中药抑制肝星状细胞活化作用的研究进展

多项研究表明中药可通过抑制星状细胞活化而干预肝纤维化的形成和发展.其途径主要有两种:第一是抑制星状细胞的激活.第二是使已活化的星状细胞数量减少.但目前研究仍存在一些问题:(1)中药产地、剂型、品系存在差异.如何统一其疗效作用;(2)需进一步明确复方制剂相互作用的机制及各自作用的靶点,以最好的发挥中药协同抗纤维化的作用:(3)现有的中药制剂可抗纤维化和延缓纤维化的形成,但对已形成的肝纤维化无明显疗效;(4)部分中药对肝功能存在不可避免的损害.这些都将成为今后抗纤维化研究的重要课题.     

中药有效成分作用于肝星状细胞抗肝纤维化分子机制研究进展

肝纤维化是多种慢性肝病进展至肝硬化的中间过程,抑制肝星状细胞(HSC)激活,促进HSC凋亡两方面成为预防和治疗肝纤维化的关键。中药能够多途径、多靶点,通过多种细胞因子及细胞通路作用于HSC,发挥抗肝纤维化作用。该文总结HSC激活及凋亡主要分子机制,及近几年有关中药有效成分作用于HSC抗肝纤维化分子机制研究,为深入开展抗肝纤维化提供参考。     

基于细胞信号通路探讨姜黄素抗肝纤维化的研究进展

肝纤维化是以肝星状细胞活化与增殖、细胞外基质沉积为主要特征的肝慢性疾病发展而来的一种修复反应。目前临床上尚无理想的治疗肝纤维化特效药物。近年来经研究证实，姜黄素具有良好的抗肝纤维化效应。通过检索并总结国内外近年姜黄素影响肝纤维化进程的各个通路相关文献发现，姜黄素可以通过调控TGF-β1/Smad、NF-κB、PPARγ、Wnt/β-catenin、Nrf2/HO-1、PI3K/Akt、p38MAPK、Hedgehog多条信号通路，发挥减少肝脏炎症反应，抑制肝星状细胞活化与增殖，促进肝星状细胞凋亡，降低肝组织内氧化应激水平，减少胶原蛋白合成和细胞外基质沉积等多方面作用，达到抗肝纤维化效应。本文为姜黄素介导多种信号途径治疗肝纤维化提供理论依据，显示出从多靶点、多途径、多层次相互作用的机制特点。     

基于PI3K/Akt信号通路探讨中药活性成分抗肝纤维化的研究现状

肝纤维化是肝脏对慢性损伤的一种病理性修复反应,是慢性肝病进展的关键环节,主要以肝星状细胞活化与细胞外基质弥漫性沉积为主要特征。目前临床上尚无理想的治疗肝纤维化的特效药物。近年来,随着中医药抗肝纤维化的发展和进步,中医药以其治疗效果明显,不良反应少等优势受到了广泛的关注。磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B(Akt)信号通路是影响肝纤维化形成与发展重要的信号通路,其主要通过抑制肝星状细胞的活化与增殖、促进肝星状细胞的凋亡、减轻肝细胞氧化应激、减少细胞外基质沉积及增强肝细胞自噬等发面发挥肝纤维化效应。该文通过梳理中药单体靶向调控PI3K/Akt信号通路,总结中药单体调控PI3K/Akt发挥肝纤维化的作用机制及与其他信号通路的相互协同作用,以期为中医药治疗肝纤维化和临床新药研发给予一定的理论依据与参考。     

中药复方抗肝纤维化作用机制研究概况

肝纤维化是各种致病因素导致肝内结缔组织异常增生的肝内弥散性细胞外基质过度沉积的病理过程．近年来对中药复方抗肝纤维化的作用机制研究已取得了一定的进展，其机理主要为抗肝损伤、促进细胞外基质的降解、抑制肝星状细胞的活化与增殖、促进肝星状细胞凋亡、拮抗细胞因子的中介作用等，这些作用机理的揭示为指导临床用药提供了可靠的药理学依据。     

丹参有效成分抗肝纤维化作用机制的研究进展

肝纤维化是多种病因引起肝损害后经一系列连锁反应最终可进展为肝硬化的病理过程。通过大量研究现已证实肝纤维化可被逆转,而中药以其多途径的治疗特点在抗肝纤维化治疗上具有极大优势。丹参是临床常用的抗肝纤维化的中药,具有很好的疗效,主要成分有丹参酮、丹酚酸和丹参单体IH764-3。已有大量研究阐明了丹参抗肝纤维化的分子机制,其对肝纤维化形成的各个环节均有影响,如抗炎症反应、抑制炎症因子释放、抗氧自由基损伤、抑制星状细胞活化、抑制胶原过度沉积、改善微循环障碍等。本文即对丹参有效成分在肝纤维化治疗中的多种作用及机制做一综述。     

中药抑制肝星状细胞活化治疗肝纤维化研究进展

肝纤维化（Hepatic fibrosis, HF）是肝脏受到损伤时产生的病理变化。其实质是肝脏受到慢性损伤后,肝星状细胞（Hepatic stellate cells, HSCs）产生大量细胞外基质并在肝脏中过度堆积形成瘢痕组织,是慢性肝病发展到肝硬化的重要环节。中药能够通过多靶点、多途径作用于HSCs,抑制细胞外基质的大量堆积,达到抗纤维化的作用。本综述通过总结HSCs活化机制、中药活性成分、中药有效部位、中药复方抑制HSCs活化的研究进展,为深入研究中药治疗HF提供理论依据。     

软肝冲剂对肝细胞影响及星状细胞活化机制的干预作用

目的：观察软肝冲剂抗肝纤维化的作用及机理。方法：体外培养四氯化碳（CCL4）肝纤维化大鼠肝细胞（HC）、星状细胞（HSC），观察软肝冲剂含药血清对其影响。结果：软肝冲剂有保护肝细胞、减轻CCl4对肝细胞损伤，抑制HSC活化，促肝细胞再生的作用。结论：软肝冲剂具有抗脂质过氧化和抑制HSC活化的作用，从而抑制肝纤维化的形成。     

软肝冲剂对肝细胞影响及星状细胞活化机制的干预作用

目的:观察软肝冲剂抗肝纤维化的作用及机理。方法:体外培养四氯化碳(CCL4)肝纤维化大鼠肝细胞(HC)、星状细胞(HSC),观察软肝冲剂含药血清对其影响。结果:软肝冲剂有保护肝细胞、减轻CC l4对肝细胞损伤,抑制HSC活化,促肝细胞再生的作用。结论:软肝冲剂具有抗脂质过氧化和抑制HSC活化的作用,从而抑制肝纤维化的形成。     

中药血清与肝星状细胞研究进展

肝星状细胞（hepatic stellate cells,HSCs）的活化、增殖是肝纤维化形成和发展的中心环节。利用中药血清药理学研究方法发现,中药血清可干预肝纤维化形成和发展。综述了中药血清与肝星状细胞的研究进展,指出中药血清从抑制HSCs活化、HSCs增殖、HSCs收缩,促进HSCs凋亡等多靶点作用于肝星状细胞。可能是一种有效的抗肝纤维化治疗方法。     

从虚论治肝纤维化相关方剂的现代药理作用研究进展

肝纤维化表现为炎症细胞浸润、肝星状细胞激活、细胞外基质沉积及瘢痕组织形成，是各类慢性肝病向各类终末期肝病转变的关键病理过程。近年来，中医药被证明在防治肝纤维化方面成果突出，中医学对肝纤维化具有极富特色的诊疗理念，认为肝纤维化基本证候病机中“虚损”为其根本，并集中表现为气虚络瘀、肝郁脾虚和肝肾阴虚等证型，通过对以上3种常见肝纤维化证型总结相应常用效验方剂的临床及药理学研究进展，归纳其调控肝星状细胞命运、调节胆汁酸代谢、促进细胞外基质降解、抑制肝窦内皮血管化等潜在作用机制，为临床防治肝纤维化提供新思路。     

天然产物抗肝纤维化作用及其机制研究进展

肝纤维化(liver fibrosis/hepatic fibrosis,LF/HF)是多数慢性肝病所共有的病理特征,其持续恶化会逐步发展形成肝硬化,最终导致肝癌。目前临床用于治疗肝纤维化的药物种类众多,但西药靶点单一、不良反应多,中药大多作用机制、活性成分不明确,缺乏统一的诊疗标准。因此,寻找物质基础明确的抗肝纤维化有效药物至关重要。天然产物具有结构多样性、毒性较低、来源广泛等特点,在抗肝纤维化方面有着独特的优势和巨大的潜力。本文主要通过CNKI,Sciencedirect,百度学术等数据库对近年来国内外有抗肝纤维化作用的天然产物进行综述,归纳为生物碱类、多糖类、黄酮类、多肽类、萜类、多酚类,并总结其抗肝纤维化的作用机制,包括抑制肝脏炎症反应,抗脂质过氧化损伤,抑制肝星状细胞的活化和增殖,影响促纤维化因子的合成与分泌,调节细胞外基质合成与降解等,以期为抗肝纤维化药物的研制提供参考。     

黄酮类成分抗肝纤维化作用及其机制的研究进展

肝纤维化是肝脏对各种急慢性肝损伤进行的一种创伤修复过程,以细胞外基质的过度增生与异常沉积为主要病理特征,其持续发展会恶化为肝硬化、肝癌等疾病。肝纤维化具有可逆性,减轻或逆转肝纤维化被认为是预防肝硬化、肝癌的重要手段。研究表明,黄酮类成分具有抗肝纤维化的作用,其作用机制与抗炎、抗氧化应激、抗凋亡、抑制细胞外基质的异常堆积等有关。黄酮类成分通过多通路、多靶点减轻或逆转肝纤维化进程,近年来备受学者重视。对近10年来国内外报道的具有抗肝纤维化活性的黄酮类成分及其作用机制进行总结,以期为开发黄酮类抗肝纤维化药物提供参考。     

Effects of novel Fufang Biejia Ruangan Tablets with sheep placenta as substitute for hominis placenta on CCl4-induced liver fibrosis

Objective Fufang Biejia Ruangan Tablet (FBRT) is widely used for the treatment of liver fibrosis. However, Hominis Placenta (HP), as an important adjuvant of FBRT, has been restricted for medicinal using due to the limited availability, ethical controversy and safety issues. The present study aimed to investigate the therapeutic effects of novel FBRT (N-FBRT) with sheep placenta (SP) as substitute for HP on liver fibrosis and explore its possible mechanisms. Different dosages of SP in N-FBRT were also evaluated. Methods Rats were subcutaneously injected with CCl4 to induce liver fibrosis and then treated with N-FBRT and FBRT. The anti-hepatic fibrosis effect was determined based on biomarkers analysis of liver function and hepatic fibrosis, and the liver pathology was visualized by H&E staining and Masson staining. The oxidative stress and inflammatory cytokines were also detected. Immunohistochemical staining of α-SMA, real time PCR and Western blotting were performed to evaluate hepatic stellate cells (HSCs) activation and TGF-β1/Smad signaling pathway. Results N-FBRT and FBRT could ameliorate CCl4-induced liver fibrosis and improve liver function, as evidenced by lowering serum biomarkers levels of liver function and hepatic fibrosis, and decreasing hepatic Hyp content and collagen deposition, and improving the hepatic morphology and architecture changes. Moreover, the anti-liver fibrosis effect was better when the dosage of SP used in N-FBRT was 1/2 of HP in FBRT. Administration of N-FBRT markedly alleviated oxidative stress and inflammatory cytokines, and inhibited α-SMA expression. Furthermore, the mRNA expression of Col I, Col III, α-SMA and TGF-β1, and proteins expression of α-SMA, TGF-β1, Smad2/3 and p-Smad2/3 were significantly down-regulated by N-FBRT treatment. Conclusion SP can be used as substitute for HP to prepare N-FBRT for the treatment of liver fibrosis and the anti-liver fibrosis effect of N-FBRT is achieved by eliminating oxidative stress and inflammation, and inhibiting HSCs activation and ECM production by blocking TGF-β1/Smad signaling pathway.     

下瘀血汤全药与组分处方抗猪血清肝纤维化的比较研究

目的:比较下瘀血汤全药与组分处方抗肝纤维化的作用差异.方法:Wistar大鼠随机分为正常组、造模组.造模组大鼠ip猪血清复制肝纤维化模型,每次0.5 mL/只,每周2次,共12周.造模成功后造模组大鼠随机分为模型组、下瘀血汤组、组分处方组,第8周开始下瘀血汤组、组分处方组大鼠造模同时ig给药,按10 mL·kg-1容积,下瘀血汤组每日2.34 g·kg -1,组分处方组每日0.648 g·kg-1.连续4周.正常组、模型组大鼠ig同体积生理盐水.12周末,处死动物,获取标本,检测血清肝功能、肝脏病理.结果:与模型组相比,下瘀血汤组、组分处方组大鼠肝质量明显减少(P＜0.05);肝体比、脾质量、脾体比均有下降趋势;总蛋白(TP),球蛋白( Glb)含量明显减少(P＜0.05),A/G比值倒置情况明显改善(P＜0.05);白蛋白(Alb)含量均有升高趋势.下瘀血汤组与组分处方组相比较,大鼠肝质量、肝体比、脾质量、脾体比均有好转趋势;Alb含量有升高趋势,TP,Glb含量有下降趋势,A/G比值倒置情况有改善趋势.与正常组相比,模型组、下瘀血汤组、组分处方组纤维化分级差异有显著性(P＜0.05);与模型组相比,下瘀血汤组、组分处方组纤维化分级差异有显著性(P＜0.05).提示二者均有一定改善肝功能、改善肝脏病理作用,且下瘀血汤组有优于组分处方组的趋势.结论:降低免疫反应和保护肝细胞是下瘀血汤全药和组分处方抗肝纤维化的主要作用机制,且下瘀血汤全药处方作用优于组分处方.     

中药及其复方抗肝纤维化作用机制的研究进展

肝纤维化是指由各种致病因子所致肝内结缔组织异常增生,导致肝脏中细胞外基质(ECM)的过度积累,纤维性瘢痕形成的病理过程。其持续恶化会逐步发展成肝硬化、肝衰竭、肝癌等严重肝脏疾病。由于肝纤维化及肝硬化早期可以逆转,因此控制肝纤维化这一可逆过程,对于肝硬化和肝癌的预防及治疗至关重要。近年来研究发现,中药治疗肝纤维化具有多靶点、毒副作用小、效果好等特点。该文对中药及其复方抗肝纤维化作用机制进行了归纳总结,包括中药可通过调节转化生长因子-β(TGF-β),血小板衍生生长因子(PDGF),血管内皮生长因子(VEGF),结缔组织生长因子(CTGF)等生长因子来抑制肝星状细胞(HSCs)活化和诱导活化的HSCs凋亡,促进脂联素的表达和抑制瘦素的分泌,抑制肝脏炎症反应,抗氧化应激,抑制肝窦内皮细胞毛细血管化等多个层面有效阻止肝纤维化的进展。因此中药能通过多机制和多层面抑制肝纤维化的发展,是治疗肝纤维化疾病的重要手段之一。     

A Chinese herbal medicine, Gexia-Zhuyu Tang (GZT), prevents dimethylnitrosamine-induced liver fibrosis through inhibition of hepatic stellate cells proliferation

Ethnopharmacological evidence

Gexia-Zhuyu Tang (GZT), also called Gexiazhuyu decoction (GXZYD), is a traditional Chinese herbal medicine for chronic liver diseases such as cirrhosis and liver fibrosis.

Aim of the study

In this study, we have investigated the affects of GZT on a rat model of dimethylnitrosamine (DMN)-induced liver fibrosis.

Materials and methods

In this study, the protective effects of GZT on DMN-induced liver fibrosis were measured using a rat model. Following 5 weeks of DMN-treatment (8 mg/kg, i.p., given 3 consecutive days each week), oral administration of GZT at 1.8 g/kg daily via oral gavage for 2 weeks beginning at week 13.

Results

Both body and liver weights were significantly decreased. The reductions in body and liver weights corresponded with increasing liver damage severity. Furthermore, GZT-treatment remarkably decreased the levels of serum GOT (glutamate oxaloacetate transaminase) and GPT (glutamic pyruvic transaminase), and the mRNA expression levels of collagen alpha-1(I) and alpha-smooth muscle actin (alpha-SMA) in DMN-induced hepatic fibrosis. In addition, hepatic stellate cells (HSCs) play a major role in various types of liver fibrosis through initial myofibroblast transformation. The proliferation of HSCs was inhibited by GZT. Treatment with GZT also induced HSC apoptosis in a dose- and time-dependent manner. GZT treatment induced HSC apoptosis by facilitating Ca²⁺ release from the mitochondria within 6 h. Subsequently, caspases 3 and 12 were elevated by 72 h after treatment.

Conclusions

Our studies indicate that GZT exhibited both hepatoprotective and antifibrogenic effects in DMN-induced hepatic injury. These findings suggest that GZT may be useful in preventing the development of hepatic fibrosis.     

化纤复肝方抗肝纤维化的临床研究

[目的]观察中药化纤复肝方在抗肝纤维化方面的疗效.[方法]选取62例肝纤维化患者随机分为两组,治疗组32例.对照组30例.治疗6个月.观察治疗前后两组患者的症状、体征、肝功能及肝纤维化指标的变化,评价中药化纤复肝方抗肝纤维化的疗效.[结果]治疗组改善肝纤维化患者的症状、恢复肝功能、降低血清肝纤维化指标明显优于对照组(P<0.05).[结论]化纤复肝方有比较良好的抗肝纤维化的效果.     

Ganoderma lucidum extract attenuates the proliferation of hepatic stellate cells by blocking the PDGF receptor

Hepatic fibrosis is an outcome of chronic liver diseases. The activation and proliferation of hepatic stellate cells (HSCs) is a key event in liver injury. The fruiting body of Ganoderma lucidum has long been a popular oriental medicine for treating liver diseases. The aim of this present study was to investigate the antiproliferative effects of the triterpenoid‐rich extract (GLT) of G. lucidum in a cell line of rat HSCs (HSC‐T6) stimulated with platelet‐derived growth factor (PDGF)‐BB. DNA synthesis was investigated by bromodeoxyuridine (BrdU) incorporation. Flow cytometry using propidium iodide (PI) labeling was carried out to analyse the cell cycle distribution and apoptosis. α‐Smooth muscle actin (α‐SMA) was used to evaluate extracellular matrix deposition, and western blotting was performed to measure cyclins D1 and D2, and phosphorylation of the PDGFβ‐receptor (PDGFβR), Akt and JNK. The results indicated that the GLT attenuated BrdU incorporation in a concentration‐dependent manner with an IC₅₀ of 8.52 ± 0.33 µg/mL. The inhibitory effect of the GLT was associated with downregulation of cyclins D1 and D2, and PDGFβR and Akt phosphorylation, upregulation of JNK phosphorylation, and a reduction in α‐SMA expression. These results indicated that G. lucidum inhibits PDGF‐BB‐activated HSC proliferation possibly through blocking PDGFβR phosphorylation, thereby indicating its efficacy for preventing and treating hepatic fibrosis. Copyright © 2008 John Wiley & Sons, Ltd.