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Effect of Sosiho-tang on a Thioacetamide-induced Liver Fibrosis Mouse Model

소시호탕(小柴胡湯)이 thioacetamide로 유발된 간섬유증 동물 모델에 미치는 영향

  • Lee, Se Hui (Dept. of Herbology, College of Korean Medicine, Daegu Haany University) ;
  • Oh, Min Hyuck (Dept. of Herbology, College of Korean Medicine, Daegu Haany University) ;
  • Shin, Mi-Rae (Dept. of Herbology, College of Korean Medicine, Daegu Haany University) ;
  • Lee, Ji Hye (Dept. of Oriental Medicine, College of Oriental Medicine, Semyung University) ;
  • Roh, Seong-Soo (Dept. of Herbology, College of Korean Medicine, Daegu Haany University)
  • 이세희 (대구한의대학교 한의과대학 본초약리학교실) ;
  • 오민혁 (대구한의대학교 한의과대학 본초약리학교실) ;
  • 신미래 (대구한의대학교 한의과대학 본초약리학교실) ;
  • 이지혜 (세명대학교 한의과대학 한의예과) ;
  • 노성수 (대구한의대학교 한의과대학 본초약리학교실)
  • Received : 2021.09.08
  • Accepted : 2021.12.20
  • Published : 2021.12.30

Abstract

Objectives: The aim of the current study was to investigate the effect of Sosiho-tang on thioacetamide (TAA)-induced liver fibrosis in mice and to elucidate its underlying mechanisms. Methods: The mice were divided into 4 groups: Normal mice (Normal), TAA-induced control mice (Control), TAA-induced and silymarin-treated (50 mg/kg) mice (Silymarin), and TAA-induced and Sosiho-tang treated (200 mg/kg) mice (SSHT). Liver fibrosis was induced via intraperitoneal injection of TAA three times a week for 8 weeks. Silymarin and Sosiho-tang were concomitantly administered for 8 weeks. Serum and liver tissues were then collected and the anti-oxidant and inflammatory protein levels in the liver tissues were evaluated using western blotting. Results: SSHT administration significantly reduced the levels of AST, ALT, ammonia, and MPO in the serum. SSHT also significantly down-regulated liver NADPH oxidase and regulated the Nrf2/Keap1 signaling pathway. SSHT treatment downregulated the liver NF-κB levels and suppressed inflammatory cytokines. SSHT treatment also decreased bile acid-related factors, such as CYP7A1 and NTCP, and fibrosis-related factors, such as α-SMA and Collagen I. Conclusions: Taken together, these data suggest that SSHT administration suppressed the progression of liver fibrosis by activating the Nrf2/Keap1 pathway and inhibiting NF-κB.

Keywords

Acknowledgement

정부(과학기술정보통신부)의 재원으로 한국연구재단의 지원(No. 2018R1A5A2025272)을 받아 수행된 연구입니다.

References

  1. Feng J, Chen K, Xia Y, Wu L, Li J, Li S, et al. Salidroside ameliorates autophagy and activation of hepatic stellate cells in mice via NF-kappaB and TGF-beta1/Smad3 pathways. Drug Des Devel Ther 2018;12:1837-53. https://doi.org/10.2147/DDDT.S162950
  2. Tu T, Calabro SR, Lee A, Maczurek AE, Budzinska MA, Warner FJ, et al. Hepatocytes in liver injury: Victim, bystander, or accomplice in progressive fibrosis? J Gastroenterol Hepatol 2015;30(12):1696-704. https://doi.org/10.1111/jgh.13065
  3. Nieto N, Friedman SL, Cederbaum AI. Stimulation and proliferation of primary rat hepatic stellate cells by cytochrome P4502E1-derived reactive oxygen species. Hepatology 2002;35(1):62-73. https://doi.org/10.1053/jhep.2002.30362
  4. Sanchez-Valle V, Chavez-Tapia NC, Uribe M, Mendez-Sanchez N. Role of oxidative stress and molecular changes in liver fibrosis: a review. Curr Med Chem 2012;19(28):4850-60. https://doi.org/10.2174/092986712803341520
  5. 大韓藥師會. 韓藥調劑指針解說. 서울: 여강출판사; 1995.
  6. Li J, Hu R, Xu S, Li Y, Qin Y, Wu Q, et al. Xiaochaihutang attenuates liver fibrosis by activation of Nrf2 pathway in rats. Biomedicine & Pharmacotherapy 2017;96:847-53. https://doi.org/10.1016/j.biopha.2017.10.065
  7. Shao S, Jia R, Zhao L, Zhang Y, Guan Y, Wen H, et al. Xiao-Chai-Hu-Tang ameliorates tumor growth in cancer comorbid depressive symptoms via modulating gut microbiota-mediated TLR4/MyD88/NF-κB signaling pathway. Phytomedicine 2021;88:153606. https://doi.org/10.1016/j.phymed.2021.153606
  8. Chang JS, Wang KC, Liu HW, Chen MC, Chiang LC, Lin CC. Sho-saiko-to (Xiao-Chai-Hu-Tang) and crude saikosaponins inhibit hepatitis B virus in a stable HBV-producing cell line. Am J Chin Med 2007;35(2):341-51. https://doi.org/10.1142/S0192415X07004862
  9. Jin J, Chen B, Zhan X, Zhou Z, Liu H, Dong Y, et al. Network pharmacology and molecular docking study on the mechanism of colorectal cancer treatment using Xiao-Chai-Hu-Tang. PLoS One 2021;16(6):e0252508. https://doi.org/10.1371/journal.pone.0252508
  10. Seo SH, Oh SY, Lee JY, Cho WK, Kim TS, Ma JY. Efects of Soshiho-tang on Hydrogen Peroxide-induced Oxidative Damage in Hepatocyte. Korean J Orient Int Med 2011;32(4):487-96.
  11. Kim DH, Yoon SH. Hepatoprotective Effects of Sosihotang on CCl4 induced Liver Injury in Rats. J Korean Soc Hygienic Sciences 1998;4(2):1-6.
  12. Lin CC, Lin LT, Yen MH, Cheng JT, Hsing CH, Yeh CH. Renal Protective Effect of Xiao-Chai-Hu-Tang on Diabetic Nephropathy of Type 1-Diabetic Mice. Evidence Based Complement Alternative Med 2012;2012:984024.
  13. Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol 2011;6:425-56. https://doi.org/10.1146/annurev-pathol-011110-130246
  14. Fitzhugh OG, Nelson AA. Liver tumors in rats fed thiourea or thioacetamide. Sci 1948;108(2814):626-8. https://doi.org/10.1126/science.108.2814.626
  15. Hunter AL, Hosche MA, Neal RA. Thioacetamide -induced hepatic necrosis. Involvement of the mixed-function oxidase enzyme system. J Pharmacol Exp Ther 1977;200(2):439-48.
  16. Satyabhama S, Padmanaban G. Effects of thioacetamide on cytochrome P450 synthesis in rat liver. Biochem J 1984;218(2):371-7. https://doi.org/10.1042/bj2180371
  17. Kong DZ, Liang N, Yang GL, Zhang Z, Liu Y, Li J, et al. Xiao Chai Hu Tang, a herbal medicine, for chronic hepatitis B. Cochrane Database Syst Rev 2019;2019(11):CD13090.
  18. Hsu LM, Huang YS, Tsay SH, Chang FY, Lee SD. Acute Hepatitis Induced by Chinese Hepatoprotective Herb, Xiao-Chai-Hu-Tang. J Chin Med Assoc 2006;69(2):86-8. https://doi.org/10.1016/S1726-4901(09)70119-4
  19. Liang S, Kisseleva T, Brenner DA. The Role of NADPH Oxidases (NOXs) in Liver Fibrosis and the Activation of Myofibroblasts. Front Physiol 2016;7:17.
  20. Xu W, Hellerbrand C, Kohler UA, Bugnon P, Kan YW, Werner S. The Nrf2 transcription factor protects from toxin-induced liver injury and fibrosis. Lab Invest 2008;88(10):1068-78. https://doi.org/10.1038/labinvest.2008.75
  21. Schreck R, Albermann K, Baeuerle PA. Nuclear factor kappa B: an oxidative stress-responsive transcription factor of eukaryotic cells (a review). Free Radic Res Commun 1992;17(4):221-37. https://doi.org/10.3109/10715769209079515
  22. Yu Q, Cheng P, Wu J, Guo C. PPARγββ/NF-κB and TGF-β1/Smad pathway are involved in the anti-fibrotic effects of levotetrahydropalmatine on liver fibrosis. J Cell Mol Med 2021;25(3):1645-60. https://doi.org/10.1111/jcmm.16267
  23. Fathy M, Khalifa EMMA, Fawzy MA. Modulation of inducible nitric oxide synthase pathway by eugenol and telmisartan in carbon tetrachloride -induced liver injury in rats. Life Sciences 2019; 216:207-14. https://doi.org/10.1016/j.lfs.2018.11.031
  24. Britton RS, Bacon BR. Role of free radicals in liver diseases and hepatic fibrosis. Hepatogastroenterology 1994;41(4):343-8.
  25. Wang M, Liu F, Yao Y, Zhang Q, Lu Z, Zhang R, et al. Network pharmacology-based mechanism prediction and pharmacological validation of Xiaoyan Lidan formula on attenuating alpha-naphthylisothiocyanate induced cholestatic hepatic injury in rats. J Ethnopharmacol 2021;270:113816. https://doi.org/10.1016/j.jep.2021.113816
  26. Li N, Wang B, Wu Y, Luo X, Chen Z, Sang C, et al. Modification effects of SanWei GanJiang Powder on liver and intestinal damage through reversing bile acid homeostasis. Biomed Pharmacother 2019;116:109044. https://doi.org/10.1016/j.biopha.2019.109044
  27. Zhang Y, Zhou Q, Ding X, Ma J, Tan G. Chemical profile of Swertia mussotii Franch and its potential targets against liver fibrosis revealed by cross-platform metabolomics. J Ethnopharmacol 2021;274:114051. https://doi.org/10.1016/j.jep.2021.114051
  28. Wu JZ, Li YJ, Huang GR, Xu B, Zhou F, Liu RP, et al. Mechanisms exploration of Angelicae Sinensis Radix and Ligusticum Chuanxiong Rhizoma herb-pair for liver fibrosis prevention based on network pharmacology and experimental pharmacologylogy. Chin J Nat Med 2021;19(4):241-54.