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Background/aim: Our recent study revealed that the expression of lipoxygenase (LOX) and cyclooxygenase (COX) enzymes in the hypothalamus is activated by nesfatin-1, leading to the liberation of leukotrienes and prostaglandins (PG), respectively. Moreover, our prior report explained that intracerebroventricular (ICV) nesfatin-1 treatment triggers cardiovascular responses mediated by central LOX and COX enzymes. Building upon our prior reports, the present investigation sought to clarify the role of cardiovascularly active central COX products, such as thromboxane (TX) A2, PGF2α, PGE, and PGD, in orchestrating nesfatin-1-evoked reactions in mean arterial pressure (MAP) and heart rate (HR). Materials and methods: The Sprague Dawley rats, which had guide cannula in the lateral ventricle for intracerebroventricular (ICV) injections and catheter in arteria femoralis for monitoring MAP and HR, were underwent central pretreatment with furegrelate (the TXA2 synthase inhibitor), PGF2α-dimethylamine (PGF2α-DA, the PGF2α receptor antagonist), or AH6809 (the PGE and PGD receptor antagonist), 5 min prior to ICV nesfatin-1 administration. The cardiovascular parameters were observed and recorded for 60 min posttreatment Results: Nesfatin-1 induced cardiovascular responses in rats leading to pressor effect in MAP, and tachycardia following bradycardia in HR. Interestingly, ICV furegrelate, PGF2α-DA, or AH6809 pretreatment partially mitigated the cardiovascular effects revealed by nesfatin-1. Conclusion: The findings illuminate the role of nesfatin-1 in modulating MAP and HR through the central activation of specifically TXA2, PGF2α, PGE, and PGD from COX metabolites. Additionally, the study may also suggest the potential involvement of other central COX or LOX metabolites beyond these COX metabolites in mediating the cardiovascular effects produced by nesfatin-1. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety in the first 12 h, efficacy and maternal satisfaction of a double balloon catheter (DBC) with vaginal prostaglandin (PGE) for induction of labour (IOL). Methods: We conducted a multicentre randomised controlled study of 420 patients from 1st January 2016 to 31st December 2017 to evaluate the use of DBC in IOL in an Asian population looking at the adverse effects in the first 12 h after insertion. Women were assigned randomly to cervical ripening with either a DBC or a prostaglandin pessary. The adverse events in the 12 h after DBC or first prostaglandin inserted, the efficacy of a DBC to a prostaglandin in labour induction and maternal satisfaction were evaluated. Results: There were significantly less women with uterine hyperstimulation in the DBC (2 vs 24, p ≤ 0.0001) compared to the prostaglandin group. There were no women with uterine hyperstimulation and non-reassuring foetal status in the DBC while there were 5 women with uterine hyperstimulation and foetal distress in the prostaglandin group. Use of entonox was significantly less in the DBC group (p = 0.009). There were no significant differences in both groups in caesarean section, vaginal deliveries and time to delivery, although significant less time was needed to achieve cervical os dilation more than 4 cm in the DBC group (p ≤ 0.0001). Neonatal birth outcomes were similar. Women's pain scores were similar for both methods. 80.1% of women allocated the DBC and 76.8% of women allocated the PGE were keen to recommend their method of induction. Conclusion: Double balloon catheter remains a good alternative method for inducing women in view of a good safety profile with low risk of hyperstimulation and high maternal satisfaction. Clinical trial registration: ClinicalTrials.gov Identifier: NCT02620215. [ABSTRACT FROM AUTHOR]

Copyright of Progress in Modern Biomedicine is the property of Publishing House of Progress in Modern Biomedicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

While searching for a counterpart to cyclic AMP, a new compound was found to inhibit adenylate cyclase. It was identified as prostaglandyl‐(15‐4′)‐myo‐inositol (1′:2′‐cyclic)‐phosphate (cyclic PIP). The substrates for its biosynthesis are prostaglandin E (PGE) and the novel inositol phosphate, guanosine diphospho‐4‐myo‐inositol 1:2‐cyclic phosphate (n‐IP). The basic regulatory properties of cyclic PIP are to inhibit dose‐dependently protein kinase A (PKA) and to seven‐fold activate protein ser/thr phosphatase holoenzyme. These regulations occur as rapidly as the activation of PKA by cyclic AMP. Such regulatory properties are essential for the meticulous regulation of the equilibrium between the phospho‐ and de‐phospho‐form of interconvertible enzymes. The synthesis of cyclic PIP is stimulated by insulin and noradrenaline (α‐receptor action). The insulin‐stimulated cyclic PIP synthase is active in a tyrosine‐phosphorylated state. A comparable characterization of the adrenaline‐stimulated cyclic PIP synthase is still incomplete. In streptozotocin‐diabetic rats, the hormonal stimulation of cyclic PIP synthesis decreases with time. Cyclic PIP synthesis is activated by biguanides as metformin two to four‐fold and by antihypertensive drugs two‐fold. Inhibition of cyclic PIP synthesis leads to a metabolic state as observed in early‐stage type‐2 diabetes. In summary, all living cells synthesize cyclic PIP, which switches on anabolism, whereas cyclic AMP triggers catabolism. [ABSTRACT FROM AUTHOR]

The inhibitory effects of Mitrella kentii leaf and stem extracts on the production prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) and antagonist effect on platelet-activating factor (PAF) receptor binding were evaluated. The inhibition of PGE2 and TXB2 productions were determined using the radioimmunoassay technique, and the inhibitory effect of PAF receptor binding to rabbit platelet was determined using the 3H-PAF as a ligand. Among the extracts tested, ethyl acetate, methanol and hexane leaf extracts, and methanol stems extract showed inhibitory effects on PGE2 and TXB2 productions and antagonistic effect on PAF receptor binding. M. kentii extracts may have the potential of being developed as supplements for inflammatory conditions. [ABSTRACT FROM AUTHOR]

Aims: To further explore the effects of a novel EP2 and EP3 dual agonist, ONO‐8055, on detrusor contractility, we investigated the responses of bladder strips from sham and lumbar canal stenosis (LCS) rats to this agonist, its effects on lower urinary tract function in normal rats, and mRNA expression of EP2 and EP3 receptors in the sham and LCS rats. Methods: The responses of bladder strips from sham and LCS rats to ONO‐8055 were measured. The effects of ONO‐8055 on LUT function of normal rats were investigated with awake cystometry and intraurethral perfusion pressure (Pura) measurements. The relative mRNA of bladder and urethral tissue of the sham and LCS rats was quantified using specific probes for EP1, EP2, EP3, and EP4 genes. Results: Compared with the vehicle, the muscle tensions of both the sham and LCS rats were significantly increased after adding this agonist. On awake cystometry of normal rats, bladder capacity and Pura were decreased in the ONO‐8055 groups, but a statistically significant difference in mean changes was demonstrated only between the vehicle group and the group receiving the highest dose. Compared with the sham rats, mRNA expressions of the four EP receptors in the lower urinary tract of the LCS rats did not show a statistically significant difference. Conclusions: This agonist did not augment bladder contractility or urethral relaxation in normal rats. [ABSTRACT FROM AUTHOR]

Abstract: Abdominal aortic aneurysm (AAA) is a progressive disease that has an increasing prevalence with aging, but no effective pharmacological therapy to attenuate AAA progression is currently available. We reported that the prostaglandin E receptor EP4 plays roles in AAA progression. Here, we show the effect of CJ‐42794, a selective EP4 antagonist, on AAA using two mouse models (angiotensin II‐ and CaCl2‐induced AAAs) and human aortic smooth muscle cells isolated from AAA tissue. Oral administration of CJ‐42794 (0.2 mg/kg per day) for 4 weeks significantly decreased AAA formation in ApoE−/− mice infused with angiotensin II (1 μg/kg per min), in which elastic fiber degradation and activations of matrix metalloproteinase (MMP)‐2 and MMP‐9 were attenuated. Interleukin‐6 (IL‐6) proteins were highly expressed in the medial layer of angiotensin II‐induced mouse AAA tissues, whereas this expression was significantly decreased in mice treated with CJ‐42794. AAA formation induced by periaortic CaCl2 application in wild‐type mice was also reduced by oral administration of CJ‐42794 for 4 weeks. After oral administration of CJ‐42794 beginning 2 weeks after periaortic CaCl2 application and continuing for an additional 4 weeks, the aortic diameter and elastic fiber degradation grade were significantly smaller in CJ‐42794‐treated mice than in untreated mice. Additionally, in smooth muscle cells isolated from human AAA tissues, stimulation of CJ‐42794 inhibited PGE2‐induced IL‐6 secretion in a dose‐dependent manner and decreased PGE2‐induced MMP‐2 activity. These data suggest that inhibition of EP4 has the potential to be a pharmacological strategy for attenuation of AAA progression. [ABSTRACT FROM AUTHOR]

Prostaglandin E2 (PGE2) has been introduced as an important factor for embryo implantation. So the present study was carried out to evaluate the effect of seminal fluid (SF) on PGE2 pathway in uterus tissues of mice during window of preimplantation. The messenger RNA (mRNA) expressions of microsomal PGE synthase (mPGES) and cytosolic PGE synthase (cPGES) as well as protein expression of PGE receptor 2 and 4 (EP2 and EP4) were determined in uterine tissue of control and seminal vesicle–excised (SVX)–mated female mice during days 1 to 5 of pregnancy using real-time polymerase chain reaction (qRT-PCR) and Western blotting, respectively. We found that mRNA expression of mPGES at day 1 and 2 of pregnancy was significantly higher in the control group than the SVX-mated group (P < .05), but such result was not obtained for cPGES expression. The protein levels of EP2 at day 1 to 4 of pregnancy were significantly higher in the control group compared with the SVX-mated group (P < .05), also the EP4 levels were significantly different between the control and SVX-mated groups at the first day of pregnancy (P < .05). Implantation rate was higher in the control group and also there were positive correlations between mPGES and EP2 expressions in the fifth day of pregnancy with implantation rate. Our results demonstrated significant effect of SF on uterine expressions of the evaluated factors, especially mPGES and EP2. Regarding the correlations between levels of these factors and implantation rate, we suggest that possibly one of the important mechanisms of SF in affecting female pregnancy is through mPGES and EP2. [ABSTRACT FROM AUTHOR]

Scutellaria root, the root of Scutellaria baicalensis Georgi, is a crude drug used for inflammatory diseases. In our previous report, the combination of flavonoids contained in Scutellaria root have been found to inhibit PGE production more strongly than individual flavonoids. Here, to investigate the mechanism of the synergistic effect, we examined the effects of an equimolar mixture (F-mix) of baicalein ( 1), wogonin ( 2) and oroxylin A ( 3) on the production of PGE in LPS-treated J774.1 cells. Although 1 and 3 inhibited COX-2 activity, the F-mix showed no synergistic effect on COX-2 inhibition. Therefore, we investigated the steps leading to the activation of COX-2 protein. Compounds 1- 3 and F-mix inhibited the expression of COX-2 protein. However, only 2 inhibited the expression of COX-2 mRNA among the flavonoids, and the F-mix showed no synergistic effect. Only 1 inhibited NF-κB translocation into the nucleus, and the F-mix showed no synergistic effect. Although 2 did not affect NF-κB translocation, it strongly inhibited NF-κB-dependent transcriptional activity, and the F-mix inhibited the activity slightly more than 2. Compounds 1- 3 also inhibited NO production, and the F-mix showed a synergistic effect. However, the effects of each flavonoid on the expression of iNOS mRNA were not consistent with those on COX-2 mRNA. Because the flavonoids inhibit different steps in the production of PGE and NO, and their mixture did not show apparent synergistic effects in each step, we conclude that the synergistic effect of the flavonoid mixture reflects the total effect of the flavonoids inhibiting different steps in the NF-κB signalling pathway. [ABSTRACT FROM AUTHOR]

Curcumin is an important molecule found in turmeric plants and has been reported to exhibit some profound anti-inflammatory activities by interacting with several important molecular targets found in the mitogen-activated protein kinase and NF-κβ pathways. As part of our continuing effort to search for new anti-inflammatory agents with better in vitro and in vivo efficacies, we have synthesized a series of new unsymmetrical dicarbonyl curcumin derivatives and tested their effects on prostaglandin E secretion level in interferon-γ/lipopolysaccharide-activated macrophage cells. Among those, five compounds exhibited remarkable suppression on prostaglandin E production with IC values ranging from 0.87 to 18.41 µM. The most potent compound 17f was found to down-regulate the expression of cyclooxygenase-2 mRNA suggesting that this series of compounds could possibly target the mitogen-activated protein kinase signal transduction pathway. Whilst the compound did not affect the expression of the conventional mitogen-activated protein kinases, the results suggest that it could disrupt the phosphorylation and activation of the proteins particularly the c-Jun N-terminal kinases. Finally, the binding interactions were examined using the molecular docking and dynamics simulation approaches. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Zhejiang University: Science B is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: To find an inhibitor of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) that rapidly metabolises Prostaglandin E (PGE) as a mediator of wound healing, we examined seven flavonoids for this role. Results: 7,3′,4′-Trimethoxyflavone (TMF) had the lowest IC value of 0.34 µM for 15-PGDH inhibition but >400 µM for cytotoxicity, indicating a high therapeutic index. TMF elevated PGE levels in a concentration-dependent manner in both A549 lung cancer and HaCaT cells. It also significantly increased mRNA expression of multidrug resistance-associated protein 4 (MRP4) and of prostaglandin transporter (PGT) slightly in HaCaT cells. In addition, TMF facilitated in vitro wound healing in a HaCaT scratch model, which was completely inhibited by adding both 15-PGDH and NAD as cofactor, confirming the involvement of PGE in its wound healing effect. Conclusion: TMF with a high therapeutic index can facilitate wound healing through PGE elevation by 15-PGDH inhibition. [ABSTRACT FROM AUTHOR]

Platelets are anucleated cells that circulate in the blood as sentinels of tissue integrity. In fact, they are rich in a plethora of proteins and other factors stored in different granules which they selectively release upon stimulation. Moreover, platelets synthesize a vast number of lipids and release various types of vesicles, including exosomes which are rich in genetic material. Platelets possess a central function to interact with other cell types, including inflammatory cells and cancer cells. Recent findings have enlightened the capacity of platelets to induce changes in the phenotype of cancer cells which acquire invasiveness thus enhancing their metastatic potential. Thus, it has been hypothesized that targeting the platelet may represent a novel strategy to prevent the development and progression of cancer. This is supported by the efficacy of the antiplatelet agent low-dose aspirin. Studies are ongoing to verify whether other antiplatelet agents share the anticancer effectiveness of aspirin. [ABSTRACT FROM AUTHOR]

Mechanisms of vascular disorders in β-thalassemia/HbE patients remain poorly understood. In the present study, we aimed to determine the presence of endothelial dysfunction and its association with altered vascular mediators in this population. Forty-three β-thalassemia/HbE patients without clinically documented vascular symptoms and 43 age-sex-matched healthy controls were enrolled. Endothelial function was assessed using flow-mediated dilatation (FMD) before and after administration of nitroglycerine (NTG). β-Thalassemia/HbE patients showed a significant endothelial dysfunction using FMD. The percentage change in the brachial artery diameter before NTG was significantly lower in the thalassemia group compared to the control (5.0 ± 5.9 vs. 9.0 ± 4.0%, p < 0.01) while no significant differences after NTG (18.4 ± 8.3 vs. 17.8 ± 6.3%, p = 0.71). Plasma nitric oxide metabolites (NO x ) and prostaglandin E2 (PGE2) levels were significantly decreased in β-thalassemia/HbE (117.2 ± 27.3 vs. 135.8 ± 11.3 µmol/L, p < 0.01) and (701.9 ± 676.0 vs. 1374.7 ± 716.5 pg/mL, p < 0.01), respectively, while a significant elevation in soluble thrombomodulin levels in β-thalassemia/HbE (3587.7 ± 1310.0 vs. 3093.9 ± 583.8 pg/mL, p = 0.028). NO x and PGE2 levels were significantly correlated with FMD (r = 0.27, p = 0.025) and (r = 0.35, p = 0.003), respectively. These findings suggest roles for endothelial mediators and a new mechanism underlying endothelial dysfunction in β-thalassemia/HbE patients. [ABSTRACT FROM AUTHOR]

Copyright of Gynecological Endocrinology is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Prostaglandin E (PGE) is a key proinflammatory mediator that contributes to inflammatory hyperalgesia. Voltage-gated sodium channel 1.7 (Na1.7) plays an important role in inflammatory pain. However, the modulation of Na1.7 in inflammatory pain remains poorly understood. We hypothesized that PGE might regulate Na1.7 expression in inflammatory pain. We here showed that treatment of rat trigeminal ganglion (TG) explants with PGE significantly upregulated the mRNA and protein expressions of Na1.7 through PGE receptor EP2. This finding was confirmed by studies on EP2-selective antagonist PF-04418948. We also demonstrated that Na1.7 and COX-2 expressions, as well as PGE levels, were upregulated in the TG after induction of rats' temporomandibular joint (TMJ) inflammation. Correspondingly, hyperalgesia, as indicated by head withdrawal threshold, was observed. Moreover, TMJ inflammation-induced upregulation of Na1.7 expression and PGE levels in the TG could be reversed by COX-2-selective inhibitor meloxicam given by oral gavage, and meanwhile, the hyperalgesia of inflamed TMJ was also mitigated. So we concluded that PGE upregulated trigeminal ganglionic Na1.7 expression to contribute to TMJ inflammatory pain in rats. Our finding suggests that PGE was an important regulator of Na1.7 in TMJ inflammatory pain, which may help increase understanding on the hyperalgesia of peripheral inflammation and develop a new strategy to address inflammatory pain. [ABSTRACT FROM AUTHOR]

Background: Airplane Headache (AH) occurs during flights and often appears as an intense, short lasting headache during take-off or landing. Reports are limited on pathological mechanisms underlying the occurrence of this headache. Proper diagnosis and treatments would benefit from identification of potential pathways involved in AH pathogenesis. This study aimed at providing a simulated airplane headache condition as a proxy towards identification of its underlying mechanisms. Methods: Fourteen participants including 7 volunteers suffering from AH and 7 healthy matched controls were recruited after meeting the diagnostic and safety criteria based on an approved study protocol. Simulation of AH was achieved by entering a pressure chamber with similar characteristics of an airplane flight. Selected potential biomarkers including salivary prostaglandin E (PGE), cortisol, facial thermo-images, blood pressure, pulse, and saturation pulse oxygen (SPO) were defined and values were collected before, during and after flight simulation in the pressure chamber. Salivary samples were analyzed with ELISA techniques, while data analysis and statistical tests were handled with SPSS version 22.0. Results: All participants in the AH-group experienced a headache attack similar to AH experience during flight. The non-AH-group did not experience any headaches. Our data showed that the values for PGE, cortisol and SPO were significantly different in the AH-group in comparison with the non-AH-group during the flight simulation in the pressure chamber. Conclusion: The pressure chamber proved useful not only to provoke AH-like attack but also to study potential biomarkers for AH in this study. PGE, and cortisol levels together with SPO presented dysregulation during the simulated AH-attack in affected individuals compared with healthy controls. Based on these findings we propose to use pressure chamber as a model to induce AH, and thus assess new potential biomarkers for AH in future studies. [ABSTRACT FROM AUTHOR]

Introduction: Discussion of the relevance of suitable experimental models for the effective translation of drug effects to clinical inflammatory diseases has a long history. Much emphasis is placed these days on genetically transformed mice, which may have developmental drawbacks. But are established models redundant? Findings: Drawn from personal experience, examples are provided of the success of tinkering with technology in the context of inflammation. These include the use of specific dietary deficiency conditions, the development of new applications for established drugs and the introduction of a variety of readouts to assess outcome in studies on established disease models. Such approaches have been used to demonstrate inflammation-modulating effects of prostaglandin E, in the development of ebselen, for the introduction of immunomodulatory macrolide drugs and in new approaches to the therapy of multiple sclerosis. Conclusion: Fine tuning of experimental approaches and evaluation technologies can often still provide innovative, clinically relevant insights into the potential beneficial effects of drugs and pharmacological agents. [ABSTRACT FROM AUTHOR]

Background and Aim: Recent observational studies have shown therapeutic benefits of acetylsalicylic acid (ASA) in several types of cancer. We examined whether ASA exerts antitumor activity in esophageal adenocarcinoma (EAC).Methods: Human EAC cells (OE33) were treated with ASA (0-5 mM) to evaluate proliferation, apoptosis, and migration. In vivo model: OE33-derived tumors were subcutaneously implanted into athymic mice which were allocated to ASA (5 or 50 mg/kg/day)/vehicle (5-6 animals/group). Tumor growth was assessed every 2-3 days, and after 40 days, mice were euthanized. Plasma drug levels were determined by high-performance liquid chromatography. Histological and immunohistochemical (Ki67, activated caspase-3) analysis of tumors were performed. The effect of ASA on tumor prostaglandin E2 (PGE2) levels was also evaluated.Results: In vitro cell proliferation and migration were significantly inhibited while apoptosis increased (p < 0.05) by ASA. Although ASA did not induce tumor remission, tumor progression was significantly lower in ASA-treated mice when compared to non-treated animals (478 % in mice treated with 5 mg/kg/day ASA vs. 2696 % control; 748 % in mice treated with 50 mg/kg/day ASA vs. 2670 % control). Maximum tumor inhibition was 92 and 85 %, respectively. This effect was associated with a significant decrease of proliferation index in tumors. ASA 5 mg/kg/day did not modify tumor PGE2 levels. Whereas tumor PGE2 content in mice treated with ASA 50 mg/kg was lower than in control mice, the difference was not significant.Conclusion: Although these results need to be confirmed in other EAC cells, our data suggest a role for ASA in the treatment of this tumor. [ABSTRACT FROM AUTHOR]

Gnaphalium affine is an annual herbaceous plant that is used as a traditional medicine in some Latin American and Asian countries. However, systematic studies on its anti-inflammatory activity and signaling pathways have not yet been reported. In this study, we investigated the anti-inflammatory effect of G. affine methanol extract in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophage cells and fractioned the methanol extract into hexane, chloroform, ethyl acetate (EtOAc), butyl alcohol (BuOH), and distilled water (DW) by measuring the generation of nitric oxide (NO). G. affine inhibited the generation of NO and prostaglandin E. The chloroform-soluble fraction most effectively inhibited LPS-stimulated NO production. We also examined the cytotoxicity of G. affine in three normal cell lines: RAW264.7, HEK293, and HaCaT. Cell viability assays showed that the methanol extract and chloroform-soluble fraction of G. affine had no cytotoxic effect on normal cell lines. The expression of pro-inflammatory mediators was also investigated. Western blotting and immunofluorescence showed that G. affine reduces the expression of iNOS, COX-2, and MAPKs, as well as activation of NF-κB in LPS-stimulated RAW264.7 cells. RT-PCR showed that G. affine also negatively regulates inflammatory cytokines at the gene expression level. Taken together, G. affine exerts its anti-inflammatory activity through inhibition of NO generation as a result of inhibiting NF-κB and MAPKs-related inflammatory signaling pathways. In addition, the result of GC-MS analysis revealed the presence of nineteen different types of constituents including guaiacol in the chloroform-soluble fraction of G. affine. [ABSTRACT FROM AUTHOR]

Although Radix Angelicae dahuricae ( Angelica) has been traditionally used in patients with rheumatism arthralgia, its bioactive ingredients remain to be determined. In this study, the essential oil extract of Radix Angelicae dahuricae (EOAD) was assessed for its anti-inflammatory activities against xylene-induced acute ear swelling and carrageenan-induced acute paw edema in mice as well as its anti-inflammatory and immunomodulating properties in Freund's complete adjuvant (FCA)-induced arthritis in rats. We found that EOAD at 100 mg/kg significantly alleviated xylene-induced ear swelling and carrageenan-induced paw edema in mice. Moreover, in the FCA-induced rat arthritis model, EOAD significantly improved hind paw swelling, lowered the adjuvant arthritis score, mitigated synovial hyperplasia, inflammatory cell infiltration, and cartilage destruction in the ankle joint, and reduced the serum levels of inflammatory mediators such as nitric oxide, tumor necrosis factor-α, and prostaglandin E as well as serum nitric oxide synthase activity. These findings support the fact that the essential oil extract of Angelica contains important active constituents responsible for its anti-inflammatory activities and therefore help to understand the phytotherapeutic effects of Angelica in the treatment of aseptic inflammation. [ABSTRACT FROM AUTHOR]

Amomum tsao-ko ( A. tsao-ko) has been used as a traditional medicine for the treatment of infectious and digestive disorders. In the present study, we report the anti-inflammatory activity and molecular mechanism of 2,8-decadiene-1,10-diol (DDO) isolated from the extract of A. tsao-ko in lipopolysaccharide-stimulated RAW 264.7 cells. DDO treatment inhibited the production of nitric oxide and prostaglandin E by downregulating inducible nitric oxide synthase and cyclooxygenase-2 expression, respectively. Moreover, DDO suppressed the production of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-α. These inhibitory effects of DDO on the expression of inflammatory proteins were found to be mediated through the inactivation of mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase, c-Jun-N-terminal kinase and p38, and inhibition of nuclear factor-κB (NF-κB) pathways including degradation of inhibitor of κB-α and nuclear localization of NF-κB. Taken together, these findings demonstrate the pharmacological roles and molecular mechanisms of DDO in regulating inflammatory responses, and suggest further evaluation and development of DDO as a potent therapeutic agent for the treatment of inflammatory disorders. [ABSTRACT FROM AUTHOR]

Background: Anti-ischemic effects of NO releasing by nitroglycerin (NTG) and the release of calcitonin gene-related peptide (CGRP) are involved in the decrease of vascular remodeling in different cardiovascular diseases. Using a nitrate-free period is still generally required to prevent nitrate tolerance and should be used as the first-line option to maintain adequate symptom control and on an individual basis. Personalized anti-ischemic concerns require the urgent change of paradigm from interventional measures to predictive, preventive, and personalized treatment with organic nitrates and its combination with drugs that may improve prognosis and drugs that can be added for patients who remain symptomatic despite therapy with the other classes of agents. The purpose of this study was to evaluate the influence of human calcitonin gene-related peptide antagonist (CGRP) on cardiohemodynamic events, prostaglandin E (PGE) plasma concentration, the severity of ventricular arrhythmias, and mortality occurring during acute myocardial infarction (AMI) in NTG-tolerant and nontolerant rats. Methods: In the pilot study of efficacy of calcitonin gene-related peptide antagonist (CGRP), 58 male Wistar rats were included. All procedures were performed according to protocols approved by the General Animal Care and Use Committee. Adult male rats underwent surgery to induce AMI by ligating the left anterior descending coronary artery or SHAM. ECG was used to confirm myocardial ischemia. In each experiment, a rat was maintained under anesthesia for the duration of the experiment. At the end of the experiment, the rat was killed by an overdose of pentobarbital. All animals in accordance with the received pharmacological agent were randomized into three groups: I-received only NTG, 50 mg/kg daily, s.c. injections b.i.d. 3 days prior to AMI; II-received NTG by the same dose, route, and frequency of administration + CGRP antagonist (CGRP), 10 μg/kg two times daily by a similar period of administration; and III-served as control (C) group without preliminary tolerance to NTG. Results: Subcutaneous injections of NTG (50 mg/kg) 30 min prior to AMI in NTG-tolerant animals (group I) and in NTG-tolerant rats + CGRP antagonist (group II) caused minor changes in blood pressure and heart period that was accompanied before NTG s.c. administration with blunted baroreflex sensitivity in response to i.v. administration of sodium nitroprusside in these groups of rats (0.66 ± 0.05 and 0.56 ± 0.04 ms/mmHg, P < 0.05, respectively) in comparison to C (group III) animals (0.9 ± 0.1 ms/mmHg). AMI 1 h duration was associated with a high incidence of ventricular arrhythmia and significant mortality in group I (70 %) and especially in group II (90 %) animals at 72 h after reperfusion as compared with group III rats (56 %), that correlated to a decrease of PGE plasma content in group II (2.2 ± 0.4 ng/ml, P < 0.001) and group I (3.6 ± 0.2 ng/ml, P < 0.01) vs. control group of rats (4.8 ± 0.3 ng/ml). Conclusions: CGRP could be involved in the mechanism of nitrate tolerance via the inhibition of release of the potent vasodilator CGRP leading to exacerbation of acute myocardial ischemia. The influence of CGRP antagonist could enhance this condition. [ABSTRACT FROM AUTHOR]

Background: Methylprednisolone (MPD) is a rapid acting highly effective cluster headache preventive and also suppresses the recurrence of migraine attacks. Previously, we could demonstrate that elevated CGRP plasma levels in a cluster headache bout are normalized after a course of high dose corticosteroids. Here we assess whether MPD suppresses interleukin-1β (IL-1β)- and prostaglandin E (PGE)-induced CGRP release in a cell culture model of trigeminal ganglia cells, which could account for the preventive effect in migraine and cluster headache. Metoprolol(MTP), a migraine preventive with a slow onset of action, was used for comparison. Methods: Primary cultures of rat trigeminal ganglia were stimulated for 24 h with 10 ng/ml IL-1β or for 4 h with 10 μM PGE following the exposure to 10 or 100 μM MPD or 100 nM or 10 µM MTP for 45 min or 24 h. CGRP was determined by using a commercial enzyme immunoassay. Results: MPD but not MTP blocked IL-1β-induced CGRP release from cultured trigeminal cells. PGE-stimulated CGRP release from trigeminal ganglia cell culture was not affected by pre-stimulation whether with MPD or MTP. Conclusion: MPD but not MTP suppresses cytokine (IL-1β)-induced CGRP release from trigeminal ganglia cells. We propose that blockade of cytokine mediated trigeminal activation may represent a potential mechanism of action that mediates the preventive effect of MTP on cluster headache and recurrent migraine attacks. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Mesenchymal stem cells (MSCs) can exert an immunosuppressive effect on any component of the immune system, including dendritic cells (DCs), by direct contact, the release of soluble markers and extracellular vesicles (EVs). We evaluated whether MSCs and MSC-derived EVs have an immunomodulatory effect on monocyte-derived DCs in type 1 diabetes. Methods: Bone marrow derived MSCs were characterised and EVs were obtained by ultracentrifugation. DCs were differentiated from CD14 cells, obtained from nine type 1 diabetic patients at disease onset, pulsed with antigen GAD65 and cultured with MSCs or EVs. Levels of DC maturation and activation markers were evaluated by flow cytometry. GAD65-pulsed DCs and autologous CD14 cell were co-cultured and IFN-γ enzyme-linked immunosorbent spot responses were assayed. Secreted cytokine levels were measured and Th17 and regulatory T cells were analysed. Results: MSC- and EV-conditioned DCs acquired an immature phenotype with reduced levels of activation markers and increased IL-10 and IL-6 production. Conditioned DC plus T cell co-cultures showed significantly decreased IFN-γ spots and secretion levels. Moreover, higher levels of TGF-β, IL-10 and IL-6 were detected compared with unconditioned DC plus T cell co-cultures. Conditioned DCs decreased Th17 cell numbers and IL-17 levels, and increased FOXP3 regulatory T cell numbers. EVs were internalised by DCs and EV-conditioned DCs exhibited a similar effect. Conclusions/interpretation: In type 1 diabetes, MSCs induce immature IL-10-secreting DCs in vitro, thus potentially intercepting the priming and amplification of autoreactive T cells in tissue inflammation. These DCs can contribute to the inhibition of inflammatory T cell responses to islet antigens and the promotion of the anti-inflammatory, regulatory responses exerted by MSCs. [ABSTRACT FROM AUTHOR]

Fourteen compounds, coumarin ( 1), demethylsuberosin ( 2), xanthotoxin ( 3), psoralen ( 4), decursinol ( 5), decursin ( 6), decursinol angelate ( 7), chikusetsusaponin IVa ( 8), chikusetsusaponin IVa methyl ester ( 9), ethyl caffeate ( 10), syringaresinol ( 11), cnidilide ( 12), farnesol ( 13), and linoleic acid ( 14), were isolated from phytopharmaceutical PG201 (Layla) by activity-guided fractionation utilizing inhibitory activity on nitric oxide (NO) production in vitro. The isolates 1- 14 were evaluated for their inhibitory activity on LPS-induced NO and prostaglandin E (PGE) productions in RAW 264.7 cells. All the compounds except 14 displayed suppressive effects on LPS-induced NO and PGE production with IC values ranging from 8 to 60 μM. Among these, compound 10 showed the most potent inhibitory effect on NO production from RAW 264.7 cells with an IC value of 8.25 μM. Compounds 2, 9, and 10 exhibited high inhibitory effects on PGE production with the IC values of 9.42, 7.51, and 6.49 μM, respectively. These findings suggest that compounds 2, 9, and 10 are the potential anti-inflammatory active constituents of PG201 and further study may be needed to explain their mechanism of action. [ABSTRACT FROM AUTHOR]

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The ductus arteriosus (DA), a fetal arterial connection between the pulmonary arteries and aorta, normally closes after birth. Persistent DA patency usually has life-threatening consequences. In certain DA-dependent congenital heart diseases, however, patient survival depends on maintaining DA patency. Complete closure of the DA involves both functional closure, induced by muscle contraction, and anatomical closure, achieved through morphological and molecular remodeling. Anatomical closure of the DA is associated with the formation of intimal thickening, which is characterized by deposition of extracellular matrix in the subendothelial region, sparse elastic fiber formation, and migration of medial smooth muscle cells into the subendothelial space. In addition, fetal molecular remodeling that is suitable for postnatal muscle contraction has been observed in the DA. After the second trimester, high concentration of prostaglandin E2 (PGE2) causes the DA to dilate through the remainder of the fetal period. Emerging evidence from studies using pharmacological approaches and genetically modified mice suggests that, in addition to its vasodilatory effect, this chronic exposure to PGE2 promotes DA-specific anatomical and molecular remodeling through EP4, one of four receptor subtypes for PGE2. Signals that are downstream of PGE2-EP4, such as cyclic AMP (cAMP)-protein kinase A (PKA), exchange protein activated by cAMP (Epac), phospholipase C, and Wnt/β-catenin, may be involved in the regulation of intimal thickening, elastogenesis, and contraction-related genes. Understanding the physiological role of PGE2 in DA remodeling could enable more effective regulation of PDA, both in isolation and in the context of congenital cardiac anomalies. [ABSTRACT FROM AUTHOR]

In this study, non-rigid analogs of thalidomide have been designed in order to develop potentially active, more effective and safer lead molecules for disorders caused or contributed by inflammation. Five different series of acylaminoacetamide compounds were synthesized, and the biological inhibitory potency of the title compounds has been determined by evaluating their effects on COX-2 isoenzyme expression and PGE production in A549 (human lung adenocarcinoma) cell lines. Among the studied series, N-[2-(isopropylamino)-2-oxoethyl]isonicotinamide is the most active inhibitory compound on COX-2 isoenzyme expression, and N-[2-oxo-2-(pyrolydine-1-yl)etyl]isonicotinamide is the most active inhibitory compound on the biosynthesis of PGE. Molecular docking studies and molecular dynamics simulations were also applied to investigate non-covalent interactions of the most active compounds inside the active side of the crystal structure of murine cyclooxygenase 2 (mCOX-2) isoenzyme. [ABSTRACT FROM AUTHOR]

Although acetylshikonin (ACS) is known to have antioxidant and antitumor activities, whether ACS regulates the expression of proinflammatory mediators in lipopolysaccharide (LPS)-stimulated microglial cells remains unclear. In this study, it was found that ACS isolated from Lithospermum erythrorhizon inhibits LPS-induced nitric oxide (NO) and prostaglandin E (PGE) release by suppressing the expression of inducible NO synthase ( iNOS) and cyclooxygenase- 2 ( COX- 2) in BV2 microglial cells. Furthermore, ACS reduced the LPS-induced DNA-binding activity of nuclear factor-κB (NF-κB) and subsequently suppressed iNOS and COX- 2 expression. Consistent with these data, ACS attenuated the phosphorylation of PI3K and Akt and suppressed the DNA-binding activity of NF-κB by inducing the generation of reactive oxygen species (ROS) in LPS-stimulated cells. In addition, ACS enhanced heme oxygenase-1 (HO-1) expression via nuclear factor-erythroid 2-related factor 2 (Nrf2) activation. Zinc protoporphyrin, a specific HO-1 inhibitor, partially attenuated the antagonistic effects of ACS on LPS-induced NO and PGE production. By contrast, the presence of cobalt protoporphyrin, a specific HO-1 inducer, potently suppressed LPS-induced NO and PGE production. These data indicate that ACS downregulates proinflammatory mediators such as NO and PGE by suppressing PI3K/Akt-dependent NF-κB activity induced by ROS as well as inducing Nrf2-dependent HO-1 activity. Taken together, ACS might be a good candidate to regulate LPS-mediated inflammatory diseases. [ABSTRACT FROM AUTHOR]

It has recently become clear that regulation of mRNA stability plays an important role in the development of cell responses to stimulation of toll-like receptors during inflammation. This discovery motivated a search for low molecular weight substances modulating the stability of mRNA encoding proteins involved in inflammatory responses. In this work, regulation of the cyclooxygenase 2 (COX-2) expression by rosiglitazone-a promising drug for regulation of inflammation-was studied on rat glioma cell line C6. Inflammatory response was induced by lipopolysaccaride (LPS). The concentration of prostaglandin E (PGE) was measured by ELISA, the level of COX-2 mRNA was determined by real-time PCR. It was shown that treatment with LPS caused a 6-fold increase in the PGE synthesis, which correlated with an increase in the COX-2 mRNA expression. Rosiglitazone induced a 2-fold decrease of the LPS-stimulated PGE release and reduced the levels of COX-2 transcripts. To explore the molecular mechanisms of the rosiglitazone effect, we estimated the stability of COX-2 mRNA. Cells were incubated in the presence of LPS for 1 h, and then de novo mRNA transcription was blocked with actinomycin D. The levels of mRNA were determined at various time points. Treatment with rosiglitazone was carried out for 30 min before the LPS addition. The COX-2 mRNA half-life in native cells was found to be 75 min. LPS stimulation slowed down the mRNA degradation so that its half-life time was 120 min, and the treatment with rosiglitazone restored this process back to the normal level. The results suggest that rosiglitazone regulates the stability of COX-2 mRNA. This opens up new perspectives for therapeutic applications of this drug. [ABSTRACT FROM AUTHOR]

Prostaglandin E (PGE) is well known to modulate urinary bladder functions, but it is also thought to be involved in the pathophysiology of lower urinary tract dysfunctions, since high levels of PGE have been found in overactive bladder (OAB) patients. β-Adrenoceptors are major players in detrusor muscle relaxation, and the selective β-adrenoceptor (AR) agonist mirabegron was recently approved for the treatment of overactive bladder (OAB). β-Adrenoceptor modulation of PGE excitatory effects on bladder detrusor muscle was investigated by i.v. mirabegron after intravesical PGE infusion in conscious rats. Non-voiding activity (NVA) was assessed under isovolumetric conditions. In addition, mirabegron and isoprenaline (0.01-10 μM) were studied on PGE-increased micro-contractile activity during isometric tension recordings of intact isolated bladder muscle strips. Our investigations showed that PGE dramatically increased NVA in vivo and spontaneous micro-contractions in vitro. In vivo administration of mirabegron (0.1, 0.3 and 3 mg/kg) reduced PGE-augmented NVA in dose-dependent manner, while the PGE-increased micro-contractions in isolated bladder strips were poorly inhibited. Isoprenaline inhibited PGE-augmented micro-contractions in a concentration-dependent manner and had a higher potency compared to mirabegron. The apparent pKB of 7.25 for metoprolol at the isoprenaline concentration-response curve for PGE-augmented micro-contractions suggests a β-AR-mediated. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the effects of cadmium in concentrations relevant to those detected in human serum on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) expression at mRNA, protein, and enzyme activity levels in THP-1 macrophages. Macrophages were incubated with various cadmium chloride (CdCl) solutions for 48 h at final concentrations of 5 nM, 20 nM, 200 nM, and 2 μM CdCl. The mRNA expression and protein levels of COXs were analyzed with RT-PCR and Western blotting, respectively. Prostaglandin E (PGE) and stable metabolite of thromboxane B (TXB) concentrations in culture media were determined using ELISA method. Our study demonstrates that cadmium at the highest tested concentrations modulates COX-1 and COX-2 at mRNA level in THP-1 macrophages; however, the lower tested cadmium concentrations appear to inhibit COX-1 protein expression. PGE and TXB production is not altered by all tested Cd concentrations; however, the significant stimulation of PGE and TXB production is observed when macrophages are exposed to both cadmium and COX-2 selective inhibitor, NS-398. The stimulatory effect of cadmium on COXs at mRNA level is not reflected at protein and enzymatic activity levels, suggesting the existence of some posttranscriptional, translational, and posttranslational events that result in silencing of those genes' expression. [ABSTRACT FROM AUTHOR]

Background: Activity of cyclooxygenase 2 (COX-2) in mouse oligodendrocyte precursor cells (OPCs) modulates vulnerability to excitotoxic challenge. The mechanism by which COX-2 renders OPCs more sensitive to excitotoxicity is not known. In the present study, we examined the hypothesis that OPC excitotoxic death is augmented by COX-2-generated prostaglandin E2 (PGE2) acting on specific prostanoid receptors which could contribute to OPC death. Methods: Dispersed OPC cultures prepared from mice brains were examined for expression of PGE2receptors and the ability to generate PGE2 following activation of glutamate receptors with kainic acid (KA). OPC death in cultures was induced by either KA, 3'-O-(Benzoyl) benzoyl ATP (BzATP) (which stimulates the purinergic receptor P2X7), or TNFα, and the effects of EP3 receptor agonists and antagonists on OPC viability were examined. Results: Stimulation of OPC cultures with KA resulted in nearly a twofold increase in PGE2. OPCs expressed all four PGE receptors (EP1-EP4) as indicated by immunofluorescence and Western blot analyses; however, EP3 was the most abundantly expressed. The EP3 receptor was identified as a candidate contributing to OPC excitotoxic death based on pharmacological evidence. Treatment of OPCs with an EP1/EP3 agonist 17 phenyl-trinor PGE2 reversed protection from a COX-2 inhibitor while inhibition of EP3 receptor protected OPCs from excitotoxicity. Inhibition with an EP1 antagonist had no effect on OPC excitotoxic death. Moreover, inhibition of EP3 was protective against toxic stimulation with KA, BzATP, or TNFα. Conclusion: Therefore, inhibitors of the EP3 receptor appear to enhance survival of OPCs following toxic challenge and may help facilitate remyelination. [ABSTRACT FROM AUTHOR]

The consumption of omega-3 polyunsaturated fatty acids (n-3 PUFA) is associated with a reduced risk of breast cancer. Studies in animals and in vitro have demonstrated mechanisms that could explain this apparent effect, but clinical and epidemiological studies have returned conflicting results on the practical benefits of dietary n-3 PUFA for prevention of breast cancer. Effects are often only significant within a population when comparing the highest n-3 PUFA consumption group to the lowest n-3 group or highest n-6 group. The beneficial effects of n-3 PUFA eicosapentaenoic and docosahexaenoic on the risk of breast cancer are dose dependent and are negatively affected by total n-6 consumption. The majority of the world population, including the most highly developed regions, consumes insufficient n-3 PUFA to significantly reduce breast cancer risk. This review discusses the physiological and dietary context in which reduction of breast cancer risk may occur, some proposed mechanisms of action and meaningful recommendations for consumption of n-3 PUFA in the diet of developed regions. [ABSTRACT FROM AUTHOR]

Epigallocatechin gallate (EGCG), a major polyphenol in green tea, possesses antioxidant properties and regulates various cell functions. Here, we examined the function of EGCG in inflammatory bone resorption. In calvarial organ cultures, lipopolysaccharide (LPS)-induced bone resorption was clearly suppressed by EGCG. In osteoblasts, EGCG suppressed the LPS-induced expression of COX-2 and mPGES-1 mRNAs, as well as prostaglandin E2 production, and also suppressed RANKL expression, which is essential for osteoclast differentiation. LPS-induced bone resorption of mandibular alveolar bones was attenuated by EGCG in vitro , and the loss of mouse alveolar bone mass was inhibited by the catechin in vivo . [ABSTRACT FROM AUTHOR]

Purpose: Surgery during pregnancy can be a cause of preterm labor or birth, possibly resulting from anesthetic agents or direct effects of surgery. This study was aimed to investigate the effect of propofol on uterine contractility by examining prostaglandin E (PGE) production and the expression of PGE synthase 2 (PGES2) and cyclooxygenase-2 (COX-2) in amniotic membrane cells. Methods: Amniotic membranes were collected from healthy full-term women who underwent cesarean section at 37-40 weeks of gestation. The amniotic cells were cultured in α-modified-Eagle's medium with 10 % fetal bovine serum for 24 h at 5 % CO in a 37 °C incubator. Then, various doses of propofol (0.01-10 μg/ml) were used for treatment for 3 h. PGE concentrations in conditioned media were evaluated using ELISA. PGES2 and COX-2 expression were examined using RT-PCR and Western blot. Cell viability and apoptosis were examined by MTT, ATP assays, and the TUNEL method. Results: PGE production significantly decreased at 0.1 and 1.0 μg/ml propofol concentrations compared to controls. COX-2 and PGES2 mRNA expression was decreased in a dose-dependent manner with a significant difference at 0.1 μg/ml propofol compared to controls. The protein expression of COX-2 showed a similar result to mRNA expression, but protein expression of PGES2 was not significantly decreased. No effect of propofol was found in cell viability. Conclusions: This study showed that propofol reduced the production of PGE and the expression of COX-2 and PGES2 without affecting cell viability. [ABSTRACT FROM AUTHOR]

The present study was conducted to evaluate the effect of methanol extract of Corydalis Tuber (CTE) on the levels of inflammatory mediators in Raw264.7 cells activated by lipopolysaccharide (LPS), and on paw edema in rats. CTE dose-dependently decreased release of nitric oxide (NO) and prostaglandin E (PGE), which elevated by LPS. The inhibitions of NO and PGE by CTE were due to the suppression of iNOS expression and of COX-2 activity, respectively. CTE also inhibited the nuclear translocation of nuclear factor kappa B (NF-κB) and the phosphorylation of inhibitory kappa B (IκB), determined by western blot analysis. In addition, CTE inhibited the production of TNF-α, interleukin-1β (IL-1β) and interleukin-6 (IL-6). Furthermore, administration of CTE significantly inhibited the formation of paw edema by carrageenan in rats. Histopathologically, CTE effectively inhibited increases of hind paw skin thickness and inflammatory cell infiltrations. These findings demonstrate that CTE has inhibitory effect on inflammatory markers in LPS-activated Raw264.7 cells and on paw edema in carrageenan-stimulated rats, showing the possibility of anti-inflammatory use of Corydalis Tuber. [ABSTRACT FROM AUTHOR]

Clinical studies indicate that prostaglandins of E class (PGEs) may promote healing of tissue injury e.g., gastroduodenal and dermal ulcers. However, the precise roles of PGEs, their E-prostanoid (EP) receptors, signaling pathways including cAMP and cAMP response elementbinding protein (CREB), and their relation to VEGF and angiogenesis in the tissue injury healing process remain unknown, forming the rationale for this study. Using an esophageal ulcer model in rats, we demonstrated that esophageal mucosa expresses predominantly EP2 receptors and that esophageal ulceration triggers an increase in expression of the EP2 receptor, activation of CREB (the downstream target of the cAMP signaling), and enhanced VEGF gene expression. Treatment of rats with misoprostol, a PGE1 analog capable of activating EP receptors, enhanced phosphorylation of CREB, stimulated VEGF expression and angiogenesis, and accelerated esophageal ulcer healing. In cultured human esophageal epithelial (HET-1A) cells, misoprostol increased intracellular cAMP levels (by 163-fold), induced phosphorylation of CREB, and stimulated VEGF expression. A cAMP analog (Sp-cAMP) mimicked, whereas an inhibitor of cAMPdependent protein kinase A (Rp-cAMP) blocked, these effects of misoprostol. These results indicate that the EP2/cAMP/protein kinase A pathway mediates the stimulatory effect of PGEs on angiogenesis essential for tissue injury healing via the induction of CREB activity and VEGF expression. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Mesenchymal stem cells (MSCs) have been shown to abrogate in vitro the proinflammatory response in type 1 diabetes. The mechanism involves paracrine factors, which may include microvesicles (MVs). We evaluated whether MVs derived from heterologous bone-marrow MSCs exert an immunomodulatory effect on T cell responses against GAD (glutamic acid decarboxylase) antigen in type 1 diabetes. Methods: MVs were purified from heterologous human MSCs by differential centrifugation. Peripheral blood mononuclear cells (PBMCs) were obtained from patients with type 1 diabetes at disease onset, and responses to GAD65 stimulation were assessed by IFN-γ enzyme-linked immunosorbent spot analysis. Levels of cytokines and prostaglandin E (PGE) were measured in the supernatant fraction, and T helper 17 (Th17) and regulatory T cell analysis was performed. Results: MVs were internalised by PBMCs, as assessed by confocal microscopy and flow cytometry analyses. MVs significantly decreased IFN-γ spots and levels in GAD65-stimulated PBMCs, and significantly increased transforming growth factor-β (TGF-β), IL-10, IL-6 and PGE levels. Furthermore, MVs decreased the number of Th17 cells and the levels of IL-17, and increased FoxP3 regulatory T cells in GAD65-stimulated PBMCs. Conclusions/interpretation: These results provide evidence that MSC-derived MVs can inhibit in vitro a proinflammatory response to an islet antigenic stimulus in type 1 diabetes. The action of MVs involves PGE and TGF-β signalling pathways and IL-10 secretion, suggesting a switch to an anti-inflammatory response of T cells. [ABSTRACT FROM AUTHOR]

Background: Because oral nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects on kidney function, patients with kidney diseases are administered these drugs as transdermal patches. Little is known about the effects of NSAID patches on renal function. We therefore assessed the effects of topical loxoprofen sodium on kidney function in type 2 diabetic patients with overt nephropathy. Methods: Twenty patients with type 2 diabetes and overt proteinuria and with knee and/or low back pain were treated with skin patches containing 100 mg loxoprofen on the knee or back for 24 h per day for 5 consecutive days. The degree of pain was assessed using a visual analogue scale (VAS). Blood and 24-h urine samples were obtained at baseline and at the end of the study. Glomerular filtration rate (GFR) was estimated from serum creatinine and cystatin C concentrations. Results: The 20 patients consisted of 11 males and 9 females, of mean age 61.6 ± 13.9 years. Loxoprofen-containing patches significantly reduced VAS pain without affecting blood pressure, GFR or urinary prostaglandin E concentration. Serum concentrations of loxoprofen and its active trans-OH metabolite did not correlate with GFR. Conclusions: Loxoprofen-containing patches do not affect renal function in type 2 diabetic patients with overt nephropathy over a short-term period. Long-term studies are needed to clarify the safety of loxoprofen-containing patches in patients with chronic kidney diseases. [ABSTRACT FROM AUTHOR]

Prostaglandin E (PGE) is a major prostanoid produced under inflammatory situations. There have been controversial reports showing contractile or relaxant effect of PGE on vascular tone in various types of blood vessels. Thus, it is still elusive whether and how PGE modulates vascular tone. We here assessed the effects of PGE on vascular contractility using different types of vasculatures isolated form rat. In endothelium-denuded aortas and mesenteric arteries, PGE (1 nM-10 μM) concentration-dependently enhanced the contraction elicited by K (35.4 mM) or norepinephrine (10 nM). In pulmonary arteries, PGE did not alter the both-induced contraction. Tail arteries were relaxed by a low dose of PGE (1-100 nM), but this response shifted to contraction by the higher dose of PGE (300 nM-10 μM). There are four types of PGE receptors EP1-4. RT-PCR showed that aortas and mesenteric arteries abundantly expressed EP3, while tail arteries abundantly expressed EP4. We next revealed that selective EP3 agonism enhanced the contraction in mesenteric arteries, whereas EP4 agonism induced relaxation in tail arteries. Taken together, PGE causes different contractile responses depending on the type of vascular bed. This phenomenon may be due to the difference in expression pattern and activity of EP receptors. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetic patients. Effective therapies to prevent the development of this disease and to improve advanced kidney injury are required. Berberine (BBR) has preventive effects on diabetes and its complications. This study is to investigate the effects of BBR on the expression of E-prostanoid receptors (EPs) in rats with high-fat diet and streptozotocin (STZ)-induced DN and underlying molecular mechanisms of BBR on DN rats. DN model was induced in male Sprague-Dawley rats with high-fat diet and low dose of STZ injection. BBR (50, 100, 200 mg/kg/d) were orally administered to rats after STZ injection and conducted for 8 weeks. The levels of interleukin-6 (IL-6) and prostaglandin E (PGE) in renal cortex were measured by enzyme-linked immunosorbent assay. Expression of EPs receptors (EP1-EP4) were determined by western blotting. Remarkable renal damage, hyperglycemia and hyperlipidemia were observed in DN rats. BBR could restore renal functional parameters, suppress alterations in histological and ultrastructural changes in the kidney tissues, improve glucose and lipid metabolism disorders, and increase cAMP levels compared with those of DN model group (Wang et al. in Mol Biol Rep 40:2405-2418, ). The level of IL-6 and PGE were significantly increased in DN model group compared with normal group, BBR could apparently reduced the level of IL-6 and PGE. Furthermore, the expression of EP1 and EP3 were both increased and EP4 was lessened in the DN model group compared with normal group, BBR could down-regulate total protein expression of EP1 and EP3 of renal cortex in DN rats and up-regulate the expression of EP4, and there is no significant difference on the expression of EP2 among all groups. These studies demonstrate, for the first time, that BBR exerts renoprotection in high-fat diet and STZ-induced DN rats by modulating the proteins expression of EPs in EP-G protein-cAMP signaling pathway. [ABSTRACT FROM AUTHOR]

Using an animal model of vertebrobasilar insufficiency (VBI), in which brainstem circulatory disturbance was induced in rats, we examined how prostaglandin E (PG-E) affects brainstem blood flow (BBF) to clarify whether it is effective against VBI. Fifteen healthy male Wister rats that displayed positive responses to Preyer's reflex were used. Their BBF was continuously measured on the left side of the midline of the brainstem using laser Doppler flowmetry. A rat model of VBI, a pathological condition that presents with decreased BBF, was prepared by applying a vertebral artery clamp ipsilateral to the BBF measuring site and inducing hypotension of 60-70 mmHg by blood withdrawal. Saline as a control ( n = 5), 5 ng/kg/min ( n = 5) or 10 ng/kg/min ( n = 5) PG-E at a dose was continuously administered to the rats using a motor-driven syringe pump. The effects of the drugs on the rats' BBF were evaluated. BBF, which was decreased by the unilateral vertebral artery clamping combined with blood withdrawal-induced hypotension, recovered in a dose-dependent manner after the administration of 5 or 10 ng/kg/min PG-E, and complete recovery to the baseline level was achieved by 60 min treatment; however, no such effect was observed for intravenous saline. These results suggest that PG-E acts on local vessels and improves blood flow insufficiency in the brainstem in our animal model of VBI. PG-E might be useful as a cerebral vasodilator for VBI. [ABSTRACT FROM AUTHOR]

Purpose: Contrast-induced nephropathy (CIN) is an important complication in the use of iodinated contrast media. The present study aimed to assess the safety and efficacy of prostaglandin E (PGE) in prevention of CIN in patients with high-risk factors undergoing percutaneous coronary intervention (PCI). Methods: The study group consisted of 163 patients who had undergone a coronary intervention procedure between January 1, 2012 and October 31, 2012. Study participants were randomly assigned to either the PGE group (82 patients) or the control group (81 patients). Patients in the PGE group received PGE intravenous infusion of 20 ng/kg/min for 6 h before and after the administration of contrast media. The control group received 0.9 % sodium chloride solution for routine hydration only. A nonionic, low-osmolality contrast agent was used in our laboratory at this time. Serum creatinine (Scr) values and estimated glomerular filtration rate were measured before and within 48 h of the administration of contrast agents. CIN was defined as an increase of ≥0.5 mg/dL or ≥ a 25 % increase in Scr concentrations over baseline within 48 h of angiography. Results: The amount of contrast agent administered was similar for the PGE and control groups (156 ± 63 vs. 161 ± 68 mL, P > 0.05). The incidence of CIN was lower in the PGE group than in the control group (3.7 vs. 11.1 %, P < 0.05). No serious adverse effects were observed. Conclusions: In patients with high-risk factors undergoing PCI, the use of PGE for prevention of CIN is safe and efficacious. [ABSTRACT FROM AUTHOR]

Components of tumorigenesis include uncontrolled proliferation and defects in cell death pathways, as well as increased angiogenesis, in which tumors develop their own blood supply, and metastasis, which enables tumor dissemination. Most anticancer drugs are designed to kill cancer cells but are relatively ineffective against some phases of tumorigenesis. Alternate strategies to prevent tumorigenesis are urgently required and considerable evidence has emerged that ω-3 polyunsaturated fatty acids (PUFAs) derived from certain plants and oily fish are important modulators of tumor cell proliferation, apoptosis, angiogenesis and metastasis. Epidemiological studies in man, as well as experimental studies in animal models and cells, have reported that while ω-6 PUFA accelerate tumorigenesis, ω-3 PUFA have anticancer properties. The over-expression of certain PUFA-metabolizing enzymes in tumors, including cyclooxygenases, lipoxygenases and cytochromes P450 (CYP), has provided the impetus for studies on the roles of biotransformation products in the cancer-modulatory actions of PUFAs. Some ω-6 PUFA metabolites, including PGE, 5-HETE and the CYP-derived EETs, stimulate tumorigenesis by activating prostanoid receptors, nuclear receptors and intracellular signal transduction cascades. In contrast, ω-3 PUFA both inhibit the formation of pro-tumorigenic ω-6 PUFA metabolites and generate ω-3 metabolites that are anti-tumorigenic in their own right, including PGE and the 17,18-epoxide of epoxyeicosapentaenoic acid (HETE). Some of these naturally occurring metabolites of ω-3 PUFA formed in human cells may be useful lead compounds for the development of novel agents that inhibit cancer. [ABSTRACT FROM AUTHOR]

The cyclooxygenase pathway is strongly implicated in breast cancer progression but the role of this pathway in the biology of breast cancer stem/progenitor cells has not been defined. Recent attention has focused on targeting the cyclooxygenase 2 (COX-2) pathway downstream of the COX-2 enzyme by blocking the activities of individual prostaglandin E (EP) receptors. Prostaglandin E receptor 4 (EP4) is widely expressed in primary invasive ductal carcinomas of the breast and antagonizing this receptor with small molecule inhibitors or shRNA directed to EP4 inhibits metastatic potential in both syngeneic and xenograft models. Breast cancer stem/progenitor cells are defined as a subpopulation of cells that drive tumor growth, metastasis, treatment resistance, and relapse. Mammosphere-forming breast cancer cells of human (MDA-MB-231, SKBR3) or murine (66.1, 410.4) origin of basal-type, Her-2 phenotype and/or with heightened metastatic capacity upregulate expression of both EP4 and COX-2 and are more tumorigenic compared to the bulk population. In contrast, luminal-type or non-metastatic counterparts (MCF7, 410, 67) do not increase COX-2 and EP4 expression in mammosphere culture. Treatment of mammosphere-forming cells with EP4 inhibitors (RQ-15986, AH23848, Frondoside A) or EP4 gene silencing, but not with a COX inhibitor (Indomethacin) reduces both mammosphere-forming capacity and the expression of phenotypic markers (CD44/CD24, aldehyde dehydrogenase) of breast cancer stem cells. Finally, an orally delivered EP4 antagonist (RQ-08) reduces the tumor-initiating capacity and markedly inhibits both the size of tumors arising from transplantation of mammosphere-forming cells and phenotypic markers of stem cells in vivo. These studies support the continued investigation of EP4 as a potential therapeutic target and provide new insight regarding the role of EP4 in supporting a breast cancer stem cell/tumor-initiating phenotype. [ABSTRACT FROM AUTHOR]

Objective: To study possible immunobiological potential of Osmunda japonica Thunb. Methods: Immunomodulatory effects of ethanol extracts prepared from rhizomes of O. japonica and phenolic compounds isolated from the extracts were investigated under the in vitro conditions using the rat peritoneal cells (2×10/mL; 24 h culture). Biosynthesis of nitric oxide (NO) was assayed by Griess reagent, production of prostaglandin E (PGE) and secretion of cytokines were determined by enzyme-linked immunoabsorbent assay. Results: The extracts activated dose dependently, with the onset at 2.5-5 μmol/L concentrations, the high output NO production, and secretion of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Mild enhancement of NO was produced by the aldehyde-type phenolics 4-hydroxybenzaldehyde and 3,4-hydroxybenzaldehyde. In contrasts, the acetone-type phenolics 4-hydroxybenzalacetone and 3,4-hydroxybenzalacetone inhibited production of immune mediators including cytokines (TNF-α, IL-1β, IL-6), NO, and PGE. The 3,4-hydroxybenzalacetone was more effective than 4-hydroxybenzaldehyde. The ICs estimates ranged within the interval of 5-10 μmol/L. No signs of cytotoxicity were observed up to the 50 μmol/L concentration of the compounds. Conclusion: Phenolic compounds contained in medicinal herb Osmunda japonica possess distinct immunomodulatory activity. [ABSTRACT FROM AUTHOR]

Background/Aims Lubiprostone, a chloride channel type 2 (ClC-2) activator, was thought to treat constipation by enhancing intestinal secretion. It has been associated with increased intestinal transit and delayed gastric emptying. Structurally similar to prostones with up to 54% prostaglandin E2 activity on prostaglandin E receptor 1 (EP1), lubiprostone may also exert EP1-mediated procontractile effect on intestinal smooth muscles. We investigated lubiprostone's effects on intestinal smooth muscle contractions and pyloric sphincter tone. Methods Isolated murine small intestinal (longitudinal and circular) and pyloric tissues were mounted in organ baths with modified Krebs solution for isometric recording. Basal muscle tension and response to electrical field stimulation (EFS; 2 ms pulses/10 V/6 Hz/30 sec train) were measured with lubiprostone (10-10-10-5 M) ± EP1 antagonist. Significance was established using Student t test and P < 0.05. Results Lubiprostone had no effect on the basal tension or EFS-induced contractions of longitudinal muscles. With circular muscles, lubiprostone caused a dose-dependent increase in EFS-induced contractions (2.11 ± 0.88 to 4.43 ± 1.38 N/g, P = 0.020) that was inhibited by pretreatment with EP1 antagonist (1.69 ± 0.70 vs. 4.43 ± 1.38 N/g, P = 0.030). Lubiprostone had no effect on circular muscle basal tension, but it induced a dose-dependent increase in pyloric basal tone (1.07 ± 0.01 to 1.97 ± 0.86 fold increase, P < 0.05) that was inhibited by EP1 antagonist. Conclusions In mice, lubiprostone caused a dose-dependent and EP1-mediated increase in contractility of circular but not longitudinal small intestinal smooth muscles, and in basal tone of the pylorus. These findings suggest another mechanism for lubiprostone's observed clinical effects on gastrointestinal motility. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the effect of oral combined contraceptive pills on Prostaglandin E levels and lipid profiles. Methods: The enzyme-linked immune absorbent assay method and spectrophotometric assay were used for the evaluation of PGE levels and lipid profiles, respectively, in 50 healthy women with normal menstrual cycles who served as the control group and 50 women taking contraceptive pill. Results: The data obtained for serum Prostaglandin E, LDL-C, and cholesterol concentrations in contraceptive pill consumers were significantly upper ( P = 0.04, 0.002, and 0.05, respectively) than control group. The age of contraceptive pill consumption and the duration of pill intake beyond 36 months had no significant effect on the prostaglandin E concentration. Conclusion: It is suggested that the increase of Prostaglandin E and atherogenic lipid levels may be related to their probable effects in response to various pathological and physiological properties of COCs. [ABSTRACT FROM AUTHOR]