4-hydroxy-2-nonenal and Cholestasis

Liver injuries can trigger a cascade of inflammatory responses and as a result, initiate the process of hepatic regeneration and fibrogenesis. Resveratrol (RSV) has multiple health-promoting benefits. This study evaluated the potential protective effects and mechanism of RSV as related to cholestatic liver injury. RSV was given (4 mg/kg/day, i.p.) for either 3 days or 7 days after bile duct ligation (BDL) injury. RSV significantly reduced serum ALT, AST but not T-bil on Day 3. At this early stage of injury, RSV significantly reduced TNF-α and IL-6 mRNA and decreased the number of Kupffer cells (CD68(+) ) recruited in the injured liver. RSV decreased hepatic fibrosis and reduced collagen Iα1 and TIMP-1 mRNA on Day 7. At the later stages of injury, RSV increased the number of Ki67(+) hepatocytes indicating that RSV promoted hepatocyte proliferation. Additionally, it resulted in decreased expression of 4-hydroxynonenal and increased expression of the hepatocyte growth factor protein and mRNA in the RSV-treated BDL group. Meanwhile, RSV reduced the mortality rate of BDL mice. In conclusion, RSV attenuated inflammation and reduced Kupffer cells activation. RSV decreased fibrosis and promoted hepatocyte regeneration, which increased the survival of BDL mice. RSV was beneficial for the treatment of cholestatic liver injury.

Topics: Aldehydes; Animals; Bile Ducts; Cell Proliferation; Cholestasis; Collagen Type I; Hepatocytes; Inflammation; Interleukin-6; Kupffer Cells; Ligation; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Resveratrol; RNA, Messenger; Stilbenes; Tissue Inhibitor of Metalloproteinase-1; Tumor Necrosis Factor-alpha

Several studies have reported green tea catechin to have both antifibrotic and anti-oxidative effects. The goal of this study was to evaluate the effect of green tea cathechin therapy in hepatic tissue injury using cholestatic rats with bile duct ligation.. We performed bile duct ligation on cholestatic seven-week-old male Wistar rats and classified them into three groups according to the method of treatment. The groups comprised the SHAM group, the NT-group (no-treatment-group), and the T-group (treatment-group). The rats were orally administered green tea catechin at a dose of 50mg/kg/day and were sacrificed on the 17th postoperative day. We subsequently investigated the levels of fibrosis and antioxidant activity associated with various clinical markers. We evaluated the serum AST and ALT levels and performed immunohistochemical analyses for 4-hydroxynonenal (4-HNE), 8-oxo-2'deoxyguanosine (8-OHdG) and transforming growth factor-beta1 (TGF-beta1). We also evaluated the levels of activator protein-1 m-RNA (AP-1 m-RNA) and tissue inhibitor metalloproteinase-1 m-RNA (TIMP-1 m-RNA) by Real Time PCR. Finally, we performed Azan staining and immunohistochemical staining of alpha-smooth muscle actin (alpha-SMA) to evaluate the degree of fibrosis.. The values of serum AST, serum ALT, AP-1 m-RNA, alpha-SMA, TGF-beta1, 4-HNE, and 8-OHdG in the T-Group were significantly lower than those in NT-Group. Therefore, the administration of green tea catechin might have suppressed the oxidative stress, controlled the stellate cell activation and consequently reduced the fibrosis.. Green tea catechin may reduce hepatic fibrosis by suppressing oxidative stress and controlling the transcription factor expression involved in stellate cell activation.

Topics: Actins; Alanine Transaminase; Aldehydes; Animals; Antioxidants; Aspartate Aminotransferases; Camellia sinensis; Catechin; Cholestasis; Deoxyguanosine; Disease Models, Animal; Hepatic Stellate Cells; Liver; Liver Cirrhosis; Male; Oxidative Stress; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-1; Transcription Factor AP-1; Transforming Growth Factor beta1

Topics: Aldehydes; Antioxidants; Cholestasis; Humans; Liver Cirrhosis; Liver Transplantation; Malondialdehyde; Oxidation-Reduction; Postoperative Complications; Postoperative Period; Regression Analysis; Reperfusion Injury; Syndrome

4-Hydroxy-2,3-nonenal is a major aldehydic end-product of lipid peroxidation known to exert several biological and cytotoxic effects and to be produced during conditions of chronic cholestasis. Here we report that viable hepatocytes isolated from cholestatic livers of bile duct-ligated rats (BDL hepatocytes) show a significantly lower rate of HNE metabolism than control cells. This feature is likely to be the consequence of a significant inhibition in the activity of HNE-metabolizing cytosolic glutathione-S-transferase and alcohol dehydrogenase in BDL hepatocytes. Particulate NADP-dependent aldehyde dehydrogenase was also inhibited. No significant change was found for aldehyde reductase activity. A decreased hepatocellular metabolism of HNE can expose liver parenchymal and non-parenchymal cells to cytotoxic as well as pro-inflammatory and pro-fibrogenic effects of HNE, contributing to the development of chronic cholestatic liver damage.

Topics: Alcohol Dehydrogenase; Aldehydes; Animals; Bile Ducts; Cholestasis; Glutathione Transferase; Kinetics; Lipid Peroxidation; Liver; Male; NAD; NADP; Rats; Rats, Wistar; Reference Values; Subcellular Fractions