何首乌致肝损伤的信号通路及其作用机制

梁子晗; 李佳辉; 程爽; 袁卓雅; 荣文雅; 刘亚杰; 郝玉洁; 王睿林

doi:10.12449/JCH240332

何首乌致肝损伤的信号通路及其作用机制

DOI: 10.12449/JCH240332

1.
河南中医药大学第一临床医学院，郑州 450000
2.
南方医科大学中医药学院，广州 510405
3.
解放军总医院第五医学中心中医肝病科，北京 100039

基金项目:

国家自然科学基金面上项目 (81673806);

中国医药教育协会2020重大科学攻关问题和医药技术难题 (2020KTY001)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：梁子晗负责课题设计，资料分析，撰写论文；李佳辉、程爽、袁卓雅、荣文雅、刘亚杰、郝玉洁参与收集数据，修改论文；王睿林负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
王睿林， wrl7905@163.com （ORCID： 0000-0002-7129-016X）

计量
- 文章访问数: 562
- HTML全文浏览量: 271
- PDF下载量: 65
- 被引次数: 0
出版历程
- 收稿日期: 2023-07-08
- 录用日期: 2023-08-21
- 出版日期: 2024-03-20

Mechanism of action of Polygonum multiflorum in inducing liver injury： A study based on signaling pathways

1.
First Clinical Medical College of Henan University of Chinese Medicine，Zhengzhou 450000，China
2.
School of Traditional Chinese Medicine，Southern Medical University，Guangzhou 510405，China
3.
Department of Traditional Chinese Medicine Hepatology，The Fifth Medical Center of PLA General Hospital，Beijing 100039，China

Research funding:

National Natural Science Foundation of China （General Program） (81673806);

Major Scientific and Technological Issues and Challenges in Medicine and Pharmacy 2020 by the China Association of Medical Education (2020KTY001)

More Information

Corresponding author: WANG Ruilin， wrl7905@163.com （ORCID： 0000-0002-7129-016X）

摘要

摘要: 何首乌是一种临床常用的补益类中草药，相关肝损伤事件近年来被频繁报道，其安全性问题逐渐引起国内外关注。本文梳理近年来何首乌致药物性肝损伤信号通路及作用机制的研究进展，基于信号通路角度，为临床正确合理应用何首乌提供新思路。现有研究证据表明，何首乌参与调控多条信号通路，通过破坏线粒体功能、加重胆汁酸淤积、诱发免疫应激、氧化应激、内质网应激等多种途径导致肝细胞死亡，多靶点、多途径、多层次诱导药物性肝损伤的发生发展。
- 何首乌 /
- 化学性与药物性肝损伤 /
- 信号传导
Abstract: Polygonum multiflorum （PM）， a commonly used Chinese herbal medicine in clinical practice， has been associated with frequent reports of liver injury in recent years， and the medication safety of PM has attracted more and more attention in China and globally. This article reviews the recent research advances in the signaling pathways and mechanisms of PM in causing drug-induced liver injury （DILI） and aims to provide new ideas for the proper and rational use of PM in clinical practice. The results show that PM is involved in the regulation of various signaling pathways， and it leads to the death of hepatocytes by destroying mitochondrial function， exacerbating bile acid accumulation， and inducing immune response， oxidative stress， and endoplasmic reticulum stress， thereby inducing the development and progression of DILI through multiple targets， pathways， and levels.
- Polygoni Multiflori Radix /
- Chemical and Drug Induced Liver Injury /
- Signal Transduction

HTML全文

图 1 线粒体介导的细胞死亡机制

注： Bid， BH3相互作用域死亡激动剂；tBid， Bid的截短形式；Bmf，Bcl-2修饰因子；Bim，Bcl-2相互作用的模块。^{［ 9］}

Figure 1. Mitochondria-mediated cellular death mechanism^［9］

下载: 全尺寸图片幻灯片

图 2 线粒体介导的DILI机制^［7］

Figure 2. Mechanism of mitochondria-mediated DILI^［7］

下载: 全尺寸图片幻灯片

图 3 FXR维护胆汁稳态机制

Figure 3. Mechanism of FXR-maintained bile homeostasis

下载: 全尺寸图片幻灯片

图 4 PM致DILI信号通路

Figure 4. Signaling pathways of polygonum multiflorum-induced DILI

下载: 全尺寸图片幻灯片

参考文献(59)

[1]	YU YC, MAO YM, CHEN CW, et al. CSH guidelines for the diagnosis and treatment of drug-induced liver injury[J]. Hepatol Int, 2017, 11( 3): 221- 241. DOI: 10.1007/s12072-017-9793-2.
[2]	BYEON JH, KIL JH, AHN YC, et al. Systematic review of published data on herb induced liver injury[J]. J Ethnopharmacol, 2019, 233: 190- 196. DOI: 10.1016/j.jep.2019.01.006.
[3]	YANG JB, GAO BW, SUN H, et al. Research progress on material basis of liver toxicity of Polygonum Multiflorum Thunb[J]. Chin J Pharmacovigil, 2022, 19( 6): 610- 614. DOI: 10.19803/j.1672-8629.2022.06.06. 杨建波, 高博闻, 孙华, 等. 何首乌肝毒性物质基础研究进展[J]. 中国药物警戒, 2022, 19( 6): 610- 614. DOI: 10.19803/j.1672-8629.2022.06.06.
[4]	CÁRDENAS A, RESTREPO JC, SIERRA F, et al. Acute hepatitis due to Shen-Min: A herbal product derived from Polygonum Multiflorum[J]. J Clin Gastroenterol, 2006, 40( 7): 629- 632. DOI: 10.1097/00004836-200608000-00014.
[5]	ZHAI XR, ZOU ZS, WANG JB, et al. Herb-induced liver injury related to Reynoutria multiflora(thunb.) moldenke: Risk factors, molecular and mechanistic specifics[J]. Front Pharmacol, 2021, 12: 738577. DOI: 10.3389/fphar.2021.738577.
[6]	WANG WR, HONG B, SHAN GS. Research progress on mechanism of hepatotoxicity of Ploygoni Multiflori Radix[J]. Drugs Clin, 2020, 35( 2): 378- 382. DOI: 10.7501/j.issn.1674-5515.2020.02.039. 王婉茹, 洪滨, 单国顺. 何首乌肝毒性作用机制的研究进展[J]. 现代药物与临床, 2020, 35( 2): 378- 382. DOI: 10.7501/j.issn.1674-5515.2020.02.039.
[7]	HAN D, SHINOHARA M, YBANEZ MD, et al. Signal transduction pathways involved in drug-induced liver injury[J]. Handb Exp Pharmacol, 2010( 196): 267- 310. DOI: 10.1007/978-3-642-00663-0_10.
[8]	BOCK FJ, TAIT SWG. Mitochondria as multifaceted regulators of cell death[J]. Nat Rev Mol Cell Biol, 2020, 21( 2): 85- 100. DOI: 10.1038/s41580-019-0173-8.
[9]	KAPLOWITZ N. Biochemical and cellular mechanisms of toxic liver injury[J]. Semin Liver Dis, 2002, 22( 2): 137- 144. DOI: 10.1055/s-2002-30100.
[10]	WESTON CR, DAVIS RJ. The JNK signal transduction pathway[J]. Curr Opin Cell Biol, 2007, 19( 2): 142- 149. DOI: 10.1016/j.ceb.2007.02.001.
[11]	ONG MMK, LATCHOUMYCANDANE C, BOELSTERLI UA. Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities[J]. Toxicol Sci, 2007, 97( 1): 205- 213. DOI: 10.1093/toxsci/kfl180.
[12]	OU L. Study on the mechanism of liver injury caused by Polygonum multiflorum thunb based on different kidney deficiency syndrome[D]. Chengdu: Chengdu University of TCM, 2016. 欧莉. 基于不同肾虚证候的何首乌致肝损伤机制研究[D]. 成都: 成都中医药大学, 2016.
[13]	LIN LF, LIU YL, FU S, et al. Inhibition of mitochondrial complex function-the hepatotoxicity mechanism of emodin based on quantitative proteomic analyses[J]. Cells, 2019, 8( 3): 263. DOI: 10.3390/cells8030263.
[14]	QUAN YY. Investigation on the hepatotoxic material basis and mechanism of polygoni multiflori Radix with zebrafish(Danio rerio) model[D]. Chengdu: Chengdu University of TCM, 2019. 全云云. 基于斑马鱼模型的何首乌肝毒性物质基础及其作用机制研究[D]. 成都: 成都中医药大学, 2019.
[15]	WANG ST. Study on the mechanism of metabolic toxicity of cortex dictamni extract FRA and the evaluation of hepatotoxicity of Polygonum multiflorum extract HY-W-26 in vitro and its mechanism[D]. Beijing: Peking Union Medical College, 2022. 王姝廷. 白鲜皮提取物FRA的代谢毒性机制研究及何首乌提取物HY-W-26的体外肝毒性评价及机制探索[D]. 北京: 北京协和医学院, 2022.
[16]	PANDITA TK. A multifaceted role for ATM in genome maintenance[J]. Expert Rev Mol Med, 2003, 5( 16): 1- 21. DOI: 10.1017/S1462399403006318.
[17]	LIEBL MC, HOFMANN TG. The role of p53 signaling in colorectal cancer[J]. Cancers, 2021, 13( 9): 2125. DOI: 10.3390/cancers13092125.
[18]	LAI JM, CHANG JT, WEN CL, et al. Emodin induces a reactive oxygen species-dependent and ATM-p53-Bax mediated cytotoxicity in lung cancer cells[J]. Eur J Pharmacol, 2009, 623( 1-3): 1- 9. DOI: 10.1016/j.ejphar.2009.08.031.
[19]	BOUNDA GA, ZHOU W, WANG DD, et al. Rhein elicits in vitro cytotoxicity in primary human liver HL-7702 cells by inducing apoptosis through mitochondria-mediated pathway[J]. Evid Based Complement Alternat Med, 2015, 2015: 329831. DOI: 10.1155/2015/329831.
[20]	GOMEZ-OSPINA N, POTTER CJ, XIAO R, et al. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis[J]. Nat Commun, 2016, 7: 10713. DOI: 10.1038/ncomms10713.
[21]	SHIN DJ, WANG L. Bile acid-activated receptors: A review on FXR and other nuclear receptors[J]. Handb Exp Pharmacol, 2019, 256: 51- 72. DOI: 10.1007/164_2019_236.
[22]	SINAL CJ, TOHKIN M, MIYATA M, et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis[J]. Cell, 2000, 102( 6): 731- 744. DOI: 10.1016/s0092-8674(00)00062-3.
[23]	HAYASHI H, TAKADA T, SUZUKI H, et al. Transport by vesicles of glycine- and taurine-conjugated bile salts and taurolithocholate 3-sulfate: A comparison of human BSEP with rat Bsep[J]. Biochim Biophys Acta, 2005, 1738( 1-3): 54- 62. DOI: 10.1016/j.bbalip.2005.10.006.
[24]	LI X, LIU RP, YU LX, et al. Alpha-naphthylisothiocyanate impairs bile acid homeostasis through AMPK-FXR pathways in rat primary hepatocytes[J]. Toxicology, 2016, 370: 106- 115. DOI: 10.1016/j.tox.2016.09.020.
[25]	LIEN F, BERTHIER A, BOUCHAERT E, et al. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk[J]. J Clin Invest, 2014, 124( 3): 1037- 1051. DOI: 10.1172/JCI68815.
[26]	WANG X, HAN LF, BI YJ, et al. Paradoxical effects of emodin on ANIT-induced intrahepatic cholestasis and herb-induced hepatotoxicity in mice[J]. Toxicol Sci, 2019, 168( 1): 264- 278. DOI: 10.1093/toxsci/kfy295.
[27]	SUN M, YU QW, XIANG T, et al. 2, 3, 5, 4′-Tetrahydroxystibane-2-O-β-D-glucoside induces liver injury by disrupting bile acid homeostasis and phospholipids efflux[J]. China J Chin Mater Med, 2021, 46( 1): 139- 145. DOI: 10.19540/j.cnki.cjcmm.20200818.401. 孙萌, 俞沁玮, 向婷, 等. 二苯乙烯苷扰乱胆汁酸平衡并抑制磷脂分泌诱导肝损伤[J]. 中国中药杂志, 2021, 46( 1): 139- 145. DOI: 10.19540/j.cnki.cjcmm.20200818.401.
[28]	INAGAKI T, CHOI M, MOSCHETTA A, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis[J]. Cell Metab, 2005, 2( 4): 217- 225. DOI: 10.1016/j.cmet.2005.09.001.
[29]	DI CIAULA A, BONFRATE L, BAJ J, et al. Recent advances in the digestive, metabolic and therapeutic effects of farnesoid X receptor and fibroblast growth factor 19: From cholesterol to bile acid signaling[J]. Nutrients, 2022, 14( 23): 4950. DOI: 10.3390/nu14234950.
[30]	ZHANG GQ, SUN JH, LIU MQ, et al. Polygoni multiflori radix exacerbates idiosyncratic inflammatory liver injury through the FXR-SHP pathway and altered pharmacokinetic behavior[J]. Biomed Pharmacother, 2023, 160: 114233. DOI: 10.1016/j.biopha.2023.114233.
[31]	DAI YH, JIA ZX, FANG C, et al. Polygoni Multiflori Radix interferes with bile acid metabolism homeostasis by inhibiting Fxr transcription, leading to cholestasis[J]. Front Pharmacol, 2023, 14: 1099935. DOI: 10.3389/fphar.2023.1099935.
[32]	HAN ZP, ZHUO FX, LI F, et al. The effect and mechanism of FXR signaling pathway on lipid accumulation induced by Polygonum multiflorum thumb[J]. New Chin Med, 2021, 52( 10): 759- 763. DOI: 10.3969/j.issn.0253-9802.2021.10.007. 韩宗萍, 卓飞霞, 李芳, 等. FXR信号通路介导何首乌导致脂质沉积的作用及机理研究[J]. 新医学, 2021, 52( 10): 759- 763. DOI: 10.3969/j.issn.0253-9802.2021.10.007.
[33]	SUN M, YU QW, XIANG T, et al. 2,3,5,4′-Tetrahydroxystibane-2-O-β-D-glucoside induces liver injury by disrupting bile acid homeostasis and phospholipids efflux[J]. China J Chin Materia Med, 2021, 46( 1): 139- 145. DOI: 10.19540/j.cnki.cjcmm.20200818.401. 孙萌, 俞沁玮, 向婷, 等. 二苯乙烯苷扰乱胆汁酸平衡并抑制磷脂分泌诱导肝损伤[J]. 中国中药杂志, 2021, 46( 1): 139- 145. DOI: 10.19540/j.cnki.cjcmm.20200818.401.
[34]	KAISHO T, AKIRA S. Toll-like receptor function and signaling[J]. J Allergy Clin Immunol, 2006, 117( 5): 979- 987. DOI: 10.1016/j.jaci.2006.02.023.
[35]	LIM KH, STAUDT LM. Toll-like receptor signaling[J]. Cold Spring Harb Perspect Biol, 2013, 5( 1): a011247. DOI: 10.1101/cshperspect.a011247.
[36]	VON BERNUTH H, PICARD C, JIN ZB, et al. Pyogenic bacterial infections in humans with MyD88 deficiency[J]. Science, 2008, 321( 5889): 691- 696. DOI: 10.1126/science.1158298.
[37]	CHEN X, DENG CL. Research progress in roles of TLR4 in liver damage[J]. Med Recapitul, 2008, 14( 19): 2897- 2899. DOI: 10.3969/j.issn.1006-2084.2008.19.007. 陈炘, 邓存良. TLR4在肝脏损伤中的作用研究进展[J]. 医学综述, 2008, 14( 19): 2897- 2899. DOI: 10.3969/j.issn.1006-2084.2008.19.007.
[38]	XIE LH. Mechanistic research on hepatotoxicity of ethanol extracts from Polygonum multiflorum during LPS activated in rats[D]. Guangzhou: Guangdong Pharmaceutical University, 2016. 谢丽华. 何首乌醇提液对LPS诱导致大鼠肝损伤机制研究[D]. 广州: 广东药科大学, 2016.
[39]	PAN YZ. Study on specific heterogeneous liver injury evaluation and mechanism of cis- and trans-biphenyl glucoside based on NLRP3 inflammasome[D]. Nanjing: Nanjing University of Chinese Medicine, 2021. 潘韵铮. 基于NLRP3炎症小体的顺式和反式二苯乙烯苷特异质肝损伤评价及机制研究[D]. 南京: 南京中医药大学, 2021.
[40]	LONG TT, LIU ZJ, SHANG JC, et al. Polygonatum sibiricum polysaccharides play anti-cancer effect through TLR4-MAPK/NF-κB signaling pathways[J]. Int J Biol Macromol, 2018, 111: 813- 821. DOI: 10.1016/j.ijbiomac.2018.01.070.
[41]	LI CY. Preliminary study on specific liver injury of Polygonum multiflorum Thunb based on immune stress[D]. Chengdu: Chengdu University of TCM, 2015. 李春雨. 基于免疫应激的何首乌特异质肝损伤的初步研究[D]. 成都: 成都中医药大学, 2015.
[42]	PÅLSSON-MCDERMOTT EM, LAJ O’NEILL. Signal transduction by the lipopolysaccharide receptor, toll-like receptor-4[J]. Immunology, 2004, 113( 2): 153- 162. DOI: 10.1111/j.1365-2567.2004.01976.x.
[43]	MAO HM, XIE LH, FAN X, et al. Effect of ethanol extracts from Polygonum multiflorum Thunb on expressions of signal pathway TLR4/TRIF/IRF-3 in LPS induced rats liver[J]. J Int Pharm Res, 2016, 43( 3): 496- 503. DOI: 10.13220/j.cnki.jipr.2016.03.018. 毛宏梅, 谢丽华, 樊星, 等. 何首乌醇提物对脂多糖诱导大鼠肝TLR4/TRIF/IRF-3信号通路的影响[J]. 国际药学研究杂志, 2016, 43( 3): 496- 503. DOI: 10.13220/j.cnki.jipr.2016.03.018.
[44]	GONG J, XIE XK. Effect of endoplasmic reticulum stress and autophagy on hepatocyte apoptosis[J]. J Clin Hepatol, 2019, 35( 12): 2828- 2832. DOI: 10.3969/j.issn.1001-5256.2019.12.041. 弓晶, 解新科. 内质网应激和细胞自噬对肝细胞凋亡的影响[J]. 临床肝胆病杂志, 2019, 35( 12): 2828- 2832. DOI: 10.3969/j.issn.1001-5256.2019.12.041.
[45]	PU S, PAN Y, ZHANG Q, et al. Endoplasmic reticulum stress and mitochondrial stress in drug-induced liver injury[J]. Molecules, 2023, 28( 7): 3160. DOI: 10.3390/molecules28073160.
[46]	FUJII J, HOMMA T, KOBAYASHI S, et al. Mutual interaction between oxidative stress and endoplasmic reticulum stress in the pathogenesis of diseases specifically focusing on non-alcoholic fatty liver disease[J]. World J Biol Chem, 2018, 9( 1): 1- 15. DOI: 10.4331/wjbc.v9.i1.1.
[47]	ZHANG LP, MENG Y, YUAN XD, et al. Research progress of endoplasmic reticulum stress and apoptosis mediated signal transduction[J]. Biomed Eng Clin Med, 2018, 22( 2): 214- 220. DOI: 10.13339/j.cnki.sglc.20180313.021. 张利平, 孟燕, 元小冬, 等. 内质网应激及介导细胞凋亡信号转导研究进展[J]. 生物医学工程与临床, 2018, 22( 2): 214- 220. DOI: 10.13339/j.cnki.sglc.20180313.021.
[48]	ZHANG ZQ. Study on the mechanism of enhanced hepatotoxicity induced by CYP1A metabolism and activation of emodin in Polygonum multiflorum thunb[D]. Nanchang: Jiangxi University of Traditional Chinese Medicine, 2022. 张祖奇. 何首乌中大黄素经CYP1A代谢活化致肝毒性增强机理研究[D]. 南昌: 江西中医药大学, 2022.
[49]	ROTH RA, LUYENDYK JP, MADDOX JF, et al. Inflammation and drug idiosyncrasy: Is there a connection?[J]. J Pharmacol Exp Ther, 2003, 307( 1): 1- 8. DOI: 10.1124/jpet.102.041624.
[50]	LI CC, YANG HT, HOU YC, et al. Dietary fish oil reduces systemic inflammation and ameliorates sepsis-induced liver injury by up-regulating the peroxisome proliferator-activated receptor gamma-mediated pathway in septic mice[J]. J Nutr Biochem, 2014, 25( 1): 19- 25. DOI: 10.1016/j.jnutbio.2013.08.010.
[51]	HELAN Z, YIN P, MENG YK, et al. Study on the mechanism of PPAR-γ dependent immunological idiosyncrasy liver injury induced by Polygonum multiflorum[J]. Acta Pharm Sin, 2017, 52( 7): 1027- 1032. DOI: 10.16438/j.0513-4870.2016-0774. 贺兰芝, 尹萍, 孟雅坤, 等. PPAR-γ依赖的何首乌免疫性特异质肝损伤机制研究[J]. 药学学报, 2017, 52( 7): 1027- 1032. DOI: 10.16438/j.0513-4870.2016-0774.
[52]	MENG YK, LI CY, LI RY, et al. Cis-stilbene glucoside in Polygonum multiflorum induces immunological idiosyncratic hepatotoxicity in LPS-treated rats by suppressing PPAR-Γ[J]. Acta Pharmacol Sin, 2017, 38( 10): 1340- 1352. DOI: 10.1038/aps.2017.32.
[53]	BRUGGE J, HUNG MC, MILLS GB. A new mutational AKTivation in the PI3K pathway[J]. Cancer Cell, 2007, 12( 2): 104- 107. DOI: 10.1016/j.ccr.2007.07.014.
[54]	LIN LF. Study on components and mechanism of liver injury caused by Polygonum multiflorum Thunb[D]. Beijing: Beijing University of Chinese Medicine, 2016. 林龙飞. 何首乌致肝损伤成分及作用机制研究[D]. 北京: 北京中医药大学, 2016.
[55]	HUANG H, XIONG WN, TANG XJ, et al. Screening of hepatotoxic components and CYP450 inhibitors of polygoni multiflori Radix based on network toxicology and molecular docking[J]. Genom Appl Biol, 2021, 40( S2): 2863- 2873. DOI: 10.13417/j.gab.040.002863. 黄洪, 熊万娜, 汤小军, 等. 基于网络毒理学和分子对接筛选何首乌致肝毒性成分和CYP450抑制剂[J]. 基因组学与应用生物学, 2021, 40( S2): 2863- 2873. DOI: 10.13417/j.gab.040.002863.
[56]	GONZALEZ FJ. Role of cytochromes P450 in chemical toxicity and oxidative stress: Studies with CYP2E1[J]. Mutat Res, 2005, 569( 1-2): 101- 110. DOI: 10.1016/j.mrfmmm.2004.04.021.
[57]	WANG MX, WANG YG, XU HH, et al. Effects of emodin in Polygonum multiflorum on liver cytotoxicity and CYP450 isoenzymes expression in L02 cells[J]. Chin Pharmacol Bull, 2016, 32( 11): 1543- 1548. DOI: 10.3969/j.issn.1001-1978.2016.11.013. 汪美汐, 王宇光, 徐焕华, 等. 何首乌中大黄素对L02肝细胞CYP亚酶表达及细胞毒性的影响[J]. 中国药理学通报, 2016, 32( 11): 1543- 1548. DOI: 10.3969/j.issn.1001-1978.2016.11.013.
[58]	SHIU TY, HUANG T, HUANG SM, et al. Nuclear factor κB down-regulates human UDP-glucuronosyltransferase 1A1: A novel mechanism involved in inflammation-associated hyperbilirubinaemia[J]. Biochem J, 2013, 449( 3): 761- 770. DOI: 10.1042/BJ20121055.
[59]	HUANG CW, LIU YJ, WANG L, et al. Hepatocytotoxic mechanism of different processing products of Heshouwu(Polygonum Multiflorum) based on transcriptomics[J]. J Hunan Univ Chin Med, 2023, 43( 6): 1028- 1034. DOI: 10.3969/j.issn.1674-070X.2023.06.010. 黄超文, 刘艳娟, 王璐, 等. 基于转录组学探讨何首乌不同炮制品的肝细胞毒性作用机制[J]. 湖南中医药大学学报, 2023, 43( 6): 1028- 1034. DOI: 10.3969/j.issn.1674-070X.2023.06.010.