BackgroundSeveral immune‐mediated diseases have been shown to be associated with an increased risk of cardiovascular disease. However, studies evaluating the association between inflammatory bowel disease and risk of cardiovascular disease reported inconsistent results. We assessed the association between inflammatory bowel disease and risk of ischemic heart disease in a meta‐analysis of cohort studies.Methods and ResultsWe conducted a literature search of PubMed and Embase up to October 2016 to identify relevant studies. The summary relative risks were calculated using the random‐effects models. To explore the source of heterogeneity, we performed subgroup and sensitivity analysis. We included 10 cohort studies that satisfied our inclusion criteria. Patients with inflammatory bowel disease were associated with an increased risk of ischemic heart disease (relative risk: 1.244; 95% CI, 1.142–1.355). Considerable heterogeneity was observed. Crohn's disease showed a significantly increased risk of ischemic heart disease (relative risk=1.243; 95% CI, 1.042–1.482) and a positive association was also observed in ulcerative colitis (relative risk=1.206; 95% CI, 1.170–1.242).ConclusionsBased on meta‐analysis of cohort studies, we found an increased risk of ischemic heart disease in patients with inflammatory bowel disease. Large long‐term prospective studies are warranted to confirm our results.

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Cyclooxygenase 2 (COX-2) has been suggested to be associated with liver carcinogenesis. Several reports have shown that NSAIDs inhibit the growth of hepatocellular carcinoma cell lines. There is little evidence of how COX-2 inhibitors regulate the proliferation of hepatocellular carcinoma cells or the mechanism involved. In our study, we investigated the growth-inhibitory mechanism of a selective COX-2 inhibitor, NS-398, in 4 hepatocellular carcinoma cell lines by studying cell growth, COX-2 and proliferating cell nuclear antigen (PCNA) expression, cell cycle distribution and the evidence of apoptosis. NS-398 inhibited the growth of all 4 cell lines in a time-and dose-dependent manner and the inhibitory effects were independent of the level of COX-2 protein expression. PCNA expression was downregulated by NS-398 in a dose-independent manner. NS-398 caused cell cycle arrest in the S phase with a reduction in cell numbers and cell accumulation in the G0/G1 phase, for all 4 cell lines. No evidence of apoptosis was observed in our present study. Key words: selective COX-2 inhibitor; cell growth; cell cycle; hepatocellular carcinoma cellsCyclooxygenases (COX) are key rate-limiting enzymes involved in the conversion of arachidonic acid to prostaglandin H2, the precursor of various compounds including prostaglandins (PGs), prostacyclin and thromboxanes. There are at least 2 isoforms of COX: COX-1 and COX-2. COX-1 is expressed constitutively in a wide variety of tissues whereas COX-2 is highly inducible and is expressed in response to a variety of proinflammatory agents and cytokines. 1,2 Overexpression of COX-2 has been demonstrated in various tumor tissues such as colon cancer, pancreatic cancer and hepatocellular carcinoma. [3][4][5][6][7] Although several studies have shown the upregulation of COX-2 in cirrhotic tissues adjacent to hepatocellular carcinoma (HCC) and welldifferentiated HCC, the precise role of COX-2 in carcinogenesis remains unclear. 7,8 A few reports have shown that NSAIDs inhibited the growth of various cancer cell lines including those derived from hepatocellular carcinoma. 9 -11 The question arises whether COX-2 also is a target for the prevention or treatment of hepatocellular carcinoma, as it is for colon cancer. 12 There is little evidence, however, of how COX-2 inhibitors regulate the proliferation of hepatocellular carcinoma cells or the mechanism involved. In our study, we investigated the growth-inhibitory mechanism of a selective COX-2 inhibitor, NS-398, in hepatocellular carcinoma cell lines. MATERIAL AND METHODS Cell lines and cell cultureFour human hepatocellular carcinoma cell lines, PLC/PRF5, HepG2, Mahlavu and HuH-7, were obtained from the American Type Culture Collection. Cells (2 ϫ 10 5 cells) were grown for 24 hr in DMEM (PLC/PRF5 and HepG2) (ICN; Biomedicals Inc., Aurora, MI), minimum essential Eagle's medium (Mahlavu) (ICN) and RPMI 1640 (HuH-7) (ICN) supplemented with 10% FBS at 37°C under 5% CO 2 /95% air in 100 mm 2 cell culture dishes. Then, NS-398 (Cayman Chemical, Ann Ar...