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Nonalcoholic fatty liver disease (NAFLD) includes a series of diseases affected by various complex factors. Mitochondrial dysfunction often occurs in NAFLD and may lead to the progression of hepatitis and liver fibrosis. This article reviews the important role of mitochondrial oxidative stress, respiration, energy metabolism, quality control, and mitochondrial DNA in NAFLD and summarizes the current status of mitochondria-targeted therapy for NAFLD, hoping to provide a new direction for the research and clinical treatment of NAFLD.
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Background:High-fat diet leads to intestinal mucosa barrier dysfunction,but the mechanism is not clear. High-fat diet can induce increase of bile acid. Aims:To investigate whether the high bile acid induced by high-fat diet could act on intestinal stem cell to disrupt stem cell differentiation and imparing the intestinal mucosa. Methods:Twenty-four rats were divided into 3 groups:fed with regular diet,high-fat diet and high-fat diet + cholestyramine,respectively,for 2 weeks. Serum bile acid was detected by ELISA. Ileal diameter was measured and HE staining was performed to observe histology of intestinal mucosa. Expression of Lgr5 gene was determined by RT-qPCR. Ileal tissue fed with regular diet was cultured with deoxycholic acid(DCA)or DCA + cholestyramine for 24 hours in vitro,expression of Lgr5 gene was determined by RT-qPCR. Results:Compared with control group,serum bile acid was significantly increased(P < 0. 05),ileal diameter was significantly decreased,height of intestinal crypts and villus was significantly decreased(P < 0. 05),and expression of Lgr5 gene was significantly decreased in high-fat diet group(P < 0. 01). All the above-mentioned indices were significantly ameliorated in high-fat diet + cholestyramine group(P < 0. 05). In vitro study showed that expression of Lgr5 gene was significantly decreased in DCA group than in control group(P < 0. 01),and cholestyramine could significantly increase expression of Lgr5 gene(P < 0. 05). Conclusions:High-fat diet induced increasing of circulatory bile acid can cause injury of intestinal mucosa by inhibiting stem cell function,which can be ameliorated by cholestyramine.
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<p><b>OBJECTIVE</b>To investigate the role of TGF-beta1 and STAT3 signaling in liver fibrosis using a rat model system and to determine the therapeutic mechanism of AG490 in relation to this signaling pathway.</p><p><b>METHODS</b>Rats were randomly divided into a control group and DENA-induced liver fibrosis model group, and then subdivided into AG490 treatment groups. During fibrosis development, liver tissue samples were collected at different time points (0, 4 and 8 weeks) and evaluated according to the Scheuer scoring system. Expression of STAT3, TGFbeta1, alpha-SMA, E-cadherin, MMP2 and TIMP1 was measured by PCR (mRNA) and immunohistochemistry and western blotting (protein).</p><p><b>RESULTS</b>Increasing degrees of inflammation and fibrosis were observed in liver tissues of DENA-treated rats throughout model establishment. The mRNA expression of TGFbeta1 and STAT3 was significantly increased in DENA-induced rats with advanced fibrosis (AF) compared to those with early fibrosis (EF) (P = 0.034 and P = 0.012 respectively). The protein expression of TGF-beta1, phospho-Smad2, alpha-SMA, E-cadherin, STAT3 and phospho-STAT3 was significantly increased in DENA-induced rats with AF compared to the unmodeled control group (P = 0.048, P = 0.003, P = 0.002, P = 0.028, P = 0.009 and P = 0.039). The protein expression of E-cadherin was lower in the DENA-induced rats with AF than in those with EF (P = 0.026). STAT3 and TGF-beta1 co-expression was detected in AF tissues. DENA-induced AG490-treated rats with AF showed substantially lower protein expression of STAT3, TGF-beta1, MMP2 and TIMP1 compared to DENA-induced untreated rats with AF (P = 0.006, P = 0.018, P = 0.010 and P = 0.005); in addition, the degrees of fibrosis and inflammation were also greatly reduced in the DENA-induced AG490-treated rats with AF compared to DENA-induced untreated rats with AF (P = 0.042 and P = 0.021). Conclusions STAT3 signal transduction may regulate the TGF-beta1 pathway and affect liver fibrosis, especially in the advanced phase. AG490 can inhibit TGFbeta1-STAT3 signaling, resulting in reversal of liver fibrosis.</p>
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Animals , Rats , Disease Models, Animal , Liver Cirrhosis , Metabolism , Rats, Sprague-Dawley , STAT3 Transcription Factor , Metabolism , Signal Transduction , Transforming Growth Factor beta1 , Metabolism , Tyrphostins , PharmacologyABSTRACT
Objective To evaluate the therapeutic effect of endoscopy for patients with anastomotic or nonanastomotic biliary strictures after liver transplantation.Methods Clinical and follow-up data of 56 patients,38 (67.9％) with anastomotic strictures (AS),and 18 (32.1％) with nonanastomotic strictures (NAS) after liver transplantation,who underwent endoscopic therapy were collected and analyzed.Results Compared to AS patients,NAS patients showed shorter time from liver transplantation to initial presentation (4.45 ± 1.47 vs.8.00 ±2.31 months,P =0.000),underwent more ERCP procedures (6.20 ±1.28 vs.4.11 ± 1.51,P =0.000) and received more stents (10.20 ±3.59 vs.7.53 ±2.12,P =0.001).Although the success rate was not statistically different,patients with NAS needed longer treatment duration and had higher recurrence rate (50.0％ vs.18.2％,P =0.033) as well as shorter duration from treatment to recurrence.Among patients with AS,the treatment failure group had longer stricture length (13.00 ±3.61 vs.6.63 ±2.09,P =0.000) than the success group and the patients who experienced recurrence had longer stricture length (10.48 ± 1.07 vs.5.86 ± 1.55,P =0.000) and narrower stricture diameter (1.52 ± 0.38 vs.1.94 ± 0.32,P =0.001).Among NAS patients,the multiple biliary strictures group had lower success rate and higher recurrence rate,but with no statistical significance (62.5％ vs.90.0％,P =0.275 and 66.7％ vs.37.5％,P =0.592,recpectively).Conclusion NAS patients have lower response to endoscopic treatment than AS patients.The length and diameter of biliary stricture in AS as well as the number of stricture in NAS may influent the effect of endoscopic treatment.
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Objective To evaluate the effect of small endoscopic sphincterotomy and endoscopic balloon dilatation in the treatment of common duct stones (CDS) in patients with atypical papillae (combined with diverticula; after surgical operation; combined with abnormal duodenal lumen with no definite cause).MethodsOne hundred and three patients with CDS and with atypical papillae treated from July 2007 to March 2010 were randomly divided into three groups.Thirty-four patients received endoscopic sphincterotomy (EST group),34 patients received endoscopic balloon dilatation (EBD group) and the remaining 35 patients received small endoscopic sphincterotomy and endoscopic balloon dilatation (EST+EBD group).The general state of the patients in the 3 groups showed no significant difference (P＞0.05).We tried to remove all CDS using baskets and/or balloons after the procedures on the papillae.In some patients the stones were crushed by using a basket mechanical lithotriptor (BML).In some patients with huge stones,we could only placed in a plastic stent because of the high risk of removing the stones in a single procedure.ResultsSuccessful endoscopic retrograde cholangiopancreatography (ERCP) was carried out in 96 patients.Patients in the EST+ EBD group had less complications,especially hemorrhage,when compared with the EST group (P＜0.05).Also,the EST+EBD group had a significantly higher success rate of complete stone removal (P＜0.05),decreased use of BML (P＜0.05) and decreased rate of acute pancreatitis when compared with the EBD group (P＜0.05).ConclusionsThe success rate of ERCP in managing patients with CDS with atypical papillae remained high.Small endoscopic sphincterotomy and endoscopic balloon dilatation had a higher success rate of removing stones at the first attempt and a decreased rate of complications.