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Alzheimer's disease (AD) is a prevalent neurodegenerative condition affecting a substantial portion of the global population. It is marked by a complex interplay of factors, including the accumulation of amyloid plaques and tau tangles within the brain, leading to neuroinflammation and neuronal damage. Recent studies have underscored the role of free lipids and their derivatives in the initiation and progression of AD. Eicosanoids, metabolites of polyunsaturated fatty acids like arachidonic acid (AA), emerge as key players in this scenario. Remarkably, eicosanoids can either promote or inhibit the development of AD, and this multifaceted role is determined by how eicosanoid signaling influences the immune responses within the brain. However, the precise molecular mechanisms dictating the dual role of eicosanoids in AD remain elusive. In this comprehensive review, we explore the intricate involvement of eicosanoids in neuronal function and dysfunction. Furthermore, we assess the therapeutic potential of targeting eicosanoid signaling pathways as a viable strategy for mitigating or halting the progression of AD. [ABSTRACT FROM AUTHOR]

Abstract Bovine endometritis is the most common uterine disease following parturition. The role of prostaglandin E 2 (PGE 2) in regulating normal physiological function in the bovine endometrium has been clearly established. Although PGE 2 accumulation is observed in multiple inflammatory diseases, such as endometritis, its association with pathogen-induced inflammatory damage in the endometrium is unclear. To clarify the role of PGE 2 in lipopolysaccharide (LPS)-induced endometritis in cultured bovine endometrial explants, the levels of PGE 2 secretion, prostaglandin synthetases, pro-inflammatory factors, and damage-associated molecular patterns (DAMPs) were evaluated in the present study. Significant PGE 2 accumulation in response to LPS stimulation, up-regulation of prostaglandin-endoperoxide synthase-2 (PTGS-2), microsomal prostaglandin E synthase-1 (mPGES-1), pro-inflammatory factors including interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and induced nitric oxide synthase (iNOS)/nitric oxide (NO) and DAMPs including hyaluronan binding protein 1 (HABP1) and high mobility group box-1 (HMGB1), were observed compared to the control group. LPS induced distinct damage in the bovine endometrium, characterized by morphological changes and increases in HABP1 and HMGB1 expression. PTGS-2 inhibitors CAY10404 and NS398 effectively decreased the secretion of PGE 2 and the expression of prostaglandin synthetases, pro-inflammatory factors and DAMPs, and alleviated LPS-induced tissue damage. These results indicate that PGE 2 accumulates via PTGS-2 and mPGES-1 and induces tissue damage by upregulating pro-inflammatory factors and DAMPs in LPS-treated bovine endometrial explants. These findings provide a basis for the effect of PGE 2 on LPS-treated bovine endometrium, and suggest a potential target for curing endometritis. [ABSTRACT FROM AUTHOR]

Abstract Nimesulide is a relatively selective cyclooxygenase (COX)-2 inhibitor, non-steroidal anti-inflammatory drug; it has been discovered in 1971 and firstly commercialized in Italy in 1985. There is much evidence that the pharmacological profile of nimesulide is peculiar and not shared with the other COX-2 selective inhibitors, suggesting that other molecular mechanisms besides inhibition of COX-2 derived prostaglandins are involved. Similarly, experimental data suggest that the gastrointestinal safety of nimesulide cannot be ascribed only to a COX-1 sparing effect. On the inflammatory process, the efficacy of nimesulide is dependent upon a wide spectrum of actions, due to the combination of effects on immune and non–immune cells. Early data demonstrated a central role for cyclic AMP (cAMP) in the anti-inflammatory effect of nimesulide; more recently, we have shown the involvement of the pathway ecto-5′-nucleotidase/adenosine A 2A receptor. To date, the molecular mechanism(s) that confers uniqueness to nimesulide have not yet been defined. To go inside the mechanism of action of an existing drug, such as nimesulide, would be helpful to refine its therapeutic use but also to identify new targets for novel therapeutic anti-inflammatory approach. Here, we focus on accumulated evidence for a peculiar pharmacological profile of nimesulide. [ABSTRACT FROM AUTHOR]

Prostaglandin (PG) D 2 , a commonly considered vasodilator through D prostanoid receptor-1 (DP1), might also evoke vasoconstriction via acting on the thromboxane (Tx)-prostanoid receptor (the original receptor of TxA 2 ; TP) and/or E prostanoid receptor-3 (one of the vasoconstrictor receptors of PGE 2 ; EP3). This study aimed to test the above hypothesis in the mouse renal vascular bed (main renal arteries and perfused kidneys) and/or mesenteric resistance arteries and determine how the vasoconstrictor mechanism influences the overall PGD 2 effect on systemic blood pressure under in vivo conditions. Experiments were performed on control wild-type (WT) mice and mice with deficiencies in TP (TP−/−) and/or EP3 (EP3−/−). Here we show that PGD 2 indeed evoked vasoconstrictor responses in the above-mentioned tissues of WT mice, which were however not only reduced by TP−/− or EP3−/−, but also reversed by TP−/−/EP3−/− in some of the above tissues (mesenteric resistance arteries or perfused kidneys) to dilator reactions that were reduced by non-selective DP antagonism. A slight or mild pressor response was also observed with PGD 2 under in vivo conditions, and this was again reversed to a depressor response in TP−/− or TP−/−/EP3−/− mice. Non-selective DP antagonism reduced the PGD 2 -evoked depressor response in TP−/−/EP3−/− mice as well. These results thus demonstrate that like other PGs, PGD 2 activates TP and/or EP3 to evoke vasoconstrictor activities, which can outweigh its concurrent vasodepressor activity mediated mainly through DP1, and hence result in a pressor response, although the response might only be of a slight or mild extent. [ABSTRACT FROM AUTHOR]

Abstract Prostaglandin (PG) D 2 , a prostanoid known to have hypotensive effect, can evoke increased in vitro prepartum myometrial contraction resulting from up-regulation of the F prostanoid (FP) receptor. The present study further determined postpartum rat uterine responses to PGD 2 to evaluate the possibility of the prostanoid becoming a therapeutic for postpartum uterine atony, a major cause of postpartum hemorrhage that can lead to maternal morbidity. In vitro and in vivo postpartum uterine responses to PGD 2 were determined and compared to those of prepartum rats. Here we show that in postpartum myometrial strips PGD 2 did evoke a contraction sensitive to FP receptor antagonism. Interestingly, this response was not only to a greater extent than that of prepartum rats, but also comparable with the contraction obtained with PGF 2α , a therapeutic for postpartum uterine atony but contradicted in conditions including hypertension. Indeed, PGD 2 was also found to cause increases of basal uterine contraction under in vivo conditions. Western blots revealed that the expression of FP receptors in postpartum myometrium was higher than that of prepartum rats. Moreover, we noted that the amount of PGD 2 produced in postpartum uteri, although lower than that of prepartum rats, was increased compared to non-pregnant conditions. These results thus demonstrate that due to a further up-regulation or high expression of myometrial FP receptors, PGD 2 can evoke potent uterine contraction postpartum, and hence the prostanoid, which is naturally synthesized in uterine tissues, could be a potential therapeutic for postpartum uterine atony, especially in settings, such as hypertension. [ABSTRACT FROM AUTHOR]

Extracellular pH is an important physiological determinant of vascular tone that is normally maintained within 7.35–7.45. Any change outside this range leads to severe pathological repercussions. We investigated the unknown effects of extracellular acidosis on relaxation in the superior mesenteric artery (SMA) of goat. SMA rings were employed to maintain isometric contractions at extracellular pH (pH o ) 7.4 and 6.8. We analyzed the effect of acidosis (pH o 6.8) compared to physiological pH (pH o 7.4) on three signaling mediators of endothelium-dependent hyperpolarization: nitric oxide (NO), prostaglandin I 2 (PGI 2 ), and myoendothelial gap junctions (MEGJ). NO and cyclic guanosine monophosphate (cGMP) levels were compared between normal and acidic pH. Quantitative real-time PCR (qPCR) studies determined the change in expression of vascular connexin (Cx), Cx37 , Cx40, and Cx43 . Under acidosis, acetyl choline-induced relaxation was augmented in an endothelium-dependent manner via eNOS-NO-cGMP signaling. Conversely, at normal pH, acetyl choline-induced vasorelaxation was mediated primarily via COX-PGI 2 pathway. The functional activity of MEGJ was increased under acidosis as evident from increased sensitivity of connexin blockers and upregulated gene and protein expression of connexins. In conclusion, acetyl choline-induced augmented vasorelaxation under acidosis is mediated by NOS-NO-cGMP, with a partial role of MEGJ as EDH mediators in the SMA. Present data suggest a novel role of connexin as therapeutic targets to attenuate the detrimental effect of acidosis on vascular tone. [ABSTRACT FROM AUTHOR]

Mast cells are an exceptionally rich source of prostaglandin D 2 (PGD 2 ). PGD 2 is pro-inflammatory and can cause bronchoconstriction. The enzyme cyclooxygenase (COX) is central to the generation of prostanoids such as PGD 2 . Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX. COX exists as two isoforms, COX-1 and COX-2. The principal aim of this study was to establish whether COX-1 and/or COX-2 mediates PGD 2 generation from human lung mast cells. Mast cells were isolated from human lung tissue and purified by flotation over Percoll and immunomagnetic bead separations. The cells were activated with anti-IgE or Stem Cell Factor (SCF). The generation of PGD 2 was determined by ELISA. The effects of NSAIDs (aspirin, ibuprofen, diclofenac, naproxen, indomethacin), COX-1 selective (FR122047), and COX-2 selective (celecoxib) inhibitors on PGD 2 generation were determined. The expression of COX-1 and COX-2 in mast cells was determined by Western blotting. All the NSAIDs tested abrogated stimulated PGD 2 generation from mast cells except aspirin which was only weakly effective. FR122047 was an effective inhibitor of PGD 2 generation (EC 50 ~25 nM) from mast cells whereas celecoxib was ineffective. Immunoblotting indicated that COX-1 was strongly expressed in all mast cell preparations while COX-2 expression was weak. No induction of COX-2 was observed following activation of mast cells. These findings indicate that COX-1 is the principal isoform involved in generating PGD 2 from human lung mast cells. These studies provide insight into the potential behaviour of NSAIDs in the context of respiratory diseases. [ABSTRACT FROM AUTHOR]

This study aimed to determine whether prostaglandin D 2 (PGD 2 ) is a major uterine cyclooxygenase (COX) product and if so, we wanted to examine the underlying mechanism, its relation to COX-1-mediated metabolism, and how it influences the in vitro myometrial contraction during the late stage of pregnancy. The production of PGD 2 or responses evoked by the prostanoid were determined in uteri isolated from prepartum and/or non-pregnant C57Bl/6 wild-type (WT) or COX-1 -/- mice. Results showed that PGD 2 , which was not detected in non-pregnant counterparts, appears as the major prostanoid in prepartum (<24 h prior to parturition) mouse uteri. No signal of PGD 2 or other COX-derived products was detected in similar tissues of COX-1 −/− mice. Western blot or real-time PCR revealed that expressions of COX-1 and PGD 2 synthase (PGDS) in prepartum uteri were higher than those of non-pregnant mice, while both were diminished by the removal of endometrium. Also, we noted that in endometrium-removed prepartum uteri PGD 2 evoked an increased contraction compared to that of non-pregnant mice. Antagonizing the F prostanoid (FP) receptor but not D prostanoid receptors abolished the contraction. Moreover, the level of FP receptor mRNAs in endometrium-removed prepartum uteri was increased compared to that of non-pregnant mice. These results imply that due to up-regulations of COX-1 and PGDS in endometrium, PGD 2 becomes the major prostanoid produced in prepartum uteri where it can evoke an increased in vitro myometrial contraction, possibly resulting from up-regulation of the FP receptor, the mediator of such a response in mouse uteri. [ABSTRACT FROM AUTHOR]

Success of the long-term glaucoma therapy and preservation of the visual function strongly depend on patients' compliance which may be affected by the inconvenience of treatment and its side effects. Recently, introduction of preservative-free anti-glaucoma agents has become an important step towards improved glaucoma care by eliminating the negative effects of preservatives on the eye surface. Although, newly developed eye drop formulations do not contain standard preservatives, they still can be harmful to ocular surface due to other excipients. In this study, we compared tolerability of commercial preservative-free (pf) prostaglandin analogues (pf tafluprost, pf latanoprost and pf bimatoprost) in long-term topical application in rabbits in vivo . We found that after eight weeks treatment, pf latanoprost was the worst tolerated among the tested drops. It expressed increased conjunctival redness and blinking frequency. Furthermore, it caused increased LDH release in the aqueous humour, infiltration of macrophages in the eyelids and visible defects in conjunctival goblet cells. However, we did not detect increased levels of inflammatory markers in the tear fluid or in the aqueous humour. Based on our study, we suspect that these negative effects are related to excipients included in pf latanoprost formulation. [ABSTRACT FROM AUTHOR]

Polyunsaturated fatty acids (PUFAs) are vital for normal growth and development and physiological function of various tissues in humans. PUFAs have immunomodulatory actions in addition to their ability to modulate inflammation, vascular reactivity, neurotransmission and stem cell biology. PUFAs and their metabolites possess both pro- and anti-inflammatory properties that underlie their actions and involvement in several diseases. Aspirin, a non-steroidal anti-inflammatory drug (NSAID), possesses both cyclo-oxygenase (COX) and lipoxygenase (LOX) inhibitory action and enhances the production of anti-inflammatory lipoxin A4 {(called as epi-lipoxin A4, aspirin-triggered lipoxins (ATLs))}. In addition, at low doses aspirin may not interfere with the production of prostacyclin (PGI2). Both lipoxin A4 and PGI2 have vasodilator, platelet anti-aggregator and anti-inflammatory actions that may underlie the beneficial actions of aspirin. Paradoxically, other NSAIDs may not have the same actions as that of aspirin on PUFA metabolism. Similar anti-inflammatory compounds are formed from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by the action of aspirin termed as resolvins (from EPA and DHA) and protectins and maresins from DHA. PUFAs: arachidonic acid (AA), EPA and DHA and their various products modulate not only inflammation and immune response but also possess actions on various genes, nuclear factors, cyclic AMP and GMP, G-protein coupled receptors (GPRs), hypothalamic neurotransmitters, hormones, cytokines and enzymes, and interact with nitric oxide, carbon monoxide, and hydrogen sulfide to regulate their formation and action and to form new compounds that have several biological actions. These pleiotropic actions of PUFAs and their metabolites may explain their ability to play a role in several physiological actions and diseases. The big challenge is to harness these actions to prevent and manage clinical conditions. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor γ (PPARγ) belongs to the family of nuclear nuclear receptors and is mainly expressed in adipose tissue, hematopoietic cells and the large intestine. Contrary to other nuclear receptors that mainly bind a single specific ligand, there are numerous natural PPARγ ligands, in particular fatty acids or their derivatives called eicosanoids. PPARγ have pleiotropic functions: (i) glucose and lipid metabolism regulation, (ii) anti-inflammatory properties, (iii) oxidative stress inhibition, (iv) improvement of endothelial function. Its role has been mainly studied by the use synthetic agonists. In this review, we will focus on the effects of PPARγ mediated through fatty acids and how these have beneficial health properties. [ABSTRACT FROM AUTHOR]

Prostaglandin E 2 (PGE 2 ) is a prostanoid with diverse actions in health and disease. In chronic respiratory diseases driven by inflammation, PGE 2 has both positive and negative effects. An enhanced understanding of the receptor-mediated cellular signalling pathways induced by PGE 2 may help us separate the beneficial properties from unwanted actions of this important prostaglandin. PGE 2 is known to exert anti-inflammatory and bronchoprotective actions in human airways. To date however, whether PGE 2 increases production of the anti-inflammatory protein MAPK phosphatase 1 (MKP-1) was unknown. We address this herein and use primary cultures of human airway smooth muscle (ASM) cells to show that PGE 2 increases MKP-1 mRNA and protein upregulation in a concentration-dependent manner. We explore the signalling pathways responsible and show that PGE 2 -induces CREB phosphorylation, not p38 MAPK activation, in ASM cells. Moreover, we utilize selective antagonists of EP2 (PF-04418948) and EP4 receptors (GW 627368X) to begin to identify EP-mediated functional outcomes in ASM cells in vitro . Taken together with earlier studies, our data suggest that PGE 2 increases production of the anti-inflammatory protein MKP-1 via cAMP/CREB-mediated cellular signalling in ASM cells and demonstrates that EP2 may, in part, be involved. [ABSTRACT FROM AUTHOR]

Selective prostaglandin EP 1 antagonists have been suggested for the treatment of bladder dysfunction. This study assessed the contractile prostanoid receptor subtypes in human and non-human bladder in vitro. Classical tissue bath studies were conducted using bladder strips exposed to prostanoid agonists and antagonists. Prostaglandin E 2 (PGE 2 ) contracted rat, macaque and human bladder smooth muscle strips (pEC 50 7.91±0.06 ( n =7), 6.40±0.13 ( n =7), and 6.07±0.11 ( n =5), respectively). The EP 1 receptor antagonist, PF2907617 (300 nM), caused a rightward shift of the PGE 2 concentration–response curve in the rat bladder only (p K B 8.40±0.15, n =3). PGE 2 responses in rat and macaque bladders, but not human, were antagonised by the EP 3 antagonist CJ24979 (1 µM). Sulprostone, a mixed EP 1 /EP 3 /FP receptor agonist, induced potent contractions of rat bladder muscle (pEC 50 7.94±0.31, n =6). The FP receptor agonist, prostaglandin F 2α (PGF 2α ), induced bladder contraction in all species tested, but with a lower potency in rat. The selective FP receptor agonist latanoprost caused potent contractions of macaque and human bladder strips only. SQ29548, a selective TP antagonist, and GW848687X, a mixed EP 1 /TP antagonist caused rightward shifts of the concentration–response curves to the selective TP agonist, U46619 (p K B estimates 8.53±0.07 and 7.56±0.06, n =3, respectively). Responses to U46619 were absent in rat preparations. These data suggest significant species differences exist in bladder contractile prostanoid receptor subtypes. We conclude that the EP 1 subtype does not represent the best approach to the clinical treatment of bladder disorders targeting inhibition of smooth muscle contraction. [ABSTRACT FROM AUTHOR]

DAA-I (des-aspartate-angiotensin I), an endogenous angiotensin, had been shown earlier to ameliorate animal models of cardiovascular diseases via the angiotensin AT 1 receptor and prostaglandins. The present study investigated further the action of DAA-I on the release of PGE 2 , PGI 2 , PGF 2α and TXA 2 in HUVEC. 10 −11 –10 −8 M DAA-I and 15 min incubation specifically released PGE 2 and PGI 2 . The release was inhibited by losartan and indomethacin but not by PD123319 and NS398 indicating that the angiotensin AT 1 receptor and COX-1 mediate the release. At concentrations higher than 10 −7 M, DAA-I mimics the action of angiotensin II by releasing TXA 2 but had no effect on the production of PGF 2α . At similar concentrations and 4 h incubation, DAA-I increased the release of the 4 prostaglandins via the angiotensin AT 1 receptor and COX-2, again mimicking the action of angiotensin II. HUVEC that were preincubated with DAA-I or angiotensin II, released similar profiles of prostaglandins when incubated with arachidonic acid after the angiotensin had been washed off. We postulate that the internalized DAA-I/receptor complex remains active and mediates the conversion of arachidonic acid to the respective prostaglandins. The release of PGE 2 and PGI 2 via the angiotensin AT 1 receptor and COX-1 is a novel specific action of DAA-I and is likely responsible for its beneficial effects seen in earlier studies. This specific action is definable as a biased agonism of the angiotensin AT 1 receptor, which identifies DAA-I as a novel biased agonist and potential therapeutic that is able to produce specific prostaglandins at nanomolar concentrations. [ABSTRACT FROM AUTHOR]

The soluble guanylyl cyclase/cGMP system plays an important role in the vasodilator response to nitric oxide (NO) in various vascular beds. However, in rat retinal arterioles, the cyclooxygenase-1/cAMP-mediated pathway contributes to the vasodilator effects of NO, although the specific prostanoid involved remains to be elucidated. In the present study, we investigated the role of prostaglandin I 2 and its receptor (prostanoid IP receptor) system in NO-induced vasodilation of rat retinal arterioles in vivo . Fundus images were captured using a digital camera that was equipped with a special objective lens. Changes in diameter of retinal arterioles were assessed. The NO donor (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3) increased the diameter of retinal arterioles but decreased systemic blood pressure in a dose-dependent manner. Treatment of rats with indomethacin, a non-selective cyclooxygenase inhibitor, markedly attenuated the retinal vasodilator, but not depressor responses to NOR3. The prostanoid IP receptor antagonist 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imadazol-2-amine (CAY10441), and the prostaglandin I 2 synthase inhibitor 9α,11α-azoprosta-5Z,13E-dien-1-oic acid (U-51605), both showed similar preventive effects against the NOR3-induced retinal vasodilator response. Neither CAY10441 nor U-51605 showed any significant effects on the depressor response to NOR3. NOR3 enhanced the release of prostaglandin I 2 from cultured human retinal microvascular endothelial cells and the NOR3-induced prostaglandin I 2 release was almost completely abolished by the cyclooxygenase-1 inhibitor SC-560, but not by the cyclooxygenase-2 inhibitor NS-398. However, NOR3 did not increase the release of prostaglandin I 2 from human intestinal microvascular endothelial cells. These results suggest that NO exerts its dilatory effect via cyclooxygenase-1/prostaglandin I 2 /prostanoid IP receptor signaling mechanisms in the retinal vasculature. [ABSTRACT FROM AUTHOR]

Endotoxemia induces various physiological adaptive responses such as tachycardia. There is evidence to show that inflammatory tachycardia might be linked to a direct action of prostanoids on the cardiac pacemaker cells. Recent reports have indicated that systemic inflammation may uncouple of cardiac pacemaker from cholinergic neural control in experimental animals; however, the exact mechanism of this phenomenon is uncertain. This study was aimed to explore the hypothesis that prostanoids modulate atrial chronotropic hyporesponsiveness to cholinergic stimulation in endotoxemic rats. Male albino rats were given intraperitoneal injection of either saline or lipopolysaccharide (LPS, 1 mg/kg). 3 h after saline or LPS injection, the atria were isolated and chronotropic responsiveness to cholinergic stimulation was evaluated in an organ bath. The expression of atrial cyclooxygenases (COX)-1, COX-2 and COX-3 mRNA was assessed by quantitative real-time RT-PCR and cytosocalcium-dependent phospholipase A 2 (cPLA 2 ) activity was measured in the atria. The expression of atrial COX-2 mRNA and cPLA 2 activity increased significantly in endotoxemic atria ( P <0.05). Incubation with prostaglandin F 2α (PGF 2α , 100 pM) could significantly decrease chronotropic response to cholinergic stimulation in vitro . Likewise, LPS injection could induce a significant hyporesponsiveness to cholinergic stimulation, and incubation of isolated atria with either indomethacin (5 µM) or AL-8810 (a PGF 2α antagonist, 10 µM) could reverse it ( P< 0.01, P< 0.05, respectively), while SQ29548 (a thromboxane A 2 antagonist, 10 nM) was failed ( P >0.05). Our data showed that PGF 2α may contribute to the atrial chronotropic hyporesponsiveness to cholinergic stimulation in endotoxemic rats. [ABSTRACT FROM AUTHOR]

Hypothyroidism impairs endothelium-dependent dilatations, while hyperthyroidism augments the production of endothelial nitric oxide. Thus, experiments were designed to determine if thyroid hormone causes endothelium-dependent responses, or alleviates diabetic endothelial dysfunction. Isometric tension was measured in rings with or without endothelium of arteries from normal and diabetic Sprague-Dawley rats. Release of 6-keto prostaglandin F 1α and thromboxane B 2 were measured by enzyme linked immunosorbent assay and protein levels [endothelial nitric oxide synthase (eNOS), cyclooxygenases (COX)] by immunoblotting. Triiodothyronine (T 3 ) caused concentration-dependent (3×10 −6 –3×10 −5 M) relaxations in mesenteric (pEC 50 , 4.96±0.19) and femoral (pEC 50 , 4.57±0.35) arteries without endothelium. In femoral arteries of rats with diabetes, 5-methylamino-2-[[(2 S ,3 R ,5 R ,8 S ,9 S )-3,5,9-trimethyl-2-(1-oxo-(1 H -pyrrol-2- -yl)propan-2-yl)-1,7-dioxaspiro-(5,5)undecan-8-yl]methyl]benzooxazole-4-carboxylic acid (A23187, 3×10 −7 to 10 −6 M) caused partly endothelium-dependent contractions. After chronic T 3 -treatment with (10 μg/kg/day; four weeks), the contractions to A23187 of preparations with and without endothelium were comparable, the thromboxane B 2 -release was reduced (by 38.1±9.2%). The pEC 50 of 9, 11-dideoxy-11α, 9α-epoxymethanoprostaglandin F 2α (U46619, TP-receptor agonist) was increased in T 3 -treated diabetic rats compared with controls (8.53±0.06 vs 7.94±0.09). The protein expression of eNOS increased (by 228%) but that of COX-1 decreased (by 35%) after chronic T 3 treatment. In human umbilical vein endothelial cells incubated for one week with T 3 (10 −10 –10 −7 M) in the presence but not in the absence of interleukin-1β (1 ng/ml), the expression of eNOS was increased compared to control. In conclusion, thyroid hormone acutely relaxes mesenteric and femoral vascular smooth muscle, but given chronically reduces the release of endothelium-derived vasoconstrictor prostanoids while enhancing the responsiveness of TP receptors of vascular smooth muscle. [ABSTRACT FROM AUTHOR]

The role of kinins, well known as peripheral inflammatory mediators, in the modulation of brain inflammation is not completely understood. The present data show that bradykinin, a B 2 receptor agonist, enhanced both basal and lipopolysaccharide (LPS)-induced cyclooxygenase-2 mRNA and protein levels and prostaglandin E 2 synthesis in primary rat astrocytes. By contrast, Lys-des-Arg 9 -bradykinin, which is a bradykinin breakdown product and a selective kinin B 1 receptor agonist, attenuated both basal and LPS-induced astrocyte cyclooxygenase-2 mRNA levels and prostaglandin E 2 production. Pre-treating the cells with p42/p44 MAPK but not with JNK or p38 inhibitors completely abrogated PGE 2 synthesis in cells stimulated with LPS in the presence of bradykinin or bradykinin B 1 receptor agonist. Bradykinin, but not the bradykinin B 1 receptor agonist, augmented p42/p44 MAPK phosphorylation. The phosphorylation of JNK and p38 was not altered upon exposure to Bradykinin or the bradykinin B 1 receptor agonist. These results suggest that the dual delayed effect of kinins on PGE 2 synthesis may be due to differential regulation of COX-2 and signaling molecules such as p42/p44 MAPKs. Thus, kinins may exert opposing actions on brain inflammation and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the peripheral effect of 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) in albumin-induced arthritis in temporomandibular joint (TMJ) of rats. Antigen-induced arthritis (AIA) was generated in rats with methylated bovine serum albumin (mBSA) diluted in complete Freund׳s adjuvant. Pretreatment with an intra-articular injection of 15d-PGJ 2 (100 ng/TMJ) before mBSA intra-articular injection (10 µg/TMJ) (challenge) in immunized rats significantly reduced the albumin-induced arthritis inflammation. The results demonstrated that 15d-PGJ 2 was able to inhibit plasma extravasation, leukocyte migration and the release of inflammatory cytokines IL-6, IL-12, IL-18 and the chemokine CINC-1 in the TMJ tissues. In addition, 15d-PGJ 2 was able to increase the expression of the anti-adhesive molecule CD55 and the anti-inflammatory cytokine IL-10. Taken together, it is possible to suggest that 15d-PGJ 2 inhibit leukocyte infiltration and subsequently inflammatory process, through a shift in the balance of the pro- and anti-adhesive properties. Thus, 15d-PGJ 2 might be used as a potential anti-inflammatory drug to treat arthritis-induced inflammation of the temporomandibular joint. [ABSTRACT FROM AUTHOR]

Abstract: The (+)-isomer of indeloxazine AS1069562 exerts multiple pharmacological actions including the inhibition of serotonin (5-HT) and norepinephrine reuptake and analgesia in experimental animal pain models. Here, we evaluated the antinociceptive effects of AS1069562 and the antidepressants duloxetine and amitriptyline in mouse models of prostaglandin-induced spinal hypersensitivity. Prostaglandin E2 (PGE2) and F2α (PGF2α ) were intrathecally administered to induce spinal hypersensitivity, causing tactile allodynia in mice. Allodynia induced by PGF2α but not by PGE2 was suppressed by desensitization of C-fibers with systemic pretreatment with resiniferatoxin. C-fiber hyperexcitability might therefore play a role in allodynia induced by PGF2α but not PGE2. In the PGE2-induced allodynia model, AS1069562 and duloxetine significantly suppressed allodynia, whereas amitriptyline did not. In the PGF2α -induced allodynia model, AS1069562 and amitriptyline significantly ameliorated allodynia, whereas duloxetine did not. To demonstrate the broad effects of AS1069562 compared to duloxetine, additional studies were conducted to elucidate other target mechanisms of AS1069562 beyond 5-HT and norepinephrine reuptake inhibition. AS1069562 exhibited affinity for both 5-HT1A and 5-HT3 receptors, and the analgesic effect of AS1069562 on PGF2α -induced allodynia was significantly blocked by the 5-HT1A receptor antagonist (S)–WAY100135 and the 5-HT3 receptor agonist SR57227. Taken together, these results indicate that AS1069562 inhibits both C-fiber- and non-C-fiber-dependent prostaglandin-induced allodynia, while duloxetine inhibits only non-C-fiber-triggered allodynia, and amitriptyline inhibits only C-fiber-triggered allodynia. These broad antinociceptive effects of AS1069562 may be due not only to 5-HT and norepinephrine reuptake inhibition but also to its effects on 5-HT receptors such as 5-HT1A and 5-HT3 receptors. [Copyright &y& Elsevier]

Abstract: Angiotensin converting enzyme inhibitors (ACEIs) have been shown to lower intraocular pressure (IOP). Since, the ACEIs cause increased tissue prostaglandin levels, we hypothesized that the mechanisms of ACEI-induced IOP reduction have similarity with those of prostaglandin analogs. The present study investigated the involvement of matrix metalloproteinases (MMPs) and cytokine activity modulation as the underlying mechanisms of ACEI-induced ocular hypotension. The IOP lowering effect of single drop of enalaprilat dehydrate 1% was evaluated in rats pretreated with a broad spectrum MMP inhibitor or a cytokine inhibitor. Effect of angiotensin receptor blocker, losartan potassium 2%, was also studied to evaluate involvement of angiotensin II receptor type 1 (AT1) in IOP lowering effect of ACEI. Topical treatment with single drop of enalaprilat resulted in significant IOP reduction in treated eye with mean peak reduction 20.3% at 3h post-instillation. Treatment with losartan resulted in a peak IOP reduction of 13.3%, which was significantly lower than enalaprilat, indicating involvement of mechanisms in addition to AT1 blockade. Pretreatment with a broad spectrum MMP inhibitor or a cytokine inhibitor significantly attenuated the enalprilat-induced IOP reduction with mean peak IOP reduction of 11.2% and 13.6% respectively. The IOP-lowering effect of enalaprilat seems to be attributed to reduced angiotensin II type 1 receptor stimulation and modulation of MMP and cytokines activities. [Copyright &y& Elsevier]

Although methylglyoxal (MGO), a highly reactive dicarbonyl compound, influences the functioning of the vasculature, modulating its effects on vascular reactivity to various substances remains unclear, especially purinoceptor ligands. Therefore, we sought to investigate the direct effects of MGO on relaxation induced by adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) in isolated rat carotid arteries. When carotid arteries were exposed to MGO (420 μM for 1 h), relaxation induced by acetylcholine or sodium nitroprusside was not affected by MGO. However, ATP- and UTP-induced relaxation was impaired by MGO compared with the control. In both ATP- and UTP-induced relaxation, endothelial denudation, incubation with the nitric oxide (NO) synthase inhibitor N G -nitro-L-arginine or the selective P2Y purinoceptor 2 (P2Y 2 ) receptor antagonist AR-C118925XX reduced relaxation in both the control and MGO groups, while the differences between the control and MGO groups were eliminated. The cyclooxygenase (COX) inhibitor indomethacin inhibited the differences in ATP/UTP-mediated relaxations between the control and MGO groups. Moreover, N-acetyl-L-cysteine (NAC), an antioxidant, could augment carotid arterial relaxation induced by ATP/UTP in the presence of MGO. MGO increased arachidonic acid-induced contraction, which was suppressed by NAC. Following both ATP/UTP stimulation, MGO increased the release of prostanoids. These results suggest that MGO impaired ATP- and UTP-induced relaxation in carotid arteries, which was caused by suppressed P2Y 2 receptor-mediated signaling and reductions in endothelial NO. Moreover, MGO partially contributed to COX-derived vasoconstrictor prostanoids through increased oxidative stress., Competing Interests: Declaration of competing interest We declare no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Abstract: Increased expressions of cyclooxygenase-2 (COX-2) and its downstream metabolite, prostaglandin E2 (PGE2), are well documented events in the development of colorectal cancer. Interestingly, PGE2 itself can induce the expression of COX-2 thereby creating the potential for positive feedback. Although evidence for such a positive feedback has been previously described, the specific E-type prostanoid (EP) receptor subtype that mediates this response, as well as the relevant signaling pathways, remain unclear. We now report that the PGE2 stimulated induction of COX-2 expression in human colon cancer HCA-7 cells is mediated by activation of the prostanoid EP4 receptor subtype and is followed by coupling of the receptor to Gαi and the activation of phosphatidylinositol 3-kinase. Subsequent activation of metalloproteinases releases membrane bound heparin-binding epidermal growth factor-like growth factor resulting in the transactivation of epidermal growth factor receptors and the activation of the extracellular signal-regulated kinases and induction of COX-2 expression. This induction of COX-2 expression by PGE2 stimulation of the prostanoid EP4 receptor may underlie the upregulation of COX-2 during colorectal cancer and appears to be an early event in the process of tumorigenesis. [Copyright &y& Elsevier]

Abstract: The effects of a snake venom Lys-49 phospholipase A2 (PLA2) homolog named MT-II, devoid of enzymatic activity, on the biosynthesis of prostaglandins and protein expression of cyclooxygenase-2 (COX-2) and signaling pathways involved were evaluated in mouse macrophages in culture and in peritoneal cells ex vivo. Stimulation of macrophages with MT-II leads to production of prostaglandin D2 (PGD2) and prostaglandin E2 (PGE2) and protein expression of COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1). Inhibition of cytosolic PLA2 (cPLA2), but not Ca2+ independent PLA2 (iPLA2) reduced release of PGD2 and PGE2 and expression of COX-2 induced by MT-II. Inhibition of nuclear factor κB (NF-κB) significantly reduced MT-II-induced PGE2, but not PGD2 production and COX-2 expression. Inhibitors of either protein kinase C (PKC), protein tyrosine kinase (PTK), or extracellular signal-regulated kinase (ERK) pathways abrogated MT-II-induced NF-κB activation and reduced COX-2 expression and PGE2 release, whereas the p38 mitogen-activated protein kinase (MAPK) inhibitor reduced MT-II-induced COX-2 expression and PGD2 production. Inhibition of phosphatidylinositol-3-kinase (PI3K) pathway abrogated MT-II-induced NF-κB activation, but affected neither prostaglandins production nor COX-2 expression. MT-II-induced production of PGD2 and PGE2 and COX-2 expression were also observed in vivo after intraperitoneal injection into mice. Collectively, our data demonstrate that a catalytically-inactive PLA2 homolog is capable of inducing prostaglandins biosynthesis and COX-2 expression in macrophages in both in vitro and in vivo models, indicating that the enzymatic activity of PLA2 is not necessary to trigger these effects. MT-II-activated NF-κB, cPLA2 and distinct protein kinases are the principal steps involved in these cellular events. [Copyright &y& Elsevier]

Abstract: The role of cyclooxygenase-2 (COX-2) in restoring the functions of impaired endothelium is attracting considerable attention, notably the function of COX-2-derived vasodilatory prostaglandins is disputed in the context of the regulation function in the impaired vascular beds. We have examined the hypothesis that COX-2 activity contributes more to vasodilation in hyperglycemic animals than in healthy counterparts, and that COX-2 derived vasodilatory prostaglandins (PGI2 and PGE2) are responsible for this effect. Using the Langendorff heart perfusion system, the effects of COX-2 inhibition were monitored on both basal and bradykinin-induced coronary flows in Sprague–Dawley rats given 8-week streptozotocin-induced diabetes and in age-matched controls (n=15). Secretions of PGI2 and PGE2, both total and the COX-2 dependent pools, have also been compared. The selective COX-2 inhibitor, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398), had no effect on coronary flow in the diabetic group of animals. Thus, the compensatory role of COX-2 in regulation of vascular tone in experimental diabetes found in other experimental models was not confirmed. However, COX-2 activity significantly contributed to PGI2 synthesis in healthy rats, with prostacyclin secretion being two-fold decreased by NS-398. Contrary to our hypothesis, neither prostacyclin nor PGE2 production differed between the experimental groups under the basal conditions. Bradykinin had no effect on the secretion of PGI2 in either group, but increased PGE2 synthesis in healthy animals, although not in the streptozotocin group. PGE2 production in response to bradykinin was COX-2-dependent in control animals. We conclude that, in rats with 8-week streptozotocin-induced diabetes, the activity of COX-2 in coronary vasculature is not significantly enhanced. [Copyright &y& Elsevier]

Abstract: The cyclooxygenase (COX) pathway and prostanoids may critically contribute to the early allergic airway response. In the rat lung, serotonin (5-HT) is a major mediator of antigen-induced contractions. The aim of this study was therefore to examine the relative role of the COX pathway and serotonin for antigen-induced contractions in the rat lung. Airway responses were studied in rat precision-cut lung slices (PCLS). Lung slices were stimulated with ovalbumin or serotonin after pretreatment with COX inhibitors or specific TP or EP receptor antagonists. Changes in airway size (contractions/relaxations) were measured by a digital video camera. The supernatants were analysed for changes in prostaglandin and serotonin release. Airway contractions to ovalbumin were attenuated by the unselective COX inhibitor indomethacin, the selective COX-1 inhibitor FR-122047 and COX-2 inhibitor celecoxib. The EP1 receptor antagonist ONO-8713 reduced the contractions, whereas the EP4 receptor antagonist L-161,982 significantly increased the contractile response to ovalbumin. The 5-HT2A receptor antagonist ketanserin completely inhibited the ovalbumin-induced contractions. The different COX inhibitors decreased the production of prostaglandins but did not affect the synthesis of serotonin. The serotonin-induced bronchoconstriction was attenuated by celecoxib and ONO-8713, but not by methacholine. Taken together, our data indicate that PGE2 is the main prostanoid involved in the early allergic airway response in the rat lung. PGE2 appears to act both as a primary mediator of antigen-induced airway contraction via the EP4 receptor and as a downstream modulator of serotonin-induced bronchoconstriction via the EP1 receptor. [Copyright &y& Elsevier]

Abstract: Bioavailability of nitric oxide (NO) is mostly studied in isolated blood vessels. We investigated changes in basal and receptor-stimulated endothelial NO synthase (eNOS) activity after isolation of wild-type and Marfan mouse aorta. Starting 1h after dissection, basal NO release was assessed at hourly intervals by its ability to suppress isometric contractions in aortic segments. Relaxation induced by acetylcholine or α 2-adrenoceptor agonist 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK14304) was used to study stimulated NOS activity. One hour after dissection, phenylephrine- or prostaglandin F 2α -induced force attained only 17±4% or 31±7% of maximum tension in the presence of N Ω -nitro-l-arginine-methylesther ( l -NAME), and contractions increased to 63±6% and 82±11%, respectively at 5h. In contrast, acetylcholine or UK14304 relaxation curves changed minimally. l -NAME and eNOS-deficiency abolished basal NO production, unlike inhibitors of neuronal (N Ω -propyl-l-arginine) or inducible (1400W) NOS. Acetylcholine-induced relaxation was abolished by l -NAME, strongly suppressed by eNOS-deficiency and attenuated by N Ω -propyl-l-arginine. In a bioassay based on diethylamine NONOate concentration-response curves the suppression of contractile forces was interpolated into NO equivalents. This showed exponential decay of basal NO, which occurred three times faster in aortas from mice with Marfan syndrome, while acetylcholine-induced relaxation remained unaltered. Immunoblotting showed unchanged eNOS expression, or phosphorylation at Ser1177, Ser617 or Thr495 between 1h and 4h, but Akt phosphorylation declined gradually. The dramatic loss of basal NO release after tissue isolation shows that timing is crucial when studying NO responses. The preservation of receptor-induced relaxation implies differential regulation of basal and stimulated eNOS activity, and phosphoinositide-3-kinase/Akt signalling seems specifically associated with basal eNOS activity. [Copyright &y& Elsevier]

Abstract: Prostaglandin E2 (PGE2) is an inflammatory mediator implicated in several gastrointestinal pathologies that cause diarrhoea. The aim of this study was to establish the contributions of the four different EP receptors (EP1–4) to PGE2-induced anion secretion in human and mouse colon mucosa. Electrogenic anion secretion (short-circuit current; I sc) was measured across colonic mucosae or T84 monolayers placed in Ussing chambers in response to EP receptor agonists and antagonists. PGE2 and PGE1-alcohol increased I sc in human colon mucosa, T84 epithelia and mouse colon mucosa, and these responses were inhibited by the EP4 receptor antagonist, GW627368X alone. In addition, the EP2 agonist, butaprost increased I sc in all three preparations and these responses were inhibited by the non-selective EP1,2,3 receptor antagonist, AH6809 but not by GW627368X. Conversely, responses mediated by EP1 and EP3 receptors were not observed in human colon or T84 monolayers. However, in mouse colon mucosa the EP3-preferring agonist, sulprostone reduced I sc, indicative of G iα -signalling. Taken together these results indicate that PGE2-induced ion secretion is mediated predominantly by Gs-coupled EP4 receptors and also by EP2 receptors in human mucosa. Furthermore, tumour necrosis factor alpha (TNFα) and interleukin 1beta (IL1β) increased I sc and these responses were also inhibited by the EP4 receptor antagonist in human colon mucosa. This study establishes the EP receptor pharmacology present in human epithelial preparations, and suggests that EP4 receptors may be a therapeutic target for the treatment of secretory diarrhoea where PGE2 is implicated in the aetiology. [Copyright &y& Elsevier]

Abstract: Anandamide, an endocannabinoid, prostaglandins derived from cyclooxygenase-2 and nitric oxide synthesized by nitric oxide synthase (NOS), are relevant mediators of embryo implantation. We adopted a pharmacological approach to investigate if anandamide modulated NOS activity in the receptive rat uterus and if prostaglandins mediated this effect. As we were interested in studying the changes that occur at the maternal side of the fetal–maternal interface, we worked with uteri obtained from pseudopregnant rats. Females were sacrificed on day 5 of pseudopregnancy, the day in which implantation would occur, and the uterus was obtained. Anandamide (2ng/kg, i.p.) inhibited NOS activity (P<0.001) and increased the levels of prostaglandin E2 (P<0.001) and prostaglandin F2α (P<0.01). These effects were mediated via cannabinoid receptor type 2, as the pre-treatment with SR144528 (10mg/kg, i.p.), a selective cannabinoid receptor type 2 antagonist, completely reverted anandamide effect on NOS activity and prostaglandin levels. The pre-treatment with a non-selective cyclooxygenase inhibitor (indomethacin 2.5mg/kg, i.p.) or with selective cyclooxygenase-2 inhibitors (meloxicam 4mg/kg, celecoxib 3mg/kg, i.p.) reverted anandamide inhibition on NOS, suggesting that prostaglandins are derived from cyclooxygenase-2 mediated anandamide effect. Thus, anandamide levels seemed to modulate NOS activity, fundamental for implantation, via cannabinoid receptor type 2 receptors, in the receptive uterus. This modulation depends on the production of cyclooxygenase-2 derivatives. These data establish cannabinoid receptors and cyclooxygenase enzymes as an interesting target for the treatment of implantation deficiencies. [Copyright &y& Elsevier]

Abstract: To identify anti-inflammatory flavonoid derivatives with optimal chemical structures, various 8-heterocyclic-substituted chrysin derivatives were previously synthesized and their effects on prostaglandin E2 (PGE2) production from the lipopolysaccharide (LPS)-treated mouse macrophage cell line, RAW 264.7, were evaluated. Through this screening procedure, 5,7-dihydroxy-8-(pyridine-4yl)flavone (C-721) among the derivatives was selected for further pharmacological study. Contrary to the parent molecule, chrysin, C-721 was found to potently inhibit PGE2 and NO production by LPS-treated RAW cells. The IC50 values of C-721 were 6.2 and 22.6μM, respectively, for cyclooxygenase-2 (COX-2) mediated PGE2 and inducible nitric oxide (iNOS)-mediated NO production. Western blotting and reverse transcriptase-polymerase chain reaction analysis demonstrated that this compound inhibited PGE2 production, at least in part, via COX-2 down-regulation and COX-2 inhibition, while C-721 primarily inhibited NO via down-regulation of iNOS expression. In addition, C-721 inhibited TNF-α and IL-6 production at 10–50μM. An in vivo study revealed that oral and intraperitoneal administration of C-721 showed 25.2%–44.3% inhibition against λ-carrageenan-induced paw edema in mice at 10–100mg/kg. Furthermore, this compound significantly inhibited collagen-induced arthritis in mice when administered by intraperitoneal injection at 50mg/kg three times/week. Taken together, these results suggest that C-721 has the potential for use as a synthetic lead compound for development of a new anti-inflammatory agent. [Copyright &y& Elsevier]

Abstract: Prostaglandin D2 (PGD2), released through mast cell activation, is used as a non-invasive biomarker in patients with asthma. Since PGD2 can elicit opposing effects on airway tone via activation of the PGD2 receptors DP1 and DP2 as well as the thromboxane receptor TP, the aim of this study was to characterize the receptors that are activated by PGD2 in the guinea pig lung parenchyma. PGD2 and the thromboxane analog U46619 induced concentration-dependent contractions. U46619 was more potent and caused stronger effect than PGD2. The specific TP receptor antagonist SQ-29548 and the combined TP and DP2 receptor antagonist BAYu3405 concentration-dependently shifted the curves for both agonists to the right. The DP1 receptor agonist BW245 induced a weak relaxation at high concentrations, whereas the DP1 receptor antagonist BWA868C did not affect the PGD2 induced contractions. The specific DP2 receptor agonist 13,14-dihydro-15-keto-PGD2 showed neither contractile nor relaxant effect in the parenchyma. Furthermore, studies in precision-cut lung slices specified that airways as well as pulmonary arteries and veins contracted to both PGD2 and U46619. When the lung parenchyma from ovalbumin sensitized guinea pigs were exposed to ovalbumin, both thromboxane B2 and PGD2 were released. Ovalbumin also induced maximal contractions at similar level as PGD2 in the parenchyma, which was partly reduced by SQ-29548. These data show that PGD2 should be recognized as a TP receptor agonist in the peripheral lung inducing contraction on airways, arteries and veins. Therefore, a TP receptor antagonist can be useful in combination treatment of allergic responses in asthma. [Copyright &y& Elsevier]

Abstract: We investigated the role of hematopoietic prostaglandin D synthase (H-PGDS) in biphasic nasal obstruction in allergic rhinitis using a new specific inhibitor, (N-methoxy-N-methyl)-4-(5-benzoylbenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxamide hydrochloride (TAS-204). First, we developed a novel guinea pig model of allergic rhinitis. Guinea pigs sensitized to ovalbumin without adjuvant were challenged with intranasal exposure to ovalbumin once a week. After the 3rd antigen challenge, they exhibited biphasic nasal obstruction. Additionally, analysis of nasal lavage fluid revealed an increase in the level of prostaglandin D2 in both early and late phases. Treatment with oral TAS-204 for 15days during the period of antigen challenges suppressed increases in nasal airway resistance in both phases. It is noteworthy that the late phase nasal obstruction was almost completely abrogated by inhibiting H-PGDS alone. Eosinophil infiltration in nasal lavage fluid and nasal hyperresponsiveness to histamine was also reduced by TAS-204 administration. These findings suggest that H-PGDS plays a critical role in the development of allergic rhinitis, especially in the induction of late phase nasal obstruction. [Copyright &y& Elsevier]

Abstract: Resveratrol, a polyphenol found in grapes and peanuts, exerts beneficial effects on a number of diseases of cardiovascular and central nervous system. However, effects of resveratrol on the urinary system have not been fully investigated. In the present study, we examined effects of resveratrol on bradykinin-induced contraction and release of prostaglandin E2 in isolated rat urinary bladders. The effects of resveratrol on contractions induced by several agonists (prostaglandin E2, prostaglandin F2α and carbachol) and high K+ were also examined. We found that resveratrol concentration-dependently reduced the bradykinin-induced contraction in the rat urinary bladder preparations. The higher concentration of resveratrol (100μM) abolished the bradykinin-induced prostaglandin E2 release. Similar results were obtained when the cyclooxygenase inhibitor indomethacin (10μM) was used instead of resveratrol. Resveratrol also attenuated the prostaglandin E2-, prostaglandin F2α-, and to a lesser extent carbachol-induced contractions. Contractile responses to bradykinin, prostaglandin E2 and carbachol were largely prevented by blockade of Ca2+ channels with diltiazem. Both resveratrol and diltiazem prevented contractions induced by an addition of Ca2+ (2.5–10mM) into Ca2+-free/50mM K+ solution or by 50mM K+ solution containing normal Ca2+ (2.5mM). These results suggest that resveratrol prevents bradykinin-induced contractions by attenuating not only the production of prostaglandins but also actions of them. The effect of resveratrol on contractile actions seems to be in part due to inhibition of Ca2+ influx. Because bradykinin plays an important role in pathological conditions of urinary bladder function, resveratrol may exert beneficial effects on the urinary bladder diseases. [Copyright &y& Elsevier]

Abstract: Prostaglandin E2 (PGE2) is one major prostanoid produced under inflammatory situation. Although PGE2 is known to induce vascular contraction, its detailed mechanism remains unknown. In the present study, we investigated the signaling pathway underlying PGE2-induced smooth muscle contraction in rat mesenteric artery. PGE2 (0.3–30μM) concentration-dependently caused contraction in endothelium-denuded artery. RT-PCR showed that this artery expresses mRNAs for all four prostanoid EP receptors (prostanoid EP1–4). Among selective agonists for PGE2 receptors, only a prostanoid EP3 receptor agonist, ONO-AE-248 (0.3–30μM) induced contraction. Consistently, pretreatment with a prostanoid EP3 antagonist (L-798106, 1μM) significantly but not completely inhibited the PGE2-induced contraction. Interestingly, pretreatment with a prostanoid FP antagonist (AL8810, 1μM) or a TP antagonist (SQ29548, 10nM) also partially inhibited the PGE2-induced contraction. Since ONO-AE-248 (10μM) did not influence intracellular Ca2+ concentration in mesenteric artery, we next examined the involvement of Ca2+-independent contractile pathway including PKCs and ROCK in prostanoid EP3-mediated contraction. Pretreatment with bisindolyl-maleimide I (a general PKC inhibitor, 1μM), Ro-31-8425 (a conventional PKC and PKCε inhibitor, 1μM), rottlerin (a selective PKCδ inhibitor, 1μM) and Y-27632 (a ROCK inhibitor, 1μM) but not Go 6976 (a conventional PKC inhibitor, 1μM) attenuated 10μM ONO-AE-248-induced vascular contraction. In western blot analysis, we confirmed that the treatment with ONO-AE-248 (10μM, 30min) phosphorylated PKCδ (Thr505) and PKCε (Ser729). These results suggest that PGE2 induces vascular smooth muscle contraction via prostanoid EP3, FP and TP receptors in rat mesenteric artery. Prostanoid EP3-mediated contraction is ascribed to Ca2+-independent contractile pathway including PKCδ, ε and ROCK. [Copyright &y& Elsevier]

Abstract: The present study investigated the actions of des-aspartate-angiotensin I (DAA-I) on infarct size and three early inflammatory events in acute myocardial ischemia-reperfusion injury in rats. The rationale was based on earlier findings showing that chronic daily administration of DAA-I attenuated infarct size of ischemic-reperfused rat heart, and cardiac hypertrophy in pressure overload rats. Anesthetized rats were subjected to 45min of ischemia and 5h of reperfusion. Infarcted area, serum creatine kinase, and tissue myeloperoxidase activity were determined. The expression of intercellular adhesion molecule-1 (ICAM-1) was also investigated by immunohistochemistry and Western blotting. Intravenous administration of DAA-I at 5min post reperfusion reduced myocardial infarct size by 45.5%, lowered serum creatine kinase activity, decreased myeloperoxidase activity in cardiac tissue, and inhibited the expression of ICAM-1 in cardiac capillary endothelium. The maximum effective dose was 1013pmol/kg, and the cardioprotective actions of DAA-I were blocked by indomethacin. The data showed that the cardioprotection accorded by DAA-I was the result of its anti-inflammatory actions on early inflammatory processes in myocardial ischemia-reperfusion injury. The anti-inflammatory processes were indomethacin sensitive and probably mediated by prostaglandins. [Copyright &y& Elsevier]

Abstract: To investigate the abnormal function of T and B lymphocytes involved in collagen-induced arthritis in DBA/1 mice and the regulation role of TACI-Ig on T and B lymphocytes, collagen-induced arthritis models were established in DBA/1 mice. Mice were divided randomly into eight groups, including normal, collagen-induced arthritis model, TACI-Ig (0.350, 1.105, 3.333, 10, and 30 mg/kg) and IgG-Fc (10mg/kg) treated groups. The effect of TACI-Ig on collagen-induced arthritis was evaluated by arthritis scores, joints and spleens histopathology, paws radiology, and indices of thymus and spleen. T and B lymphocyte proliferations were assayed by [3H]-TdR method. B lymphocyte stimulator and prostaglandin E2 in serum were assayed by enzyme linked immunosorbent assay. The subsets of T and B lymphocytes were assayed by flow cytometry. Results showed that the onset of paw-swelling was on day 31 after immunization. The peak of inflammation appeared on day 42 and then declined after day 63. Compared with normal mice, collagen-induced arthritis mice have increased arthritis scores, spleen and thymus indices, radiograph scores of joints, and pathology scores of joints and spleens. TACI-Ig could ameliorate these changes and reduce the increased serum level of B lymphocyte stimulator and prostaglandin E2. Further studies showed that TACI-Ig inhibited T and B lymphocyte proliferation response, and inhibited differentiation and activity of T and B lymphocytes in collagen-induced arthritis mice. In conclusion, TACI-Ig has a good therapeutic action on collagen-induced arthritis mice, which might be related to the regulation of TACI-Ig on inflammation mediators and abnormal function of T and B lymphocytes. [Copyright &y& Elsevier]

Abstract: Prostanoid IP receptors coupled to Gs are thought to be the primary target for prostacyclin (PGI2) analogues. However, these agents also activate prostanoid EP1–4 receptor subtypes to varying degrees, which are positively (EP2/4) or negatively (EP3) coupled to adenylate cyclase through Gs or Gi, respectively. We investigated the role of these receptors in modulating relaxation to PGI2 analogues cicaprost, iloprost and treprostinil in pre-contracted segments of rat tail artery. Prostanoid IP (RO1138452), EP4 (GW627368X), EP3 (L-798106), EP1–3 (AH6809), and EP1 (SC-51322) receptor antagonists were used to determine each receptor contribution. The role of Gi/o was investigated using pertussis toxin (PTX), while dependence on cAMP was determined using adenylate cyclase (2′5′dideoxyadenosine, DDA) and protein kinase A (2′-O-monobutyryladenosine- 3′,5′-cyclic monophosphorothioate, Rp- isomer, Rp-2′-O-MB-cAMPS) inhibitors, and by measurement of tissue cAMP. All analogues caused relaxation which was significantly (P <0.01) inhibited by RO1138452; with maximum response to cicaprost, iloprost and treprostinil reduced by 51%, 66% and 37%, respectively. GW627368X had no effect when used alone, but in combination with RO1138452, caused a rightward shift of the curves for cicaprost and iloprost but not treprostinil. PTX treatment potentiated relaxation to all 3 analogues (P< 0.01), as did L798106 and AH6809 but not SC-51322. Basal cAMP levels were higher in PTX-treated tissues and DDA- and Rp-2''-O-MB-cAMPs--sensitive responses increased to analogue concentrations <0.1μM. In conclusion, prostanoid EP3 receptors via Gi/o negatively modulate prostanoid IP receptor-mediated relaxation to cicaprost, iloprost and treprostinil. However, other pathways contribute to analogue-induced vasorelaxation, the nature of which remains unclear for treprostinil. [Copyright &y& Elsevier]

Abstract: It has been documented that intravenous lipopolysaccharide (LPS) in rabbits causes fever accompanied by increased levels of extracellular glutamate, hydroxyl radicals, and prostaglandin E2 (PGE2) in the hypothalamus and circulating tumor necrosis factor-alpha (TNF-α). This investigation was to determine whether central interleukin-10 (IL-10) exerted its antipyresis by reducing changes in circulating TNF-α and extracellular glutamate, hydroxyl radicals and PGE2 in the hypothalamus. The microdialysis probes were stereotaxically and chronically implanted into the preoptic anterior hypothalamus of rabbit brain for determinating extracellular glutamate, hydroxyl radicals, and PGE2 in situ. It was found that systemically injected LPS (2μg/kg, intravenously) increased the levels of core temperature, and extracellular glutamate, hydroxyl radicals, and PGE2 in the hypothalamus accompanied by increased plasma levels of TNF-α. Pretreatment with IL-10 (10–100ng, intracerebroventricularly) 1h before intravenous LPS significantly reduced the LPS-induced changes in extracellular glutamate, hydroxyl radicals, and PGE2 in the hypothalamus and fever, but not the increased levels of TNF-α in rabbits. These findings suggested that directly injected IL-10 into the lateral cerebral ventricle 1h before intravenous LPS exerted its antipyresis by inhibiting the changes in extracellular glutamate, hydroxyl radicals and PGE2 in the hypothalamus during LPS fever in rabbits. [Copyright &y& Elsevier]

Abstract: Prostaglandin E2 (PGE2) positively regulates bone resorption and formation mainly mediated through the EP4 receptor, a subtype of PGE2 receptors. ONO-4819, an EP4 receptor-selective agonist, has been shown to increase bone volume, density, and strength; however, the mechanism of these effects has yet to be fully elucidated. To explore this matter, ONO-4819 (10μg/kg) was injected into intact rats twice a day for 5weeks, and their bones were then analyzed by morphological techniques. The effects of ONO-4819 on the differentiation of bone cells were also examined in vitro. Bone morphometric analysis showed that osteoblast number, bone volume, mineral apposition rate, and bone formation rate were significantly increased by ONO-4819, whereas osteoclast number was not affected. Immunohistochemical examination demonstrated that ONO-4819 increased the number of Runx2- and Osterix-positive osteoblasts in rats. In vitro studies using the multipotent mesenchymal cell line C3H10T1/2 showed that ONO-4819 induced alkaline phosphatase (ALPase) activity and up-regulated the mRNA expression of ALPase and Osterix. In contrast, ONO-4819 reduced the mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) and inhibited adipocyte differentiation of C3H10T1/2 cells, which findings are consistent with the observation that the age-dependent increase in adipocyte number in the bone marrow was significantly suppressed in the ONO-4819-treated animals. ONO-4819 also dose-dependently increased osteoclast-like cell formation in vitro, but the required concentrations were much higher than those to induce osteoblast differentiation. These results collectively suggest that ONO-4819 increased bone formation by stimulating osteoblast differentiation and function, possibly through modulating mesenchymal cell differentiation in the bone. [ABSTRACT FROM AUTHOR]

Abstract: Tissue damage leads to pain sensitization due to peripheral and central release of excitatory mediators such as prostaglandin E2 (PGE2). PGE2 sensitizes spinal pain neurotransmitter such as calcitonin gene-related peptide (CGRP) release via activation of cyclic AMP (cAMP)/protein kinase A (PKA)-dependent signaling mechanisms. Our previous data demonstrate that sustained morphine pretreatment sensitizes adenylyl cyclase(s) (AC) toward the direct stimulator, forskolin, in cultured primary sensory neurons (AC superactivation). In the present work we investigated the hypothesis that morphine pretreatment also sensitizes ACs toward Gs-protein-coupled excitatory modulators (such as PGE2), leading to augmented PKA-dependent CGRP release from PGE2-stimulated primary sensory dorsal root ganglion (DRG) neurons. Our results show that sustained morphine treatment potentiated PGE2-mediated cAMP formation and augmented PGE2-evoked CGRP release from cultured primary sensory neurons in a PKA-dependent manner. Our data suggest that attenuation of AC superactivation in primary sensory neurons may prevent the development of opioid-induced hyperalgesia. [ABSTRACT FROM AUTHOR]

Abstract: Dopamine is linked to gastrointestinal functions. However, its exact nature in stress-induced gastric pathology is still not clear. In the present study, an attempt has been made to identify the effects of dopamine in stress-induced gastric ulcers, and concurrent alterations in various ulcer-influencing factors such as plasma corticosterone levels, gastric mucosal PGE2 content and proton pump activity. The dopamine D1 receptor agonist (A 68930) and antagonist (SCH 23390), and D2 receptor agonist (quinpirole) and antagonist (sulpiride) were used to evaluate their effects on acute stress (single immobilization for 150min) and chronic unpredictable stress (two different types of stressors for 7days) induced gastric ulcers in rats. Acute and chronic unpredictable stress significantly increased the gastric ulcer severity, adrenal hypertrophy and corticosterone levels, while gastric mucosal dopamine levels were decreased. Pretreatment of sulpiride (60mg/kg) significantly reverted the acute stress-induced alterations, while A 68930 (0.25mg/kg) significantly restored the acute and chronic unpredictable stress-induced alterations. In contrast, administration of SCH 23390 (0.1–0.5mg/kg) and quinpirole (0.1–0.5mg/kg) failed to alter acute stress-induced alterations. Further, A 68930 and sulpiride showed different response on proton pump inhibition under in-vitro condition. A 68930 (10–50μg/ml) inhibited the gastric H+ K+-ATPase activity comparable to positive control omeprazole, while sulpiride (10–50μg/ml) had no effect. A 68930 also normalized the decreased gastric PGE2 content observed during chronic unpredictable stress. The histopathological evaluation of gastric mucosal tissue supported the observations regarding the gastroprotective effect of sulpiride during acute stress and of A 68930 during both acute and chronic unpredictable stress conditions. Our results provide important insights into the mechanism of dopamine-regulated pathways, which cause an overall pathophysiology of gastric stress ulcers and implicating the importance of D1 agonist in ulcer protection. Thus, current study highlights the need to evaluate anti-stress and anti-ulcer agents in terms of their ability to modulate dopaminergic transmissions. [Copyright &y& Elsevier]

Abstract: Hydrogen sulfide (H2S) is a gaseous mediator involved in a multitude of physiological functions; however the role of H2S in the gut is far from being understood completely. The aim of this study was to determine the effect of d-l-propargylglycine (PAG), an inhibitor of H2S synthesis, on ethanol-induced gastric injury in rat and to examine the role of l-cysteine, exogenous H2S, prostaglandins, non-protein sulphydryls groups, nitric oxide and KATP channels in the gastroprotective effect of PAG. Administration of PAG (3.12 to 75mg/kg i.p.) or l-cysteine (0.3 to 300mg/kg, p.o.) exhibited a dose-dependent protective effect after intragastric administration of 1ml of ethanol to induce gastric injury. The gastroprotective effect of PAG (25mg/kg i.p.) was maintained after post-treatment with l-cysteine (10mg/kg p.o.), while NaHS (8.4mg/kg p.o.) inhibited this effect. The levels of gastric hydrogen sulfide were increased after ethanol-induced gastric damage and they were reverted by PAG while prostaglandin E2 levels in gastric tissue were decreased by ethanol and PAG did not revert to this effect. Pretreatment with indomethacin (10mg/kg i.p.) and N-ethylmaleimide (NEM, 10mg/kg s.c.) resulted in a reversion of the gastroprotective effect of PAG while NG-nitro-l-arginine methyl ester (L-NAME, 70mg/kg s.c.), glibenclamide (1mg/kg i.p.) or diazoxide (3mg/kg i.p.) did not induce any changes. These results suggest that ethanol-induced gastric injury is related with an increment of endogenous H2S levels, and therefore a decrement of H2S levels by PAG is a benefit to protect gastric injury caused by ethanol. [Copyright &y& Elsevier]

Abstract: The molecular mechanisms regulating the trafficking of the CRTH2 receptor are poorly understood. In the present study, we characterize C-terminal tail determinants involved in the agonist-induced trafficking of the CRTH2 receptor for prostaglandin D2. Our results showed that progressive deletion of C-terminal tail residues from amino acid 395 up to 337 gradually impaired CRTH2 internalization by ∼50% as measured by ELISA in HEK293 cells. Surprisingly, further deletion of the C-tail to amino acid 328 or 317 resulted in receptor mutants displaying internalization similar to the wild-type receptor. Individual mutations of Asp330, Ser331, Glu332, and Leu333 to Ala in the C-tail of the full length receptor resulted in a 45% increase in internalization of the receptor mutants relative to the wild-type receptor. Pretreatment with the recycling inhibitor monensin increased internalization of the wild-type receptor but did not affect that of the D330A, S331A, E332A and L333A mutants, indicating that these residues are part of a recycling motif. Further experiments revealed that Asp330, Ser331 and Glu332 are not only involved in receptor recycling, but are also required for promotion of CRTH2 internalization by GRK2 and GRK5. Site-directed mutagenesis identified Thr347 as a major site for PKC-induced internalization of the receptor. Confocal microscopy revealed that arrestin-3 dissociated from the receptor after agonist stimulation and internalization, suggesting that CRTH2 is a class A G protein-coupled receptor. Our study identified specific amino acids in the CRTH2 receptor C-tail implicated in the agonist-induced internalization and the recycling of the receptor. [Copyright &y& Elsevier]

Abstract: Cyclooxygenase inhibitors are often prescribed to relieve severe ischemic leg pain in critical ischemic limb patients. Prescription of high doses of aspirin and selective cyclooxygenase-2 inhibitors is reported to increase cardiovascular events through suppression of the vasodilative prostanoid prostaglandin I2 in endothelium. Here, we evaluated the influence of aspirin and etodolac, a selective cyclooxygenase-2 inhibitor, on neovascularization using a murine ischemia hind limb model. C57BL/6J mice were treated with aspirin or etodolac for twenty-eight days after induction of ischemia. We exploited a concentration of the agents that suppressed cyclooxygenase activity efficiently, especially in prostaglandin I2 production. Recovery of limb blood perfusion and capillary density in ischemic limbs was significantly suppressed by etodolac treatment when compared to the aspirin treated group and untreated group. Production of 6-keto prostaglandin F1α and prostaglandin E2 was lower in the aspirin treated group when compared with the etodolac-treated group. Also, these concentrations were lower in both treatment groups compared with the untreated group. Immunohistochemical analysis suggested cyclooxygenase-2 was expressed in endothelium but not in inflammatory cells in ischemic tissue from the acute to chronic phase. Cyclooxygenase-1 was expressed strongly in inflammatory cells in the acute phase. Furthermore, bone marrow-derived mononuclear cell transplantation improved neovascularization, whereas aspirin and etodolac did not inhibit these effects. Production of arachidonic acid metabolites by transplanted cells was independent of the improvement of neovascularization. In conclusion, cyclooxygenase-2 inhibition reduces ischemia-induced neovascularization. [Copyright &y& Elsevier]

Abstract: We evaluated the effects of NT-702 (parogrelil hydrochloride, NM-702, 4-bromo-6-[3-(4-chlorophenyl) propoxy]-5-[(pyridine-3-ylmethyl) amino] pyridazin-3(2H)-one hydrochloride), a selective phosphodiesterase 3 inhibitor, on the asthmatic response in guinea pigs. NT-702 at a concentration of 1×10−7 M elevated the cyclic adenosine monophosphate content in prostaglandin E2-treated guinea pig tracheal smooth muscle cells. Leukotriene (LT) D4- and histamine-induced contraction of isolated guinea pig tracheal strips was inhibited by NT-702, with EC50 values of 3.2×10−7 and 2.5×10−7 M, respectively. In an in vivo study, NT-702 suppressed LTD4-induced bronchoconstriction and the ovalbumin-induced immediate asthmatic response in guinea pigs through its bronchodilating effect. Furthermore, NT-702 also suppressed the ovalbumin-induced late asthmatic response, airway hyperresponsiveness, and the accumulation of inflammatory cells in the bronchoalveolar lavage fluid. These results suggest that NT-702 has an anti-inflammatory effect as well as a bronchodilating effect and might be useful as a novel potent therapeutic agent for the treatment of bronchial asthma, a new type of agent with both a bronchodilating and an anti-inflammatory effect. [Copyright &y& Elsevier]

Abstract: Our purposes were to perform the pharmacological characterization of PGF2α receptor (prostanoid FP-receptor) involved in human umbilical vein contraction and confirm its expression in this tissue. Umbilical cords from healthy patients after full-term deliveries were employed. The vein was dissected out of cords and used for either isolated organ bath or reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assays. The natural prostanoid FP-receptor agonist, PGF2α, and its selective analogues, latanoprost and bimatoprost free acids are full agonists (produce more than 80% of the maximal contractile response to 5-HT) in human umbilical vein. The agonist potency (pEC50) order was PGF2α (6.01±0.05)>latanoprost free acid (5.65±0.07)=bimatoprost free acid (5.59±0.08). The contractile effects of PGF2α and latanoprost free acid were blocked competitively by the prostanoid FP-receptor antagonist, AL-8810. The antagonist potencies (pK B) of AL-8810 vs. PGF2α (5.93±0.05) and vs. latanoprost free acid (6.40±0.08) in human umbilical vein are in good agreement with its ability to antagonize prostanoid FP receptors of rat, mouse and human cells. In all samples, clear signal was detected for cDNA amplification of prostanoid FP receptor and the specific prostanoid FP-receptor antibody recognized a protein of approximately 64 kDa. In conclusion, taking into account the obtained functional and biochemical data, we propose for the first time that human umbilical vein express prostanoid FP-receptors and these receptors could be involved in the vasoconstriction action of PGF2α in this tissue. [Copyright &y& Elsevier]

Abstract: MK-886, an inhibitor of the 5-lipoxygenase-activating protein (FLAP), potently suppresses leukotriene biosynthesis in intact cells and is frequently used to define a role of the 5-lipoxygenase (EC 1.13.11.34) pathway in cellular or animal models of inflammation, allergy, cancer, and cardiovascular disease. Here we show that MK-886 also interferes with the activities of cyclooxygenases (COX, EC 1.14.99.1). MK-886 inhibited isolated COX-1 (IC50 =8 µM) and blocked the formation of the COX-1-derived products 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid (12-HHT) and thromboxane B2 in washed human platelets in response to collagen as well as from exogenous arachidonic acid (IC50 =13–15 µM). Isolated COX-2 was less affected (IC50 =58 µM), and in A549 cells, MK-886 (33 µM) failed to suppress COX-2-dependent 6-keto-prostaglandin (PG)F1α formation. The distinct susceptibility of MK-886 towards COX-1 and -2 is apparent in automated molecular docking studies that indicate a preferred binding of MK-886 to COX-1 into the active site. MK-886 (10 µM) inhibited COX-1-mediated platelet aggregation induced by collagen or arachidonic acid whereas thrombin- or U-46619-induced (COX-independent) aggregation was not affected. Since leukotrienes and prostaglandins share (patho)physiological properties in the development and regulation of carcinogenesis, inflammation, and vascular functions, caution should be used when interpreting data where MK-886 is used as tool to determine the involvement of FLAP and/or the 5-lipoxygenase pathway in respective experimental models. [Copyright &y& Elsevier]

Abstract: Prostaglandin D2 (PGD2) is involved in a variety of physiological and pathophysiological processes, but its role in fever is poorly understood. Here we investigated the effects of central PGD2 administration on body temperature and prostaglandin levels in the cerebrospinal fluid (CSF) of rats. Administration of PGD2 into the cisterna magna (i.c.m) evoked a delayed fever response that was paralleled by increased levels of prostaglandin E2 (PGE2) in the CSF. The elevated PGE2 levels were not caused by an increased expression of cyclooxygenase 2 or microsomal prostaglandin E synthase-1 in the hypothalamus. Interestingly, i.c.m. pretreatment of animals with PGD2 considerably sustained the pyrogenic effects of i.c.m. administered PGE2. These data indicate that PGD2 might control the availability of PGE2 in the CSF and suggest that centrally produced PGD2 may play a role in the maintenance of fever. [Copyright &y& Elsevier]