Serum Prostaglandin E2 Levels Research Articles

Estimation of the novel antipyretic, anti-inflammatory, antinociceptive and antihyperlipidemic effects of silymarin in Albino rats and mice

ObjectiveTo evaluate the other pharmacological actions of silymarin in Albino rats and mice such as antipyretic, anti-inflammatory, antinociceptive and antihyperlipidemic effects. MethodsRats were injected intramuscularly with pyrogenic dose of brewer's yeast for the antipyretic test of silymarin. Another group of rats injected with 0.1 mL of 1% carrageenan solution in saline at the subplanter area of the right hind paw for the anti-inflammatory test of silymarin. Another group of mice tested by hot plate method for determination of antinociceptive effect of silymarin. Hyperlipidemia was induced using high fat diet for 2 months to estimate the antihyperlipidemic activity of silymarin. ResultsSilymarin showed a significant antipyretic effect of both doses (50 and 100 mg/kg) compared with control untreated group. Moreover, silymarin elucidated a significant anti-inflammatory effect of both doses reflected on the decrease of the rat paw edema every hour interval for 4 h after administration in comparison with control positive group. By the same taken, both doses of silymarine revealed a significant antinociceptive action in hot plate method at 30 and 60 min post administration. Besides, it lowered significantly the serum levels of prostaglandin E2, tumor necrosis factor alpha and interleukin 1 beta after 2 h of silymarin administration in carrageenan induced rat paw edema besides the significant decrease of total cholesterol, triglycerides, low density lipoprotein and significantly elevated high density lipoprotein after 2 weeks of silymarin administration. ConclusionsThese outcomes delivered a new vision into the possible pharmacological mechanisms by which silymarin advances antipyretic, anti-inflammatory, antinociceptive and antihyperlipidemic effects.

Antioxidant-mediated preventative effect of Dragon-pearl tea crude polyphenol extract on reserpine-induced gastric ulcers.

Dragon-pearl tea is a type of green tea commonly consumed in Southwest China. In the present study, the antioxidative and anti-gastric ulcer effects of Dragon-pearl tea crude polyphenols (DTCP) were determined in vitro and in vivo. Treatment with 25, 50 or 100 µg/ml DTCP resulted in notable antioxidant effects in vitro, which manifested as 2,2-diphenyl-1-picrylhydrazyl and OH radical-scavenging activity. Furthermore, using an in vivo mouse model, DTCP was shown to reduce the gastric ulcer area in the stomach, in which the 200 mg/kg DTCP dose exhibited the most marked effect, with a gastric ulcer index inhibitory rate of 72.63%. In addition, DTCP was demonstrated to improve stomach acidity conditions in vivo by increasing the pH and reducing the level of gastric juice, as compared with the reserpine-induced gastric ulcer control mice. Furthermore, DTCP altered the serum levels of a number of oxidation-related biomolecules, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), lipid peroxidation (LPO) and catalase (CAT), to subsequently exert an anti-gastric ulcer effect. Treatment with 50, 100 and 200 mg/kg DTCP increased the SOD, GSH-Px and CAT levels and reduced the MDA and LPO levels in the mouse model of gastric ulcers. These serum level alterations resulted in the modified serum levels of prostaglandin E2 (PGE2) and nitric oxide (NO), which are associated with gastric mucosal protection. A reverse transcription-quantitative polymerase chain reaction (RT-PCR) assay is a molecular biology experiment which could determine the changes of mRNA in tissues. Using the RT-PCR assay, DTCP was observed to increase the mRNA expression levels of certain genes associated with gastric ulcers: Epidermal growth factor, epidermal growth factor receptor, vascular endothelial growth factor and vascular endothelial growth factor receptor 1, while reducing gastrin expression levels. Therefore, the results indicated that DTCP induced a marked preventative effect on reserpine-induced gastric ulcers in vivo, as a result of its antioxidative capacity.

Antitumor immunostimulatory activity of polysaccharides from Salvia chinensis Benth

Ethnopharmacological relevanceSalvia chinensis Benth (S. chinensis) is a traditional herb applied in the treatment of hepatocellular carcinoma (HCC). Polysaccharides abundantly exist in this plant. However, it remains poorly understood if polysaccharides from S. chinensis (PSSC) contribute to its anti-HCC activity. Materials and methodsThe in vivo anti-HCC activity of PSSC was evaluated in Kunming mice bearing H22 ascitic hepatoma cells. An array of physiological indexes was measured to evaluate toxicological effects on host animals. Subgroups of immune cells were purified by a magnetic-activated cell sorting system and analyzed by flow cytometry. Reverse transcription real-time PCR and immunoblotting were recruited to determine the effects of PSSC on the cellular signaling of different subgroup of immune cells. ResultsPSSC suppressed in vivo proliferation of H22 cells with undetectable toxic effects on tumor-bearing mice. PSSC alleviated tumor transplantation-induced CD4+ T cell apoptosis and dysregulation of serum cytokine profiles, which elevated cytotoxic activities of natural killer and CD8+ T cells. PSSC reduced serum levels of prostaglandin E2 (PGE2). Injection of exogenous PGE2 completely abrogated the antitumor immunostimulatory activity of PSSC. Cyclic adenosine monophosphate (cAMP) is the second messager of PGE2. In CD4+ T cells, PSSC substantially declined intracellular cAMP. This event elevated protein levels of JAK3, enhancing STAT5 phosphorylation and STAT5-depedent expression of anti-apoptotic genes. Cyclooxygenase-2 is the key enzyme mediating biosynthesis of PGE2. PSSC suppressed the transcription and translation of cyclooxygenase-2 in tumor associated macrophages. ConclusionOur data clearly showed antitumor immunostimulatory activity of PSSC against transplanted H22 HCC cells. Suppressing tumor transplantation-induced PGE2 production was implicated in the anti-tumor immunostimulatory activity of PSSC. These works provides novel insights into the traditional application of S. chinensis against HCC and supported considering PSSC as an adjuvant reagent in clinical HCC treatment.

Effects of different Chinese herbal prescriptions on cytokines in autoimmune prostatitis rats

ObjectiveTo observe and compare the effects of Chinese herbal prescriptions for promoting blood circulation, clearing heat, removing toxicity, and dispersing stagnated liver-Qi on cytokines in model rats with experimental autoimmune prostatitis (EAP) to provide an experimental basis for the use of Chinese herbal prescriptions in the treatment of chronic prostatitis. MethodsOne-hundred and ten male Wistar rats were randomly divided into 11 groups: blank group; model group; Huoxuehuayu (promoting blood circulation to remove blood stasis) high, middle, and low dose groups; Qingrejiedu (clearing heat and removing toxicity) high, middle, and low dose groups; and Shuganliqi (dispersing stagnated liver-Qi) high, middle, and low dose groups. Except the blank group, rats in all groups were injected subcutaneously in multiple points on days 0 and 30 with prostatic protein extractive solution (60 mg/mL), and intraperitoneally injected with diphtheria-pertussis and tetanus vaccine (DPT vaccine) to establish the EAP model. Model rats were administrated high, middle, and low doses of Chinese herbal prescriptions and were sacrificed after 4 weeks. Pathological changes in the prostate gland were observed with HE staining and changes in serum interleukin-6 (IL-6), interleukin-8 (IL-8), and prostaglandin E2 (PGE2) levels were detected with enzyme-linked immunosorbent assay. ResultsCompared with the blank group, serum PGE2, IL-6, and IL-8 levels in the model group were significantly higher (P < 0.05). Compared with the model group, serum PGE2, IL-6, and IL-8 levels in the Qingrejiedu low dose and middle dose groups were significantly lower (P < 0.05), with the lower dose having a more obvious effect. Serum PGE2, IL-6, and IL-8 levels in the Huoxuehuayu high dose group (P < 0.05), IL-6 and IL-8 levels in the Huoxuehuayu middle dose group (P < 0.05), and the IL-8 level in the Huoxuehuayu low dose group were significantly lower than those in the model group (P < 0.05). There were significant differences in PGE2 and IL-6 levels among the different dose groups of Shuganliqi drugs (P < 0.05). Compared with the model group, serum PGE2, IL-6, and IL-8 levels in the Shuganliqi high dose group (P < 0.05) and IL-8 level in the Shuganliqi low dose group were significantly lower (P < 0.05), while the Shuganliqi middle dose group did not change significantly (P > 0.05). ConclusionTherefore, in TCM treatment of autoimmune prostatitis, different treatment methods should select different doses. For prescriptions that clear heat and remove toxicity, low doses should be used. For prescriptions that promote blood circulation to remove blood stasis and for prescriptions that disperse stagnated liver-Qi, high doses should be used.

Improved body weight and performance status and reduced serum PGE2 levels after nutritional intervention with a specific medical food in newly diagnosed patients with esophageal cancer or adenocarcinoma of the gastro-esophageal junction.

BackgroundThe majority of cancer patients loses weight and becomes malnourished during the course of their disease. Metabolic alterations and reduced immune competence lead to wasting and an increased risk of infectious complications. In the present study, the effect of a nutritionally complete medical food, which is high in protein and leucine and enriched with fish oil and specific oligosaccharides, was investigated on immune function, nutritional status, and inflammation in patients with esophageal cancer and compared with routine care.MethodsIn this exploratory double-blind study, 64 newly diagnosed esophageal cancer patients were randomized. All patients received dietary counselling and dietary advice. In the Active group, all patients received the specific medical food for 4 weeks before the start of anticancer therapy. In the routine care control arm, patients with <5% weight loss received a non-caloric placebo product, and patients with weight loss ≥5% received an iso-caloric control product to secure blinding of the study. The required study parameters of body weight and performance status were recorded at baseline and after 4 weeks of nutritional intervention, and patients were asked to complete quality of life questionnaires. In addition, blood samples were taken for the measurement of several immune, nutritional, and safety-parameters.ResultsNo effect of the specific nutritional intervention could be detected on ex vivo stimulations of blood mononuclear cells. By contrast, body weight was significantly increased (P < 0.05) and ECOG performance status was improved after intervention with the specific medical food (P < 0.05). In addition, serum Prostaglandin E2 (PGE2) levels were significantly decreased in the specific medical food group and increased in the control group (P = 0.002).ConclusionsNutritional intervention with the specific medical food significantly increased body weight and improved performance status compared with routine care in newly diagnosed esophageal cancer patients. This effect was accompanied by significantly reduced serum PGE2 levels.

Anti-M&amp;lt;sub&amp;gt;3&amp;lt;/sub&amp;gt; Muscarinic Acetylcholine Receptor Antibodies in Systemic Lupus Erythematosus

Background: Evidences have shown that anti-M3 muscarinic acetylcholine receptor IgG (anti-M3 mAChR IgG) are clinically useful autoantibody that exert a cholinergic pharmacologic effect binding and interacting with M3 mAChR at the level of exocrine gland (salivary and ocular). Aims: The aim of this study was to determine the associations between serum level of anti-M3 mAChR IgG in patients with systemic lupus erythematosus (SLE) and other autoantibodies, serum prostaglandin E2 (PGE2), and clinical manifestations. Methods: Serum autoantibodies against M3 mAChR synthetic peptide were measured by enzyme-linked immuno absorbent assay (ELISA) using, as an antigen, a 25-mer peptide K-R-T-V-P-D-N-Q-C-F-I-Q-F-L-S-N-P-A-V-T-F-G-T-A-I corresponding to the amino acid sequence of the second extracellular loop of the human M3 mAChR. Serum levels of antinuclear antibodies (ANA), anti-Smith (Sm) antibodies, anti-phospholipid (APL) antibodies, and PGE2 were determined by ELISA in patients with SLE. Results: We found significantly enhanced titers of anti-M3 mAChR IgG in sera from SLE patients compared with healthy individuals (control). In addition, serum levels of PGE2 were significantly higher in SLE patients than in control patients and were significantly higher in active than in non-active SLE. No correlation was found with other autoantibodies present in SLE. By contrast, a positive correlation was found between anti-M3 mAChR IgG and PGE2 serum levels in SLE. Conclusions: As anti-M3 mAChR antibodies present in the sera of SLE patients may be another factor in the pathogenesis of this disease, and the increment of PGE2 in the sera of SLE has a modulatory action on the inflammatory process, suggesting that the presence of these autoantibodies against M3 mAChR may contribute to sustained immune deregulation and the strong inflammatory component observed in SLE.

Oleuropein or rutin consumption decreases the spontaneous development of osteoarthritis in the Hartley guinea pig

To assess the potential protective effects of three polyphenols oleuropein, rutin and curcumin, on joint ageing and osteoarthritis (OA) development. Sixty 4-week-old Dunkin-Hartley guinea pigs were randomized into four groups and received daily during 31 weeks either standard guinea pig diet (control group) or a standard guinea pig diet enriched with oleuropein (0.025%), rutin (0.5%) or rutin/curcumin (0.5%/0.25%) association. Biomarkers of OA (Coll2-1, Coll2-1NO2, Fib3-1, Fib3-2, ARGS), as well as inflammation prostaglandin E2 (PGE2) were quantified in the serum. Histological assessments of knee cartilage and synovial membrane were performed at week 4 (five young reference guinea pigs) and week 35. At week 35, guinea pigs in the control group spontaneously developed significant cartilage lesions with mild synovial inflammation. The histological scores of cartilage lesions and synovitis were well correlated with the increased level of serum biomarkers. Histologically, all treatments significantly reduced the cartilage degradation score (P<0.01), but only oleuropein significantly decreased the synovial histological score (P<0.05) and serum PGE2 levels (P<0.01) compared to the control group. Coll2-1 was decreased by rutin and the combination of rutin/curcumin, Fib3-1 and Fib3-2 were only decreased by the rutin/curcumin mixture, while Coll2-1NO2 was significantly decreased by all treatments (P<0.05). Oleuropein and rutin±curcumin significantly slowed down the progression of spontaneous OA lesions in guinea pigs. While no additive effect was seen in the curcumin+rutin group, the differential effects of oleuropein and rutin on inflammatory and cartilage catabolic markers suggest an interesting combination for future studies in OA protection.

LC-MS/MS analysis of plasma polyunsaturated fatty acids in patients with homozygous sickle cell disease.

The aim of this study was to determine circulating omega-6, omega-3 polyunsaturated fatty acids and prostaglandin E2 (PGE2) levels in steady state sickle cell disease (SCD) patients. Blood was collected from healthy hemoglobin volunteers and steady state homozygous HbSS patients who had not received blood transfusions in the last 3months. Plasma levels of arachidonic acid (AA, C20:4n-6), dihomo-gamma-linolenic acid (DGLA, C20:3n-6), eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) were determined by an optimized multiple reaction monitoring method using ultrafast liquid chromatography coupled with tandem mass spectrometry. PGE2 was measured in serum samples by enzyme immunoassay. Plasma AA and DGLA were significantly increased while EPA and DHA were significantly decreased in SCD plasma compared to control. Serum PGE2 levels, AA/DHA and AA/EPA ratio was significantly higher in SCD patients when compared to control group. The significant increase in PGE2 levels, AA/EPA and AA/DHA ratio confirms the presence of a proinflammatory state in SCD patients.

A pilot study investigating early postoperative changes of plasma polyunsaturated fatty acids after laparoscopic sleeve gastrectomy

BackgroundThis study aimed to determine early postoperative changes of plasma polyunsaturated fatty acids (PUFAs) following laparoscopic sleeve gastrectomy (LSG).MethodsTen obese patients (mean BMI: 51.10 ± 11.59 kg/m2) underwent LSG and eleven normal weight control patients (mean BMI: 24.37 ± 2.33 kg/m2) underwent laparoscopic abdominal surgery. Fasting blood samples were collected prior to surgery, at day 1 after surgery and after postoperation oral feeding. Plasma levels of arachidonic acid (AA, C20:4n6), dihomo-gamma-linolenic acid (DGLA, C20:3n6), eicosapentaenoic acid (EPA, C20:5n3) and docosahexaenoic acid (DHA, C22:6n3) were determined by an optimized multiple reaction monitoring (MRM) method using ultra fast-liquid chromatography (UFLC) coupled with tandem mass spectrometry (MS/MS). Prostaglandin E2 (PGE2) was measured in serum samples by enzyme immunoassay.ResultsA significant decrease was observed in insulin and HOMA IR levels in sleeve gastrectomy patients after postoperation oral feeding compared to preoperation. Plasma AA levels and AA/EPA ratio were significantly increased in sleeve gastrectomy patients after postoperation oral feeding compared to postoperation day 1. Serum PGE2 levels and AA/DHA ratio was significantly higher in sleeve gastrectomy patients at preoperation, postoperation day 1 and after postoperation oral feeding when compared to control group patients.ConclusionIncreased peripheral insulin sensitivity associated with LSG may play a role in the significant increase of plasma AA levels in sleeve gastrectomy patients following postoperation oral feeding. The significant increase in PGE2 levels and AA/DHA ratio in sleeve gastrectomy group patients also confirms the presence of a proinflammatory state in obesity.

Efficacy Comparison of Korean Ginseng and American Ginseng on Body Temperature and Metabolic Parameters

Ginseng has beneficial effects in cancer, diabetes and aging. There are two main varieties of ginseng: Panax ginseng (Korean ginseng) and Panax quinquefolius (American ginseng). There are anecdotal reports that American ginseng helps reduce body temperature, whereas Korean ginseng improves blood circulation and increases body temperature; however, their respective effects on body temperature and metabolic parameters have not been studied. We investigated body temperature and metabolic parameters in mice using a metabolic cage. After administering ginseng extracts acutely (single dose of 1000 mg/kg) or chronically (200 mg/kg/day for four weeks), core body temperature, food intake, oxygen consumption and activity were measured, as well as serum levels of pyrogen-related factors and mRNA expression of metabolic genes. Acute treatment with American ginseng reduced body temperature compared with PBS-treated mice during the night; however, there was no significant effect of ginseng treatment on body temperature after four weeks of treatment. VO 2, VCO 2, food intake, activity and energy expenditure were unchanged after both acute and chronic ginseng treatment compared with PBS treatment. In acutely treated mice, serum thyroxin levels were reduced by red and American ginseng, and the serum prostaglandin E2 level was reduced by American ginseng. In chronically treated mice, red and white ginseng reduced thyroxin levels. We conclude that Korean ginseng does not stimulate metabolism in mice, whereas a high dose of American ginseng may reduce night-time body temperature and pyrogen-related factors.

Treatment with SiMiaoFang, an Anti-Arthritis Chinese Herbal Formula, Inhibits Cartilage Matrix Degradation in Osteoarthritis Rat Model

A Chinese herbal preparation, SiMiaoFang (SMF), has been used clinically for treating arthralgia by virtue of its anti-inflammatory and pain-relieving activities. However, no evidence base links SMF to anti-osteoarthritis (OA), particularly its link to inhibiting cartilage matrix degradation. In this study, we undertook a characterization of anti-OA activity of SMF using an in vivo rat model induced by anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) together with in vitro studies with chondrocytes for further molecular characterization. ACLT+MMx rats were treated with SMF at doses of 0.63, 1.25, and 2.5 grams/kg per day for 6 weeks. SMF treatments significantly inhibited cartilage matrix degradation, as indicated by increasing proteoglycan and collagen content, particularly type II collagen expression in articular cartilage, decreasing CTX-II (collagen type II degradation marker), and increasing CPII (collagen type II synthesis marker) in circulation. Moreover, SMF suppressed synovial inflammation and inhibited release of interleukin-1β (IL-1β) and tumor necrosis factor-α in serum. The levels of serum prostaglandin E₂ and nitric oxide productions were decreased via suppression of the production of cyclooxygenase-2 and inducible nitric oxide synthase, respectively. Importantly, SMF interfered with OA-augmented expression of matrix metalloproteinases (MMPs) -3 and -13 and aggrecanases (ADAMTS) -4 and -5, which are considered to be key enzymes in cartilage matrix degradation, and simultaneously augmented OA-reduced tissue inhibitors of metalloproteinases (TIMPs) -1 and -3 expression in the joints. The largest changes in these parameters were found at the highest dose. Meanwhile, SMF significantly decreased MMP-3 and -13 and increased TIMP-1 and -3 at mRNA and protein levels in IL-1β-induced chondrocytes. These findings provide the first evidence that SMF effectively treats OA by inhibiting cartilage matrix degradation.

Oligonol Supplementation Attenuates Body Temperature and the Circulating Levels of Prostaglandin E2and Cyclooxygenase-2 After Heat Stress in Humans

Oligonol, a phenolic production from lychee, has been reported to exhibit anti-oxidative and anti-inflammatory effects. This study investigated the effect of Oligonol supplementation on circulating levels of prostaglandin E2 (PGE2) and cyclooxygenase (COX)-2, as well as body temperature, after heat stress in 17 healthy human male volunteers (age, 21.6±2.1 years). All experiments were performed in an automated climate chamber (26.0°C±0.5°C, relative humidity 60%±3.0%, air velocity less than 1 m/sec) between 2 and 5 p.m. Subjects ingested an Oligonol (100 mg)-containing beverage or placebo beverage before half-body immersion into hot water (42°C±0.5°C for 30 min). Tympanic and skin temperatures were measured and mean body temperatures were calculated. Serum concentrations of PGE2 and COX-2 were analyzed before, immediately after, and 60 min after immersion. Oligonol intake significantly prevented elevation of tympanic (temperature difference: 0.17°C at Post, P<.05; 0.17°C at Re-60, P<.05) and mean body temperatures (temperature difference: 0.18°C at Post, P<.05; 0.15°C at Re-60, P<.05), and lowered concentrations of serum PGE2 (increased by 13.3% vs. 29.6% at Post, P<.05) and COX-2 (increased by 15.6% vs. 21.8% at Post, P<.05), compared to placebo beverage. Our result suggests that Oligonol has the potential to suppress increases in body temperature under heat stress, and this is associated with decreases in serum levels of PGE2 and COX-2.

Heat acclimation affects circulating levels of prostaglandin E2, COX-2 and orexin in humans

We examined serum levels of prostaglandin E2 (PGE2), cyclooxygenase (COX)-2 and orexin before and after heat acclimation (HA) to test the hypothesis that decreased basal body temperature due to HA correlate with circulating levels of these key thermoregulatory molecules. Nine healthy human male volunteers were recruited (age, 21.9±2.7 years). The subjects were exposed to half-body immersion in hot water (42±0.5°C) at the same time of day (2–5p.m.) on alternate days for 3 weeks. The HA protocol included 10 bouts of 30min immersion. All experiments were performed in an automated climate chamber (temperature, 26.0±0.5°C; relative humidity, 60±3.0%; air velocity, <1m/s). Tympanic and skin temperatures were measured, and mean body temperature was calculated. The difference in body weight was used to estimate total sweat loss. Serum levels of PGE2, COX-2 and orexin were analyzed before and after HA. Body temperature decreased significantly (P<0.05) after HA, whereas sweat volume increased significantly (P<0.01). Serum PGE2, COX-2 and orexin concentrations decreased significantly compared to those at pre-acclimation (P<0.001, P<0.01, P<0.01, respectively). Our data suggest that decreased basal body temperature after HA is associated with decreases in thermoregulatory molecules, such as PGE2, COX-2 and orexin.

Prostaglandin E2 Increase in Pachydermoperiostosis Without 15-hydroprostaglandin Dehydrogenase Mutations

Pachydermoperiostosis (PDP), a form of primary hyper­trophic osteoarthropathy (PHO), is a rare hereditary disease diagnosed by the presence of the triad of digital clubbing, periostosis, and pachydermia (1, 2). Elevated prostaglandin E2 (PGE2) levels with cytokine­mediated tissue remodelling and vascular stimulation may underlie PHO and is associated with the features such as hyper­hidrosis, acroosteolysis, pachydermia, periostosis and arthritis (3). Homozygous and compound heterozygous germline mutations in the 15­hydroxyprostaglandin dehydrogenase (HPGD) gene encoding the major PGE2 catabolizing enzyme have been described in familial PHO cases (4). We report here a case of primary PDP with increased serum PGE2 levels that was not accompanied by HPGD mutations.CASE REPORTA 53­year­old man was referred to our hospital. He began to experience idiopathic symmetrical arthral­gias of both knees at around 20 years of age. Physical examination revealed thickened skin on the face and head, and marked clubbing of the fingers (Fig. 1a, b). No other remarkable physical findings were observed, and he did not present seborrhoea, acne, folliculitis or hyperhidrosis. Family history was non-contributory. All laboratory tests including serum levels of growth hormone, insulin­like growth factor­1, thyroid fun­ction, immunoglobulins, haemoglobin A1c, and bone mineral metabolism were within normal ranges, which ruled out thyroid acropathy and acromegaly. Magnetic resonance imaging of the head revealed cutis verticis gyrate (Fig. 1c). X-ray examination of the knee region revealed periostosis with cortical thickening and ec­topic ossification (Fig. 1d). Histology of the forehead skin revealed acanthosis in the epidermis, sebaceous and sweat gland enlargement, and mucin deposits in the dermis (Fig. 2). These findings met the diagnostic criteria of the complete form of PDP.Since it has been reported that PGE2 is a mediator of this disorder, we examined PGE2 levels using a com­mercial enzyme immunoassay kit (Cayman, Cayman Biochemical, Ann Arbor, MI, USA). Consistent with the previous reports, PGE2 levels were elevated in plasma (401 pg/ml, normal 3–12) and urinary (6,086 ng/mmol creatinine, normal < 50). Intriguingly, mutational analysis using genomic DNA that was isolated from the peripheral blood did not detect HPGD mutations.DISCUSSIONMutations in HPGD have been identified in 4 families affected with PHO and in a single family with isolated congenital nail clubbing as an autosomal­recessive trait (4, 5). Impaired metabolism of PGE2 is considered critical in the pathogenesis of PHO. However, in our case, no mutations in HPGD were detected despite the elevated PGE2 levels. These findings suggest that another contributing factor may affect the PGE2 increase. Consistent with our findings, a report exists of a familial case of autosomal­dominant isolated digital clubbing without any mutations in HPGD (6). Furthermore, Seifert et al. (7) found another mutation in PG trans­porter (PGT) encoding gene,

Effect of cyclic adenosine monophosphate and prostaglandin E2 on multinucleated giant cell formation from human monocytes in sarcoidosis

Multinucleated giant cells(MGC) are characteristic cells in granulomatous disorders and derived from monocyte-macrophage lineage cells. The exact mechanisms of MGC formation are not determined. Cyclic adenosine monophosphate(cAMP) is the intracellular second messenger for immunoregulatory mediators and plays a key role in regulation of monocyte-macrophage-mediated inflammatory responses. Here we examined the effects of cAMP on MGC formation. When monocytes were cultured with ConA-stimulated mononuclear cell supernatants(CS), MGC were formed on day 3. MGC formation was significantly suppressed by adding phosphodiesterase inhibitors(PDEI). MGC formation is a complex event involving plasma membrane receptors that are responsible for adhesion, activation and the fusion process. Monocytes cultured with CS highly expressed CD11a and CD54. The addition of PDEI decreased these expressions. Sarcoidosis is a granulomatous disorder with MGC appearance. To investigate the relevance of cAMP in sarcoidosis, we measured serum cAMP level and intracellular cAMP concentration. There was no significant difference in the serum cAMP level between healthy controls(HC) and sarcoidosis patients(SP). On the other hand, there was a significant difference in the intracellular cAMP concentration in monocytes. Because prostaglandin E2(PGE2) affected the cAMP level, we determined the localization of PGE2 in the skin lesion of sarcoidosis. PGE2 was not detectable in the sarcoidal lesion. Furthermore, there was no significant difference in the serum levels of PGE2 of HC and SP. These findings indicate that up-regulation of cAMP in human monocytes inhibited the MGC formation, suggesting that cAMP is a mediator of the granuloma formation. However, PGE2 is not related to this mechanism in sarcoidosis. JSID AbstractsJournal of Dermatological ScienceVol. 69Issue 2Preview Full-Text PDF

Abstract 5440: Upregulation of prostaglandin E2 and TGF-alpha by linoleic acid enhances pro-oncogenic signaling in models of human lung and breast cancer

Abstract The omega-6 polyunsaturated fatty acid (PUFA), linoleic acid (LA), has been reported to have adverse affects in the growth and metastasis of a variety of cancer cell models. However, there has been some controversy over how much these models relate to human disease. In the current study, a novel cascade of actions behind the LA-induced upregulation of cell proliferation has been identified. It is well established that PUFAs serves as precursors for eicosanoids, and LA supplementation was found to significantly increase the levels of Prostaglandin E2 (PGE2) in a variety of lung and breast cancer cell lines. These increases in PGE2 are associated with elevations in the activity of Cyclooxygenase-2 (COX-2), increased levels of Tumor Growth Factor-alpha (TGF-alpha) and specific pro-proliferative signaling pathways. These findings were corroborated in animal xenografts derived from the same cell lines used for the in vitro studies, with serum levels of PGE2 showing significant increases in PGE2 in animals fed diets high in LA. Moreover, the omega-3 PUFA, docosahexaenoic acid (DHA), was found to have an opposing affect on PGE2 production by upregulating Thromboxane B2 (TXB2), a stable metabolite of Thromboxane A2 (TXA2), which inhibits COX-2 activity. These findings present specific mechanisms behind the upregulation of cancer cell growth due to LA supplementation that may contribute to a resolution in determining its role in human disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5440. doi:1538-7445.AM2012-5440

δ- and γ-Tocopherols, but not α-Tocopherol, Inhibit Colon Carcinogenesis in Azoxymethane-Treated F344 Rats

The cancer preventive activity of vitamin E has been extensively discussed, but the activities of specific forms of tocopherols have not received sufficient attention. Herein, we compared the activities of δ-tocopherol (δ-T), γ-T, and α-T in a colon carcinogenesis model. Male F344 rats, seven weeks old, were given two weekly subcutaneous injections of azoxymethane (AOM) each at a dose of 15 mg/kg body weight. Starting 1 week before the AOM injection, the animals were maintained on a modified AIN76A diet, or the same diet containing 0.2% of δ-T, γ-T, α-T, or a γ-T-rich mixture of tocopherols (γ-TmT), until the termination of the experiment at 8 weeks after the second AOM injection. δ-T treatment showed the strongest inhibitory effect, decreasing the numbers of aberrant crypt foci by 62%. γ-T and γ-TmT were also effective, but α-T was not. Immunohistochemical analysis showed that δ-T and γ-T treatments reduced the levels of 4-hydroxynonenal and nitrotyrosine and the expression of cyclin D1 in the colon, preserved the expression of PPAR-γ, and decreased the serum levels of prostaglandin E2 and 8-isoprostane. Supplementation with 0.2% δ-T, γ-T, or α-T increased the respective levels of tocopherols and their side-chain degradation metabolites in the serum and colon tissues. Rather high concentrations of δ-T and γ-T and their metabolites were found in colon tissues. Our study provides the first evidence for the much higher cancer preventive activity of δ-T and γ-T than α-T in a chemically induced colon carcinogenesis model. It further suggests that δ-T is more effective than γ-T.

Modulation of nitric oxide synthesis in inflammation. Relationship to oxygen-derived free radicals and prostaglandin synthesis.

The role of nitric oxide (NO) derived from constitutive (cNOS) and inducible (iNOS) nitric oxide synthases and its relationship to oxygen-derived free radicals and prostaglandins was investigated in two models of inflammation, namely, carrageenan granuloma air pouch (acute model) and Freund's adjuvant-induced arthritis (chronic model) in rats. Inflammation was assessed by measurement of NO and prostaglandin E2 (PGE2) levels and the lysosomal leakage of the enzyme N-acetyl-B-D-glucosaminidase (NAG) into the exudate of the granuloma pouch 4 h after carrageenan injection. Evaluation of paw volume and determination of serum NO, lipid peroxide (LP), and PGE2 levels were used for the assessment of adjuvant-induced arthritis after either 4 days (early phase) or 16 days (late phase) of adjuvant injection. Results of the study showed that the administration of either NG-nitro-L-arginine methyl ester (L-NAME, non-selective cNOS/iNOS inhibitor) or aminoguanidine (AG, selective iNOS inhibitor), prior to carrageenan injection or during development of adjuvant arthritis, caused a significant reduction in NO and PGE2 levels and in the NAG activity of the granuloma inflammatory exudate, whereas decreases in paw volume and in serum NO level were noticed in the adjuvant model as related to untreated rats. Similar treatment with L-arginine failed to elaborate a significant change in the parameters measured. Other observations included: no noticeable differences between the results of early and late phases of adjuvant arthritis; no clear correlation between NO, LP and PGE2 levels in the adjuvant arthritis inflammation and inability of the NOS inhibitors to modify the levels of serum LP that is increased during adjuvant-induced arthritis. The data give further evidence that NO is implicated in the development of both acute and chronic inflammation and that NOS inhibitors have potential antiinflammatory activity. Further studies are required to unravel the mechanisms by which NO interacts with other mediators of inflammation.

Effects of Intramuscular Meloxicam Administration on Prostaglandin E2 Synthesis in the North American Bullfrog (Rana catesbeiana)

Meloxicam is a commonly used nonsteroidal anti-inflammatory drug (NSAID) in veterinary medicine, but its use in amphibians has not been reported in the literature. NSAIDs are known to act by providing anti-inflammatory and analgesic actions by inhibiting the synthesis of prostaglandin E2 (PGE2). The objective of this study was to evaluate whether the intramuscular administration of meloxicam would decrease the circulating serum PGE2 levels in the North American bullfrog (Rana catesbeiana) following tissue trauma induced by a punch biopsy. Eighteen adult North American bullfrogs were randomly assigned to two treatment groups: meloxicam (0.1 mg/kg i.m.) and control (0.9% saline i.m.). Blood was obtained via cardiocentesis immediately prior to administration of the two treatment regimes and serum was frozen. A 4-mm punch biopsy was taken from the right triceps femoris muscle to induce an inflammatory response. Twenty-four hours later, a second blood sample was collected and serum was harvested and frozen. Serum PGE2 concentrations were measured using a commercial PGE2 enzyme assay (EIA) kit. Twenty-four hours following the biopsy, the mean circulating PGE2 levels of animals treated with meloxicam was 57.79 +/- 12.35 pg/ml, which did not differ significantly from animals that were treated with saline (85.63 +/- 17.55 pg/ml, P > or = 0.05). The calculated means of the absolute change between the circulating baseline PGE2 levels and the postinjury circulating PGE2 levels were significantly lower in animals treated with meloxicam (13.11 +/- 17.31 pg/ml) than in control animals treated with saline (46.14 +/- 38.02 pg/ml) (P < or = 0.05). These results suggest that the systemic administration of meloxicam at a dosage of 0.1 mg/kg once daily suppresses circulating serum PGE2 levels postinjury in the North American bullfrog.

CHEMOMODULATORY EFFECT OFNIGELLA SATIVAAND GREEN TEA AGAINST FE-NTA-MEDIATED RENAL OXIDATIVE DAMAGE IN RAT

Ferric nitrilotriacetate (Fe-NTA) is a potent nephrotoxic agent. The present study was designed to underline the protective mechanism of Nigella sativa (NS) and green tea (GT) against Fe-NTA-induced renal damage. Fe-NTA (5 mg Fe/kg body weight, i.p.) enhanced serum urea and creatinine levels, lactate dehydrogenase and N-acetyl-β-D-glucosaminidase activities. A depletion of renal glutathione content concomitant with a reduction in the activities of antioxidant and phase II metabolizing enzymes was detected. Lipid peroxidation, γ-glutamyl transpeptidase, adenosine deaminase and xanthine oxidase activities in renal tissue were markedly increased after Fe-NTA challenge. A significant deposition of iron in kidney and induction of serum prostaglandin E2 level were associated with the enhanced oxidative damage. Pretreatment of rats with either NS oil (2 mL/kg) or GT extract (100 mg/kg) by gavage for 7 consecutive days ameliorated most of the biochemical and histopathological changes induced by Fe-NTA. In conclusion, NS and GT can serve as potent chemopreventive agents to suppress oxidant-induced tissue injury and DNA damage. PRACTICAL APPLICATION Various therapeutic effects, such as anti-inflammatory, anticancer, antidiabetic and antimicrobial effects have been described for Nigella sativa and green tea. The present study is an endeavor in the direction of determining their possible mechanism of protection in Fe-NTA-mediated renal oxidative damage in rats. Our study proved that they both exhibit a renoprotective potential and, hence. they can be used as value-added agents for managing renal diseases as well as conditions associated with oxidative overload.