CN: 32-1845/R
ISSN: 2095-6975
LUO Yun-Xia, WANG Xin-Yue, HUANG Yu-Jie, FANG Shu-Huan, WU Jun, ZHANG Yong-Bin, XIONG Tian-Qin, YANG Cong, SHEN Jian-Gang, SANG Chuan-Lan, WANG Qi, FANG Jian-Song. Systems pharmacology-based investigation of Sanwei Ganjiang Prescription: related mechanisms in liver injury[J]. 中国天然药物英文, 2018, 16(10): 756-765

Systems pharmacology-based investigation of Sanwei Ganjiang Prescription: related mechanisms in liver injury

LUO Yun-Xia1, WANG Xin-Yue2, HUANG Yu-Jie1, FANG Shu-Huan1, WU Jun1, ZHANG Yong-Bin1, XIONG Tian-Qin1, YANG Cong1, SHEN Jian-Gang1,3, SANG Chuan-Lan1, WANG Qi1, FANG Jian-Song1
1 Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China;
2 Cancer Center, Sun Yat-sen University, Guangzhou 510060, China;
3 School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China
Liver injury remains a significant global health problem and has a variety of causes, including oxidative stress (OS), inflammation, and apoptosis of liver cells. There is currently no curative therapy for this disorder. Sanwei Ganjiang Prescription (SWGJP), derived from traditional Chinese medicine (TCM), has shown its effectiveness in long-term liver damage therapy, although the underlying molecular mechanisms are still not fully understood. To explore the underlining mechanisms of action for SWGJP in liver injury from a holistic view, in the present study, a systems pharmacology approach was developed, which involved drug target identification and multilevel data integration analysis. Using a comprehensive systems approach, we identified 43 candidate compounds in SWGJP and 408 corresponding potential targets. We further deciphered the mechanisms of SWGJP in treating liver injury, including compound-target network analysis, target-function network analysis, and integrated pathways analysis. We deduced that SWGJP may protect hepatocytes through several functional modules involved in liver injury integrated-pathway, such as Nrf2-dependent anti-oxidative stress module. Notably, systems pharmacology provides an alternative way to investigate the complex action mode of TCM.
关键词:    Systems pharmacology    Traditional Chinese Medicine    Sanwei Ganjiang Prescription    Liver injury    Oxidative stress   
收稿日期: 2018-05-10
WANG Qi,;FANG Jian-Song,
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[1] Luedde T, Schwabe RF. NF-κB in the liver-linking injury, fibrosis and hepatocellular carcinoma[J]. Nat Rev Gastroenterol Hepatol, 2011, 8(2):108-118.
[2] Papa S, Bubici C, Zazzeroni F, et al. Mechanisms of liver disease:cross-talk between the NF-κB and JNK pathways[J]. Biol Chem, 2009, 390(10):965-976.
[3] Li S, Tan HY, Wang N, et al. The role of oxidative stress and antioxidants in liver diseases[J]. Int J Mol Sci, 2015, 16(11):25942.
[4] Cichoż-Lach H, Michalak A. Oxidative stress as a crucial factor in liver diseases[J]. World J Gastroenterol, 2014, 20(25):8082-8091.
[5] Zhao CQ, Zhou Y, Ping J, et al. Traditional Chinese medi-cine for treatment of liver diseases:progress, challenges and opportunities[J]. J IntegrI Med, 2014, 12(5):401-408.
[6] Cao H, Zhang A, Zhang H, et al. The application of metabolomics in traditional Chinese medicine opens up a dialogue between Chinese and Western medicine[J]. Phytother Res, 2015, 29(2):159-166.
[7] Xiong T, Li H. Study on protective effect of Jiagasong Tang for liver injury animal model and cell oxidative stress model in vitro[J]. Pharmacol Clin Chin Mater Med, 2013, 29(1):132-135.
[8] Ya FU, Xiong T, Rendawa ZE, et al. Effects of Sanwei Ganjiang powder on expression of Nrf2/Bach1 factors in rats with chronic liver injury[J]. Tradit Chin Drug Res Clin Pharmacol, 2014, 25(5):527-531.
[9] Liao JY, Xiong TQ, Kang Suolangqimei, et al. Jiagasong decoction contained serum protect liver cells from oxidative damage via regulating Nrf2 and bach1 protein expression[J]. Chin J Exp Tradit Med Form, 2015, 21(3):118-124
[10] Fang J, Liu C, Wang Q, et al. In silico polypharmacology of natural products[J]. Brief Bioinform, 2017:bbx045-bbx045.
[11] Chen Y, Kern TS, Kiser PD, et al. Eyes on systems pharmacology[J]. Pharmacol Res, 2016, 114:39-41.
[12] Fang J, Cai C, Wang Q, et al. Systems pharmacology-based discovery of natural products for precision oncology through targeting cancer mutated genes[J]. CPT Pharmacometrics Syst Pharmacol, 2017, 6(3):177-187.
[13] Fang J, Wang L, Wu T, et al. Network pharmacol-ogy-based study on the mechanism of action for herbal medicines in Alzheimer treatment[J]. J Ethnopharmacol, 2017, 196:281-292.
[14] Li J, Zhao P, Li Y, et al. Systems pharmacology-based dissection of mechanisms of Chinese medicinal formula Bufei Yishen as an effective treatment for chronic obstructive pulmonary disease[J]. Sci Rep, 2015, 5:15290.
[15] Ru J, Li P, Wang J, et al. TCMSP:a database of systems pharmacology for drug discovery from herbal medicines[J]. J Cheminform, 2014, 6:13.
[16] Fang J, Wu Z, Cai C, et al. Quantitative and systems pharmacology. 1. in silico prediction of drug-target interactions of natural products enables new targeted cancer therapy[J]. J Chem Inf Model, 2017, 57(11):2657-2671.
[17] Wu Z, Lu W, Wu D, et al. In silico prediction of chemical mechanism of action via an improved network-based inference method[J]. Br J Pharmacol, 2016, 173(23):3372-3385.
[18] Smoot ME, Ono K, Ruscheinski J, et al. Cytoscape 2.8:new features for data integration and network visualization[J]. Bioinformatics, 2011, 27(3):431-432.
[19] Bindea G, Mlecnik B, Hackl H, et al. ClueGO:a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks[J]. Bioinformatics, 2009, 25(8):1091-1093.
[20] Qiu J. A culture in the balance[J]. Nature, 2007, 448:126-128.
[21] Ma XH, Zheng CJ, Han LY, et al. Synergistic therapeutic actions of herbal ingredients and their mechanisms from molecular interaction and network perspectives[J]. Drug Discov Today, 2009, 14(11):579-588.
[22] Duarte S, Baber J, Fujii T, et al. Matrix metalloproteinases in liver injury, repair and fibrosis[J]. Matrix Biol, 2015, 44-46:147-156.
[23] Roderfeld M. Matrix metalloproteinase functions in he-patic injury and fibrosis[J]. Matrix Biol, 2018, 68-69:452-462.
[24] Koneru M, Sahu BD, Gudem S, et al. Polydatin alleviates alcohol-induced acute liver injury in mice:Relevance of matrix metalloproteinases (MMPs) and hepatic antioxidants[J]. Phytomedicine, 2017, 27:23-32.
[25] Amer MG, Mazen NF, Mohamed AM. Caffeine intake decreases oxidative stress and inflammatory biomarkers in experimental liver diseases induced by thioacetamide:Biochemical and histological study[J]. Int J Immunopathol Pharmacol, 2017, 30(1):13-24.
[26] Chen C, Hennig GE, Whiteley HE, et al. Peroxisome proliferator-activated receptor alpha-null mice lack resistance to acetaminophen hepatotoxicity following clofibrate exposure[J]. Toxicol Sci, 2000, 57(2):338-344.
[27] Shan W, Nicol CJ, Ito S, et al. Peroxisome prolifera-tor-activated receptor-β/δ protects against chemically induced liver toxicity in mice[J]. Hepatology, 2008, 47(1):225-235.
[28] Yuan GJ, Zhang ML, Gong ZJ. Effects of PPARg agonist pioglitazone on rat hepatic fibrosis[J]. World J Gastro-enterol, 2004, 10(7):1047-1051.
[29] Sieprath T, Corne TD, Nooteboom M, et al. Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates[J]. Nucleus, 2015, 6(3):236-246.
[30] Sieprath T, Darwiche R, De Vos WH. Lamins as mediators of oxidative stress[J]. Biochem Biophys Res Commun, 2012, 421(4):635-639.
[31] Miao W, Hu L, Scrivens PJ, et al. Transcriptional regula-tion of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway:direct cross-talk between phase I and Ⅱ drug-metabolizing enzymes[J]. J Biol Chem, 2005, 280(21):20340-20348.
[32] Kiefer FW, Vernochet C, O'Brien P, et al. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue[J]. Nat Med, 2012, 18(6):918-925.
[33] Cho YE, Moon PG, Lee JE, et al. Integrative analysis of proteomic and transcriptomic data for identification of pathways related to simvastatin-induced hepatotoxicity[J]. Proteomics, 2013, 13(8):1257-1275.
[34] Lassen N, Bateman JB, Estey T, et al. Multiple and addi-tive functions of ALDH3A1 and ALDH1A1:cataract phenotype and ocular oxidative damage in Aldh3a1(-/-)/Aldh1a1(-/-) knock-out mice[J]. J Biological Chem, 2007, 282(35):25668-25676.
[35] Bak MJ, Ok S, Jun M, et al. 6-shogaol-rich extract from ginger up-regulates the antioxidant defense systems in cells and mice[J]. Molecules (Basel, Switzerland), 2012, 17(7):8037-8055.
[36] Hikino H, Kiso Y, Kato N, et al. Antihepatotoxic actions of gingerols and diarylheptanoids[J]. J Ethnopharmacol, 1985, 14(1):31-39.
[37] Zhuang X, Deng ZB, Mu J, et al. Ginger-derived nanopar-ticles protect against alcohol-induced liver damage[J]. J Extracell Vesicles, 2015, 4:28713.
[38] Nurtjahja-Tjendraputra E, Ammit AJ, Roufogalis BD, et al. Effective anti-platelet and COX-1 enzyme inhibitors from pungent constituents of ginger[J]. Thromb Res, 111(4):259-265.
[39] Lim DW, Kim H, Park JY, et al. Amomum cardamomum L. ethyl acetate fraction protects against carbon tetrachloride-induced liver injury via an antioxidant mechanism in rats[J]. BMC Complement Altern Med, 2016, 16(1):155.
[40] Ciftci O, Ozdemir I, Tanyildizi S, et al. Antioxidative effects of curcumin, beta-myrcene and 1, 8-cineole against 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin-induced oxidative stress in rats liver[J]. Toxicol Ind Health, 2011, 27(5):447-453.
[41] Santos FA, Silva RM, Tome AR, et al. 1, 8-cineole protects against liver failure in an in-vivo murine model of endotoxemic shock[J]. J Pharm PharmacoL, 2001, 53(4):505-511.
[42] Murata S, Ogawa K, Matsuzaka T, et al. 1, 8-Cineole ameliorates steatosis of pten liver specific ko mice via akt inactivation[J]. Int J Mol Sci, 2015, 16(6):12051-12063.
[43] Luedde T, Schwabe RF. NF-κB in the liver-linking injury, fibrosis and hepatocellular carcinoma[J]. Nat Rev Gastroenterol Hepatol, 2011, 8(2):108.
[44] Greiner JF, Muller J, Zeuner MT, et al. 1, 8-Cineol inhibits nuclear translocation of NF-kappaB p65 and NF-kappaB-dependent transcriptional activity[J]. Biochim Biophys Acta, 2013, 1833(12):2866-2878.
[45] Gupta AD, Bansal VK, Babu V, et al. Chemistry, antioxi-dant and antimicrobial potential of nutmeg (Myristica fragrans Houtt)[J]. J Genetic Engineer Biotechnol, 2013, 11(1):25-31.
[46] Morita T, Jinno K, Kawagishi H, et al. Hepatoprotective effect of myristicin from nutmeg (Myristica fragrans) on lipopolysaccharide/d-galactosamine-induced liver injury[J]. J Agric Food Chem, 2003, 51(6):1560-1565.
[47] Smith AG, Clothier B, Carthew P, et al. Protection of the cyp1a2(-/-) null mouse against uroporphyria and hepatic injury following exposure to 2, 3, 7, 8-tetrachloro-dibenzo-p-dioxin[J]. Toxicol App Pharmacol, 2001, 173(2):89-98.
[48] Uno S, Dalton TP, Sinclair PR, et al. Cyp1a1(-/-) male mice:protection against high-dose TCDD-induced lethality and wasting syndrome, and resistance to intrahepatocyte lipid accumulation and uroporphyria[J]. Toxicol Appl Pharmacol, 2004, 196(3):410-421.
[49] Uno S, Dalton TP, Shertzer HG, et al. Benzo[a]pyrene-induced toxicity:paradoxical protection in cyp1a1(-/-) knockout mice having increased hepatic BaP-DNA adduct levels[J]. Biochem Biophys Res Commun, 2001, 289(5):1049-1056.
[50] Yang AH, He X, Chen JX, et al. Identification and characterization of reactive metabolites in myristicin-mediated mechanism-based inhibition of CYP1A2[J]. Chem Biol Interact, 2015, 237:133-140.
[51] Jeong HG, Lee SS, Kim HK, et al. Murine Cyp1a-1 in-duction in mouse hepatoma Hepa-1C1C7 cells by myristicin[J]. Biochem Biophys Res Commun, 1997, 233(3):619-622.
[52] Iorga A, Dara L, Kaplowitz N. Drug-induced liver injury:cascade of events leading to cell death, apoptosis or necrosis[J]. Int J Mol Sci, 2017, 18(5):1018.
[53] Dara L, Kaplowitz N. Cell death in drug-induced liver injury. In:Ding WX, Yin XM, et al. Cellular Injury in Liver Diseases[M]. Cham:Springer International Publishing, 2017:1-35.
[54] Gómez-Lechón MJ, Ponsoda X, O'Connor E, et al. Diclofenac induces apoptosis in hepatocytes by alteration of mitochondrial function and generation of ROS[J]. Biochem Pharmacol, 2003, 66(11):2155-2167.
[55] Xue M, Momiji H, Rabbani N, et al. Frequency modulated translocational oscillations of Nrf2 mediate the antioxidant response element cytoprotective transcriptional response[J]. Antioxid Redox Signal, 2015, 23(7):613-629.
[56] Levonen AL, Hill BG, Kansanen E, et al. Redox regulation of antioxidants, autophagy, and the response to stress:Implications for electrophile therapeutics[J]. Free Radic Biol Med, 2014, 71:196-207.
[57] Espinosa-Diez C, Miguel V, Mennerich D, et al. Antioxi-dant responses and cellular adjustments to oxidative stress[J]. Redox Biol, 2015, 6:183-197.
[58] Gao Y, Chu S, Shao Q, et al. Antioxidant activities of ginsenoside Rg1 against cisplatin-induced hepatic injury through Nrf2 signaling pathway in mice[J]. Free Radic Res, 2017, 51(1):1-13.
[59] Cai Z, Lou Q, Wang F, et al. N-acetylcysteine protects against liver injure induced by carbon tetrachloride via activation of the Nrf2/HO-1 pathway[J]. Int J Clin Exp Pathol, 2015, 8(7):8655-8662.
[60] Li L, Dong H, Song E, et al. Nrf2/ARE pathway activation, HO-1 and NQO1 induction by polychlorinated biphenyl quinone is associated with reactive oxygen species and PI3K/AKT signaling[J]. Chem Biol Interact, 2014, 209:56-67.
[61] Alkhouri N, Carter-Kent C, Feldstein AE. Apoptosis in nonalcoholic fatty liver disease:diagnostic and therapeutic implications[J]. Expert Rev Gastroenterol Hepatol, 2011, 5(2):201-212.
[62] Shehu AI, Ma X, Venkataramanan R. Mechanisms of drug-induced hepatotoxicity[J]. Clin Liver Dis, 2017, 21(1):35-54.
[63] Cao L, Quan XB, Zeng WJ, et al. Mechanism of hepatocyte apoptosis[J]. J Cell Death, 2016, 9:19-29.
[64] Elmore S. Apoptosis:a review of programmed cell death[J]. Toxicol Pathol, 2007, 35(4):495-516.
[65] Wei MC, Zong WX, Cheng EHY, et al. Proapoptotic BAX and BAK:a requisite gateway to mitochondrial dysfunction and death[J]. Science, 2001, 292(5517):727-730.
[66] Yang J, Liu X, Bhalla K, et al. Prevention of apoptosis by Bcl-2:release of cytochrome c from mitochondria blocked[J]. Science, 1997, 275(5303):1129-1132.
[67] MacFarlane M. Compensatory caspase activation:a cau-tionary tale[J]. Trends Pharmacol Sci, 2001, 22(2):60.
[68] Papa S, Bubici C, Zazzeroni F, et al. Mechanisms of liver disease:cross-talk between the NF-kappaB and JNK pathways[J]. Biol Chem, 2009, 390(10):965-976.
[69] Waters JP, Pober JS, Bradley JR. Tumour necrosis factor in infectious disease[J]. J Pathol, 2013, 230(2):132-147.
[70] Mao SA, Glorioso JM, Nyberg SL. Liver regeneration[J]. Transl Res, 2014, 163(4):352-362.
[71] Fredriksson L, Herpers B, Benedetti G, et al. Diclofenac inhibits tumor necrosis factor-α-induced nuclear factor-кB activation causing synergistic hepatocyte apoptosis[J]. Hepatology, 2011, 53(6):2027-2041.
[72] Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death[J]. Science, 1996, 274(5288):782-784.

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