Effect of Propyl Gallate on Activity of Cyclooxygenase 1 and 2 in Mice's Peritoneal Macrophages*

Objective: To investigate the effect of Red Peony 801 (propyl gallate,PrG) on cyclooxygenase (COX) activity in murine peritoneal macrophages. Methods: A screening model for COX inhibitors in vitro based on murine peritoneal macrophages was used. COX-1 activity was reflected by the level of 6-ketoprostaglandin F1α(6-keto-PGF1α) in supernatants of cultured macrophages which were stimulated with calcium ionophore A23187 for a short-term, while COX-2 activity was reflected by the level of prostaglandin E2 (PGE2) in supernatants of cultured macrophages which were stimulated with lipopolysaccharide (LPS) for a long-term. Results: PrG did not affect A23187-induced, COX-1-derived 6-keto-PGF1α synthesis at the concentrations of 1×10-5, 5×10-6 mol/L (P>0.05), but enhanced 6-keto-PGF1α synthesis at the concentrations of 1×10-6, 5×10-7, 1×10-7 mol/L (P<0.01) in vitro, and showed a good dose-dependent manner. It inhibited LPS-induced, COX-2-derived PGE2 synthesis at the concentrations of 1×10-5,1×10-6 mol/L (P< 0. 05). Conclusion: Within the range of 1×10-5 to 1×10-7 mol/L, PrG activated COX-1 at lower concentrations and inhibited COX-2 at higher concentrations in murine peritoneal macrophages.

Selective Cyclooxygenase-2 Inhibitors: Design and Synthesis

The discovery of COX-2 provides a novel target developing more effective NSAIDs with fewer side effects. On the basis of results from the structure-activity relationships (SAR) of selective COX-2 inhibitors, we have designed and synthesized some promising compounds.

Expression of cyclooxygenase-1 and -2 in extra-hepatic cholangiocarcinoma

Objective: To investigate the expression of cyclooxy- genase-1 (COX-1) and cyclooxygenase-2 (COX-2) in extra-hepatic cholangiocarcinoma and the relation- ship between their expression and clinicopathological parameters. Methods: COX-1 and COX-2 were detected in 56 ex- tra-hepatic cholangiocarcinomas, including 31 matched tissues originating from non-tumorous bile ductal tissue adjacent to tumours and 6 normal bile ductal tissues, by immunohistochemistry strept avi- din-biotin complex using isozyme selective antibod- ies. Results: There was no difference in expression of COX-1 between carcinomas (96%, 54/56) and non- cancerous specimens (94%, 29/31, P>0.05) or normal bile ductal tissues (100%, 6/6, P>0.05). The positive rate of COX-2 expression in extra-hepat- ic cholangiocarcinomas (86%, 48/56) was signifi- cantly higher than their matched tissues (39%, 12/ 31, P<0.01) and normal bile ductal tissues (0%, 0/6, P<0.01). Overexpression of COX-2 in extra- hepatic cholangiocarcinoma was related to the metas- tasis of lymph nodes, distant organs or tissues (P< 0.05) as well as the degree of tumour differentiation (P<0.05). Conclusions: The overexpression of COX-2 plays a crucial role in the carcinogenesis and development of extra-hepatic cholangiocarcinoma, indicating that COX-2 may serve as a target for chemoprevention of extra-hepatic cholangiocarcinoma.

Cyclooxygenase 2 polymorphism and colorectal cancer:-765G>C variant modifies risk associated with smoking and body mass index

AIM： To explore whether cyclooxygenase 2 （COX-2） -765G〉C polymorphism is associated with susceptibility of colorectal cancer （CRC） and to evaluate the risk of colorectal cancer in relation to environmental exposures and polymorphism. METHODS： We conducted a case-control study of 137 patients with colorectal cancer and 199 cancerfree controls in northeast China. Multivariate logistic regression analysis was performed to calculate the adjusted odds ratio （OR） and 95% confidence interval （95% CI）. RESULTS： The -765G〉C polymorphism was not independently associated with CRC risk. However, risk associated with the polymorphism differed by smoking and body mass index （BMI）. Smoking and BMI associated risks were stronger among those with -765GG genotype, showing that smokers had a 2.682-fold greater risk of CRC than nonsmokers （51/43 vs 68/126, P = 0.006）. Compared to those with a normal body mass index （BMI 18.5-22.9）, those with overweight （BMI 23-24.9） had a 3.909-fold higher risk of CRC （OR = 3.909, 95% CI = 2.081-7.344; P 〈 0.001）, while those with obesity （BMI 〉 25） had a 2.031- fold higher risk of CRC （OR = 1.107, 95% CI = 1.107-3.726; P = 0.022）. is not associated with an increased risk of CRC, -765GG genotype appears to be related to an increased risk in the presence of smoking and higher BMI.

Expression of cyclooxygenase in hyperdynamic portal hypertensive rats

BACKGROUND: By detecting hemodynamic changes, concentration of plasm prostacyclin ( PGI2) and expression of cyclooxygenase( COX) in vasculature and splanchnic tissues, we evaluated the relative contributions of PGI2 and COX mRNA expression to the hyperdynamic circulatory state in chronic portal hypertensive rats. METHODS: Fifty male Sprague-Dawley rats were divided into 3 groups: intrahepatic portal hypertension (IHPH, n = 18) by injection of CCl4, prehepatic portal hypertension (PHPH, n = 18) by partial stenosis of the portal vein, and sham-operated controls (SO, n =14). Splanchnic hemodynamics was measured by radioactive microsphere techniques and the concentration of PGI2 was detected by specific radioimmunoassay for its stable hydrolysis product 6-keto-PGF1α. Semi-quantitive reverse transcriptase-polyme-rase chain reaction (RT-PCR) was performed to measure the levels of COX-1 mRNA and COX-2 mRNA in the thoracic aorta, superior mesenteric artery( SMA),and small intestine of IHPH, PHPH and SO rats, respectively. RESULTS: Hyperdynamic circulatory state was characterized by increased splanchnic blood flow and decreased splanchnic vascular resistance in IHPH and PHPH rats. The concentration of plasma 6-keto-PGF1α ( pg/ml) in IHPH (1093.75 ± 142.15) and PHPH (897. 42 ± 53. 29) rats was significantly higher than that in SO rats (730.13 ± 98. 67) (P <0.05). The expression of COX-1 mRNA in the thoracic aorta, SMA and small intestine was enhanced, whereas COX-2 mRNA expression was not detected in either of these vessels or the small intestine. The plasma 6-keto-PGF1α concentration and the expression of COX-1 mRNA in these vessels and the small intestine were closely correlated with such hemodynamic parameters as portal venous inflow (PVI), splanchnic vascular resistance (SVR) and free portal venous pressure (FPP) (P<0.05). CONCLUSION: The expression of COX-1 mRNA and the levels of PGI2 were closely related to the hyperdynamic circulatory state of portal hypertensive rats.

Relationship between expression and distribution of cyclooxygenase-2 and bcl-2 in human gastric adenocarcinoma

AIM: To explore expression and distribution features of COX-2 and bcl-2 in human gastric adenocarcinoma tissues and to study its biological significance.METHODS: Totally 36 human gastric carcinoma samples were enrolled in this study (cardiac adenocarcinoma 16 cases, distal gastric adenocarcinoma 20 cases). The expressions of COX-2 and bcl-2 in cancerous tissues and corresponding para-cancerous tissues were investigated by immunohistochemistry using COX-2 polyclonal antibody and bcl-2 monoclonal antibody. The normal gastric mucosa tissues were used as control.RESULTS: The expressions of COX-2 and bcl-2 in gastric carcinoma were significantly higher than that in the paracancerous tissues (77.8% vs 47.2%, P＜0.01, 80.56% vs 58.33%, P＜0.05). The expression of COX-2 in cardiac adenocarcinoma was remarkably higher than that in the distal gastric carcinoma (93.8% vs 65.0%, P＜0.01). The expression of COX-2 was mainly localized in the cytoplasm of tumor cells and partly in the nucleus. There is a transition of the COX-2 cytoplasmic positivity to nucleic in tumor cells with the increase of gastric carcinoma pathological grade. Interstitial macrophages, fibroblasts and vascular endothelial cells also expressed COX-2. The tissues with higher expression of COX-2 also expressed high level of bcl-2 protein.CONCLUSION: Abnormal expression pattern of COX-2within the tissues of human gastric cancer is correlated with tumor location and lymph node metastasis. COX-2may regulate expression of apoptosis suppressor gene (bcl-2) through interaction of tumor cells and stromal cells and play an important role in the generation and development of tumors, which will be of great help in developing new methods for antitumor therapy.

Cyclooxygenase-2 promotes angiogenesis by increasing vascular endothelial growth factor and predicts prognosis in gallbladder carcinoma

AIM: To investigate the relationships between the expression of cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and the degree of vascularization, clinicopathologic feature, survival time of patients with gallbladder carcinomas. METHODS: Sixty-four gallbladder carcinoma specimens were evaluated for COX-2, VEGF expression by immunohi stochemical methods. Microvessel counts (MVC) were determined using CD34. The relationships between COX-2, VEGF expression, CD34-stained MVC, clinicopathologic features and survival time were analyzed. The correlations between COX-2 and VEGF expression, CD34-stained MVC were also investigated. RESULTS: COX-2, VEGF immunoreactivity were observed in 71.9% (46/64) and 54.7% (35/64) specimens, respectively. The average MVC in 64 cases of gallbladder carcinoma was 57±14 per high power vision field. The status of MVC was closely correlated with Nevin staging, tumor differentiation and lymph node metastasis (P<0.01, 0.002, and 0.003, 0.000, respectively). Increased VEGF expression was significantly correlated with tumor differentiation (poorly and moderately>well differentiated, P<0.05, P = 0.016). Clinical stages had no relation with the expression of VEGF (P>0.05, P = 0.612). There was a positive correlation between COX-2 expression and clinical stages. The positive rate of COX-2 was higher in cases of Nevin stages S4-S5 (81.8%) than in those of Nevin stages S1-S3 (50.0%) with a statistical significance (P0.01, P = 0.009). The expression of COX-2 did not vary with differentiation (P>0.05, P= 0.067). Statistically significant differences were also observed according to lymph node metastasis, COX-2 expression and VEGF expression (P<0.01,0.000, and 0.001, respectively). There was no relation between VEGF, COX-2 expression, MVC and the age and sex of patients. MVC and VEGF positive rate in the COX-2 positive gallbladder carcinoma tissue was higher than that in the COX-2 negative tissue (P<0.05, 0.000, and 0.032, respectively). Patients with VEGF, COX-2 positive tumors had a significantly shorter survival time than those with negative tumors (P<0.05,0.004, 0.01, respectively). CONCLUSION: Augmented tumor neovascularization induced by VEGF may be one of the several effects of COX-2 responsible for poor prognosis of human gallbladder carcinoma. COX-2 inhibitor, either in combination therapy with other agents, or for chemoprevention, may be effective via suppression of angiogenesis in this fatal disease.

Indoleamine-2,3-dioxygenase 1/cyclooxygenase 2 expression prediction for adverse prognosis in colorectal cancer

AIM To evaluate indoleamine-2,3-dioxygenase 1/cyclooxygenase 2(IDO1/COX2) expression as an independent prognostic biomarker for colorectal cancer(CRC) patients.METHODS We retrospectively studied the medical records of 95 patients who received surgical resection from August 2008 to January 2010. All patients were randomly assigned to adjuvant treatment with or without celecoxib groups after surgery. We performed standard immunohistochemistry to assess the expression levels of IDO1/COX2 and evaluated the correlation of IDO1/COX2 with clinicopathological factors and overall survival(OS) outcomes.RESULTS The expression of nuclear IDO1 was significantly correlated with body mass index(P < 0.001), and IDO1 expression displayed no association with sex, age, tumor differentiation, T stage, N stage, carcinoembryonic antigen, cancer antigen 19-9, CD3+ and CD8+ tumor infiltrating lymphocytes, and COX2. In univariate analysis, we found that nuclear IDO1(P = 0.039), nuclear/cytoplasmic IDO1 [hazard ratio(HR) = 2.044, 95% confidence interval(CI): 0.871-4.798, P = 0.039], nuclear IDO1/COX2(HR = 3.048, 95%CI: 0.868-10.7, P = 0.0049) and cytoplasmic IDO1/COX2(HR = 2.109, 95%CI: 0.976-4.558, P = 0.022) all yielded significantly poor OS outcomes. Nuclear IDO1(P = 0.041), nuclear/cytoplasmic IDO1(HR = 3.023, 95%CI: 0.585-15.61, P = 0.041) and cytoplasmic IDO1/COX2(HR = 2.740, 95%CI: 0.764-9.831, P = 0.038) have significantly poor OS outcomes for the CRC celecoxib subgroup. In our multivariate Cox model, high coexpression of cytoplasmic IDO1/COX2 was found to be an independent predictor of poor outcome in CRC(HR = 2.218, 95%CI: 1.011-4.48, P = 0.047) and celecoxib subgroup patients(HR = 3.210, 95%CI: 1.074-9.590, P = 0.037).CONCLUSION Our results showed that cytoplasmic IDO1/COX2 coexpression could be used as an independent poor predictor for OS in CRC.

Influence of nitric oxide synthase and cyclooxygenase blockade on expression of cyclooxygenase and hemodynamics in rats with portal hypertension

BACKGROUND : The importance of nitric oxide (NO) in the pathogenesis of portal hypertension (PHT) has been extensively studied, but whether or not prostacyclin (PGI2) plays a role in formation and development of hyperdynamic circutatory state in PHT has not been verified. The present study was undertaken to investigate the possible interaction between prostacyclin (PGI2) and nitric oxide (NO) in the hyperdynamic circulatory state of rats with chronic portal hypertension (PHT), by measuring the hemodynamic changes and expression of cyclooxygenase (COX) mRNA in vessels and small intestine after administration of Nω- nitro-L-arginine (L-NNA) or indomethacin (INDO) either in the short-term (7 days) or long-term (15 days). METHODS: Ninety-seven male Sprague-Dawley rats were divided into three groups: intrahepatic portal hypertension (IHPH) induced by injection of CCl4, prehepatic portal hypertension (PHPH) induced by partial stenosis of the portal vein, and sham-operated controls (SO). Animals of each group received L-NNA or INDO either for 7 or 15 days, with saline as control. Splanchnic hemodynamics was measured by the radioactive microsphere technique. The concentration of NO in serum was determined as the nitrate; nitrite ratio (NO2-/NO3-, μmol/L) by a colorometric method, and that of PGI2 was measured by specific radioimmunoassay for its stable hydrolysis product 6-keto-PGF1α (pg/ml). The reverse transcription- polymerase chain reaction measured the levels of COX-1 mRNA in the superior mesenteric artery, thoracic aorta, and small intestine of these rats.RESULTS: Compared with SO rats, COX-1 mRNA expression and the concentrations of plasma 6-keto- PGF1α and serum NO2-/NO3- were enhanced in both IHPH and PHPH rats; splanchnic vascular resistance (SVR) decreased, but portal venous inflow (PVI) markedly increased (P<0.05). Seven or 15 days of L-NNA treatment reduced COX-1 mRNA expression in these vessels and the small intestine, concomitant with a significant decrease in the concentration of plasma PGI2 and serum NO in IHPH and PHPH rats (P<0.05). At the same time, PVI decreased but SVR increased significantly (P<0.05). In both IHPH and PHPH rats, the COX-1 mRNA expression and the concentration of plasma PGI2 after No synthase (NOS) blockade for 15 days were higher than those for 7 days, whereas the hyperdynamic circulatory state was improved after NOS blockade for 15 days compared with 7 days. The concentration of PGI2 treated by INDO for 15 days was not significantly different from that after 7-day COX blockade, and hemodynamics restored hyperdynamic circulatory state. CONCLUSIONS: The hyperdynamic circulatory state in rats with PHT is correlated with the concentration of serum NO. There is a possible interaction between PGI2 and NO in the hyperhemodynamics of PHT. PGI2 is probably not the mediator in the formation and development of the hyperdynamic circulatory state in rats with chronic PHT.

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.

Aspirin, cyclooxygenase inhibition and colorectal cancer

Colorectal cancer(CRC)is the third most common type of cancer worldwide.Screening measures are far from adequate and not widely available in resourcepoor settings.Primary prevention strategies therefore remain necessary to reduce the risk of developing CRC.Increasing evidence from epidemiological studies,randomized clinical trials and basic science supports the effectiveness of aspirin,as well as other non-steroidal anti-inflammatory drugs,for chemoprevention of several types of cancer,including CRC.This includes the prevention of adenoma recurrence and reduction of CRC incidence and mortality.The detectable benefit of daily low-dose aspirin(at least 75 mg),as used to prevent cardiovascular disease events,strongly suggests that its antiplatelet action is central to explaining its antitumor efficacy.Daily low-dose aspirin achieves complete and persistent inhibition of cyclooxygenase(COX)-1 in platelets(in pre-systemic circulation)while causing alimited and rapidly reversible inhibitory effect on COX-2and/or COX-1 expressed in nucleated cells.Aspirin has a short half-life in human circulation(about 20 minutes);nucleated cells have the ability to resynthesize acetylated COX isozymes within a few hours,while platelets do not.COX-independent mechanisms of aspirin have been suggested to explain its chemopreventive effects but this concept remains to be demonstrated in vivo at clinical doses.

Haplotype of prostaglandin synthase 2/cyclooxygenase 2 is involved in the susceptibility to inflammatory bowel disease

AIM： Prostaglandin G/H synthase 2 （PTGS2 or COX2） is one of the key factors in the cellular response to inflammation. PTGS2 is expressed in the affected intestinal segments of patients with inflammatory bowel diseases （IBD）. In IBD patients, non-steroidal anti-inflammatory drugs, which have been shown to reduce both the production and activity of PTGS2, may activate IBD and aggravate the symptoms. We aimed at examining genetic variants of PTGS2 that may be risk factors for IBD. METHODS： We genotyped 291 individuals diagnosed with IBD and 367 controls from the Dutch population for the five most frequent polymorphisms of the PTG52 gene. Clinical data were collected on all patients. DNA was extracted via normal laboratory methods. Genotyping was carried out using multiplex PCR followed by the Invader Assay and the 5＇ exonuclease assay （TaqMan）. New polymorphism screening was performed by pre-screening with denaturing high-performance liquid chromatography, followed by fluorescent sequencing. RESULTS： Allele 5209G was weakly associated with Crohn＇s disease （odds ratio [OR] 1.63, 95% confidence interval [CI] 1.03-2.57）, and allele 8473T with ulcerativecolitis （OR 1.50, 95%CI 1.00-2.27）. The haplotype including both alleles showed a strong association with IBD （OR 13.15, 95%CI 3.17-116.15）. This haplotype, while rare （-0.3%） in the general population, is found more frequently in patients （3.5%）. CONCLUSION： Our data suggest that this haplotype of PTGS2 contributes to the susceptibility of IBD.

Interplay between post-translational cyclooxygenase-2 modifications and the metabolic and proteomic profile in a colorectal cancer cohort

BACKGROUND Colorectal cancer(CRC) is the second most common cause of cancer death worldwide. It is broadly described that cyclooxygenase-2(COX-2) is mainly overexpressed in CRC but less is known regarding post-translational modifications of this enzyme that may regulate its activity, intracellular localization and stability. Since metabolic and proteomic profile analysis is essential for cancer prognosis and diagnosis, our hypothesis is that the analysis of correlations between these specific parameters and COX-2 state in tumors of a high number of CRC patients could be useful for the understanding of the basis of this cancer in humans.AIM To analyze COX-2 regulation in colorectal cancer and to perform a detailed analysis of their metabolic and proteomic profile.METHODS Biopsies from both healthy and pathological colorectal tissues were taken under informed consent from patients during standard colonoscopy procedure in the University Hospital of Bellvitge(Barcelona, Spain) and Germans Trias i Pujol University Hospital(Campus Can Ruti)(Barcelona, Spain). Western blot analysis was used to determine COX-2 levels. Deglycosylation assays were performed in both cells and tumor samples incubating each sample with peptide N-glycosidase F(PNGase F). Prostaglandin E2(PGE2) levels were determined using a specific ELISA. 1 H high resolution magic angle spinning(HRMAS) analysis was performed using a Bruker AVIII 500 MHz spectrometer and proteomic analysis was performed in a nano-liquid chromatography-tandem mass spectrometer(nano LC-MS/MS) using a QExactive HF orbitrap MS.RESULTS Our data show that COX-2 has a differential expression profile in tumor tissue of CRC patients vs the adjacent non-tumor area, which correspond to a glycosylated and less active state of the protein. This fact was associated to a lesser PGE2 production in tumors. These results were corroborated in vitro performing deglycosylation assays in HT29 cell line where COX-2 protein profile was modified after PNGase F incubation, showing higher PGE2 levels. Moreover,HRMAS analysis indicated that tumor tissue has altered metabolic features vs non-tumor counterparts, presenting increased levels of certain metabolites such as taurine and phosphocholine and lower levels of lactate. In proteomic experiments, we detected an enlarged number of proteins in tumors that are mainly implicated in basic biological functions like mitochondrial activity,DNA/RNA processing, vesicular trafficking, metabolism, cytoskeleton and splicing.CONCLUSION In our colorectal cancer cohort, tumor tissue presents a differential COX-2 expression pattern with lower enzymatic activity that can be related to an altered metabolic and proteomic profile.

Expression of inducible nitric oxide synthase and cyclooxygenase-2 in pancreatic adenocarcinoma:Correlation with microvessel density

AIM:Cydooxygenases (COX) are key enzymes for conversion of arachidonic acid to prostaglandins.Nitric oxide synthase (NOS) is the enzyme responsible for formation of nitric oxide. Both have constitutive and inducible isoforms.The inducible isoforms (iNOS and COX-2) are of great interest as regulators of tumor angiogenesis,tumorigenesis and inflammatory processes.This study was to clarify their role in pancreatic adenocarcinomas. METHODS:We investigated the immunohistochemical iNOS and COX-2 expression in 40 pancreatic ductal adenocardnomas of different grade and stage.The results were compared with microvessel density and dinicopathological data. RESULTS:Twenty-one (52.5%) of the cases showed iNOS expression,15 (37.5%) of the cases were positive for COX-2. The immunoreaction was heterogeneously distributed within the tumors.Staining intensity was different between the tumors.No correlation between iNOS and COX-2 expression was seen.There was no relationship with microvessel density. However,iNOS positive tumors developed more often distant metastases and the more malignant tumors showed a higher COX-2 expression.There was no correlation with other clinicopathological data. CONCLUSION:Approximately half of the cases expressed iNOS and COX-2.These two enzymes do not seem to be the key step in angiogenesis or carcinogenesis of pancreatic adenocarcinomas.Due to a low prevalence of COX-2 expression,chemoprevention of pancreatic carcinomas by COX-2 inhibitors can only achieve a limited success.

Comparative analysis of clinicopathological correlations of cyclooxygenase-2 expression in resectable pancreatic cancer

AIM:To perform a comparative analysis of clinicopathological correlations of cyclooxygenase2 (COX2) expression in pancreatic cancer, examined by monoclonal and polyclonal antibodies.METHODS: The COX2 expression in 85 resection specimens of pancreatic ductal adenocarcinoma was immunohistochemically examined using both monoclonal and polyclonal antibodies. The final immunoscores were obtained by multiplying the percentage of positive cells with the numeric score reflecting the staining intensity.COX2 expression levels were classified into three categories (0, 1+, and 2+) and the clinicopathological correlations were statistically evaluated and analyzed.RESULTS: The positive tumor expression rates of COX2 were 80.5% using monoclonal antibody and 69.4% using polyclonal antibody. In the KaplanMeier analysis, no significant correlations were found between levels of COX2 expression and overall survival (OS), but trends to longer OS were found in COX2 negative cases using monoclonal antibody. Significantly longer disease free survival was revealed in COX2 negative cases using monoclonal antibody (P = 0.019). No correlations between COX2 expression levels and grade (G), tumor (T) status and nodal (N) status were demonstrated. Low histological grade showed a strong association with a longer OS (P < 0.001). Correlation of survival and T status revealed a shorter OS in T3 tumors, but the results reached only marginal statistical significance (P = 0.070). In the multivariate Cox proportional hazards regression model, histological grade, T and N status remained valuable predictors of a worse survival with borderline significance for T [hazards ratio (HR) = 4.18 for G (if G = 3, P < 0.001); HR = 1.64 for T (if T = 3, P = 0.065); HR = 2.53 for N (if N = 1, P = 0.006)]. Higher grade, T or N status was associated with a worse OS. CONCLUSION: The immunohistochemically assessed level of COX2 expression does not seem to represent a valuable independent prognostic factor and is not superior to the conventional prognostic factors.

Cyclooxygenase-2在急性胰腺炎大鼠肺微循环障碍中的作用

目的初步探讨急性胰腺炎大鼠肺组织Cyclooxygenase-2(Cox-2)的表达及其在急性胰腺炎肺微循环障碍中的作用。方法逆行胰胆管注射灭菌的4%牛磺胆酸钠诱导Sprague-Dawley大鼠急性出血坏死性胰腺炎(AHNP)模型。实验随机分为假手术组、AHNP组及Celecoxib预处理组,术后3、6、12和24h处死动物,取肺组织HE染色进行肺损伤的组织学评价,Mallory氏磷钨酸苏木精染色观察血管中的纤维素性血栓,免疫组化检测Cox-2蛋白表达。结果AHNP组肺组织Cox-2表达和病理学评分进行性增加,两者呈正相关(r=0.503,P=0.012)。在AHNP早期就可发现肺组织微血栓形成,其密度和损伤评分亦呈正相关(r=0.604,P=0.004);Celecoxib预处理在各时相点均减轻了肺损伤的程度、微血栓密度和Cox-2的表达水平(P<0.05);Celecoxib下调Cox-2表达程度与其改善肺组织病理损伤强度正相关,而与其降低微血栓形成的程度无明显相关性。结论肺微血栓形成所致的肺微循环障碍可能是诱导肺损伤发生的早期事件,并可能是始动因素;Cox-2过表达可能具有促凝血活性而在肺微血栓形成中扮演关键角色。

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.

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.