Inhibition Of Prostaglandin Synthesis Research Articles

Yersinia enterocolitica and Lactobacillus fermentum induces differential cellular and behavioral responses during diclofenac biotransformation in rat gut

Non-steroidal anti-inflammatory drugs (NSAIDs) can induce small-intestinal injuries through inhibition of prostaglandin synthesis. Gut has an important role in building and maintaining the barriers to avoid the luminal gut microbiota from invading the host, and cytoskeleton plays a crucial role in the maintenance of cellular barrier. The recent advances suggest a bi-directional interaction between the drugs and gut microbiota, where gut microbes can metabolize the drugs, and in response drugs can alter the composition of gut microbiota. In the present study, we evaluated the effect of diclofenac on rat gut, when co-administrated with either Yersinia enterocolitica strain 8081 (an enteropathogen) or Lactobacillus fermentum strain 9338 (a probiotic). The LC-MS/MS based label-free quantitation of rat gut proteins revealed 51.38% up-regulated, 48.62% down-regulated in diclofenac-Y. enterocolitica strain 8081 (D*Y), and 74.31% up-regulated, 25.69% down-regulated in diclofenac-L. fermentum strain 9338 (D*L) experiments. The identified proteins belonged to cytoskeleton, metabolism, heme biosynthesis and binding, stress response, apoptosis and redox homeostasis, immune and inflammatory response, and detoxification and antioxidant defence. Further, the histopathological and biochemical analysis indicated more pronounced histological alterations and oxidative stress (enhanced malonaldehyde and altered antioxidant levels) in D*Y rats than D*L rats, compared to control rats. Elevated plus maze (EPM) test performed to determine the behavioral changes, suggested increased anxiety in D*Y rats than D*L rats, compared to control rats. These results together suggest the differential role of either bacterium in biotransformation of diclofenac, and inflammatory and cellular redox response.

Comparative Study of Intravenous Paracetamol Infusion versus Intramuscular Tramadol as an Intrapartum Labor Analgesia

Context: Paracetamol exerts its analgesic effect by inhibiting prostaglandin synthesis in the central nervous system and peripheral action by blocking the generation of pain impulses. It has also a serotonergic (5Ht) mechanism and a cannabinoid agonist mechanism. Aims: We planned this study to compare intravenous and intramuscular tramadol as labor analgesia. Settings and Design: This prospective single-blinded randomized study was conducted in primigravida labor patients at tertiary care hospital between January 2016 and December 2018 after getting the permission of the ethical committee. Methods: Patients were randomly divided into two groups using a computer-generated random table in the Paracetamol group (Group A) and Tramadol group (Group B). Group A (60 patients) received IV PCM 1000 mg in the active phase of labor single dose over 15 min. Group B, received intramuscular tramadol hydrochloride 100 mg. Labor was monitored using partograph, pain intensity was recorded before, 1 h, and 3 h of drug administration using the Mac Gill pain intensity scale. Statistical Analysis Used: We did statistical analysis using IBM SPSS version 22.0 software. We used an independent t-test to analyze the difference in continuous dependent variables in two groups. The MacGill's pain intensity scale score was examined using repeated measures of analysis of variance for mean scores on 3 outcome measures: Before drug delivery, 1 h after drug delivery and 3 h after drug delivery. Results: Overall paracetamol was well tolerated as compared to tramadol. Patients who received paracetamol experienced fewer side effects including nausea and vomiting. The difference was statistically significant (Chi-square = 8.091; df = 2; P = 0.018). In the paracetamol group, 8 (15%) patients had nausea and 1 (2%) experienced vomiting; while in the tramadol group, 6 (11%) patients had nausea and 10 (19%) patients experienced vomiting. Conclusions: Paracetamol is safe labor analgesic as compared to intramuscular tramadol. Further studies consisting of a greater number of patients are needed to validate the results of this study.

Change of Urinary Nitrite Excretion in Primary Enuresis after Indomethacin Treatment

Various treatment modalities have been used in primary Nocturnal Enuresis (PNE). Inhibition of prostaglandin synthesis may have value in the management of PNE. The effect of PGs on the urinary system are similar to those of Nitrous oxide (No), so there might be a link between No production and PNE. We can use nitrite as a good indicator of both PG and No because it is a stable metabolite of No. Our objective in this study was to assess urinary nitrite excretion in patients with enuresis and to evaluate the effect of indomethacin (a potent prostaglandin synthesis inhibitor) on urinary nitrite excretion. Sixty children participated in this study with age range 5-14 years and were divided into three groups: Group A comprised 20 children with PNE and were given 50 mg indomethacin suppositories each night for 1 month, group B comprised also 20 children with PNE not receiving treatment. Both groups were assessed by frequency of bed wetting episodes as well as by measuring urinary nitrites. In addition, 20 normal comparable controls were assessed as regards their urinary nitrites to show the difference in its values between enuretics and normal individuals. The results showed increase in nitric acid level in enuretic children than controls with marked decrease in its levels after receiving Indomethacin and marked improvement in the frequency of bed-wetting.

Design, Synthesis and Biological Evaluation of New N-Acyl Hydrazones with a Methyl Sulfonyl Moiety as Selective COX-2 Inhibitors.

The mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) is inhibition of specific prostaglandin (PG) synthesis by inhibition of cyclooxygenase (COX) enzymes. The two COX isoenzymes show 60 % similarity. It is known that the nonspecific side effects of conventional NSAIDs are physiologically caused by inhibition of the COX-1 enzyme. Therefore, the use of COX-2 selective inhibitors is seen to be a more beneficial approach in reducing these negative effects. However, some of the existing COX-2 selective inhibitors show cardiovascular side effects. Therefore, studies on the development of new selective COX-2 inhibitors remain necessary. It is important to develop new COX-2 inhibitors in the field of medicinal chemistry. Accordingly, novel N-acyl hydrazone derivatives were synthesized as new COX-2 inhibitors in this study. The hydrazone structure, also known for its COX activity, is important in terms of many biological activities and was preferred as the main structure in the design of these compounds. A methyl sulfonyl pharmacophore was added to the structure in order to increase the affinity for the polar side pocket present in the COX-2 enzyme. It is known that methyl sulfonyl groups are suitable for polar side pockets. The synthesis of the compounds (3a-3j) was characterized by spectroscopic methods. Evaluation of in vitro COX-1/COX-2 enzyme inhibition was performed by fluorometric method. According to the enzyme inhibition results, the obtained compounds displayed the predicted selectivity for COX-2 enzyme inhibition. Compound 3j showed important COX-2 inhibition with a value of IC50 =0.143 uM. Interaction modes between the COX-2 enzyme and compound 3j were investigated by docking studies.

Protective effect of indomethacin on vanadium-induced adrenocortical and testicular damages in rat

Vanadium toxicity is a globally recognized threat to the reproductive health of man and animal. However the mechanism of vanadium-induced damage to the testicular and adrenocortical tissues is not fully characterized. It was hypothesized that prostaglandins may partially mediate the inflammatory response to vanadate damage. In this study prostaglandin (PG) mediated effects of vanadate on testicular and adrenocortical functions was substantiated by using indomethacin to block prostaglandin synthesis. Significant inhibition of spermatogenesis, decreased serum level of testosterone and gonadotropins in the vanadium-exposed group of rats indicated the damaging effects of vanadium-induced reactive oxygen species. This was also reflected in the appreciable increase in testicular lipid peroxidation (LPO) level and decline in the activities of steroidogenic and antioxidant enzymes. Histopathological studies revealed regressive and degenerative changes in testis. However, inhibition of cyclooxygenase activity by indomethacin increased steroid hormone production, gonadotropin level, elevated the specific activities of enzymes and decreased LPO level in rat testis exposed to vanadium. Vanadium also caused prostaglandin mediated adrenocortical hyperactivity, as inhibition of PG synthesis abolished these adrenal responses to vanadium. The studies showed that vanadium toxicity is directly linked to stimulation of prostaglandin synthesis. Therefore, indomethacin can be a good prospect to alleviate vanadium induced male infertility.

Transcriptome-wide In Vitro Effects of Aspirin on Patient-derived Normal Colon Organoids.

Mechanisms underlying aspirin chemoprevention of colorectal cancer remain unclear. Prior studies have been limited because of the inability of preclinical models to recapitulate human normal colon epithelium or cellular heterogeneity present in mucosal biopsies. To overcome some of these obstacles, we performed in vitro aspirin treatment of colon organoids derived from normal mucosal biopsies to reveal transcriptional networks relevant to aspirin chemoprevention. Colon organoids derived from 38 healthy individuals undergoing endoscopy were treated with 50 μmol/L aspirin or vehicle control for 72 hours and subjected to bulk RNA sequencing. Paired regression analysis using DESeq2 identified differentially expressed genes (DEG) associated with aspirin treatment. Cellular composition was determined using CIBERSORTx. Aspirin treatment was associated with 1,154 significant (q < 0.10) DEGs prior to deconvolution. We provide replication of these findings in an independent population-based RNA-sequencing dataset of mucosal biopsies (BarcUVa-Seq), where a significant enrichment for overlap of DEGs was observed (P < 2.2E-16). Single-cell deconvolution revealed changes in cell composition, including a decrease in transit-amplifying cells following aspirin treatment (P = 0.01). Following deconvolution, DEGs included novel putative targets for aspirin such as TRABD2A (q = 0.055), a negative regulator of Wnt signaling. Weighted gene co-expression network analysis identified 12 significant modules, including two that contained hubs for EGFR and PTGES2, the latter being previously implicated in aspirin chemoprevention. In summary, aspirin treatment of patient-derived colon organoids using physiologically relevant doses resulted in transcriptome-wide changes that reveal altered cell composition and improved understanding of transcriptional pathways, providing novel insight into its chemopreventive properties. PREVENTION RELEVANCE: Numerous studies have highlighted a role for aspirin in colorectal cancer chemoprevention, though the mechanisms driving this association remain unclear. We addressed this by showing that aspirin treatment of normal colon organoids diminished the transit-amplifying cell population, inhibited prostaglandin synthesis, and dysregulated expression of novel genes implicated in colon tumorigenesis.

Antidiarheal activity of catechol and ethyl 5, 8,11,14,17 – icosapentanoate-rich fraction of Annona senegalensis stem bark

Background and aimSecretory diarrhea is the most common type of diarrhea. This study aimed at exploring the possible mechanism of antisecretory action of Annona senegalensis stem bark and to identify the bioactive compounds. Experimental procedureThe ability of three crude extract; aqueous, dichloromethane and hexane stem bark extracts to inhibit castor oil-induced stooling in albino rats were assessed. Bioactivity guided fractionation of the most active extract was done using solvent-solvent partitioning (with hexane, dichloromethane, ethylacetate) and column chromatography. In vitro antioxidant activity of the most active sub-fraction was done using standard methods. The most active sub-fraction (25 mg/kg b. wt.) was administered to castor oil-induced diarrheal rats. Diarrheal rats small intestinal malondialdehyde concentration, antioxidant enzyme, cyclooxygenase II and Na+- K+ ATPase activities were determined using standard procedures. GC-MS analysis was done to identify the chemical compounds in the sub-fraction. Result and conclusionAqueous extract significantly decreased the number of wet stools. Sub-fraction 1 of ethylacetate fraction of aqueous stem bark extract (EFAS1) showed the highest stool inhibition. The H2O2 scavenging activity of EFAS1 was significantly greater than ascorbic acid. The sub-fraction significantly increased (p < 0.05) the activity of catalase and Na+- K+ ATPase activities but significantly decreased the concentration of malondialdehyde and cyclooxygenase II activity. GC-MS analysis revealed that EFAS1 is rich in catechol, n-hexadecanoic acid and ethyl-5,8,11,14,17-icosapentanoate. The sub-fraction exerts its antisecretory activity by its antioxidative, inhibition of prostaglandin synthesis and stimulation of Na+- K+ ATPase properties due to the presence of catechol, n-hexedecanoic acid and ethyl-5,8,11,14,17-icosapentanoate.

COMPARISON OF NONSTEROIDAL ANTI-INFLAMMATORY OF COX-1 AND COX-2 REGARDING SIDE EFFECTS IN THE ASTROINTESTINAL TRACT

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat symptoms caused by rheumatoid arthritis due to their ability to inhibit prostaglandin synthesis by inhibiting cyclooxygenase (COX). The side effects of NSAIDs are also associated with inhibiting prostaglandin production. Consequently, their application is problematic. NSAID selective COX-2 inhibitors give minor gastrointestinal complications. Our study aims to compare nonsteroidal anti-inflammatory inhibitors of COX-1 and COX-2 regarding side effects in the gastrointestinal tract of patients with rheumatoid arthritis. Keywords: Nonsteroidal anti-infammatory drugs, rheumatoid arthtritis, COX-2, gastrointestinal tract, PPIs .

Approaches to Potentiated Neuroprotective Treatment in the Rodent Model of Ischemic Optic Neuropathy.

Nonarteritic anterior ischemic optic neuropathy (NAION) commonly causes sudden optic nerve (ON)-related vision loss. The rodent NAION model (rAION) closely resembles NAION in presentation and physiological responses. We identified early rAION-associated optic nerve head (ONH) inflammatory gene expression responses and the anti-inflammatory prostaglandin PGJ2’s effects on those responses. We hypothesized that blocking pro-inflammatory prostaglandin (PGE2) production by inhibiting monoacylglycerol lipase or cyclooxygenase activity and co-administering PGJ2 would potentiate RGC survival following ischemic neuropathy. Deep sequencing was performed on vehicle- and PGJ2-treated ONHs 3d post-rAION induction. Results were compared against responses from a retinal ischemia model. Animals were treated with PGJ2 and MAGL inhibitor KML29, or PGJ2 + COX inhibitor meloxicam. RGC survival was quantified by stereology. Tissue PG levels were quantified by ELISA. Gene expression was confirmed by qPCR. PGJ2 treatment nonselectively reduced inflammatory gene expression post-rAION. KML29 did not reduce PGE2 1d post-induction and KML29 alone increased RGC loss after rAION. Combined treatments did not improve ONH edema and RGC survival better than reported with PGJ2 alone. KML29′s failure to suppress PGE2 ocular synthesis, despite its purported effects in other CNS tissues may result from alternative PG synthesis pathways. Neither KML29 nor meloxicam treatment significantly improved RGC survival compared with vehicle. While exogenous PGJ2 has been shown to be neuroprotective, treatments combining PGJ2 with these PG synthesis inhibitors do not enhance PGJ2’s neuroprotection.

Metabolomic Profiling and Toxicokinetics Modeling to Assess the Effects of the Pharmaceutical Diclofenac in the Aquatic Invertebrate Hyalella azteca.

The exposure of ecologically critical invertebrate species to biologically active pharmaceuticals poses a serious risk to the aquatic ecosystem. Yet, the fate and toxic effects of pharmaceuticals on these nontarget aquatic invertebrates and the underlying mechanisms are poorly studied. Herein, we investigated the toxicokinetic (TK) processes (i.e., uptake, biotransformation, and elimination) of the pharmaceutical diclofenac and its biotransformation in the freshwater invertebrate Hyalella azteca. We further employed mass spectrometry-based metabolomics to assess the toxic effects of diclofenac on the metabolic functions of H. azteca exposed to environmentally relevant concentrations (10 and 100 μg/L). The TK results showed a quick uptake of diclofenac by H. azteca (maximum internal concentration of 1.9 μmol/kg) and rapid formation of the conjugate diclofenac taurine (maximum internal concentration of 80.6 μmol/kg), indicating over 40 times higher accumulation of diclofenac taurine than that of diclofenac in H. azteca. Depuration kinetics demonstrated that the elimination of diclofenac taurine was 64 times slower than diclofenac in H. azteca. Metabolomics results suggested that diclofenac inhibited prostaglandin synthesis and affected the carnitine shuttle pathway at environmentally relevant concentrations. These findings shed light on the significance of the TK process of diclofenac, especially the formation of diclofenac taurine, as well as the sublethal effects of diclofenac on the bulk metabolome of H. azteca. Combining the TK processes and metabolomics provides complementary insights and thus a better mechanistic understanding of the effects of diclofenac in aquatic invertebrates.

Optimizing Anti-inflammatory Activities of Arabica Coffee Ground (Coffea arabica L.) Nanoparticle Gel

Background: Arabica coffee ground nanoparticles gel is known to possess good physicochemical properties and high phenolic contents in which the phenolics are famous for their anti-inflammatory activities. Objectives: : This study aimed to investigate the anti-inflammatory activities of the arabica coffee ground nanoparticles gel on carrageenan-induced male mice for 6 h. The positive control was commercial medicine (Voltaren gel), and the control negative was base gel. Methods: The inflammatory inhibition of arabica coffee ground nanoparticles gel is determined by measuring the edema volume of the carrageenan-induced mice foot using a plethysmometer. Anti-inflammatory activities of arabica coffee ground nanoparticles gel were optimized using Box-Behnken Design of the response surface methodology. Results: The anti-inflammatory activities or inflammatory inhibition of arabica coffee ground nanoparticles gel was determined by measuring the edema volume of the carrageenan-induced mice foot. The increase of edema volume of the mice foot from the first to 180th min was caused by the release of inflammation mediator such as histamine, prostaglandins, bradykinins, and serotonin on the tissue; meanwhile, at the 240th min, the edema of the mice foot experienced a decrease due to the inhibition of prostaglandins synthesis to the tissue. The obtained results indicated that the arabica coffee ground nanoparticles gel has average value of anti-inflammatory activities of 27.75%. The obtained optimum formulation is 0.500% Carbopol 940, 0.400% triethanolamine, and 2.313% nanoparticle, giving 29.360% and 29.670% for the predicted and experimental inflammatory inhibition values, with 0.812 desirability value, respectively. Conclusions: The Box-Behnken design can be used to determine the optimal gel formulation of arabica coffee grounds for inflammatory inhibition.

69-Year-Old Man With Nasal Congestion and Pre-Syncope

69-Year-Old Man With Nasal Congestion and Pre-Syncope

Assessing the effectiveness of ketorolac in pain management of traumatic injuries in prehospital emergency care services

Objective: Pain is usually one of the most common symptoms among all traumatic injuries. One of the drugs that has recently entered the Iranian prehospital emergency system is ketorolac. Ketorolac is a non-steroidal anti-inflammatory drug (NSAID) that inhibits prostaglandin synthesis by inhibiting cyclooxygenase activity and reduces pain and inflammation. It can be considered as the strongest analgesic drug in this category. The aim of this study was to evaluate the effectiveness of ketorolac in pain management of traumatic injuries in a prehospital setting. Methods: This descriptive cross-sectional study was undertaken to evaluate the effectiveness of a treatment method in the pain management of traumatic injuries in the prehospital environment of Lorestan province in Iran. We included 134 injured patients from road emergency bases of Lorestan province. In order to control the pain of these injured patients, 30 mg of ketorolac was injected slowly intravenously in one minute. Pain was measured in the time interval of zero minutes (before injection), 15 minutes, 30 minutes, and 45 minutes by visual acuity scale (VAS). The analysis of the obtained data was performed by SPSS software version 23. Results: The mean age of participants was 37.42±23.6. There were 47 female injuries (35.1%) and 87 male injuries (64.9%). In terms of pain intensity, 49 patients (36.6%) had moderate pain (VAS=4-6) and 85 patients (63.4%) had severe pain (VAS=7-10). The average of pain relief in the injured group with severe and moderate pain 15 minutes after the injection was 0.471 and 0.878 (P=0.001), respectively. In addition, the mean of pain relief in the injured group with severe and moderate pain 30 minutes after the injection was 1.124 and 1.796, respectively (P=0.001). Pain reduction in the group of severely injured patients with moderate pain in the first 30 minutes was statistically significant. Conclusion: Findings revealed that ketorolac is a suitable drug in pain management for trauma patients with moderate and severe pain in trauma patients. On the other hand, due to the peak effect (more than 30 minutes), it is not an effective drug for trauma patients with severe pain in a short period transferred to the prehospital environment.

Effect of Acetamınophen on Ovulation and Implantation in Female Mice

Acetaminophen is known to inhibit prostaglandin synthesis and activate the endocannabinoid system, thereby has been linked to the regulation of mammalian reproductive processes through the same. Growing evidence tends to link acetaminophen reproductive effects in the regulation of ovulation and/or implantation. To provide further evidence, this study was designed to determine the effect of acetaminophen on ovulation and/or implantation. Female Swiss white mice were randomly divided into two experiments, one testing effects on ovulation and the other testing effects on implantation. The two groups were further sub-divided into treatment and control groups, each having N=5 mice. The mice in the treatment groups (TG1 and TG2) received 200mg/kg of acetaminophen while those in the control groups (CG1 and CG2) received the same quantities of normal saline. Mice in experiment group one (TG1, CG1) received acetaminophen/placebo before mating. Those in experiment group two (TG2, CG2) received acetaminophen/placebo for seven days post-mating. The presence of a vaginal plug confirmed mating success. The mice were sacrificed on the 7th day of pregnancy, the uterus harvested and all observed implantation sites counted and recorded. In both treatment groups (TG1 and TG2), a significant reduction in the number of implantation sites (P≤0.05) was observed when compared with the respective control group (CG1 and CG2). The observation points towards a role of acetaminophen in the regulation of ovulation and implantation in female mice reproduction.

Poisons affecting the kidney

The kidney has an essential role in maintaining normal physiological functions but it can be affected by various drugs and chemicals. A common seasonal cause of renal failure in cats is ingestion of antifreeze containing ethylene glycol. It is not the ethylene glycol itself which causes renal failure but toxic metabolites which result in deposition of calcium oxalate crystals in the renal tubules. Various non-steroidal anti-inflammatory drugs, particularly those used in human medicine such as ibuprofen, flurbiprofen and naproxen, cause renal effects through inhibition of prostaglandin synthesis which results in reduced renal blood flow and disruption of normal renal function and homeostatic mechanisms. For some common substances, such as lilies in cats and grapes and their dried fruit in dogs, kidney injury occurs through unknown mechanisms. Management of poison-induced kidney injury is supportive with monitoring and support of renal function. Although haemodialysis and other extracorporeal techniques can be used, they are rarely available in veterinary medicine and therefore preventive measures are used. This includes aggressive intravenous fluid therapy before onset of signs for lily and grape poisoning and early use of the antidote (ethanol) in ethylene glycol poisoning to prevent formation of toxic metabolites, allowing excretion of the parent compound. In most cases, once kidney injury is advanced, prognosis is poor.

Sevoflurane sedation and nephrogenic diabetes insipidus in patients affected with severe acute respiratory syndrome coronavirus 2.

Sevoflurane sedation and nephrogenic diabetes insipidus in patients affected with severe acute respiratory syndrome coronavirus 2.

POS-294 COX-2 INHIBITION AND KIDNEY HEMODYNAMICS: THE EFFECT OF SEX

Animal studies suggest that kidney vasculature in males may be more dependent on vasodilatory prostaglandins than females, though the role of prostaglandins in kidney hemodynamics in healthy humans is unknown. We sought to determine the effect of cyclooxygenase-2 (COX-2) inhibition and resultant inhibition of prostaglandin synthesis on kidney hemodynamics and renin angiotensin aldosterone system (RAAS) activity, and to explore whether differences in COX-2 effects exist between sexes.

Effects of topically applied diclofenac and ketoprofen on prostaglandin E2 and Stat3 sera levels and body temperature in two different acute inflammation models in rats.

IntroductionCytokines exert biological function through signal transducer and activator of transcription factors. Prostaglandins have function as promotors, where play a key role in generation of the inflammatory response and as ones that solve inflammatory process.Non-steroidal anti-inflammatory drugs, inhibit prostaglandin synthesis but the existence of additional mechanisms is present. Thus, we aimed to explore effects of topically applied NSAIDs on the levels of PGE2 and Stat3 in the setting of two in vivo induced acute inflammation models.MethodsMale Wistar rats were randomized into five equal groups: 4 treated and a control group. Diclofenac or ketoprofen patches were applied in two different doses, i.e. equivalent to human therapeutic dose, and three times higher dose. Three hours later either model of inflammation (with 20% yeast, or with 1% carrageenan) was induced.Blood samples were taken 3 hours after and concentration levels of PGE 2 and Stat3 were determined using ELISA. Body temperature was measured at 0. 1st, 3rd and 5th hour after inflammation induction and presented in Celsius degrees. Shapiro-Wilk, Leven’s, Welch’s One-Way ANOVA, Kruskal-Wallis test and adjustment by Bonferroni correction were applied.ResultsIn both inflammation models, no differences in the mean values of PGE 2 between control, low and high dose groups treated by either diclofenac or ketoprofen were found. In yeast inflammation, the mean value of Stat3 was significantly higher in both dose ketoprofen groups compared to control group. After ketoprofen application, no significant differences in body temperature between groups at hour 0 and 5 in either model of inflammation induced, while at 1st hour after carrageenan inflammation, significant differences were found with significantly higher values in low dose ketoprofen group compared to control group. In yeast application, significant differences in body temperature were found at hour 3 after inducing inflammation and post hoc pairwise comparison test revealed significant higher values in low dose ketoprofen group compared to control.ConclusionElevated Stat3 values post ketoprofen application in yeast model of induced inflammation were detected. Further investigation of cytokine microenvironment as well as the mechanisms of ketoprofen influence on inflammation are needed.

Early closure mechanisms of the ductus arteriosus in immature infants.

According to experimental studies, cardiopulmonary distress decreases after closure of patent ductus arteriosus. However, early closure of the ductus using ibuprofen or indomethacin has failed to increase survival without serious morbidity. We review relevant data aiming to define optimal early management strategies that promote early closure of ductus arteriosus without serious adverse effects. Literature in English was searched selectively focusing on the potential of using acetaminophen for early closure of the ductus. Prophylactic ibuprofen or indomethacin intended to close the ductus, predisposes infants to ischaemia, bleeding and immune dysfunction. Acetaminophen appears to have a similar efficacy as indomethacin or ibuprofen, and all three dose-dependently constrict the ductus. Ibuprofen and indomethacin cause non-specific inhibition of prostaglandin synthesis, while acetaminophen predominantly inhibits prostaglandin E synthesis. Owing to low CYP450 activity in infancy, acetaminophen toxicity has been rarely evident. However, increasing the dosage increases the oxidative stress. We review prophylactic treatments that may increase the safety and efficacy of acetaminophen. These include vitamin A, cysteine and glutamine, and low-dose corticosteroid supplementation. The current challenge is to define a safe perinatal management practice that promotes cardiorespiratory adaptation in immature infants, particularly the seamless closure of the ductus before significant cardiopulmonary distress develops.

Eicosanoid‐induced calcium signaling mediates cellular immune responses of Tenebrio molitor

AbstractCalcium signaling is associated with actin cytoskeleton rearrangement. It is required for expressing cellular immune responses of insect hemocytes. Eicosanoids mediate immune responses by cytoskeleton rearrangement against various pathogen infections in insects. The objective of this study was to investigate cellular immune responses of a mealworm, Tenebrio molitor L. (Coleoptera: Tenebrionidae). The hypothesis tested was that immune responses would be mediated by calcium signaling associated with eicosanoid mediation. Larvae of T. molitor possessed at least four morphological types of hemocytes, most (almost 75%) of which were granulocytes and plasmatocytes. They all exhibited a hemocyte‐spreading behavior by F‐actin extension. Upon bacterial infection, hemocytes exhibited phagocytosis and formed hemocytic nodules. Intracellular calcium was detected in hemocytes. Its amount increased with increasing incubation time after bacterial infection. Inhibition of calcium influx or release from endoplasmic reticulum using specific inhibitors prevented cellular immune responses. Interestingly, treatment with an eicosanoid biosynthesis inhibitor suppressed calcium signals induced by bacterial challenge. Furthermore, treatment with naproxen, a prostaglandin (PG) synthesis inhibitor, or esculetin, a leukotriene synthesis inhibitor, also inhibited the increase of calcium concentration in hemocytes. Among eicosanoids, PGE2 highly stimulated the increase of calcium signals. These results suggest that cellular immune responses of T. molitor are triggered by calcium signaling, which is up‐regulated by eicosanoids.