Deciphering the pharmacological mechanism of Guan-Jie-Kang in treating rat adjuvant-induced arthritis using omics analysis

Abstract

Traditional Chinese medicine (TCM) formulas have attracted increasing attention worldwide in the past few years for treating complex disease including rheumatoid arthritis. However, their mechanisms are complex and remain unclear. Guan-Jie-Kang (GJK), a prescription modified from “Wu Tou Decoction,” was found to significantly relieve arthritis symptoms in rats with adjuvant-induced arthritis after 30-day treatment, especially in the 24 g/kg/day group. By analyzing 1749 targets related to 358 compounds in the five herbs of GJK, we identified the possible anti-arthritis pathways of GJK, including the calcium signaling and metabolic pathways. Bone damage levels were assessed by micro-computed tomography, and greater bone protective effect was observed with GJK treatment than with methotrexate. Receptor activator of nuclear factor κB ligand (RANKL)–RANK signaling, which is related to calcium signaling, was significantly regulated by GJK. Moreover, a target metabolomics assay of serum was conducted; 17 metabolic biomarkers showed significant correlations with treatment. An integrated pathway analysis revealed that pyruvate metabolism, purine metabolism, and glycolysis metabolism were significantly associated with the effects of GJK in arthritis treatment. Thus, this study establishes a new omics analytical method integrated with bioinformatics analysis for elucidating the multi-pathway mechanisms of TCM.

Keywords

rheumatoid arthritis / traditional Chinese medicine / pharmacological mechanism / metabolism / adjuvant-induced arthritis / omics analysis

References

[1] Mikuls TR. Co-morbidity in rheumatoid arthritis. Best Pract Res Clin Rheumatol 2003; 17(5): 729–752

[2] Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010; 376(9746): 1094–1108

[3] Gabriel SE. The epidemiology of rheumatoid arthritis. Rheum Dis Clin North Am 2011; 27(2): 269–281

[4] Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003; 423(6937): 356–361

[5] Cooper NJ. Economic burden of rheumatoid arthritis: a systematic review. Rheumatology (Oxford) 2000; 39(1): 28–33

[6] Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, Vaysbrot E, McNaughton C, Osani M, Shmerling RH, Curtis JR, Furst DE, Parks D, Kavanaugh A, O’Dell J, King C, Leong A, Matteson EL, Schousboe JT, Drevlow B, Ginsberg S, Grober J, St Clair EW, Tindall E, Miller AS, McAlindon T. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 2016; 68(1): 1–26

[7] Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, Ghogomu ET, Tugwell P. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Sao Paulo Med J 2010; 128(5): 309–310

[8] Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity 2017; 46(2): 183–196

[9] Koch AE. The pathogenesis of rheumatoid arthritis. Am J Orthop (Belle Mead NJ) 2007; 36(7 Suppl): 5–8

[10] Haro I, Sanmartí R. Rheumatoid arthritis: current advances in pathogenesis, diagnosis and therapy. Curr Top Med Chem 2013; 13(6): 697

[11] Wang XR, Su Y, An Y, Zhou YS, Zhang XY, Duan TJ, Zhu JX, Li XF, Wang CH, Wang LZ, Wang YF, Yang R, Wang GC, Lu X, Zhu P, Chen LN, Wang Y, Wang XY, Jin HT, Liu JT, Chen HY, Wei P, Wang JX, Liu XY, Sun L, Cui LF, Shu R, Liu BL, Zhang ZL, Li GT, Li ZB, Yang J, Li JF, Jia B, Zhnag, FX, Tao JM, Lin JY, Wei MQ, Liu XM, Ke D, Hu SX, Ye C, Han SL, Yang XY, Li H, Huang CB, Gao M, Lai P, Song LJ, Mu R, Li ZG. Survey of tumor necrosis factor inhibitors application in patients with rheumatoid arthritis in China. J Peking Univ (Health Sci) (Beijing Da Xue Xue Bao Yi Xue Ban) 2012. 44(2): p. 182–7 (in Chinese)

[12] Xu C, Wang X, Mu R, Yang L, Zhang Y, Han S, Li X, Wang Y, Wang G, Zhu P, Jin H, Sun L, Chen H, Cui L, Zhang Z, Li Z, Li J, Zhang F, Lin J, Liu X, Hu S, Yang X, Lai B, Li X, Wang X, Su Y, Li Z. Societal costs of rheumatoid arthritis in China: a hospital-based cross-sectional study. Arthritis Care Res (Hoboken) 2014; 66(4): 523–531

[13] Liu J, Sun Y. How does Chinese medicine target cytokine imbalance in rheumatoid arthritis? Chin J Integr Med 2013; 19(11): 874–880

[14] Liu J, Chen Z. Traditional Chinese medicine in the new century. Front Med 2011; 5(2): 111–114

[15] Xiang Z, Wang X, Liu T, Lv D. Thoughts and exploration on studying pharmacological mechanism of traditional Chinese medicine using network biology approach. China J Chin Materia Medica (Zhongguo Zhong Yao Za Zhi) 2012; 37(2): 146–151 (in Chinese)

[16] Wu J, Xie Y, Xiang Z, Wang C, Zhou H, Liu L. Simultaneous determination of multiple components in Guanjiekang in rat plasma via the UPLC-MS/MS method and its application in pharmacokinetic study. Molecules 2016; 21(12): E1732

[17] Ma Y, Zhou K, Fan J, Sun S. Traditional Chinese medicine: potential approaches from modern dynamical complexity theories. Front Med 2016; 10(1): 28–32

[18] Xue R, Fang Z, Zhang M, Yi Z, Wen C, Shi T. TCMID: traditional Chinese medicine integrative database for herb molecular mechanism analysis. Nucleic Acids Res 2013; 41(Database issue): D1089–D1095

[19] Li S, Zhang B. Traditional Chinese medicine network pharmacology: theory, methodology and application. Chin J Nat Med 2013; 11(2): 110–120

[20] Wang C, Xie Y, Xiang Z, Zhou H, Liu L. Simultaneous determination of thirteen major active compounds in Guanjiekang preparation by UHPLC-QQQ-MS/MS. J Pharm Biomed Anal 2016; 118: 315–321

[21] Cai X1, Wong YF, Zhou H, Liu ZQ, Xie Y, Jiang ZH, Bian ZX, Xu HX, Liu L. Manipulation of the induction of adjuvant arthritis in Sprague-Dawley rats. Inflamm Res 2006; 55(9): 368–377

[22] Zuo J, Xia Y, Li X, Chen JW. Therapeutic effects of dichloromethane fraction of Securidaca inappendiculata on adjuvant-induced arthritis in rat. J Ethnopharmacol 2014; 153(2): 352–358

[23] Lemmey AB. Rheumatoid cachexia: the undiagnosed, untreated key to restoring physical function in rheumatoid arthritis patients? Rheumatology (Oxford) 2016; 55(7): 1149–1150

[24] Komarova SV, Pilkington MF, Weidema AF, Dixon SJ, Sims SM. RANK ligand-induced elevation of cytosolic Ca²⁺ accelerates nuclear translocation of nuclear factor κ B in osteoclasts. J Biol Chem 2003; 278(10): 8286–8293

[25] Zhang P, Li J, Han Y, Yu XW, Qin L. Traditional Chinese medicine in the treatment of rheumatoid arthritis: a general review. Rheumatol Int 2010; 30(6): 713–718

[26] Hemon P, Renaudineau Y, Debant M, Le Goux N, Mukherjee S, Brooks W, Mignen O. Calcium signaling: from normal B cell development to tolerance breakdown and autoimmunity. Clin Rev Allergy Immunol 2017; 53(2): 141–165

[27] Kajiya H. Calcium signaling in osteoclast differentiation and bone resorption. Adv Exp Med Biol 2012; 740: 917–932

[28] Negishi-Koga T, Takayanagi H. Ca²⁺-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol Rev 2009; 231(1): 241–256

[29] Leah E. Rheumatoid arthritis. Assessment of CVD in patients with RA by strain imaging. Nat Rev Rheumatol 2013; 9(9): 506

[30] Paul BJ, Kandy HI, Krishnan V. Pre-rheumatoid arthritis and its prevention. Eur J Rheumatol 2017; 4(2): 161–165

[31] da Cunha VR, Brenol CV, Brenol JC, Xavier RM. Rheumatoid arthritis and metabolic syndrome. Rev Bras Reumatol 2011; 51(3): 260–268

[32] Chang X, Wei C. Glycolysis and rheumatoid arthritis. Int J Rheum Dis 2011; 14(3): 217–222

[33] Yang Z, Shen Y, Oishi H, Matteson EL, Tian L, Goronzy JJ, Weyand CM. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci Transl Med 2016; 8(331): 331ra38

[34] Gray LR, Tompkins SC, Taylor EB. Regulation of pyruvate metabolism and human disease. Cell Mol Life Sci 2014; 71(14): 2577–2604

[35] Perl A. Review: Metabolic control of immune system activation in rheumatic diseases. Arthritis Rheumatol 2017; 69(12): 2259–2270

[36] Weyand CM, Goronzy JJ. Immunometabolism in early and late stages of rheumatoid arthritis. Nat Rev Rheumatol 2017; 13(5): 291–301

[37] Cronstein BN. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev 2005; 57(2): 163–172

Acknowledgements

This work was financially supported by grants from the Macau Science and Technology Development Fund (No. 102/2016/A3).

Compliance with ethics guidelines

Hudan Pan, Yanfang Zheng, Zhongqiu Liu, Zhongwen Yuan, Rutong Ren, Hua Zhou, Ying Xie, and Liang Liu declare that they have no conflicts of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.

Electronic Supplementary Material&chsp;ƒSupplementary materials are available in the online version of this article at https://doi.org/10.1007/s11684-018-0676-2 and are accessible for authorized users.

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