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COX-2 Expression (cox-2 + expression)
Kinds of COX-2 Expression Selected AbstractsOverexpression of cyclooxygenase-2 is associated with chemoradiotherapy resistance and prognosis in esophageal squamous cell carcinoma patientsDISEASES OF THE ESOPHAGUS, Issue 8 2008W.-Z. Huang SUMMARY Our objective was to investigate whether cyclooxygenase-2 (COX-2) expression can predict the patient's response to chemoradiotherapy (CRT) and ensuing prognosis in esophageal squamous cell carcinoma (ESCC). The clinicopathological and follow-up data of 112 patients with ESCC who underwent CRT from January 2001 to June 2006 were analyzed retrospectively. The immunohistochemical expression level of COX-2 was examined for all biopsy specimens of primary tumors, and the correlation of COX-2 expression with the patient's response to CRT and prognosis was examined. COX-2 positive immunostaining was detected in 111 (99.1%) of the patients, including overexpression in 54 (48.2%) patients and low expression in 58 (51.8%) of the patients. The response of tumors with a low level expression of COX-2 (70.7%, 41/58) was significantly higher than that of tumors with COX-2 overexpression (42.6%, 23/54; P = 0.003). Patients with a low level of COX-2 expression had a higher downstaged rate than those with a high level of COX-2 expression (9/13 vs 2/8), but the difference was not statistically significant (P = 0.08). In the definitive CRT group (91 cases), COX-2 overexpression was significantly associated with poor 3-year overall survival (P = 0.028). Multivariate analysis showed that only metastatic stage (nonregional node metastasis) was an independent prognosis factor. The assessment of COX-2 status may provide additional information to identify ESCC patients with poor chances of response to CRT and potential candidates for more individualized treatment. [source] Effect of celecoxib on cyclooxygenase-2 expression and possible variants in a patient with Barrett's esophagusDISEASES OF THE ESOPHAGUS, Issue 3 2007G. A. Jacobson SUMMARY., Cyclooxygenase-2 (COX-2) expression is increased in metaplastic and dysplastic Barrett's esophageal epithelium and it is thought that selective COX-2 inhibitors could offer hope as chemoprevention therapy. The aim of the study was to investigate the in vivo effect of celecoxib on COX-2 expression in patients with Barrett's esophagus and no recent history of non-steroidal anti-inflammatory drug use. Endoscopic mucosal biopsy specimens were collected at baseline and after 28 days of therapy in a patient treated with celecoxib 200 mg twice daily. Samples were analyzed for COX-2 expression by immunoblot analysis with chemiluminescence detection. COX-2 expression was found to decline 20% and 44% at two different biopsy sites compared to the baseline sample. Longer exposures revealed a number of previously unidentified proteins above and below the 67 kDa COX-2 protein including 38 kDa and 45 kDa proteins which were present only at study completion consistent with up-regulation after celecoxib therapy. Further investigations of the 38 kDa and 45 kDa proteins were undertaken using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) with immunoblot and MALDI-TOF (matrix assisted laser desorption ionization , time of flight) analysis but no matches were found and results were inconclusive. Unmatched masses from MALDI-TOF peptide mass fingerprinting were compared with human COX-2 (67 kDa) and COX-2b (39 kDa) using unspecific cleavage. Peptide sequence homology with COX-2 and COX-2b was found for a length of 19 amino acids. Based on immunodetection, molecular weight and equivical MALDI-TOF results, one of these up-regulated proteins may be COX-2b. [source] Prediction of poor survival by cyclooxygenase-2 in patients with T4 nasopharyngeal cancer treated by radiation therapy: Clinical and in vitro studiesHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 6 2005Wen-Cheng Chen MD Abstract Background. This study was undertaken to determine the status of cyclooxygenase-2 (COX-2) in nasopharyngeal cancer (NPC) in Taiwanese patients and its relationship to survival after radiotherapy (RT). In addition, the effect of NS-398, a potent selective COX-2 inhibitor, was tested in vitro alone and in combination with radiation on NPC-BM1 human NPC cells as a prelude to using this drug along with RT in the treatment of patients with NPC. Methods. Thirty-seven patients diagnosed with T4N0,3M0 NPC were enrolled into this study. COX-2 expression was determined by immunohistochemical staining of formalin-fixed, paraffin-embedded tumor tissue. Patient survival was the clinical end point. The effects of COX-2 expression on cell survival and radioresistance was tested in vitro using the selective COX-2 inhibitor NS-398 in conjunction with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) and clonogenic assays. Results. COX-2 immunoreactivity was detected in 62% of NPC tumors, and expression levels were high in 43%. Survival analysis showed the 5-year overall survival rates for patients who had high COX-2 expression was 27% compared with 60% for those with low/absent expression (p = .047). Pattern of failure analysis showed no significant difference between high and low COX-2 expression in locoregional failure (27% vs 25%, p = .91). However, patients with N0 to N1 disease and high COX-2 expression had a significantly higher incidence of distant metastasis compared with patients with stage N0 to N1 disease and low COX-2 expression (83% vs 15%, p = .004). This difference was not observed in patients with N2 to N3 disease. This difference contributed to worse survival of patients whose tumors had high COX-2 expression levels. The selective COX-2 inhibitor NS-398 was directly cytotoxic to NPC-BM1 cells in vitro, as judged in an MTT assay (viable cells decreased from 92% to 76%, 52%, and 22%, with increases of NS-398 from 20 to 40, 60, and 80 ,M, respectively). Radiation-induced cell death was also increased by treatment with NS-398. At a 10% survival level, 40 ,M NS-398 increased radiation cytotoxicity by a factor of 1.37, whereas 60 ,M increased it by a factor of 4.9. Conclusions. COX-2 overexpression is a predictor for poor survival for advanced stage NPC. In vitro, NS-398 radiosensitizes the NPC-BM1 cell line, providing a basis for testing the combination of COX-2 inhibitors with radiation in the treatment of patients with NPC. © 2005 Wiley Periodicals, Inc. Head Neck27: XXX,XXX, 2005 [source] Enhanced Activation of Cyclooxygenase-2 Downregulates Th1 Signaling Pathway in Helicobacter pylori -infected Human Gastric MucosaHELICOBACTER, Issue 3 2007Antonia Pellicaṇ Abstract Background:, Evidence suggests that an impaired T-cell response against Helicobacter pylori plays a role in the pathogenesis of H. pylori -related diseases. Cyclooxygenase (COX) 2 has been shown to inhibit the production of T-helper (Th) 1 cytokines. This study aimed to ascertain whether COX-2 downregulates Th1 signaling pathway in human gastric mucosa colonized by H. pylori. Methods:, COX-2 expression and prostaglandin E2 (PGE2) production were determined in total proteins extracted from freshly obtained gastric biopsies of H. pylori -infected and uninfected patients by Western blotting and enzyme-linked immunosorbent assay (ELISA). Phosphorylated (p)STAT4, pSTAT1, T-bet, and pSTAT6 expression and interleukin (IL)-12, interferon (IFN)-,, and IL-4 production were also determined by Western blotting and ELISA, respectively, in total protein extracts from gastric biopsy cultures of H. pylori -infected patients treated without and with COX-2 inhibitor NS-398. Results:, Enhanced expression of COX-2 and production of PGE2 was found in H. pylori -infected compared to uninfected patients. COX-2 inhibition significantly increased expression of Th1 transcription factors along with production of IL-12 and IFN-,. By contrast, no changes in the expression of STAT6 and production of IL-4 were found. Conclusion:, This study provides a mechanism by which H. pylori may actually interfere with normal T-cell activation in human gastric mucosa, possibly enhancing its pathogenicity. The use of COX-2 selective inhibitors as immunomodulators in the course of H. pylori infection deserves investigations. [source] Impact of Helicobacter pylori Eradication Therapy on Histologic Change in the Distal EsophagusHELICOBACTER, Issue 4 2006Masanori Toyoda Abstract Background:, Although cases of reflux esophagitis (RE) developing after treatment to eradicate Helicobacter pylori have been discussed in some detail, no reports are available concerning the histologic examination of RE both before and after eradication therapy. Materials and methods:, Sixty-one patients and 111 specimens were investigated using endoscopic and histologic techniques. The histologic findings including basal zone height, papillar height, Ki-67 labeling index, and COX-2 expression before and after treatment for H. pylori infection were compared with those in normal controls and patients with endoscopic RE. Results:, Twelve months after eradication therapy, the incidence of newly developed endoscopic RE was 20% (5/25). Basal zone height and papillar height had increased at 1 month, but had returned to pretreatment levels after 12 months of eradication therapy. The Ki-67 labeling index was significantly increased 1 and 12 months after eradication therapy compared to values before treatment. COX-2 expression gradually increased after the treatment. The phenomena linked to esophagitis appeared after eradication therapy. However, the severity and extent of these signs were not so high after the treatment of H. pylori than those in patients with overt reflux esophagitis. Focusing on the patients with hiatal hernia, papillar height and Ki-67 labeling index increased significantly after eradication therapy, values being almost the same as those in the patients with endoscopic RE. Conclusions:, Hiatal hernia plays an important role in the possible occurrence of hidden RE after treatment for a H. pylori infection. [source] The Effect of Ascorbic Acid on Helicobacter pylori Induced Cyclooxygenase 2 Expression and Prostaglandin E2 Production by Gastric Epithelial Cells in vitroHELICOBACTER, Issue 1 2005Geoff V. Smith ABSTRACT Background., Cyclooxygenase 2 (COX-2) is induced by the presence of Helicobacter pylori (H. pylori) on the gastric mucosa as part of the inflammatory response; this results in the synthesis of prostaglandins that amplify the local inflammatory response. The presence of H. pylori inhibits the secretion of ascorbate into the gastric lumen. Interestingly, ascorbate inhibits the growth of H. pylori and low dietary levels are associated with an increased risk of gastric adenocarcinoma. We therefore investigated the effect of ascorbate on H. pylori mediated COX-2 induction and prostaglandin production in vitro. Methods.,H. pylori was cocultured with gastric epithelial cells in the presence of ascorbate at physiological concentrations. The expression of COX-2 was assessed by Western blotting and prostaglandin E2 (PGE2) was assessed by ELISA. Results., Ascorbate inhibited gastric cell PGE2 synthesis but not in COX-2 expression in response to H. pylori. In the absence of the organism, ascorbate also reduced PGE2 expression in cells that constitutively express COX-2, again with no reduction of COX-2 protein expression. Conclusions., Physiological concentrations of ascorbate inhibit PGE2 but not COX-2 expression in response to H. pylori in gastric epithelial cells. [source] COX-2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cellsHEPATOLOGY, Issue 3 2002Ugochukwu C. Nzeako Fas expression has been shown to negatively regulate the progression of cholangiocarcinoma cells in xenografts. However, many human cholangiocarcinomas express Fas, suggesting these cancers have developed mechanisms to inhibit Fas-mediated apoptosis. Cyclooxygenase-2 (COX-2), which generates prostanoids, is expressed by many cholangiocarcinomas. Therefore, our aim was to determine whether COX-2 expression inhibits death receptor,mediated apoptosis in KMBC cells, a cholangiocarcinoma cell line. These cells express messenger RNA for the death receptors Fas, tumor necrosis factor receptor 1 (TNF-R1), death receptor 4 (DR4), and DR5. Agonists for these death receptors, CH-11, TNF-,, and TRAIL all induced apoptosis. However, COX-2, whether induced by proinflammatory cytokines or transient transfection, only significantly inhibited Fas-mediated apoptosis. The COX-2 inhibitor NS-398 restored Fas-mediated apoptosis in COX-2 transfected cells. Prostaglandin E2 reduced apoptosis and mitochondrial depolarization after treatment with the Fas agonist CH-11. Of a variety of antiapoptotic proteins examined, COX-2/prostaglandin E2 only increased expression of Mcl-1, an antiapoptotic member of the Bcl-2 family. In conclusion, these data suggest that prostanoid generation by COX-2 specifically inhibits Fas-mediated apoptosis, likely by up-regulating Mcl-1 expression. Pharmacologic inhibition of COX-2 may be useful in augmenting Fas-mediated apoptosis of cholangiocarcinoma cells. [source] Lipoxin A4 inhibited hepatocyte growth factor-induced invasion of human hepatoma cellsHEPATOLOGY RESEARCH, Issue 9 2009Xiao-Yan Zhou Aim:, Inflammation is a critical component of tumor progression. Lipoxin A4 (LXA4) has been approved for potent anti-inflammatory properties. Recently, it was reported that LXA4 repressed the expression and activity of cyclooxygenase-2 (COX-2), which is essential for invasion. However, there are few reports dealing with its effects on cancer. To explore whether LXA4 regulate invasion, the effects of LXA4 and its receptor agonist BML-111 on hepatocyte growth factor (HGF)-induced invasion of hepatoma cells and the possible mechanisms were researched. Methods:, Lipoxin A4 receptor (ALX) expression in HepG2 cells were measured through reverse transcription polymerase chain reaction and western blot. Cytotoxicity of LXA4 and BML-111 to HepG2 cells was detected by MTT and (3H)-TdR incorporation assay. Cell migration and invasion assays were performed using a Boyden chemotaxis chamber. COX-2 expression was detected by real-time polymerase chain reaction and western blot, respectively. Moreover, the expressions of matrix metalloproteinases (MMP)-2, MMP-9, I,B, and nuclear factor-,B (NF-,B) p65 were observed via western blot, and NF-,B transcriptional activity was tested by transfections and luciferase activities assay. Results:, ALX expression was detected in HepG2 cells, and suitable concentrations of LXA4 and BML-111 had no cytotoxicity to cells. LXA4 and BML-111 inhibited HGF-induced migration and invasion; downregulated COX-2, MMP-2 and -9; restrained HGF-induced I,B, degradation, NF-,B translocation and the transcriptional activity of NF-,B in HepG2 cells. Furthermore, exogenous PGE2 could reverse the inhibitory effects of LXA4 also BML-111 on HGF-induced invasion and migration partially. Conclusion:, LXA4 inhibited HGF-induced invasion of HepG2 cells through NF-,B/COX-2 signaling pathway partially. [source] Defective arachidonate release and PGE2 production in Gi,2-deficient intestinal and colonic subepithelial myofibroblastsINFLAMMATORY BOWEL DISEASES, Issue 3 2006Robert Andrew Edwards MD Abstract Background: Mice lacking the pertussis toxin-sensitive G-protein subunit Gi,2 spontaneously develop colitis and colon cancer. In the gut, arachidonate-derived prostaglandin E2 (PGE2) modulates intestinal immune responses and epithelial restitution and is derived largely from subepithelial myofibroblasts. Methods: We tested whether known decreases in arachidonate release in cells lacking Gi,2 would result in decreased PGE2 production and tissue PGE2 levels. PGE2 levels were significantly decreased in the colon of Gi,2,/, mice. Results: Gi,2,/, myofibroblasts from the small intestine and colon both released ,50% less arachidonate and 3- to 7-fold less PGE2 and 6-keto PGF1, in response to adenosine triphosphate, thrombin, tumor necrosis factor-,, or lipopolysaccharide, in a partially cyclooxygenase (COX)-2-dependent manner. Decreased arachidonate release did not appear to be caused by a defect in cPLA2 translocation in the absence of Gi,2. Basal myofibroblast COX-1 and COX-2 expression was downregulated in Gi,2,/, cells. No differences in proliferation rates were found between serum-starved or serum-activated wild-type (WT) and Gi,2,/, myofibroblasts. Finally, treatment of Gi,2,/, mice with the EP4 -specific PGE2 receptor agonist ONO-AE1-329 significantly decreased the severity of established colitis. Conclusions: These findings confirm a requirement for Gi,2 in intestinal and colonic myofibroblast-derived prostanoid production and confirm the importance of mucosal PGE2 in the suppression of colitis. [source] Pak1 and Pak2 are activated in recurrent respiratory papillomas, contributing to one pathway of Rac1-mediated COX-2 expressionINTERNATIONAL JOURNAL OF CANCER, Issue 9 2010Rong Wu Abstract Recurrent respiratory papillomas are premalignant tumors of the airway caused by human papillomaviruses (HPVs), primarily Types 6 and 11. We had reported that respiratory papillomas overexpress the epidermal growth factor receptor (EGFR), the small GTPase Rac1 and cyclooxygenase-2 (COX-2), and have enhanced nuclear factor-,B (NF,B) activation with decreased levels of I,B-, but not I,B-,. We also showed that EGFR-activated Rac1 mediates expression of COX-2 through activation of p38 mitogen-activated protein kinase. We have now asked whether the p21-activated kinases Pak1 or Pak2 mediate activation of p38 by Rac1 in papilloma cells. Pak1 and Pak2 were constitutively activated in vivo in papilloma tissue compared with normal epithelium, and Rac1 siRNA reduced the level of both phospho-Pak1 and phospho-Pak2 in cultured papilloma cells. Reduction in Pak1 and Pak2 with siRNA decreased the COX-2 expression in papilloma cells, increased the levels of I,B-, and reduced the nuclear localization of NF-,B, but had no effect on p38 phosphorylation. Our studies suggest that Rac1 , Pak1/Pak2 , NF,B is a separate pathway that contributes to the expression of COX-2 in HPV-induced papillomas, independently of the previously described Rac1 , p38 , COX-2 pathway. [source] Selective cyclooxygenase-2 inhibitor downregulates the paracrine epithelial,mesenchymal interactions of growth in scirrhous gastric carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Masakazu Yashiro Abstract The importance of cancer-mesenchymal interactions in the aggressive behavior of scirrhous gastric cancer is supported by experimental and clinical evidences. We have previously reported that gastric fibroblasts secretion of keratinocyte growth factor (KGF) underline the remarkable proliferation of scirrhous gastric cancer cells. Cyclooxygenase-2 (COX-2) is not only expressed in cancer cells, but also in interstitial fibroblasts in gastric carcinoma. To clarify the mechanisms responsible for the antiproliferation effect of COX-2 inhibitors, effect of COX-2 inhibitor on the paracrine epithelial,mesenchymal interactions of growth was examined. Scirrhous gastric cancer cell line, OCUM-2M, gastric fibroblasts, NF-21, and COX-2 inhibitor, JTE-522, were used. Growth-interaction was examined by calculating the number of cancer cells or by measuring [3H] thymidine incorporation of cancer cells. Effect of JTE-522 on KGF expression from NF-21 cells and OCUM-2M cells was analyzed by ELISA and RT-PCR. The conditioned medium from gastric fibroblasts significantly stimulated the growth of scirrhous gastric cancer cells. JTE-522 at the concentrations of 10,5 and 10,6 M significantly decreased the growth-stimulating activity of gastric fibroblasts. JTE-522 reduced the expression of KGF mRNA and the production of KGF from gastric fibroblasts. Oral administration of JTE-522 significantly decreased the size of xenografted tumor coinoculated with OCUM-2M cells and NF-21 cells in nude mice. JTE-522 decreased COX-2 expression and Ki67 labeling index within the coinoculated tumor. These findings suggested that a selective COX-2 inhibitor, JTE-522, downregulates KGF production from gastric fibroblasts, resulting in the inhibition of paracrine epithelial,mesenchymal interactions of proliferation between scirrhous gastric cancer cells and gastric fibroblasts. © 2006 Wiley-Liss, Inc. [source] Cyclooxygenase-2 inhibitor celecoxib augments chemotherapeutic drug-induced apoptosis by enhancing activation of caspase-3 and -9 in prostate cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2005Devendra S. Dandekar Abstract Many tumors constitutively express high levels of the inducible form of proinflammatory enzyme, cyclooxygenase-2 (COX-2). Increased COX-2 expression is associated with tumor cell resistance to many cytotoxic chemotherapy drugs. Furthermore, increased resistance to cytotoxic antitumor drugs is also known to be dependent on associated stromal cells in many tumors. We investigated whether prostate tumor-associated stromal cells, marrow-derived osteoblasts, affect cytotoxicity of 2 antitumor drugs, COL-3 and docetaxel (TXTR), and whether it is dependent on COX-2 activity. We further examined whether inhibiting the activity of COX-2 negate the stroma-induced decrease in drug sensitivity in tumor cells. COX-2-specific inhibitor celecoxib (CXB) was used to inhibit COX-2 activity and associated alteration in cell death signaling was investigated. Coculturing PC-3ML cells with osteoblasts decreased the cytotoxicity of the tested antitumor drugs and was associated with increased COX-2 activity in PC-3ML cells. A significant decrease in drug-induced PGE2 increase and an increase in cytotoxicity were observed when cells were treated with COL-3 or TXTR combined with CXB. Cytotoxicity of single or combination treatment increased apoptosis, which was associated with caspase-3 and -9 activation, PARP cleavage, increased BAD protein, but decreased protein levels of XIAP and BCL- xL. Oral administration of CXB (40 mg/kg) to mice with PC-3ML tumors for 42 days increased tumor latency, decreased tumor growth and enhanced tumor control with COL-3 or TXTR. Overall, a synergistic enhancement of antitumor activity in combination treatment was observed in vitro and an additive effect in vivo. These observations suggest a potential clinical use of combined dosing of COX-2 inhibitors and cytotoxic drugs at lower, nontoxic dose than currently used to treat advanced prostate cancer. © 2005 Wiley-Liss, Inc. [source] The effect of nitric oxide on cyclooxygenase-2 (COX-2) overexpression in head and neck cancer cell linesINTERNATIONAL JOURNAL OF CANCER, Issue 5 2003Seok-Woo Park Abstract The overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) has been previously reported in head and neck squamous cell carcinoma (HNSCC), as well as in many cancers. We hypothesized that endogenous nitric oxide (NO) might increase the expression of COX-2 in cancer cells. Therefore, we investigated the cross-talk between NO and the prostaglandin (PG) pathways in HNSCC cell lines. We found that COX-2 and iNOS expressions were elevated simultaneously. On adding the NO donor, SNAP, the PGE2 level was increased 2,20 times due to increased COX-2 expression. This increase of COX-2 expression by SNAP or PMA (potent inducer of both iNOS and COX-2) was blocked to various degrees by NO scavengers and NOS inhibitors (L-NAME and 1400W). Also, the expression of COX-2 in resting cells was inhibited by NOS inhibitors. Moreover, COX-2 expression, induced by SNAP, was inhibited by ODQ, a soluble guanylate cyclase (sGC) inhibitor. The effect of dibutyryl-cGMP on COX-2 expression was similar to that of SNAP. These results imply that endogenous or exogenous NO activates sGC and that the resulting increase of cGMP induces a signaling that upregulates the expression of COX-2 in HNSCC cell lines. We also observed that NO increased COX-2 expression in different cancer cell lines, including cervic and gastric cancer cell lines. These findings further support the notion that NO can be associated with carcinogenesis through the upregulation of COX-2, and that NOS inhibitor may be also useful for cancer prevention. © 2003 Wiley-Liss, Inc. [source] A comparative study of the preventative effects exerted by three probiotics, Bifidobacterium lactis, Lactobacillus casei and Lactobacillus acidophilus, in the TNBS model of rat colitisJOURNAL OF APPLIED MICROBIOLOGY, Issue 4 2007L. Peran Abstract Aims:, The intestinal anti-inflammatory effects of three probiotics with immunomodulatory properties, Lactobacillus casei, Lactobacillus acidophilus and Bifidobacterium lactis, were evaluated and compared in the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. Methods and Results:, Colitis was induced in rats by intracolonic administration of 10 mg of TNBS dissolved in 0·25 ml of 50% ethanol. Each probiotic was administered orally (5 × 108 CFU suspended in 0·5 ml of skimmed milk) for 3 weeks, starting 2 weeks before the administration of TNBS. Colonic damage was evaluated histologically and biochemically 1 week after TNBS instillation. The results obtained revealed that all probiotics assayed showed intestinal anti-inflammatory effects, macroscopically evidenced by a significant reduction in the colonic weight/length ratio. Only B. lactis showed a lower incidence of diarrhoea in comparison with untreated rats. Biochemically, all probiotics restored colonic glutathione levels, depleted as a consequence of the oxidative stress of the inflammatory process. Bifidobacterium lactis treatment reduced colonic tumour necrosis factor (TNF)-, production, and inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) expression; L. acidophilus administration reduced colonic leukotriene B4 production and iNOS expression and L. casei intake was associated with a decrease in colonic COX-2 expression. Conclusion:, The three probiotics assayed have shown intestinal anti-inflammatory activity in the TNBS model of rat colitis, although each probiotic shows its own anti-inflammatory profile. Significance and Impact of the Study:, These probiotics could be considered as potential adjuvants in the treatment of inflammatory bowel disease, although more studies are required in order to demonstrate their efficacy in humans. [source] Bone Morphogenetic Protein 2 Induces Cyclo-oxygenase 2 in Osteoblasts via a Cbfa1 Binding Site: Role in Effects of Bone Morphogenetic Protein 2 In Vitro and In VivoJOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2005Daichi Chikazu Abstract We tested the hypothesis that induction of cyclo-oxygenase (COX) 2 mediates some effects of bone morphogenetic protein (BMP) 2 on bone. BMP-2 induced COX-2 mRNA and prostaglandin (PG) production in cultured osteoblasts. BMP-2 increased luciferase activity in calvarial osteoblasts from mice transgenic for a COX-2 promoter-luciferase reporter construct (Pluc) and in MC3T3-E1 cells transfected with Pluc. Deletion analysis identified the -300/-213-bp region of the COX-2 promoter as necessary for BMP-2 stimulation of luciferase activity. Mutation of core-binding factor activity 1 (muCbfa1) consensus sequence (5,-AACCACA-3,) at -267/-261 bp decreased BMP-2 stimulation of luciferase activity by 82%. Binding of nuclear proteins to an oligonucleotide spanning the Cbfa1 site was inhibited or supershifted by specific antibodies to Cbfa1. In cultured osteoblasts from calvariae of COX-2 knockout (-/-) and wild-type (+/+) mice, the absence of COX-2 expression reduced the BMP-2 stimulation of both ALP activity and osteocalcin mRNA expression. In cultured marrow cells flushed from long bones, BMP-2 induced osteoclast formation in cells from COX-2+/+ mice but not in cells from COX-2,/, mice. In vivo, BMP-2 (10 ,g/pellet) induced mineralization in pellets of lyophilized collagen implanted in the flanks of mice. Mineralization of pellets, measured by microcomputed tomography (,CT), was decreased by 78% in COX-2,/, mice compared with COX-2+/+ mice. We conclude that BMP-2 transcriptionally induces COX-2 in osteoblasts via a Cbfa1 binding site and that the BMP-2 induction of COX-2 can contribute to effects of BMP-2 on osteoblastic differentiation and osteoclast formation in vitro and to the BMP-2 stimulation of ectopic bone formation in vivo. [source] Thrombin induces cyclooxygenase-2 expression and prostaglandin E2 release via PAR1 activation and ERK1/2- and p38 MAPK-dependent pathway in murine macrophagesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2009Huey-Ming Lo Abstract Thrombin levels increase at sites of vascular injury and during acute coronary syndromes. It is also increased several fold by sepsis with a reciprocal decrease in the anti-thrombin III levels. In this study we investigate the effects of thrombin on the induction of cyclooxygenase-2 (COX-2) and prostaglandin (PG) production in macrophages. Thrombin-induced COX-2 protein and mRNA expression in RAW264.7 and primary cultured peritoneal macrophages. A serine proteinase, trypsin, also exerted a similar effect. The inducing effect by thrombin in macrophages was not affected by a lipopolysaccharide (LPS)-binding antibiotic, polymyxin B, excluding the possibility of LPS contamination. The increase of COX-2 expression by thrombin was functionally linked to release of PGE2 and PGI2 but not thromboxane A2 into macrophage culture medium. Thrombin-induced COX-2 expression and PGE2 production were significantly attenuated by PD98059 and SB202190 but not by SP600125, suggesting that ERK1/2 and p38 MAPK activation were involved in this process. This was supported by the observation that thrombin could directly activate ERK1/2 and p38 MAPK in macrophages. A further analysis indicated that the proteinase-activated receptor 1 (PAR1)-activating agonist induced effects similar to those induced by thrombin in macrophages and the PAR1 antagonist-SCH79797 could attenuate thrombin-induced COX-2 expression and PGE2 release. Taken together, we provided evidence demonstrating that thrombin can induce COX-2 mRNA and protein expression and PGE2 production in macrophages through PAR1 activation and ERK1/2 and p38 MAPK-dependent pathway. The results presented here may explain, at least in part, the possible contribution of thrombin and macrophages in these pathological conditions. J. Cell. Biochem. 108: 1143,1152, 2009. © 2009 Wiley-Liss, Inc. [source] Site-specific proteolysis of cyclooxygenase-2: A putative step in inflammatory prostaglandin E2 biosynthesisJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2007Arturo Mancini Abstract Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in inflammatory prostanoid biosynthesis. Transcriptional, post-transcriptional, and post-translational covalent modifications have been defined as important levels of regulation for COX-2 gene expression. Here, we describe a novel regulatory mechanism in primary human cells involving regulated, sequence-specific proteolysis of COX-2 that correlates with its catalytic activity and ultimately, the biosynthesis of prostaglandin E2 (PGE2). Proinflammatory cytokines induced COX-2 expression and its proteolysis into stable immunoreactive fragments of 66, 42,44, 34,36, and 28 kDa. Increased COX-2 activity (PGE2 release) was observed coincident with the timing and degree of COX-2 proteolysis with correlation analysis confirming a linear relationship (R2,=,0.941). Inhibition of induced COX-2 activity with non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 selective inhibitors also abrogated cleavage. To determine if NSAID inhibition of proteolysis was related to drug-binding-induced conformational changes in COX-2, we assayed COX-inactive NSAID derivatives that fail to bind COX-2. Interestingly, these compounds suppressed COX-2 activity and cleavage in a correlated manner, thus suggesting that the observed NSAID-induced inhibition of COX-2 cleavage occurred through COX-independent mechanisms, presumably through the inhibition of proteases involved in COX-2 processing. Corroborating this observation, COX-2 cleavage and activity were mutually suppressed by calpain/cathepsin protease inhibitors. Our data suggest that the nascent intracellular form of COX-2 may undergo limited proteolysis to attain full catalytic capacity. J. Cell. Biochem. 101: 425,441, 2007. © 2006 Wiley-Liss, Inc. [source] ,2,1 integrin signalling enhances cyclooxygenase-2 expression in intestinal epithelial cellsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2006Oliver Jay Broom Inflammatory bowel diseases (IBD) are linked to an increased risk of developing colon cancer, by inflammatory mediators and alterations to the extracellular matrix (ECM). The events induced by inflammatory mediators lead to dysregulated activation and induction of inflammatory genes such as cyclooxygenase-2 (COX-2). COX-2 is involved in the conversion of arachidonic acid to biologically active prostanoids and is highly upregulated in colon cancer. Since inflammation-induced changes to the extracellular matrix could affect integrin activities, we here investigated the effect of integrin signalling on the level of COX-2 expression in the non-transformed intestinal epithelial cell lines, Int 407 and IEC-6. Adhesion of these cells to a collagen I- or IV-coated surface, increased surface expression of ,2,1 integrin. Activation of integrins with collagen caused an increased cox-2 promoter activity, with a subsequent increase in COX-2 expression. The signalling cascade leading to this increased expression and promoter activity of cox-2, involves PKC,, the small GTPase Ras and NF,B but not Erk1/2 or Src activity. The integrin-induced increase in cellular COX-2 activity is responsible for an elevated generation of reactive oxygen species (ROS) and increased cell migration. This signalling pathway suggests a mechanism whereby inflammation-induced modulations of the ECM, can promote cancer transformation in the intestinal epithelial cells. J. Cell. Physiol. 209: 950,958, 2006. © 2006 Wiley-Liss, Inc. [source] Reduction of intracellular pH inhibits constitutive expression of Cyclooxygenase-2 in human colon cancer cellsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2004Daniela Pirkebner Cyclooxygenase-2 (COX-2) over-expression is critically involved in tumor formation. Intracellular pH (pHi) has been shown to be alkaline in cancer cells, and to be an important trigger for cell proliferation. This study therefore analyzed the relationship between pHi and COX-2 expression. HRT-18 and Caco-2 cells cultured in medium with bicarbonate maintained a pHi of ,7.6, which is higher than that of non-neoplastic cells. Cells grown in bicarbonate-free medium with a pH at 6.8 showed a reduction in pHi to approximately 7.0. Importantly, reduction of pHi resulted in a complete inhibition of COX-2 mRNA and protein expression. When cells were grown in bicarbonate-supplemented medium at pH 6.8, pHi maintained at ,7.6 and COX-2 expression was not inhibited. Additionally, analysis utilizing protein synthesis inhibitor cycloheximide demonstrated that pHi mediated inhibition of COX-2 mRNA expression requires de novo protein synthesis of regulatory protein(s). These data strongly suggest that an alkaline pHi is an important trigger for constitutive COX-2 expression. Defining pHi -mediated mechanisms that govern the constitutive COX-2 expression may help in developing new strategies to block COX-2 over-expression in cancer cells. J. Cell. Physiol. 198: 295,301, 2004© 2003 Wiley-Liss, Inc. [source] Expression of retinoic acid receptor , in dermatofibrosarcoma protuberansJOURNAL OF CUTANEOUS PATHOLOGY, Issue 11 2009Zhou Xiaoli Background:, Retinoic acid receptor , (RAR ,) has been shown to act as a tumor suppressor in many solid human tumors. To investigate the putative role of RAR , in dermatofibrosarcoma protuberans (DFSP), we examined the expression of RAR , in DFSPs and analyzed the correlation of expression patterns between RAR , and cyclooxygenase (COX)-2 as well as clinicopathological variables. Methods:, Using tissue microarray and immunohistochemistry, we evaluated nuclear RAR , staining and cytoplasm COX-2 staining in 53 DFSPs. Results:, 48 DFSPs (90.58%) were immunopositive for RAR ,, while 32 DFSPs (60.38%) were immunopositive for COX-2. RAR , staining was significantly inversely correlated with COX-2 staining (p < 0.001; r =,0.668). Conclusions:, Our data indicated that RAR , expressed in DFSPs and correlated with COX-2 expression. RAR , may be a potential therapeutic target for unresectable DFSP cases. [source] Effect of Helicobacter pylori infection on cyclooxygenase-2 expression in gastric antral mucosaJOURNAL OF DIGESTIVE DISEASES, Issue 2 2002Hong LU OBJECTIVE: Helicobacter pylori infection is a major etiological cause of chronic gastritis. Inducible cyclooxygenase (COX-2) is an important regulator of mucosal inflammation. Recent studies indicate that expression of COX-2 may contribute to gastrointestinal carcinogenesis. The aim of this study was to investigate the effects of H. pylori infection and eradication therapy on COX-2 expression in gastric antral mucosa. METHODS: Antral biopsies were taken from 46 H. pylori- infected patients, who also had chronic gastritis, both before and after anti- H. pylori treatment. The COX-2 protein was stained by using immunohistochemical methods and COX-2 expression was quantified as the percentage of epithelial cells expressing COX-2. Gastritis and H. pylori infection status were graded according to the Sydney system. RESULTS: Cyclooxygenase-2 expression was detected in the cytoplasm of gastric antral epithelial cells both before and after the eradication of H. pylori. Cyclooxygenase-2 expression in mucosa with H. pylori infection was compared with the corresponding mucosa after successful H. pylori eradication (20.1 ± 13.1%vs 13.8 ± 5.9%; P < 0.05). At the same time, COX-2 expression in H. pylori -infected mucosa was compared with the normal controls (18.0 ± 14.1%vs 12.3 ± 4.6%, P < 0.05). Expression of COX-2 was correlated with the degree of chronic inflammation (r= 0.78, P < 0.05). CONCLUSIONS: Our results showed that H. pylori infection leads to gastric mucosal overexpression of COX-2 protein, suggesting that the enzyme is involved in H. pylori -related gastric pathology in humans. [source] Role of cyclooxygenase-2 and inducible nitric oxide synthase in pancreatic cancerJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 8 2002Gu Kong Abstract Background and Aim: Recently, it has been recognized that both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) produce important endogenous factors of human tumor progression. However, the clinicopathological and biological significance of the expression of COX-2 and iNOS in pancreatic cancer remains unclear. The objective of this study is to find the possible roles and clinical significance of COX-2 and iNOS expression in pancreatic cancer. Methods: Seventy-two pancreatic adenocarcinoma tissue specimens were obtained through surgical resection. We investigated the immunohistochemical expression of COX-2 and iNOS in respect to variable clinicopathological characteristics, proliferation activity (by Ki-67 expression), apoptosis (by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling stain), and microvessel density (by CD34 expression; angiogenesis). Results: Immunohistochemical investigations demonstrated immunolabeling of tumor cells with the primary antibodies, bovine anti-iNOS and anti-COX-2 antibodies. The COX-2 and iNOS positive rates were 41.7 and 66.7%, respectively. There was significant correlation between positive COX-2 and positive iNOS expression (P = 0.043). The proliferation index (Ki-67 labeling index) was higher in COX-2 positive specimens compared to COX-2 negative specimen (P = 0.015). The apoptotic index of positive iNOS expressions was significantly higher than negative expressions (P < 0.001). The expression of COX-2 and iNOS proteins did not correlate with age, sex, serum bilirubin, CA-19,9, location, size, American Joint Committee on Cancer stage, differentiation, distant metastasis, patient survival, or microvessel density. Conclusions: Although the pattern of positive expression was similar in both enzymes, the effect on tumor progression differed; iNOS expression may play a role in apoptosis of tumor cell, while COX-2 expression may contribute to tumor proliferation. However, COX-2 and iNOS expression is not related to prognosis in patients with pancreatic cancer. © 2002 Blackwell Publishing Asia Pty Ltd [source] Synthesis of [11C]celecoxib: a potential PET probe for imaging COX-2 expressionJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 12 2005Jaya Prabhakaran Abstract [11C]Labeling of celecoxib, a COX-2 selective inhibitor and prescription drug for arthritis and pain has been achieved. The precursor molecule for the radiolabeling was synthesized from 4-bromoacetophenone in 4 steps with 23% overall yield. Stille reaction of N-[bis -(4-methoxyphenyl)phenylmethyl]-4-[5-(4-tributylstannylphenyl)-3-trifluoromethylpyrazol-1-yl]benzenesulfonamide (5) with methyl iodide in presence of catalytic amounts of Pd2(dba)3, tri- o -tolylphosphine, CuCl and excess of K2CO3 in DMF followed by deprotection of the sulfonamide with 20% trifluoroaceticacid yielded 4-(5- p -tolyl-3-trifluoromethylpyrazol-1-yl)benzenesulfonamide or celecoxib (6) in 30% yield. However, under identical conditions, synthesis of [11C]celecoxib ([11C]6) was unsuccessful. Instead, trapping [11C]CH3I in an argon purged solution of catalytic amounts of Pd2(dba)3 and tri- o -tolylphosphine followed by the addition of the precursor 5 in DMF under argon and heating the mixture at 135°C for 4 min resulted in the incorporation of [11C]CH3 group. Removal of the dimethoxytrityl (DMT) with 20% trifluoroacetic acid afforded [11C]celecoxib in 40 min (EOB) and 8±2% yield (EOB) along with a specific activity of 1080±180 Ci/mmol (n=6) (EOB). Copyright © 2005 John Wiley & Sons, Ltd. [source] Triptolide inhibits COX-2 expression and PGE2 release by suppressing the activity of NF-,B and JNK in LPS-treated microgliaJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Yuntao Gong Abstract Activated microglia participate in neuroinflammation which contributes to neuronal damage in neurodegenerative diseases. Inhibition of microglial activation may have potential anti-inflammatory effects. Our laboratory has previously reported that triptolide, a natural biologically active compound extracted from Tripterygium wilfordii, could protect dopaminergic neurons from inflammation-mediated damage. However, the mechanism by which triptolide inhibits inflammation remains unknown. We reported here that inhibition of prostaglandin E2 (PGE2) production could be a potential mechanism of triptolide to suppress inflammation. Triptolide suppressed c- jun NH2-terminal kinase (JNK) phosphorylation, cyclooxygenase 2 (COX-2) expression and PGE2 production in microglial cultures treated with lipopolysaccharide (LPS). Triptolide also greatly inhibited the transcriptional activity, but not the DNA-binding activity of nuclear factor-,B (NF-,B) in microglia following LPS stimulation. These results indicate that triptolide might suppress NF-,B activity to down-regulate COX-2 expression. The LPS-stimulated transcriptional activity of NF-,B was suppressed by inhibition of p38MAPK, but not by that of JNK and extracellular signal-regulated kinase. Furthermore, the LPS-induced PGE2 production was reduced by inhibiting these kinases. Taken together, these results suggest that triptolide may suppress neuroinflammation via a mechanism that involves inactivation of two parallel signaling pathways: p38-NF-,B-COX-2-PGE2 and JNK-PGE2. [source] Interleukin-1, Induces Cyclooxygenase-2 and Prostaglandin E2 Synthesis in Human Neuroblastoma CellsJOURNAL OF NEUROCHEMISTRY, Issue 5 2000Involvement of p38 Mitogen-Activated Protein Kinase, Nuclear Factor- Abstract: Prostaglandins (PGs), which are generated by the enzymatic activity of cyclooxygenase (COX)-1 and -2, modulate several functions in the CNS such as the generation of fever, the sleep/wake cycle, and the perception of pain. Moreover, the neuronal induction of COX-2 has been linked to neuroinflammatory aspects of Alzheimer's disease (AD). The regulation of COX expression in neuronal cells is only partly understood and has been mainly linked to synaptic activity. In pathophysiological situations, however, cytokines may be potent stimulators of neuronal COX expression. Here we show that interleukin (IL)-1, induces COX-2 mRNA and protein synthesis and the release of PGE2 in the human neuroblastoma cell line SK-N-SH. We further demonstrate that both a free radical scavenger and an inhibitor of p38 mitogen-activated protein kinase (MAPK) reduce IL-1,-induced synthesis of COX-2. IL-1, induces p38 MAPK phosphorylation and activation of the nuclear factor-,B independently from each other. Our data suggest that IL-1,-induced COX-2 expression in SK-N-SH cells is regulated by different mechanisms, presumably involving mRNA transcription and mRNA stability. The ability of p38 MAPK to augment COX-2 expression in human neuroblastoma cells, as shown here, suggests that p38 MAPK may be involved in neuronal expression of COX-2 in AD. [source] Lipopolysaccharides enhance the action of bradykinin in enteric neurons via secretion of interleukin-1, from enteric glial cellsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 9 2009Matsuka Murakami Abstract Functional changes of the enteric nervous system have been observed under inflammatory states of inflammatory bowel disease increasing the endotoxin level. The aim of the present study was to determine the effect of lipopolysaccharides (LPS) on myenteric neuron,glia interaction in vitro. We examined the increase of the intracellular Ca2+ concentration ([Ca2+]i) and the release of interleukin-1, (IL-1,) or prostaglandin E2 (PGE2) and COX-2 expression in myenteric plexus cells from the rat intestine induced by LPS. LPS potentiated BK-induced [Ca2+]i increases in both myenteric neurons and enteric glial cells, which were suppressed by a B1R antagonist. Only in enteric glial cells, a B1R agonist increased [Ca2+]i. The effects of LPS were blocked by pretreatment with an interleukin-1 receptor antagonist or by reducing the density of enteric glial cells in culture. LPS prompted the release of IL-1, from enteric glial cells. The augmenting effects of IL-1, on the BK-induced neural [Ca2+]i increase and PGE2 release from enteric glial cells were abolished by a phospholipase A2 (PLA2) inhibitor and a COX inhibitor, and partly suppressed by a COX-2 inhibitor. IL-1, up-regulated the COX-2 expression in enteric glial cells. LPS promotes IL-1, secretion from enteric glial cells, resulting in augmentation of the neural response to BK through PGE2 release via glial PLA2 and COX-2. The alteration of the regulatory effect of glial cells may be the cause of the changes in neural function in the enteric nervous system in inflammatory bowel disease. © 2009 Wiley-Liss, Inc. [source] The expression of cyclooxygenase-2 in human temporomandibular joint samples: an immunohistochemical studyJOURNAL OF ORAL REHABILITATION, Issue 12 2002H. Yoshida summary, The aim of this investigation was to evaluate the immunohistochemical expression of cyclooxygenase-2 (COX-2) in the temporomandibular joint (TMJ) and to compare it with that control specimens. Expression of COX-2 in the TMJ disc and the synovial membrane in 26 human TMJ samples (internal derangement of TMJ; n=16, and control; n=10) was measured by an immunohistological technique using paraffin-embedded tissue and specific antihuman COX-2 polyclonal antibody. There were obvious distinction of COX-2 immunoreactivity between the control specimens and internal derangement cases, in the region of posterior and/or anterior loose connective tissues. In particular, intensive COX-2 expression was detected in the synovial membrane of internal derangement cases. The findings of the present study suggest that COX-2 might be an important mechanism regulating inflammation in the synovial membrane with internal derangement of TMJ. [source] Aging stimulates cyclooxygenase-2 expression and prostaglandin E2 production in human periodontal ligament cells after the application of compressive forceJOURNAL OF PERIODONTAL RESEARCH, Issue 1 2007Kotoe Mayahara Background and Objectives:, Some clinical studies show that alveolar crestal bone loss is higher in adults than in young patients during orthodontic treatment, but the causes of such a phenomenon have not been elucidated. It is known that prostaglandin E2 (PGE2) is a proinflammatory agent and one of the potent osteoclast-inducing factors, and is produced by human periodontal ligament cells in response to orthodontic force. The aim of this study was to investigate age-related change in the biosynthetic capacity of PGE2 and its regulatory gene, cyclooxygenase 2 (COX-2) from periodontal ligament cells in response to mechanical stress. Methods:, Compressive force of 2 g/cm2 was applied for 3,48 h to periodontal ligament cells obtained from human donors aged 9,50 years, and COX-2 mRNA expression in and PGE2 production by the periodontal ligament cells in response to the compressive force were examined. Results:, Application of a compressive force of 2 g/cm2 for 3,48 h significantly stimulated these factors in both time- and age-dependent manners. Furthermore, these increases were dramatically larger in periodontal ligament cells obtained from donors over the age of 35. Conclusions:, Periodontal ligament cells obtained from old donors have significantly greater COX-2 expression and PGE2 production in response to compressive force than those from younger donors. The turning point of aging, where significantly larger amounts of theses factors begin production, appears to be around the age of 35. These results may be positively related to the acceleration of alveolar crestal bone loss during orthodontic treatment in adult patients. [source] Bis-(3-hydroxyphenyl) diselenide inhibits LPS-stimulated iNOS and COX-2 expression in RAW 264.7 macrophage cells through the NF- kB inactivationJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2009Kyung-Min Shin Abstract Objectives Previously, we reported that diaryl diselenide compounds have strong inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophages. In this study, we investigated the molecular mechanisms underlying NO suppression and prostaglandin E2 (PGE2) production by diaryl diselenide compounds, bis-(2-hydroxyphenyl) diselenide (DSE-A), bis-(3-hydroxyphenyl) diselenide (DSE-B), bis-(4-hydroxyphenyl) diselenide (DSE-C), dipyridyl diselenide (DSE-D) and diphenyl diselenide (DSE-E). Methods The effect of these compounds on NO suppression and PGE2 production was investigated in RAW 264.7 macrophages. Key findings Our data indicate that of the above, DSE-B most potently inhibits NO and PGE2 production, and that it also significantly reduces the releases of tumour necrosis factor (TNF)-,, interleukin(IL)-1, and IL-6. Consistent with these observations, DSE-B also reduced the protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and the mRNA levels of iNOS, COX-2, TNF-,, IL-1, and IL-6. Furthermore, DSE-B inhibited LPS-induced nuclear factor-,B (NF-,B) activation, which was associated with the prevention of the inhibitor ,B-, (I,B-,) degradation and a subsequent reduction in nuclear p65 protein levels. Conclusions Taken together, our data suggest that the anti-inflammatory properties of DSE-B are due to reduction in the expression of iNOS, COX-2, TNF-,, IL-1, and IL-6 through the down-regulation of NF-,B binding activity. [source] Byakangelicol, isolated from Angelica dahurica, inhibits both the activity and induction of cyclooxygenase-2 in human pulmonary epithelial cellsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2002C. H. Lin ABSTRACT We examined the inhibitory mechanism of byakangelicol, isolated from Angelica dahurica, on interleukin-1, (IL-1,)-induced cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) release in human pulmonary epithelial cell line (A549). Byakangelicol (10,50 ,m) concentration-dependently attenuated IL-1,-induced COX-2 expression and PGE2 release. The selective COX-2 inhibitor, NS-398 (0.01,1 ,m), and byakangelicol (10,50 ,m) both concentration-dependently inhibited the activity of the COX-2 enzyme. Byakangelicol, at a concentration up to 200 ,m, did not affect the activity and expression of COX-1 enzyme. IL-1,-induced p44/42 mitogen-activated protein kinase (MAPK) activation was inhibited by the MAPK/extracellular signal-regulated protein kinase (MEK) inhibitor, PD 98059 (30 ,m), while byakangelicol (50 ,m) had no effect. Treatment of cells with byakangelicol (50 ,m) or pyrrolidine dithiocarbamate (PDTC; 50 ,m) partially inhibited IL-1,-induced degradation of 1,B-, in the cytosol, translocation of p65 NF-,B from the cytosol to the nucleus and the NF-,B-specific DNA-protein complex formation. Taken together, we have demonstrated that byakangelicol inhibits IL-1,-induced PGE2 release in A549 cells; this inhibition may be mediated by suppression of COX-2 expression and the activity of COX-2 enzyme. The inhibitory mechanism of byakangelicol on IL-1,-induced COX-2 expression may be, at least in part, through suppression of NF-,B activity. Therefore, byakangelicol may have therapeutic potential as an anti-inflammatory drug on airway inflammation. [source] | |||||||||||||||||||||||||||||||||||||