of this research suggest that both EMD and Bio-Oss Collagen are effective treatment modalities for stimulating the formation of new bone at extraction sites prior to implant surgery.

Inhibition of the entomopathogenic fungus Metarhizium anisopliae in vitro by the bed bug defensive secretions (E)-2-hexenal and (E)-2-octenal

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The two major aldehydes (E)-2-hexenal and (E)-2-octenal emitted as defensive secretions by bed bugs Cimex lectularius L. (Hemiptera: Cimicidae), inhibit the in vitro growth of Metarhizium anisopliae (Metsch.) Sokorin (Hypocreales: Clavicipitaceae). These chemicals inhibit fungal growth by direct con...

Modulation of enhanced vascular permeability by prostaglandins through alterations in blood flow (hyperemia). [/sup 85/Sr tracer technique

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Johnston, M G; Hay, J B; Movat, H Z

1976-11-01

The enhanced vascular permeability induced by histamine or bradykinin in the skin of the guinea-pig and rabbit was significantly augmented by small amounts of prostaglandins of the E type. When injected alone these prostaglandins had little effect on vascular permeability. Furthermore, E type prostaglandins were found to be more potent at inducing hyperemia than either histamine or bradykinin. Prostaglandin F/sub 2/ alpha did not enhance the vascular permeability induced by histamine or bradykinin nor did it produce hyperemia in the skin. In the rat, prostaglandins alone enhanced vascular permeability but they also increased the effect of histamine, serotonin and bradykinin. Using /sup 85/Sr-microspheres to measure blood flow a correlation was found between the degree of hyperemia produced by prostaglandins and the degree to which they augmented enhanced vascular permeability due to histamine, serotonin or bradykinin. Prostaglandins therefore can directly mimic the hyperemia of the inflammatory process and can also modulate the changes in vascular permeability caused by other mediators of inflammation.

16,16-dimethyl prostaglandin E2 increases survival of murine intestinal stem cells when given before photon radiation

International Nuclear Information System (INIS)

Hanson, W.R.; Thomas, C.

1983-01-01

A variety of prostaglandins (PG) protect the gastric and intestinal mucosa when given before damaging agents as absolute ethanol, acidified taurocholate, boiling water, or nonsteroidal anti-inflammatory agents (NSAI). A synthetic prostaglandin, 16,16-dimethyl PGE 2 , shown to be cytoprotective at physiologic levels to the above agents was given to mice 1 h before or 15 min after 137 Cs gamma(γ) whole-body irradiation. The survival of intestinal stem cells measured by their ability to form in situ colonies of regenerating epithelium was increased stem cells measured by their ability to form in situ colonies of regenerating epithelium was increased when 16,16-dimethyl PGE 2 was given before but not after 137 Cs γ irradiation. The maximum degree of 16,16-dimethyl PGE 2 -induced radioprotection was seen when the drug was given 1 h before irradiation. No radioprotection was seen when the interval between drug and irradiation was 3 h or longer. When the time between 16,16-dimethyl PGE 2 and irradiation was kept at 1 h, the degree of radioprotection was dependent on the PG drug dose. There was a steep rise in the number of surviving cells at low doses of PG. These results imply that tumors which secrete PGE 2 may in part be protected from the lethal effects of ionizing photon radiation

TGF-β2 inhibits AKT activation and FGF-2-induced corneal endothelial cell proliferation

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Lu Jiawei; Lu Zhenyu; Reinach, Peter

2006-01-01

The corneal endothelial cells form a boundary layer between anterior chamber and cornea. This single cell layer is important to maintain cornea transparency by eliciting net fluid transport into the anterior chamber. Injuries of the corneal endothelial layer in humans lead to corneal swelling and translucence. This hindrance is thought to be due to limited proliferative capacity of the endothelial layer. Fibroblast growth factor 2 (FGF-2) and transforming growth factor-beta 2 (TGF-β2) are both found in aqueous humor, and these two cytokines promote and inhibit cell growth, respectively. The intracellular signaling mechanisms by which TGF-β2 suppresses the mitogenic response to FGF-2, however, remain unclear. We have addressed this question by investigating potential crosstalk between FGF-2-induced and TGF-β2-regulated intracellular signaling events in cultured bovine corneal endothelial (BCE) cells. We found that TGF-β2 and FGF-2 oppositely affect BCE cell proliferation and TGF-β2 can override the stimulating effects of FGF-2 by increasing COX-2 expression in these cells. Consistent with these findings, overexpression of COX-2 significantly reduced FGF-2-induced cell proliferation whereas a COX-2 specific inhibitor NS398 reversed the effect of TGF-β2 on FGF-2-induced cell proliferation. The COX-2 product prostaglandin E2 (PGE-2) blocks FGF-2-induced cell proliferation. Whereas FGF-2 stimulates cell proliferation by activating the AKT pathway, TGF-β2 and PGE-2 both inhibit this pathway. In accordance with the effect of PGE-2, cAMP also inhibits FGF-2-induced AKT activation. These findings suggest that the mitogenic response to FGF-2 in vivo in the corneal endothelial layer may be inhibited by TGF-β2-induced suppression of the PI3-kinase/AKT signaling pathway

Prostaglandin E2 Activates YAP and a Positive-Signaling Loop to Promote Colon Regeneration After Colitis but Also Carcinogenesis in Mice.

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Kim, Han-Byul; Kim, Minchul; Park, Young-Soo; Park, Intae; Kim, Tackhoon; Yang, Sung-Yeun; Cho, Charles J; Hwang, DaeHee; Jung, Jin-Hak; Markowitz, Sanford D; Hwang, Sung Wook; Yang, Suk-Kyun; Lim, Dae-Sik; Myung, Seung-Jae

2017-02-01

Prostaglandin E 2 (PGE 2 ) is mediator of inflammation that regulates tissue regeneration, but its continual activation has been associated with carcinogenesis. Little is known about factors in the PGE 2 signaling pathway that contribute to tumor formation. We investigated whether yes-associated protein 1 (YAP1), a transcriptional co-activator in the Hippo signaling pathway, mediates PGE 2 function. DLD-1 and SW480 colon cancer cell lines were transfected with vectors expressing transgenes or small hairpin RNAs and incubated with recombinant PGE 2 , with or without pharmacologic inhibitors of signaling proteins, and analyzed by immunoblot, immunofluorescence, quantitative reverse-transcription polymerase chain reaction, transcriptional reporter, and proliferation assays. Dextran sodium sulfate (DSS) was given to induce colitis in C57/BL6 (control) mice, as well as in mice with disruption of the hydroxyprostaglandin dehydrogenase 15 gene (15-PGDH-knockout mice), Yap1 gene (YAP-knockout mice), and double-knockout mice. Some mice also were given indomethacin to block PGE 2 synthesis. 15-PGDH knockout mice were crossed with mice with intestine-specific disruption of the salvador family WW domain containing 1 gene (Sav1), which encodes an activator of Hippo signaling. We performed immunohistochemical analyses of colon biopsy samples from 26 patients with colitis-associated cancer and 51 age-and sex-matched patients with colorectal cancer (without colitis). Incubation of colon cancer cell lines with PGE 2 led to phosphorylation of cyclic adenosine monophosphate-responsive element binding protein 1 and increased levels of YAP1 messenger RNA, protein, and YAP1 transcriptional activity. This led to increased transcription of the prostaglandin-endoperoxide synthase 2 gene (PTGS2 or cyclooxygenase 2) and prostaglandin E-receptor 4 gene (PTGER4 or EP4). Incubation with PGE 2 promoted proliferation of colon cancer cell lines, but not cells with knockdown of YAP1. Control mice

Role of adrenal hormones and prostaglandins in the control of mouse thymocytes lysis.

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Durant, S; Seillan, C; Duval, D; Homo-Delarche, F

1984-01-01

The cytolytic actions of glucocorticoids and of agents increasing cyclic AMP were studied in vitro in thymocyte suspensions isolated from adrenalectomized or hydrocortisone-treated mice. Although considered as corticoresistant cells, the thymocytes isolated from hydrocortisone-treated mice were lysed to the same extent although more slowly in vitro by dexamethasone than whole thymocyte populations (i.e. corticosensitive cells). Moreover, these two cell populations were shown to contain comparable amounts of glucocorticoid receptors and to be almost equally sensitive to the metabolic effects of glucocorticoids when measured by inhibition of RNA and DNA synthesis. Studies performed with corticosensitive cells showed that prostaglandin E2, isoproterenol and dibutyrilcyclic AMP were also able to induce cell lysis and that, isoproterenol and dexamethasone exerted additive cytolytic action in vitro. In vivo experiments showed also an additive effect of steroids and isoproterenol on thymus atrophy. In contrast, cells isolated from hydrocortisone-treated animals were not sensitive to the cytotoxic action of prostaglandin E2, isoproterenol and dibutyril cyclic AMP. This difference between the two populations was not associated with any difference in the responsiveness of adenylate cyclase as determined following isoproterenol-induced accumulation of cyclic AMP. The cytolytic action of dexamethasone but also that of prostaglandin E2 and isoproterenol, could be blocked in the presence of cycloheximide, an inhibitor of protein synthesis, thus suggesting that glucocorticoids and agents increasing cyclic AMP control the synthesis of some proteins involved in the triggering of cell lysis. Among the hypotheses proposed to explain the differences between in vitro and in vivo sensitivity of lymphoid cell to glucocorticoids, it was suggested that the drug may in vivo indirectly control the viability or the proliferation of thymocytes through the release of other mediators. We have

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

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

2012-01-01

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

Presence of crevicular fluid Prostaglandin E2 in relation with clinical and radiographic periodontal status

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Javier Elpidio Monzón

2016-07-01

Full Text Available Background and Objectives: Prostaglandin E2 (PGE2 is present in gingival crevicular fluid the (GCF and is evidenced in periodontal disease (PD. However, there are no enough reports to correlate the PGE2 concentrations in GCF in periodontal health and disease with clinical and radiographic indicators, age and gender. Hence, the present study is aimed to estimate the levels of PGE2 in GCF of subjects without periodontal disease (SEP and periodontal disease (CEP. Materials and Methods: 99 subjects were selected, 33 without PD (G1 and 66 with PD, 33 with gingivitis (G2 and 33 with periodontitis (G3, which were submitted to a clinical and radiographic diagnosis, registering samples FGC, being stored, centrifuged and refrigerated for preservation. Subsequently the concentration of crevicular PGE2 was measured by using the enzyme linked immunosorbent assay (ELISA, determining the concentration of each subject. Results: PGE2 was detected in all the samples. The G1 presented a concentration of 28.82 ± 2.88 pg / mL, G2 44.91 ± 4.37 pg / mL and G3 148.67 ± 74.74 pg / mL (0.0001. PGE2 levels were significantly correlated with bleeding on probing, probing depth, attachment loss and bone loss (0.05. PGE2 levels were modified by age, but not gender. Conclusion: It is well known that activated inflammatory cells produce inflammatory mediators that stimulate the production of PGE2. The findings of this study demonstrate an increased concentration of PGE2 in FCG according to the presence of greater severity of PD. PGE2 may be considered as a biomarker in PD progression. However, controlled, longitudinal studies are needed to confirm this possibility.

Tumor necrosis factor alpha inhibits in vitro bovine embryo development through a prostaglandin mediated mechanism

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Jackson Lauren R

2012-03-01

Full Text Available Abstract Mastitis or other infectious diseases have been related to reduced fertility in cattle. Inflammatory cytokines such as tumor necrosis factor α (TNFα are released in response to infection and may have negative effects on embryo development. In the current study the effect of exposure to TNFα on the development of in vitro fertilized bovine embryos was examined. Indomethacin, a prostaglandin synthesis inhibitor, was used to determine if blockade of prostaglandin synthesis would alter the effects of TNFα. Ovaries were obtained from a local abattoir and immature COC were isolated from 2-10 mm follicles, in vitro matured and fertilized. After fertilization, groups of presumptive zygotes were randomly placed into either control development medium, medium containing 25 ng/mL TNFα or medium containing 25 ng/mL TNFα plus 1 μg/mL indomethacin. The proportion of blastocysts formed was assessed at day 7 of culture. Fewer embryos exposed to TNFα alone reached the blastocyst stage (17.5 ± 2.4%, P

Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins[S

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Subra, Caroline; Grand, David; Laulagnier, Karine; Stella, Alexandre; Lambeau, Gérard; Paillasse, Michael; De Medina, Philippe; Monsarrat, Bernard; Perret, Bertrand; Silvente-Poirot, Sandrine; Poirot, Marc; Record, Michel

2010-01-01

Exosomes are bioactive vesicles released from multivesicular bodies (MVB) by intact cells and participate in intercellular signaling. We investigated the presence of lipid-related proteins and bioactive lipids in RBL-2H3 exosomes. Besides a phospholipid scramblase and a fatty acid binding protein, the exosomes contained the whole set of phospholipases (A2, C, and D) together with interacting proteins such as aldolase A and Hsp 70. They also contained the phospholipase D (PLD) / phosphatidate phosphatase 1 (PAP1) pathway leading to the formation of diglycerides. RBL-2H3 exosomes also carried members of the three phospholipase A2 classes: the calcium-dependent cPLA2-IVA, the calcium-independent iPLA2-VIA, and the secreted sPLA2-IIA and V. Remarkably, almost all members of the Ras GTPase superfamily were present, and incubation of exosomes with GTPγS triggered activation of phospholipase A2 (PLA2)and PLD2. A large panel of free fatty acids, including arachidonic acid (AA) and derivatives such as prostaglandin E2 (PGE2) and 15-deoxy-Δ12,14-prostaglandinJ2 (15-d PGJ2), were detected. We observed that the exosomes were internalized by resting and activated RBL cells and that they accumulated in an endosomal compartment. Endosomal concentrations were in the micromolar range for prostaglandins; i.e., concentrations able to trigger prostaglandin-dependent biological responses. Therefore exosomes are carriers of GTP-activatable phospholipases and lipid mediators from cell to cell. PMID:20424270

Prostaglandin PGE2: a possible mechanism for bone destruction in calcinosis circumscripta.

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Caniggia, A; Gennari, C; Vattimo, A; Runci, F; Bombardieri, S

1978-02-28

A patient showed evident osteolysis in phalanges and heavy periarticular calcium deposits of the fingers, wrists and toes which avidly took up 47Ca. The dense, white, tooth-paste like fluid contained in the periarticular calcium deposits has been studied by two different X-ray diffraction methods, by Ubatuba's bioassay for prostaglandin, by thin layer chromatography and by mass spectrometry. The calcium deposits were hydroxyapatite and prostaglandin PGE2 was detected in them. The bone resorption stimulating activity of PGE2 would be expected to result in increased bone destruction with release of calcium salts and this could be a working hypothesis of the pathogenesis of calcinosis circumscripta.

Identification of Francisella novicida mutants that fail to induce prostaglandin E2 synthesis by infected macrophages.

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Matthew Dale Woolard

2013-02-01

Full Text Available Francisella tularensis is the causative agent of tularemia. We have previously shown that infection with F. tularensis Live Vaccine Strain (LVS induces macrophages to synthesize prostaglandin E2 (PGE2. Synthesis of PGE2 by F. tularensis infected macrophages results in decreased T cell proliferation in vitro and increased bacterial survival in vivo. Although we understand some of the biological consequences of F. tularensis induced PGE2 synthesis by macrophages, we do not understand the cellular pathways (neither host nor bacterial that result in up-regulation of the PGE2 biosynthetic pathway in F. tularensis infected macrophages. We took a genetic approach to begin to understand the molecular mechanisms of bacterial induction of PGE2 synthesis from infected macrophages. To identify F. tularensis genes necessary for the induction of PGE2 in primary macrophages, we infected cells with individual mutants from the closely related strain Francisella tularensis subspecies novicida U112 (U112 two allele mutant library. Twenty genes were identified that when disrupted resulted in U112 mutant strains unable to induce the synthesis of PGE2 by infected macrophages. Fourteen of the genes identified are located within the Francisella pathogenicity island (FPI. Genes in the FPI are required for F. tularensis to escape from the phagosome and replicate in the cytosol, which might account for the failure of U112 with transposon insertions within the FPI to induce PGE2. This implies that U112 mutant strains that do not grow intracellularly would also not induce PGE2. We found that U112 clpB::Tn grows within macrophages yet fails to induce PGE2, while U112 pdpA::Tn does not grow yet does induce PGE2. We also found that U112 iglC::Tn neither grows nor induces PGE2. These findings indicate that there is dissociation between intracellular growth and the ability of F. tularensis to induce PGE2 synthesis. These mutants provide a critical entrée into the pathways used

Carbon monoxide is not responsible for the cigarette smokeinduced changes in the pulmonary metabolism of arachidonic acid and prostaglandin E2

International Nuclear Information System (INIS)

Maennistoe, J.; Puustinen, T.; Uotila, P.

1985-01-01

Cigarette smoke is known to interfere with the pulmonary metabolism of arachidomic acid and prostaglandin E 2 (PGE 2 ). We investigated the possible role of carbon monoxide in these cigarette smoke-infuced alterations. 4 C-Arachidonic acid (50 nmol) was indused into the pulmonary circulation of isolated perfused hamster lungs and the radioactive metabolites in the perfusion effluent, as well as the distribution of incorporated radioactive arachidonic acid within the lung lipids, were analysed. Carbon monoxide, added into the ventilatory air, had no effect on the oxidative metabolism of arachidonic acid or on the distribution of radioactive arachidonic acid within the lung. In addition, carbon monoxide had no effect on the metabolism of PGE 2 following infusion of 100 nmol of 14 C-PGE 2 into the rat pulmonary circulation. The present study suggests that carbon monoxide is not responsible for the cigarette smoke-induced changes in the pulmonary metabolism of arachidonic acid and PGE 2 . (author)

Decreased Prostaglandin D2 Levels in Major Depressive Disorder Are Associated with Depression-Like Behaviors.

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Chu, Cuilin; Wei, Hui; Zhu, Wanwan; Shen, Yan; Xu, Qi

2017-09-01

Prostaglandin (PG) D2 is the most abundant prostaglandin in the mammalian brain. The physiological and pharmacological actions of PGD2 in the central nervous system seem to be associated with some of the symptoms exhibited by patients with major depressive disorder. Previous studies have found that PGD2 synthase was decreased in the cerebrospinal fluid of major depressive disorder patients. We speculated that there may be a dysregulation of PGD2 levels in major depressive disorder. Ultra-performance liquid chromatography-tandem mass spectrometry coupled with a stable isotopic-labeled internal standard was used to determine PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice. A total of 32 drug-free major depressive disorder patients and 30 healthy controls were recruited. An animal model of depression was constructed by exposing mice to 5 weeks of chronic unpredictable mild stress. To explore the role of PGD2 in major depressive disorder, selenium tetrachloride was administered to simulate the change in PGD2 levels in mice. Mice exposed to chronic unpredictable mild stress exhibited depression-like behaviors, as indicated by reduced sucrose preference and increased immobility time in the forced swimming test. PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice were both decreased compared with their corresponding controls. Further inhibiting PGD2 production in mice resulted in an increased immobility time in the forced swimming test that could be reversed by imipramine. Decreased PGD2 levels in major depressive disorder are associated with depression-like behaviors. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Effects of nonhypotensive endotoxemia in conscious rats: Role of prostaglandins

International Nuclear Information System (INIS)

Burnier, M.; Waeber, B.; Aubert, J.F.; Nussberger, J.; Brunner, H.R.

1988-01-01

A nonhypotensive dose of endotoxin was administered to normal conscious rats to evaluate the vascular and humoral effects of endotoxemia per se. Mean blood pressure and heart rate remained stable during the 45 min infusion of Escherichia coli endotoxin. However, a marked increase in plasma renin activity plasma epinephrine and plasma norepinephrine was observed during infusion in endotoxin-treated rats when compared with the vehicle-treated animals. In addition, the blood pressure response to exogenous norepinephrine was significantly reduced during nonhypotensive endotoxemia. Significant changes in regional blood flow distribution, as assessed by radiolabeled microspheres, were observed in endotoxemic rats; in particular a decrease in renal blood flow, and an increase in coronary blood flow were found. The role of prostaglandins in the vascular and humoral alterations induced by nonhypotensive endotoxemia was also examined. Pretreatment with indomethacin (5 mg) prevent the increase in plasma renin activity as well as plasma catecholamine levels. On the contrary, the decreased vascular reactivity and the reduction in renal blood flow observed during endotoxemia were not affected by prostaglandin synthesis inhibition. Thus significant vascular and humoral changes have been found during endotoxemia even in absence of hypotension. The humoral but not the vascular effects of endotoxemia were abolished when prostaglandin synthesis was inhibited

Inhibition of mitochondrial division through covalent modification of Drp1 protein by 15 deoxy-Δ12,14-prostaglandin J2

International Nuclear Information System (INIS)

Mishra, Nandita; Kar, Rekha; Singha, Prajjal K.; Venkatachalam, Manjeri A.; McEwen, Donald G.; Saikumar, Pothana

2010-01-01

Arachidonic acid derived endogenous electrophile 15d-PGJ2 has gained much attention in recent years due to its potent anti-proliferative and anti-inflammatory actions mediated through thiol modification of cysteine residues in its target proteins. Here, we show that 15d-PGJ2 at 1 μM concentration converts normal mitochondria into large elongated and interconnected mitochondria through direct binding to mitochondrial fission protein Drp1 and partial inhibition of its GTPase activity. Mitochondrial elongation induced by 15d-PGJ2 is accompanied by increased assembly of Drp1 into large oligomeric complexes through plausible intermolecular interactions. The role of decreased GTPase activity of Drp1 in the formation of large oligomeric complexes is evident when Drp1 is incubated with a non-cleavable GTP analog, GTPγS or by a mutation that inactivated GTPase activity of Drp1 (K38A). The mutation of cysteine residue (Cys644) in the GTPase effector domain, a reported target for modification by reactive electrophiles, to alanine mimicked K38A mutation induced Drp1 oligomerization and mitochondrial elongation, suggesting the importance of cysteine in GED to regulate the GTPase activity and mitochondrial morphology. Interestingly, treatment of K38A and C644A mutants with 15d-PGJ2 resulted in super oligomerization of both mutant Drp1s indicating that 15d-PGJ2 may further stabilize Drp1 oligomers formed by loss of GTPase activity through covalent modification of middle domain cysteine residues. The present study documents for the first time the regulation of a mitochondrial fission activity by a prostaglandin, which will provide clues for understanding the pathological and physiological consequences of accumulation of reactive electrophiles during oxidative stress, inflammation and degeneration.

MEL-18 interacts with HSF2 and the SUMO E2 UBC9 to inhibit HSF2 sumoylation.

Science.gov (United States)

Zhang, Jie; Goodson, Michael L; Hong, Yiling; Sarge, Kevin D

2008-03-21

In a previous study we found that sumoylation of the DNA-binding protein heat shock factor 2 (HSF2) is up-regulated during mitosis, but the mechanism that mediates this regulation was unknown. Here we show that HSF2 interacts with the polycomb protein MEL-18, that this interaction decreases during mitosis, and that overexpression and RNA interference-mediated reduction of MEL-18 result in decreased and increased HSF2 sumoylation, respectively. Other results suggest that MEL-18 may also function to inhibit the sumoylation of other cellular proteins. The results also show that MEL-18 is able to interact with the small ubiquitin-like modifier (SUMO) ubiquitin carrier protein (E2) enzyme UBC9 and that MEL-18 inhibits the ability of UBC9 to transfer the SUMO protein to target proteins. Together, the results in this work suggest a mechanism in which MEL-18 bound to HSF2 inhibits its sumoylation by binding to and inhibiting the activity of UBC9 enzymes in the vicinity of HSF2. These results provide an explanation for how mitotic HSF2 sumoylation is regulated and suggest that MEL-18, in contrast to the sumoylation-stimulating activities of the polycomb protein PC2, actually functions like an anti-SUMO ubiquitin-protein isopeptide ligase (E3), interacting both with HSF2 and the SUMO E2 UBC9 but acting to inhibit UBC9 activity to decrease sumoylation of a target protein, in this case that of HSF2.

16,16-dimethyl prostaglandin E/sub 2/ increases survival of murine intestinal stem cells when given before photon radiation

Energy Technology Data Exchange (ETDEWEB)

Hanson, W.R.; Thomas, C.

1983-11-01

A variety of prostaglandins (PG) protect the gastric and intestinal mucosa when given before damaging agents as absolute ethanol, acidified taurocholate, boiling water, or nonsteroidal anti-inflammatory agents (NSAI). A synthetic prostaglandin, 16,16-dimethyl PGE/sub 2/, shown to be cytoprotective at physiologic levels to the above agents was given to mice 1 h before or 15 min after /sup 137/Cs gamma(..gamma..) whole-body irradiation. The survival of intestinal stem cells measured by their ability to form in situ colonies of regenerating epithelium was increased stem cells measured by their ability to form in situ colonies of regenerating epithelium was increased when 16,16-dimethyl PGE/sub 2/ was given before but not after /sup 137/Cs ..gamma.. irradiation. The maximum degree of 16,16-dimethyl PGE/sub 2/-induced radioprotection was seen when the drug was given 1 h before irradiation. No radioprotection was seen when the interval between drug and irradiation was 3 h or longer. When the time between 16,16-dimethyl PGE/sub 2/ and irradiation was kept at 1 h, the degree of radioprotection was dependent on the PG drug dose. There was a steep rise in the number of surviving cells at low doses of PG. These results imply that tumors which secrete PGE/sub 2/ may in part be protected from the lethal effects of ionizing photon radiation.

Effusanin E suppresses nasopharyngeal carcinoma cell growth by inhibiting NF-κB and COX-2 signaling.

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Mingzhu Zhuang

Full Text Available Rabdosia serra is well known for its antibacterial, anti-inflammatory and antitumor activities, but no information has been available for the active compounds derived from this plant in inhibiting human nasopharyngeal carcinoma (NPC cell growth. In this study, we isolated and purified a natural diterpenoid from Rabdosia serra and identified its chemical structure as effusanin E and elucidated its underlying mechanism of action in inhibiting NPC cell growth. Effusanin E significantly inhibited cell proliferation and induced apoptosis in NPC cells. Effusanin E also induced the cleavage of PARP, caspase-3 and -9 proteins and inhibited the nuclear translocation of p65 NF-κB proteins. Moreover, effusanin E abrogated the binding of NF-κB to the COX-2 promoter, thereby inhibiting the expression and promoter activity of COX-2. Pretreatment with a COX-2 or NF-κB-selective inhibitor (celecoxib or ammonium pyrrolidinedithiocarbamate had an additive effect on the effusanin E-mediated inhibition of proliferation, while pretreatment with an activator of NF-κB/COX-2 (lipopolysaccharides abrogated the effusanin E-mediated inhibition of proliferation. Effusanin E also significantly suppressed tumor growth in a xenograft mouse model without obvious toxicity, furthermore, the expression of p50 NF-κB and COX-2 were down-regulated in the tumors of nude mice. These data suggest that effusanin E suppresses p50/p65 proteins to down-regulate COX-2 expression, thereby inhibiting NPC cell growth. Our findings provide new insights into exploring effusanin E as a potential therapeutic compound for the treatment of human nasopharyngeal carcinoma.

Enzymatic synthesis of tritium-labelled prostaglandin D[sub 2] and its conversion to other prostaglandins

Energy Technology Data Exchange (ETDEWEB)

Shram, S.I.; Lazurkina, T.Yu.; Shevchenko, V.P.; Nagaev, I.Yu.; Myasoedov, N.F. (AN SSSR, Moscow (Russian Federation). Inst. Molekulyarnoj Genetiki)

1994-04-01

The one-stage enzymatic synthesis of tritium-labelled prostaglandin D[sub 2] from labelled arachidonic acid was performed by using the enzyme system PGH-synthetase/PGH-PGD-isomerase. By enzymatic and chemical transformation of [[sup 3]H]PGD[sub 2] the following compounds were obtained: 15-keto-13,14-dihydro-[[sup 3]H]PGD[sub 2], 9[alpha],11[beta]-[[sup 3]H]PGF[sub 2], 9-deoxy-[Delta][sup 9]-[[sup 3]H]-PGD[sub 2] ([[sup 3]H]PGJ[sub 2]) and [Delta][sup 12]-13,14-dihydro-[[sup 3]H]PGJ[sub 2]. It was found that L-selectride is a more effective reducing agent than sodium borohydride in the synthesis of 9[alpha], 11[beta]-[[sup 3]H]PGF[sub 2]. (Author).

Intra-arterial infusion of prostaglandin E1 in normal subjects and patients with peripheral arterial disease

DEFF Research Database (Denmark)

Nielsen, P E; Nielsen, S L; Holstein, P

1976-01-01

Acute vasodilatation was produced by infusion of prostaglandin E1 (PGE1) in the femoral artery in 6 patients with occlusive arterial disease of the legs and in 3 normal subjects. The effect on blood flow and on blood pressure was measured at different segments of the leg with the strain gauge...

Gastric bicarbonate secretion and release of prostaglandin E2 are increased in duodenal ulcer patients, but not in Helicobacter pylori positive healthy subjects

DEFF Research Database (Denmark)

A, Mertz-Nielsen; Hillingsø, Jens; Frøkiær, Hanne

1996-01-01

Background: Duodenal ulcer (DU) patients have impaired proximal duodenal mucosal bicarbonate secretion at rest and in response to luminal acid with higher acid-stimulated mucosal release of prostaglandin (PG) E(2) than healthy subjects. Our purpose was to determine whether this abnormality...... was present also in the stomach of DU patients. Methods: Simultaneous determinations of gastric and duodenal bicarbonate secretion and luminal release of PGE(2) were performed in 16 healthy volunteers (5 Helicobacter pylori-positive) and 8 inactive DU patients (all H. pylori-positivr). Results: In healthy...... be responsible for the abnormally high gastric secretion of bicarbonate in inactive DU patients. Th; defective duodenal secretion of bicarbonate observed in these patients may be a consequence of previous ulceration rather than the mere presence of H. pylori infection....

[Effects of exogenous prostaglandin E2 on collagen content of Achilles tendon of rabbits in vivo].

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Li, Hui; Tang, Kanglai; Deng, Yinshuan; Xie, Meiming; Chang, Dehai; Tao, Xu; Xu, Jianzhong

2012-03-01

Prostaglandin E2 (PGE2) production increases in human tendon fibroblasts after the tendon injuries and repetitive mechanical loading in vitro. To analyze the relations between PGE2 and tendinopathy by observing the changes of collagen content and proportion after the Achilles tendon of rabbits is repeatedly exposed to PGE2. Twenty-four Japanese rabbits (aged 3-4 months, weighing 2.0-2.5 kg, and male or female) were equally randomized into 2 groups according to injection dose of PGE2: low dose group (50 ng) and high dose group (500 ng). Corresponding PGE2 (0.2 mL) was injected into the middle segment of the Achilles tendon of hindlimb, the same dose saline into the same site of the other side as controls once a week for 4 weeks or 8 weeks. The Achilles tendons were harvested at 4 and 8 weeks after injection. HE staining was used to observe the cell structure and matrix, and picric acid-sirius red staining to observe the distribution and types of collagen fibers, and transmission electron microscopy was used to measure the density of the unit area and diameter of collagen fibers. HE staining showed that collagen structural damage was observed in low dose and high dose groups. Picric acid-sirius red staining showed that the content of type I collagen significantly decreased while the content of type III collagen significantly increased in experimental side of 2 groups at 4 and 8 weeks after injection when compared with control sides (P Achilles tendon of rabbit to PGE2 can cause the decrease of type I collagen, the increase of type III collagen, the reverse ratio of type I to type III, reduced unit density of collagen fibers, and thinner collagen fibers diameter, which is related with tendinopathy.

Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration

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Maria Emilia Figueiredo-Pereira

2015-01-01

Full Text Available The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia and prion diseases. Cyclooxygenases (COX -1 and COX-2, which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1 exert their actions, (2 potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3 disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4 contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury, and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects.

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

DEFF Research Database (Denmark)

Myren, Maja; Olesen, Jes; Gupta, Saurabh

2012-01-01

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

A novel antipyretic action of 15-deoxy-Delta12,14-prostaglandin J2 in the rat brain.

Science.gov (United States)

Mouihate, Abdeslam; Boissé, Lysa; Pittman, Quentin J

2004-02-11

Fever is an important part of the host defense response, yet fever can be detrimental if it is uncontrolled. We provide the first evidence that 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), can attenuate the febrile response to lipopolysaccharide (LPS) in rats via an action on the brain. Furthermore, we show that PPARgamma is expressed in the hypothalamus, an important locus in the brain for fever generation. In addition, 15d-PGJ2 and its synthesizing enzyme (PGD2 synthase) were present in rat cerebrospinal fluid, and their levels were enhanced in response to systemic injection of LPS. The antipyretic effect of 15d-PGJ2 was associated with reduction in LPS-stimulated cyclooxygenase-2 expression in the hypothalamus but not in p44/p42 mitogen-activated protein kinase phosphorylation or in the expression of the PPARgamma. Thus it is likely that there is a parallel induction of an endogenous prostanoid pathway in the brain capable of limiting deleterious actions of the proinflammatory prostaglandin E2-dependent pathway.

Oleamide suppresses lipopolysaccharide-induced expression of iNOS and COX-2 through inhibition of NF-kappaB activation in BV2 murine microglial cells.

Science.gov (United States)

Oh, Young Taek; Lee, Jung Yeon; Lee, Jinhwa; Lee, Ju Hie; Kim, Ja-Eun; Ha, Joohun; Kang, Insug

2010-05-03

Oleamide (cis-9-octadecenamide) is an endogenous sleep-inducing fatty acid amide that accumulates in the cerebrospinal fluid of the sleep-deprived animals. Microglia are the major immune cells involved in neuroinflammation causing brain damage during infection, ischemia, and neurodegenerative disease. In this study, we examined the effects of oleamide on LPS-induced production of proinflammatory mediators and the mechanisms involved in BV2 microglia. Oleamide inhibited LPS-induced production of NO and prostaglandin E2 as well as expression of iNOS and COX-2. We showed that oleamide blocked LPS-induced NF-kappaB activation and phosphorylation of inhibitor kappaB kinase (IKK). We also showed that oleamide inhibited LPS-induced phosphorylation of Akt, p38 MAPK, and ERK, activation of PI 3-kinase, and accumulation of reactive oxygen species (ROS). Finally, we showed that a specific antagonist of the CB2 receptor, AM630, blocked the inhibitory effects of oleamide on LPS-induced production of proinflammatory mediators and activation of NF-kappaB. Taken together, our results suggest that oleamide shows an anti-inflammatory effect through inhibition of NF-kappaB activation in LPS-stimulated BV2 microglia. 2010 Elsevier Ireland Ltd. All rights reserved.

15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits Homing of Bone Marrow-Derived Mesenchymal Stem Cells Triggered by Chronic Liver Injury via Redox Pathway

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Xin Liu

2015-01-01

Full Text Available It has been reported that bone marrow-derived mesenchymal stem cells (BMSCs have capacity to migrate to the damaged liver and contribute to fibrogenesis in chronic liver diseases. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARγ, is considered a new inhibitor of cell migration. However, the actions of 15d-PGJ2 on BMSC migration remain unknown. In this study, we investigated the effects of 15d-PGJ2 on the migration of BMSCs using a mouse model of chronic liver fibrosis and primary mouse BMSCs. Our results demonstrated that in vivo, 15d-PGJ2 administration inhibited the homing of BMSCs to injured liver by flow cytometric analysis and, in vitro, 15d-PGJ2 suppressed primary BMSC migration in a dose-dependent manner determined by Boyden chamber assay. Furthermore, the repressive effect of 15d-PGJ2 was blocked by reactive oxygen species (ROS inhibitor, but not PPARγ antagonist, and action of 15d-PGJ2 was not reproduced by PPARγ synthetic ligands. In addition, 15d-PGJ2 triggered a significant ROS production and cytoskeletal remodeling in BMSCs. In conclusion, our results suggest that 15d-PGJ2 plays a crucial role in homing of BMSCs to the injured liver dependent on ROS production, independently of PPARγ, which may represent a new strategy in the treatment of liver fibrosis.

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

DEFF Research Database (Denmark)

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

2007-01-01

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

Cysteinyl leukotriene E4 activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D2 and epithelial cytokines.

Science.gov (United States)

Salimi, Maryam; Stöger, Linda; Liu, Wei; Go, Simei; Pavord, Ian; Klenerman, Paul; Ogg, Graham; Xue, Luzheng

2017-10-01

Group 2 innate lymphoid cells (ILC2s) are a potential innate source of type 2 cytokines in the pathogenesis of allergic conditions. Epithelial cytokines (IL-33, IL-25, and thymic stromal lymphopoietin [TSLP]) and mast cell mediators (prostaglandin D 2 [PGD 2 ]) are critical activators of ILC2s. Cysteinyl leukotrienes (cysLTs), including leukotriene (LT) C 4 , LTD 4 , and LTE 4 , are metabolites of arachidonic acid and mediate inflammatory responses. Their role in human ILC2s is still poorly understood. We sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s. For ex vivo studies, fresh blood from patients with atopic dermatitis and healthy control subjects was analyzed with flow cytometry. For in vitro studies, ILC2s were isolated and cultured. The effects of cysLTs, PGD 2 , IL-33, IL-25, TSLP, and IL-2 alone or in combination on ILC2s were defined by using chemotaxis, apoptosis, ELISA, Luminex, quantitative RT-PCR, and flow cytometric assays. The effect of endogenous cysLTs was assessed by using human mast cell supernatants. Human ILC2s expressed the LT receptor CysLT 1 , levels of which were increased in atopic subjects. CysLTs, particularly LTE 4 , induced migration, reduced apoptosis, and promoted cytokine production in human ILC2s in vitro. LTE 4 enhanced the effect of PGD 2 , IL-25, IL-33, and TSLP, resulting in increased production of type 2 and other proinflammatory cytokines. The effect of LTE 4 was inhibited by montelukast, a CysLT 1 antagonist. Interestingly, addition of IL-2 to LTE 4 and epithelial cytokines significantly amplified ILC2 activation and upregulated expression of the receptors for IL-33 and IL-25. CysLTs, particularly LTE 4 , are important contributors to the triggering of human ILC2s in inflammatory responses, particularly when combined with other ILC2 activators. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

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

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О. V. Tymoshchuk

2018-02-01

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

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

Science.gov (United States)

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

2011-10-01

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

Comparison of Foley catheter and prostaglandin E2 tablets for the induction of labor at term

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Ana Daneva Markova

2013-12-01

Full Text Available The aim of the paper was to assess success rates and associated maternal and fetal risks, to determine the different methods of induction for labor at term, compare induction with Foley catheter and induction with naturally occurring prostaglandin E2 (PGE2 tablets in women with gestational age at term. Two hundred and twelve women at term were included into the study, one group with Foley catheter, the second group with PGE2 tablets, with a maximum of two doses. The primary outcome measures were the admission-to-delivery interval and the induction-to-delivery interval. Secondary outcomes included cesarean section rate, mode of delivery, and maternal and neonatal safety outcome. Results were calculated by applying the Fisher’s exact test, c2-test, t-test and calculating the P-value using an alpha level of 0.05 for Type I errors. The mean time from admission to delivery was 13.53h in the Foley catheter group and 12.30h in the PGE2 group (P=0.090. The induction-to-delivery interval was also comparable between the groups (10.75h vs 9.37h, while the cesarean section rate did not differ significantly between them (7.61% vs 15.30%. More women in the misoprostol group had an instrumental delivery (12.38% vs 2.94%. The only significant difference in neonatal outcome was a larger number of babies born with Apgar score < 7 at 1 min in the Foley group. Maternal outcomes were not significantly different, except for a higher number of digital examinations in the Foley group. Foley catheter is equally efficacious in labor induction and demonstrates a similar fetal and maternal safety profile to PGE2.

Putative role of prostaglandin receptor in intracerebral hemorrhage

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Shekher eMohan

2012-10-01

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

The Bibenzyl Canniprene Inhibits the Production of Pro-Inflammatory Eicosanoids and Selectively Accumulates in Some Cannabis sativa Strains.

Science.gov (United States)

Allegrone, Gianna; Pollastro, Federica; Magagnini, Gianmaria; Taglialatela-Scafati, Orazio; Seegers, Julia; Koeberle, Andreas; Werz, Oliver; Appendino, Giovanni

2017-03-24

Canniprene (1), an isoprenylated bibenzyl unique to Cannabis sativa, can be vaporized and therefore potentially inhaled from marijuana. Canniprene (1) potently inhibited the production of inflammatory eicosanoids via the 5-lipoxygenase pathway (IC 50 0.4 μM) and also affected the generation of prostaglandins via the cyclooxygenase/microsomal prostaglandin E 2 synthase pathway (IC 50 10 μM), while the related spiranoid bibenzyls cannabispiranol (2) and cannabispirenone (3) were almost inactive in these bioassays. The concentration of canniprene (1) was investigated in the leaves of 160 strains of C. sativa, showing wide variations, from traces to >0.2%, but no correlation was found between its accumulation and a specific phytocannabinoid profile.

Reversibility of cortical hyperostosis following long-term prostaglandin E1 therapy in infants with ductus-dependent congenital heart disease

DEFF Research Database (Denmark)

Høst, A; Halken, S; Andersen, P E

1988-01-01

Two neonates with complex cyanotic congenital heart disease, receiving long-term prostaglandin E1 infusion, for 59 and 78 days respectively, demonstrated significant radiographic changes of symmetric cortical hyperostosis of the long bones. Bone biopsies from one of the patients elucidated...

Defibrotide modulates prostaglandin production in the rat mesenteric vascular bed.

Science.gov (United States)

Peredo, H A

2002-10-01

Defibrotide 1 microM, a polydeoxyribonucleotide extracted from mammalian organs, reduced the contractile responses to noradrenaline (NA) in the rat isolated and perfused mesenteric vascular bed, in intact as well as in de-endothelialized preparations. Defibrotide was without effect on the acetylcholine-induced relaxations of U-46619-precontracted mesenteric vascular beds. Moreover, defibrotide increased 6-keto prostaglandin (PG) F(2alpha) (stable metabolite of prostacyclin) release sixfold in the presence, but not in the absence of the endothelium, with no modification on the release of other prostanoids. Defibrotide also inhibited the NA-induced increase in PGF(2alpha) release, in both intact and de-endothelialized mesenteric vascular beds. In conclusion, the present results show that defibrotide modulates PG production in the mesenteric bed and that the observed inhibition of the contractile responses should be due to the impairment of the NA-induced increase in PGF(2alpha) release.

Adenovirus E4 open reading frame 4-induced dephosphorylation inhibits E1A activation of the E2 promoter and E2F-1-mediated transactivation independently of the retinoblastoma tumor suppressor protein

DEFF Research Database (Denmark)

Mannervik, M; Fan, S; Ström, A C

1999-01-01

of the viral E4 open reading frame 4 (E4-ORF4) protein. This effect does not to require the retinoblastoma protein that previously has been shown to regulate E2F activity. The inhibitory activity of E4-ORF4 appears to be specific because E4-ORF4 had little effect on, for example, E4-ORF6/7 transactivation......Previous studies have shown that the cell cycle-regulated E2F transcription factor is subjected to both positive and negative control by phosphorylation. Here we show that in transient transfection experiments, adenovirus E1A activation of the viral E2 promoter is abrogated by coexpression...... of the E2 promoter. We further show that the repressive effect of E4-ORF4 on E2 transcription works mainly through the E2F DNA-binding sites in the E2 promoter. In agreement with this, we find that E4-ORF4 inhibits E2F-1/DP-1-mediated transactivation. We also show that E4-ORF4 inhibits E2 mRNA expression...

Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis.

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Kida, Taiki; Ayabe, Shinya; Omori, Keisuke; Nakamura, Tatsuro; Maehara, Toko; Aritake, Kosuke; Urade, Yoshihiro; Murata, Takahisa

2016-01-01

Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

Effect of synthetic prostaglandin E1 analog on gastric emptying of meals in man.

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Moore, J G; Alazraki, N; Clay, G D

1986-01-01

Forty-five subjects with healed duodenal ulcer were administered either a placebo or a low-dose or high-dose regimen of misoprostol, a synthetic PGE1 analog, in a double-blind, random, parallel-group design to assess the effect of this prostaglandin compound on the gastric emptying of liquid-solid meals. A dual-radionuclide technique to measure liquid- and solid-phase gastric emptying rates of physiological meals by external gamma camera imaging was used. All subjects had a pretreatment control (baseline) evaluation, followed one week later by a treatment-influenced emptying study. The results demonstrated that misoprostol did not significantly alter gastric emptying of either liquids or solids; however, these results cannot be extrapolated to other prostaglandin compounds because of the diverse and sometimes paradoxical effects of different prostaglandins on gastric motility.

Oestradiol and prostaglandin F2α regulate sexual displays in females of a sex-role reversed fish

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Gonçalves, David; Costa, Silvia Santos; Teles, Magda C.; Silva, Helena; Inglês, Mafalda; Oliveira, Rui F.

2014-01-01

The mechanisms regulating sexual behaviours in female vertebrates are still poorly understood, mainly because in most species sexual displays in females are more subtle and less frequent than displays in males. In a sex-role reversed population of a teleost fish, the peacock blenny Salaria pavo, an external fertilizer, females are the courting sex and their sexual displays are conspicuous and unambiguous. We took advantage of this to investigate the role of ovarian-synthesized hormones in the induction of sexual displays in females. In particular, the effects of the sex steroids oestradiol (E2) and testosterone (T) and of the prostaglandin F2α (PGF2α) were tested. Females were ovariectomized and their sexual behaviour tested 7 days (sex steroids and PGF2α) and 14 days (sex steroids) after ovariectomy by presenting females to an established nesting male. Ovariectomy reduced the expression of sexual behaviours, although a significant proportion of females still courted the male 14 days after the ovary removal. Administration of PGF2α to ovariectomized females recovered the frequency of approaches to the male's nest and of courtship displays towards the nesting male. However, E2 also had a positive effect on sexual behaviour, particularly on the frequency of approaches to the male's nest. T administration failed to recover sexual behaviours in ovariectomized females. These results suggest that the increase in E2 levels postulated to occur during the breeding season facilitates female mate-searching and assessment behaviours, whereas PGF2α acts as a short-latency endogenous signal informing the brain that oocytes are mature and ready to be spawned. In the light of these results, the classical view for female fishes, that sex steroids maintain sexual behaviour in internal fertilizers and that prostaglandins activate spawning behaviours in external fertilizers, needs to be reviewed. PMID:24452030

Effect of bone marrow depletion on prostaglandin E-producing suppressor macrophages in mouse spleen

International Nuclear Information System (INIS)

Shibata, Y.; Volkman, A.

1985-01-01

The i.p. injection of Corynebacterium parvum (CP) into CBA/J mice effected increases in macrophage colony-forming cells (M-CFC) when spleen cells were cultured with L cell culture filtrate as a source of colony-stimulating factor. Significant increases in phagocytic macrophages (M phi) with Fc receptors for IgG2a and IgG2b immune complexes were additionally noted among the spleen cells in these mice. These M phi effectively inhibited Con A-induced lymphocyte proliferation, probably reflecting a 10-fold increase above normal controls in prostaglandin E to 47 ng/3 X 10(6) spleen cells/ml. To determine whether the suppressor M phi are immediate derivatives of splenic M-CFC, we tried to induce suppressor M phi by the injection of CP into mice depleted of bone marrow M-CFC by the earlier administration of the bone-seeking isotope, 89Sr. This procedure reduced M-CFC in the bone marrow to less than 1% of normal for more than 30 days. Monocytes in the blood fell to 5% of normal by day 10 and were 30% on day 30. Levels of resident peritoneal M phi showed relatively little change in this period. By contrast, splenic M-CFC increased to 20-fold higher than the cold 88Sr controls. CP-induced suppressor M phi activity, however, was sharply reduced in 89Sr marrow-depleted mice on day 10, despite the striking increase in M-CFC. There was a threefold increase in the number of phagocytic M phi binding IgG2a immune complexes, with no significant increase in IgG2b binding M phi. The kinetics of recovery of suppressor M phi activity showed that on days 20, 30, and 50 after 89Sr injection the activities reached 20%, 30%, and 70% of the cold control, respectively, and correlated with the recovery of significant levels of M-CFC in the bone marrow. Taken together, these observations suggest that splenic M-CFC are not an immediate source of PGE-suppressor M phi in vivo

Maternal exposure to prostaglandin E2 modifies expression of Wnt genes in mouse brain – An autism connection

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Ravneet Rai-Bhogal

2018-07-01

Full Text Available Prostaglandin E2 (PGE2 is a lipid signaling molecule important for brain development and function. Various genetic and environmental factors can influence the level of PGE2 and increase the risk of developing Autism Spectrum Disorder (ASD. We have previously shown that in neuronal cell lines and mouse brain, PGE2 can interfere with the Wnt canonical pathway, which is essential during early brain development. Higher levels of PGE2 increased Wnt-dependent motility and proliferation of neuroectodermal stem cells, and modified the expression of Wnt genes previously linked to autism disorders. We also recently established a cross-talk between these two pathways in the prenatal mouse brain lacking PGE2 producing enzyme (COX-/-. The current study complements the published data and reveals that PGE2 signaling also converges with the Wnt canonical pathway in the developing mouse brain after maternal exposure to PGE2 at the onset of neurogenesis. We found significant changes in the expression level of Wnt-target genes, Mmp7, Wnt2, and Wnt3a, during prenatal and early postnatal stages. Interestingly, we observed variability in the expression level of these genes between genetically-identical pups within the same pregnancy. Furthermore, we found that all the affected genes have been previously associated with disorders of the central nervous system, including autism. We determined that prenatal exposure to PGE2 affects the Wnt pathway at the level of β-catenin, the major downstream regulator of Wnt-dependent gene transcription. We discuss how these results add new knowledge into the molecular mechanisms by which PGE2 may interfere with neuronal development during critical periods.

Skin Inqjuries Reduce Survival and Modulate Corticosterone, C-Reactive Protein, Complement Component 3, IgM, and Prostaglandin E2 after Whole-Body Reactor-Produced Mixed Field (n + γ-Photons Irradiation

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Juliann G. Kiang

2013-01-01

Full Text Available Skin injuries such as wounds or burns following whole-body γ-irradiation (radiation combined injury (RCI increase mortality more than whole-body γ-irradiation alone. Wound-induced decreases in survival after irradiation are triggered by sustained activation of inducible nitric oxide synthase pathways, persistent alteration of cytokine homeostasis, and increased susceptibility to systemic bacterial infection. Among these factors, radiation-induced increases in interleukin-6 (IL-6 concentrations in serum were amplified by skin wound trauma. Herein, the IL-6-induced stress proteins including C-reactive protein (CRP, complement 3 (C3, immunoglobulin M (IgM, and prostaglandin E2 (PGE2 were evaluated after skin injuries given following a mixed radiation environment that might be found after a nuclear incident. In this report, mice received 3 Gy of reactor-produced mixed field (n+γ-photons radiations at 0.38 Gy/min followed by nonlethal skin wounding or burning. Both wounds and burns reduced survival and increased CRP, C3, and PGE2 in serum after radiation. Decreased IgM production along with an early rise in corticosterone followed by a subsequent decrease was noted for each RCI situation. These results suggest that RCI-induced alterations of corticosterone, CRP, C3, IgM, and PGE2 cause homeostatic imbalance and may contribute to reduced survival. Agents inhibiting these responses may prove to be therapeutic for RCI and improve related survival.

Efficacy of dendritic cells matured early with OK-432 (Picibanil), prostaglandin E2, and interferon-alpha as a vaccine for a hormone refractory prostate cancer cell line.

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Yoo, Changhee; Do, Hyun-Ah; Jeong, In Gab; Park, Hongzoo; Hwang, Jung-Jin; Hong, Jun Hyuk; Cho, Jin Seon; Choo, Myong-Soo; Ahn, Hanjong; Kim, Choung-Soo

2010-09-01

Dendritic cells (DCs) are potent antigen-presenting cells. OK432 (Picibanil) was introduced as a potent stimulator of DC maturation in combination with prostaglandin-E(2) and interferon-alpha. We compared the efficacy of a DC-prostate cancer vaccine using early-mature DCs stimulated with OK432, PGE2 and INF-alpha (OPA) with that of vaccines using other methods. On days 3 or 7 of DC culture, TNF-alpha (T), TNF-alpha and LPS (TL) or OPA were employed as maturation stimulators. DU145 cells subjected to heat stress were hybridized with mature DCs using polyethyleneglycol. T cells were sensitized by the hybrids, and their proliferative and cytokine secretion activities and cytotoxicity were measured. The yields of early-mature DCs were higher, compared to yields at the conventional maturation time (P<0.05). In the early maturation setting, the mean fusion ratios, calculated from the fraction of dual-positive cells, were 13.3%, 18.6%, and 39.9%, respectively (P=0.051) in the T only, TL, and OPA-treated groups. The function of cytotoxic T cells, which were sensitized with the hybrids containing DCs matured early with OPA, was superior to that using other methods. The antitumor effects of DC-DU145 hybrids generated with DCs subjected to early maturation with the OPA may be superior to that of the hybrids using conventional maturation methods.

Inhibition of Release of Vasoactive and Inflammatory Mediators in Airway and Vascular Tissues and Macrophages by a Chinese Herbal Medicine Formula for Allergic Rhinitis

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George Binh Lenon

2007-01-01

Full Text Available Herbal therapies are being used increasingly for the treatment of allergic rhinitis. The aim of this study was to investigate the possible pharmacological actions and cellular targets of a Chinese herbal formula (RCM-101, which was previously shown to be effective in reducing seasonal allergic rhinitis symptoms in a randomized, placebo-controlled clinical trial. Rat and guinea pig isolated tissues (trachea and aorta were used to study the effects of RCM-101 on responses to various mediators. Production of leukotriene B4 in porcine neutrophils and of prostaglandin E2 and nitric oxide (NO in Raw 264.7 cells were also measured. In rat and guinea pig tracheal preparations, RCM-101 inhibited contractile responses to compound 48/80 but not those to histamine (guinea pig preparations or serotonin (rat preparations. Contractile responses of guinea pig tracheal preparations to carbachol and leukotriene C4, and relaxant responses to substance P and prostaglandin E2 were not affected by RCM-101. In rat aortic preparations, precontracted with phenylephrine, endothelium-dependent relaxant responses to acetylcholine and endothelium-independent relaxant responses to sodium nitroprusside were not affected by RCM-101. However, RCM-101 inhibited relaxations to l-arginine in endothelium-denuded rat aortic preparations, which had been pre-incubated with lipopolysaccharide. RCM-101 did not affect leukotriene B4 formation in isolated porcine neutrophils, induced by the calcium ionophore A23187; however, it inhibited prostaglandin E2 and NO production in lipopolysaccharide-stimulated murine macrophages (Raw 264.7 cells.The findings indicate that RCM-101 may have multiple inhibitory actions on the release and/or synthesis of inflammatory mediators involved in allergic rhinitis.

FATTY ACID COMPOSITION AND PROSTAGLANDIN CONTENT OF THE RED SEAWEED Gracilaria sp. FROM INDONESIA

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Muhammad Ikbal Illijas

2012-06-01

Full Text Available High content of polyunsaturated fatty acids (PUFAs such as arachidonic and eicosapentaenoic acids are typical for the red alga. Analysis of fatty acid composition and prostaglandin content was conducted in the red alga Gracilaria sp. from Indonesia. Total lipid of the alga was extracted with CHCl3-MeOH (2:1, v/v. Analysis of the fatty acids composition was performed on gas chromatography (GC equipped with omega wax column (30 m x 0,32 mm i.d., Supelco, PA, USA and analysis of prostaglandins were carried out by HPLC on ODS column (Mightysil RP-18 GP, 250 mm x 4.6 mm, 5 μm. The content of fatty acids high for were palmitic acid (50% and arachidonic acid (26.9%, whereas prostaglandin E2 was identified and found lower concentration (44.2 μg/gram total lipid.

Up-regulation of eEF1A2 promotes proliferation and inhibits apoptosis in prostate cancer

International Nuclear Information System (INIS)

Sun, Yue; Du, Chengli; Wang, Bo; Zhang, Yanling; Liu, Xiaoyan; Ren, Guoping

2014-01-01

Highlights: • The expression of eEF1A2 is up-regulated in prostate cancer tissues. • Suppression of eEF1A2 inhibits the proliferation and promotes apoptosis. • Inhibition of eEF1A2 enhances the expression of apoptotic relevant proteins. • The expressions of eEF1A2 and cleavage-caspase3 are inversely correlated. - Abstract: Background: eEF1A2 is a protein translation factor involved in protein synthesis, which possesses important function roles in cancer development. This study aims at investigating the expression pattern of eEF1A2 in prostate cancer and its potential role in prostate cancer development. Methods: We examined the expression level of eEF1A2 in 30 pairs of prostate cancer tissues by using RT-PCR and immunohistochemical staining (IHC). Then we applied siRNA specifically targeting eEF1A2 to down-regulate its expression in DU-145 and PC-3 cells. Flow cytometer was used to explore apoptosis and Western-blot was used to detect the pathway proteins of apoptosis. Results: Our results showed that the expression level of eEF1A2 in prostate cancer tissues was significantly higher compared to their corresponding normal tissues. Reduction of eEF1A2 expression in DU-145 and PC-3 cells led to a dramatic inhibition of proliferation accompanied with enhanced apoptosis rate. Western blot revealed that apoptosis pathway proteins (caspase3, BAD, BAX, PUMA) were significantly up-regulated after suppression of eEF1A2. More importantly, the levels of eEF1A2 and caspase3 were inversely correlated in prostate cancer tissues. Conclusion: Our data suggests that eEF1A2 plays an important role in prostate cancer development, especially in inhibiting apoptosis. So eEF1A2 might serve as a potential therapeutic target in prostate cancer

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

International Nuclear Information System (INIS)

Saussy, D.L. Jr.

1986-01-01

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

Fetal placental prostaglandin metabolism in the peripartum cow

International Nuclear Information System (INIS)

Gross, T.S.; Williams, W.F.; Lewis, G.S.

1986-01-01

Previous results demonstrate that fetal placental tissue synthesizes prostaglandin E (PGE) prior to parturition. When placental membranes do not separate postpartum, PGE synthesis is maintained, while prostaglandin F (PGF) synthesis predominates when the membranes separate. Concurrent with separation is a decline in fetal placental binucleate cell (BNC) numbers. These data suggest a fetal placental conversion of PGE to PGF. For this experiment, placentomes were collected at ten days prepartum (PRE, n=12) and within 1 hr postpartum. Nine of the postpartum animals had fetal membrane separation within 12 hr postpartum (S) and eight did not exhibit membrane separation (NS). For each placentome, fetal (villi) components were manually isolated and examined for the ability to interconvert 3 H labeled PGE 2 and PGF 2 . All villi were unable to convert PGE 2 to PGF 2 (P > .05). The PRE and NS villi were able to convert PGF 2 to PGE 2 (P 2 to PGE 2 (P 2 to PGE 2 also declines (P < .05). These data suggest that peripartum fetal placental tissue might synthesize PGF which is then converted to PGE. It is possible that the BNC are directly converting PGF to PGE or that they are modulating this conversion. Therefore, with a decline in BNC numbers, PGF synthesis would predominate

Oestrous synchronization and fertility in cycling Damascus does using the synthetic prostaglandin F2α, iliren

International Nuclear Information System (INIS)

Zarkawi, M.

2008-01-01

To assess the effect of synthetic prostaglandin F2α (PGF2α) Iliren, on oestrous synchronisation and other related parameters, 9 intact indigenous Damascus does each were either intramuscularly injected twice with 2 ml of synthetic prostaglandin F2α, Iliren (0.3 mg Tiaprost) at an interval of 12 d (P) or served as control (C) with no treatments. Doses in group P responded to the treatment and exhibited oestrus at an average of 96 h; whereas, does in group C exhibited oestrus at an average of 199 h after bucks introduction. The treatment had no significant effect (P>0.05) on duration of pregnancy, fecundity rate of does, birth or weaning weight of kids at 3 months of age. At the second injection of PGF2α, there were active corpora lutea formed in some ovaries of the does treated with Iliren as indicated by the high concentration of progesterone. It could be concluded that it is possible to use the synthetic prostaglandin F2α, Iliren, at a dose of 2 ml (0.3 mg Tiaprost) given twice at an interval of 12 d for oestrous synchronisation in local Damascus does during the breeding season with no adverse effect on the reproductive or growth parameters. (author)

Effects of intraluteal implants of prostaglandin E1 or E2 on angiogenic growth factors in luteal tissue of Angus and Brahman cows.

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Weems, Yoshie S; Ma, Yan; Ford, Stephen P; Nett, Terry M; Vann, Rhonda C; Lewis, Andrew W; Neuendorff, Don A; Welsh, Thomas H; Randel, Ronald D; Weems, Charles W

2014-12-01

Previously, it was reported that intraluteal implants containing prostaglandin E1 or E2 (PGE1 and PGE2) in Angus or Brahman cows prevented luteolysis by preventing loss of mRNA expression for luteal LH receptors and luteal unoccupied and occupied LH receptors. In addition, intraluteal implants containing PGE1 or PGE2 upregulated mRNA expression for FP prostanoid receptors and downregulated mRNA expression for EP2 and EP4 prostanoid receptors. Luteal weight during the estrous cycle of Brahman cows was reported to be lesser than that of Angus cows but not during pregnancy. The objective of this experiment was to determine whether intraluteal implants containing PGE1 or PGE2 alter vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), angiopoietin-1 (ANG-1), and angiopoietin-2 (ANG-2) protein in Brahman or Angus cows. On Day 13 of the estrous cycle, Angus cows received no intraluteal implant and corpora lutea were retrieved, or Angus and Brahman cows received intraluteal silastic implants containing vehicle, PGE1, or PGE2 on Day 13 and corpora lutea were retrieved on Day 19. Corpora lutea slices were analyzed for VEGF, FGF-2, ANG-1, and ANG-2 angiogenic proteins via Western blot. Day-13 Angus cow luteal tissue served as preluteolytic controls. Data for VEGF were not affected (P > 0.05) by day, breed, or treatment. PGE1 or PGE2 increased (P Angus cows compared with Day-13 and Day-19 Angus controls but decreased (P Angus controls. There was no effect (P > 0.05) of PGE1 or PGE2 on ANG-1 in Angus luteal tissue when compared with Day-13 or Day-19 controls, but ANG-1 was decreased (P Angus Vehicle controls when compared with Day-13 Angus controls, which was prevented (P Angus cows. There was no effect (P > 0.05) of PGE1 or PGE2 on ANG-2 in Brahman cows. PGE1 or PGE2 may alter cow luteal FGF-2, ANG-1, or ANG-2 but not VEGF to prevent luteolysis; however, species or breed differences may exist. Published by Elsevier Inc.

Evaluation of prostaglandin D2 as a CSF leak marker: implications in safe epidural anesthesia

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Kondabolu S

2011-07-01

Full Text Available Sirish Kondabolu, Rishimani Adsumelli, Joy Schabel, Peter Glass, Srinivas PentyalaDepartment of Anesthesiology, School of Medicine, Stony Brook Medical Center, Stony Brook, New York, USABackground: It is accepted that there is a severe risk of dural puncture in epidural anesthesia. Of major concern to anesthesiologists is unintentional spinal block. Reliable identification of cerebrospinal fluid (CSF from the aspirate is crucial for safe epidural anesthesia. The aim of this study was to determine whether prostaglandin D2 could be clinically used as a marker for the detection of CSF traces.Methods: After obtaining Institutional Review Board approval and patient consent, CSF was obtained from patients undergoing spinal anesthesia, and blood, urine, and saliva were obtained from normal subjects and analyzed for prostaglandin D2 (PGD. CSF (n=5 samples were diluted with local anesthetic (bupivacaine, normal saline and blood in the ratios of 1:5 and 1:10. PGD levels in the CSF samples were analyzed with a PGD-Methoxime (MOX EIA Kit (Cayman Chemicals, MI. This assay is based on the conversion of PGD to a stable derivative, which is analyzed with antiserum specific for PGD-MOX. Results: Different concentrations of pure PGD-MOX conjugate were analyzed by EIA and a standard curve was derived. PGD levels in CSF and CSF with diluents were determined and the values were extrapolated onto the standard curve. Our results show a well-defined correlation for the presence of PGD both in straight CSF samples and in diluted CSF (dilution factor of 1:5 and 1:10. Conclusion: Prostaglandin D2 was reliably identified in CSF by enzyme-linked immunosorbent assay when diluted with local anesthetic, saline, and serum, and can be used as a marker to identify the presence of CSF in epidural aspirates.Keywords: epidural, cerebrospinal fluid, leak, marker, prostaglandin D2

Efficacy of Dendritic Cells Matured Early with OK-432 (Picibanil®), Prostaglandin E2, and Interferon-α as a Vaccine for a Hormone Refractory Prostate Cancer Cell Line

Science.gov (United States)

Yoo, Changhee; Do, Hyun-Ah; Jeong, In Gab; Park, Hongzoo; Hwang, Jung-Jin; Hong, Jun Hyuk; Cho, Jin Seon; Choo, Myong-Soo; Ahn, Hanjong

2010-01-01

Dendritic cells (DCs) are potent antigen-presenting cells. OK432 (Picibanil®) was introduced as a potent stimulator of DC maturation in combination with prostaglandin-E2 and interferon-α. We compared the efficacy of a DC-prostate cancer vaccine using early-mature DCs stimulated with OK432, PGE2 and INF-α (OPA) with that of vaccines using other methods. On days 3 or 7 of DC culture, TNF-α (T), TNF-α and LPS (TL) or OPA were employed as maturation stimulators. DU145 cells subjected to heat stress were hybridized with mature DCs using polyethyleneglycol. T cells were sensitized by the hybrids, and their proliferative and cytokine secretion activities and cytotoxicity were measured. The yields of early-mature DCs were higher, compared to yields at the conventional maturation time (P<0.05). In the early maturation setting, the mean fusion ratios, calculated from the fraction of dual-positive cells, were 13.3%, 18.6%, and 39.9%, respectively (P=0.051) in the T only, TL, and OPA-treated groups. The function of cytotoxic T cells, which were sensitized with the hybrids containing DCs matured early with OPA, was superior to that using other methods. The antitumor effects of DC-DU145 hybrids generated with DCs subjected to early maturation with the OPA may be superior to that of the hybrids using conventional maturation methods. PMID:20808670

Indomethacin inhibits the uptake of 22sodium by ovine trophoblastic tissue in vitro

International Nuclear Information System (INIS)

Lewis, G.S.

1986-01-01

Blastocysts from several species synthesize prostaglandins in vitro, but the exact functions of the prostaglandins are unknown. The purpose of this study was to determine if indomethacin, an inhibitor of prostaglandin synthesis, would inhibit the uptake of 22sodium ([22Na]) by ovine trophoblastic tissue. To determine the concentration of indomethacin that would inhibit the synthesis of PGF2 alpha and 13,14-dihydro-15-keto-PGF2 alpha (PGFM) by blastocysts, blastocysts were collected from ewes 16 days after mating, sliced into pieces approximately 2 mm in length and incubated for 48 h at 37 degrees C in 2 ml of medium containing either 0, 0.2, 0.4, 0.8 or 1.6 mM of indomethacin. Concentrations of indomethacin greater than or equal to 0.2 mM reduced (P less than .01) trophoblastic release (ng/micrograms DNA) of PGF2 alpha from 205 +/- 71.2 to less than or equal to 3.3 +/- 0.2, reduced PGFM from 0.7 +/- 0.1 to less than or equal to 0.17 +/- 0.01, and inhibited formation of trophoblastic vesicles. In a second experiment, blastocysts were recovered from ewes 16 days after mating and pieces of trophoblast were incubated with [22Na] and either 0 or 0.4 mM of indomethacin. Indomethacin reduced the uptake of [22Na], which is an indirect measure of the transport of water across epithelia, from 3680 +/- 1118 to 934 +/- 248 cpm/micrograms DNA (P less than .03) and prevented formation of trophoblastic vesicles. Prostaglandins produced by ovine blastocysts might be involved in controlling uptake of water, which is essential for expansion of blastocysts

Central pathway for spontaneous and prostaglandin E2-evoked cutaneous vasoconstriction.

Science.gov (United States)

Rathner, Joseph A; Madden, Christopher J; Morrison, Shaun F

2008-07-01

A reduction of heat loss to the environment through increased cutaneous vasoconstrictor (CVC) sympathetic outflow contributes to elevated body temperature during fever. We determined the role of neurons in the dorsomedial hypothalamus (DMH) in increases in CVC sympathetic tone evoked by PGE2 into the preoptic area (POA) in chloralose/urethane-anesthetized rats. The frequency of axonal action potentials of CVC sympathetic ganglion cells recorded from the surface of the tail artery was increased by 1.8 Hz following nanoinjections of bicuculline (50 pmol) into the DMH. PGE2 nanoinjection into the POA elicited a similar excitation of tail CVC neurons (+2.1 Hz). Subsequent to PGE2 into the POA, muscimol (400 pmol/side) into the DMH did not alter the activity of tail CVC neurons. Inhibition of neurons in the rostral raphé pallidus (rRPa) eliminated the spontaneous discharge of tail CVC neurons but only reduced the PGE2-evoked activity. Residual activity was abolished by subsequent muscimol into the rostral ventrolateral medulla. Transections through the neuraxis caudal to the POA increased the activity of tail CVC neurons, which were sustained through transections caudal to DMH. We conclude that while activation of neurons in the DMH is sufficient to activate tail CVC neurons, it is not necessary for their PGE2-evoked activity. These results support a CVC component of increased core temperature elicited by PGE2 in POA that arises from relief of a tonic inhibition from neurons in POA of CVC sympathetic premotor neurons in rRPa and is dependent on the excitation of CVC premotor neurons from a site caudal to DMH.

Indomethacin causes prostaglandin D(2)-like and eotaxin-like selective responses in eosinophils and basophils.

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Stubbs, Victoria E L; Schratl, Petra; Hartnell, Adele; Williams, Timothy J; Peskar, Bernhard A; Heinemann, Akos; Sabroe, Ian

2002-07-19

We investigated the actions of a panel of nonsteroidal anti-inflammatory drugs on eosinophils, basophils, neutrophils, and monocytes. Indomethacin alone was a potent and selective inducer of eosinophil and basophil shape change. In eosinophils, indomethacin induced chemotaxis, CD11b up-regulation, respiratory burst, and L-selectin shedding but did not cause up-regulation of CD63 expression. Pretreatment of eosinophils with indomethacin also enhanced subsequent eosinophil shape change induced by eotaxin, although treatment with higher concentrations of indomethacin resulted in a decrease in the expression of the major eosinophil chemokine receptor, CCR3. Indomethacin activities and cell selectivity closely resembled those of prostaglandin D(2) (PGD(2)). Eosinophil shape change in response to eotaxin was inhibited by pertussis toxin, but indomethacin- and PGD(2)-induced shape change responses were not. Treatment of eosinophils with specific inhibitors of phospholipase C (U-73122), phosphatidylinositol 3-kinase (LY-294002), and p38 mitogen-activated protein kinase (SB-202190) revealed roles for these pathways in indomethacin signaling. Indomethacin and its analogues may therefore provide a structural basis from which selective PGD(2) receptor small molecule antagonists may be designed and which may have utility in the treatment of allergic inflammatory disease.

Prostaglandin E1 in conjunction with high doses of vitamin B12 improves nerve conduction velocity of patients with diabetic peripheral neuropathy

Institute of Scientific and Technical Information of China (English)

Jilai Li; Zhirong Wan

2008-01-01

BACKGROUND: Prostaglandin E1 improves diabetic peripheral neuropathy in symptoms and sensory threshold. Vitamin B1 and methyl-vitamin B12 improve microcirculation to peripheral nerve tissue and promote neurotrophy.OBJECTIVE: To observe motor nerve and sensory nerve conduction velocity in patients with diabetic peripheral neuropathy, prior to and after treatment with prostaglandin E1, vitamin B1 and different doses of vitamin B12.DESIGN, TIME AND SETTING: Randomized, controlled experiment, performed at the Department of Neurology. Beijing Hantian Central Hospital, between February 2002 and September 2007.PARTICIPANTS: A total of 122 patients with type 2 diabetic peripheral neuropathy; 73 males and 49 females were included. All patients met the diagnostic criteria of diabetes mellitus, as determined by the World Health Organization in 1999 and 2006, and also the diagnostic criteria of diabetic peripheral neuropathy. For each subject, conduction disorders in the median nerve and in the common peroneal nerve were observed using electromyogram. Also, after diet and drug treatment, the blood glucose level of subjects was observed to be at a satisfactory level for more than two weeks, and the symptoms of diabetic peripheral neuropathy were not alleviated.METHODS: All patients were randomly divided into the following three groups. A control group (n=40), in which, 100mg vitamin B1 and 500μg vitamin B12 were intramuscularly injected. A vitamin B12 low-dose treated group (n=42), in which 10μg prostaglandin E1 in 250mL physiological saline was intravenously injected once a day and 100mg vitamin B1 and 500μg vitamin B12 was intramuscularly injected once a day. Lastly, a vitamin B12 high-dose treated group (n=40), in which administration was the same as in the vitamin B12 low-dose treated group, except that 500μg vitamin B12 was replaced by 1mg vitamin B12. Administration was performed for four weeks for each group.MAIN OUTCOME MEASURES: The motor nerve and sensory nerve

Expression of prostaglandin synthases (pgds and pges) during zebrafish gonadal differentiation

DEFF Research Database (Denmark)

Jørgensen, Anne; Nielsen, John E; Nielsen, Betina Frydenlund

2010-01-01

The present study aimed at elucidating whether the expression pattern of the membrane bound form of prostaglandin E2 synthase (pges) and especially the lipocalin-type prostaglandin D2 synthase (pgds) indicates involvement in gonadal sex differentiation in zebrafish as has previously been found....... In this study, a sexually dimorphic expression of pgds was found in gonads of adult zebrafish with expression in testis but not in ovaries. To determine whether the sex-specific expression pattern of pgds was present in gonads of juvenile zebrafish and therefore could be an early marker of sex in zebrafish, we...... microdissected gonads from four randomly selected individual zebrafish for every second day in the period 2-20 days post hatch (dph) and 0-1 dph. The temporal expression of pgds and pges was investigated in the microdissected gonads, however, no differential expression that could indicate sex-specific difference...

Oenothera laciniata inhibits lipopolysaccharide induced production of nitric oxide, prostaglandin E2, and proinflammatory cytokines in RAW264.7 macrophages.

Science.gov (United States)

Yoon, Weon-Jong; Ham, Young Min; Yoo, Byoung-Sam; Moon, Ji-Young; Koh, Jaesook; Hyun, Chang-Gu

2009-04-01

We elucidated the pharmacological and biological effects of Oenothera laciniata extracts on the production of inflammatory mediators in macrophages. The CH(2)Cl(2) fraction of O. laciniata extract effectively inhibited LPS-induced NO, PGE(2), and proinflammatory cytokine production in RAW264.7 cells. These inhibitory effects of the CH(2)Cl(2) fraction of O. laciniata were accompanied by decreases in the expression of iNOS and COX-2 proteins and iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6 mRNA. Asiatic acid and quercetin were present in the HPLC fingerprint of the O. laciniata extract. We tested the potential application of O. laciniata extract as a cosmetic material by performing primary skin irritation tests. In New Zealand white rabbits, primary irritation tests revealed that application of O. laciniata extracts (1%) did not induce erythema or edema formation. Human skin primary irritation tests were performed on the normal skin (upper back) of 30 volunteers to determine if any material in O. laciniata extracts had irritation or sensitization potential. In these assays, O. laciniata extracts did not induce any adverse reactions. Based on these results, we suggest that O. laciniata extracts be considered possible anti-inflammatory candidates for topical application.

Perbedaan Kadar Prostaglandin F2α Cairan Darah Haid (Menstrual Fluid) Pada Dismenore Primer, Sekunder Dan Non Dismenore

OpenAIRE

Prahatama, Apriza

2016-01-01

Introduction: Prevalence of dysmenorrhea, pain at lower abdomen during menstruation, is increasing in reproductive women. Prostaglandin plays an important role in pain stimuli, but no its level is unknown each classification dysmenorrhea. Objective: To determine differences of prostaglandin F2α levels between primary, secondary and non dysmenorrhea. Methods: This study is a comparative analytical study with cross sectional design conducted in H. Adam Malik Hospital from November 2015 to...

Suppression of annexin A2 by prostaglandin E₂ impairs phagocytic ability of peritoneal macrophages in women with endometriosis.

Science.gov (United States)

Wu, Meng-Hsing; Chuang, Pei-Chin; Lin, Yiu-Juian; Tsai, Shaw-Jenq

2013-04-01

Is annexin A2 involved in the reduced phagocytic ability of macrophages in endometriosis? Data from women with endometriosis and a murine model of the disease show that expression of annexin A2 in peritoneal macrophages is inhibited by prostaglandin E2 (PGE2) and this impairs the phagocytic ability of macrophages. Endometriosis is a chronic inflammatory disease that recruits many immune cells, especially macrophages, to the peritoneal cavity. The phagocytic ability of peritoneal macrophages isolated from women with endometriosis is reduced. A laboratory study. Thirty-five patients (20 with and 15 without endometriosis) of reproductive age with normal menstrual cycles were recruited. Peritoneal macrophages isolated from women with or without endometriosis were cultured and treated with vehicle, PGE2 and different EP receptor agonists, and the expression of annexin A2 was quantified by RT-PCR and western blotting. Annexin A2 was knocked down (by small interfering RNA) in normal macrophages or overexpressed (by treatment with recombinant protein) in endometriotic macrophages and their phagocytic ability was measured by flow cytometry. Peritoneal macrophages were isolated from a mouse model of endometriosis and treated with PGE2 or cyclo-oxygenase (COX) inhibitors, and annexin A2 mRNA was quantified. Levels of annexin A2 were markedly reduced in peritoneal macrophages from women with endometriosis versus controls (mRNA: P endometriosis versus control) via the EP2/EP4 receptor-dependent signaling pathway. Treatment with PGE2 or knockdown of annexin A2 inhibited the phagocytic ability of macrophages (P peritoneal macrophages were markedly reduced in mice treated with PGE2 (P peritoneal macrophages (P peritoneal cells from patients with endometriosis or that their endometriotic fluid contains increased amounts of PGE2 when compared with control subjects. Inhibiting PGE2 signaling, in order to restore or enhance the phagocytic capability of macrophages, may represent a new

Anti-allergic activity of 2,4,6-trihydroxy-3-geranylacetophenone (tHGA) via attenuation of IgE-mediated mast cell activation and inhibition of passive systemic anaphylaxis

Energy Technology Data Exchange (ETDEWEB)

Tan, Ji Wei; Israf, Daud Ahmad; Harith, Hanis Hazeera; Md Hashim, Nur Fariesha [Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400 (Malaysia); Ng, Chean Hui; Shaari, Khozirah [Faculty of Science, Universiti Putra Malaysia, Serdang 43300 (Malaysia); Tham, Chau Ling, E-mail: chauling@upm.edu.my [Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400 (Malaysia)

2017-03-15

tHGA, a geranyl acetophenone compound originally isolated from a local shrub called Melicope ptelefolia, has been previously reported to prevent ovalbumin-induced allergic airway inflammation in a murine model of allergic asthma by targeting cysteinyl leukotriene synthesis. Mast cells are immune effector cells involved in the pathogenesis of allergic diseases including asthma by releasing cysteinyl leukotrienes. The anti-asthmatic properties of tHGA could be attributed to its inhibitory effect on mast cell degranulation. As mast cell degranulation is an important event in allergic responses, this study aimed to investigate the anti-allergic effects of tHGA in cellular and animal models of IgE-mediated mast cell degranulation. For in vitro model of IgE-mediated mast cell degranulation, DNP-IgE-sensitized RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA to induce degranulation. For IgE-mediated passive systemic anaphylaxis, Sprague Dawley rats were sensitized by intraperitoneal injection of DNP-IgE before challenged with DNP-BSA. Both in vitro and in vivo models showed that tHGA significantly inhibited the release of preformed mediators (β-hexosaminidase and histamine) as well as de novo mediators (interleukin-4, tumour necrosis factor-α, prostaglandin D{sub 2} and leukotriene C{sub 4}). Pre-treatment of tHGA also prevented IgE-challenged RBL-2H3 cells and peritoneal mast cells from undergoing morphological changes associated with mast cell degranulation. These findings indicate that tHGA possesses potent anti-allergic activity via attenuation of IgE-mediated mast cell degranulation and inhibition of IgE-mediated passive systemic anaphylaxis. Thus, tHGA may have the potential to be developed as a mast cell stabilizer for the treatment of allergic diseases in the future. - Highlights: • The in vitro and in vivo mast cell stabilizing effects of tHGA were examined. • tHGA counteracts the plasma membrane deformation in degranulating mast

Anti-allergic activity of 2,4,6-trihydroxy-3-geranylacetophenone (tHGA) via attenuation of IgE-mediated mast cell activation and inhibition of passive systemic anaphylaxis

International Nuclear Information System (INIS)

Tan, Ji Wei; Israf, Daud Ahmad; Harith, Hanis Hazeera; Md Hashim, Nur Fariesha; Ng, Chean Hui; Shaari, Khozirah; Tham, Chau Ling

2017-01-01

tHGA, a geranyl acetophenone compound originally isolated from a local shrub called Melicope ptelefolia, has been previously reported to prevent ovalbumin-induced allergic airway inflammation in a murine model of allergic asthma by targeting cysteinyl leukotriene synthesis. Mast cells are immune effector cells involved in the pathogenesis of allergic diseases including asthma by releasing cysteinyl leukotrienes. The anti-asthmatic properties of tHGA could be attributed to its inhibitory effect on mast cell degranulation. As mast cell degranulation is an important event in allergic responses, this study aimed to investigate the anti-allergic effects of tHGA in cellular and animal models of IgE-mediated mast cell degranulation. For in vitro model of IgE-mediated mast cell degranulation, DNP-IgE-sensitized RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA to induce degranulation. For IgE-mediated passive systemic anaphylaxis, Sprague Dawley rats were sensitized by intraperitoneal injection of DNP-IgE before challenged with DNP-BSA. Both in vitro and in vivo models showed that tHGA significantly inhibited the release of preformed mediators (β-hexosaminidase and histamine) as well as de novo mediators (interleukin-4, tumour necrosis factor-α, prostaglandin D 2 and leukotriene C 4 ). Pre-treatment of tHGA also prevented IgE-challenged RBL-2H3 cells and peritoneal mast cells from undergoing morphological changes associated with mast cell degranulation. These findings indicate that tHGA possesses potent anti-allergic activity via attenuation of IgE-mediated mast cell degranulation and inhibition of IgE-mediated passive systemic anaphylaxis. Thus, tHGA may have the potential to be developed as a mast cell stabilizer for the treatment of allergic diseases in the future. - Highlights: • The in vitro and in vivo mast cell stabilizing effects of tHGA were examined. • tHGA counteracts the plasma membrane deformation in degranulating mast cells. • t

Alteration effect of the PGFsub(2α) inhibition on the 3H-norepinephrine release caused by α2 receptor blocking, sodium loading and 4-aminopyridine addition in isolated pulmonary arteries of rabbit

International Nuclear Information System (INIS)

Bunyevacs, Zs.; Toeroek, T.; Hadhazy, P.; Magyar, K.; Feher, L.; Vizi, E.Sz.

1983-01-01

The tritium labelled norepinephrine release was measured in isolated pulmonary artery of rabbit. If the 3 H-norepinephrine release was induced by nerves stimulated with electric current, the PGFsub(2α) inhibited the release by 62%. In the presence of Yohimbin the inhibitory effect of FGFsub(2α) was increased to 78.8%. If the Na + pump activity was reduced by potassium-free medium the PGFsub(2α) inhibition remained at 62%. In the presence of 4-aminopyridine the potassium channel was blocked and the PGFsub(2α) inhibition decreased to 32.1%. The endogen prostaglandin may serve as a modulator of the neurotransmitter release. (L.G.)

Defining the therapeutic time window for suppressing the inflammatory prostaglandin E2 signaling after status epilepticus

Science.gov (United States)

Du, Yifeng; Kemper, Timothy; Qiu, Jiange; Jiang, Jianxiong

2016-01-01

Neuroinflammation is a common feature in nearly all neurological and some psychiatric disorders. Resembling its extraneural counterpart, neuroinflammation can be both beneficial and detrimental depending on the responding molecules. The overall effect of inflammation on disease progression is highly dependent on the extent of inflammatory mediator production and the duration of inflammatory induction. The time-dependent aspect of inflammatory responses suggests that the therapeutic time window for quelling neuroinflammation might vary with molecular targets and injury types. Therefore, it is important to define the therapeutic time window for anti-inflammatory therapeutics, as contradicting or negative results might arise when different treatment regimens are utilized even in similar animal models. Herein, we discuss a few critical factors that can help define the therapeutic time window and optimize treatment paradigm for suppressing the cyclooxygenase-2/prostaglandin-mediated inflammation after status epilepticus. These determinants should also be relevant to other anti-inflammatory therapeutic strategies for the CNS diseases. PMID:26689339

Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade

Directory of Open Access Journals (Sweden)

Richa Tyagi

2015-02-01

Full Text Available Rheb, a ubiquitous small GTPase, is well known to bind and activate mTOR, which augments protein synthesis. Inhibition of protein synthesis is also physiologically regulated. Thus, with cell stress, the unfolded protein response system leads to phosphorylation of the initiation factor eIF2α and arrest of protein synthesis. We now demonstrate a major role for Rheb in inhibiting protein synthesis by enhancing the phosphorylation of eIF2α by protein kinase-like ER kinase (PERK. Interplay between the stimulatory and inhibitory roles of Rheb may enable cells to modulate protein synthesis in response to varying environmental stresses.

The Aryl Hydrocarbon Receptor Binds to E2F1 and Inhibits E2F1-induced Apoptosis

Science.gov (United States)

Marlowe, Jennifer L.; Fan, Yunxia; Chang, Xiaoqing; Peng, Li; Knudsen, Erik S.; Xia, Ying

2008-01-01

Cellular stress by DNA damage induces checkpoint kinase-2 (CHK2)-mediated phosphorylation and stabilization of the E2F1 transcription factor, leading to induction of apoptosis by activation of a subset of proapoptotic E2F1 target genes, including Apaf1 and p73. This report characterizes an interaction between the aryl hydrocarbon (Ah) receptor (AHR), a ligand-activated transcription factor, and E2F1 that results in the attenuation of E2F1-mediated apoptosis. In Ahr−/− fibroblasts stably transfected with a doxycycline-regulated AHR expression vector, inhibition of AHR expression causes a significant elevation of oxidative stress, γH2A.X histone phosphorylation, and E2F1-dependent apoptosis, which can be blocked by small interfering RNA-mediated knockdown of E2F1 expression. In contrast, ligand-dependent AHR activation protects these cells from etoposide-induced cell death. In cells expressing both proteins, AHR and E2F1 interact independently of the retinoblastoma protein (RB), because AHR and E2F1 coimmunoprecipitate from extracts of RB-negative cells. Additionally, chromatin immunoprecipitation assays indicate that AHR and E2F1 bind to the Apaf1 promoter at a region containing a consensus E2F1 binding site but no AHR binding sites. AHR activation represses Apaf1 and TAp73 mRNA induction by a constitutively active CHK2 expression vector. Furthermore, AHR overexpression blocks the transcriptional induction of Apaf1 and p73 and the accumulation of sub-G0/G1 cells resulting from ectopic overexpression of E2F1. These results point to a proproliferative, antiapoptotic function of the Ah receptor that likely plays a role in tumor progression. PMID:18524851

Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/PKA- and EP1/Ca2+-mediated mechanism in the human pancreatic carcinoma cell line PANC-1.

Science.gov (United States)

Chang, Hui-Hua; Young, Steven H; Sinnett-Smith, James; Chou, Caroline Ei Ne; Moro, Aune; Hertzer, Kathleen M; Hines, Oscar Joe; Rozengurt, Enrique; Eibl, Guido

2015-11-15

Obesity, a known risk factor for pancreatic cancer, is associated with inflammation and insulin resistance. Proinflammatory prostaglandin E2 (PGE2) and elevated insulin-like growth factor type 1 (IGF-1), related to insulin resistance, are shown to play critical roles in pancreatic cancer progression. We aimed to explore a potential cross talk between PGE2 signaling and the IGF-1/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway in pancreatic cancer, which may be a key to unraveling the obesity-cancer link. In PANC-1 human pancreatic cancer cells, we showed that PGE2 stimulated mTORC1 activity independently of Akt, as evaluated by downstream signaling events. Subsequently, using pharmacological and genetic approaches, we demonstrated that PGE2-induced mTORC1 activation is mediated by the EP4/cAMP/PKA pathway, as well as an EP1/Ca(2+)-dependent pathway. The cooperative roles of the two pathways were supported by the maximal inhibition achieved with the combined pharmacological blockade, and the coexistence of highly expressed EP1 (mediating the Ca(2+) response) and EP2 or EP4 (mediating the cAMP/PKA pathway) in PANC-1 cells and in the prostate cancer line PC-3, which also robustly exhibited PGE2-induced mTORC1 activation, as identified from a screen in various cancer cell lines. Importantly, we showed a reinforcing interaction between PGE2 and IGF-1 on mTORC1 signaling, with an increase in IL-23 production as a cellular outcome. Our data reveal a previously unrecognized mechanism of PGE2-stimulated mTORC1 activation mediated by EP4/cAMP/PKA and EP1/Ca(2+) signaling, which may be of great importance in elucidating the promoting effects of obesity in pancreatic cancer. Ultimately, a precise understanding of these molecular links may provide novel targets for efficacious interventions devoid of adverse effects. Copyright © 2015 the American Physiological Society.

Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells.

Science.gov (United States)

Dinarello, C A; Cannon, J G; Mancilla, J; Bishai, I; Lees, J; Coceani, F

1991-10-25

Fever induced by endogenous as well as exogenous pyrogens is often prevented by cyclooxygenase inhibitors; endogenous pyrogens stimulate prostaglandin E2 (PGE2) in or near the thermoregulatory centers of the brain. The cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), are two pyrogens which stimulate brain PGE2 formation during fever and also increase PGE2 synthesis in human mononuclear cells in vitro. In the present study, we examined whether interleukin-6 (IL-6) stimulates PGE2 formation in a manner similar to IL-1 and TNF. Both glycosylated and non-glycosylated forms of recombinant human IL-6 were tested. Following intravenous injection into rabbits, the glycosylated IL-6 was more pyrogenic than the non-glycosylated form and there was no evidence of synergy in the production of fever when IL-6 and IL-1 were given simultaneously. IL-6 fever was blocked by prior administration of the cyclooxygenase inhibitor ibuprofen. IL-6 was also pyrogenic in the cat by either the systemic or the intraventricular route. However, in both species, IL-6 was less effective than IL-1 beta. When given intraventricularly to cats, IL-6 produced an increase in PGE2 levels of the cerebrospinal fluid in parallel with the rise in body temperature. In the latter respect, IL-6 imitated IL-1 beta; however, IL-6 from 0.15-15 micrograms/ml did not increase mononuclear cell PGE2 production in vitro whereas IL-1 beta induced 20-30-fold increases in PGE2 at 100 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of Pro-inflammatory Mediators and Cytokines by Chlorella Vulgaris Extracts.

Science.gov (United States)

Sibi, G; Rabina, Santa

2016-01-01

The aim of this study was to determine the in vitro anti-inflammatory activities of solvent fractions from Chlorella vulgaris by inhibiting the production of pro-inflammatory mediators and cytokines. Methanolic extracts (80%) of C. vulgaris were prepared and partitioned with solvents of increasing polarity viz., n-hexane, chloroform, ethanol, and water. Various concentrations of the fractions were tested for cytotoxicity in RAW 264.7 cells using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and the concentrations inducing cell growth inhibition by about 50% (IC50) were chosen for further studies. Lipopolysaccharide (LPS) stimulated RAW 264.7 cells were treated with varying concentrations of C. vulgaris fractions and examined for its effects on nitric oxide (NO) production by Griess assay. The release of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) were quantified using enzyme-linked immunosorbent assay using Celecoxib and polymyxin B as positive controls. MTT assay revealed all the solvent fractions that inhibited cell growth in a dose-dependent manner. Of all the extracts, 80% methanolic extract exhibited the strongest anti-inflammatory activity by inhibiting NO production (P < 0.01), PGE2 (P < 0.05), TNF-α, and IL-6 (P < 0.001) release in LPS induced RAW 264.7 cells. Both hexane and chloroform fractions recorded a significant (P < 0.05) and dose-dependent inhibition of LPS induced inflammatory mediators and cytokines in vitro. The anti-inflammatory effect of ethanol and aqueous extracts was not significant in the study. The significant inhibition of inflammatory mediators and cytokines by fractions from C. vulgaris suggests that this microalga would be a potential source of developing anti-inflammatory agents and a good alternate for conventional steroidal and nonsteroidal anti-inflammatory drugs. C. vulgaris extracts have potential anti-inflammatory activitySolvent extraction using methanol

Chloroquine, quinine, procaine, quinidine and clomipramine are prostaglandin agonists and antagonists.

Science.gov (United States)

Manku, M S; Horrobin, D F

1976-11-01

Chloroquine, quinine, procaine, quinidine and clomipramine behave as prostaglandin (PG) antagonists in a rat mesenteric vascular bed preparation. The ID50 concentrations were within the range of therapeutically effective human plasma levels in each case. Antagonism to PGE2 was studied in detail and seemed to be at least in part competitive. The drugs also antagonized the effects of PGs A1, A2, F2alpha and E1. Each drug also had weak prostaglandin agonist activity but only over a very narrow range of concentrations. It is possible that some of the clinical actions of these drugs may depend on blockade or imitation of natural PG effects. The findings suggest new approaches to the search for PG antagonists, a new screening technique for anti-inflammatory drugs and possible new uses for these established drugs. A preliminary study suggests that chloroquine may be successful in closing a patent ductus arteriosus in infants.

Sustained Release of Prostaglandin E2 in Fibroblasts Expressing Ectopically Cyclooxygenase 2 Impairs P2Y-Dependent Ca2+-Mobilization

Directory of Open Access Journals (Sweden)

María Pimentel-Santillana

2014-01-01

Full Text Available The nucleotide uridine trisphosphate (UTP released to the extracellular milieu acts as a signaling molecule via activation of specific pyrimidine receptors (P2Y. P2Y receptors are G protein-coupled receptors expressed in many cell types. These receptors mediate several cell responses and they are involved in intracellular calcium mobilization. We investigated the role of the prostanoid PGE2 in P2Y signaling in mouse embryonic fibroblasts (MEFs, since these cells are involved in different ontogenic and physiopathological processes, among them is tissue repair following proinflammatory activation. Interestingly, Ca2+-mobilization induced by UTP-dependent P2Y activation was reduced by PGE2 when this prostanoid was produced by MEFs transfected with COX-2 or when PGE2 was added exogenously to the culture medium. This Ca2+-mobilization was important for the activation of different metabolic pathways in fibroblasts. Moreover, inhibition of COX-2 with selective coxibs prevented UTP-dependent P2Y activation in these cells. The inhibition of P2Y responses by PGE2 involves the activation of PKCs and PKD, a response that can be suppressed after pharmacological inhibition of these protein kinases. In addition to this, PGE2 reduces the fibroblast migration induced by P2Y-agonists such as UTP. Taken together, these data demonstrate that PGE2 is involved in the regulation of P2Y signaling in these cells.

Oryza sativa (Rice) Hull Extract Inhibits Lipopolysaccharide-Induced Inflammatory Response in RAW264.7 Macrophages by Suppressing Extracellular Signal-regulated Kinase, c-Jun N-terminal Kinase, and Nuclear Factor-κB Activation.

Science.gov (United States)

Ha, Sang Keun; Sung, Jeehye; Choi, Inwook; Kim, Yoonsook

2016-01-01

Rice ( Oryza sativa ) is a major cereal crop in many Asian countries and an important staple food source. Rice hulls have been reported to possess antioxidant activities. In this study, we evaluated the antiinflammatory effects of rice hull extract and associated signal transduction mechanisms in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We found that rice hull extract inhibited nitric oxide (NO) and prostaglandin E 2 by suppressing the expression of inducible NO synthase and cyclooxygenase-2, respectively. The release of interleukin-1β and tumor necrosis factor-α was also reduced in a dose-dependent manner. Furthermore, rice hull extract attenuated the activation of nuclear factor-kappa B (NF-κB), as well as the phosphorylation of mitogen-activated protein kinases, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), in LPS-stimulated RAW264.7 cells. This suggests that rice hull extract decreases the production of inflammatory mediators by downregulating ERK and JNK and the NF-κB signal pathway in RAW 264.7 cells. Rice hull extract inhibits the lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages.Rice hull extract inhibited nitric oxide and prostaglandin E 2 by suppressing the expression of inducible NO synthase and cyclooxygenase-2, respectively.Rice hull extract exerted anti-inflammatory effect through inhibition of nuclear factor-kappa B, extracellular signal-regulated kinase and c-Jun N-terminal kinase signaling pathways.Rice hull extract may provide a potential therapeutic approach for inflammatory diseases. Abbreviations used: COX-2: cyclooxygenase-2, ERK: extracellular signal-regulated kinase, IκB: inhibitory kappa B, IL-1β: interleukin-1β, iNOS: inducible NO synthase, JNK: c-Jun N-terminal kinase, LPS: lipopolysaccharide, MAPKs: mitogen-activated protein kinases, NF-κB: nuclear factor-κB, NO: nitric oxide, PGE2: prostaglandin E2, RHE: rice hull extract, ROS: reactive oxygen species

Preoperative immunonutrition decreases postoperative complications by modulating prostaglandin E2 production and T-cell differentiation in patients undergoing pancreatoduodenectomy.

Science.gov (United States)

Aida, Toshiaki; Furukawa, Katsunori; Suzuki, Daisuke; Shimizu, Hiroaki; Yoshidome, Hiroyuki; Ohtsuka, Masayuki; Kato, Atsushi; Yoshitomi, Hideyuki; Miyazaki, Masaru

2014-01-01

An immune-enhancing diet has been used to alter eicosanoid synthesis, cytokine production, and immune function in an attempt to limit the undesired immune reactions after injury from surgery. This prospective randomized study was designed to investigate the effect of preoperative immunonutrition on operative complications, and the participation of prostaglandin E2 (PGE2) on T-cell differentiation in patients undergoing a severely stressful surgery. The enrolled patients who were scheduled to undergo pancreatoduodenectomy were randomized into two groups. Patients in the immunonutrition group (n = 25) received oral supplementation containing arginine, ω-3 fatty acids, and RNA for 5 days before the procedure in addition to a 50% reduction in the amount of regular food. Patients in the control group (n = 25) received no artificial nutrition and were allowed to consume regular food before surgery. All patients received early postoperative enteral infusion of a standard formula intended to provide 25 kcal/kg/day. The primary endpoint was the rate of infectious complications; the secondary endpoint was immune responses. This study is registered with ClinicalTrials.gov (NCT01256034). Infectious complication rate and severity of complications (Clavien-Dindo classification) were lesser in the immunonutrition group than in the control group. mRNA expression levels of T-bet were greater in the immunonutrition group than in the control group (P production and T-cell differentiation and may protect against the aggravation of operative complications in patients undergoing pancreatoduodenectomy. Copyright © 2014 Mosby, Inc. All rights reserved.

Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms

International Nuclear Information System (INIS)

Rasmusson, Ida; Ringden, Olle; Sundberg, Berit; Le Blanc, Katarina

2005-01-01

Human mesenchymal stem cells (MSCs) have immuno-modulatory properties. They inhibit T-cell proliferation to mitogens and alloantigens in vitro and prolong skin graft survival in vivo. We found that MSCs inhibited the proliferation of peripheral blood lymphocytes (PBLs) to phorbol myristate acetate (PMA), suggesting that MSCs exert an inhibitory effect downstream of the receptor level. We analyzed cytokine profiles of PBLs co-cultured with MSCs. MSCs increased interleukin (IL)-2 and soluble IL-2 receptor in mixed lymphocyte cultures (MLCs), while IL-2 and IL-2R decreased in phytohemagglutinin (PHA)-stimulated PBL cultures. MSCs inhibited IL-2 induced proliferation, without absorbing IL-2. IL-10 levels increased in MLCs co-cultured with 10% MSCs, while the levels were not affected in PHA cultures. In MLCs inhibited by MSCs, antibodies against IL-10 further suppressed proliferation but had no effect in PHA cultures. Addition of indomethacin, an inhibitor of prostaglandin-synthesis, restored part of the inhibition by MSCs in PHA cultures. However, indomethacin did not affect MSC-induced inhibition in MLCs. To conclude, our data indicate that MSC-induced suppression is a complex mechanism affecting IL-2 and IL-10 signaling and may function differently, depending on T-cell stimuli. Prostaglandins are important in the inhibition by MSCs when the T cells were activated by PHA, but not alloantigens

Prostaglandins in the kidney: developments since Y2K.

Science.gov (United States)

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

2007-10-01

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

The effects of histamine and prostaglandin D2 on rat mast-cell cyclic AMP and mediator release

International Nuclear Information System (INIS)

Wescott, S.; Kaliner, M.

1981-01-01

The possibility that histamine may play a functional role in modulating mast-cell secretion, as has been suggested for basophil degranulation, has both physiologic and pharmacologic implications. Therefore the capacity of histamine to influence rat peritoneal mast-cell (RPMC) cyclic AMP levels and reversed anaphylatic degranulation as reflected in the release of 3H-serotonin (5-HT) was examined. To ascertain that RPMC were functionally responsive to exogenous hormonal stimulation, assessment of prostaglandin (PG) D2 effects on cyclic AMP and 5-HT release were determined in parallel. Although PGD2 (100 microM) increased cyclic AMP and inhibited 5-HT release in the presence of 50 microM aminophylline, histamine (up to 1000 microM) was ineffective was ineffective in both. However, 1000 microM histamine in the presence of 500 microM aminophylline was capable of transiently increasing RPMC cyclic AMP (for 15 to 30 sec) and under these conditions of suppressing 5-HT release. The receptor subtype involved in the suppressive actions of histamine appeared to be of the H-1 type as reflected in the capacity of specific H-1 agonists to reproduce the inhibition of 5-HT release, whereas neither H-2 agonists nor H-2 antagonists had any influence. Thus, under conditions in which phosphodiesterase enzymatic action is impaired, histamine in extremely high concentrations is able to modulate mast-cell secretion. However, it seems very unlikely that this action of histamine has any physiologic significance

Simultaneous use of two prostaglandin radioimmunoassays employing two antisera of differing specificity. II. Relative stability of prostaglandins E1, E2, and F1alpha in cell cultures of BALB/c 3T3 and SV3T3 mouse fibroblasts

International Nuclear Information System (INIS)

Ritzi, E.M.; Stylos, W.A.

1976-01-01

The relative stability of Prostaglandins (PGs) E1, E2 and F1α in cultures of BALB/c 3T3 and SV3T3 cells has been evaluated using 3 different approaches. First, total recovery of tritium in the ethyl acetate phase following incubation and extraction of PGF1α and PGE1 demonstrated greater stability for PGF1α (88.8 percent) than PGE1 (65.9 percent). Second, analysis of incubated, extracted, tritiated PGs by thin layer chromatography revealed decreases of up to 23 percent in the PGE zone following incubation of 3H-PGE1. With increasing time of incubation, decreases in the PGE zone were accompanied by increase in PGA-like compounds. 3H-PGF1α demonstrated greater stability, having greater than 90 percent recovery of the tritium in the PGF zone. A third approach to the assessment of PG stability in culture was the comparison of the production of individual PGs by radioimmunoassay (RIA). The data obtained by RIA indicated a lag in the increase of PGA and PGB, until an initial rise in PGE was noted, suggesting that PGA and PGB may be secondary products arising from PGE which exhibits only partial stability in culture. By employing two RIAs, one for total PGE and one for PGA and PGB, the composite determination PG [E + (A + B)] can be used to provide a more meaningful determination of PG production because of the instability of the PGs. On the other hand, individual determinations are helpful in assessing the stability of PGEs in cell cultures

Suppression of the cutaneous immune response following topical application of the prostaglandin PGE2

International Nuclear Information System (INIS)

Rheins, L.A.; Barnes, L.; Amornsiripanitch, S.; Collins, C.E.; Nordlund, J.J.

1987-01-01

UVB irradiation (290-320 nm) and topical applications of arachidonic acid (AA) in mice decrease the number of identifiable Langerhans cells and alter the cutaneous immune response. Application of contact allergens such as dinitrofluorobenzene (DNFB) to irradiated or AA-treated skin induces antigen-specific tolerance. Indomethacin (IM), a cyclooxygenase inhibitor, administered orally to mice prior to UVB irradiation or prior to the topical application of arachidonic acid, abrogates suppression of contact hypersensitivity (CHS) to DNFB. This suggests a byproduct of arachidonic acid generated through the cyclooxygenase pathway may be involved in the immune suppression. Topical application of various prostaglandins (PGE2, PGD2, PGF2 alpha, and CTXA2) did not cause alterations in the population density of the identifiable Ia+ dendritic Langerhans cells. PGE2, but no other tested agent, produced a suppression of the CHS response to DNFB. These observations suggests that of the various prostaglandins, PGE2 might be one of several biochemical signals which mediate the suppression of contact hypersensitivity reactions following ultraviolet radiation exposure. However, the mechanisms by which PGE2 produces its suppressive effects have not been identified

Interleukin-1 inhibits the synthesis of collagen by fibroblasts.

Science.gov (United States)

Bhatnagar, R; Penfornis, H; Mauviel, A; Loyau, G; Saklatvala, J; Pujol, J P

1986-10-01

Human dermal fibroblasts, exposed to human or porcine Interleukin-1, responded by an inhibition of collagen synthesis in a dose dependent manner. Incubation with Il-1 for more than 8 h was required to see an appreciable effect. The phenomenon was not dependent on the presence of serum in the culture medium. Since a stimulation of prostaglandin E2 secretion was also observed in presence of Il-1, we investigated the eventual role of arachidonic acid metabolites in the phenomenon. Inhibitors interfering with arachidonate metabolism, namely indomethacin, acetyl salicylic acid, BW 755 C and NDGA had no influence on the inhibition of collagen synthesis caused by Il-1. These data suggest that both cyclooxygenase and lipoxygenase derived metabolites of arachidonic acid are unlikely to play a role in the mechanism.

v-src induction of the TIS10/PGS2 prostaglandin synthase gene is mediated by an ATF/CRE transcription response element.

OpenAIRE

Xie, W; Fletcher, B S; Andersen, R D; Herschman, H R

1994-01-01

We recently reported the cloning of a mitogen-inducible prostaglandin synthase gene, TIS10/PGS2. In addition to growth factors and tumor promoters, the v-src oncogene induces TIS10/PGS2 expression in 3T3 cells. Deletion analysis, using luciferase reporters, identifies a region between -80 and -40 nucleotides 5' of the TIS10/PGS2 transcription start site that mediates pp60v-src induction in 3T3 cells. This region contains the sequence CGTCACGTG, which includes overlapping ATF/CRE (CGTCA) and E...

Relation between acid back-diffusion and luminal surface hydrophobicity in canine gastric mucosa: Effects of salicylate and prostaglandin

International Nuclear Information System (INIS)

Goddard, P.J.

1989-01-01

The stomach is thought to be protected from luminal acid by a gastric mucosal barrier that restricts the diffusion of acid into tissue. This study tested the hypothesis that the hydrophobic luminal surface of canine gastric mucosa incubated in Ussing chambers, impedes the back-diffusion of luminal acid into the tissue. Isolated sheets of mucosa were treated with cimetidine to inhibit spontaneous acid secretion, and incubated under conditions that prevented significant secretion of luminal bicarbonate. By measuring acid loss from the luminal compartment using the pH-stat technique, acid back-diffusion was continuously monitored; potential difference (PD) was measured as an index of tissue viability. Tissue luminal surface hydrophobicity was estimated by contact angle analysis at the end of each experiment. Addition of 16,16-dimethyl prostaglandin E 2 to the nutrient compartment enhanced luminal surface hydrophobicity, but did not reduce acid back-diffusion in tissues that maintained a constant PD. 10 mM salicylate at pH 4.00 in the luminal compartment reduced surface hydrophobicity, but this decrease did not occur if 1 ug/ml prostaglandin was present in the nutrient solution. Despite possessing relatively hydrophilic and relatively hydrophobic surface properties, respectively, acid back-diffusion in the absence of salicylate was not significantly different between these two groups. Neither group maintained a PD after incubation with salicylate. Lastly, radiolabeled salicylate was used to calculate the free (non-salicylate associated) acid loss in tissues incubated with salicylate and/or prostaglandin. No significant correlation was found between free acid back-diffusion and luminal surface hydrophobicity. These data do not support the hypothesis that acid back-diffusion in impeded by the hydrophobic surface presented by isolated canine gastric mucosa

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

DEFF Research Database (Denmark)

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

2007-01-01

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

Topical or systemic 16,16 dm prostaglandin E2 or WR-2721 (WR-1065) protects mice from alopecia after fractionated irradiation

International Nuclear Information System (INIS)

Geng, L.; Malkinson, F.D.; Hanson, W.R.

1992-01-01

Previous studies in mice demonstrated that systemic or topical 16,16 dm PGE 2 protected against single dose radiation-induced hair loss. The authors have now investigated prostaglandin, or WR-2721, protection against murine alopecia produced by varying doses and schedules of fractionated radiation. In some studies with the radioprotectors given systematically, WR-2721 afforded slightly greater radioprotection than 16,16 dm PGE 2 . The two compounds were essentially equally radioprotective in the topical application studies. Since both systemic and topical applications of the agents tested enhanced hair regrowth following radiation, the authors conclude that clinical use of these compounds may provide some protection of hair follicles, and perhaps other tissues, lying within a radiation therapy field. (author)

Bovine milk-derived α-lactalbumin inhibits colon inflammation and carcinogenesis in azoxymethane and dextran sodium sulfate-treated mice.

Science.gov (United States)

Yamaguchi, Makoto; Takai, Shoko; Hosono, Akira; Seki, Taiichiro

2014-01-01

Cyclooxygenase-2 is expressed early in colon carcinogenesis and plays crucial role in the progress of the disease. Recently, we found that α-lactalbumin had anti-inflammatory activity by inhibiting cyclooxygenase-2. In experiment 1, we investigated the effects of α-lactalbumin on the colon carcinogenesis initiated with azoxymethane (AOM) followed by promotion with dextran sodium sulfate (DSS) in mice. Dietary treatment with α-lactalbumin decreased fecal occult blood score at 3 days after DSS intake. α-Lactalbumin also decreased the colon tumor at week 9. In experiment 2, AOM-treated mice were sacrificed at 7 days after DSS intake. The plasma and colon prostaglandin E2 (PGE2) levels in AOM/DSS-treated mice were higher than those in the DSS-treated mice without initiation by AOM. α-Lactalbumin decreased PGE2 in both plasma and colon. These results suggest that α-lactalbumin effectively inhibited colon carcinogenesis, and the inhibition may be due to the decreased PGE2 by inhibiting cyclooxygenase-2 at cancer promotion stages.

Prostaglandin E synthase interacts with inducible heat shock protein 70 after heat stress in bovine primary dermal fibroblast cells.

Science.gov (United States)

Richter, Constanze; Viergutz, Torsten; Schwerin, Manfred; Weitzel, Joachim M

2015-01-01

Exposure to heat stress in dairy cows leads to undesired side effects that are reflected by complex alterations in endocrine parameters, such as reduced progesterone, estradiol, and thyroid hormone concentrations. These endocrine maladaptation leads to failure to resume cyclicity, a poor uterine environment and inappropriate immune responses in postpartum dairy cows. Prostaglandins (PG's) are lipid mediators, which serve as signal molecules in response to various external stimuli as well as to cell-specific internal signal molecules. A central role in PG synthesis plays prostaglandin E synthase (PGES) that catalyzes the isomerization of PGH2 to PGE2 .The present study was conducted to investigate heat stress associated PGES expression. Expression of PGES and inducible heat shock protein 70 (HSP70), as a putative chaperonic protein, was studied in bovine primary fibroblasts under different heat shock conditions. Bovine primary fibroblasts produce PGE2 at homoiothermical norm temperature (38.5°C in bovine), but reduce PGE2 production rates under extreme heat stress (at 45°C for 6 h). By contrast, PGE2 production rates are maintained after a milder heat stress (at 41.5°C for 6 h). PGE2 synthesis is abolished by application of cyclooxygenase inhibitor indomethacin, indicating de novo synthesis. Heat stress increases HSP70 but not PGES protein concentrations. HSP70 physically interacts with PGES and the PGES-HSP70 complex did not dissociate upon heat stress at 45°C even after returning the cells to 37°C. The PGE2 production negatively correlates with the portion of PGES-HSP70 complex. These results suggest a protein interaction between HSP70 and PGES in dermal fibroblast cells. Blockage of PGES protein by HSP70 seems to interfere with the regulatory processes essential for cellular adaptive protection. © 2014 International Society for Advancement of Cytometry. © 2014 International Society for Advancement of Cytometry.

Expression of prostaglandin synthases (pgds and pges) duringzebrafishgonadal differentiation

DEFF Research Database (Denmark)

Jørgensen, Anne; Nielsen, John E.; Nielsen, Betina F.

2010-01-01

The present study aimed at elucidating whether the expression pattern of the membrane bound form of prostaglandin E-2 synthase (pges) and especially the lipocalin-type prostaglandin D-2 synthase (pgds) indicates involvement in gonadal sex differentiation in zebrafish as has previously been found...... In this study, a sexually dimorphic expression of pgds was found in gonads of adult zebrafish with expression in testis but not in ovaries. To determine whether the sex-specific expression pattern of pgds was present in gonads of juvenile zebrafish and therefore could be an early marker of sex in zebrafish, we...... microdissected gonads from four randomly selected individual zebrafish for every second day in the period 2-20 days post hatch (dph) and 0-1 dph The temporal expression of pgds and pges was investigated in the microdissected gonads, however, no differential expression that could indicate sex-specific difference...

Human interleukin 1β (IL-1β), a more powerful inducer of bone demineralization than interleukin 1α (IL-1α), parathyroid hormone (PTH) or prostaglandin E2 (PGE2) in vitro

International Nuclear Information System (INIS)

Chin, R.C.; Hodges, Y.C.; Allison, A.C.

1986-01-01

Effects of human IL-1α and IL-1β, prepared by recombinant DNA technology on cultures of rat fetal long bones, prelabelled with 45 Ca were studied. IL-1β was found to be the most powerful inducer of bone calcium loss so far known. Maximal activity (2.5 times the control rate of calcium loss) was induced by IL-1β at concentrations between 1 x 10 -10 M to 6 x 10 -12 M. With IL-1α maximal activity (1.5 times the control rate of calcium loss) was obtained at 6 x 10 -10 M. With bovine PTH (1-34) maximal activity (1.8 times the control rate of calcium loss) was obtained at 1 x 10 -8 M. With PGE 2 maximal activity (1.6 times the control rate of calcium loss) was obtained at 1 x 10 -7 M. The calcium loss induced by IL-1β was inhibited in the presence of 1 x 10 -7 M indomethacin, 5 x 10 -5 M naproxen or ketorolac, or 5 x 10 -6 M cyclohexamide. These findings suggest that protein synthesis and prostaglandin formation are required to mediate bone demineralization induced by IL-1β