Inhibition Of Prostaglandin Synthesis Research Articles

Diclofenac-Choline Antioxidant Activity Investigated by means of Luminol Amplified Chemiluminescence of Human Neutrophil Bursts and Electron Paramagnetic Resonance Spectroscopy

A new diclofenac salt called diclofenac-choline (DC) has recently been proposed for the symptomatic treatment of oropharyngeal inflammatory processes and pain because its greater water solubility allows the use of high concentrations, which are useful when the contact time between the drug and the oropharyngeal mucosa is brief, as in the case of mouthwashes or spray formulations. The antioxidant activity of DC has not yet been investigated, and so the aim was to use luminol-amplified-chemiluminescence (LACL) to verify whether various concentrations of DC (1.48, 0.74 and 0.37 mg/mL for incubation times of 2, 4 and 8 min) interfere with oxygen and nitrogen radicals during the course of human neutrophils respiratory bursts; electron paramagnetic resonance (EPR) spectroscopy was used to investigate its direct antiradical (scavenger) activity. The EPR findings showed that DC has concentration-dependent scavenging activity against the ABTS, the DPPH, and the hydroxyl radicals, but no activity on superoxide anion, as has been previously reported in the case of other NSAIDs. LACL revealed an inhibitory effect that was statistically significant after only 2 min of incubation, and similar after 4 and 8 min. The effects on the peroxynitrite radical paralleled those observed in the previous test. High concentrations and short incubation times showed that there is no interference on PMN viability, and so the inhibitory findings must be attributed to the effect of the drug. The anti-inflammatory effects of DC cannot be attributed solely to the inhibition of prostaglandin synthesis, but its effects on free radicals and neutrophil bursts suggest that they may contribute to its final therapeutic effect.

Tu1232 Expressions of CYP3A and P-Glycoprotein Were Decreased in the Secondary Inflammatory Response of Dextran Sodium Sulfate-Induced Mice Colitis and Its Contribution to the Blood Concentration of Cyclosporine A

Background: Small intestinal lesions induced by NSAIDs are of great concern in clinical settings. Various hypotheses, mainly of which related to the inhibition of prostaglandin synthesis, have been proposed for the origin of these inflammatory responses, however, the precise mechanism is yet to be known. The cellular process of the lesions must involve upand down-regulations of a large number of proteins and complex interactions between them. To elucidate it, global and systematic identification of the proteins in intestinal cells affected by non-steroidal anti-inflammatory drugs (NSAIDs) is essential. Two-dimensional polyacrylamide gel electrophoresis allows the analysis of total proteins from both cells and tissues, so it can help to elucidate the complex interactions and mechanisms inside cells. Aims: To identify the proteins that play a critical role in NSAIDs toxicity in intestinal cells and to clarify the mechanism of intestinal mucosal injuries induced by NSAIDs. Materials and Methods: We performed 2-DE on IEC-6 rat normal intestinal cells that were treated with indomethacin (200 μΜ, 24 h) or a vehicle control. The differentially displayed proteins were identified through matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Results: We found 18 up-regulated and 8 down-regulated proteins that showed a statistically significant difference of p < 0.05 and a ≥1.5 average fold difference in spot volume as a result of indomethacin treatment. Among these, we found that collagen I and the proteins involved in collagen I synthesis and maturation were all down-regulated. Consistent with this, immunohistochemical analysis showed that the indomethacin-treated rat intestinal mucosal cells exhibits decreased collagen I expression on its apical surface. Furthermore, the cell-protective effect of collagen I on intestinal mucosal cells was demonstrated by the use of a collagen-synthesis inhibitor and cell cultivation on collagen-coated plates versus uncoated plates. Conclusions: For the first time in the literature, a proteomic approach was employed to identify the global proteome alterations of the intestinal mucosa using indomethacin-treated and untreated IEC-6 cells. These results show that collagen I may play an important role in cytoprotection against indomethacin-induced intestinal mucosal injury. Insights gained from the current study may facilitate the development of new therapeutic strategies against NSAID-induced intestinal injury.

Abstract 510: Neuronal Voltage-Dependent Calcium Channel 2.1 RNA Increased in Animal Models With Contrast-Induced Nephropathy

Objectives: Contrast media has been widely used in imaging studies and endovascular procedures. However, contrast induced nephropathy (CIN) has been a major concern in the patients undergoing angiography and less invasive endovascular surgery. The current available main test for the diagnosis of CIN is to measure serum creatinine (Cr); however, It is non-specific and maybe due to underline renal disease. The objectives of this study were to analyze the changes of different proteins in CIN animal models, and to discover potential biomarker(s) for the early diagnosis of CIN. Materials &amp; Methods: C57B1/6J mice were used to create CIN model. A prostaglandin synthesis inhibitor (indomethacin, 10 mg/kg) and a nitric oxide synthase inhibitor (Nω-Nitro-L-arginine methyl ester, L-NAME, 10mg/kg) were injected intraperitoneally (ip) before giving Iodixanol, a commonly-used intravenous contrast, (320 mg iodine/ml, 4.9 g iodine/kg ip). Sham mice received ip injections of normal saline instead of Iodixanol. Mice kidneys were harvested at day1, day2 and day3 in different groups. RNA was extracted from half of the kidney specimen. qRT -PCR were used to quantify Kidney Injury Molecule-1 (KIM-1), neuronal voltage-dependent calcium channel 2.1 (CaV 2.1) and Cystatin C RNA expression, using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as endogenous control. The other half of the specimen was fixed with formalin, embedded in paraffin, and then stained with Hematoxylin and Eosin (H&amp;E) for histopathology evaluation. Results: H&amp;E staining demonstrated histological damages in Iodixanol-treated groups but not in controls. KIM-1 and Cystatin C expressions were not increased after receiving Iodixanol. CaV 2.1 RNA levels were significantly increased on day 3 in Iodixanol group (p &lt; 0.05), which was consistent with the contrast-induced damage based on histological examination. CaV 2.1 levels were also elevated on Day1 and Day 2 following iodixanol administration, although not statistically significant. Conclusions: Cav 2.1 gene expression is significantly increased in CIN animal models. Cav 2.1 may be involved in the mechanisms of CIN development, and could be a potential biomarker for the diagnosis of CIN. Further clinical investigation is needed.

Tu1230 Comparative Proteome Analysis of Indomethacin-Treated Intestinal Cells Reveals Down-Regulation of Collagen I in NSAID-Induced Intestinal Injury

Background: Small intestinal lesions induced by NSAIDs are of great concern in clinical settings. Various hypotheses, mainly of which related to the inhibition of prostaglandin synthesis, have been proposed for the origin of these inflammatory responses, however, the precise mechanism is yet to be known. The cellular process of the lesions must involve upand down-regulations of a large number of proteins and complex interactions between them. To elucidate it, global and systematic identification of the proteins in intestinal cells affected by non-steroidal anti-inflammatory drugs (NSAIDs) is essential. Two-dimensional polyacrylamide gel electrophoresis allows the analysis of total proteins from both cells and tissues, so it can help to elucidate the complex interactions and mechanisms inside cells. Aims: To identify the proteins that play a critical role in NSAIDs toxicity in intestinal cells and to clarify the mechanism of intestinal mucosal injuries induced by NSAIDs. Materials and Methods: We performed 2-DE on IEC-6 rat normal intestinal cells that were treated with indomethacin (200 μΜ, 24 h) or a vehicle control. The differentially displayed proteins were identified through matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Results: We found 18 up-regulated and 8 down-regulated proteins that showed a statistically significant difference of p < 0.05 and a ≥1.5 average fold difference in spot volume as a result of indomethacin treatment. Among these, we found that collagen I and the proteins involved in collagen I synthesis and maturation were all down-regulated. Consistent with this, immunohistochemical analysis showed that the indomethacin-treated rat intestinal mucosal cells exhibits decreased collagen I expression on its apical surface. Furthermore, the cell-protective effect of collagen I on intestinal mucosal cells was demonstrated by the use of a collagen-synthesis inhibitor and cell cultivation on collagen-coated plates versus uncoated plates. Conclusions: For the first time in the literature, a proteomic approach was employed to identify the global proteome alterations of the intestinal mucosa using indomethacin-treated and untreated IEC-6 cells. These results show that collagen I may play an important role in cytoprotection against indomethacin-induced intestinal mucosal injury. Insights gained from the current study may facilitate the development of new therapeutic strategies against NSAID-induced intestinal injury.

Tu1234 Effects of the Dipeptidyl Peptidase-4 Inhibitor, Sitagliptin, on Indomethacin-Induced Intestinal Mucosal Injury in a Model of Type 2 Diabetes

Background: Small intestinal lesions induced by NSAIDs are of great concern in clinical settings. Various hypotheses, mainly of which related to the inhibition of prostaglandin synthesis, have been proposed for the origin of these inflammatory responses, however, the precise mechanism is yet to be known. The cellular process of the lesions must involve upand down-regulations of a large number of proteins and complex interactions between them. To elucidate it, global and systematic identification of the proteins in intestinal cells affected by non-steroidal anti-inflammatory drugs (NSAIDs) is essential. Two-dimensional polyacrylamide gel electrophoresis allows the analysis of total proteins from both cells and tissues, so it can help to elucidate the complex interactions and mechanisms inside cells. Aims: To identify the proteins that play a critical role in NSAIDs toxicity in intestinal cells and to clarify the mechanism of intestinal mucosal injuries induced by NSAIDs. Materials and Methods: We performed 2-DE on IEC-6 rat normal intestinal cells that were treated with indomethacin (200 μΜ, 24 h) or a vehicle control. The differentially displayed proteins were identified through matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Results: We found 18 up-regulated and 8 down-regulated proteins that showed a statistically significant difference of p < 0.05 and a ≥1.5 average fold difference in spot volume as a result of indomethacin treatment. Among these, we found that collagen I and the proteins involved in collagen I synthesis and maturation were all down-regulated. Consistent with this, immunohistochemical analysis showed that the indomethacin-treated rat intestinal mucosal cells exhibits decreased collagen I expression on its apical surface. Furthermore, the cell-protective effect of collagen I on intestinal mucosal cells was demonstrated by the use of a collagen-synthesis inhibitor and cell cultivation on collagen-coated plates versus uncoated plates. Conclusions: For the first time in the literature, a proteomic approach was employed to identify the global proteome alterations of the intestinal mucosa using indomethacin-treated and untreated IEC-6 cells. These results show that collagen I may play an important role in cytoprotection against indomethacin-induced intestinal mucosal injury. Insights gained from the current study may facilitate the development of new therapeutic strategies against NSAID-induced intestinal injury.

Tu1231 Inhibition of RAC-1 Ameliorates Dextran Sodium Sulfate-Induced Colitis in Mice

Background: Small intestinal lesions induced by NSAIDs are of great concern in clinical settings. Various hypotheses, mainly of which related to the inhibition of prostaglandin synthesis, have been proposed for the origin of these inflammatory responses, however, the precise mechanism is yet to be known. The cellular process of the lesions must involve upand down-regulations of a large number of proteins and complex interactions between them. To elucidate it, global and systematic identification of the proteins in intestinal cells affected by non-steroidal anti-inflammatory drugs (NSAIDs) is essential. Two-dimensional polyacrylamide gel electrophoresis allows the analysis of total proteins from both cells and tissues, so it can help to elucidate the complex interactions and mechanisms inside cells. Aims: To identify the proteins that play a critical role in NSAIDs toxicity in intestinal cells and to clarify the mechanism of intestinal mucosal injuries induced by NSAIDs. Materials and Methods: We performed 2-DE on IEC-6 rat normal intestinal cells that were treated with indomethacin (200 μΜ, 24 h) or a vehicle control. The differentially displayed proteins were identified through matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Results: We found 18 up-regulated and 8 down-regulated proteins that showed a statistically significant difference of p < 0.05 and a ≥1.5 average fold difference in spot volume as a result of indomethacin treatment. Among these, we found that collagen I and the proteins involved in collagen I synthesis and maturation were all down-regulated. Consistent with this, immunohistochemical analysis showed that the indomethacin-treated rat intestinal mucosal cells exhibits decreased collagen I expression on its apical surface. Furthermore, the cell-protective effect of collagen I on intestinal mucosal cells was demonstrated by the use of a collagen-synthesis inhibitor and cell cultivation on collagen-coated plates versus uncoated plates. Conclusions: For the first time in the literature, a proteomic approach was employed to identify the global proteome alterations of the intestinal mucosa using indomethacin-treated and untreated IEC-6 cells. These results show that collagen I may play an important role in cytoprotection against indomethacin-induced intestinal mucosal injury. Insights gained from the current study may facilitate the development of new therapeutic strategies against NSAID-induced intestinal injury.

Selenium supplementation in thyroid associated ophthalmopathy: an update.

The therapeutic effect of selenium (Se) has already been proven in thyroid disease and thyroid associated ophthalmopathy (TAO). In spite of clear scientific proof of its benefits in TAO, there appears to be no clear agreement among the clinicians regarding its optimum dose, duration of the treatment, efficacy and safety to date. In this review, the author summarises the findings of 135 English language articles published on this subject over the past four decades from 1973 to 2013. The regulation and metabolism of thyroid hormones require a steady supply of Se and recent studies have revealed several possible mechanisms by which Se improves the severity of thyroid disease and TAO. These mechanisms include 1) inhibitory effect of HLA-DR molecule expression on thyrocytes; 2) profound reductions of thyroid stimulating hormone (TSH) receptor antibodies (TSHR-Ab) and TPO antibodies (TPO-Ab); 3) prevention of dysregulation of cell-mediated immunity and B cell function; 4) neutralising reactive oxygen species (ROS) and inhibition of redox control processes required for the activation, differentiation and action of lymphocytes, macrophages, neutrophils, natural killer cells involved in both acute and chronic orbital inflammation in TAO; 5) inhibition of expression of pro-inflammatory cytokines and 6) inhibition of prostaglandin and leukotriene synthesis. An increased oxidative stress has been observed in both acute and chronic phases of thyroid disease with raised tissue concentrations of ROS. The benefits of Se supplementation in individuals with TAO appear to be proportionate to the degree of systemic activity of the thyroid disease. The maximal benefit of Se supplementation is therefore seen in the subjects who are hyperthyroid. Restoration of euthyroidism is one of the main goals in the management of TAO and when anti-thyroid drugs are combined with Se, the patients with Graves' disease (GD) and autoimmune thyroiditis (AIT) achieved euthyroidism faster than those treated with anti-thyroid drugs alone. Se status of normal adult humans can vary widely and Se supplementation may confer benefit only if serum Se levels are insufficient. The author recommends that serum Se levels of patients with TAO to be assessed prior to and during Se supplementation at regular intervals to avoid potential iatrogenic chronic Se overdose.

Metabolic Signatures of Cultured Human Adipocytes from Metabolically Healthy versus Unhealthy Obese Individuals

Background and AimsAmong obese subjects, metabolically healthy and unhealthy obesity (MHO/MUHO) can be differentiated: the latter is characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Aim of this study was, to identify adipocyte-specific metabolic signatures and functional biomarkers for MHO versus MUHO.Methods10 insulin-resistant (IR) vs. 10 insulin-sensitive (IS) non-diabetic morbidly obese (BMI >40 kg/m2) Caucasians were matched for gender, age, BMI, and percentage of body fat. From subcutaneous fat biopsies, primary preadipocytes were isolated and differentiated to adipocytes in vitro. About 280 metabolites were investigated by a targeted metabolomic approach intracellularly, extracellularly, and in plasma.Results/InterpretationAmong others, aspartate was reduced intracellularly to one third (p = 0.0039) in IR adipocytes, pointing to a relative depletion of citric acid cycle metabolites or reduced aspartate uptake in MUHO. Other amino acids, already known to correlate with diabetes and/or obesity, were identified to differ between MUHO's and MHO's adipocytes, namely glutamine, histidine, and spermidine. Most species of phosphatidylcholines (PCs) were lower in MUHO's extracellular milieu, though simultaneously elevated intracellularly, e.g., PC aa C32∶3, pointing to increased PC synthesis and/or reduced PC release. Furthermore, altered arachidonic acid (AA) metabolism was found: 15(S)-HETE (15-hydroxy-eicosatetraenoic acid; 0 vs. 120pM; p = 0.0014), AA (1.5-fold; p = 0.0055) and docosahexaenoic acid (DHA, C22∶6; 2-fold; p = 0.0033) were higher in MUHO. This emphasizes a direct contribution of adipocytes to local adipose tissue inflammation. Elevated DHA, as an inhibitor of prostaglandin synthesis, might be a hint for counter-regulatory mechanisms in MUHO.Conclusion/InterpretationWe identified adipocyte-inherent metabolic alterations discriminating between MHO and MUHO.

Down-regulation of collagen I biosynthesis in intestinal epithelial cells exposed to indomethacin: A comparative proteome analysis

In contrast to accumulated knowledge about gastroduodenal injury associated with nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin, small intestinal mucosal injuries have been noticed only recently, and the precise mechanism remains to be elucidated. To clarify the mechanism, we performed 2-DE on IEC-6 rat normal intestinal cells that were treated with indomethacin (200μΜ, 24h) or a vehicle control and identified 18 up-regulated and 8 down-regulated proteins through MALDI-TOF/TOF mass spectrometry. Among these proteins, collagen I and proteins involved in collagen I biosynthesis and maturation, including prolyl 4-hydroxylase subunit α1, protein disulfide isomerase A3 (PDIA3), calreticulin, and endoplasmin, were all down-regulated by indomethacin. Immunohistochemical staining of the intestinal mucosa of indomethacin-administered rats showed a decrease of collagen I on the apical surface of intestinal cells. Cell death induced by indomethacin was prominently suppressed when IEC-6 cells were grown on collagen I-coated plates. cis-4-Hydroxy-l-proline, a proline analog that inhibits collagen synthesis, depressed IEC-6 cell viability in a concentration-dependent manner. Cell death was also induced by short interfering RNA knockdown of endogenous collagen I in IEC-6 cells. In conclusion, by comparative proteome analysis, we identified down-regulation of collagen I as an important mechanism in NSAID-induced intestinal injury. Small intestinal lesions induced by NSAIDs are of great concern in clinical settings. Various hypotheses have been proposed for the origin of these inflammatory responses, such as reduction in the blood flow, intestinal hypermotility, abnormal intestinal mucosal permeability, mitochondrial dysfunction, and reactive oxygen species, many of which are related to the inhibition of prostaglandin synthesis. However, the precise mechanism is yet to be known. The cellular process of the lesions must involve up- and down-regulations of a large number of proteins and complex interactions between them. To elucidate it, global and systematic identification of the proteins in intestinal cells affected by NSAIDs is essential. We found that the proteins exhibiting reduced expression by indomethacin treatment are collagen I and the proteins involved in collagen I synthesis and maturation. Consistent with this, immunohistochemical analysis showed that the indomethacin-treated rat intestinal mucosal cells exhibits decreased collagen I expression on its apical surface. Furthermore, the cell-protective effect of collagen on intestinal mucosal cells was demonstrated by the use of a collagen-synthesis inhibitor, short interfering RNA (siRNA) knockdown of endogenous collagen I, and cell cultivation on collagen I-coated plates versus uncoated plates. These results give important information on the role of the collagen synthesis in intestinal mucosa in the mechanism of NSAID-induced small intestinal lesions.

Effects of tenoxicam in experimental corrosive esophagitis model

Esophageal stricture, one of the important complications of corrosive esophagus, develops following edema and granulation tissue that forms during and after the inflammatory reactions. Tenoxicam, a non-steroid anti-inflammatory drug with a long half-life, prevents various leukocyte functions including phagocyte and histamine secretion by inhibiting prostaglandin synthesis and removes various oxygen radicals in the region of inflammation. We designed this as a histopathological study using tenoxicam in rats for which we created a corrosive esophagus model. After necessary authorizations were obtained, the study was performed in Çanakkale 18 Mart University experimental animal laboratory. Twenty-four Wistar albino rats, weighing 220-240 g, were used for the experiment. Experimental animals were randomized into three groups: tenoxicam group (group T, n:8), control group (group C, n:8), and sham group (group S, n:8). Tenoxicam 0.5 mg/kg/day was administered to animals in group T, where esophageal burn was developed experimentally, 5 mg/kg 0.9% NaCL was administered i.p. to rats in group C for 15 days, once in 24 hours. No procedure was applied to rats in group S. After 15 days, all animals were sacrificed under general anesthesia and their esophagi were extracted. As a result of histopathological evaluation, inflammation and fibroblast proliferation was not observed in rats in the sham group (group S). Intense inflammation was observed in six rats (6+/2-) in the control group, and fibroblast proliferation was observed as 5+/3-. And in treatment groups, inflammation was evaluated as 3+/5-, and fibroblast proliferation as 3+/5-. In our study, histopathologic damage score was higher in the control group (P < 0.005). We deduce that tenoxicam can be useful in the treatment of caustic esophageal injuries in the acute phase, but think that these drugs require further researches and clinical studies before routine clinical use.

NSAIDs Inhibit Tumorigenesis, but How?

Numerous epidemiologic studies have reported that the long-term use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with a significant decrease in cancer incidence and delayed progression of malignant disease. The use of NSAIDs has also been linked with reduced risk from cancer-related mortality and distant metastasis. Certain prescription-strength NSAIDs, such as sulindac, have been shown to cause regression of precancerous lesions. Unfortunately, the extended use of NSAIDs for chemoprevention results in potentially fatal side effects related to their COX-inhibitory activity and suppression of prostaglandin synthesis. Although the basis for the tumor growth-inhibitory activity of NSAIDs likely involves multiple effects on tumor cells and their microenvironment, numerous investigators have concluded that the underlying mechanism is not completely explained by COX inhibition. It may therefore be possible to develop safer and more efficacious drugs by targeting such COX-independent mechanisms. NSAID derivatives or metabolites that lack COX-inhibitory activity, but retain or have improved anticancer activity, support this possibility. Experimental studies suggest that apoptosis induction and suppression of β-catenin-dependent transcription are important aspects of their antineoplastic activity. Studies show that the latter involves phosphodiesterase inhibition and the elevation of intracellular cyclic GMP levels. Here, we review the evidence for COX-independent mechanisms and discuss progress toward identifying alternative targets and developing NSAID derivatives that lack COX-inhibitory activity but have improved antineoplastic properties.

Prostaglandin E2 (EP) Receptors Mediate PGE2-Specific Events in Ovulation and Luteinization Within Primate Ovarian Follicles

Prostaglandin E2 (PGE2) is a key mediator of ovulation. All 4 PGE2 receptors (EP receptors) are expressed in the primate follicle, but the specific role of each EP receptor in ovulatory events is poorly understood. To examine the ovulatory events mediated via these EP receptors, preovulatory monkey follicles were injected with vehicle, the PG synthesis inhibitor indomethacin, or indomethacin plus PGE2. An ovulatory dose of human chorionic gonadotropin was administered; the injected ovary was collected 48 hours later and serially sectioned. Vehicle-injected follicles showed normal ovulatory events, including follicle rupture, absence of an oocyte, and thickening of the granulosa cell layer. Indomethacin-injected follicles did not rupture and contained oocytes surrounded by unexpanded cumulus; granulosa cell hypertrophy did not occur. Follicles injected with indomethacin plus PGE2 were similar to vehicle-injected ovaries, indicating that PGE2 restored the ovulatory changes inhibited by indomethacin. Additional follicles were injected with indomethacin plus an agonist for each EP receptor. EP1, EP2, and EP4 agonists each promoted aspects of follicle rupture, but no single EP agonist recapitulated normal follicle rupture as seen in follicles injected with either vehicle or indomethacin plus PGE2. Although EP4 agonist-injected follicles contained oocytes in unexpanded cumulus, the absence of oocytes in EP1 agonist- and EP2 agonist-injected follicles suggests that these EP receptors promote cumulus expansion. Surprisingly, the EP3 agonist did not stimulate any of these ovulatory changes, despite the high level of EP3 receptor expression in the monkey follicle. Therefore, agonists and antagonists selective for EP1 and EP2 receptors hold the most promise for control of ovulatory events in women.

A review of in vitro and in vivo studies on the efficacy of herbal medicines for primary dysmenorrhea.

Purpose. Primary dysmenorrhea (PD) is a common gynecological complaint among adolescent girls and women of reproductive age. This study aims to review the findings of published articles on the in vitro and in vivo efficacy of herbal medicines for PD. Methods. In vitro and in vivo studies of herbal compounds, individual herbal extracts, or herbal formula decoctions published from their inception to April 2014 were included in this review. Results. A total of 18 studies involving herbal medicines exhibited their inhibitory effect on PD. The majority of in vitro studies investigated the inhibition of uterine contractions. In vivo studies suggest that herbal medicines exert a peripheral analgesic effect and a possible anti-inflammatory activity via the inhibition of prostaglandin (PG) synthesis. The mechanisms of herbal medicines for PD are associated with PG level reduction, suppression of cyclooxygenase-2 expression, superoxide dismutase activation and malondialdehyde reduction, nitric oxide, inducible nitric oxide synthase, and nuclear factor-kappa B reduction, stimulation of somatostatin receptor, intracellular Ca2+ reduction, and recovery of phospholipid metabolism. Conclusions. Herbal medicines are thought to be promising sources for the development of effective therapeutic agents for PD. Further investigations on the appropriate herbal formula and their constituents are recommended.

Insulin causes airway hyper-reactivity

Background: We explored the acute effects of insulin and one possible mechanism underlying the acute contractile effects of insulin on isolated tracheal smooth muscle of guinea pig in vitro. Methods: Effects of increasing concentrations of histamine (10 −7 -10 −3 M), insulin (10 −7 -10 −3 M), insulin pretreated with a fixed concentration of indomethacin (10 −6 M) were studied on isolated tracheal tissue of guinea pig in vitro by constructing cumulative concentration response curves. The tracheal smooth muscle contractions were recorded with transducer on four channel oscillograph. Results: Histamine and insulin produced a concentration-dependent reversible contraction of isolated tracheal muscle of guinea pig. The mean±standard error of the mean of maximum amplitudes of contraction with histamine, insulin and insulin pretreated with indomethacin were 92.5±1.20 mm, 35±1.13 mm and 14.55±0.62 mm respectively. Indomethacin shifted the concentration-response curve of insulin to the right and downwards. Conclusions: Insulin has acute contractile effects on guinea pig airways, which were significantly inhibited by prostaglandin synthesis inhibitor indomethacin confirming the involvement of contractile prostaglandins in insulin-induced airway hyper-responsiveness.

Drug-interaction-induced hemodynamically mediated acute renal failure in postsurgical patient

Acute renal failure is a life threatening condition. Nonsteroidal antiinflammatory drugs (NSAIDs) and cephalosporins are widely used postoperative drugs. NSAID-induced acute renal failure has been reported in the past. In this case, drug interaction and decompensated state of the patient precipitate the condition. NSAIDs inhibit prostaglandins synthesis and thus aggravate ischemia to the kidney that is already facing volume crisis due to surgery. Due to renal dysfunction, plasma ceftriaxone level increases due to decrease clearance and it also acts as nephrotoxic by unknown mechanism. On the other hand, ceftriaxone on its interaction with diclofenac for renal tubular clearance also increases the level of diclofenac and thus further aggravate the ischemia. It is a reversible condition with excluding diclofenac from the treatment regimen and giving adequate hydration to the patient. This highlights the importance of hydration and knowledge of drugs interactions in a postsurgical patient.

Effect of sulpiride treatment during the periovulatory period on ovulation and LUF formation

The most common pathological anovulatory condition that occurs in the mare is the hemorrhagic anovulatory follicle (HAF). The exact cause is still unknown, but it is likely that many factors are involved in the inhibition of follicle rupture. The inhibition of prostaglandin synthesis by flunixin-meglumine during the periovulatory period resulted in a high percentage of luteinized unruptured follicles (LUF) in the mare [Cuervo-Arango et al., Theriogenology 2011; 76: 361-73]. High plasma prolactin (PRL) has been regarded as another possible cause of LUF. A recent study showed a 56% incidence on LUF development in mares with high PRL concentration after long term treatment with sulpiride [Zagrajczuk and Okolski, Reprod Dom Anim 2010;45(Suppl.3):62]. In vitro experiments have demonstrated that PRL during the periovulatory period inhibits ovulation by reducing ovarian plasmin generation in rabbits (Yoshimura et al., 1994). The aim of the present study was to determine the effect of sulpiride on ovulation during the periovulatory period in mares. Sixteen estrous cycles from 10 cyclic mares between February and June in Spain were randomly assigned to a control or sulpiride group (n1⁄48 each). All mares received 1500 IU of hCG (Hour 0) when they reached a follicular diameter 32 mm and presence of endometrial oedema. Mares were scanned every 12 h until ovulation or LUF formation. In the

Prenatal effects of maternal consumption of polyphenol‐rich foods in late pregnancy upon fetal ductus arteriosus

Fetal circulation has characteristic features, being morphologically and functionally different from extrauterine circulation. The ductus arteriosus plays a fundamental role in directing the blood flow to fetal inferior body parts. Basically, the ductus arteriosus directs 80–85% of the right ventricular output arising from the superior vena cava, coronary sinus, and a small part from the inferior vena cava to descending aorta. Its histological structure is made up predominantly by a thick muscular layer, differently from the aorta and the pulmonary artery, which increases with gestational age. The fibers have a circumferential orientation, especially at the external layers, facilitating and making effective ductal constriction. These factors may generate lumen alterations which may cause fetal and neonatal complications, such as heart failure, hydrops, neonatal pulmonary hypertension, and even death. Classically, maternal administration of indomethacin and/or other antiinflammatory drugs interfere in prostaglandins metabolism, causing ductal constriction. However, many cases of fetal ductal constriction, as well as of persistent neonatal pulmonary artery hypertension, remain without an established etiology, being referred as “idiopathic.” In recent years, a growing body of evidence has shown that herbs, fruits, nuts, and a wide diversity of substances commonly used in daily diets have definitive effects upon the metabolic pathway of inflammation, with consequent inhibition of prostaglandins synthesis. This antiinflammatory action, especially of polyphenols, when ingested during the third trimester of pregnancy, may influence the dynamics of fetal ductus arteriosus flow. The goal of this review is to present these new observations and findings, which may influence dietary orientation during pregnancy. Birth Defects Research (Part C) 99:256–274, 2013. © 2013 Wiley Periodicals, Inc.

Appropriate Assessment of the Functional Consequences of Platelet Cyclooxygenase-1 Inhibition by Aspirin in vivo

Chronic use of low dose aspirin (acetylsalicylic acid) is generally an effective and relatively low cost strategy for preventing and treating cardiovascular disease [1]. John Vane reported the inhibition of prostaglandin synthesis as a mechanism of action of aspirin-like drugs in 1971 by demonstrating a dose-dependent inhibition of prostaglandin synthesis by aspirin, sodium salicylate and indomethacin [2]. Thromboxane A2 (TxA2) was subsequently identified by Samuelsson’s group as the potent vasoconstrictor and platelet agonist the synthesis of which was inhibited by aspirin [3].

MECHANISMS OF ANTI-INFLAMMATORY ACTIVITY OF THE LEAF EXTRACT AND FRACTIONS OF MILLETTIA ABOENSIS

The acute and chronic anti - inflammatory effect of the crude extracts and fractions of Millettia aboensis leaves, a popular Nigerian traditional anti inflammation remedy and possible mechanism of effect was investigated. Phytochemical analysis of the crude and fraction revea led the presence of anti inflammatory phy to - compounds – terpenoids, steroids, flavonoids, tannins, saponins and glycosides. No death was recorded from acute toxicity study. The crude and methanol fraction at 300 and 200 mg/kg showed significant (p < 0.05) inhibition of egg albumin induced paw ede ma. Effect of the extract and fraction on topical o edema induced by xylene on mouse ear revealed that methanol fraction at 5 mg/ear had the highest activity with percentage inh ibition of 61.90 % compared to the 54.76 % inhibition produced by Indomethacin. Methanol fraction at 300 mg/kg produced a significant (p < 0.05) inhibition of formaldehyde induced arthritis with percentage inhibition of 40.93 %. Result of the ulcergenic effect in rat demonstrated that both the crude and methanol fraction possess ulcer genic effect though lower than that produced by Indomethacin. Methanol fraction at 400 mg/kg also produced significant (p < 0.05) inhibition of leucocytes migration compared with the control. Both extract and methanol fraction produced stabilization effec t on the heat - induced and hypotonicity induced red blood cell haemolysis. These results suggest that the ethanol leaf extract of M. aboensis possess acute and chronic anti - inflammatory activity that is most active in the methanol fraction. The activity may be as a result of combined inhibition of prostaglandin synthesis, leukocyte migration and membrane stabilization effect. Keyword: Millettia aboensis ; Anti - inflammation; Paw edema, Arthritis; Leucocytes migration; Membrane stabilization.

Activation of PAF-receptor induces regulatory dendritic cells through PGE2 and IL-10

Activation of the platelet-activating factor receptor (PAFR) in macrophages is associated with suppressor phenotype. Here, we investigated the PAFR in murine dendritic cells (DC). Bone marrow-derived dendritic cells (BALB/c) were cultured with GM-CSF and maturation was induced by LPS. The PAFR antagonists (WEB2086, WEB2170, PCA4248) and the prostaglandin (PG) synthesis inhibitors (indomethacin, nimesulide and NS-398) were added before LPS. Mature and immature DCs expressed PAFR. LPS increased MHCII, CD40, CD80, CD86, CCR7 and induced IL-10, IL-12, COX-2 and PGE2 expression. IL-10, COX-2 and PGE2 levels were reduced by PAFR antagonists and increased by cPAF. The IL-10 production was independent of PGs. Mature DCs induced antigen-specific lymphocyte proliferation. PAFR antagonists or PG-synthesis inhibitors significantly increased lymphocyte proliferation. It is proposed that PAF has a central role in regulatory DC differentiation through potentiation of IL-10 and PGE2 production.