Cyclooxygenase-2 (COX-2) is involved in different liver diseases but little is known about the significance of COX-2 in the development and progression of non-alcoholic steatohepatitis (NASH). This study was designed to elucidate the role of COX-2 expression in hepatocytes in the pathogenesis of steatohepatitis and hepatic fibrosis. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were either fed methionine-and-choline deficient (MCD) diet to establish an experimental non-alcoholic steatohepatitis (NASH) model or injected with carbon tetrachloride (CCl4) to induce liver fibrosis. In our animal model, hCOX-2-Tg mice fed MCD diet showed lower grades of steatosis, ballooning and inflammation than Wt mice, in part by reduced recruitment and infiltration of hepatic macrophages, with a corresponding decrease in serum levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tg mice showed a significant attenuation of the MCD diet-induced increase in oxidative stress and hepatic apoptosis observed in Wt mice. Even more, hCOX-2-Tg mice treated with CCl4 had significantly lower stages of fibrosis and less hepatic content of collagen, hydroxyproline and pro-fibrogenic markers than Wt controls. Collectively, our data indicates that constitutive hepatocyte COX-2 expression ameliorates NASH and liver fibrosis development in mice by reducing inflammation, oxidative stress and apoptosis and by modulating activation of hepatic stellate cells, respectively, suggesting a possible protective role for COX-2 induction in NASH/NAFLD progression.
The effect of resveratrol was studied on the life span and motor activity of Drosophila melanogaster treated with manganese (Mn). Two days after emerging from the pupa, male wild type D. melanogaster were fed for 13 days with corn media containing 15 mM Mn. Thereafter, Drosophila were divided into six groups of 300 flies each: (1) the flies remained treated with Mn; (2) began treatment with 0.43 mM resveratrol (Mn-resveratrol group); (3) received no additional treatment (Mn-no treatment group); (4) simultaneously fed with Mn and resveratrol (Mn þ resveratrol group). In addition, a control (5) with no treatment and another group (6) fed only with resveratrol after emerging from the pupa were included. All Mn-treated flies (group 1) were dead on the 25th day. The life span in the resveratrol group was 91 AE 0.33 days (mean AE S.E.M.) and in Mn-resveratrol flies was 83 AE 2 days. These two values were significantly higher than those detected in the control (5) and Mn-no treatment (group 3) flies whose life span were 68 AE 0.33 and 67 AE 2.31 days, respectively. The Mn þ resveratrolfed flies had a markedly higher life span (31 AE 1.53 days) than Mn-fed flies (23 AE 0.88 days). In the flies that received Mn (Mn and Mn þ resveratrol groups), the motor activity decreased significantly with respect to control (groups 5) and the Mn-resveratrol and resveratrol groups. In conclusion, resveratrol increased significantly the life span of Mn-treated D. melanogaster.
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