药学学报, 2021, 56(7): 1789-1796
引用本文:
武文星, 郭盛, 吴励萍, 夏玲, 赵明, 李全, 王恒斌, 段金廒. 免疫应激介导的赤芍缓解补骨脂肝脏毒性作用评价及其调控代谢网络分析[J]. 药学学报, 2021, 56(7): 1789-1796.
WU Wen-xing, GUO Sheng, WU Li-ping, XIA Ling, ZHAO Ming, LI Quan, WANG Heng-bin, DUAN Jin-ao. Paeoniae Rubra Radix decreases the hepatotoxicity of Psoraleae Fructus in an immunologically stressed rat model: a metabolic network analysis[J]. Acta Pharmaceutica Sinica, 2021, 56(7): 1789-1796.

免疫应激介导的赤芍缓解补骨脂肝脏毒性作用评价及其调控代谢网络分析
武文星1, 郭盛1*, 吴励萍1, 夏玲1, 赵明1, 李全2, 王恒斌2, 段金廒1*
1. 南京中医药大学, 中药资源产业化与方剂创新药物国家地方联合工程研究中心/江苏省中药资源产业化过程协同创新中心/江苏省方剂高技术研究重点实验室, 江苏 南京 210023;
2. 雷允上药业集团有限公司, 江苏 苏州 215003
摘要:
本研究基于免疫应激大鼠模型,研究补骨脂与赤芍配伍前后对其特异质肝损伤作用的影响及其代谢网络调控机制。采用低剂量脂多糖(lipopolysaccharide,LPS)注射致免疫应激SD大鼠模型,分别比较补骨脂单用及补骨脂-赤芍配伍给药后,模型动物肝脏谷草转氨酶(aspartate aminotransferase,AST)、谷丙转氨酶(alanine aminotransferase,ALT)的活性及肝脏病理变化;通过UHPLC-QTOF/MS分析不同组别大鼠血清代谢轮廓特征,结合主成分分析法(principal component analysis,PCA)、偏最小二乘判别分析法(orthogonal partial least squares discriminant analysis,OPLS-DA),研究补骨脂与赤芍配伍后对特异质肝损伤大鼠血清中内源性代谢产物的影响,并应用HMDB数据库及MetaboAnalyst在线通路富集工具进行生物标志物的鉴定和代谢通路富集分析。结果显示,对于LPS致免疫应激大鼠模型,补骨脂组AST、ALT均显著升高(P<0.01),肝脏切片可见明显的病理损伤,而其配伍赤芍后肝损伤作用显著降低。代谢组学分析显示赤芍主要通过调节花生四烯酸代谢和甘油磷脂代谢等信号通路改善补骨脂致肝毒性大鼠体内的血清代谢异常。
关键词:    补骨脂      赤芍      特异质肝损伤      代谢组学     
Paeoniae Rubra Radix decreases the hepatotoxicity of Psoraleae Fructus in an immunologically stressed rat model: a metabolic network analysis
WU Wen-xing1, GUO Sheng1*, WU Li-ping1, XIA Ling1, ZHAO Ming1, LI Quan2, WANG Heng-bin2, DUAN Jin-ao1*
1. National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of Traditional Chinese Medicine Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China;
2. Leiyunshang Pharmaceutical Co. Limited, Suzhou 215003, China
Abstract:
An immunologically stressed rat model was used in a metabolomics study on the ability of Paeoniae Rubra Radix to reduce the liver toxicity of Psoraleae Fructus. Different groups of rats were given the extracts of Psoraleae Fructus and Psoraleae Fructus together with Paeoniae Rubra Radix or combined with a non-toxic dose of lipopolysaccharide (LPS). The biochemical indices of liver function and pathological changes in liver tissue were used to evaluate histopathological changes. UHPLC-QTOF/MS was used to analyze the metabolic profile of serum samples, combined with principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) methods. The HMDB database and Metabo Analyst online tool were used for biomarker identification and metabolic pathway-enrichment analysis. The results show that the co-treatment Psoraleae Fructus and LPS resulted in significant liver injury, indicated by the elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, as well as obvious pathological changes. Liver injury was significantly decreased by treatment with Paeoniae Rubra Radix. Metabolomic analysis showed that the addition of Paeoniae Rubra Radix ameliorated the abnormal serum metabolism in rats mainly through regulation of arachidonic acid metabolism and glycerophospholipid metabolism pathways.
Key words:    Psoraleae Fructus    Paeoniae Rubra Radix    idiosyncratic hepatotoxicity    metabolomics   
收稿日期: 2021-02-23
DOI: 10.16438/j.0513-4870.2021-0255
基金项目: 国家自然科学基金资助项目(81873189,81673532);江苏省高校自然科学研究重大项目(18KJA360006).
通讯作者: 郭盛,Tel:86-25-85811917,E-mail:guosheng@njucm.edu.cn;段金廒,Tel:86-25-85811291,E-mail:dja@njucm.edu.cn
Email: guosheng@njucm.edu.cn;dja@njucm.edu.cn
相关功能
PDF(683KB) Free
打印本文
0
作者相关文章
武文星  在本刊中的所有文章
郭盛  在本刊中的所有文章
吴励萍  在本刊中的所有文章
夏玲  在本刊中的所有文章
赵明  在本刊中的所有文章
李全  在本刊中的所有文章
王恒斌  在本刊中的所有文章
段金廒  在本刊中的所有文章

参考文献:
[1] Jung B, Jang EH, Hong D, et al. Aqueous extract of Psoralea corylifolia L. inhibits lipopolysaccharide-induced endothelial-mesenchymal transition via downregulation of the NF-κB-SNAIL signaling pathway[J]. Oncol Rep, 2015, 34:2040-2046.
[2] Don MJ, Lin LC, Chiou WF. Neobavaisoflavone stimulates osteogenesis via p38-mediated up-regulation of transcription factors and osteoid genes expression in MC3T3-E1 cells[J]. Phytomedicine, 2012, 19:551-561.
[3] Mao H, Wang H, Ma S, et al. Bidirectional regulation of bakuchiol, an estrogenic-like compound, on catecholamine secretion[J]. Toxicol Appl Pharmacol, 2014, 274:180-189.
[4] Xin D, Wang H, Yang J, et al. Phytoestrogens from Psoralea corylifolia reveal estrogen receptor-subtype selectivity[J]. Phytomedicine, 2010, 17:126-131.
[5] Tian WY, Lan S, Zhang L, et al. Safety evaluation and risk control measures of Psoralea corylifolia[J]. China J Chin Mater Med (中国中药杂志), 2017, 42:4059-4066.
[6] Adverse Drug Reaction Information Bulletin (Issue 16) Be alert to liver damage caused by Zhuanggu Joint Pill[EB/OL]. Beijing:National Medical Products Administration, 2008-08-09[2021-02-23]. https://www.nmpa.gov.cn/xxgk/yjjsh/ypblfytb/20080809162301345.html.
[7] Guo S, Tang YP, Su SL, et al. Progress in studies on reducing the toxicity of Chinese medicines by using compatibility in the last ten years[J]. Chin J Exp Med Form (中国实验方剂学杂志), 2008, 14:74-79.
[8] Li R, Guo W, Fu Z, et al. Hepatoprotective action of Radix Paeoniae Rubra aqueous extract against CCl4-induced hepatic damage[J]. Molecules, 2011, 16:8684-8694.
[9] Zhao Y, Ma X, Wang J, et al. Paeoniflorin alleviates liver fibrosis by inhibiting HIF-1α through mTOR-dependent pathway[J]. Fitoterapia, 2014, 99:318-327.
[10] Zhao Y, Ma X, Wang J, et al. Large dose means significant effect-dose and effect relationship of Chi-Dan-Tui-Huang decoction on alpha-naphthylisothiocyanate-induced cholestatic hepatitis in rats[J]. BMC Complement Altern Med, 2015, 15:104.
[11] Fan YF, Xie Y, Liu L, et al. Paeoniflorin reduced acute toxicity of aconitine in rats is associated with the pharmacokinetic alteration of aconitine[J]. J Ethnopharmacol, 2012, 141:701-708.
[12] Su YJ, Jiang ZZ, Zhang Y, et al. Advances in researches on idiosyncratic drug induced liver injury and its occurrence mechanism[J]. Prog Pharm Sci (药学进展), 2012, 36:546-551.
[13] Wang JB, Cui HR, Bai ZF, et al. Precision medicine-oriented safety assessment strategy for traditional Chinese medicines:disease-syndrome-based toxicology[J]. Acta Pharm Sin (药学学报), 2016, 51:1681-1688.
[14] Roth RA, Luyendyk JP, Maddox JF, et al. Inflammation and drug idiosyncrasy-is there a connection?[J]. J Pharmacol Exp Ther, 2003, 307:1-8.
[15] Gao Y, Wang Z, Tang J, et al. New incompatible pair of TCM:Epimedii Folium combined with Psoraleae Fructus induces idiosyncratic hepatotoxicity under immunological stress conditions[J]. Front Med. 2020, 14:68-80.
[16] Li CY, He Q, Tang JF, et al. Metabolomic study on immunological stress-mediated hepatotoxicity of Polygonum multiflorum and its processed products of nine times steaming and nine times sunning[J]. Acta Pharm Sin (药学学报), 2017, 52:1069-1076.
[17] Wen P, Chen SD, Zheng B, et al. Protective effect and mechanism of polysaccharides from Cordyceps cicadae on acute liver injury induced by D-GlaN in mice[J]. Chin J Exp Med Form (中国实验方剂学杂志), 2018, 24:108-113.
[18] Liu P, Shang EX, Zhu Y, et al. Comparative analysis of compatibility effects on invigorating blood circulation for Cyperi Rhizoma Series of herb pairs using untargeted metabolomics[J]. Front Pharmacol, 2017, 8:677.
[19] Chen CC, Yin QC, Tian JS, et al. The mechanism of the anti-depression effect of the Radix Bupleuri-Radix Paeoniae Alba herb pair determined by liver metabolomics[J]. Acta Pharm Sin (药学学报), 2020, 55:941-949.
[20] Wang P, Wang Q, Yang B, et al. The progress of metabolomics study in traditional Chinese medicine research[J]. Am J Chin Med, 2015, 43:1281-1310.
[21] Feng X, Zhou YZ, Chai JX, et al. Scutellaria baicalensis Georgi leaf and tea extracts prolong lifespan and alter the metabolomic aging profile in a Drosophila melanogaster aging model[J]. Acta Pharm Sin (药学学报), 2020, 55:1214-1221.
[22] Xiao XH, Tang JY, Mao YM, et al. Technical guidelines for clinical evaluation of Chinese medicine-induced liver injury[J]. Acta Pharm Sin (药学学报), 2018, 53:1931-1942.
[23] Bai ZF, Gao Y, Zuo XB, et al. Progress in research on the pathogenesis of immune regulation and idiosyncratic drug-induced liver idiosyncratic drug-induced liver injury[J]. Acta Pharm Sin (药学学报), 2017, 52:1019-1026.
[24] Leuti A, Maccarrone M, Chiurchiù V. Proresolving lipid mediators:Endogenous modulators of oxidative stress[J]. Oxid Med Cell Longev, 2019, 2019:8107265.
[25] Shindou H, Hishikawa D, Harayama T, et al. Generation of membrane diversity by lysophospholipid acyltransferases[J]. J Biochem, 2013, 154:21-28.
[26] Makide K, Kitamura H, Sato Y, et al. Emerging lysophospholipid mediators, lysophosphatidylserine, lysophosphatidylthreonine, lysophosphatidylethanolamine and lysophosphatidylglycerol[J]. Prostaglandins Other Lipid Mediat, 2009, 89:135-139.
[27] Sevastou I, Kaffe E, Mouratis MA, et al. Lysoglycero-phospholipids in chronic inflammatory disorders:the PLA (2)/LPC and ATX/LPA axes[J]. Biochim Biophys Acta, 2013, 1831:42-60.
[28] Ma W, Paik DC, Barile GR. Bioactive lysophospholipids generated by hepatic lipase degradation of lipoproteins lead to complement activation via the classical pathway[J]. Invest Ophthalmol Vis Sci, 2014, 55:6187-6193.
[29] Gräler MH, Goetzl EJ. Lysophospholipids and their G protein-coupled receptors in inflammation and immunity[J]. Biochim Biophys Acta, 2002, 1582:168-174.
[30] Kihara A, Mitsutake S, Mizutani Y, et al. Metabolism and biological functions of two phosphorylated sphingolipids, sphingosine 1-phosphate and ceramide 1-phosphate[J]. Prog Lipid Res, 2007, 46:126-144.
[31] Chalfant CE, Spiegel S. Sphingosine 1-phosphate and ceramide 1-phosphate:expanding roles in cell signaling[J]. J Cell Sci, 2005, 118:4605-4612.
[32] St-Pierre MV, Kullak-Ublick GA, Hagenbuch B, et al. Transport of bile acids in hepatic and non-hepatic tissues[J]. J Exp Biol, 2001, 204:1673-1686.
[33] Claudel T, Staels B, Kuipers F. The farnesoid X receptor:a molecular link between bile acid and lipid and glucose metabolism[J]. Arterioscler Thromb Vasc Biol, 2005, 25:2020-2030.
[34] Li T, Chiang JY. Bile acid signaling in liver metabolism and diseases[J]. J Lipids, 2012, 2012:754067.
[35] Ma X, Wang J, He X, et al. Large dosage of chishao in formulae for cholestatic hepatitis:a systematic review and meta-analysis[J]. Evid Based Complement Alternat Med, 2014, 2014:328152.
[36] Ma X, Chi YH, Niu M, et al. Metabolomics coupled with multivariate data and pathway analysis on potential biomarkers in cholestasis and intervention effect of Paeonia lactiflora Pall[J]. Front Pharmacol, 2016, 7:14.
[37] Zhao Y, Zhao G, Wang J, et al. Paeoniflorin protects against ANIT-induced cholestasis by ameliorating oxidative stress in rats[J]. Food Chem Toxicol, 2013, 58:242-248.
[38] Chen Z, Zhu Y, Zhao Y, et al. Serum metabolomic profiling in a rat model reveals protective function of paeoniflorin against ANIT induced cholestasis[J]. Phytother Res, 2016, 30:654-662.
相关文献:
1.李春雨, 何琴, 唐进法, 沙孟晨, 涂灿, 张乐, 刘振兴, 王伽伯, 肖小河.免疫应激介导的何首乌“九蒸九晒”炮制减毒作用及代谢组学研究[J]. 药学学报, 2017,52(7): 1069-1076
2.李春雨, 何琴, 唐进法, 沙孟晨, 涂灿, 张乐, 刘振兴, 王伽伯, 肖小河.免疫应激介导的何首乌“九蒸九晒”炮制减毒作用及代谢组学研究[J]. 药学学报,