Mechanisms of anti-inflammation of taurochenodeoxycholic acid based on network pharmacology
(2.Shanxi Animal Disease Control Center, Taiyuan, China 030027)
(3.Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture and Rual, College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, China 010018)
【Abstract】To investigate the anti-inflammatory mechanisms of taurochenodeoxycholic acid (TCDCA), the molecule structure file of TCDCA was downloaded from PubChem database, PharmMapper and GeneCards were used to predict and screen the targets of TCDCA. STRING database and Cytoscape software were used to construct protein interactions network. GO and KEGG analysis was preformed through STRING database. The key targets were validated by molecular docking and the targets type was attributed by DisGeNET database. The network showed that 89 targets were involved in 68 biological processes including response to stimulus, multicellular organismal process, single-multicellular organism process, response to chemical, response to organic substance, by adjusting 51 signaling pathways, such as pathways in cancer, progesterone-mediated oocyte maturation, MAPK signaling pathway, proteoglycans in cancer. These findings provide an overview of anti-inflammation of TCDCA, which reflects the characteristic of multi-targets and multi-pathways of TCDCA. It pointed out the direction for further research on anti-inflammatory mechanism of TCDCA.
【Keywords】 taurochenodeoxycholic acid; inflammation; network pharmacology; pharmacological mechanism; molecular docking;
 Yuan S, Zhao W, Wang J. Research progress on pharmacological activities and clinical application of Sus scrofa domestica Brisson bile [J]. Acta Chin Med Pharmacol (中医药学报), 2014, 42: 166–168.
 Zhao W, Wang Y, Lu Y, et al. Medicinal research on animal bile [J]. Inform Tradit Chin Med (中医药信息), 1999, 16: 14–15.
 Jiang J, Yang P, Shi X, et al. Research progress on components and pharmacological activities of animal bile [J]. Food Drug (食品与药品), 2017, 19: 227–231.
 Hu X, Shi C. Comparison of tauro conjugated bile acids with the corresponding free bile acids in antitussive, expectorant and anti-inflammatory effects [J]. Chin J Clin Pharm (中国临床药学杂志), 2001, 10: 85–88.
 Li P, Guan H, Baiyin J. Studies on antipyretic and analgesic effects of taurine and cholic acid in mice and rats [J]. J Tradit Chin Veter Med (中兽医医药杂志), 2003, 22: 3–5.
 Hasi S, Li P, Cao J, et al. Studies on antibacterial effects of taurine and cholic [J]. J Tradit Chin Veter Med (中兽医医药杂志), 2001, 20: 3–6.
 Li P, Guan H, Hasi S, et al. Studies on anti-inflammatory effects of taurine and cholic [J]. J Tradit Chin Veter Med (中兽医医药杂志), 2002, 21: 7–10.
 He X, Li P, Guan H, et al. Effect of taurochenodeoxycholic acid on immune function in mice [J]. J Chin Med Mater (中药材), 2005, 28: 1 089–1 092.
 Li F. Study on the Matrix Selection for Cultivating Bear Bile Powder Analogue in vitro Based on Compositions Similarity (基于物质成分相似性的体外培育拟天然熊胆粉的基质选择研究) [D]. Chongqing: Chongqing University (重庆大学), 2015.
 Li PF, He XL, Guan H, et al. Taurochenodeoxycholic acid (TCDCA) anti-inflammatory mechanism [J]. Chin J Veter Sci (中国兽医学报), 2008, 28: 1 317–1 320.
 Wang X, Shen Y, Wang S, et al. PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database [J]. Nucleic Acids Res, 2017, 45: W356–W360.
 Chen C, Huang H, Wu CH. Protein bioinformatics databases and resources [J]. Methods Mol Biol, 2017, 1558: 3–39.
 Rebhan M, Chalifa-Caspi V, Prilusky J, et al. GeneCards: integrating information about genes, proteins and diseases [J]. Trends Genet, 1997, 13: 163.
 Szklarczyk D, Morris JH, Cook H, et al. The STRINGdatabase in 2017: quality-controlled protein–protein association networks, made broadly accessible [J]. Nucleic Acids Res, 2017, 45: D362–D368.
 Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks [J]. Genome Res, 2003, 13: 2 498–2 504.
 Hsin KY, Matsuoka Y, Asai Y, et al. SystemsDock: a web server for network pharmacology-based prediction and analysis [J]. Nucleic Acids Res, 2016, 44: W507–W513.
 Pinero J, Bravo A, Queralt-Rosinach N, et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants [J]. Nucleic Acids Res, 2017, 45: D833–D839.
 Wu D, Gao Y, Xiang H, et al. Exploration into mechanism of antidepressant of Bupleuri radix based on network pharmacology [J]. Acta Pharma Sin (药学学报), 2018, 53: 210–219.
 Zhou H, Hylemon PB. Bile acids are nutrient signaling hormones [J]. Steroids, 2014, 86: 62–68.
 Guo C, Xie S, Chi Z, et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome [J]. Immunity, 2016, 45: 802–816.
 de Aguiar VT, Tarling EJ, Edwards PA. Pleiotropic roles of bile acids in metabolism [J]. Cell Metab, 2013, 17: 657–669.
 Fiorucci S, Distrutti E. Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders [J]. Trends Mol Med, 2015, 21: 702–714.
 Liu M, Mao W, Guan H, et al. Effects of taurochenodeoxycholic acid on adjuvant arthritis in rats [J]. Int Immunopharmacol, 2011, 11: 2 150–2 158.
 Li L, Liu C, Li P. Effect of taurochenodeoxycholic acid on the expression of ICAM-1 in fibroblast-like synoviocytes of adjuvant arthritis in rats [J]. Chin J Veter Sci (中国兽医学报), 2017, 37: 1 144–1 148.
 Li L, Liu C, Liu M, et al. Taurochenodeoxycholic acid induces apoptosis of fibroblast-like synoviocytes [J]. Eur JPharmacol, 2013, 706: 36–40.
 Plotnikov A, Zehorai E, Procaccia S, et al. The MAPKcascades: signaling components, nuclear roles and mechanisms of nuclear translocation [J]. Biochim Biophys Acta, 2011, 1813: 1 619–1 633.
 Dong X, Zhao H, Ma X. Low concentration of cholic acid up-regulates JNK protein expression: can it promote synthesis of liver cell DNA? [J]. J Clin Rehab Tiss Engin Res (中国组织工程研究与临床康复), 2010, 14: 5 818–5 822.
 Alpini G, Kanno N, Phinizy JL, et al. Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via Ca2+-, PKC-, and MAPK-dependent pathways [J]. Am J Physiol Gastrointest Liver Physiol, 2004, 286: G973–G982.
 Ko WK, Lee SH, Kim SJ, et al. Anti-inflammatory effects of ursodeoxycholic acid by lipopolysaccharide-stimulated inflammatory responses in RAW 264.7 macrophages [J]. PLoS One, 2017, 12: e180673.
 Wang X, Zhang Z, He X, et al. Taurochenodeoxycholic acid induces NR8383 cells apoptosis via PKC/JNK-dependent pathway [J]. Eur J Pharmacol, 2016, 786: 109.
 Zhang LL, Wei W, Wang QT, et al. Cross-talk between MEK1/2–ERK1/2 signaling and G protein-couple signaling in synoviocytes of collagen-induced arthritis rats [J]. Chin Med J, 2008, 121: 2 278–2 283.
 Zhang L. The Cross Talk between G Protein–AC–cAMPSignaling and Ras–Raf–MEK–ERK Signaling in Fibroblasts Like Synoviocytes of Rat with Collagen-induced Arthritis and Regulation of Paeoniflorin (胶原性关节炎大鼠成纤维样滑膜细胞G蛋白–AC–cAMP与Ras–Raf–MEK–ERK信号转导的交叉对话及芍药苷的调节作用) [D]. Hefei: Anhui Medical University (安徽医科大学), 2008.
 Im E, Martinez JD. Ursodeoxycholic acid (UDCA) can inhibit deoxycholic acid (DCA)-induced apoptosis via modulation of EGFR/Raf-1/ERK signaling in human colon cancer cells [J]. J Nutr, 2004, 134: 483–486.
 Feldman R, Martinez JD. Growth suppression by ursodeoxycholic acid involves caveolin-1 enhanced degradation of EGFR [J]. Biochim Biophys Acta, 2009, 1793: 1 387–1 394.
 Rust C, Karnitz LM, Paya CV, et al. The bile acid taurochenodeoxycholate activates a phosphatidylinositol 3-kinasedependent survival signaling cascade [J]. J Biol Chem, 2000, 275: 20 210–20 216.
 Liu MQ. Studies on The Therapeutic Action and Mechanism of TCDCA in Adjuvant-induced Arthritis Rats (TCDCA对佐剂性关节炎模型大鼠的治疗作用及其作用机制研究) [D]. Hohhot: Inner Mongolia Agricultural University (内蒙古农业大学), 2012.
 Kline CL, Olson TL, Irby RB. Src activity alters alpha3integrin expression in colon tumor cells [J]. Clin Exp Metastasis, 2009, 26: 77–87.
 Hiscox S, Morgan L, Green TP, et al. Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells [J]. Breast Cancer Res Treat, 2006, 97: 263–274.
 Lee YG, Lee WM, Kim JY, et al. Src kinase-targeted anti-inflammatory activity of davallialactone from Inonotus xeranticus in lipopolysaccharide-activated RAW264.7 cells [J]. Br J Pharmacol, 2008, 154: 852–863.
 Yu T, Lee S, Yang WS, et al. The ability of an ethanol extract of Cinnamomum cassia to inhibit Src and spleen tyrosine kinase activity contributes to its anti-inflammatory action [J]. J Ethnopharmacol, 2012, 139: 566–573.
 Dieterle AM, Bohler P, Keppeler H, et al. PDK1 controls upstream PI3K expression and PIP3 generation [J]. Oncogene, 2014, 33: 3 043–3 053.
 Wu N, He C, Zhu B, et al. 3-Phosphoinositide dependent protein kinase-1 (PDK-1) promotes migration and invasion in gastric cancer cells through activating the NF-κB pathway [J]. Oncol Res, 2017, 25: 1 153–1 159.
 Du L, Xie Y, Liu M. Expression and significance of PDK1 and NF-κB in the middle ear cholesteatoma [J]. J Clin Otorhinolaryngol Head Neck Surg (临床耳鼻咽喉头颈外科杂志), 2016, 33: 770–773.
 Chaurasia B, Mauer J, Koch L, et al. Phosphoinositidedependent kinase 1 provides negative feedback inhibition to Toll-like receptor-mediated NF-κB activation in macrophages [J]. Mol Cell Biol, 2010, 30: 4 354–4 366.
 He X, Li P, Guan H, et al. Effect of TCDCA on the contents of IL-1β, IL-6, TNF-α and IgG in AA rat serum [J]. Prog Veter Med (动物医学进展), 2010, 31: 49–51.
 Wang X, Zhang Z, Li P. Effects of taurochenodeoxycholic acid on the production of tumor necrosis factor-α induced by TGR5 in NR8383 [J]. Chin J Veter Sci (中国兽医学报), 2016, 36: 108–111.