Enhanced apoptosis in post-liver transplant hepatitis C:Effects of virus and immunosuppressants

Hepatitis C(HCV)-infected patients have a poorer survival post-liver transplantation compared to patients transplanted for other indications,since HCV recurrence post-transplant is universal and commonly follows an aggressive course.There is increasing evidence that in the non-transplant setting,induction of hepatocyte apoptosis is one of the main mechanisms by which HCV drives liver inflammation and fibrosis,and that HCV proteins directly promote apoptosis.Recent studies have shown that post-liver transplant,there is a link between high levels of HCV replication,enhanced hepatocyte apoptosis and the subsequent development of rapidly progressive liver fibrosis.Although the responsible mechanisms remain unclear,it is likely that immunosuppressive drugs play an important role.It is well known that immunosuppressants impair immune control of HCV,thereby allowing increased viral replication.However there is also evidence that immunosuppressants may directly induce apoptosis and this may be facilitated by the presence of high levels of HCV replication.Thus HCV and immunosuppressants may synergistically interact to further enhance apoptosis and drive more rapid fibrosis.These findings suggest that modulation of apoptosis within the liver either by changing immunosuppressive therapy or the use of apoptosis inhibitors may help prevent fibrosis progression in patients with post-transplant HCV disease.

Change of choline compounds in sodium selenite-induced apoptosis of rats used as quantitative analysis by in vitro 9.4T MR spectroscopy

AIM: To study liver cell apoptosis caused by the toxicity of selenium and observe the alteration of choline compounds using in vitro 9.4T high resolution magnetic resonance spectroscopy. METHODS: Twenty male Wistar rats were randomly divided into two groups. The rats in the treatment group were intraperitoneally injected with sodium selenite and the control group with distilled water. All rats were sacrifi ced and the livers were dissected. 1H-MRS data were collected using in vitro 9.4T high resolution magnetic resonance spectrometer. Spectra were processed using XWINNMR and MestRe-c 4.3. HE and TUNEL staining was employed to detect and confi rm the change of liver cells. RESULTS: Good 1H-MR spectra of perchloric acid extract from liver tissue of rats were obtained. The conventional metabolites were detected and assigned. Concentrations of different ingredient choline compounds in treatment group vs control group were as follows: total choline compounds,5.08 ± 0.97 mmol/L vs 3.81 ± 1.16 mmol/L (P = 0.05); and free choline,1.07 ± 0.23 mmol/L vs 0.65 ± 0.20 mmol/L (P = 0.00). However,there was no statistical signif icance between the two groups. The hepatic sinus and cellular structure of hepatic cells in treatmentgroup were abnormal. Apoptosis of hepatic cells was confi rmed by TUNEL assay. CONCLUSION: High dose selenium compounds can cause the rat liver lesion and induce cell apoptosis in vivo. High resolution 1H-MRS in vitro can detect diversified metabolism. The changing trend for different ingredient of choline compounds is not completely the same at early period of apoptosis.

Implication of altered proteasome function in alcoholic liverinjury

The proteasome is a major protein-degrading enzyme, which catalyzes degradation of oxidized and aged proteins, signal transduction factors and cleaves peptides for antigen presentation. Proteasome exists in the equilibrium of 26S and 20S particles. Proteasome function is altered by ethanol metabolism, depending on oxidative stress levels： low oxidative stress induces proteasome activity, while high oxidative stress reduces it. The proposed mechanisms for modulation of proteasome activity are related to oxidative modification of proteasomal proteins with primary and secondary products derived from ethanol oxidation. Decreased proteolysis by the proteasome results in the accumulation of insoluble protein aggregates, which cannot be degraded by proteasome and which further inhibit proteasome function. Mallory bodies, a common signature of alcoholic liver diseases, are formed by liver cells, when proteasome is unable to remove cytokeratins. Proteasome inhibition by ethanol also promotes the accumulation of pro-apoptotic factors in mitochondria of ethanol-metabolizing liver cells that are normally degraded by proteasome. In addition, decreased proteasome function also induces accumulation of the negative regulators of cytokine signaling （I-~B and SOCS）, thereby blocking cytokine signal transduction. Finally, ethanol-elicited blockade of interferon type 2 and 2 signaling and decreased proteasome function impairs generation of peptides for MHC class Ⅰ-restricted antigen presentation.

Beneficial mechanisms of aerobic exercise on hepatic lipid metabolism in non-alcoholic fatty liver disease

BACKGROUND：Non-alcoholic fatty liver disease（NAFLD）refers to any fatty liver disease that is not due to excessive use of alcohol.NAFLD probably results from abnormal hepatic lipid metabolism and insulin resistance.Aerobic exercise is shown to improve NAFLD.This review aimed to evaluate the molecular mechanisms involved in the beneficial effects of aerobic exercise on NAFLD.DATA SOURCE：We searched articles in English on the role of aerobic exercise in NAFLD therapy in Pub Med.RESULTS： The mechanisms of chronic aerobic exercise in regulating the outcome of NAFLD include： （i） reducing in- trahepatic fat content by down-regulating sterol regulatory element-binding protein-lc and up-regulating peroxisome proliferator-activated receptor y expression levels; （ii） decreas- ing hepatic oxidative stress through modulating the reactive oxygen species, and enhancing antioxidant enzymes such as catalase and glutathione peroxidase; （iii） ameliorating hepatic inflammation via the inhibition of pro-inflammatory media- tors such as tumor necrosis factor-alpha and interleukin-1 beta; （iv） attenuating mitochondrial dependent apoptosis by reducing cytochrome C released from the mitochondria to the cytosol; and （v） inducing hepato-protective autophagy. CONCLUSION： Aerobic exercise, via different mechanisms, significantly decreases the fat content of the liver and improves the outcomes of patients with NAFLD.

Mechanism of apoptotic effects induced by 5 fluorouracil on human liver carcinoma Bel7402 cell line

Objective To evaluate the effect of endogenous nitric oxide (NO) on the ability of 5 fluourouracil (5 FU) to induce apoptosis in the liver carcinoma Bel7402 cell line, and to observe the anti tumor mechanism and effective adjuvant of 5 FU Methods Cells were cultured under routine conditions with Dulbecco's modified Eagle's medium (DMEM) without L arginine (L Arg) We observed the expression of inducible nitric oxide synthase (iNOS) and apoptosis of cells induced by 5 FU with L Arg added to the medium The production of nitric oxide was determined by the cell expression of iNOS detected by immunohistochemical staining, and by the concentrations of nitrite and nitrate in the supernatant Results 5 fluourouracil significantly increased the iNOS expression to 0 1687±0 01968 ( P <0 05, vs control group), and the concentration of nitric oxide to 213±30 2 μmol/L ( P <0 05, vs control group) The apoptotic cell rate increased significantly to 17 85±0 78%, while the necrotic cell rate decreased to 32 99±0 83% ( P <0 05, compared with the 5 FU group) N ω nitro L Arginine methyl ester (L NAME), the antagonist of L Arg, can block the apoptotic effects of endogenous nitric oxide Conclusions 5 FU had a synergistic effects with L Arg by increasing the production of endogenous nitric oxide Endogenous nitric oxide plays an important role in the process where 5 FU induces apoptosis in liver carcinoma cells L Arg may be a good adjuvant for chemotherapy with 5 FU

Antineoplastic mechanism of Octreotide action in human hepatoma

Objectives To investigate whether apoptosis can be induced by Octreotide in human hepatoma cells in vitro and elucidate the antineoplastic mechanism of Octreotide in hepatoma.Methods A cultured human hepatoma cell line,BEL-7402,was exposed to Octreotide and apoptosis was evaluated by cytochemical staining(Hochesst 33258),transmission electron microscopy,agarose gel electrophoresis and flow cytometry(FCM).Results After exposure to 0.2 μg/ml Octreotide,apoptosis with nuclear chromatin condensation as well as fragmentation,cell shrinkage and the formation of apoptotic bodies was observed using cytochemical staining and transmission electron microscopy.A DNA ladder in agarose gel electrophoresis was also displayed.FCM showed that the apoptotic cell number rose with an increase in the concentration of Octreotide(0- 2 iμg/ml).There was a positive correlation between Octreotide concentration and apoptotic rate in BEL-7402 cells(r=0.809,P＜0.05).Conclusion Apoptosis in human hepatoma cells can be induced by Octreotide,which may be related to the mechanism of antineoplastic action of Octreotide in hepatoma.