药学学报

Active ingredient	Structure	Pharmacological activity
Total saponins of astragalus	Astragaloside Ⅳ		Hypoglycemic effect^[18] Improve the function of cardiovascular^[19] Anti-cancer effect^[20] Anti-brain ischemia activities^[21]
Cycloastragenol		Suppress oxidative insults and neuroinflammation^[22] Anti-aging effect^[23]
Astragaloside Ⅰ		Anti-tumor effect^[24]
Astragalus polysaccharides			Immunomodulatory effects^[25] Antioxidation^[26] Hypoglycemic effect^[27]
Total flavonoids of astragalus	Calycosin		Anti-tumor effect^[28] Suppressing oxidative stress and inflammation^[29]
Quercetin		Anti-cancer effect^[30] Neuroprotective effect^[31]

Active ingredient	Structure	Pharmacological activity
Total saponins of astragalus	Astragaloside Ⅳ		Hypoglycemic effect^[18] Improve the function of cardiovascular^[19] Anti-cancer effect^[20] Anti-brain ischemia activities^[21]
Cycloastragenol		Suppress oxidative insults and neuroinflammation^[22] Anti-aging effect^[23]
Astragaloside Ⅰ		Anti-tumor effect^[24]
Astragalus polysaccharides			Immunomodulatory effects^[25] Antioxidation^[26] Hypoglycemic effect^[27]
Total flavonoids of astragalus	Calycosin		Anti-tumor effect^[28] Suppressing oxidative stress and inflammation^[29]
Quercetin		Anti-cancer effect^[30] Neuroprotective effect^[31]

黄芪有效成分防治器官纤维化的研究进展

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李世粉 , 杨若轩 , 孙健 , 梁海海 ^*

药学学报 | 综述 2023,58(8): 2168-2179

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药学学报 |综述 2023 , 58 (8) : 2168 -2179

黄芪有效成分防治器官纤维化的研究进展

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李世粉, 杨若轩, 孙健, 梁海海^*

作者信息

哈尔滨医科大学药学院, 黑龙江哈尔滨 150081

通讯作者:

*梁海海, Tel: 86-451-86671354, E-mail: lianghaihai@ems.hrbmu.edu.cn

Research progress of effective components of Astragalus on prevention and treatment of organ fibrosis

Shi-fen LI, Ruo-xuan YANG, Jian SUN, Hai-hai LIANG^*

Affiliations

College of Pharmacy, Harbin Medical University, Harbin 150081, China

出版时间: 2023-08-12 doi: 10.16438/j.0513-4870.2023-0313

文章导航

摘要

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黄芪首载于《神农本草经》, 为豆科草本植物膜荚黄芪或蒙古黄芪的干燥根。其有效成分皂苷类(astragalus membranaceus saponins, AMS)、多糖类(astragalus polysaccharides, APS)、黄酮类(astragalus flavonoids, AFS) 等具有抗肿瘤、降血糖、调节脂质代谢、抗氧化和保护心血管等功效。纤维化可发生于多种器官, 特别是肺、肝、心、肾等重要器官, 主要病理过程为肌成纤维细胞异常增多及细胞外基质(extracellular matrix, ECM) 过度沉积, 导致瘢痕组织形成, 最终诱发器官功能丧失及器官衰竭, 严重威胁人类健康和生命。近年来, 研究表明黄芪在抗器官纤维化方面有较好的疗效。本文就黄芪有效成分在防治肺、肝、心、肾等重要器官纤维化的研究进展进行综述。

关键词

黄芪 / 黄芪多糖 / 黄芪甲苷 / 黄芪黄酮 / 器官纤维化 / 细胞外基质

Abstract

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Astragalus, which was first documented in Shennong Bencao Jing, is the dried root of Astragalus membranaceus (Fisch.) Bge. or Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao. The active ingredients astragalus membranaceus saponins (AMS), astragalus polysaccharides (APS) and astragalus flavonoids (AFS) have pharmacological effects such as anti-tumor properties, lowering blood sugar, regulating lipid metabolism, cardiovascular protection, anti-oxidation, bone protection, anti-fibrosis, etc. Fibrosis affects almost all organs, particularly vital organs such as the lungs, liver, heart and kidneys. The primary pathological changes of fibrosis involve abnormal increase of myofibroblasts and excessive deposition of extracellular matrix (ECM) components, which lead to the formation of scar tissue, ultimately resulting in fibrosis and even functional loss or failure of organs, which seriously threatens human health and life. Recent, studies have shown that Astragalus membranaceus has a good therapetuic effect on organ fibrosis. This article reviews the current advances of Astragalus in the prevention and treatment of fibrosis of lungs, liver, heart, kidneys and other important organs.

Key words

astragalus / astragalus polysaccharide / astragalus membranaceus saponin / astragalus flavonoid / organ fibrosis / extracellular matrix

引用本文

李世粉, 杨若轩, 孙健, 梁海海. 黄芪有效成分防治器官纤维化的研究进展. 药学学报, 2023 , 58 (8) : 2168 -2179 . DOI: 10.16438/j.0513-4870.2023-0313

Shi-fen LI, Ruo-xuan YANG, Jian SUN, Hai-hai LIANG. Research progress of effective components of Astragalus on prevention and treatment of organ fibrosis[J]. Acta Pharmaceutica Sinica, 2023 , 58 (8) : 2168 -2179 . DOI: 10.16438/j.0513-4870.2023-0313

正文

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器官纤维化是多病因导致的慢性组织损伤, 主要病理改变为细胞外基质(extracellular matrix, ECM) 过度沉积导致瘢痕组织形成, 持续进展可致器官结构破坏和功能丧失^[1]。纤维化累及多个器官, 特别是肺、肝、心、肾等重要器官, 一些慢性疾病, 如糖尿病、高血压、慢性病毒性肝炎、心力衰竭、心肌病、肺动脉高压、硬皮病、癌症等都与纤维化密切相关^[2]。器官纤维化是许多疾病致残、致死的主要原因, 据不完全统计, 全世界范围内, 受纤维化相关疾病影响的人数已将近人口总数的25%^[3]。随着对黄芪的不断深入研究, 越来越多的基础实验和临床证据表明黄芪中的皂苷类、多糖类、黄酮类等有效成分对改善器官纤维化有很好的治疗效果。本文针对当前黄芪有效成分对不同器官纤维化的防治作用研究进展进行综述。

1 器官纤维化的发病机制

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纤维化是由不同触发因素导致的复杂的细胞和分子级联反应^[4]。当组织遭受反复或严重损伤, 导致促炎因子和生长因子等过度表达, 形成促纤维化的病理环境诱导肌成纤维细胞大量激活和增殖, 促进ECM大量产生。促纤维化的病理过程反过来刺激这些因子进一步释放, 放大炎症反应, 形成恶性循环。最后持续活化的肌成纤维细胞合成ECM的速度超过其降解速度, 导致ECM大量堆积, 纤维化病灶形成(图 1)。

1.1 肌成纤维细胞与器官纤维化

肌成纤维细胞是纤维化的主要效应细胞。在病理性瘢痕形成过程中, 肌成纤维细胞对趋化因子、细胞因子等信号高度敏感, 产生过多胶原蛋白、纤维连接蛋白等细胞外基质成分从而导致器官纤维化发生^[5]。成纤维细胞是肌成纤维细胞最主要的来源。在纤维形成过程中, 细胞因子促进成纤维细胞增殖迁移到创面部位并促进其向肌成纤维细胞分化。来自肺、肝脏和肾脏的上皮细胞可以在转化生长因子β1 (transforming growth factor-β1, TGF-β1) 等促纤维化因子的刺激下发生上皮-间质转化(epithelial-mesenchymal transition, EMT), 分化为肌成纤维细胞。间皮细胞在TGF-β1等刺激下可发生基因重组转变为间充质细胞, 这一转变过程称为间皮-间充质转化(mesothelial to mesenchymal transition, MMT), 参与肌成纤维细胞形成及纤维化进程。此外, 肌成纤维细胞也可来源于内皮细胞、周皮细胞等^{[5, 6]}。在生理性损伤愈合过程中, 活化的肌成纤维细胞会通过凋亡从创面清除。然而, 当创伤修复过程发生异常时, 肌成纤维细胞不断被激活且不能正常凋亡, 产生过多的ECM导致器官纤维化发生。因此, 靶向肌成纤维细胞激活并促进损伤区域肌成纤维细胞凋亡是防治器官纤维化的有效途径。

1.2 细胞因子与器官纤维化

生长因子、炎症因子和肿瘤坏死因子等多种细胞因子在炎症过程和纤维化的发生发展过程中发挥重要作用。TGF-β1是最直接的促纤维生长因子, 能够参与炎症细胞募集、促进α-平滑肌肌动蛋白(α-smooth muscle actin, α-SMA) 阳性的肌成纤维细胞增殖分化、诱导EMT, 促进胶原等基质蛋白分泌和沉积并抑制其降解, 进而导致纤维化发生。血小板衍生生长因子(platelet-derived growth factor, PDGF) 通过酪氨酸激酶受体介导其生物学效应, 可诱导PI3K和Akt磷酸化参与成纤维细胞激活、增殖、迁移, 以及激活间充质干细胞和/或祖细胞, 从而在疾病进展过程中促进肌成纤维细胞形成, 促进肺纤维化和心肌纤维化的形成^{[2, 7]}。

基质金属蛋白酶(matrix metalloproteinase, MMPs) 是参与细胞外基质降解的主要酶, 其活性在正常情况下较低, 但在组织修复或重塑过程中显著增加。基质金属蛋白酶抑制剂(matrix-metalloproteinase inhibitor, TIMPs) 可抑制MMPs的活性而促进纤维化发生^[8]。

白细胞介素(interleukin, IL)-1β、IL-6、IL-13、IL-33是白细胞介素细胞因子家族, 在几乎所有类型的炎症反应中具有多效应活性。体内研究表明, 用IL-1β处理的纤维母细胞会分化为肌纤维母细胞, 导致ECM沉积增加。IL-13通过直接诱导胶原蛋白和结缔组织生长因子(connective tissue growth factor, CTGF) 等肝纤维化相关基因表达促进肝纤维化形成。IL-33可通过抑制MMP-9表达而促进TIMP-1表达, 诱导二者失衡来促进肺纤维化发生^{[2, 8, 9]}。肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α) 是器官肺脏、肝脏、肾脏和心脏纤维形成过程中重要的炎症信号分子。它主要由巨噬细胞分泌, 与特定受体结合启动信号级联反应, 激活NF-κB调控炎症反应, 并触发细胞激活、分化、细胞因子产生和细胞凋亡, 参与纤维化进展^[2]。

细胞因子可以通过自分泌或旁分泌的方式与特定受体结合并启动特定的细胞内信号通路, 调节下游基因表达促进器官纤维化发生发展。靶向调节细胞因子的基因表达和生物学活性对于防治器官纤维化具有重要意义。

1.3 信号通路与器官纤维化

器官纤维化涉及复杂的细胞分子级联反应。TGF-β1/Smad信号通路是介导器官纤维化最经典的信号通路。TGF-β1与受体结合, 导致Smad2和Smad3磷酸化, 活化的Smad2和Smad3与Smad4形成三聚物复合物, 这些三聚复合物转运至细胞核中调节靶基因的转录促进成纤维细胞、间质细胞增殖分化并分泌Ⅰ、Ⅲ、Ⅳ型胶原, 诱导TIMP-1产生同时抑制MMP-1, 抑制细胞外基质降解导致ECM沉积与组织纤维化^[10]。

非Smad依赖的其他信号途径也是介导信号从细胞表面传递到细胞核内的重要传递者, 其中p38-MAPK、ERK1/2是丝裂原活化蛋白激酶家族(mitogen-activated protein kinases, MAPKs) 重要成员, 在纤维化过程中发挥重要作用。激活p38-MAPK信号通路下游TGF-β1、α-SMA等炎症相关因素诱发特定基因表达发挥促纤维化作用。ERK1/2信号通路参与Ras-Raf-MEK-ERK信号转导通路, 在TGF-β1启动Smad信号通路中具有协同作用^[11]。

此外, 受体络氨酸酶(receptor tyrosine kinase, RTK) 介导衍生的PI3K/Akt是另一个明显与器官纤维化病理生理学有关的信号通路, 哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR) 是PI3K/Akt信号通路下游的效应蛋白, 它控制炎症细胞的存活、增殖和分化, 调节细胞因子和趋化因子表达, 促进细胞外基质重塑和纤维化。PI3K/Akt信号通路也通过激活下游p70S6K、p-S6等蛋白参与纤维化疾病的核心环节, 与肌成纤维细胞的过度增殖密切相关^{[11, 12]}。证据表明, Hippo/YAP/TAZ信号通路可显著刺激特发性肺纤维化(idiopathic pulmonary fibrosis, IPF) 中成纤维细胞增殖分化并促进纤维化相关基因的转录^[13]。刺猬信号(hedgehog signaling, HH) 在包括肾脏在内的多个器官的上皮细胞中表达。在体外实验中, 刺猬信号通过激活胶质瘤1抑制E-钙黏蛋白表达, 并诱导α-SMA、desmin、Snail1、纤连蛋白和Ⅰ型胶原蛋白表达, 说明HH信号在调节肌成纤维细胞活化和细胞外基质生成中发挥关键作用^[14]。

器官纤维化发展过程存在多种信号通路交互作用, 通过抑制信号通路上下游相关基因表达, 选择性中断细胞因子信号可能对各类器官纤维化的治疗起到重要作用。

2 器官纤维化的治疗药物

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器官纤维化过程复杂, 目前尚未完全阐明机制。临床上治疗器官纤维化的药物种类少且疗效有限。目前, 国内批准用于IPF治疗的药物仅有吡非尼酮(pirfenidone)、尼达尼布(nintedanib)。而在一项评估尼达尼布和吡非尼酮联合治疗IPF患者安全性和耐受性的Ⅳ期临床试验(NCT02598193) 中, 17.98%患者存在严重不良反应事件。美国FDA已批准芦可替尼(ruxolitinib) 用于中高危骨髓纤维化患者。而一项评估芦可替尼治疗贫血性骨髓纤维化患者疗效和安全性的Ⅱ期研究(NCT02966353) 中, 患者全因死亡率达13.73%, 严重不良反应事件占33.33%。Momelotinib (NCT02124746)、elafibranor (NCT02704403) 等小分子或化合物在动物研究阶段分别表现出良好的抗骨髓纤维化和抗肝纤维化作用, 但临床试验往往达不到预期治疗效果或有严重不良反应, 器官纤维化新药研发面临重大挑战。中药作为传统医学的重要组成部分, 在预防和治疗疾病方面存在巨大潜力。活血化瘀类、疏肝理气类、益气补阴类、清热解毒类等中药可用于器官纤维化防治^[15]。黄芪作为一种扶正益气中药, 其多种有效成分已被证实具有优良抗纤维化作用。

3 黄芪有效成分

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黄芪作为补中益气之要药, 在临床上使用广泛。黄芪有效成分主要为多糖类、皂苷类、黄酮类、氨基酸类、生物碱类和微量元素等。黄芪多糖是黄芪中占比最多、活性最强的成分, 主要有葡聚糖和杂多糖, 其中葡聚糖分为水溶性α (1→4) (1→6) 葡聚糖和水不溶性α (1→4) 葡聚糖。黄芪中的杂多糖多为水溶性酸性杂多糖, 主要有鼠李糖、葡萄糖、半乳糖、阿拉伯糖, 少量含有半乳糖醛酸和葡萄糖醛酸组成的糖醛酸; 部分杂多糖仅由葡萄糖、阿拉伯糖组成。皂苷类化合物是黄芪中另一重要有效组分, 主要有黄芪皂苷Ⅰ~Ⅷ、异黄芪皂苷Ⅰ~Ⅳ、乙酰黄芪皂苷Ⅰ、大豆皂苷等4大类, 黄芪中的皂苷类化合物多以9, 19-环羊毛甾烷型的四环三萜为苷元。其中, 黄芪甲苷(又称黄芪皂苷Ⅳ, astragaloside Ⅳ, AS-Ⅳ) 为羊毛酯醇形的四环三萜皂苷, 是黄芪的主要活性成分之一^[16]。环黄芪醇(cycloastragenol, CAG) 是黄芪甲苷水解得到的次生代谢产物。黄酮类化合物是黄芪的另一活性成分, 黄芪中主要含黄酮、异黄酮、异黄烷和紫檀素型黄酮等50余种黄酮类化合物, 其中异黄酮的种类最多^[17], 主要有毛蕊异黄酮(calycosin)、槲皮素(quercetin)、山柰酚、鼠李柠檬素、鼠李异柠檬素、美迪紫檀苷和芒柄花素等。黄芪有效成分具有抗肿瘤、降低血糖、调节脂质代谢、保护心血管、抗氧化、骨保护和抗纤维化等药理作用, 对心血管系统、免疫系统和呼吸系统等疾病发挥积极治疗作用(表 1)^[18-31]。

4 中药黄芪防治器官纤维化研究进展

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黄芪作为多组分中药迄今已有2 000多年药用历史, 研究发现其有效成分黄芪甲苷、黄芪总黄酮和黄芪多糖等可通过作用于经典Smad依赖和非Smad依赖信号通路上下游靶点, 调节氧化应激、炎症反应和自噬, 抑制肌成纤维细胞增殖分化和ECM沉积, 调控器官纤维化进程(图 2)。

4.1 黄芪抗肺纤维化作用及机制

肺纤维化是由中毒、自身免疫、药物、感染或创伤性损伤等多种因素引起的正常肺泡组织损坏, 刺激肌成纤维细胞大量增殖, 伴有ECM的过度沉积和不可逆的瘢痕形成, 导致正常肺组织结构异常、功能丧失。

肌成纤维细胞持续激活并导致胶原蛋白等ECM的过度沉积在肺纤维化的进程中发挥重要作用。AS-Ⅳ可抑制肺纤维化模型中肌成纤维细胞增殖、减少高迁移率族蛋白B1 (high mobility group box 1 protein, HMGB1) 释放, 抑制ECM生成对肺纤维化具有明显的干预作用^{[32, 33]}。EMT是肺纤维化中成纤维细胞/肌成纤维细胞的直接贡献者, 黄芪总皂苷、黄芪多糖可抑制TGF-β1/Smad信号通路激活, 降低EMT作用从而抑制胶原蛋白的合成与沉积^{[34, 35]}。miRNA表达异常与IPF过程中EMT的发生发展具有密切关系, 黄芪总黄酮可通过抑制miRNA-21, 增加TGF-β1/Smad通路的负向调控子Smad7表达, 从而抑制TGF-β1/Smad通路激活, 抑制EMT进程^[36]。高表达TGF-β1可激活PI3K/Akt/mTOR信号而抑制细胞自噬活性, 促进α-SMA的表达, 促进EMT发展。AS-Ⅳ可使博来霉素诱导的肺纤维化模型小鼠肺组织中TGF-β1表达下调, 抑制TGF-β1/PI3K/Akt/mTOR信号, 增强细胞自噬活性而阻止EMT进程^[37]。有研究发现AS-Ⅳ可抑制TGF-β1/PI3K/Akt诱导的FOXO3a过度磷酸化, 从而防止博来霉素诱导肺纤维化EMT进程^[38]。

多种促纤维化因子在肺纤维化进程中起着关键作用。TGF-β1是肺纤维发展过程中重要的促纤维化细胞因子, 其表达水平能反映肺纤维化严重程度。Luan等^[39]用黄芪糖蛋白(Huang Qi glycoprotein, HQGP) 干预肺纤维化小鼠后, 肺组织中TGF-β1蛋白表达明显降低。碱性成纤维细胞生长因子(basic fibroblast growth factor, bFGF) 在气道重塑中起重要作用, 血管内皮生长因子(vascular endothelial growth factor, VEGF) 是调节生理和病理血管新生、增加血管通透性的一个重要细胞因子, 二者均参与了肺纤维化进程。用AS-Ⅳ干预肺纤维化大鼠模型, 发现模型中bFGF、VEGF和血管内皮生长因子受体2 (vascular endothelial growth factor receptor 2, VEGFR2) mRNA表达下调, 证明AS-Ⅳ干预大鼠肺间质纤维化进程与抑制bFGF和VEGF表达有关^{[40, 41]}。除AS-Ⅳ外, 黄芪多糖、黄芪总黄酮也可抑制TGF-β1和VEGF表达, 减轻肺纤维化小鼠的炎症反应, 发挥抗肺纤维化作用^[42]。纤维化早期存在“Th2优势”, 研究发现黄芪多糖^[43]干预博莱霉素所致大鼠肺纤维化后, 血清干扰素-γ (interferon-γ, IFN-γ) 含量、IFN-γ/IL-4比值升高, 而Ⅱ型细胞因子IL-4含量降低, 推测黄芪多糖和黄芪甲苷阻抑肺纤维化的发生可能是通过调节Th1/Th2型细胞因子平衡实现的。肺纤维化模型组织中CD34表达增强, 存在微血管生成, 用AS-Ⅳ干预后, 肺组织CD34表达水平较模型组同期下降, 说明AS-Ⅳ可以下调大鼠模型肺组织CD34的表达干预大鼠肺纤维化微血管生成^[44]。瘦素广泛存在于人体外周几乎所有的组织细胞中, 是一种具有多种生物学效应的细胞因子。此前的研究表明, 瘦素可能在多个组织发生增生、肥大及纤维化的过程中发挥关键作用。He等^[45]对博来霉素诱导的肺纤维化大鼠经胃管灌服AS-Ⅳ, 发现AS-Ⅳ组瘦素蛋白表达显著降低, 提示AS-Ⅳ可能通过降低瘦素表达抑制肺纤维化发生。但更具体的信号传导和细胞因子间的相互作用有待进一步研究。

氧化应激和炎症是加速肺纤维化进程的重要因素。有研究发现黄芪总皂苷干预肺纤维化大鼠后, 肺组织中丙二醛(malondialdehyde, MDA) 及一氧化氮(nitric oxide, NO) 水平降低, 超氧化物歧化酶(superoxide dismutase, SOD) 表达水平升高^[46]。进一步实验证明黄芪总皂苷中的AS-Ⅳ可以通过调控miRNA-29b, 降低活性氧(reactive oxygen species, ROS) 和MDA含量, 提高SOD含量, 提高机体抗氧化水平从而减轻肺纤维化程度^[47]。TGF-β通过Smad信号启动炎症反应, 是促进肺部炎症和慢性肺纤维化的关键调节因子, AS-Ⅳ可抑制TGF-β1/Smad2/3信号通路激活, 降低炎症反应和氧化应激来预防矽肺纤维化^[48]。NF-κB是控制炎症信号的转录调节剂, 活化钙蛋白酶1能激活NF-κB并促进其下游炎症因子表达, 产生炎症反应和纤维化反应。Liu等^[49]发现黄芪多糖可抑制钙蛋白酶1/NF-κB信号通路, 改善肺组织炎症反应和肺纤维化程度。自噬是细胞利用溶酶体降解自身受损的细胞器和蛋白质的过程, 过度激活会表现出细胞损伤乃至自噬性细胞死亡。焦亡是通过依赖于caspase-1炎症小体激活介导的细胞死亡形式, 是炎症反应的重要途径之一。近年来越来越多研究表明, 焦亡与自噬可能是IPF发生发展的重要原因。研究发现, AS-Ⅳ能显著提高LC3 Ⅱ蛋白表达并抑制p62蛋白积累, 同时能降低caspase-1、IL-1β和IL-18等焦亡相关蛋白表达, 表明AS-Ⅳ抗纤维化机制与增强自噬并抑制焦亡蛋白表达有关^[50]。

4.2 黄芪抗肝纤维化作用及机制

肝纤维化是由病毒性肝炎、酒精性肝病、非酒精性脂肪性肝炎、自身免疫性疾病等多种慢性肝病引起的瘢痕形成过程。其特点是肌成纤维细胞过度增殖, 促进胶原蛋白等ECM合成和分泌增加。

血清透明质酸(hyaluronic acid, HA)、层黏连蛋白(laminin, LN)、Ⅲ型前胶原(pro-collagen Ⅲ, PCⅢ)、Ⅳ型胶原(Ⅳ collagen, CⅣ) 含量与肝纤维化程度呈正相关, 被认为是较好的诊断肝纤维化的血清学指标, 谷丙转氨酶(alanine aminotransferase, ALT)、谷草转氨酶(aspartate aminotransferase, AST) 也是影响进展性肝纤维化的相关因素之一。Li等^[51]研究观察发现, 黄芪提取物可降低血清ALT、AST活性和HA、TNF-α含量, 使肝纤维化程度明显减轻, 推测黄芪提取物抗肝纤维化作用可能与降低HA和TNF-α含量有关。后续实验发现黄芪总皂苷提取物能明显降低肝纤维化模型大鼠血清ALT、AST、HA、LN、PCⅢ、CⅣ及组织羟脯氨酸(hydroxyproline, HYP) 含量, 同时病理学组织观测结果显示肝细胞变性和坏死均有不同程度减轻。进一步说明黄芪总皂苷可能通过抑制胶原增生、保护细胞对肝纤维化具有良好的治疗效果^[52]。Du等^[53]相关实验研究也表明肝纤维化大鼠每日灌服黄芪水煎剂浓缩液12周后大鼠血清HA、CⅣ显著降低, 同时肝组织中MMP-1含量明显升高而TIMP-1含量明显降低, 表明黄芪改善肝纤维化可能是通过提高肝组织中MMP1的含量, 降低TIMP1的含量, 使得ECM降解增多、合成减少, 从而抑制ECM堆积。在细胞水平上, 研究确定黄芪皂苷Ⅰ、黄芪内酯A和毛蕊异黄酮联合应用可抑制人肝星状细胞LX-2增殖, 降低HYP含量和α-SMA表达, 减少胶原等ECM过度沉积^[54]。新的研究表明黄芪总皂苷中的黄芪皂苷Ⅰ和环黄芪醇能显著减低胆汁淤积性肝病(cholestatic liver disease, CLD) 小鼠HYP含量, 降低肝组织中胆管上皮细胞特异性标志物细胞角蛋白-19 (cytokeratin 19, CK19) 和α-SMA蛋白及mRNA表达, 改善CLD小鼠的血管反应和肝纤维化^[55]。

HSCs活化进一步转化为肌成纤维细胞是ECM合成和分泌的关键环节。黄芪总皂苷对肝纤维化模型的干预实验发现, 黄芪总皂苷能显著提高模型组降低的mmu_circ_34116表达水平, 抑制HSCs活化, 发挥抗肝纤维化^[56]。其他研究也表明毛蕊异黄酮抗肝纤维化机制与法尼醇X受体(farnesoid X receptor, FXR) 激活, 从而抑制HSCs活化有关^[57]。HSCs糖酵解在肝纤维化中具有重要作用, 抑制糖酵解途径可抑制HSCs增殖、阻断HSCs向肌成纤维细胞转化、抑制并改善肝纤维化, 有报道称AS-Ⅳ水解产物CAG对四氯化碳(CCl₄) 诱导的小鼠肝纤维化有改善作用, 同时降低了其体内糖酵解关键酶和产物水平, 但其机制是否与抑制HSCs的糖酵解有关还需进一步的实验验证^[58]。EMT被认为是肝纤维化中产生肌成纤维细胞的机制之一。研究证明AS-Ⅳ导致肝纤维化模型大鼠组织中TGF-β1、神经钙黏附蛋白(N-cadherin)、α-SMA蛋白表达水平下降, 上皮钙黏附蛋白(E-cadherin) 表达水平升高, 抑制EMT发挥抗肝纤维化作用^[59]。

TGF-β1是肝损伤后促进全面肝纤维化的一个关键细胞因子。在Xu等^[60]的研究中发现, 对胆汁淤积性肝纤维化模型用黄芪多糖干预后, 大鼠肝组织HYP含量显著降低, 纤维组织的增生程度明显减轻, 进一步采用Western blot及免疫组化研究TGF-β1在肝组织表达发现, 肝组织TGF-β1蛋白表达量显著降低, 提示黄芪多糖可有效地抑制大鼠肝纤维化模型肝组织TGF-β1表达, 进而干预治疗胆汁淤积性肝纤维化。作为重要的促肝纤维化生长因子, TGF-β1通过经典Smad信号途径在肝纤维化中发挥关键作用。黄进等^[61]用黄芪多糖干预大鼠肝纤维化模型后, 肝组织TGF-β1、Smad3、Smad4表达明显降低, Smad7表达显著升高, 血清肝功水平、肝纤维化程度明显降低, 表明黄芪多糖通过作用于TGF-β1/Smad信号通路发挥抗肝纤维化作用。也有关于黄芪总黄酮通过抑制TGF-β1/Smad信号通路介导的炎症反应发挥抗肝纤维化作用的研究^[62]。此外, TGF-β1介导的MAPK等非Smad依赖信号途径在肝纤维化进程中同样重要。Li等^[63]证实AS-Ⅳ通过调控氧化应激介导的p38-MAPK途径抑制HSC活化和胶原生成。同时其他研究发现, AS-Ⅳ通过抑制Notch1信号通路, 从而抑制胆道上皮细胞的异常增殖来预防胆道肝纤维化^[64]。

4.3 黄芪抗心肌纤维化作用及机制

心肌纤维化主要是因为心脏成纤维细胞(cardiac fibroblasts, CFs) 在多种促纤维化因子刺激作用下, 经过不同信号通路的介导, 转分化为肌成纤维细胞。肌成纤维细胞分泌大量细胞外基质成分, 最终导致心肌纤维化的产生。

黄芪中黄芪甲苷、黄芪多糖、异黄酮等成分均具有抗心肌纤维化作用, 可通过调节心肌纤维化相关因子表达发挥作用。研究发现AS-Ⅳ可抑制充血性心力衰竭(congestive heart failure, CHF) 大鼠的心肌纤维化, 具体作用机制与剂量依赖性地抑制心肌组织中TGF-β1、CTGF过度表达有关^{[65, 66]}。同时, 有报道称黄芪多糖通过下调心肌组织TGF-β1表达、上调过氧化物酶体增殖物激活受体-γ (peroxisome proliferators-activated receptor-γ, PPAR-γ) 表达, 进而改善自发性高血压大鼠心功能和心肌纤维化^[67]。也有研究表明, 黄芪中的黄酮类成分花蕊异黄酮通过抑制转化生长因子β受体1 (transforming growth factor-beta receptor 1, TGFBR1) 减轻TGF-β1诱导的心脏成纤维细胞增殖和胶原沉积, 缓解小鼠心肌梗死后心肌纤维化和心功能障碍^[68]。

黄芪有效成分也可通过作用于心肌纤维化相关通路发挥作用。研究发现AS-Ⅳ能抑制TGF-β/Smad通路, 降低TGF-β1和α-SMA生成, 对心肌纤维化具有预防作用^{[69, 70]}。其他研究也证实AS-Ⅳ通过靶向miR-135a-TRPM7-TGF-β/Smads通路抑制心肌纤维化^[71]。Zhang等^[72]研究首次发现AS-Ⅳ通过下调ROS/caspase-1/GSDMD信号通路, 减少巨噬细胞的焦亡, 显著减弱心肌梗死引起的心功能障碍和炎症反应。Akt1-mTOR-RPS6KB1信号通路在自噬调控中起关键作用, 黄芪甲苷水解产物CAG可诱导Akt1和RPS6KB1磷酸化, 抑制Akt1-RPS6KB1信号通路促进心肌细胞自噬, 改善心功能障碍和心肌重构^[73]。此外, 相关报道称黄芪总皂苷对柯萨奇病毒(coxsackie virus, CVB3) 诱导的扩张型心肌病心肌纤维化及X线诱导的心脏成纤维细胞纤维化损伤效应具有抑制作用, 这可能与调控TGF-β1/Smad和p38-MAPK通路有关^{[74, 75]}。朱晓雨等^[76]研究发现黄芪多糖通过抑制TGF-β1/Smad信号通路对异丙肾上腺素(isoprenaline, ISO) 所致的心肌纤维化有一定防治作用。

此外, 黄芪有效成分可通过抑制炎症反应、氧化应激, 影响苯丙氨酸代谢来发挥抗纤维化作用。毛蕊异黄酮通过激活H9C2细胞、成纤维细胞中的PI3K-Akt通路, 抑制急性心肌梗死后大鼠炎症和纤维化^[77]。Lu等^[78]发现AS-Ⅳ通过降低TRPM7表达抑制缺氧诱导的心脏成纤维细胞增殖和分化。而相关研究表明CAG有效防止异丙肾上腺素诱导的心脏纤维化是通过抑制NLRP3炎症小体及NF-κB信号通路, 减轻氧化应激水平实现的^{[79, 80]}。此外, AS-Ⅳ大幅增加嗜黏蛋白阿克曼菌(Akkermansia)、Defluviitaleaceae_UCG-011和文肯菌属(Rikenella) 的丰度, 从而影响苯丙氨酸代谢, 最终发挥抗心脏纤维化作用^[81]。

4.4 黄芪抗肾纤维化作用及机制

肾纤维化是各种进展性肾脏疾病的终末期结果, 慢性肾脏疾病触发复杂的细胞和细胞外基质反应程序, 导致胶原等ECM异常沉积, 最终导致细胞功能障碍、实质瘢痕和肾衰竭。

抑制管状上皮细胞向α-SMA表达阳性的肌成纤维细胞转分化, 减少细胞外基质沉积, 逆转EMT是肾间质纤维化的有效治疗策略。Wang等^[82]在动物实验和细胞实验中均发现AS-Ⅳ可以上调Smad7的表达, 阻断TGF-β/Smad信号通路, 降低α-SMA、CTGF以及纤连蛋白和Ⅰ、Ⅲ胶原等ECM生成, 抑制肾小管间质纤维化。Chen等^[83]细胞实验研究进一步表明AS-Ⅳ通过抑制肾小管上皮细胞HK-2中mTORC1/p70S6K信号通路, 下调螺状细胞和扭状细胞的表达, 减少纤维连接蛋白和Ⅳ型胶原的分泌来改善高糖介导的肾小管EMT。槲皮素在植物界分布广泛, 也存在于黄芪中。已有研究证实槲皮素可以抑制mTORC1/p70S6K、超音刺猬信号通路(sonic hedgehog signaling, SHH) 以及AREG/EGFR信号, 抑制EMT进而减轻肾纤维化^[84-86]。

调节炎症反应和氧化应激是肾间质纤维化的潜在治疗策略。黄芪多糖可降低TGF-β1表达, 调节TGF-β1/ILK通路, 减轻肾脏炎症和纤维化改善肾功能^[87]。部分研究发现AS-Ⅳ通过抑制JNK、p38 MAPK和TLR4/NF-κB通路, 进而抑制细胞凋亡和炎症, 发挥抗肾小管间质纤维化的作用, 为靶向炎症细胞和上皮细胞炎症反应逆转肾脏纤维化提供了新的见解^{[88, 89]}。其他研究表明, AS-Ⅳ通过增强p62磷酸化来缓解他克莫司诱导的慢性肾毒性(tacrolimus-induced chronic nephrotoxicity, TIN), 从而增加Nrf2核易位, 缓解ROS积累和肾纤维化^[90]。

5 总结与展望

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器官纤维化是多个细胞、多个信号通路相互作用的复杂过程。尽管已有研究表明许多小分子化合物在动物模型中显示出良好的抗纤维特性, 但临床试验却未达到预期治疗效果, 并具有诸多严重不良反应。目前, 临床上仅有吡非尼酮、尼达尼布能够有效减缓肺纤维化进程, 而肝脏、心脏、肾脏等器官纤维化均无获批上市药物, 治疗方式主要以自体或异体移植为主^[3]。因此, 器官纤维化治疗药物还需要进一步深入研究。

中药复方作为传统中医药的重要组成部分, 可以通过多成分、多靶点、多通路、多环节抑制器官纤维化进程从而改善脏器功能^[91]。近年来, 已有多种中药复方用于治疗器官纤维化。肝复乐片由沉香、鳖甲(醋制)、党参、白术(炒)、黄芪、重楼、大黄、陈皮、桃仁、土鳖虫、半枝莲、败酱草等21味药制成, 发挥降低肝纤维化患者血清学指标、抑制炎症和抗肝纤维化作用。复方鳖甲软肝片由鳖甲(制)、莪术、赤芍、当归、三七、党参、黄芪、紫河车、冬虫夏草、板蓝根、连翘组成, 可用于慢性乙型肝炎肝纤维化。甲芪肝纤颗粒由黄芪、防己、茯苓、厚朴、延胡索、赤芍、牛膝、桃仁、莪术、鳖甲、土鳖虫组成, 可用于乙型肝炎肝纤维化患者中透明质酸、Ⅳ型胶原层黏连蛋白等血清学指标异常的肝郁血瘀兼脾虚湿滞者。以上用于治疗器官纤维化的中药复方均含有黄芪, 提示黄芪在治疗器官纤维化中具有重要作用。

本文对当前黄芪有效成分参与调控器官纤维化的相关研究论文进行系统分析, 发现黄芪通过多种有效成分, 作用于多个靶点对肺、肝、心肌和肾等重要器官纤维化发挥治疗作用。其中, 黄芪主要成分治疗器官纤维化研究最多的是黄芪甲苷, 其他主要成分相关研究还有黄芪多糖、黄芪总黄酮等。这些有效成分通过调节TGF-β1等细胞外因子、MMPs等胞内激酶及其抑制剂TIMPs等各种相关因子, 作用于Smad信号通路、Notch信号通路等各信号通路的上下游靶点, 抑制成纤维细胞增殖、分化及ECM沉积, 调节氧化应激、炎症反应及细胞自噬等来抑制各器官纤维化的发生发展。

然而, 由于致器官纤维化的各因子、信号通路之间相互作用、相互影响形成复杂的网络关系, 而黄芪有效成分种类多样且作用于多个靶点, 使得黄芪有效成分治疗器官纤维化的机制及关键作用靶点研究始终停留在动物模型阶段, 难以进行下一步临床研究。通过网络药理学、计算机辅助药物设计等方法对黄芪多成分、多靶点、多通路干预器官纤维化进行研究探讨, 挖掘黄芪及其有效成分抗器官纤维化的关键作用靶点和途径并开展抗纤维化临床研究具有重要意义。

作者贡献: 该文章由李世粉和杨若轩收集资料和撰写; 梁海海和孙健为文章提供了重要指导和关键意见。

利益冲突: 所有作者均声明不存在利益冲突。

基金

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国家自然科学基金资助项目(32171127)
黑龙江省杰出青年基金资助项目(JQ2022H001)

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2023年第58卷第8期

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doi: 10.16438/j.0513-4870.2023-0313

接收时间：2023-03-15
首发时间：2025-11-21
出版时间：2023-08-12

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收稿日期：2023-03-15
修回日期：2023-04-13

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国家自然科学基金资助项目(32171127)

黑龙江省杰出青年基金资助项目(JQ2022H001)

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哈尔滨医科大学药学院, 黑龙江哈尔滨 150081

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*梁海海, Tel: 86-451-86671354, E-mail: lianghaihai@ems.hrbmu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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