MicroRNAs在肝纤维化进展中的作用

肝纤维化是世界范围内高发病率和高死亡率的主要疾病之一,它是各种慢性刺激性疾病如病毒性肝炎、酒精滥用、自身免疫性疾病、代谢性疾病以及胆汁淤积性肝病等疾病长期作用于肝脏引起的共同病理现象,进一步会发展为肝硬化、肝衰竭,门脉高压甚至引起死亡,而导致肝脏结构紊乱的细胞外基质(extracellular matrix,ECM)的过度累积是肝纤维化发生发展的主要因素。microRNAs是一类22-25nt的内源性非编码小RNA,大量研究表明,microRNAs的异常表达与肝纤维化的疾病进展密切相关,该文就近些年新发现的microRNAs对肝纤维化疾病中肝星状细胞(hepatic stellate cells,HSCs)的活化、增殖、凋亡以及老化的调控作用及机制进行总结并提出展望。     

Targeted delivery of drugs for liver fibrosis

Liver fibrosis and its end stage disease cirrhosis are a major cause of mortality and morbidity around the world. There is no effective pharmaceutical intervention for liver fibrosis at present. Many drugs that show potent antifibrotic activities in vitro often show only minor effects in vivo because of insufficient concentrations of drugs accumulating around the target cell and their adverse effects as a result of affecting other non-target cells. Hepatic stellate cells (HSC) play a critical role in the fibrogenesis of liver, so they are the target cells of antifibrotic therapy. Several kinds of targeted delivery system that could target the receptors expressed on HSC have been designed, and have shown an attractive targeted potential in vivo. After being carried by these delivery systems, many agents showed a powerful antifibrotic effect in animal models of liver fibrosis. These targeted delivery systems provide a new pathway for the therapy of liver fibrosis. The characteristics of theses targeted carriers are reviewed in this paper.     

Peroxisome proliferator‐activated receptor‐δ as emerging target in liver disease

Liver fibrosis is characterized by an excessive deposition of extracellular matrix (ECM) proteins that occurs in chronic liver disease of any origin, including nonalcoholic steatohepatitis (NASH), alcohol abuse, and viral hepatitis. Cirrhosis occurs with the development of regenerating nodules of hepatocytes and is a major health burden worldwide. Patients with decompensated liver cirrhosis have a poor prognosis, with liver transplantation often being necessary. The current treatment paradigm for patients with hepatic fibrosis is to treat the underlying liver disease. However, if this cannot be achieved, there are currently no effective antifibrotic treatments for patients with chronic liver diseases. With the advent of basic molecular technology providing insight into the mechanisms of the development of hepatic fibrosis, there is now an opportunity to develop therapeutic interventions for human clinical use. In this review, the function of peroxisome proliferator‐activated receptor‐δ (PPAR δ) will be summarized with a special emphasis on ligand activation as potential use in liver disease. Drug Dev Res 2009. © 2009 Wiley‐Liss, Inc.     

Advances in ultrasound-targeted microbubble-mediated gene therapy for liver fibrosis

Hepatic fibrosis develops as a wound-healing scar in response to acute and chronic liver inflammation and can lead to cirrhosis in patients with chronic hepatitis B and C. The condition arises due to increased synthesis and reduced degradation of extracellular matrix (ECM) and is a common pathological sequela of chronic liver disease. Excessive deposition of ECM in the liver causes liver dysfunction, ascites, and eventually upper gastrointestinal bleeding as well as a series of complications. However, fibrosis can be reversed before developing into cirrhosis and has thus been the subject of extensive researches particularly at the gene level. Currently, therapeutic genes are imported into the damaged liver to delay or prevent the development of liver fibrosis by regulating the expression of exogenous genes. One technique of gene delivery uses ultrasound targeting of microbubbles combined with therapeutic genes where the time and intensity of the ultrasound can control the release process. Ultrasound irradiation of microbubbles in the vicinity of cells changes the permeability of the cell membrane by its cavitation effect and enhances gene transfection. In this paper, recent progress in the field is reviewed with emphasis on the following aspects: the types of ultrasound microbubbles, the construction of an ultrasound-mediated gene delivery system, the mechanism of ultrasound microbubble–mediated gene transfer and the application of ultrasound microbubbles in the treatment of liver fibrosis.     

肝纤维化分子机制及治疗研究进展

肝纤维化由慢性肝炎造成,若治疗不及时将发展成为肝硬化、肝癌。目前,临床上尚无理想的治疗药物。随着肝纤维化分子机制逐渐得以阐明、基因技术不断发展,使肝纤维化的治疗成为可能。目前,肝纤维化治疗主要是通过抑制肝星状细胞（HSC）活化、增殖,抑制细胞外基质（ECM）的合成,促进ECM的降解,诱导活化HSC凋亡。本文就肝纤维化的分子机制和治疗进行综述,为以后的研究提供参考。     

Specific hepatic stellate cell-penetrating peptide targeted delivery of a KLA peptide reduces collagen accumulation by inducing apoptosis

Liver fibrosis is an aberrant wound-healing process to chronic hepatic inflammation and is characterized by excessive accumulation of extracellular matrix (ECM) that is produced by activated hepatic stellate cells (HSCs). Thus, activated HSCs play a key role in the pathogenesis of liver fibrosis and are a potential target for the treatment of liver fibrosis. Herein, we report that a specific HSC-penetrating peptide reduced collagen accumulation by inducing the apoptosis of HSC-T6 cells. We first screened HSC-specific transduction peptides and identified a novel HSC-targeted cell-penetrating peptide (HTP) that specifically interacted with HSC-T6 cells. A chimeric peptide termed HTPK25 was consequently generated by coupling HTP with the antimicrobial peptide KLA, which is capable of initiating cell apoptosis in mammalian cells. HTPK25 entered cells in a dose-dependent manner, reduced the cell viability and induced apoptosis via the caspase 3 pathway in HSC-T6 cells. Furthermore, HTPK25 inhibited the α-smooth muscle actin and collagen I expression in HSC-T6 cells. Our results demonstrated that the HTP was able to specifically and efficiently deliver the KLA peptide into HSC-T6 cells to induce apoptosis, indicating that HTP-delivered functional agents may present a promising approach for liver fibrosis therapy.     

Oridonin ameliorates carbon tetrachloride-induced liver fibrosis in mice through inhibition of the NLRP3 inflammasome

Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs) and accumulation of the extracellular matrix. There are limitations in the current therapies for liver fibrosis. Recently, oridonin was shown to induce apoptosis in HSCs. Thus, we aimed to determine the roles of oridonin in chronic liver injury and fibrosis. Liver fibrosis was induced by CCl₄ in mice injected intraperitoneally with oridonin for 6 weeks. The administration of oridonin significantly attenuated liver injury and reduced ALT levels. In addition, Sirius Red staining and the expression of α-smooth muscle actin (α-SMA) were significantly reduced by oridonin in murine livers with fibrosis. The expression of NLRP3, caspase-1, and IL-1β was downregulated with the oridonin treatment. Furthermore, the expression of F4/80 in liver tissues was also decreased by oridonin treatment. These results demonstrate that oridonin ameliorates chronic liver injury and fibrosis. Mechanically, oridonin may inhibit the activity of the NLRP3 inflammasome and inflammation in the liver. These results highlight the potential of oridonin as a therapeutic agent for liver fibrosis.     

肝巨噬细胞与肝纤维化研究进展

肝纤维化是由各种病因所致慢性肝损伤的修复反应,其持续进展可发展为肝硬化甚至肝细胞癌,最终导致肝功能衰竭。目前,肝纤维化尚无有效治疗方法。肝巨噬细胞在肝内炎症反应、纤维化的进展和消退方面发挥关键作用,已成为抗肝纤维化的重要治疗靶细胞。主要就肝巨噬细胞在肝纤维化过程中的作用进行综述,以期能够为肝纤维化治疗提供思路。     

TGF-β/Smad信号转导通路与肝纤维化研究进展

肝纤维化是慢性肝病向肝硬化发展的中间过程,以胶原蛋白为主的细胞外基质（extracellular matrix,ECM）合成与降解失衡,导致过多的胶原在肝内沉积,是多条细胞信号转导通路和一系列细胞信息分子网络共同控制的结果。转化生长因子β（TGF-β）是肝纤维化病变过程中最关键的细胞因子之一。其中TGF-β/Smad信号转导通路是TGF-β信号转导调节肝星状细胞（HSC）活化促进ECM生成的主要途径。本文就TGF-β/Smad信号转导通路在肝纤维化过程中的作用及其研究进展予以综述。     

Emerging drugs for complications of end-stage liver disease

Background: The prevalence of end-stage liver disease is rising rapidly and constitutes a major healthcare burden currently. Many cases are diagnosed at a later stage when liver transplantation is the only effective treatment option. There is thus an urgent need for novel treatments to reverse the earlier stages of cirrhosis as well as to treat the many associated life-threatening complications. Objectives: To review the current drugs available for treating the complications of advanced liver disease. To address novel treatment strategies that are in development, with particular reference to the rapidly developing area of antifibrotic therapy. To assess how the obstacles that have so far impeded the development of effective new drugs for end-stage liver disease may be overcome in the future. Methods: The literature was reviewed to define current therapies and therapies in clinical trials. We used the current models of the molecular basis of liver fibrogenesis to determine potential new therapeutic targets for antifibrotic therapy. Conclusions: Insights into the pathogenesis of liver injury and fibrosis have opened up new avenues for therapy and there are now candidates and targets with real potential for the development of a new generation of antifibrotic therapies.     

Probucol attenuates ethanol‐induced liver fibrosis in rats by inhibiting oxidative stress,extracellular matrix protein accumulation and cytokine production

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TGFβ信号转导通路及以其为靶点的肝纤维化治疗

肝纤维化是指由多种慢性疾病引起的肝脏持续的创伤修复反应而导致的细胞外基质(ECM)过度沉积和肝脏功能的受损。激活的肝星状细胞(HSC)是促进ECM过度沉积的主要细胞。转化生长因子β(TGFβ)可激活HSC和调节ECM的合成和沉积,被认为是肝纤维化中最关键的因素。介导TGFβ信号进入细胞核内的最主要途径是Smad转导通路,而越来越多的证据表明,非Smad途径也参与了TGFβ的信号转导。TGFβ信号通路对维持内环境的稳态非常重要并涉及多种病理状态。这种具有多重生物活性的细胞因子对正常健康的维持同样非常重要,所以在TGFβ信号转导中通过阻断对纤维化的形成具有特异性作用的下游通路且不影响其他的生物活性而治疗肝纤维化具有重要的挑战性。     

Th17／Treg 失衡在肝纤维化中的研究进展

肝纤维化是一种机体的慢性炎症反应,其特征是细胞外基质（ECM）合成与降解的失衡,从而造成肝内 ECM的病理性沉积,导致肝功能紊乱,最终发展为肝硬化,甚至是肝癌。肝纤维化的发病机理目前尚未清楚。随着免疫学的发展,T 细胞在肝纤维化的发病过程中的作用逐步得到认识,Th17细胞与 Treg 细胞这两种 T 细胞亚型在肝纤维化的发病过程中的作用已逐渐被认可。因此,该文就这两种细胞以及这两种细胞的相互作用在肝纤维化过程中的研究进展进行综述。     

人工肝支持系统对重症肝炎肝硬化患者肝脏储备功能的影响

目的 探讨人工肝支持系统对重症肝炎肝硬化患者肝脏储备功能的影响.方法 采用回顾性对照研究方法,选取60例重症肝炎合并肝硬化患者,按照治疗方法不同分为对照组和观察组.对照组采用内科综合治疗,观察组在对照组的基础上,采用人工肝支持治疗,对两组患者肝功能指标及肝功能储备指标吲哚菁绿(ICG)15 min储留率、肝脏有效循环血量、终末期肝病模型评分进行比较.结果 两组患者治疗前后丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、血清白蛋白(ALB)、血清总胆红素(TBil)及凝血酶源总活动度(PTA)、ICG 15 min储留率、肝脏有效循环血量、终末期肝病模型评分等指标比较,差异有统计学意义(P<0.05).结论 在综合治疗的基础上,对重症肝炎合并肝硬化患者实施人工肝置换治疗,为肝细胞的自身修复创造了一个有利环境,有助于改善患者的肝脏储备功能.     

Inhibition of ALK5 as a new approach to treat liver fibrotic diseases

Liver fibrosis is the result of an unbalanced wound healing response to a chronic hepatic injury. Transforming growth factor-beta (TGF-beta) plays a major role in this process via the activation of hepatic stellate cells. Various approaches have been tested in animal models of fibrosis to block the effects of TGF-beta, including antibodies and soluble receptors. Here, we discuss the potential use of TGF-beta signaling inhibitors, acting at the TGF-beta type I receptor kinase (ALK5) level, as a possible therapy for liver fibrosis. Thus far, there is only one ALK5 inhibitor (GW6604) for which activity in models of liver fibrosis has been described, showing clear antifibrotic effects resulting in liver function improvement. However, due to the pleiotropic effects of TGF-beta, the beneficial antifibrotic effects of ALK5 inhibition should be carefully balanced against the potential risk of unwanted effects stemming from chronic treatment.     

Insights on drug and gene delivery systems in liver fibrosis

Complications of the liver are amongst the world's worst diseases. Liver fibrosis is the first stage of liver problems, while cirrhosis is the last stage, which can lead to death. The creation of effective anti-fibrotic drug delivery methods appears critical due to the liver's metabolic capacity for drugs and the presence of insurmountable physiological impediments in the way of targeting. Recent breakthroughs in anti-fibrotic agents have substantially assisted in fibrosis; nevertheless, the working mechanism of anti-fibrotic medications is not fully understood, and there is a need to design delivery systems that are well-understood and can aid in cirrhosis. Nanotechnology-based delivery systems are regarded to be effective but they have not been adequately researched for liver delivery. As a result, the capability of nanoparticles in hepatic delivery was explored. Another approach is targeted drug delivery, which can considerably improve efficacy if delivery systems are designed to target hepatic stellate cells (HSCs). We have addressed numerous delivery strategies that target HSCs, which can eventually aid in fibrosis. Recently genetics have proved to be useful, and methods for delivering genetic material to the target place have also been investigated where different techniques are depicted. To summarize, this review paper sheds light on the most recent breakthroughs in drug and gene-based nano and targeted delivery systems that have lately shown useful for the treatment of liver fibrosis and cirrhosis.     

Liver-targeted delivery of asiatic acid nanostructured lipid carrier for the treatment of liver fibrosis

Liver fibrosis is a major global health concern. Management of chronic liver disease is severely restricted in clinics due to ineffective treatment approaches. However, a lack of targeted therapy may aggravate this condition. Asiatic acid (AA), a pentacyclic triterpenoid acid, can effectively protect the liver from hepatic disorders. However, the pharmaceutical application of AA is limited by low oral bioavailability and poor targeting efficiency. This study synthesized a novel liver-targeting material from PEG-SA, chemically linked to ursodeoxycholic acid (UA), and utilized it to modify AA nanostructured lipid carriers (UP-AA-NLC) with enhanced targeting and improved efficacy. The formulation of UP-AA-NLC was optimized via the Box–Behnken Experimental Design (BBD) and characterized by size, zeta potential, TEM, DSC, and XRD. Furthermore, in vitro antifibrotic activity and proliferation of AA and NLCs were assessed in LX-2 cells. The addition of UP-AA-NLC significantly stimulated the TGF-beta1-induced expression of α-SMA, FN1, and Col I α1. In vivo near-infrared fluorescence imaging and distribution trials in rats demonstrated that UP-AA-NLC could significantly improve oral absorption and liver-targeting efficiency. Oral UP-AA-NLC greatly alleviated carbon tetrachloride-induced liver injury and fibrosis in rats in a dosage-dependent manner, as reflected by serum biochemical parameters (AST, ALT, and ALB), histopathological features (H&E and Masson staining), and antioxidant activity parameters (SOD and MDA). Also, treatment with UP-AA-NLC lowered liver hydroxyproline levels, demonstrating a reduction of collagen accumulation in the fibrotic liver. Collectively, optimized UP-AA-NLC has potential application prospects in liver-targeted therapy and holds great promise as a drug delivery system for treating liver diseases.     

Impact of inhibitors of the Renin-Angiotensin-aldosterone system on liver fibrosis and portal hypertension

Morbidity and mortality of chronic liver disease are primarily caused by liver cirrhosis and portal hypertension, both of them secondary disorders of progressive liver fibrosis. The main fibrogenic cell type in the liver, the hepatic stellate cell (HSC), is activated and stimulated by several factors, among which the renin-angiotensin-aldosterone system (RAAS) plays a major role. Angiotensin II induces various profibrotic pathways via the angiotensin II receptor type 1 (AT(1) receptor) not only in heart and kidney, but also in liver tissue. Stimulation of the AT(1) receptor promotes the transformation of the quiescent HSC into the myofibroblast like activated HSC and the synthesis of transforming growth factor-beta1 (TGF-beta), the major profibrotic cytokine in the liver. In addition, aldosterone has been suggested to induce profibrotic effects in chronic heart and liver disease. This review focuses on the concept that inhibitors of the RAAS retard or even reverse liver fibrosis and reduce portal hypertension. Angiotensin converting enzyme (ACE) inhibitors, AT(1) receptor antagonists, and aldosterone antagonists have been demonstrated to reduce the proliferation of HSC, to decrease the synthesis of profibrotic molecules, and to have the potential to improve liver fibrosis. However, side-effects such as systemic hypotension may impair the clinical application of RAAS inhibitors in patients with liver cirrhosis and portal hypertension. Also, efficacy may be limited by the downregulation of AT(1) receptors in advanced fibrosis, which has been observed in animal and human studies. Randomized clinical studies are essential to evaluate, whether this approach is beneficial in patients with chronic liver disease and progressive fibrosis.     

松弛素治疗肝纤维化的研究进展

肝纤维化是肝内细胞外基质异常增生而降解减少的一种失衡性沉积的病理结果，是多种慢性肝病向肝硬化进展的共同反应，现在还没有药物被批准用于肝纤维化临床治疗。目前，纤维化可逆性已被确定为抗纤维化药物的重要原则和靶点之一。松弛素治疗因其能减弱活化的肝星状细胞的纤维化特性并逆转已形成的纤维化而受到重视。本文从肝纤维化发病机制、治疗现状、松弛素的概述及其治疗机制进行综述，为拓展松弛素疗法提供依据和指导。     

扶正化瘀胶囊联合穴位注射治疗肝硬化疗效观察

目的 观察扶正化瘀胶囊联合穴位注射治疗肝硬化的疗效.方法 64例肝硬化患者随即分为两组,治疗组34例,服用扶正化瘀胶囊,5粒/次,3次/d,并联合丹参注射液穴位注射治疗.对照组30例,采用一般护肝以及对症治疗.观察治疗前后患者肝功能生化指标及肝纤维化指标变化,并与对照组对比.结果 两组治疗后肝功能生化指标与肝纤维化指标均有改善,治疗组肝功能生化指标的改善和肝纤维指标的下降均优于对照组,组间比较有统计学意义(P＜O.01或P＜0.05).结论 扶正化瘀胶囊联合穴位注射能有效控制肝硬化患者的肝纤维化进展,改善患者肝功能.