潜在抗肝纤维化药物与靶点相关信号通路研究进展
DOI: 10.3969/j.issn.1001-5256.2023.12.027
Research advances in signaling pathways associated with potential anti-liver fibrosis drugs and targets
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摘要: 肝纤维化是慢性肝病进展为肝硬化甚至肝癌的关键一步。近年来,大量研究表明了干预肝纤维化进程的必要性,各种抗肝纤维化药物及活性成分相继被发现。非编码RNA在调解肝纤维化进程中也发挥重要作用,寻找能够调节信号通路介导的上游非编码RNA可以为抗肝纤维化治疗提供新的见解。本文分别介绍了TGF-β、Wnt/β-catenin、PI3K/Akt/mTOR、NF-κB、Hippo和MAPK信号通路介导的肝纤维化进程,并列举了各信号通路中最新的抗肝纤维化药物或活性成分以及相关非编码RNA介导的抗肝纤维化靶点与药物的研究进展,以期为抗肝纤维化提供新的研究思路和治疗方法。Abstract: Liver fibrosis is a key step in the progression of chronic liver diseases to liver cirrhosis and even liver cancer. In recent years, a large number of studies have shown the necessity of intervening in the process of liver fibrosis, and various anti-liver fibrosis drugs and active ingredients have been discovered. Non-coding RNAs also play an important role in the process of liver fibrosis, and searching for upstream non-coding RNAs that can regulate signaling pathways can provide new insights for anti-liver fibrosis treatment. This article introduces the process of liver fibrosis mediated by the TGF-β, Wnt/β-catenin, PI3K/Akt/mTOR, NF-κβ, Hippo, and MAPK signaling pathways, lists the latest anti-liver fibrosis drugs or active components in each signaling pathway, and summarizes the research advances in anti-liver fibrosis targets and drugs mediated by related non-coding RNAs, so as to provide new research ideas and treatment methods for anti-liver fibrosis treatment.
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Key words:
- Hepatic Fibrosis /
- Signal Transduction /
- Pharmaceutical Preparations /
- RNA, Untranslated
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表 1 抗肝纤维化活性成分及潜在药物与相关信号通路与试验剂量和类型总结
Table 1. Summary of anti-hepatic fibrosis active ingredients and potential drugs with related signaling pathways and trial dosages and types
抗肝纤维化活性成分/潜在药物 相关信号通路 试验剂量 试验类型 柚木叶提取物[7] TGF-β/SMAD2/7 50、100、200 mg/kg CCl4诱导的小鼠肝纤维化模型 芝麻酚[8] TGF-β/SMAD3/7 50、100 mg/kg TAA诱导的大鼠肝纤维化模型 阿司匹林[9] TGF-β/SMAD2/3 10、20、40 mmol/L和30 mg/kg HSC-T6,TAA诱导的大鼠肝纤维化模型 柠檬素[10] TGF-β/SMAD2/3/7 5、15 μmol/L和10、20 mg/kg HSC-LX2,小鼠AML-12,CCl4诱导的小鼠肝纤维化模型 咖啡因[12] TGF-β/SMAD3和MAPK 50 mg/kg TAA诱导的大鼠肝纤维化模型 50 mg/kg 高胆固醇饮食诱导的实验性非酒精性脂肪性肝炎大鼠模型 RBO[13] TGF-β1/FAK和NF-κβ 0.2、0.4 mL/kg TAA诱导的大鼠肝纤维化模型 五味子酯甲[14] TGF-β1/TAK1/MAPK和NF-κB 5 μmol/L和1、2、4 mg/kg HSC-T6,TAA诱导的小鼠肝纤维化模型 漆黄素[16] Wnt3a/β-catenin 50、100 mg/kg TAA诱导的大鼠肝纤维化模型 HNK[17] Wnt3a/β-catenin 12.5、25、50 μmol/L HSC-LX2,HSC-T6,HepG2癌细胞 多沙唑嗪[20] PI3K/Akt/mTOR 1、2、5、10、15 μmol/L HSC-LX2 2.5、5、10 mg/kg CCl4诱导的小鼠肝纤维化模型 富马酸替诺福韦二吡呋酯[21] PI3K/Akt/mTOR 100、200 μmol/L HSC-LX2,HSC-T6,HepG2细胞 100 mg/kg TAA诱导的小鼠肝纤维化模型 委陵菜酸[22] PI3K/Akt/mTOR和NF-κB 1.5、3.0 mg/kg CCl4诱导的大鼠肝纤维化模型 二氢杨梅素[25] PI3K/Akt和NF-κB 20、40 mg/kg TAA诱导的小鼠肝纤维化模型 甲氧基丁香酚[26] NF-kB 15、30、60、125、250 μmol/L HSC-LX2,HSC-GRX 0.25、1 mg/kg CCl4诱导的小鼠肝纤维化模型 獐牙菜提取物[27] NF-κB和TGF-β/SMAD2/3 100、200、400 mg/kg CCl4诱导的大鼠肝纤维化模型 西他列汀[28] Nrf2/NF-κB 10 mg/kg Con A诱导的肝炎相关肝纤维化小鼠模型 白藜芦醇[30] Hippo 60 μmol/L和20 mg/kg HSC-LX2,CCl4诱导的小鼠肝纤维化模型 L-NAT[31] Hippo/YAP1和TGF-β1/SMAD 2.5、5 mg/kg CCl4诱导的小鼠肝纤维化模型 香芹酚[33] MAPK 25、50、100 mg/kg HSC-T6细胞,CCl4诱导的小鼠肝纤维化模型 HNK[34] p38 MAPK和TGF-β1/SMAD2/3 10、20、30 μmol/L和10 mg/kg HSC-LX2,CCl4诱导的小鼠肝纤维化模型 表 2 ncRNA及药物与肝纤维化相关通路与试验类型总结
Table 2. Summary of non-coding RNAs and drug and liver fibrosis-related pathways and trial types
ncRNA/药物 相关信号通路/分子 作用靶点 试验类型 miRNA miR-139-5p[36] TGF-β PMP22 CCl4诱导的小鼠肝纤维化模型 miR-137-3p[37] TGF-β Ppic CCl4诱导的小鼠肝纤维化模型 miR-497[38] TGF-β/SMAD SMAD7 HSC-LX2 miR-34a-5p[39] TGF-β1/SMAD4 lncRNA CCAT2 HSC-LX2,HBV肝纤维化患者及健康人群 miR-6766-3p[40] TGF-β2/SMAD TGF-β2 HSC-LX2,CCl4诱导的小鼠肝纤维化模型 miR-130b‐5p[41] AMPK/TGF-β/SMAD2/3 SIRT4 HSC-T6,CCl4诱导的小鼠肝纤维化模型,纤维化或其他肝脏疾病患者 miR-124[42] NF-κB IQGAP1 HSC-LX2,CCl4诱导的小鼠肝纤维化模型 miR-129-5p[43] NF-κB PEG3 CCl4诱导的大鼠肝纤维化模型 lncRNA lncRNA-HEIM[44] TGF-β/SMAD SMAD4 HSC-LX2 lncRNA-MBI-52[45] SMAD4 miR-466g HSC-LX2,CCl4诱导的小鼠肝纤维化模型 lncRNA-LFAR1[46] TGF-β1/SMAD2/3和Notch SMAD2/3和Notch 人HEK293T,小鼠AML-12,原代HSC和肝细胞 CCl4诱导和胆管结扎(BDL)诱导的小鼠肝纤维化模型 lncRNA-ANXA2P2(小鼠Anxa6)[47] TGF-β1/PI3K/Akt miR-9-5p CCl4诱导的小鼠肝纤维化模型 lncRNA-Met与lncRNA-Nox4[48] PI3K/Akt PI3K CCl4诱导的小鼠肝纤维化模型 lncRNA-MIAT[49] YAP/EMT miR-3085-5p 肝硬化患者,小鼠原代HSC,CCl4诱导的小鼠肝纤维化模型 lncRNA-HSER[50] Hippo-YAP和Notch C5AR1 小鼠AML-12,小鼠原代肝细胞、HSC、LSEC和KC,人L02和HEK293T 肝血管瘤患者,CCl4诱导的小鼠肝纤维化模型 circRNA circUbe2k[51] TGF-β2 miR-149-5p HSC-LX2,CCl4诱导的小鼠肝纤维化模型 circDIDO1[52] PTEN/AKT miR-141-3p HSC-LX2,肝衰竭患者 川芎嗪[53] TGF-β/SMAD miR-145 HSC-T6,乙醇诱导的胆道闭锁大鼠肝纤维化模型 达沙替尼[54] TGF-β/SMAD7 miR-17-5p TAA诱导的小鼠肝纤维化模型 Wnt5a/β-catenin miR-378-3p 艾代拉里斯(Idelalisib)[55] TGF-β/SMAD SMAD3 CCl4诱导的小鼠肝纤维化模型 PI3K/AKT miR-124-3p -
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