微小RNA-29在肝纤维化进程中的作用

微小RNA(miRNA)是一段含21~23个核苷酸的小的内源性非编码RNA,通过与靶基因mRNA的3'-UTR部分或完全互补结合抑制翻译或降解mRNA,进而调节细胞的生物学功能。肝星状细胞由静息态向活化态转化是肝纤维化发生发展的核心过程。近年研究发现,miRNA-29(miR-29)在静息态的肝星状细胞中高表达,且在肝纤维化进程中扮演重要角色,可调控参与肝纤维化形成的多种细胞因子和肝星状细胞的活化增殖等。本文针对近年来miR-29在肝星状细胞活化和肝纤维化进程中的作用进行综述。     

PDGF及TGF信号转导通路与肝星状细胞活化增殖的研究进展

肝纤维化(HF)是多种致病因素作用于肝细胞引起肝细胞变性坏死后的共同病理基础,肝纤维化是肝硬化形成的早期阶段和必经阶段,是一可逆过程,但若病因持续存在发展为肝硬化则为不可逆的.其本质是细胞外基质(ECM)在肝脏过度沉积,而肝星状细胞(HSC)是大多数ECM的细胞来源,因此该文对与HSC活化增殖密切相关的TGF及PDGF...     

肝星状细胞激活与增殖相关信号转导通路在肝纤维化中的作用及机制

肝星状细胞激活和增殖在肝纤维化的发生过程中占有重要的地位。控制肝星状细胞的激活和增殖并逆肝纤维化的进程是抗肝纤维化研究的重点之一。本综述以肝星状细胞激活与增殖相关信号转导通路为中心,探讨其在肝纤维化发病作用方面的作用机制。通过干预细胞外信号传导通路,为研究肝纤维化的发病机制和药物治疗提供新的途径。     

瘦素对肝星状细胞活化的调控及其在肝纤维化进展中的作用

摘要：瘦素是一种主要由白色脂肪组织产生的激素,与肝星状细胞活化有着密切联系。瘦素与其功能性受体结合后可以通过JAK2/STAT3、PI3K/Akt、MAPK等信号通路及相关分子对肝星状细胞的活化产生影响;而肝星状细胞活化是肝纤维化发生发展的关键环节。该文就瘦素与肝星状细胞活化的相关信号通路及分子在肝纤维化发生发展中的作用进行综述,为肝纤维化的治疗提供依据。     

以肝星状细胞为靶点的抗肝纤维化治疗进展

摘要肝纤维化是由于各种致病原因所致慢性肝损伤的修复反应。肝星状细胞的激活、增殖是肝纤维化发生的中心环节，因此以肝星状细胞为靶点，抑制其活化是抗肝纤维化治疗的关键步骤。现对目前常用的针对肝星状细胞抗肝纤维化治疗的研究进展情况予以综述。     

细胞衰老与肾纤维化

细胞衰老是指随着时间的推移或受到某些特定刺激后而被激活的一种基本细胞应答程序,细胞脱离细胞周期,呈现衰老相关分泌型,分泌多种衰老信息传递分泌物,最终不可逆的丧失生长、增殖能力。近年来对于细胞衰老分子机制的研究主要包括氧化自由基学说、DNA损伤积累和端粒缩短等。线粒体的质量、活性改变与细胞衰老密切相关。细胞衰老需要借助信号通路转导,其中最主要的2条信号途径是P16Ink4a/Rb(retinoblastoma protein)途径和P19Arf/P53/P21Cip1途径,这2条途径相互作用但又相互独立地调控细胞周期的进程。细胞衰老与肿瘤、动脉粥样硬化、肺纤维化和肝纤维化等疾病的发生发展密切相关,在肾纤维化发生过程中也扮演了重要角色。调控细胞衰老及衰老细胞产生的SASP(senescence-associated secretory phenotype)将为肾纤维化的预防和治疗提供新的策略。     

基质金属蛋白酶抑制剂-1与肝纤维化

肝纤维化是多种原因引起的慢性肝损伤的共同病理改变，其特征是细胞外基质(ECM)过度沉积和构成改变。肝星状细胞(HSC)在肝纤维化中发挥关键作用。HSC位于肝细胞与内皮细胞之间的Disse间隙，正常时呈静止状态，不合成或仅合成少量的ECM，肝脏损伤后HSC活化并持续增殖，合成和分泌大量的ECM，是肝纤维化时ECM的主要来源细胞。活化的HSC主要通过凋亡机制减少，是促进肝纤维化逆转的重要因素。     

大鼠肝纤维化时肝星形细胞免疫组化研究

肝纤维化的发生过程中,肝脏内的星状细胞起了关键的作用。这种细胞在受到肝脏损伤的信号刺激后活化,在肝细胞与肝细胞之间产生大量纤维组织成份,形成纤维组织在肝内沉积,导致肝纤维化。结果表明,视黄醛主要贮存在肝脏,其内的肝星形细胞是肝纤维化时是主要的成纤维细胞。     

PPAR-γ对肝纤维化相关信号转导途径的影响

肝纤维化是慢性肝病最重要的病理特征,其关键因素为肝星状细胞的活化使肝脏内纤维性结缔组织异常增生。过化物酶体增殖物激活受体（peroxisome proliferater-activated receptor-gamma,PPAR-γ）在肝星状细胞由静止表型向活化表型的转化中起重要作用,本文以近期研究中引人注目的肝纤维化的信号通路为重点,探讨PPAR-γ对肝纤维化信号通路的影响。     

以DJ-1蛋白为靶点治疗肝纤维化的研究进展

肝纤维化是肝硬化演变过程中的一个重要阶段,其病理学特征主要是细胞外基质在肝内过量沉积,活化的肝星状细胞是肝纤维化的病理中心环节。许多细胞因子和信号通路已被证实参与肝纤维化或肝星状细胞的激活过程,但其中很多靶点在肝纤维化中的作用尚没有完全定论。近年来,已有研究提出DJ-1蛋白将成为治疗肝纤维化潜在的分子靶点,DJ-1可通过调控肝细胞内氧自由基水平、肝Kupffer细胞氧自由基水平、炎症细胞和吞噬细胞浸润等延缓肝纤维化的进程。该文从肝纤维化与氧化应激的关系、DJ-1蛋白的概述、DJ-1在治疗肝纤维化中的作用机制等方面综述了DJ-1蛋白在治疗肝纤维化中的作用及研究进展,并分析其作为治疗肝纤维化新靶点的利弊及应用前景。     

Fucoidan partly prevents CCl4-induced liver fibrosis

Fucoidan, a sulfated polysaccharide extracted from brown algae, has a wide range of biological activities, including anti-inflammatory, anti-viral, and anti-tumor activities. In the present study, we investigated the effects of fucoidan on CCl₄-induced liver fibrosis. Administration of fucoidan reduced CCl₄-induced acute and chronic liver failure. Hepatic fibrosis induced by CCl₄ was also attenuated by injection of fucoidan. Damage to hepatocytes and activation of hepatic stellate cells are key events in liver fibrosis, and, interestingly, treatment of hepatocytes with fucoidan prevented CCl₄-induced cell death and inhibited the proliferation hepatic stellate cells. These results indicate that fucoidan might be a promising anti-fibrotic agent possessing dual functions, namely, protection of hepatocytes and inhibition of hepatic stellate cell proliferation.     

Hepatic fibrosis -- overview

The study of hepatic fibrosis, or scarring in response to chronic liver injury, has witnessed tremendous progress in the past two decades. Clarification of the cellular sources of scar, and emergence of hepatic stellate cells not only as a fibrogenic cell type, but also as a critical immunomodulatory and homeostatic regulator are among the most salient advances. Activation of hepatic stellate cells remains a central event in fibrosis, complemented by evidence of additional sources of matrix-producing cells including bone marrow, portal fibroblasts, and epithelial-mesenchymal transition from both hepatocytes and cholangiocytes. A growing range of cytokines and their receptors and inflammatory cell subsets have further expanded our knowledge about this dynamic process. Collectively, these findings have laid the foundation for continued elucidation of underlying mechanisms, and more importantly for the implementation of rationally based approaches to limit fibrosis, accelerate repair and enhance liver regeneration in patients with chronic liver disease.     

Kupffer细胞在肝纤维化形成与转归中的作用

肝纤维化是由于反复肝损伤引起持续性炎症反应、瘢痕组织形成，导致正常组织结构破坏甚至器官衰竭的一类疾病。临床研究和动物实验均证实，肝脏内慢性长期炎症是导致过量瘢痕形成的主要诱因。在肝损伤期，Kupffer细胞快速激活并释放大量可溶性调节因子(包括过氧化物、细胞因子和蛋白酶等)，刺激肝星状细胞增殖、迁移和活化。另一方面，有研究显示，Kupffer细胞还参与肝纤维化转归，其功能可能与调节星状细胞的生物学活性及促进细胞外基质的降解有关。因此，深入研究Kupffer细胞的生物学特性以及在细胞因子环境下与星状细胞间的相互作用，对于理解肝纤维形成的病理学过程和肝纤维化转归的生理学机制具有重要的指导意义。     

Aloe emodin suppresses myofibroblastic differentiation of rat hepatic stellate cells in primary culture

We have studied the inhibitory effect of aloe emodin on hepatic stellate cells activation and proliferation, as these cells play a key role in the pathogenesis of hepatic fibrosis. Rat hepatic stellate cells were activated by contact with plastic dishes, resulting in their transformation into myofibroblast-like cells. Primary hepatic stellate cells were exposed to aloe emodin (1-10 microg/ml). Possible cytotoxic effects were measured on stellate cells and hepatocytes using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of aloe emodin on production of type I collagen and smooth muscle cell alpha-actin were examined at the same concentration, by quantitative immunoprecipitation. Antiproliferative effects were examined by bromodeoxyuridine incorporation. Aloe emodin at 10 microg/ml restored the morphological changes characteristic of activated primary stellate cells, reduced DNA synthesis to 95% of control hepatic stellate cells at 10 microg/ml without affecting cell viability, and inhibited type I collagen production and smooth muscle alpha-actin expression by 86.77% and 99%, respectively, which suggest that aloe emodin is a potent inhibitor of stellate cell transformation.     

Effect of S-adenosyl-L-methionine on the activation, proliferation and contraction of hepatic stellate cells

Inhibition of hepatic stellate cell activation is an important clinical aspect for the control of liver inflammation, fibrosis and cirrhosis. S-adenosyl-L-methionine (SAM), an intermediate product of L-methionine metabolism, is a precursor of glutathione and an endogenous methyl donor. Although the hepato-protective action of SAM has been reported in several animal models, the effect of SAM on the function of hepatic stellate cells has not been elucidated. Using a primary-culture model of hepatic stellate cells, we found that SAM blunts the activation process as indicated by the suppression of expression of collagen alpha1(I) and smooth muscle alpha-actin. SAM also hampers the DNA synthesis of hepatic stellate cells stimulated with a dimer of platelet-derived growth factor-B via the inhibition of phosphorylation of PDGF receptor-beta and down-stream signaling pathways. SAM additionally inhibits the contraction of hepatic stellate cells by disturbing the formation of F-actin stress fibers and phosphorylated myosin light chains. Thus, SAM regulates the activation of hepatic stellate cells and may clinically contribute to therapy targeted at human liver fibrosis.     

肝脏细胞自噬在肝纤维化中的作用研究进展

肝纤维化是由于各种致病因子引起的肝脏结缔组织的异常增生。肝星状细胞的活化被普遍认为肝纤维化的中心环节,在肝纤维化过程中,自噬在不同的肝脏细胞中发挥着不同作用。一方面,在肝巨噬细胞、肝内皮细胞和肝实质细胞中,自噬可影响肝细胞炎症损伤反应抑制肝纤维化的发生;另一方面,在肝星状细胞中,自噬可影响氧化应激、内质网应激和脂质代谢等促进肝纤维化的发生。本文对肝脏不同细胞自噬在肝纤维化中的作用进行综述,为开发延缓和逆转肝纤维化的药物提供更完善的理论基础。     

Developing strategies for liver fibrosis treatment

Liver fibrosis represents a major worldwide healthcare burden. Current therapy is limited to removing the causal agent. This approach is successful in some diseases; particularly haemochromatosis and chronic viral hepatitis. However, for many patients treatment is not possible, while other patients present to medical attention at an advanced stage of fibrosis. There is therefore a great need for novel therapies for liver fibrosis. The hepatic stellate cell has been recognised to be responsible for most of the excess extracellular matrix observed in chronic liver fibrosis. The detailed understanding of hepatic stellate cell biology has allowed the rational design of novel antifibrotic therapies. This review describes for the general reader the novel emerging therapies for liver fibrosis.     

三七皂苷抗肝纤维化作用的现状

肝纤维化是各种慢性肝病共同的病理基础，是慢性肝病发展到肝硬化、肝癌的必经途径。寻找有效的抗肝纤维化药物是近年研究的热点，其中对三七的研究也取得了很大进展。现综述近几年三七皂苷在保护肝细胞、抑制肝星状细胞活化、促进肝星状细胞凋亡、抑制细胞外基质的合成及促使其降解等方面的作用及可能机制，同时也阐述了三七皂苷在抗肝纤维化中的重要意义及应用前景。