扶正化瘀胶囊对鼠血吸虫肝纤维化的作用及机制探讨

目的:研究扶正化瘀胶囊对实验性血吸虫病肝纤维化的影响,探讨其相关作用机制。方法:70只昆明小鼠分为正常对照组(A)、模型组(B)、吡喹酮组(C)、INF-γ组(D)、扶正化瘀胶囊低剂量组(E)、中剂量组(F)、高剂量组(G),采用日本血吸虫尾蚴30条/只攻击感染小鼠建立血吸虫性肝纤维化模型。第6周用吡喹酮驱虫治疗后予扶正化瘀胶囊干预,第14周末观察血清透明质酸、层粘连蛋白、III型前胶原、IV型胶原水平,HE染色观察肝脏病理改变及虫卵结节变化,免疫组化检测PDGF-BB和I、III型胶原的表达。结果:扶正化瘀胶囊各剂量组肝脏病理损伤减轻,虫卵肉芽肿面积和数量明显减小;血清HA、LN、PC-III、C-IV水平显著下降(P<0.05);肝组织I、III型胶原和PDGF-BB表达明显低于模型组(P<0.05)。结论:扶正化瘀胶囊具有抗血吸虫性肝纤维化作用,降低肝组织PDGF-BB的表达可能是其抗纤维化作用机制之一。     

扶正化瘀胶囊对心肌梗死大鼠心肌纤维化的影响

目的：急性心肌梗死是危害人类健康的重大疾病之一,心肌梗死后心肌纤维化是造成心脏结构破坏、心功能下降、心律失常发生、心衰甚至猝死的微观病理机制。防治心肌纤维化是当前医学研究的重点和热点。本研究主要探讨扶正化瘀胶囊对心肌梗死大鼠心肌纤维化的干预作用。方法：大鼠随机分为假手术组、模型组、扶正化瘀胶囊组和卡托普利组,采用结扎冠状动脉前降支的方法建立心肌梗死模型,假手术组只穿线,不结扎。于造模成功后第10天开始给予相应药物治疗2个月。治疗结束后,检测左心室梗死范围和心肌胶原含量。结果：与假手术组比较,模型组、扶正化瘀胶囊组和卡托普利组的非梗死区面积显著减小（P〈0.01）。与模型组比较,扶正化瘀胶囊组和卡托普利组的梗死区面积和梗死百分比显著减小（P〈0.05,P〈0.01）。在心肌胶原表达上,与假手术组比较,模型组和扶正化瘀胶囊组胶原含量显著增加（P〈0.01）。与模型组比较,卡托普利组和扶正化瘀胶囊组胶原含量显著降低（P〈0.05,P〈0.01）。结论：扶正化瘀胶囊能够改善心肌缺血,缩小心肌梗死范围,抑制心肌胶原表达,除能用于肝纤维化的治疗外,还能用于防治心肌梗死后的心肌纤维化。     

大黄素抗肝纤维化作用机制研究进展

肝纤维化是各种病因所致的慢性肝病的共同病理过程,也是向肝硬化发展的主要中间环节。研究表明,肝纤维化的病理是可逆的,只要在肝纤维化阶段进行合理治疗,完全可以达到逆转肝纤维化进程,进而缓解乃至治愈肝纤维化的目的。因此,能否终止肝纤维化的进展甚或逆转至正常,是治疗各种慢性肝病的关键。目前,临床实践证实中医药抗肝纤维化具有潜在的优势,疗效优于西医,其实验研究也日益受到重视。[第一段]     

三七总皂苷抗肝纤维化作用机制的研究进展

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、抑制肝星形细胞活化、促进肝星形细胞凋亡、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,同时也阐述了三七总皂苷在抗肝纤维化中的重要意义及应用前景。     

基于TGF-β1/Smads信号通路探讨扶正化瘀胶囊联合恩替卡韦分散片治疗慢性乙型肝炎肝纤维化的疗效机制

摘要 目的：基于转化生长因子-β1（TGF-β1）/Smads信号通路探讨恩替卡韦分散片联合扶正化瘀胶囊治疗慢性乙型肝炎肝纤维化的疗效机制。方法：纳入新疆医科大学第一附属医院2020年4月~2022年1月期间收治的慢性乙型肝炎肝纤维化患者104例,将患者根据随机数字表法分为对照组和观察组,例数各为52例。在常规治疗的基础上,对照组接受恩替卡韦分散片治疗,观察组接受扶正化瘀胶囊联合恩替卡韦分散片治疗。对比两组肝功能指标、肝纤维化指标、TGF-β1/Smads信号通路相关指标和影像学指标变化情况。结果：治疗24周后,两组丙氨酸氨基转移酶 （ALT）、天门冬氨酸氨基转移酶（AST）水平均下降,且观察组的下降程度较对照组更大（P<0.05）。治疗24周后,两组Ⅲ型前胶原（PCⅢ）、层粘连蛋白（LN）、Ⅳ型胶原（Ⅳ-C）、透明质酸（HA）水平均下降,且观察组的下降程度较对照组更大（P<0.05）。治疗24周后,两组TGF-β1mRNA、Smad2mRNA、Smad3mRNA水平下降, Smad7mRNA水平升高,且观察组的改善程度较对照组更大（P<0.05）。治疗24周后,两组门静脉内径、脾脏厚度均下降,且观察组较对照组更低（P<0.05）。结论：恩替卡韦分散片联合扶正化瘀胶囊治疗慢性乙型肝炎肝纤维化,可改善肝功能,对肝纤维化具有明显的抑制作用,可能与调控TGF-β1/Smads信号通路有关。     

抗肝纤维化药物的研究进展

肝纤维化(Iiver fibrosis)是细胞外基质(ECM)合成和降解不平衡的结果,是各种慢性肝病向肝硬化发展所共有的病理改变和必经途径.LF的致病因子包括病毒、酒精、药物等,其中乙肝病毒引起的病毒性肝炎是我国最普遍的肝病之一,因此开发抗肝纤维化药物将有利于我国肝病的治疗,本文主要介绍了抗肝纤维化药物的研究进展.     

血吸虫病肝纤维化形成的作用机制

血吸虫病(schistosomiasis)是世界上严重危害人类健康的人兽共患寄生虫病之一。在中国主要流行的是日本血吸虫病,其致病机制是由于血吸虫卵沉积于宿主肝内,形成虫卵肉芽肿,导致肝纤维化。血吸虫病肝纤维化免疫过程中,肝星状细胞、T细胞、B细胞及多种细胞因子的调节起着重要作用。现就血吸虫病肝纤维化形成机制的相关研究进展进行了综述。     

中医药的抗炎机制在治疗肝纤维化中的作用

肝脏是人体腹腔内最大的实体器官,对维持机体的基本生理功能起着至关重要的作用。肝脏疾病是威胁人类健康的常见病多发病。全球约有10%人口受到不同程度的肝脏疾病的危害,其中,肝纤维化往往成为这些疾病的晚期病理特征。由于肝纤维化的发病机制复杂,尚无有效的合成类药物能够治疗肝纤维化。中药治疗肝纤维化具有多靶点和副作用小的优势。本文综述了肝纤维化的病理特征与诱发炎症的关系,讨论了中药治疗肝纤维化的单味中药、传统配方及其化学活性成分的抗炎症机制。     

干扰素治疗肝纤维化的作用

干扰素治疗肝纤维化的作用余家宽白萍（安徽省芜湖市弋矶山医院传染科，２４１００１）（安徽省当涂县人民医院）干扰素具有多种生物作用，不仅具有抗病毒及免疫调节作用，而且对某些细胞有抑制作用，许多实验表明干扰素一定程度抑制成纤维细胞胶原合成。本文应用干扰素抗...     

肝窦内皮细胞在肝纤维化发生发展中的作用及其机制

肝窦内皮细胞(liver sinusoidal endothelial cells,LSECs)是肝脏抵御炎症和免疫反应的第一道防线,其独特的窗孔结构及功能特性决定它在肝纤维化发生发展中起重要作用。LSECs主要通过介导肝脏炎症反应、肝窦毛细血管化、活化肝星状细胞(hepatic stellate cells,HSC)、引发细胞外基质(extracellular matrix,ECM)的生成与降解失衡等途径参与肝纤维化的发生发展。靶向LSECs对治疗肝纤维化极具潜力,阐述清楚二者调控关系,将为抗肝纤维化治疗提供新的理论依据。     

扶正化瘀胶囊联合微生态制剂和恩替卡韦治疗乙型肝炎病毒感染失代偿期肝硬化的临床研究

目的:探讨扶正化瘀胶囊联合微生态制剂和恩替卡韦治疗乙型肝炎病毒(HBV)感染失代偿期肝硬化的临床效果。方法:选取2015年6月～2019年6月期间我院收治的HBV感染失代偿期肝硬化患者73例,根据随机数字表法分为对照组(n=36)和研究组(n=37),对照组患者予以微生态制剂和恩替卡韦治疗,研究组则在对照组的基础上联合扶正化瘀胶囊治疗,比较两组患者疗效、T淋巴细胞亚群、肝功能[天冬氨酸氨基转移酶(AST)、总胆红素(TBIL)]以及肝纤维化指标[透明质酸(HA)、层黏连蛋白(LN)],记录两组乙肝表面e抗原(HBeAg)、乙肝病毒基因(HBV-DNA)转阴情况,记录两组不良反应发生情况。结果:研究组治疗6个月后的临床总有效率为91.89%(34/37),高于对照组的72.22%(26/36)(P0.05)。两组治疗6个月后AST、TBIL、HA、LN、CD8+~均下降,且研究组低于对照组(P0.05)。两组治疗6个月后CD4+~、CD4+~/CD8+~升高,且研究组高于对照组(P0.05)。两组治疗6个月后HBeAg、HBV-DNA转阴率比较无统计学差异(P0.05)。两组不良反应发生率对比未见统计学差异(P0.05)。结论:扶正化瘀胶囊联合微生态制剂和恩替卡韦治疗HBV感染失代偿期肝硬化疗效显著,虽在HbeAg、HBV-DNA转阴率方面未见明显改善,但可有效改善肝功能,减轻肝纤维化,提高机体免疫功能,且不增加不良反应发生率,安全性较好。     

益气化瘀化痰方对肺纤维化大鼠的干预作用及其机制*

目的: 探讨益气化瘀化痰方对由博来霉素(BLM)诱导的大鼠肺纤维化的影响及其可能的机制。方法: 采用气管内一次性注射盐酸博来霉素5 mg/kg诱导制备肺纤维化大鼠模型。将60只SPF级SD大鼠随机分为正常对照组、模型对照组、阳性对照组、益气化瘀化痰方低浓度组(低浓度组)、益气化瘀化痰方中浓度组(中浓度组)和益气化瘀化痰方高浓度组(高浓度组),每组10只。各中药治疗组在造模4周后分别采用益气化瘀化痰方低、中、高浓度制剂(3.6 ml/(kg·d))灌胃,阳性对照组给予醋酸氢化可的松(3.6ml/(kg·d))灌胃,正常对照组和模型对照组给予同等体积的生理盐水(3.6 ml/(kg·d))灌胃,每日1次。12周后处死各组大鼠,取大鼠肺组织,称量肺质量并计算肺系数,HE染色观察组织形态学改变,Masson染色观察胶原纤维沉积情况;蛋白免疫印迹(Western blot)检测各组大鼠肺组织中转化生长因子-β1(TGF-β1)、锌指蛋白转录因子(Snail1)、E-钙黏蛋白(E-cadherin)、纤连蛋白(Fibronectin)等蛋白表达水平;实时荧光定量PCR(qRT-PCR)检测组织TGF-β1、Snail1、E-cadherin、Fibronectin等mRNA表达水平。结果: ①与模型组比较,各药物干预组肺系数均有降低(P＜0.05);②与空白组比较,模型组肺纤维化明显;各药物干预组与模型组比较,各治疗组肺间质胶原沉积减少,肺纤维化程度减轻;③治疗各组与模型组比较,各治疗组大鼠肺组织TGF-β1、Snail1、Fibronectin蛋白表达均明显减少(P＜0.05),E-cadherin蛋白表达明显升高(P＜0.05);④低、高浓度组与中浓度组比较,尤以中浓度组表达结果最显著(P＜0.05);⑤中药治疗各组与阳性组比较,表达结果优于阳性组(P＜0.05);mRNA表达与蛋白表达趋势一致。结论: 益气化瘀化痰方能显著治疗博来霉素所致的大鼠肺纤维化,其机理可能是通过下调TGF-β1调控TGF-β/Snail信号通路表达抑制大鼠的上皮细胞-间充质转化,而改善大鼠肺纤维化。     

Novel cytisine derivatives exert anti-liver fibrosis effect via PI3K/Akt/Smad pathway

A series of new cytisine derivatives with a unique endocyclic scaffold were synthesized and evaluated for their inhibitory effect on collagen α1 (I) (COL1A1) promotor in human LX2 cells, taking cytisine as the lead. Structure-activity relationship (SAR) revealed that introducing a 12N-benzyl substitution might significantly enhance the activity. Compound 5f exhibited a promising inhibitory potency against COL1A1 with an IC₅₀ value of 12.8 μM in human LX2 cells, and an inspiring inhibition activity against COL1A1 on both mRNA and protein levels. It also effectively inhibited the expression of α smooth muscle actin (α-SMA), connective tissue growth factor (CTGA), matrix metalloprotein 2 (MMP-2), and transforming growth factor β1 (TGFβ1), indicating an extensive inhibitory effect against fibrogenetic proteins. In addition, compound 5f displayed reasonable PK and safety profiles. The primary mechanism study indicated that it might repress the hepatic fibrogenesis via PI3K/Akt/Smad signaling pathway. The results provided powerful information for further structure optimization, and compound 5f was selected as a novel anti-liver fibrosis agent for further investigation.     

消痰化瘀利窍方对慢性间歇性低氧大鼠肠系膜动脉损伤的改善作用

目的:观察消痰化瘀利窍方对慢性间歇性低氧(CIH)大鼠肠系膜动脉功能损伤的作用,并探讨其可能机制。方法:48只雄性SD大鼠随机分为4组(n=12),常氧对照组(Normoxia)、慢性间歇性低氧组(CIH)、慢性间歇性低氧中药干预组(Formula+CIH)、中药对照组(Formula)。CIH与Formula+CIH组置于间歇性低氧装置,通过充入氮气、氧气使O2含量在9%至21%间循环,每循环3min;Normoxia和Formula组则充入空气。其中,Formula+CIH与Formula组于每日造模前中药水煎液灌胃(24g/kg),而CIH组与Normoxia组给予等量生理盐水。造模结束后,应用HE染色观察各组大鼠肠系膜动脉的组织病理学改变,通过微血管环技术观察ACh、L-Arg诱导的肠系膜动脉舒张反应,通过ELISA技术检测大鼠造模前及造模21d血清一氧化氮(NO)的含量并应用Westernblot技术测定肠系膜动脉eNOS和p-eNOS的蛋白水平。结果:与Normoxia组相比,CIH组大鼠肠系膜动脉内皮明显损伤、中膜增厚,ACh、L-Arg诱导的肠系膜动脉舒张反应明显减弱,血清中NO水平及肠系膜动脉p-eNOS/eNOS比值显著降低。消痰化瘀利窍方干预能够减轻大鼠肠系膜动脉的内膜与中膜病理损伤,改善肠系膜动脉舒张功能,提高血清NO含量及肠系膜动脉eNOS磷酸化水平。而单纯给予消痰化瘀利窍方大鼠与Normoxia组相比各指标均未发现显著变化。结论:消痰化瘀利窍方可以减轻慢性间歇性低氧引起的大鼠肠系膜动脉功能损伤,其机制与提高NO的生物利用度有关。     

Psoralen attenuates bleomycin‐induced pulmonary fibrosis in mice through inhibiting myofibroblast activation and collagen deposition

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by excessive deposition of extracellular matrix (ECM) and chronic inflammation with limited therapeutic options. Psoralen, a major active component extracted from Psoralea corylifolia L. seed, has several biological effects. However, the role of psoralen in IPF is still unclear. Here, we hypothesized that psoralen played an essential role in IPF in the inhibition of fibroblast proliferation and inflammatory response. A murine model of IPF was established by injecting bleomycin (BLM) intratracheally, and psoralen was administered for 14 days from the 7^th to 21^st day after BLM injection. Our results demonstrated that psoralen treatment reduced body weight loss and improved the survival rate of mice with IPF. Histological and immunofluorescent examination showed that psoralen alleviated BLM‐induced lung parenchymal inflammatory and fibrotic alteration. Furthermore, psoralen inhibited proliferation and collagen synthesis of mouse fibroblasts and partially reversed BLM‐induced expression of α‐smooth muscle actin at both the tissue and cell level. Moreover, psoralen decreased the expression of transforming growth factor‐β1, interleukin‐1β, and tumor necrosis factor‐α in the lungs of BLM‐stimulated mice. Our results reveale for the first time that psoralen exerts therapeutic effects against IPF in a BLM‐induced murine model.     

PTEN improve renal fibrosis in vitro and in vivo through inhibiting FAK/AKT signaling pathway

Renal fibrosis, the ultimate common pathway of progressive nephropathy, is characterized by excess accumulation and deposition of extracellular matrix (ECM) within the renal interstitium and glomeruli, finally resulting in end-stage kidney failure. TGFβ1 is not only abnormally increased during fibrosis but also involved in ECM induction and accumulation. Based on the bioinformative analyses, phosphatase and tensin homolog deleted on chromosome ten (PTEN) and focal adhesion kinase (FAK) signaling pathway might be involved in TGFβ1 functions on renal fibrosis development. In the present study, fibrosis was induced in HK-2 cells using TGFβ1 and PTEN expression was significantly suppressed by 24 or 48 hours TGFβ1 treatment. PTEN overexpression in HK-2 cells improved TGFβ1-induced fibrosis within α-SMA and E-cadherin. According to the KEGG signaling pathway annotation analyses on microarray profiles (GSE23338 and GSE20247) and immunoblotting validation, FAK signaling might be involved in PTEN functions in TGFβ1-induced fibrosis. PTEN overexpression significantly inhibited TGFβ1- or unilateral ureteral obstruction (UUO)-induced FAK signaling pathway activation both in vitro and in vivo; more importantly, PTEN silence enhanced TGFβ1- or UUO-induced fibrosis, while FAK inhibitor PF567721 significantly reversed the effects of PTEN silence, indicating that PTEN exerted its effects on TGFβ1- and UUO-induced fibrotic development in vitro and in vivo via inhibiting FAK signaling pathway. In summary, these findings indicate that PTEN could improve cellular fibrotic changes and renal fibrosis via inhibiting FAK/AKT signaling pathway. Restoring PTEN expression to target FAK/AKT signaling pathway might be a potent strategy for renal fibrosis treatment.     

Endoplasmic reticulum stress induces inverse regulations of major functions in portal myofibroblasts during liver fibrosis progression

Portal myofibroblasts (PMF) form a sub-population of highly proliferative and proangiogenic liver myofibroblasts that derive from portal mesenchymal progenitors. Endoplasmic reticulum (ER) stress was previously shown to modulate fibrogenesis, notably in the liver. Our aim was to determine if ER stress occurred in PMF and affected their functions. PMF were obtained after their expansion in vivo from bile duct-ligated (BDL) rats and referred to as BDL PMF. Compared to standard PMF obtained from normal rats, BDL PMF were more myofibroblastic, as assessed by higher alpha-smooth muscle actin expression and collagen 1 production. Their proangiogenic properties were also higher, whereas their proliferative and migratory capacities were lower. CHOP expression was detected in the liver of BDL rats, at the leading edge of portal fibrosis where PMF accumulate. BDL PMF displayed ER dilatation and an overexpression of the PERK pathway downstream targets, Chop, Gadd34 and Trb3, in comparison with standard PMF. In vitro, the induction of ER stress by tunicamycin in standard PMF, caused a decrease in their proliferative and migratory activity, and an increase in their proangiogenic activity, without affecting their myofibroblastic differentiation. Conversely, the treatment of BDL PMF with the PERK inhibitor GSK2656157 reduced ER stress, which caused a decrease in their angiogenic properties, and restored their proliferative and migratory capacity. In conclusion, PMF develop ER stress as they expand with the progression of fibrosis, which further increases their proangiogenic activity, but also inhibits their proliferation and migration. This phenotypic switch may restrict PMF expansion while they support angiogenesis.