Abnormal Expression Of Cyclooxygenase-2 Research Articles

Research progress of the pathogenesis of NFPA and the tumorigenicity of COX-2

Non-functioning pituitary adenoma (NFPA), lack of the clinical and biochemical characteristics of hormone overexpression, is a common type of pituitary adenoma. It could bring enormous suffering to the patients on account of the tendentiousness of being invasive macroadenoma and oppressing surrounding tissue. At present, the pathogenesis of NFPA is still unclear, thus there is no effective medical management for the disease. Although transsphenoidal surgery is the first-line treatment for NFPA, it is very difficult to achieve a cure effect. It has been found that the abnormal expression of cyclooxygenase-2 (COX-2) affects the survival and progression of cancer. Recent studies have detected the expression of COX-2 in pituitary tumors, and the expression of COX-2 in NFPA is stronger, suggesting that COX-2 may be involved in the occurrence and development of NFPA. This article reviews the pathogenesis of NFPA and the tumorigenicity of COX-2, and provides new ideas for clinical drug treatment of NFPA. Key words: Cyclooxygenase 2; Non-functioning pituitary adenoma; Pituitary neoplasms; Review

Lipoxin A4 Suppresses IL-1β-Induced Cyclooxygenase-2 Expression Through Inhibition of p38 MAPk Activation in Endometriosis

Endometriosis is an inflammation-dependent gynecologic disorder. Increased cyclooxygenase-2 (COX-2) expression plays an important role in the development and progression of endometriosis. Lipoxin A4 (LXA4) is an endogenous anti-inflammation lipid and showed inhibitory effects on the development of endometriosis; however, the mechanism remains unclear. In this study, the overexpression of COX-2 was observed in ectopic endometrium of endometriosis patients compared to the normal endometrium of controls. Lipoxin A4 efficiently suppressed IL-1β-induced COX-2 protein expression in ectopic endometriotic stromal cells (ESCs) via its receptor, formyl peptide receptor 2/lipoxin A4 receptor (FPR2/ALX). Antagonism of FPR2/ALX eliminated the inhibitory effect by LXA4. IL-1β induced the activation of mitogen-activated protein kinases (MAPKs), which can promote the expression of COX-2. Pretreatment of ESCs with LXA4 inhibited the phosphorylation of p38 MAPK induced by IL-1β. These findings suggest that inflammation and MAPKs pathways respond for the abnormal expression of COX-2, which can elucidate the pathophysiology of endometriosis. Moreover, LXA4 suppressed IL-1β-induced COX-2 expression through inhibiting the p38 MAPK signaling protein. This research contributes for better understanding of the cellular and biological events of inflammation and anti-inflammation-mediated regulation in endometriosis.

Prognostic significance of cyclooxygenase-2 protein in pancreatic cancer: a meta-analysis.

We conducted a meta-analysis of relevant cohort studies to investigate the relationships between cyclooxygenase-2 (COX-2) protein and the prognosis of pancreatic cancer. The following electronic databases were searched without language restrictions: MEDLINE (1966∼2013), the Library Database (Issue 12, 2013), EMBASE (1980∼2013), CINAHL (1982∼2013), Web of Science (1945∼2013), and the Chinese Biomedical Database (CBM) (1982∼2013). Meta-analysis was performed using the STATA statistical software. Six cohort studies with a total of 712 pancreatic cancer patients were involved in this meta-analysis. Our findings showed that COX-2-positive patients were significantly associated with a shorter overall survival (OS) than COX-2-negative patients (hazard ratio (HR) = 1.48, 95 % confidence interval (95%CI) = 1.12∼1.85, P < 0.001). A subgroup analysis by ethnicity also revealed that pancreatic cancer patients with an abnormal COX-2 expression exhibited a worse OS than COX-2-negative patients among both Asians and Caucasians (Asians: HR = 1.40, 95%CI = -0.09∼2.89, P = 0.066; Caucasians: HR = 1.49, 95%CI = 1.11∼1.87, P < 0.001, respectively). Our findings provide empirical evidence that abnormal COX-2 expression may be strongly correlated with poor prognosis for patients with pancreatic cancer. Thus, COX-2 protein may be a useful biomarker for pancreatic cancer.

Clausenamide improves COX-2 expression in diabetic rats

This study aims to investigate the effects of clausenamide on streptozotocin (STZ)-induced diabetes in rats. The diabetic rat model was established via an intraperitoneal STZ injection. The rats were randomly divided into five groups, the normal control group, the model group, the insulin treatment group, the high-dose clausenamide treatment group, and the low-dose clausenamide treatment group. Three months after drug administration, reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were carried out to measure the Cyclooxygenase-2 (COX-2) expression in the hippocampus of the rats in each group. The RT-PCR results indicate that the hippocampal COX-2 mRNA levels significantly increased in diabetic rats compared with those in the other groups. However, the hippocampal mRNA COX-2 levels in the clausenamide treatment groups significantly decreased, which indicates an inhibitory role of clausenamide on COX-2 mRNA in the diabetic rats. The immunohistochemistry results demonstrate that COX-2 expression in the hippocampus of the diabetic rats significantly increased, which suggests that an abnormal COX-2 expression is involved in the pathogenesis of learning and memory deficiencies, and that clausenamide exerts a protective role by inhibiting COX-2 expression in diabetic rats. Clausenamide has several protective effects on the brain injury induced by long-term diabetes, and significantly reduces diabetes-related learning and memory deficiency. The mechanism correlated well with the inhibition of COX-2 expression in the hippocampus. Key words: Clausenamide, diabetes, hippocampus, cycloxygenase-2 (COX-2).

Cyanidin-3-glucoside suppresses B[a]PDE-induced cyclooxygenase-2 expression by directly inhibiting Fyn kinase activity

Benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE) is a well-known carcinogen that is associated with skin cancer. Abnormal expression of cyclooxygenase-2 (COX-2) is an important mediator in inflammation and tumor promotion. We investigated the inhibitory effect of cyanidin-3-glucoside (C3G), an anthocyanin present in fruits, on B[a]PDE-induced COX-2 expression in mouse epidermal JB6 P+ cells. Pretreatment with C3G resulted in the reduction of B[a]PDE-induced expression of COX-2 and COX-2 promoter activity. The activation of activator protein-1 (AP-1) and nuclear factor-κB (NF-κB) induced by B[a]PDE was also attenuated by C3G. C3G attenuated the B[a]PDE-induced phosphorylation of MEK, MKK4, Akt, and mitogen-activated protein kinases (MAPKs), but no effect on the phosphorylation of the upstream MAPK regulator Fyn. However, kinase assays demonstrated that C3G suppressed Fyn kinase activity and C3G directly binds Fyn kinase noncompetitively with ATP. By using PP2, a pharmacological inhibitor for SFKs, we showed that Fyn kinase regulates B[a]PDE-induced COX-2 expression by activating MAPKs, AP-1 and NF-κB. These results suggest that C3G suppresses B[a]PDE-induced COX-2 expression mainly by blocking the activation of the Fyn signaling pathway, which may contribute to its chemopreventive potential.

Protective Effect of Quercetin against Arsenite-Induced COX-2 Expression by Targeting PI3K in Rat Liver Epithelial Cells

Abnormal expression of cyclooxygenase-2 (COX-2) and prostaglandin (PG)E(2) is an important mediator in inflammation and tumor promotion. Arsenite is a well-known metalloid carcinogen that is strongly associated with increased risk of liver cancer, but the underlying mechanism remains to be clarified. The present study demonstrates that COX-2 expression and PGE(2) secretion are up-regulated by arsenite in rat liver epithelial (RLE) cells. The possible inhibitory effect of quercetin, a naturally occurring dietary flavonol, on arsenite-induced COX-2 expression and PGE(2) production was investigated. Pretreatment with quercetin resulted in the reduction of arsenite-induced expression of COX-2 and production of PGE(2). The arsenite-induced phosphorylation of Akt, p70S6K, and extracellular signal-regulated protein kinases (ERKs), but not p38, was inhibited by quercetin treatment. An ex vivo kinase assay revealed that quercetin suppressed arsenite-induced phosphoinositide 3-kinase (PI3K) activity upstream of Akt in RLE cell lysates. Ex vivo pull-down assays demonstrated that quercetin directly bound with PI3K to inhibit PI3K activity. Moreover, LY294002 (a PI3K inhibitor) significantly attenuated COX-2 expression and PGE(2) production in arsenite-treated RLE cells. These results suggest that quercetin suppresses arsenite-induced COX-2 expression mainly by blocking the activation of the PI3K signaling pathway, which may contribute to its chemopreventive potential.

Myricetin Down-Regulates Phorbol Ester-Induced Cyclooxygenase-2 Expression in Mouse Epidermal Cells by Blocking Activation of Nuclear Factor Kappa B

Abnormal expression of cyclooxygenase-2 (COX-2) has been implicated in the development of cancer. There are multiple lines of evidence that red wine exerts chemopreventive effects, and 3,5,4'-trihydroxy- trans-stilbene (resveratrol), which is a non-flavonoid polyphenol found in red wine, has been reported to be a natural chemopreventive agent. However, other phytochemicals might contribute to the cancer-preventive activities of red wine, and the flavonol content of red wines is about 30 times higher than that of resveratrol. Here we report that 3,3',4',5,5',7-hexahydroxyflavone (myricetin), one of the major flavonols in red wine, inhibits 12-O-tetradecanoylphorbol-13-acetate (phorbol ester)-induced COX-2 expression in JB6 P+ mouse epidermal (JB6 P+) cells by suppressing activation of nuclear factor kappa B (NF-kappaB). Myricetin at 10 and 20 microM inhibited phorbol ester-induced upregulation of COX-2 protein, while resveratrol at the same concentration did not exert significant effects. The phorbol ester-induced production of prostaglandin E 2 was also attenuated by myricetin treatment. Myricetin inhibited both COX-2 and NF-kappaB transactivation in phorbol ester-treated JB6 P+ cells, as determined using a luciferase assay. Myricetin blocked the phorbol ester-stimulated DNA binding activity of NF-kappaB, as determined using an electrophoretic mobility shift assay. Moreover, TPCK (N-tosyl-l-phenylalanine chloromethyl ketone), a NF-kappaB inhibitor, significantly attenuated COX-2 expression and NF-kappaB promoter activity in phorbol ester-treated JB6 P+ cells. In addition, red wine extract inhibited phorbol ester-induced COX-2 expression and NF-kappaB transactivation in JB6 P+ cells. Collectively, these data suggest that myricetin contributes to the chemopreventive effects of red wine through inhibition of COX-2 expression by blocking the activation of NF-kappaB.

The significance of cyclooxygenase-2 expression in human hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the five most common malignancies in the world and is the second leading cause of death in Hong Kong. Previous studies have shown increased levels of cyclooxygenase-2 (COX-2) in a variety of human malignancies including HCC, suggesting that abnormal COX-2 expression plays an important role in carcinogenesis. In addition, some evidence suggests that selective COX-2 inhibitors suppress the formation of tumors in experimental models. However, there are no data in the literature on using COX-2 as an inhibitor target in HCC. The main objective of this article was to give a brief summary of the recent findings of the role of COX-2 in HCC. We briefly reviewed the significance of COX-2 in varies cancers, and then focused on the recent findings of the significance of COX-2 in HCC. Finally, we further evaluated the possibility of using COX-2 as a therapeutic target in HCC.

Cyclooxygenase-2 (COX-2) inhibition limits abnormal COX-2 expression and progressive injury in the remnant kidney

The pathogenesis of progressive nephropathies involves hemodynamic and inflammatory factors. In the 5/6 nephrectomy model, a selective increase of cyclooxygenase-2 (COX-2) expression was shown, whereas treatment with a nonsteroidal anti-inflammatory or a specific COX-2 inhibitor was renoprotective. We investigated in the 5/6 nephrectomy model (1) the renal distribution of COX-2; (2) the hemodynamic and cellular mechanisms by which chronic COX-2 inhibition prevents renal injury. After 5/6 nephrectomy, adult male Munich-Wistar rats were subdivided in two groups: 5/6 nephrectomy (N=20), receiving vehicle, and 5/6 nephrectomy + celecoxib (N=19), treated orally with the COX-2 inhibitor, celecoxib, 10 mg/kg/day. Untreated and treated (celecoxib) sham-operated rats were also studied. Renal hemodynamics were examined at 4 weeks, whereas renal morphologic/immunohistochemical studies were carried at 8 weeks. At 4 weeks, 5/6 nephrectomy rats exhibited marked systemic and glomerular hypertension. Celecoxib attenuated both systemic and glomerular hypertension, without affecting glomerular filtration rate (GFR). At 8 weeks, glomerulosclerosis and interstitial expansion were evident in 5/6 nephrectomy rats, and markedly attenuated in 5/6 nephrectomy rats given celecoxib. In both sham-operated and 5/6 nephrectomy rats, COX-2 was expressed at the macula densa. The extent of COX-2 expression at the macula densa was nearly tripled by celecoxib, indicating the existence of a feedback mechanism. In 5/6 nephrectomy rats, COX-2 was also expressed in glomeruli, arterioles, and the cortical interstitium, mostly at inflamed or sclerosing areas. Celecoxib markedly attenuated renal injury, inflammation, and ectopic COX-2 expression in 5/6 nephrectomy rats. Chronic COX-2 inhibition attenuated progressive nephropathy by reducing glomerular hypertension, renal inflammation, and ectopic COX-2 expression, indicating a complex contribution of COX-2 to progressive renal injury in 5/6 nephrectomy rats.

Correlation of Cyclooxygenase-2 Expression With Molecular Markers, Pathological Features and Clinical Outcome of Transitional Cell Carcinoma of the Bladder

We investigated the relationship between cyclooxygenase-2 (COX-2) expression and molecular alterations commonly found in transitional cell carcinoma (TCC) of the bladder and determined whether COX-2 immunoreactivity is associated with cancer stage, progression and survival in patients undergoing radical cystectomy. Immunohistochemical staining for COX-2 was done in archival tumor specimens from 80 patients who underwent radical cystectomy. Immunoreactivity was categorized as positive (reactivity in greater than 10% tumor cells) or negative. Microvessel density, E-cadherin, pRB, p16, p21, p53 and transforming growth factor (TGF)-beta1 and its receptors (types I and II) were also studied because evidence suggests a biological association between COX-2 and alteration of these molecules. COX-2 was over expressed in 62 patients (78%). COX-2 over expression was associated with muscle invasive pathological stage (p = 0.022), TGF-beta1 over expression (p = 0.004), decreased E-cadherin expression (p < 0.001), and altered expression of pRB (p = 0.003) and p16 (p = 0.006). At a median followup of 101 months COX-2 over expression was associated with disease progression (p = 0.038) and bladder cancer specific survival (p = 0.042). However, when adjusted for the effects of standard pathological features, only lymph node metastasis was associated with bladder cancer progression (p = 0.027) and mortality (p = 0.042). COX-2 is commonly expressed in patients with bladder TCC. Using the cutoff of 10% abnormal COX-2 expression is associated with the degree of invasiveness, alterations in TGF-beta1 and pRB/p16 pathways, and loss of cell adhesion. While COX-2 expression has limited prognostic value in patients with bladder TCC, it may serve as a target for therapy with selective COX-2 inhibitors.