Role Of Prostaglandins Research Articles

Role of prostaglandin E receptor subtypes EP2 and EP4 in autocrine and paracrine functions of vascular endothelial growth factor in the inner ear

BackgroundThe physiological effects of prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) are mediated by the prostaglandin E receptor subtypes EP1, EP2, EP3, and EP4, and the respective agonists have been purified. PGE1 and PGE2 can increase the production of vascular endothelial growth factor (VEGF), particularly through EP2 and EP4. The biological effects of VEGF are mediated by the phosphotyrosine kinase receptors fms-related tyrosine kinase-1 (Flt-1) and fetal liver kinase-1 (Flk-1). Here we examined the effects of EP2 and EP4 agonists on the production of VEGF proteins and VEGF messenger RNAs (mRNAs) in the inner ear, using an enzyme-linked immunosorbent assay and the real-time quantitative reverse transcription-polymerase chain reaction, respectively. We also examined the localization of EP2, VEGF, Flt-1, and Flk-1 in the cochlea by immunohistochemistry.ResultsThe expression of EP2 occurred in the cochlea, and the local application of an EP2 or EP4 agonist increased VEGF protein and VEGF mRNA levels in the inner ear. Furthermore, the intensity of the VEGF immunoreactivity in the spiral ganglion appeared to be increased by the local EP2 or EP4 agonist treatment. Immunoreactivity for Flt-1, and Flk-1 was found in the cochlear sensory epithelium, spiral ganglion, spiral ligament, and stria vascularis.ConclusionsThese findings demonstrate that EP2 and EP4 agonists stimulate VEGF production in the inner ear, particularly in the spiral ganglions. Moreover, the Flt-1 and Flk-1 expression observed in the present study suggests that VEGF has autocrine and paracrine actions in the cochlea. Thus, EP2 and EP4 might be involved in the mechanisms underlying the therapeutic effects of PGE1 on acute sensorineural hearing loss via VEGF production.

The role of prostaglandins on hypoxic pulmonary vasoconstriction in dogs--especially the role of PGI2

The role of prostaglandins on hypoxic pulmonary vasoconstriction in dogs--especially the role of PGI2

Gastroprotective effect of Astragaloside IV: role of prostaglandins, sulfhydryls and nitric oxide

This investigation evaluated the gastroprotective activity of Astragaloside IV, a cycloartane-type triterpene glycoside isolated from Astragalus zahlbruckneri. Gastric mucosal damage was induced in rats by intragastric ethanol (1 mL/rat). Rats treated orally with Astragaloside IV suspended in Tween 80 at 3, 10 and 30 mg kg(-1), showed 15, 37 and 52% gastroprotection, respectively. The gastroprotection observed at 30 mg kg(-1) for this compound was attenuated in rats pretreated with N(G)-nitro-L arginine methyl ester (70 mg kg(-1), i.p), a nitric oxide (NO)-synthase inhibitor, suggesting that the gastroprotective mechanism of this glycoside involves, at least in part, the participation of NO. The gastroprotective effect of Astragaloside IV was not affected by the inhibition of prostaglandin synthesis with indometacin (10 mg kg(-1), s.c.) nor by the block of endogenous sulfhydryls with N-ethylmaleimide (NEM, 10 mg kg(-1), s.c.). Carbenoxolone was used as a gastroprotective model drug and showed a dose-dependent gastroprotective effect (25, 43 and 88% of gastroprotection, at 3, 10 and 30 mg kg(-1), respectively). The partial participation of prostaglandins, sulfhydryls and NO was observed in the gastroprotective mechanism of carbenoxolone.

Prostaglandin (PG)D2 and 15-deoxy-Δ12,14-PGJ2, but not PGE2, mediate shear-induced chondrocyte apoptosis via protein kinase A-dependent regulation of polo-like kinases

Excessive mechanical loading of cartilage producing hydrostatic stress, tensile strain and fluid flow leads to chondrocyte apoptosis and osteoarthritis. High fluid flow induces cyclooxygenase-2 (COX-2) expression in sheared chondrocytes, which suppresses their antioxidant capacity and contributes to apoptosis. The pivotal role of COX-2 in shear-induced chondrocyte apoptosis and the conflicting literature data on the roles of prostaglandin (PG)E2, PGD2 and its metabolite 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) in chondrocyte apoptosis prompted us to investigate which COX-2-derived PG is involved in this process. We show that exogenously added PGD2 and 15d-PGJ2, but not PGE2, diminish the viability of human T/C-28a2 chondrocytes under static conditions. In agreement with these observations, knockdown of L-PGD synthase (L-PGDS) abolishes shear-induced chondrocyte apoptosis. Using cDNA microarrays in conjunction with clustering algorithms, we propose a novel signaling pathway by which high fluid shear mediates COX-2/L-PGDS-dependent chondrocyte apoptosis, which is validated by molecular interventions. We demonstrate that L-PGDS controls the downregulation of Protein Kinase A (PKA), which in turn regulates Polo-like kinase1 (Plk1) and Plk3. Plks target p53, which controls the transcription of p53 effectors (TP53INPs, FAS and Bax) involved in chondrocyte apoptosis. Reconstructing the signaling network regulating chondrocyte apoptosis may provide insights to optimize conditions for culturing artificial cartilage in bioreactors and for developing therapeutic strategies for arthritic disorders.

COX Inhibitors and Overactive Bladder: The Potential for Future Therapy

Studies spanning four decades suggest that prostaglandins (PGs) are synthesized at high levels within the bladder by cyclooxygenase (COX)-1 and COX-2 and that PG biosynthesis during bladder filling provides a non-neuronal vesicular volume signal. Evidence is presented that interstitial cells of Cajal within the bladder seem to play a key role in PG biosynthesis, that bladder PG concentration is a function of the degree of bladder wall stretch, and that PGs serve to 1) assist in detrusor smooth muscle length adaptation of tension during bladder storage by permitting synchronized spontaneous rhythmic contraction, 2) positively modulate sensory recognition of the bladder fill state, and 3) enhance voiding contraction. Provocative clinical and experimental data support a role for PGs in overactive bladder, but the data are of limited scope. Additional studies are needed to clarify the roles played by mechanical stretch, COX isotypes, PG species and receptor subtypes, and cell-to-cell communication in bladder biology.

Roles of prostaglandin E2, a proinflammatory mediator, in emotional adaptation to stress

Roles of prostaglandin E2, a proinflammatory mediator, in emotional adaptation to stress

Roles of prostaglandin E2 and its receptor EP1 in social withdrawal after repeated social defeat in mice

Roles of prostaglandin E2 and its receptor EP1 in social withdrawal after repeated social defeat in mice

A possible role of prostaglandin in the recycling of internalized bradykinin B2 receptor through EP3 receptor

A possible role of prostaglandin in the recycling of internalized bradykinin B2 receptor through EP3 receptor

Interleukin-11 in Endometrial Adenocarcinoma Is Regulated by Prostaglandin F 2α-F-Prostanoid Receptor Interaction via the Calcium-Calcineurin-Nuclear Factor of Activated T Cells Pathway and Negatively Regulated by the Regulator of Calcineurin-1

Interleukin-11 (IL-11) up-regulates the proliferative and invasive capacity of many cancers. Coexpression of glycoprotein 130 (GP130) and IL-11 receptor alpha (IL-11Ralpha) is necessary for high-affinity binding of IL-11 to IL-11Ralpha. This study investigated the expression of IL-11 and role of prostaglandin F(2alpha)-F-prostanoid receptor (FP receptor) signaling in the modulation of IL-11 expression in endometrial adenocarcinoma cells. Localization of IL-11, IL-11Ralpha, and GP130 expression was performed by immunohistochemistry. IL-11 and regulator of calcineurin 1 isoform 4 (RCAN1-4) mRNA and protein expression were determined by real-time RT-PCR and/or enzyme-linked immunosorbent assay/Western blot analysis using Ishikawa endometrial adenocarcinoma cells stably expressing the FP receptor (FPS cells) and endometrial adenocarcinoma explants. IL-11 mRNA expression was significantly elevated in endometrial adenocarcinoma samples compared with normal endometrium and increased with tumor grade. IL-11 protein expression localized with FP receptor, IL-11Ralpha, and GP130 in the neoplastic glandular epithelium of endometrial adenocarcinomas. Prostaglandin F(2alpha)-FP receptor signaling significantly elevated the expression of IL-11 mRNA and protein in a Gq-protein kinase C-calcium-calcineurin-nuclear factor of activated T cells-dependent manner in FPS cells. The calcineurin signaling pathway is known to be controlled by the RCAN (RCAN1-4). Indeed, RCAN1-4 expression was significantly elevated in well-differentiated endometrial adenocarcinoma compared with normal endometrium and was found to decrease with tumor grade and negatively regulate IL-11 expression in vitro. This study has highlighted a new mechanism regulating IL-11 expression in endometrial adenocarcinoma cells by the FP receptor via the calcium-calcineurin-nuclear factor of activated T cells pathway.

Roles of prostaglandins in enhancement of tumor-associated angiogenesis and lymphangiogenesis as a therapeutic target

Roles of prostaglandins in enhancement of tumor-associated angiogenesis and lymphangiogenesis as a therapeutic target

Role of prostaglandins and specific place in therapy of bimatoprost in the treatment of elevated intraocular pressure and ocular hypertension: A closer look at the agonist properties of bimatoprost and the prostamides

Bimatoprost is the only representative of a novel class of prostaglandin ethanolamide (prostamide) compounds used therapeutically as an efficacious treatment for glaucoma. The pathways through which bimatoprost works to improve uveoscleral outflow to relieve elevated intraocular pressure are similar to those of the conventional prostaglandins used in glaucoma therapy, with some evidence of a preferential action at the trabecular meshwork. The pharmacology of bimatoprost is however, unclear. Pharmacological evidence supports a specific and distinct receptor-mediated agonist activity of bimatoprost at 'prostamide' receptors, which is selective to the prostamides as a class. However, other studies have reported either activity of bimatoprost at additional prostanoid and nonprostanoid receptors, or a conversion of bimatoprost to metabolites with agonist activity at prostaglandin FP receptors in the human eye. The formation of endogenous prostamides has been demonstrated in vivo, by a novel pathway involving the cyclooxygenase-2-mediated conversion of endogenous cannabinoid (endocannabinoid) substrates. Irrespective of the pharmacology of bimatoprost and the prostamides in general, further studies are needed to determine the biological role and biochemical pathology of prostamides in the human eye, particularly in glaucoma. Such studies may improve our understanding of uveoscleral flow and may offer new treatments for controlling intraocular pressure.

Prostaglandin E2as a Regulator of Germ Cells during Ovarian Development

Context: The formation of primordial follicles occurs during fetal life yet is critical to the determination of adult female fertility. Prior to this stage, germ cells proliferate, enter meiosis, and associate with somatic cells. Growth and survival factors implicated in these processes include activin A (INHBA), the neurotrophins BDNF and NT4 (NTF5), and MCL1. The prostaglandins have pleiotrophic roles in reproduction, notably in ovulation and implantation, but there are no data regarding roles for prostaglandins in human fetal ovarian development. Objective: The aim of the study was to investigate a possible role for prostaglandin (PG) E2 in human fetal ovary development. Design: In vitro analysis of ovarian development between 8 and 20 wk gestation was performed. Main Outcome Measure(s): The expression patterns of PG synthesis enzymes and the PGE2 receptors EP2 and EP4 in the ovary were assessed, and downstream effects of PGE2 on gene expression were analyzed. Results: Ovarian germ cells express the PG...

Possible participation of prostaglandins in the increase in the bone blood flow in oophorectomized female rats.

The aim of this study was to verify the possible role of prostaglandin (PG) in the increase in the bone blood flow of female rats after oophorectomy (OOX). In two experiments we determined blood flow in the tibia and distal femur (85Sr-microspheres) and 24-h incorporation of 45Ca and 3H-proline. Acetylosalicyclic acid (ASA, 0.13% in the food for 4 weeks) was used to suppress the production of PG. There was an increase in the bone blood flow after OOX (performed 4 weeks prior to the experiment), no change after ASA alone and significant reduction by ASA of the OOX-induced increase in the bone blood flow. In both groups of OOX females there was a decrease in tibial bone density and ash weight. The changes in 45Ca incorporation were similar to those in the blood flow while the changes in 3H-proline incorporation were not significant. Thus, the effect of ASA, i.e. suppression of the OOX-induced increase in the bone blood flow, is consistent with the possible role of PG (probably PGE2) in the increase in bone blood flow of OOX female rats.

Prostaglandin E2 as a Regulator of Germ Cells during Ovarian Development

The formation of primordial follicles occurs during fetal life yet is critical to the determination of adult female fertility. Prior to this stage, germ cells proliferate, enter meiosis, and associate with somatic cells. Growth and survival factors implicated in these processes include activin A (INHBA), the neurotrophins BDNF and NT4 (NTF5), and MCL1. The prostaglandins have pleiotrophic roles in reproduction, notably in ovulation and implantation, but there are no data regarding roles for prostaglandins in human fetal ovarian development. The aim of the study was to investigate a possible role for prostaglandin (PG) E(2) in human fetal ovary development. In vitro analysis of ovarian development between 8 and 20 wk gestation was performed. The expression patterns of PG synthesis enzymes and the PGE(2) receptors EP2 and EP4 in the ovary were assessed, and downstream effects of PGE(2) on gene expression were analyzed. Ovarian germ cells express the PG synthetic enzymes COX2 and PTGES as well as the EP2 and EP4 receptors, whereas COX1 is expressed by ovarian somatic cells. Treatment in vitro with PGE(2) increased the expression of BDNF mRNA 1.7 +/- 0.16-fold (P = 0.004); INHBA mRNA, 2.1 +/- 0.51-fold (P = 0.04); and MCL1 mRNA, 1.15 +/- 0.06-fold (P = 0.04), but not that of OCT4, DAZL, VASA, NTF5, or SMAD3. These data indicate novel roles for PGE(2) in the regulation of germ cell development in the human ovary and show that these effects may be mediated by the regulation of factors including BDNF, activin A, and MCL1.

Increased glomerular cytosolic phospholipase A2 activity of OLETF rats with early diabetes.

In view of the potential role of prostaglandins (PGs) in development of glomerular hyperfiltration leading to diabetic nephropathy, we studied the temporal relationship of the activity of cytosolic phospholipase A2 (cPLA2), a rate-limiting enzyme for eicosanoid biosynthesis, with hyperfiltration and the histological changes in glomeruli using OLETF rats, a model for non-insulin-dependent diabetes mellitus (NIDDM). Diabetes mellitus and associated histopathological changes, which developed spontaneously by 30-46 weeks after birth of OLETF rats, were accompanied by approximately 65% increase in glomerular cPLA2 activity that showed significant correlations with elevated plasma glucose levels and creatinine clearance. Moreover, mesangial cells cultured for 5 days with high glucose exhibited approximately 2-fold higher cPLA2 activity than those cultured with physiologic level of glucose. These data suggest that increased glomerular cPLA2 activity leads to production of PGs, which may promote the progression of early diabetic glomerular hyperfiltration and subsequent diabetic nephropathy.

The Emerging Role of Prostaglandin E2 in Regulating Stem Cell Function

The Emerging Role of Prostaglandin E2 in Regulating Stem Cell Function

Effects of limonene and essential oil from Citrus aurantium on gastric mucosa: Role of prostaglandins and gastric mucus secretion

Essential oil from Citrus aurantium and the monoterpene limonene are widely used flavoring agents that are found in some common food items. This specie is also used medicinally throughout the world to treat gastritis and gastric disorders. Therefore, biological assays were performed in vivo on essential oil of C. aurantium (OEC) and its majority compound limonene (LIM) to evaluate their effect on gastric mucosa. The OEC (250 mg/kg, p.o.) and LIM (245 mg/kg, p.o.) provided effective (99%) gastroprotection against lesions induced by absolute ethanol and NSAID (non-steroidal anti-inflammatory drug) in rats. OEC and LIM do not interfere with gastric H + secretion, serum gastrin or glutathione (GSH) level in gastric mucosa. But the gastroprotective action of OEC and LIM occurs due to an increase in the gastric mucus production induced by conserving the basal PGE 2 levels after challenge by agents harmful to the gastric mucosa. Given that LIM and OEC are excellent flavoring agents and also present gastroprotective actions, they can be regarded as a promising target for the development of a new drug for the prevention of gastric damage.

The Role of Prostaglandins in Adaptation to Resistance Exercise

The Role of Prostaglandins in Adaptation to Resistance Exercise

Prostaglandin H Synthase-1-Catalyzed Bioactivation of Neurotransmitters, Their Precursors, and Metabolites: Oxidative DNA Damage and Electron Spin Resonance Spectroscopy Studies

The role of prostaglandin H synthase-1 (PHS-1) and a related model enzyme, horseradish peroxidase (HRP), in catalyzing the bioactivation of dopamine (DA) and epinephrine and their precursors and metabolites to potential neurodegenerative free radical intermediates was examined. To determine the potential contribution of PHS-dependent reactive oxygen species (ROS) formation, the neurotransmitter DA or its precursor and metabolites were incubated in vitro with purified ovine PHS-1 and calf thymus DNA. DA, its L-dihydroxyphenylalanine (L-DOPA), precursor, and its dihydroxyphenylacetic acid (DOPAC) metabolite were excellent PHS-1 substrates, resulting in PHS-1-dependent ROS formation that initiated oxidative DNA damage, selectively quantified as 8-oxo-2'-deoxyguanosine. Most substrates generated isotropic electron spin resonance (ESR) spectra with a resolved hyperfine structure attributable to ortho-semiquinone free radical intermediates upon autoxidation at pH 6, with up to a 18-fold increase via HRP-catalyzed oxidation. Remarkably, HRP-mediated oxidation of DOPAC and dihydroxymandelic acid (DHMA) produced asymmetric ESR spectra characteristic of an immobilized radical, possibly due to free radical intermediates and melanin or melanin-like polymers. These results show that the precursors and metabolites of endogenous neurotransmitters, while inactive in receptor binding assays, may actually play an important role in free radical formation. Additionally, ROS generated by PHS-catalyzed bioactivation produce oxidative DNA damage in the central nervous system, which may initiate neurodegeneration associated with aging.

Roles of Prostaglandin E2 and 12‐Hydroxy‐eicosatetraenoic Acid on Promotion of Angiogenesis of Choroid‐retinal Endothelial Cells by Pigment Epithelial Cells and Leukocytes under Inflammatory Conditions

PurposesTo determine the effects of choroid‐retinal endothelial cells (CREC), retinal pigment epithelial cells (RPE) and leukocytes on CREC angiogenesis including migration, vasculature formation, and proliferation. The lipid profiles in these process were also determined. Prostaglandin E2 (PGE2) and 12‐hydroxy‐eicosatetraenoic acid (12‐HETE) are chosen as targets to confirm the effects of lipids on CREC angiogenesis.MethodsCREC migration was carried out in 24‐transwell plate, RPE or leukocytes in low chambers stimulated with 2ng/ml IL‐1 β and 2ng/ml TNF‐α. Tube formation was performed on matrigel. Lipid profiles of CREC, RPE ad leukocytes were analyzed using LC‐UV‐MS/MS.Resultsstimulated with IL‐1 β and TNF‐α, EC, RPE and leukocytes could produce many kinds of lipid mediators including PGE2 and 12HETE, which promoted CREC migration and vasculature formation. CREC and leukocytes produced much more lipid mediators than RPE. High concentration of COX2 inhibitor NS398 and lipoxygenase inhibitor Baicalein inhibited expressions of PGE2 and 12‐HETE respectively, and subsequently reduce CREC migration and vasculature formation.ConclusionsCREC, RPE and leukocytes could promote angiogenesis by producing PGE2 and 12HETE under inflammation conditions.