Prostaglandin Inhibition Research Articles

A dose response study of the effect of prostaglandin E2 on thermal nociceptive sensitivity

Inhibition of prostaglandin (PG) biosynthesis has been used to relieve pain for thousands of years. Today non-steroidal anti-inflammatory drugs (which largely inhibit PG synthesis) are widely used to treat pain. Four main types of PGs (PGD2, PGE2, PGF2 and PGI2) are synthesized from arachidonic acid during inflammation and have been demonstrated to impact nociception. PGE2 has been the most studied and utilized for its pain producing properties and has been demonstrated to increase hypersensitivity in rodent nociceptive behavioral models when applied centrally and/or peripherally. Surprisingly, there are no published reports that use withdrawal from radiant light beam (Hargreaves apparatus) to examine the dose response effect of peripherally applied PGE2 on thermal nociceptive hypersensitivity. To address this gap in the literature, we performed a dose response study examining the effect of PGE2 on thermal hypersensitivity (assessed using a Hargreaves apparatus) where rats were injected with 0.003–30μg of PGE2, intradermally into the hindpaw. Thermal hypersensitivity was assessed by measuring withdraw latency from a radiant light beam (Hargreaves test) and our primary objective was to determine the dose of PGE2 causing the most pronounced increase in thermal hypersensitivity (i.e. lowest withdraw latency). A secondary objective was to determine the minimum dose of PGE2 required to cause statistically significant decreases in thermal withdrawal latency as compared to rats injected with vehicle. We found that rats injected with the 30μg dose of PGE2 exhibited the most pronounced thermal nociceptive hypersensitivity though secondary analysis showed that rats injected with PGE2 doses of 0.03–30μg had lower withdrawal latencies as compared to rats injected with vehicle. This work fills an evidence gap and provides context to guide dose selection in future rodent pain behavior studies.

Pregnancy-induced changes in metabolome and proteome in ovine uterine flushings†

Mass spectrometry (MS) approaches were used herein to identify metabolites and proteins in uterine flushings (UF) that may contribute to nourishing the conceptus. Ovine uteri collected on Day 12 of the estrous cycle (n = 5 ewes exposed to vasectomized ram) or Days 12 (n = 4), 14 (n = 5), or 16 (n = 5) of pregnancy (bred with fertile ram) were flushed using buffered saline. Metabolites were extracted using 80% methanol and profiled using ultraperformance liquid chromatography (LC) tandem mass spectrometry. The proteome was examined by digestion with trypsin, followed by the analysis of peptides with LC-MS/MS. Metabolite profiling detected 8510 molecular features of which 9 were detected only in UF from Day 14-16 pregnant ewes that function in fatty acid transport (carnitines), hormone synthesis (androstenedione like), and availability of nutrients (valine). Proteome analysis detected 783 proteins present by Days 14-16 of pregnancy in UF, 7 of which are as follows: annexin (ANX) A1, A2, and A5; calcium-binding protein (S100A11); profilin 1; trophoblast kunitz domain protein 1 (TKDP); and interferon tau (IFNT). These proteins function in endocytosis, exocytosis, calcium signaling, and inhibition of prostaglandins (annexins and S100A11); protecting against maternal proteases (TKDP); remodeling cytoskeleton (profilin 1); and altering uterine release of prostaglandin F2 alpha as well as inducing IFNT-stimulated genes in the endometrium and the corpus luteum (IFNT). Identifying metabolites and proteins produced by the uterus and conceptus advances our understanding of embryo/maternal signaling and provides insights into possible the causes of reproductive failure.

Estudio de la actividad analgésica en ratones Swiss sometidos a diferentes dosis de extracto hidroalcohólico al 30% de raíz de Eclipta alba

<p>La <em>Eclipta alba</em>, conocida como “agrião do brejo” es una planta nativa de Brasil, China y Australia, los estudios etnomédicos reportan entre otras acciones la antinflamatoria y analgésica, es precisamente esta última, la actividad abordada en este trabajo. <strong>Objetivo: </strong>Estudiar el efecto analgésico del extracto fluido hidroalcohólico al 30% de raíz de <em>Eclipta alba</em> en ratones Swis. <strong>Material y Métodos</strong>: Se utilizaron 42 ratones Swis, machos, entre 8 y 10 semanas de vida, sometidos a régimen de luz/oscuridad de 12/12 horas, temperatura constante (25ºC) y agua/comida <em>ad libitum</em>. La analgesia fue determinada a través del modelo del “plato caliente” y el indicador de la variable fue el tiempo de reacción al calor. <strong>Resultados y Discusión</strong>: Se comprobó que en los tiempos de 60,90 y 120 minutos la actividad analgésica del extracto fluido fue similar a la actividad mostrada por el Paracetamol en la dosis de 12.5 mg/Kg de masa corporal, el efecto de este último fue creciente a lo largo de los 150 minutos de experimento, evidenciando su potencia analgésica. Probablemente la inhibición de la síntesis de prostaglandinas (principalmente de la serie “E”) sea la causa de la elevación del umbral de excitación de las terminaciones nerviosas libres y por tanto analgesia en los animales tratados con el extracto. Se considera que las acciones antioxidante de fenoles y polifenoles presentes en el extracto fluido, así como la acción inhibitoria de los flavonoides sobre la fosfolipasa A2, presentes también en el extracto fluido puedan explicar los resultados encontrados en este trabajo, a través de una menor libración y por ende menor transformación del ácido araquidónico en prostaglandinas. <strong>Conclusión</strong>: Dosis de 500 y 250 mg/Kg de masa corporal de extracto fluido, mostraron efecto analgésico comparable con el Paracetamol en la dosis de 12.5 mg/Kg de masa corporal, entre 60 y 120 minutos.</p>

Sympatholytic effect of intravascular ATP is independent of nitric oxide, prostaglandins, Na+ /K+ -ATPase and KIR channels in humans.

Intravascular ATP attenuates sympathetic vasoconstriction (sympatholysis) similar to what is observed in contracting skeletal muscle of humans, and may be an important contributor to exercise hyperaemia. Similar to exercise, ATP-mediated vasodilatation occurs via activation of inwardly rectifying potassium channels (KIR ), and synthesis of nitric oxide (NO) and prostaglandins (PG). However, recent evidence suggests that these dilatatory pathways are not obligatory for sympatholysis during exercise; therefore, we tested the hypothesis that the ability of ATP to blunt α1 -adrenergic vasoconstriction in resting skeletal muscle would be independent of KIR , NO, PGs and Na+ /K+ -ATPase activity. Blockade of KIR channels alone or in combination with NO, PGs and Na+ /K+ -ATPase significantly reduced the vasodilatatory response to ATP, although intravascular ATP maintained the ability to attenuate α1 -adrenergic vasoconstriction. This study highlights similarities in the vascular response to ATP and exercise, and further supports a potential role of intravascular ATP in blood flow regulation during exercise in humans. Exercise and intravascular ATP elicit vasodilatation that is dependent on activation of inwardly rectifying potassium (KIR ) channels, with a modest reliance on nitric oxide (NO) and prostaglandin (PG) synthesis. Both exercise and intravascular ATP attenuate sympathetic α-adrenergic vasoconstriction (sympatholysis). However, KIR channels, NO, PGs and Na+ /K+ -ATPase activity are not obligatory to observe sympatholysis during exercise. To further determine similarities between exercise and intravascular ATP, we tested the hypothesis that inhibition of KIR channels, NO and PG synthesis, and Na+ /K+ -ATPase would not alter the ability of ATP to blunt α1 -adrenergic vasoconstriction. In healthy subjects, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to intra-arterial infusion of phenylephrine (PE; α1 -agonist) during ATP or control vasodilatator infusion, before and after KIR channel inhibition alone (barium chloride; n=7; Protocol 1); NO (l-NMMA) and PG (ketorolac) inhibition alone, or combined NO, PGs, Na+ /K+ -ATPase (ouabain) and KIR channel inhibition (n=6; Protocol 2). ATP attenuated PE-mediated vasoconstriction relative to adenosine (ADO) and sodium nitroprusside (SNP) (PE-mediated ΔFVC: ATP: -16±2; ADO: -38±6; SNP: -59±6%; P<0.05 vs. ADO and SNP). Blockade of KIR channels alone or combined with NO, PGs and Na+ /K+ -ATPase, attenuated ATP-mediated vasodilatation (∼35 and ∼60% respectively; P<0.05 vs. control). However, ATP maintained the ability to blunt PE-mediated vasoconstriction (PE-mediated ΔFVC: KIR blockade alone: -6±5%; combined blockade:-4±14%; P>0.05 vs. control). These findings demonstrate that intravascular ATP modulates α1 -adrenergic vasoconstriction via pathways independent of KIR channels, NO, PGs and Na+ /K+ -ATPase in humans, consistent with a role for endothelium-derived hyperpolarization in functional sympatholysis.

Abstract 123: A novel J-series prostamide mediates D-series prostamide-induced apoptosis in skin cancer: receptor-independent signaling

Abstract Non-melanoma skin cancer (NMSC) is the most common cancer in the United States. The absence of selective toxicity is a major problem that limits the utility of chemotherapeutic and radiation therapy for NMSCs. Our previous data showed that the endocannabinoid, anandamide, selectively induced apoptosis in non-melanoma skin cancer (NMSC) cells which overexpress cyclooxygenase-2. The cytotoxic effect of anandamide was mediated by the production of ethanolamide-conjugated D- and J-series prostaglandins (PGs), also known as prostamide D2 (PMD2) and prostamide J2 (PMJ2), respectively. The aim of the current study was to determine if tumorigenic keratinocytes are more sensitive to PMD2 than non-tumorigenic cells and to examine whether the cytotoxicity of PMD2 is mediated by its downstream metabolite PMJ2. To determine if PMD2 demonstrates preferential toxicity, tumorigenic (JWF2) and non-tumorigenic (HaCaT) keratinocytes were utilized. A significant reduction in cell viability was observed in JWF2 but not in HaCaT cells treated with PMD2. In tumorigenic keratinocytes, PMD2 induced apoptotic cell death, oxidative stress and increased the expression of apoptotic ER stress protein, C/EBP homologous protein-10 (CHOP10). In addition, use of the antioxidant, trolox, and ER stress inhibitor, salubrinal, inhibited the cytotoxic effect of PMD2. Furthermore, the use of prostaglandin D receptor (DP1 and DP2) antagonists did not inhibit PMD2-induced apoptosis indicating that the activity was mediated by a receptor-independent pathway. Similar effects were observed in keratinocytes treated with the structurally-related arachidonic acid metabolite, prostaglandin D2 (PGD2). Interestingly, PMD2 increased the production of J-series prostaglandins in both tumorigenic and non-tumorigenic keratinocytes. LC-ESI-MS/MS analysis detected ethanolamide- conjugated J series PG (15-deoxy, Δ12,14 prostamide J2, 15d-PMJ2) in PMD2-treated cell culture media. Since selective inhibitors of the J-series prostaglandins are not available, 15d-PMJ2 was synthesized to examine its direct activity. Exogenous 15d-PMJ2 mimicked the activity of PMD2 demonstrating preferential cytotoxicity towards tumorigenic compared to non-tumorigenic keratinocytes. In addition, 15d-PMJ2 induced oxidative stress, ER stress and apoptosis in tumorigenic keratinocytes. These findings suggest that the cytotoxicity of PMD2 is mediated by 15dPMJ2. Since PMD2 and its metabolite 15d-PMJ2 are preferentially toxic towards tumorigenic cells, PMD2 or 15d-PMJ2 may be an ideal topical treatment for NMSC that will elicit minimal toxicity in healthy surrounding skin cells. Citation Format: Eman Soliman, Daniel Ladin, Hussam Albassam, Ahmed E. Elhassanny, Andrew Morris, Allison Danell, Rukiyah Van Dross. A novel J-series prostamide mediates D-series prostamide-induced apoptosis in skin cancer: receptor-independent signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 123. doi:10.1158/1538-7445.AM2017-123

Abstract 1920: Prostaglandin E2 accumulation enhances the expansion of ALDH1-positive cells and Kras-driven tumorigenesis in the pancreas

Abstract Background: Chronic inflammation is known to be a risk factor of carcinogenesis and tumor development, and it was demonstrated that oral aspirin intake reduced cancer-related death including pancreatic ductal adenocarcinoma (PDAC) through inhibiting prostaglandin synthases. On the other hand, cancer stem cells (CSCs) refer to a subset of tumor cells that have self-renewal ability and generate plenty of non-CSC cells that comprise a tumor. Prostaglandin E2 (PGE2) and inhibition of 15-PGDH, which is an enzyme degrading PGE2, promoted hematopoietic and tissue stem cell fraction, however, little is known about the role of PGE2 accumulation for CSC fraction. A number of CSC marker candidates have been explored to date, and Aldehyde dehydrogenase 1 (ALDH1) was identified as one of CSC markers in PDAC. The aim of this study is to elucidate the functional role of PGE2 in ALDH1 positive CSC fraction during tumor development in pancreas. Methods: The clonogenic growth potential of ALDH1-positive PDAC cells was assessed in vitro by growth assays and sphere formation assays. We next investigated the expression of ALDH1 and self-renewal related genes in PDAC cell lines with PGE2 or 15-PGDH inhibitor treatment. We further conducted functional experiments using siALDH1 in PDAC progression. Furthermore, we examined the effect of PGE2 for pancreatic tumorigenesis using Kras-driven genetic mouse model treated with 15-PGDH inhibitor. Finally, ALDH1 and Ki67 expression was examined by immunohistochemistry in 121 primary surgical specimens of PDAC and analyzed a relationship with clinicopathological factors and clinical outcomes. Results: The number of ALDH1-positive cells was significantly increased by PGE2 treatment, and PGE2 promoted growth and sphere formation potential in PDAC cells. In addition, 15-PGDH inhibitor induced PGE2 accumulation and gave rise to ALDH1-positive cells harboring high proliferating potential in PDAC cells. The growth and sphere formation potential were inhibited by silencing ALDH1 expression in PDAC cells. We next found that the expression of Nanog and Oct-4 genes was regulated by PGE2-ALDH1 signaling. Furthermore, 15-PGDH inhibitor induced ALDH1 expression and promoted PanIN formation in Kras-driven genetic mouse model. Finally, a high level of ALDH1 expression was significantly associated with large tumor size and high Ki67expression, and poor prognosis in PDAC patients. Conclusion: Current findings suggested that PGE2 positively regulated ALDH1 expression, and the growth and sphere formation potential were promoted by regulating self-renewal related genes expression, resulting in poor prognosis of PDAC patients. Inhibiting PGE2-ALDH1 signaling could lead to the suppression of tumor growth in PDAC patients. Citation Format: Kota Arima, Takatsugu Ishimoto, Masaki Ohmuraya, Keisuke Miyake, Tsugio Eto, Hirohisa Okabe, Yuki Kitano, Kensuke Yamamura, Takayoshi Kaida, Katsunori Imai, Daisuke Hashimoto, Akira Chikamoto, Hideo Baba. Prostaglandin E2 accumulation enhances the expansion of ALDH1-positive cells and Kras-driven tumorigenesis in the pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1920. doi:10.1158/1538-7445.AM2017-1920

The effect of nitric oxide synthase inhibition with and without inhibition of prostaglandins on blood flow in different human skeletal muscles

Animal studies suggest that the inhibition of nitric oxide synthase (NOS) affects blood flow differently in different skeletal muscles according to their muscle fibre type composition (oxidative vs glycolytic). Quadriceps femoris (QF) muscle consists of four different muscle parts: vastus intermedius (VI), rectus femoris (RF), vastus medialis (VM), and vastus lateralis (VL) of which VI is located deep within the muscle group and is generally regarded to consist mostly of oxidative muscle fibres. We studied the effect of NOS inhibition on blood flow in these four different muscles by positron emission tomography in eight young healthy men at rest and during one-leg dynamic exercise, with and without combined blockade with prostaglandins. At rest blood flow in the VI (2.6±1.1ml/100g/min) was significantly higher than in VL (1.9±0.6ml/100g/min, p=0.015) and RF (1.7±0.6ml/100g/min, p=0.0015), but comparable to VM (2.4±1.1ml/100g/min). NOS inhibition alone or with prostaglandins reduced blood flow by almost 50% (p<0.001), but decrements were similar in all four muscles (drug×muscle interaction, p=0.43). During exercise blood flow was also the highest in VI (45.4±5.5ml/100g/min) and higher compared to VL (35.0±5.5ml/100g/min), RF (38.4±7.4ml/100g/min), and VM (36.2±6.8ml/100g/min). NOS inhibition alone did not reduce exercise hyperemia (p=0.51), but combined NOS and prostaglandin inhibition reduced blood flow during exercise (p=0.002), similarly in all muscles (drug×muscle interaction, p=0.99). NOS inhibition, with or without prostaglandins inhibition, affects blood flow similarly in different human QF muscles both at rest and during low-to-moderate intensity exercise.

Timosaponin AIII induces antiplatelet and antithrombotic activity via Gq-mediated signaling by the thromboxane A2 receptor.

The thromboxane (Tx) A2 pathway is a major contributor to the amplification of initial platelet activation and is therefore a key drug target. To identify potent small-molecule inhibitors of the thromboxane prostaglandin (TP) receptor, we screened a small steroidal saponin library using U46619-induced rat platelet aggregation assays. Timosaponin AIII (TAIII) was identified as a potent inhibitor of U46619-induced rat platelet aggregation and exhibited superior selectivity for the TP receptor versus other G protein-coupled receptors and a PKC activator. TAIII inhibited U46619-induced rat platelet aggregation independent of increases in cAMP and cGMP and the inhibition of TxA2 production. Both PKC and PLC activators restored TAIII-inhibited platelet aggregation, whereas TAIII did not inhibit platelet aggregation induced by co-activation of the G12/13 and Gz pathways. Furthermore, TAIII did not affect the platelet shape change or ROCK2 phosphorylation evoked by low-dose U46619. In vivo, TAIII prolonged tail bleeding time, reduced the mortality of animals with acute pulmonary thromboembolism and significantly reduced venous thrombus weight. Our study suggests that TAIII, by preferentially targeting Gq-mediated PLC/PKC signaling from the TP receptor, induces stronger in vitro antiplatelet activity and in vivo antithrombotic effects and may be an excellent candidate for the treatment of thrombotic disorders.

Nimesulide inhibits pathogenic fungi: PGE2-dependent mechanisms.

Certain non-steroidal anti-inflammatory drugs can inhibit fungal growth, fungal prostaglandin E2 production, and enzyme activation. This study aims to investigate the antifungal effect of nimesulide against pathogenic filamentous fungi and yeast. The experiments detailed below were also designed to investigate whether the action is dependent on E2 fungal prostaglandins. Our data showed that nimesulide exhibited potent antifungal activity, mainly against Trichophyton mentagrophytes (ATCC 9533) and Cryptococcus neoformans with MIC values of 2 and 62μg/mL, respectively. This drug was also able to inhibit the growth of clinic isolates of filamentous fungi, such as Aspergillus fumigatus, and dermatophytes, such as T. rubrum, T. mentagrophytes, Epidermophyton floccosum, Microsporum canis, and M. gypseum, with MIC values ranging from 112 to 770μg/mL. Our data also showed that the inhibition of fungal growth by nimesulide was mediated by a mechanism dependent on PGE2, which led to the inhibition of essential fungal enzymes. Thus, we concluded that nimesulide exerts a fungicidal effect against pathogenic filamentous fungi and yeast, involving the inhibition of fungal prostaglandins and fungal enzymes important to the fungal growth and colonization.

Cold burn injuries in the UK: the 11-year experience of a tertiary burns centre.

BackgroundGuidance for the management of thermal injuries has evolved with improved understanding of burn pathophysiology. Guidance for the management of cold burn injuries is not widely available. The management of these burns differs from the standard management of thermal injuries. This study aimed to review the etiology and management of all cold burns presenting to a large regional burn centre in the UK and to provide a simplified management pathway for cold burns.MethodsAn 11-year retrospective analysis (1 January 2003–31 December 2014) of all cold injuries presenting to a regional burns centre in the UK was conducted. Patient case notes were reviewed for injury mechanism, first aid administered, treatment outcomes and time to healing. An anonymized nationwide survey on aspects of management of cold burns was disseminated between 13 July 2015–5 October 2015 to British Association of Plastic Reconstructive and Aesthetic Surgeons (BAPRAS) and Plastic Surgery Trainees Association (PLASTA) members in the UK. Electronic searches of MEDLINE, EMBASE and the Cochrane Library were performed to identify relevant literature to provide evidence for a management pathway for cold burn injuries.ResultsTwenty-three patients were identified. Age range was 8 months–69 years. Total body surface area (TBSA) burn ranged from 0.25 to 5 %. Twenty cases involved peripheral limbs. Seventeen (73.9 %)cases were accidental, with the remaining six (26.1 %) cases being deliberate self-inflicted injuries. Only eight patients received first aid. All except one patient were managed conservatively. One case required skin graft application due to delayed healing. We received 52 responses from a total of 200 questionaires. Ninety percent of responders think clearer guidelines should exist. We present a simplified management pathway based on evidence identified in our literature search. ConclusionsCold burns are uncommon in comparison to other types of burn injuries. In the UK, a disproportionate number of cold burn injuries are deliberately self-inflicted, especially in the younger patient population. Our findings reflect a gap in clinical knowledge and experience. We proposed a simplified management pathway for managing cold burn injuries, consisting of adequate first aid using warm water, oral prostaglandin inhibitors, deroofing of blisters and topical antithromboxane therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s41038-016-0060-x) contains supplementary material, which is available to authorized users.

Discovery and characterization of [(cyclopentyl)ethyl]benzoic acid inhibitors of microsomal prostaglandin E synthase-1

We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies. Compound 16 showed an IC80 of 24nM for inhibition of PGE2 formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC80 in both rat (5mg/kg) and dog (3mg/kg) for over twelve hours.

In vivo studies validating multitargeting of prostanoid receptors for achieving superior anti-inflammatory effects.

The purpose of these studies was to test the hypothesis that a selected polypharmacological approach for treating the prostanoid-mediated component of inflammatory diseases would produce a therapeutic effect superior to global inhibition of prostaglandin (PG) biosynthesis by aspirin-like drugs. The compound studied was AGN 211377, which had been previously shown to produce a superior effect on cytokine release from human macrophages compared with cyclooxygenase (COX) inhibitors. AGN 211377 antagonizes prostanoid prostaglandin D2 (DP)1, DP2, prostaglandin E2 (EP)1, EP4, prostaglandin F2α, and thromboxane A2 receptors but not anti-inflammatory EP2, prostaglandin I2, or EP3 receptors. Established rodent models of ocular inflammatory diseases were used to determine therapeutic effects in living animals. The drugs were administered systemically after predetermination of their blood levels to ensure bioavailability at an appropriate dose level. Whereas compounds selective for a single prostanoid receptor typically exhibited modest but statistically significant inhibition, AGN 211377 profoundly inhibited S-antigen-induced uveitis and laser-induced retinal neovascularization. Consistent with previous polypharmacological studies on chemokine/cytokine release from human macrophages, the prostanoid EP1 receptor played a permissive role in suppressing neovascularization and inflammation in vivo Comparing AGN 211377 with a close structural congener lacking EP1 antagonism (AGN 197727), AGN 197727 was much less active than AGN 211377, but pronounced anti-inflammatory and angiostatic effects were achieved by adding the EP1 antagonist compound (SC-51322) to AGN 197727 in the systemic dosing regimen. Further, AGN 211377 produced superior anti-inflammatory activity compared with the nonsteroidal anti-inflammatory agent ketorolac. These results indicate the value of using a polypharmacological approach in the design of novel therapeutic agents in preference to compounds targeting a single receptor or enzyme. A compound such as AGN 211377 may represent more effective therapy than COX inhibitors in treating uveitis and ocular diseases where neovascularization is a significant part of the pathology.-Woodward, D. F., Wang, J. W., Ni, M., Bauer, A., Martos, J. L., Carling, R. W., Poloso, N. J. In vivo studies validating multitargeting of prostanoid receptors for achieving superior anti-inflammatory effects.

Testing the “read-across hypothesis” by investigating the effects of ibuprofen on fish

Human pharmaceuticals present in the environment have the potential to cause adverse effects on non-target organisms. The “read-across hypothesis” stipulates that pharmaceuticals will exhibit similar biological effects across species (e.g. human and fish) if the molecular target has been conserved and the effective drug concentrations are reached (Cmax). We tested this hypothesis by evaluating if ibuprofen, a non-selective inhibitor of prostaglandins and the cyclooxygenase (COX) enzyme, can mimic its primary effect in humans, on fish, at comparable plasma concentrations. The endpoints, prostaglandin E metabolite (PGEM) levels and the mRNA expression of COX (ptgs) gene, were measured in the gills of control and exposed fathead minnows (Pimephales promelas), using enzyme-immunoassay and quantitative real-time PCR (qPCR). Fish were exposed, for 24–72 h, to measured water concentrations of 9 (n = 12), 370 (n = 40) and 470 μg ibuprofen/L (n = 12). Water and blood plasma concentrations were determined using LC-MS/MS. Results showed that PGEM levels in fish exposed to 370 and 470 μg ibuprofen/L were significantly decreased compared to control fish, when mean plasma ibuprofen concentrations were 1.8–5.6-fold below the Cmax. The plasma ibuprofen concentrations and PGEM levels varied greatly between individuals. In fish exposed to 9 μg ibuprofen/L, when the mean plasma ibuprofen concentration was 224-fold below Cmax, no change in PGEM levels was observed. These data provide evidence for the read-across hypothesis, but suggest establishing a direct dose-response between internal plasma and PGEM is difficult, and would require significantly larger numbers of fish to overcome the inter-individual variation.

Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors

Here we report on novel, potent 3,3-dimethyl substituted N-aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example 14 potently inhibited PGE2 synthesis in an ex vivo human whole blood (HWB) assay with an IC50 of 7nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30μM, and failed to inhibit human mPGES-2 at 62.5μM in a microsomal prep assay. These data are consistent with selective mPGES-1-mediated reduction of PGE2. In dog, 14 had oral bioavailability (74%), clearance (3.62mL/(min*kg)) and volume of distribution (Vd,ss=1.6L/kg) values within our target ranges. For these reasons, 14 was selected for further study.

Aspirin affect on Reproduction of Male Rat an-Overview

Aspirin (Acetylsalicylic acid) is used widely in human and veterinary as cardiovascular prophylaxis and as anti-inflammatory, anti-clotting agent and to decrease cancer risk. But there is a deficiency of information about its effects on androgenic studies histology of the testes, kidneys and livers and reproductions. In this paper we tried to collect the information about it deleterious toxicity effect on male rat reproduction and the reason of its side effects. Our finding shows that Aspirin has deadly effect the production of sperm, decrease the testis weight, decrease the production of testosterone and also affect the blood profile. Effect of aspirin on the male reproductive system may be due to being a Prostaglandins inhibitor, and According to all our findings probably it indicates that aspirin have deleterious effect on reproduction and the blood chemistry of male rats

Effect of Intravenous Administration of Ketorolac As Preventive Analgesia To Pupil In Eye Surgery With General Anesthesia

Background: NSAID (Non steroid anti inflammatory drug ) inhibit cyclooxygenase enzyme and also inhibition of proinflamation prostaglandin (PG). Ketorolac has recommended for a short time use on post operation, not longer than 2 days intravenous administration. So this drugs is good for acute analgesia. The research useful for looking an effect of ketorolac administration as a preventive analgesia concern to pupil in prevent myosis in eye’s surgery within general anesthesia. Methods: it was a quasi experimental study done in Sumatera Eye Centre Hospital, Medan, Indonesia during January to June 2012. Sampling was taken using total sampling method with 44 patients. Results: There is no significant difference in myosis for patient with ketorolac as preventive analgesia in eye surgery

Effectiveness of Tocolytic Agents on Prevention of Preterm Delivery, Neonatal Morbidity, and Mortality: Is There a Consensus? A Review of the Literature.

Preterm delivery presents the main cause of neonatal morbidity and mortality worldwide. The rate of preterm delivery is 12% to 13% in the United States, of which 29% concerns preterm deliveries before 34 weeks of gestation. Basic parameter of prevention strategy is implementation of tocolytic therapy in cases of threatened preterm labor. Several therapeutic approaches have been proposed, among which betamimetic agonists, calcium channel blockers, magnesium sulfate, oxytocin receptor blockers, nitrates, and prostaglandin inhibitors, whereas new alternatives such as usage of thiocolchicoside have also been reported. This article is one among few that aims to review the comparative effectiveness of various tocolytic agents regarding prevention of preterm delivery, impact on perinatal morbidity and mortality, neonatal health status, and maternal complications. Main conclusions of recent randomized control trials and meta-analyses are summarized to assess about which agents consensus already exists on their effectiveness, which agents should be further studied to achieve conclusions, as well as those that are rather unlikely to have significant tocolytic impact or any other benefit on neonatal outcome.

PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection.

The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischemia. Indeed, acute kidney injury (AKI) affects 3% of all hospitalized patients.1,2 Here we show that the mitochondrial biogenesis regulator, PGC1α,3,4 is a pivotal determinant of renal recovery from injury by regulating NAD biosynthesis. Following renal ischemia, PGC1α−/− mice developed local deficiency of the NAD precursor niacinamide (Nam), marked fat accumulation, and failure to re-establish normal function. Remarkably, exogenous Nam improved local NAD levels, fat accumulation, and renal function in post-ischemic PGC1α−/− mice. Inducible tubular transgenic mice (iNephPGC1α) recapitulated the effects of Nam supplementation, including more local NAD and less fat accumulation with better renal function after ischemia. PGC1α coordinately upregulated the enzymes that synthesize NAD de novo from amino acids whereas PGC1α deficiency or AKI attenuated the de novo pathway. Nam enhanced NAD via the enzyme NAMPT and augmented production of the fat breakdown product beta-hydroxybutyrate (β-OHB), leading to increased prostaglandin PGE2, a secreted autocoid that maintains renal function.5 Nam treatment reversed established ischemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of β-OHB signaling or prostaglandins similarly abolished PGC1α-dependent renoprotection. Given the importance of mitochondrial health in aging and the function of metabolically active organs, the results implicate Nam and NAD as key effectors for achieving PGC1α-dependent stress resistance.

Inhibition of Dimethylbenz(a)anthracene (DMBA) - Croton Oil-Induced Mouse Skin Tumorigenesis by Gmelina arborea with Potential Anti-Inflammatory Activity.

In traditional Indian medicine, the plant Gmelina arborea Linn. (GA) is described to have the ability to relieve edema. The present study evaluates the anticancer property of GA stem bark against 7,12-dimethylbenz(a) anthracene (DMBA)-croton oil-induced skin tumorigenesis along with the evaluation of anti-inflammatory activity. The observed inhibition of inflammation in carrageenan-induced (41.8%) and formalin-induced (34.07%) models may be due to inhibition of prostaglandins (PGs). Skin papilloma was induced by a single topical application of DMBA (470 nmol/200 µL acetone), followed by repeated application of croton oil (1% in 200 µL acetone). Low-concentration GA (GALC; 5% in 200 µL distilled water) and high-concentration GA (GAHC; 10% in 200 µL distilled water) were applied topically 30 min before croton oil application. The GALC and GAHC groups showed 85.7% and 57.14% tumor incidence, respectively. The number of papillomas per mouse was observed to be significantly (p ≤ 0.01) reduced in the treated groups. The onset of papilloma development was delayed considerably from 6 (control) to 12 wk (GAHC). Thus, results from the study give insights into the anticancer efficacy of Gmelina arborea, which may be due to prevention of inflammation-mediated tumor promotion by inhibiting PGs.

The Role of Prostaglandin E2 in Tumor-Associated Immunosuppression

Tumor-associated inflammation can create an immunosuppressive microenvironment allowing tumor cells to escape immunosurveillance. Inhibiting immunosuppression remains one of the major challenges in cancer immunotherapy via checkpoint inhibitors. Recent preclinical data from the Reis e Sousa group may provide a strong rationale for developing new therapeutics to subvert tumor-induced immunosuppression via prostaglandin inhibition.