Morin enhances hepatic Nrf2 expression in a liver fibrosis rat model

AIM To investigate whether morin can reduce hepatic fibrosis by activating the NF-E2-related factor 2(Nrf2) signaling pathway.METHODS Twenty male Sprague-Dawley rats were randomly divided into four groups: control group, morin group, carbon tetrachloride(CCl4) group, and morin + CCl4 group. Rats in both the CCl4 and morin + CCl4 groups were injected intraperitoneally with CCl4 at a dose of 2 mL/kg twice a week. Rats in both the morin and morin + CCl4 groups were treated orally with morin at a dose of 50 mg/kg twice a week. Control rats were treated with vehicle only twice a week. At the end-point of the 8 wk of the experimental period, serum AST, ALT, and ALP were measured, and the liver specimenswere obtained for pathological assessment. Real-time PCR and Western blot methods were used to analyze the expression of α-smooth muscle actin(α-SMA), collagen Ⅰ, collagen Ⅲ, Nrf2, heme oxygenase(HO-1), and quinone oxidoreductase 1(NQO1) using frozen liver specimens.RESULTS Morin-treated rats in the morin + CCl4 group had less hyperplasia of fiber tissue, minimal inflammatory cells, and less body weight loss with favorable liver enzyme measurements compared to rats treated with CCl4 only. Additionally, morin-treated rats had significantly lower m RNA and protein expression of α-SMA, collagen Ⅰ, and collagen Ⅲ, but significantly higher m RNA and protein expression of Nrf2, HO-1, and NQO1 compared to rats treated with CCl4 only(P 0.05).CONCLUSION Morin could play a protective role by inducing the expression of Nrf2 and its downstream antioxidant factors(HO-1 and NQO1) and reducing the expression of α-SMA, collagen Ⅰ, and collagen Ⅲ in CCl4-induced liver fibrosis rats.     

Liver transplantation in metabolic liver diseases

Abstract   Two types of metabolic disorders are treated with transplantation: those associated with severe liver damage, like alpha-1 antitrypsin deficiency, progressive familial cholestatic syndromes, tyrosinaemia, glycogen storage diseases, or cystic fibrosis; and those in which the liver is structurally normal, but is genetically unable to produce an essential protein, usually an enzyme, with consequent lethal systemic disease, like Crigler-Najjar syndrome, familial hypercholesterolaemia, propionic acidaemia, or urea cycle defects. The first group of diseases, among which the most common is alpha-1 antitrypsin deficiency, are treated by substitution of the whole liver with the donor liver, while the second group can be treated by auxiliary transplantation, to provide sufficient production of the deficient protein by the donor liver segment, while the native liver provides a safety net should the transplant fail and remains available for possible future gene therapy. In recent years, attempts have been made to treat these conditions by isolated human hepatocyte transplantation, with temporary success.     

Liver fibrosis in paediatric liver diseases

Numerous paediatric liver diseases from different origins may be complicated by development of liver fibrosis and progression to cirrhosis. Although fibrogenesis, which represents a major driving force for the development of liver fibrosis, has common tracts whatever the aetiology, liver fibrosis has different histopathological patterns in paediatric liver disease. In these diseases management choices may depend upon the stage of liver fibrosis. Thus, the accurate estimation of histological pattern of liver fibrosis is important for the prevention of the subsequent complications. Liver biopsy has long been considered as a gold standard diagnostic method for assessing liver fibrosis. However, due to its several disadvantages, in the last decades alternative and accurate non-invasive means to estimate fibrosis are developed. In this review, we characterised the most frequent histological patterns of liver fibrosis in paediatric liver diseases. Furthermore, we describe use of liver biopsy in diagnosis and staging of liver fibrosis, list the alternative non-invasive techniques that have an emerging role in the assessment of liver fibrosis, and propose a management algorithm.     

Liver transplantation in autoimmune liver diseases

Liver transplantation is indicated for terminal phases of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis. Indications for transplantation in autoimmune liver diseases are similar to those used in other acute or chronic liver diseases. Therapeutic advances have reduced the need for transplantation for autoimmune hepatitis and primary biliary cirrhosis but not for primary sclerosing cholangitis. Overall, outcomes of transplantation for autoimmune liver diseases are excellent. However, recurrence of autoimmune liver diseases in the allograft has variable impacts on graft and patient survivals. Treatment of recurrent diseases requires changes in immunosuppression or addition of ursodeoxycholic acid. Among autoimmune liver diseases, only autoimmune hepatitis occurs de novo in recipients transplanted for other diseases. Patients transplanted for autoimmune hepatitis or primary sclerosing cholangitis are at risk for reactivation or de novo onset of ulcerative colitis. Better understanding of the pathogenesis of recurrent autoimmune liver diseases is needed to devise effective means of prevention and treatment.     

Role of Nrf2 in chronic liver disease

Nuclear erythroid 2-related factor 2 (Nrf2) is a central regulator of antioxidative response elements-mediated gene expression. It has a significant role in adaptive responses to oxidative stress by interacting with the antioxidant response element, which induces the expression of a variety of downstream targets aimed at cytoprotection. Previous studies suggested oxidative stress and associated damage could represent a common link between different forms of diseases. Oxidative stress has been implicated in various liver diseases, including viral hepatitis, nonalcoholic fatty liver disease/steatohepatitis, alcoholic liver disease and drug-induced liver injury. Nrf2 activation is initiated by oxidative or electrophilic stress, and aids in the detoxification and elimination of potentially harmful exogenous chemicals and their metabolites. The expression of Nrf2 has been observed throughout human tissue, with high expression in detoxification organs, especially the liver. Thus, Nrf2 may serve as a major regulator of several cellular defense associated pathways by which hepatic cells combat oxidative stress. We review the relevant literature concerning the crucial role of Nrf2 and its signaling pathways against oxidative stress to protect hepatic cell from oxidative damage during development of common chronic liver diseases. We also review the use of Nrf2 as a therapeutic target to prevent and treat liver diseases.     

Liver transplantation for metabolic liver diseases

Liver transplantation has become an accepted treatment for several metabolic liver diseases. With advances in organ transplantation and immunosuppressive strategies, survival rates following liver transplantation are generally excellent. When the primary metabolic defect is hepatic in origin, liver transplantation not only replaces the dysfunctional organ but also cures the underlying metabolic defect. For conditions in which the primary metabolic defect is extrahepatic, liver transplantation is usually performed for hepatic complications, although disease recurrence may occur. This article reviews common metabolic liver diseases treated with liver transplantation in the adult population.     

Liver physiology and liver diseases in the elderly

The liver experiences various changes with aging that could affect clinical characteristics and outcomes in patients with liver diseases.Both liver volume and blood flow decrease significantly with age.These changes and decreased cytochrome P450 activity can affect drug metabolism,increasing susceptibility to drug-induced liver injury.Immune responses against pathogens or neoplastic cells are lower in the elderly,although these individuals may be predisposed to autoimmunity through impairment of dendritic cell maturation and reduction of regulatory T cells.These changes in immune functions could alter the pathogenesis of viral hepatitis and autoimmune liver diseases,as well as the development of hepatocellular carcinoma.Moreover,elderly patients have significantly decreased reserve functions of various organs,reducing their tolerability to treatments for liver diseases.Collectively,aged patients show various changes of the liver and other organs that could affect the clinical characteristics and management of liver diseases in these patients.     

核因子E2相关因子2与细胞自噬对肝纤维化的影响

肝纤维化是慢性肝病发展到肝硬化的必经阶段,在全世界范围保持着较高的发病率。肝纤维化的发生机制复杂,其发生发展受到许多细胞因子及信号通路的影响,人们对肝纤维化的认识也越来越深入。简述了核因子E2相关因子2(Nrf2)介导的抗氧化应激系统在对抗各种类型肝纤维化中的作用和细胞自噬对肝纤维化的影响,以及Nrf2和自噬的相互影响在肝纤维化中可能的作用机制。认为将Nrf2和细胞自噬联合研究是未来肝纤维化发生机制的研究方向,为肝纤维化的治疗提供了新思路。     

非酒精性脂肪性肝病合并胆结石患者代谢相关基因表达的研究

目的 探讨非酒精性脂肪性肝病合并胆结石患者外周血单个核细胞代谢相关基因的表达情况.方法选择体重指数(BMI)≥27的肥胖人群,分为三组,单纯肥胖组(n=10),非酒精性脂肪性肝病组(NAFLD组,n=7)和NAFLD伴胆结石组(n=16),另设两组对照,BMI<25的正常人(n=10)和单纯胆结石组(n=16).检测比较各组调节脂肪酸合成转录因子甾醇调节因子结合蛋白-lc(SREBP-lc)、调节脂肪酸氧化的过氧化酶体增殖物激活受体α(PPARα)和瘦素长型受体(Leptin Rb)在外周血单个核细胞的表达.结果 三种基因PPARα、SREBP-lc和Leptin Rb的mRNA在五组人群的外周血单个核细胞中均有不同程度表达,其中Leptin Rb的表达在单纯肥胖组和NAFLD伴胆结石组、单纯胆结石组和NAFLD伴胆结石组、NAFLD组和NAFLD伴胆结石组、单纯肥胖组和正常对照组同差异有统计学意义(P值分别=0.037、0.050、0.044和0.038).NAFLD伴胆结石组Leptin Rb的mRNA表达最低.结论NAFLD合并胆结石患者外周血单个核细胞Leptin Rb mRNA呈低表达;胆结石可能增加胰岛素抵抗的程度,促进NAFLD进展.     

终末期酒精性肝病的肝移植

西方国家常见的酒精性肝病（ALD）近年来在我国也有明显的增加.由于没有疗效确切的药物,肝移植成为目前治疗终末期酒精性肝病（EALD）最有效的手段,而与其他良性终末期肝病肝移植比较,EALD肝移植存在诸多特殊的临床问题.我们回顾分析我院11例EALD肝移植的临床资料及随访结果,对受者的选择、术前的评估及围手术期的处理等问题进行探讨.     

肝吸虫与肝胆疾病

肝吸虫是寄生于脊椎动物肝胆管的复殖吸虫。人因误食寄生在鱼体的活肝吸虫囊蚴而被感染。肝吸虫感染与一些肝胆疾病,特别是胆管癌有关。可能的致癌机制包括慢性刺激,内源性致癌物形成增加及代谢酶活化等。该文对与肝吸虫感染相关的肝胆疾病的流行病学、临床、实验研究及病理学资料进行了综述。     

Nrf2-Keap1抗氧化系统与肝脏疾病

核转录相关因子(NF-E2-related factor 2, Nrf2)是重要的转录因子, 在氧化应激等情况下被激活与Kelch样ECH联合蛋白1(Kelch-like ECH-associated protein1, Keap1)解离进入胞质启动Ⅱ相解毒酶及抗氧化酶基因的表达, 增加细胞对氧化应激和亲电子化学物质的抗性. 活性氧族和氧化应激在肝脏疾病的发病中取着重要的作用. 本文对Nrf2-Keap1抗氧化系统与肝脏疾病的关系进行探讨.     

核转录因子E2相关因子2启动子CpG岛甲基化对其蛋白表达及COPD的影响

核转录因子E2相关因子2 (nuclear factor erythroid-2-related factor 2,Nrf2)在人体氧化与抗氧化平衡过程中起了重要的作用.氧化与抗氧化失衡是COPD的重要发病机制之一.近来有研究发现 Nrf2启动子CpG岛甲基化能够影响 Nrf2蛋白的表达,从而影响抗氧化防御过程.明确 Nrf2启动子CpG岛甲基化与 Nrf2蛋白表达及COPD的关系,对今后临床上治疗 COPD寻找新途径具有重要意义.     

Liver transplantation for pediatric inherited metabolic liver diseases

Liver transplantation(LT) remains the gold standard treatment for end stage liver disease in the pediatric population. For liver based metabolic disorders(LBMDs),the decision for LT is predicated on a different set of paradigms. With improved outcomes post-transplantation, LT is no longer merely life saving, but has the potential to also significantly improve quality of life. This review summarizes the clinical presentation, medical treatment and indications for LT for some of the common LBMDs. We also provide a practical update on the dilemmas and controversies surrounding the indications for transplantation, surgical considerations and prognosis and long terms outcomes for pediatric LT in LBMDs. Important progress has been made in understanding these diseases in recent years and with that we outline some of the new therapies that have emerged.