Exploration of cyclooxygenase-2 inhibitory peptides from walnut dreg proteins based on in silico and in vitro analysis

Walnut dreg protein hydrolysates(WDPHs)exhibit a variety of biological activities,however,the cyclooxygenase-2(COX-2)inhibitory peptide of WDPHs remain unclear.The aim of this study was to rapidly screen for such peptides in WDPHs through a combination of in silico and in vitro analysis.In total,1262 peptide sequences were observed by nano liquid chromatography/tandem mass spectrometry(nano LC-MS/MS)and 4 novel COX-2 inhibitory peptides(AGFP,FPGA,LFPD,and VGFP)were identified.Enzyme kinetic data indicated that AGFP,FPGA,and LFPD displayed mixed-type COX-2 inhibition,whereas VGFP was a non-competitive inhibitor.This is mainly because the peptides form hydrogen bonds and hydrophobic interactions with residues in the COX-2 active site.These results demonstrate that computer analysis combined with in vitro evaluation allows for rapid screening of COX-2 inhibitory peptides in walnut protein dregs.

Lafoensia pacari alleviates intestinal damage by modulating cyclooxygenase-2:In silico and in vivo evaluation in a colitis model

BACKGROUND Inflammatory bowel diseases(IBD)are a worldwide health problem and mainly affect young people,consequently affecting the workforce.Available treatments are often associated with side effects,and new therapeutic options are needed.For centuries,plants have represented important substrates in the field of drug development.Lafoensia pacari(L.pacari)is a plant whose pharmaceutical potential has been described,and may have biological activity relevant to the treatment of IBD symptoms.AIM To investigate the activity of keto-alcoholic extracts of L.pacari with respect to ameliorating the inflammatory and nociceptive symptoms of acute experimental colitis in mice.METHODS Keto-alcoholic extracts of L.pacari leaves and bark were administered to male andfemale Swiss mice weighing 25 g to 30 g(n=8 male mice and n=8 female mice).The effect of these extracts was observed in an acetic acid-induced acute experimental model of colitis with regard to antinociception/analgesia and inflammatory tissue damage.Recorded macroscopic indices included the Wallace score and the colon weight obtained using a precision scale.Mechanical hyperalgesia was determined using an electronic analgesimeter.Behavior related to overt pain was determined by quantifying the number of writhing instances within 20 min of administration of acetic acid.Molecular docking was performed using human and murine cyclooxygenase-2(COX-2)with 3 flavonoids(ellagic acid,kaempferol,and quercetin)on the AutoDock Vina software.Analysis of variance followed by Tukey’s posttest was used with P<0.05 indicating significance.RESULTS In this murine model of colitis,administration of extracts from L.pacari ameliorated acetic acidinduced writhing and colitis-associated inflammatory pain.These improvements may be attributable to the reduction in edema,inflammation(e.g.,ulcers,hyperemia,and bowel wall damage),and the intensity of abdominal hyperalgesia.The keto-alcoholic extracts of L.pacari leaves and bark administered at a dose of either 100 mg/kg or 300 mg/kg significantly reduced the number of writhing events when compared to the negative control(P<0.05).Additionally,extracts of L.pacari bark also performed better than Dipyrone.Leaf extracts administered at 10 mg/kg,30 mg/kg,and 100 mg/kg and bark extracts administered at 30 mg/kg significantly reduced or prevented the development of edema in the colon of treated mice,while mesalazine did not.Moreover,using molecular docking,we observed that the flavonoids present in L.pacari extracts bind to COX-2,an event not unique to ellagic acid.CONCLUSION The results of this study demonstrate a potential novel application of L.pacari extracts for the reduction of inflammation and promotion of antinociception/analgesia as demonstrated by our findings in a murine model of colitis.These findings were also corroborated by in silico analyses,and suggest that L.pacari extracts may be a promising therapeutic agent in the treatment of IBD.

Clinical implications of forkhead box M1, cyclooxygenase-2, and glucose-regulated protein 78 in breast invasive ductal carcinoma

BACKGROUND Breast infiltrating ductal carcinoma(BIDC)represents the largest heterotypic tumor group,and an in-depth understanding of the pathogenesis of BIDC is key to improving its prognosis.AIM To analyze the expression profiles and clinical implications of forkhead box M1(FOXM1),cyclooxygenase-2(COX-2),and glucose-regulated protein 78(GRP78)in BIDC.METHODS A total of 65 BIDC patients and 70 healthy controls who presented to our hospital between August 2019 and May 2021 were selected for analysis.The peripheral blood FOXM1,COX-2,and GRP78 levels in both groups were measured and the association between their expression profiles in BIDC was examined.Additionally,we investigated the diagnostic value of FOXM1,COX-2,and GRP78 in patients with BIDC and their correlations with clinicopathological features.Furthermore,BIDC patients were followed for 1 year to identify factors influencing patient prognosis.RESULTS The levels of FOXM1,COX-2,and GRP78 were significantly higher in BIDC patients compared to healthy controls(P<0.05),and a positive correlation was observed among them(P<0.05).Receiver operating characteristic analysis demonstrated that FOXM1,COX-2,and GRP78 had excellent diagnostic value in predicting the occurrence of BIDC(P<0.05).Subsequently,we found significant differences in FOXM1,COX-2,and GRP78 levels among patients with different histological grades and metastasis statuses(with vs without)(P<0.05).Cox analysis revealed that FOXM1,COX-2,GRP78,increased histological grade,and the presence of tumor metastasis were independent risk factors for prognostic death in BIDC(P<0.001).CONCLUSION FOXM1,COX-2,and GRP78 exhibit abnormally high expression in BIDC,promoting malignant tumor development and closely correlating with prognosis.These findings hold significant research implications for the future diagnosis and treatment of BIDC.

Expression of Cyclooxygenase-2 in Nasopharyngeal Carcinoma and Its Relation to Angiogenesis and Prognosis

Objective： The purpose of this study was to evaluate cyclooxygenase-2 （COX-2） expression in nasopharyngeal carcinoma （NPC） and its correlation with clinicopathologic features, angiogenesis, and prognosis. Methods： The expressions of COX-2 and vascular endothelial growth factor （VEGF） and microvascular density （MVD） were determined with immunohistochemical methods in eighty-six NPC patients followed up over 5 years. Results： Sixty-three tumors （73.3%） were classified as COX-2 positive. COX-2 expression was positively related to VEGF expression （r=0.438, P〈0.01） and correlated with the tumor pathological grade, extent of primary lesion, lymph node metastasis, distant metastasis and shorter survival. Conclusion： Our results suggest that COX-2, being highly expressed and strongly correlated with angiogenesis in nasopharyngeal carcinoma, is apt to be used as a predictor of prognosis, including local recurrence and distant metastasis.

Role of cyclooxygenase-2 in gastric cancer development and progression

Although the incidence of gastric cancer has been declining in recent decades,it remains a major public health issue as the second leading cause of cancer death worldwide.In China,gastric cancer is still the main cause of death in patients with malignant tumors.Most patients are diagnosed at an advanced stage and mortality is high.Cyclooxygenase-2(COX-2)is a ratelimiting enzyme in prostanoid synthesis and plays an important role in the development and progression of gastric cancer.The expression of COX-2 in gastric cancer is upregulated and its molecular mechanisms have been investigated.Helicobacter pylori infection,tumor suppressor gene mutation and the activation of nuclear factor-kappa B may be responsible for the elevated expression of COX-2 in gastric cancer.The mechanisms of COX-2 in the development and progression of gastric cancer are probably through promoting the proliferation of gastric cancer cells,while inhibiting apoptosis,assisting angiogenesis and lymphatic metastasis,and participating in cancer invasion and immunosuppression.This review is intended to discuss,comment and summarize recent research progress on the role of COX-2 in gastric cancer development and progression,and elucidate the molecular mechanisms which might be involved in the carcinogenesis.

Role of cyclooxygenase-2 in the carcinogenesis of gastrointestinal tract cancers: A review and report of personal experience

Selective cyclooxygenase （COX）-2 inhibitors （coxibs） were developed as one of the anti-inflammatory drugs to avoid the various side effects of non-steroidal anti-inflammatory drugs （NSAIDs）. However, coxibs also have an ability to inhibit tumor development of various kinds the same way that NSAIDs do. Many experimental studies using cell lines and animal models demonstrated an ability to prevent tumor proliferation of COX-2 inhibitors. After performing a randomized study for polyp chemoprevention study in patients with familial adenomatous polyposis （FAP）, which showed that the treatment with celecoxib, one of the coxibs, significantly reduced the number of colorectal polyps in 2000, the U.S. Food and Drug Administration （FDA） immediately approved the clinical use of celecoxib for FAP patients. However, some coxibs were recently reported to increase the risk of serious cardiovascular events including heart attack and stroke. In this article we review a role of COX-2 in carcinogenesis of gastrointestinal tract, such as the esophagus, stomach and colorectum, and also analyze the prospect of coxibs for chemoprevention of gastrointestinal tract tumors.

Tumor cyclooxygenase-2 levels correlate with tumor invasiveness in human hepatocellular carcinoma

ABM: Recent studies suggested that cyclooxygenase-2 (COX-2) enhances tumor angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Although COX-2 expression has been demonstrated in hepatocellular carcinoma (HCC), the significance of COX-2 in progression of HCC remains unclear. This study evaluated the clinico-pathological correlation of COX-2 level and its relationship with VEGF level in HCC. METHODS: Fresh tumor tissues were obtained from 100 patients who underwent resection of HCC. COX-2 protein expression was examined by immunohistochemistry, and quantitatively by an enzyme immunometric assay (EIA) of tumor cytosolic COX-2 levels. Tumor cytosolic VEGF levels were measured by an ELISA. RESULTS: Immunostaining showed expression of COX-2 in tumor cells. Tumor cytosolic COX-2 levels correlated with VEGF levels (r = 0.469,P<0.001). Correlation with clinicopathological features showed significantly higher tumor cytosolic COX-2 levels in the presence of multiple tumors (P = 0.027), venous invasion (P = 0.030), microsatellite lesions (P=0.037) and advanced tumor stage (P = 0.008). Higher tumor cytosolic COX-2 levels were associated with worse patient survival. CONCLUSION: This study shows that elevated tumor COX-2 levels correlate with elevated VEGF levels and invasiveness in HCC, suggesting that COX-2 plays a significant role in the progression of HCC.

Immunoexpression of cyclooxygenase-2 in primary gastric carcinomas and lymph node metastases

AIM: To evaluate immunoexpression of cyclooxygenase-2 (COX-2) in primary gastric carcinomas and respective lymph node metastases. METHODS: Immunohistochemistry to analyze COX-2 expression was performed on tissue microarray slices obtained from 36 specimens of gastrectomy and satellite lymph nodes from patients with gastric carcinoma. RESULTS: Immunostaining was seen in most cases, and COX-2 expression was higher in lymph node me-tastases than in corresponding primary gastric tumors of intestinal, diffuse and mixed carcinomas, with a statistically signif icant difference in the diffuse histotype (P = 0.0108). CONCLUSION: COX-2 immunoexpression occurs frequently in primary gastric carcinomas, but higher expression of this enzyme is observed in lymph node metastases of the diffuse histotype.

Helicobacter pylori infection, gastrin and cyclooxygenase-2 in gastric carcinogenesis

Gastric cancer is one of the most frequent neoplasms and a main cause of death worldwide, especially in China and Japan. Numerous epidemiological, animal and experimental studies support a positive association between chronic Helicobacter pylori(H. pylori) infection and the development of gastric cancer. However, the exact mechanism whereby H. pylori causes gastric carcinogenesis remains unclear. It has been demonstrated that expression of cyclooxygenase-2(COX-2) is elevated in gastric carcinomas and in their precursor lesions. In this review, we present the latest clinical and experimental evidence showing the role of gastrin and COX-2 in H. pylori-infected patients and their possible association with gastric cancer risk.

Cyclooxygenase-2 and the inflammogenesis of breast cancer

Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that constitutive overexpression of cyclooxygenase-2(COX-2) is a ubiquitous driver of mammary carcinogenesis, and reciprocally, that COX-2 blockade has strong potential for breast cancer prevention and therapy. Key findings include the following:(1) COX-2 is constitutively expressed throughout breast cancer development and expression intensifies with stage at detection, cancer progression and metastasis;(2) essential features of mammary carcinogenesis(mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis and immunosuppression) are linked to COX-2-driven prostaglandin E2(PGE-2) biosynthesis;(3) upregulation of COX-2 and PGE-2 expression induces transcription of CYP-19 and aromatase-catalyzed estrogen biosynthesis which stimulates unbridled mitogenesis;(4) extrahe-patic CYP-1B1 in mammary adipose tissue converts paracrine estrogen to carcinogenic quinones with mutagenic impact; and(5) agents that inhibit COX-2 reduce the risk of breast cancer in women without disease and reduce recurrence risk and mortality in women with breast cancer. Recent sharp increases in global breast cancer incidence and mortality are likely driven by chronic inflammation of mammary adipose and upregulation of COX-2 associated with the obesity pandemic. The totality of evidence clearly supports the supposition that mammary carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive overexpression of COX-2 and the prostaglandin cascade in the "inflammogenesis of breast cancer".

Cyclooxygenase-2 polymorphisms and the risk of esophageal adeno-or squamous cell carcinoma

AIM： TO determine whether -1195 A→G and/or -765 G→C polymorphisms in Cyclooxygenase-2 CCOX-2） may have a risk modifying effect on the development of esophageal carcinoma in a Dutch Caucasian population. METHODS： Two study groups were recruited, 252 patients with esophageal carcinoma and 240 healthy controls, matched for race, age, gender and recruiting area. DNA was isolated from whole blood and used for genotyping. PCR products were digested with restriction enzymes and products were analyzed by agarose gel electrophoresis. Odds ratios （OR） and 95% confidence intervals （CI） were estimated. RESULTS： The distribution of the -1195A→G polymorphism was significantly different in esophageal cancer patients compared to controls. The -1195 GG genotype resulted in a higher risk of developing esophageal adenocarcinoma （OR = 3.85, 95% CI： 1.45-10.3） compared with the -1195AA genotype as a reference. The -765 G→C genotype distribution was not different between the two groups. The GG/ GG haplotype was present more often in esophageal adenocarcinoma patients than in controls （OR = 3.45, 95% CI： 1.24-9.58; with AG/AG as a reference）. The same trends were observed in patients with squamous cell carcinomas, however, the results did not reach statistical significance. CONCLUSION： Presence of the COX-2 -1195 GG genotype and of the GG/GG haplotype may result in a higher risk of developing esophageal carcinoma.

Interaction between cyclooxygenase-2,Snail,and E-cadherin in gastric cancer cells

AIM:To investigate the mechanisms of how cyclooxygenase-2(COX-2)regulates E-cadherin in gastric cancer cells.METHODS:COX-2 expression in human gastric cancer cell lines SGC-7901,BGC-823,MGC-803 and AGS were measured at the mRNA and protein level.COX-2 rich cell line SGC-7901 was chosen for subsequent experiments.siRNA mediated gene knockdown was used to investigate the impact of COX-2 on nuclear factor-κB (NF-κB),Snail,and E-cadherin in gastric cancer cells.Gene expression was determined by Western blot and real-time polymerase chain reaction.To analyze whether NF-κB inhibition could interrupt the modulatory effect of COX-2 or prostaglandin E2(PGE2)on E-cadherin,gastric cancer cells were treated with celecoxib or PGE2,in the presence of NF-κB specific siRNA.RESULTS:Highest expression level of COX-2 was found in SGC-7901 cells,both at mRNA and protein levels.siRNA mediated down-regulation of COX-2 led to a reduced expression of NF-κB and Snail,but an increased expression of E-cadherin in SGC-7901 cells.siRNA mediated down-regulation of NF-κB also led to a reduced expression of E-cadherin and Snail in SGC-7901 cells.However,COX-2 expression did not alter after cells were treated with NF-κB specific siRNA in SGC-7901 cells.Treatment of SGC-7901 cells with celecoxib led to a reduced expression of Snail but an increased expression of E-cadherin.In contrast,treatment of SGC-7901 cells with PGE2 led to an increased Snail and a decreased E-cadherin.However,siRNAmediated knockdown of NF-κB partially abolished the effect of celecoxib and PGE2 on the regulation of E-cadherin and Snail in SGC-7901 cells.CONCLUSION:COX-2 likely functions upstream of NF-κB and regulates the expression of E-cadherin via NF-κB/Snail signaling pathway in gastric cancer cells.

Expression of cyclooxygenase-2 in gastric cancer and its relation to liver metastasis and long-term prognosis

AIM: To investigate the expression of cyclooxygenase-2(COX-2) in gastric cancer and its relation with the liver metastasis and prognosis.METHODS: Expression of COX-2 mRNA and protein was examined in gastric cancer and its paired substantial normal tissue by semi-quantitative reverse transcriptionpolymerase chain reaction and immunohistochemistry.The relation between COX-2 expression and prognosis was investigated in 195 cases.RESULTS: The expression of COX-2 mRNA in gastric cancer tissue was significantly higher than that in normal tissue in 47 cases (w= 792, P＜0.01). The COX-2 mRNA in pT3-4 tissue expressed higher than that in pT1-2tissue (w = 204, P＜0.05). The positive expression rate of COX-2 protein was 57.9% (113/195). The COX-2expression was significantly related to histological type,lymphnode metastasis, venous invasion and liver metastasis (P＜0.05). No relation was found between COX-2 expression and invasion depth, peritoneal metastasis and International Union against Cancer TNMstage. The multiple regression analysis showed that the COX-2 expression and venous invasion were obviously associated with liver metastasis (P＜0.05). However,there was no significant correlation between COX-2immunoreactivity and prognosis.CONCLUSION: COX-2 may play an important role in the development of gastric cancer, and the over-expression of COX-2 protein may be a high risk factor for liver metastasis.

Expression of cyclooxygenase-2 in colorectal cancer and its clinical significance

AIM: To clarify the clinicopathologic significance of COX-2 expression in human colorectal cancer. METHODS: A total of 128 surgically resected colorectal cancer specimens were immunohistochemically analyzed with the use of anti-COX-2, anti-VEGF and anti-MMP-2 antibodies. The relationship between the cyclooxygenase-2 expression in primary lesions of colorectal cancer and clinicopathoiogic parameters was evaluated by chi-square test. RESULTS: Among 128 cases of colorectal cancer, 87 (67.9%) were positive for cyclooxygenase-2. The expression of cyclooxygenase-2 was significantly correlated with the depth of invasion, stage of disease, and metastasis (lymph node and liver). Patients in T3-T4, stages Ⅲ-Ⅳand with metastasis had much higher expression of cyclooxygenase-2 than ones in T1-T2, stages Ⅰ-Ⅱ and without metastasis (P<0.05). Among 45 cases of colorectal cancer with lymph node metastasis, the COX-2-positive rate was 86.7% (39/45) for primary lesions and diffuse cytoplasmic staining for COX-2 protein was detected in cancer cells in 100% of metastatic lesions of the lymph nodes. VEGF expression was detected in 49 tumors (38.3%), and VEGF expression was closely correlated with COX-2 expression. The positive expression rate of VEGF (81.6%) in the cyclooxygenase-2-positive group was higher than that in the cyclooxygenase-2-negative group (18.4%, P<0.05). MMP-2 expression was detected in 88 tumors (68.8%), and MMP-2 expression was closely correlated with COX-2 expression. The positive expression rate of MMP-2 (79.6%) in the positive COX-2 group was higher than that in the negative COX-2 group (20.4%, P<0.05). CONCLUSION: Cyclooxygenase-2 may be associated with tumor progression by modulating the angiogenesis and cancer cell motility and invasive potential in colorectal cancer and it can be used as a possible biomarker.

Involvement of eicosanoids in the pathogenesis of pancreatic cancer: the roles of cyclooxygenase-2 and 5-lipoxygenase

The interplay between inflammation and cancer progression is a growing area of research. A combination of clinical, epidemiological, and basic science investigations indicate that there is a relationship between inflammatory changes in the pancreas and neoplastic progression. Diets high in &#x003c9;-6 polyunsaturated fatty acids provide increased substrate for arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) to form eicosanoids. These eicosanoids directly contribute to pancreatic cancer cell proliferation. Both COX-2 and 5-LOX are upregulated in multiple cancer types, including pancreatic cancer. In vitro studies using pancreatic cancer cell lines have demonstrated upregulation of COX-2 and 5-LOX at both the mRNA and protein levels. When COX-2 and 5-LOX are blocked via a variety of mechanisms, cancer cell proliferation is abrogated both in vitro and in vivo. The mechanism of COX-2 has been shown to include effects on apoptosis as well as angiogenesis. 5-LOX has been implicated in apoptosis. The use of COX-2 and 5-LOX inhibitors in clinical studies in patients with pancreatic cancer has been limited. Patient enrollment has been restricted to those with advanced disease which makes evaluation of these drugs as chemopreventive agents difficult. COX-2 and 5-LOX expression have been shown to be present during the early neoplastic changes of pancreatic cancer, well before progression to invasive disease. This indicates that the ideal role for these interventions is early in the disease process as preventive agents, perhaps in patients with chronic pancreatitis or hereditary pancreatitis.

Cyclooxygenase-2 plays a central role in the genesis of pancreatitis and associated lung injury

BACKGROUND: The exact mechanism by which cyclooxy- genase-2 (COX-2) promotes inflammation in pancreatitis in obscure. This study was undertaken to investigate the role of COX-2 inhibition in an animal model of pancreati- tis , a disease process characterized by a systemic inflamma- tory response and ensuing neutrophil-mediated lung injury. METHODS: Pancreatitis was induced in 24 Sprague-Daw- ley rats by intraperitoneal injection of 20% L-arginine (500 mg/100 g body weight). The animals were randomized into 3 groups (8 rats in each group); controls and rats with pancreatitis intravenously resuscitated with either normal saline (0.9% NaCl 3 ml/kg) at 24 and 48 hours or COX-2 inhibitor (parecoxib 1 mg/kg). Pancreatic and lung inju- ries were assessed histologically. Lung injury was assessed utilizing wet;dry ratio and myeloperoxidase activity to in- dicate pulmonary neutrophil infiltration. A Western blot was used to determine COX-2 protein expression in pancrea- tic tissue. RESULTS: The animals treated with COX-2 inhibitors dis- played significantly less pancreatic and lung injuries than their normal saline counterparts. Histological pancreatic and lung injury scores were significantly reduced (P <0.05) in the COX-2 treated group. Lung wet: dry ratios were sig- nificantly improved and pulmonary neutrophil infiltration was attenuated in the COX-2 group (P<0.05). Western blot analysis confirmed attenuated COX-2 protein expression. CONCLUSION: This study shows, for the first time in a rat model, that adjuvant COX-2 inhibition significandy attenu- ates the severity of both pancreatitis and its associated sys- temic inflammatory response and end-organ injury.

Effects of bile acids on cyclooxygenase-2 expression in a rat model of duodenoesophageal anastomosis

AIM: To examine the expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in rat esophageal lesions induced by reflux of duodenal contents.

Cyclooxygenase-2 expression after preoperative chemoradiotherapy correlates with more frequent esophageal cancer recurrence

AIM： To investigate the relationship between cycloo- xygenase-2 （COX-2）, and vascular endothelial growth factor （VEGF）, and to determine the clinical significance of this relationship in esophageal cancer patients undergoing chemoradiotherapy （CRT）. METHODS： Immunohistochemical staining was used to evaluate COX-2 and VEGF expression in 40 patients with histologically-confirmed esophageal squamous carcinoma （ESCC） who were undergoing preoperative CRT. RESULTS： Fourteen out of 40 ESCC patients showed a pathological complete response （CR） after CRT. COX-2 and VEGF protein expressions were observed in the cytoplasm of 17 and 13 tumors, respectively, with null expression in 9 and 13 tumors, respectively. COX-2 expression was strongly correlated with VEGF expression （P 〈 0.05）. There were also significant associations between COX-2 expression, tumor recurrence, and lymph-node involvement （P = 0.0277 and P = 0.0095, respectively）. COX-2 expression and VEGF expression had significant prognostic value for disease-free survival （log-rank test; P = 0.0073 and P = 0.0341, respectively）, but not for overall survival, as assessed by univariate analysis. expression correlates with VEGF expression and might be a useful prognostic factor for more frequent tumor recurrence in ESCC patients undergoing neoadjuvant CRT. These findings support the use of anti-angiogenic COX-2 inhibitors in the treatment of ESCC.

No association between cyclooxygenase-2 and uridine diphosphate glucuronosyltransferase 1A6 genetic polymorphisms and colon cancer risk

AIM：To investigate the association of variations in the cyclooxygenase-2 （COX2） and uridine diphosphate glucuronosyltransferase 1A6 （UGTIA6） genes and non-steroidal anti-inflammatory drugs （NSAIDs） use with risk of colon cancer.METHODS： NSAIDs, which are known to reduce the risk of colon cancer, act directly on COX2 and reduce its activity. Epidemiological studies have associated variations in the COX2 gene with colon cancer risk, but others were unable to replicate this finding. Similarly,enzymes in the UGT1A6 gene have been demonstrated to modify the therapeutic effect of NSAIDs on colon adenomas. Polymorphisms in the UGTIA6 gene have been statistically shown to interact with NSAID intake to influence risk of developing colon adenomas, but not colon cancer. Here we examined the association of tagging single nucleotide polymorphisms （SNPs） in the COX2 and UGTIA6 genes, and their interaction with NSAID consumption, on risk of colon cancer in a population of 422 colon cancer cases and 481 population controls.RESULTS： No SNP in either gene was individually statistically significantly associated with colon cancer, nor did they statistically significantly change the protective effect of NSAID consumption in our sample. Like others, we were unable to replicate the association of variants in the COX2 gene with colon cancer risk （P 〉 0.05）,and we did not observe that these variants modify the protective effect of NSAIDs （P 〉 0.05）. We were able to confirm the lack of association of variants in UGT1A6 with colon cancer risk, although further studies will have to be conducted to confirm the association of these variants with colon adenomas.CONCLUSION： Our study does not support a role of COX2 and UGTIA6 genetic variations in the development of colon cancer.

Curcumin-attenuated trinitrobenzene sulphonic acid induces chronic colitis by inhibiting expression of cyclooxygenase-2

AIM： To explore the possible mechanisms of curcumin in rat colitis induced by trinitrobenzene sulfonic （TNBS） acid. METHODS： Rats with TNBS acid-induced colitis were treated with curcumin （30 mg/kg or 60 mg/kg per day ip）. Changes of body weight and histological scores as well as survival rate were evaluated. Leukocyte infiltration was detected by myeloperoxidase （MPO） activity assay. The expression of cyclooxygenase-2 （COX-2） was detected by RT-PCR and Western blot. Inflammation cytokines were determined by RT-PCR. Local concentration of prostaglandin E2 （PGE2） in colon mucosa was determined by ELISA. RESULTS： Curcumin improved survival rate and histological image, decreased the macroscopic scores and MPO activity. Also curcumin reduced the expression of COX-2 and inflammation cytokines. In addition, treatment with curcumin increased the PGE2 level. CONCLUSION： Curcumin has therapeutic effects on TNBS acid-induced colitis, the mechanisms seem to be related to COX-2 inhibition and PGE2 improvement.