Biomedical Science Letters (대한의생명과학회지)

The Korean Society for Biomedical Laboratory Sciences (대한의생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Hepatoprotective Effect of Uncaria rhynchophylla on Thioacetamide-Induced Liver Fibrosis Model

  • Choi, Jeong Won (Department of Herbology, College of Korean Medicine, Daegu Haany University) ;
  • Shin, Mi-Rae (Department of Herbology, College of Korean Medicine, Daegu Haany University) ;
  • Lee, Ji Hye (College of Korean Medicine, Semyung University) ;
  • Roh, Seong-Soo (Department of Herbology, College of Korean Medicine, Daegu Haany University)
  • Received : 2021.08.26
  • Accepted : 2021.09.14
  • Published : 2021.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Liver fibrosis is a wound-healing response to chronic liver injury, which is caused by the continuous and excess deposition of extracellular matrix (ECM). The aim of this study is to investigate whether Uncaria rhynchophylla water extract (UR) can ameliorate thioacetamide (TAA)-induced liver fibrosis. The liver fibrosis model was induced on C57BL/6 mice by intraperitoneal injection with TAA three times a week for 8 weeks. UR (200 mg/kg) or silymarin (50 mg/kg) was administered orally daily for 8 weeks. Biochemical analyses including AST, ALT, MPO, and Ammonia levels were measured in serum. In the mice liver tissues, western blot and histological staining were analyzed. As a result, UR dramatically reduced the levels in serum AST, ALT, MPO, and Ammonia levels. UR treatment regulated NADPH oxidase factors expression, and antioxidant enzymes except for GPx-1/2 were significantly increased via Nrf2 activation. Furthermore, pro-inflammatory mediators, such as COX-2 and iNOS were markedly suppressed through the inhibition of NF-κB activation. Expressions of ECM-related protein including α-SMA and Collagen I were noticeably decreased. The additional histological evaluation confirmed that hepatocyte damage and collagenous fiber accumulation were attenuated. Taken together, these data suggest that UR possessed hepatoprotective effects in TAA-induced liver fibrosis via the NF-κB inactivation and Nrf2 activation. Therefore, UR may act as a potential therapeutic drug against liver fibrosis.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No.2018R1A5A2025272).

References

  1. Araujo LCC, Feitosa KB, Murata GM, et al. Uncaria tomentosa improves insulin sensitivity and inflammation in experimental NAFLD. Sci Rep. 2018. 8: 11013. https://doi.org/10.1038/s41598-018-29044-y
  2. Bataille AM, Manautou JE. Nrf2: a potential target for new therapeutics in liver disease. Clin Pharmacol Ther. 2012. 92: 340-348. https://doi.org/10.1038/clpt.2012.110
  3. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005. 115: 209-218. https://doi.org/10.1172/JCI24282
  4. Blois MS. Antioxidant determinations by the use of a stable free radical. Nature. 1958. 181: 1199-1200. https://doi.org/10.1038/1811199a0
  5. Brandes RP, Miller FJ, Beer S, et al. The vascular NADPH oxidase subunit p47phox is involved in redox-mediated gene expression. Free Radic Biol Med. 2002. 32: 1116-1122. https://doi.org/10.1016/S0891-5849(02)00789-X
  6. Carpino G, Morini S, Ginanni Corradini S, et al. Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation. Dig Liver Dis. 2005. 37: 349-356. https://doi.org/10.1016/j.dld.2004.11.009
  7. da Silva BS, Paulino AMB, Taffarel M, et al. High sucrose diet attenuates oxidative stress, inflammation and liver injury in thioacetamide-induced liver cirrhosis. Life Sci. 2021. 267: 118944. https://doi.org/10.1016/j.lfs.2020.118944
  8. Friedman SL. Liver fibrosis - from bench to bedside. J Hepatol. 2003. 38 Suppl 1: S38-S53. https://doi.org/10.1016/S0168-8278(02)00429-4
  9. Gan D, Zhang W, Huang C, et al. Ursolic acid ameliorates CCl4-induced liver fibrosis through the NOXs/ROS pathway. J Cell Physiol. 2018. 233: 6799-6813. https://doi.org/10.1002/jcp.26541
  10. Hajovsky H, Hu G, Koen Y, et al. Metabolism and toxicity of thioacetamide and thioacetamide S-oxide in rat hepatocytes. Chem Res Toxicol. 2012. 25: 1955-1963. https://doi.org/10.1021/tx3002719
  11. Han JT, Oh SJ, Kim HY, Park YD, Baek NI. Hyperin, Antioxidant compounds isolated from the branch of Uncaria rhynchophylla Miq. J Appl Biol Chem. 2000. 43: 78-80.
  12. Han M, Liu X, Liu S, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic stellate cell (HSC) activation and liver fibrosis in C57BL6 mouse via activating Akt and NF-κB signaling pathways. Toxicol Lett. 2017. 273: 10-19. https://doi.org/10.1016/j.toxlet.2017.03.013
  13. Han NK, Jung MG, Jeong YJ, et al. Plasma fibrinogen-like 1 as a potential biomarker for radiation-induced liver injury. Cells. 2019. 8: 1042. https://doi.org/10.3390/cells8091042
  14. Heitzman ME, Neto CC, Winiarz E, Vaisberg AJ, Hammond GB. Ethnobotany, phytochemistry and pharmacology of Uncaria (Rubiaceae). Phytochemistry. 2005. 66: 5-29. https://doi.org/10.1016/j.phytochem.2004.10.022
  15. Islam T, Hasan MR, Roy A, et al. Screening of in-vitro antioxidant, brine shrimp lethality bioassay and antimicrobial activities of extracts of Bridelia retusa (L.) Spreng. fruit. Int J Pharm. 2015. 5: 1058-1067.
  16. Jia R, Cao LP, Du JL, et al. Effects of carbon tetrachloride on oxidative stress, inflammatory response and hepatocyte apoptosis in common carp (Cyprinus carpio). Aquat Toxicol. 2014. 152: 11-19. https://doi.org/10.1016/j.aquatox.2014.02.014
  17. Kim HS, Lee YS, Oh SK, et al. Effect of ramulus et uncus uncariae on glucose oxidase-induced toxicity in cultured cerebral neurons. J Physiol & Pathol Korean Med. 2002. 16: 1016-1019.
  18. Kim HY. Effects of water extracts of black tea on hepatic functional improvement and anti-fibrosis in rats. J East Asian Soc Diet Life. 2013. 23: 44-52.
  19. Kim KH, Bae JH, Cha SW, Han SS, Park KH, Jeong TC. Role of metabolic activation by cytochrome P450 in thioacetamide-induced suppression of antibody response in male BALB/c mice. Toxicol Lett. 2000. 114: 223-235.
  20. Kim ST, Kim JD, Lyu YS, Lee MY, Kang HW. Neuroprotective effect of some plant extracts in cultured CT105-induced PC12 cells. Biol Pharm Bull. 2006. 29: 2021-2024. https://doi.org/10.1248/bpb.29.2021
  21. Koop AC, Thiele ND, Steins D, et al. Therapeutic targeting of myeloperoxidase attenuates NASH in mice. Hepatol Commun. 2020. 4: 1441-1458. https://doi.org/10.1002/hep4.1566
  22. Lackner C, Tiniakos D. Fibrosis and alcohol-related liver disease. J Hepatol. 2019. 70: 209-304. https://doi.org/10.1016/j.jhep.2018.09.016
  23. Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol. 2011. 25: 195-206. https://doi.org/10.1016/j.bpg.2011.02.005
  24. Li J, Hu R, Xu S, et al. Xiaochaihutang attenuates liver fibrosis by activation of Nrf2 pathway in rats. Biomed Pharmacother. 2017. 96: 847-853. https://doi.org/10.1016/j.biopha.2017.10.065
  25. 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.
  26. Liu A, Shen Y, Du Y, et al. Esculin prevents lipopolysaccharide/D-Galactosamine-induced acute liver injury in mice. Microb Pathog. 2018. 125: 418-422. https://doi.org/10.1016/j.micpath.2018.10.003
  27. Loh YC, Ch'ng YS, Tan CS, Ahmad M, Asmawi MZ, Yam MF. Mechanisms of action of Uncaria rhynchophylla ethanolic extract for its vasodilatory effects. J Med Food. 2017. 20: 895-911. https://doi.org/10.1089/jmf.2016.3804
  28. Marciniak S, Wnorowski A, Smolinska K, et al. Kynurenic acid protects against thioacetamide-induced liver injury in rats. Anal Cell Pathol (Amst). 2018: 2018. 1270483. https://doi.org/10.1155/2018/1270483
  29. Nam Y, Ko SK, Sohn UD. Hepatoprotective effect of ultrasonicated ginseng berry extract on a rat mild bile duct ligation model. J Ginseng Res. 2019. 43: 606-617. https://doi.org/10.1016/j.jgr.2018.07.007
  30. Ninan J, Feldman L. Ammonia levels and hepatic encephalopathy in patients with known chronic liver disease. J Hosp Med. 2017. 12: 659-661. https://doi.org/10.12788/jhm.2794
  31. Park YM, Kim JA, Kim CH, Lim JH, Seo EW. Effects of cultured acer tegmentosum cell extract against hepatic injury induced by D-galactosamine In SD-rats. Korean J. Plant Res. 2015. 28: 551-560. https://doi.org/10.7732/KJPR.2015.28.5.551
  32. Park YM, Lee JE, Seo EW. Effect of semisulcospira libertina extract on hepatic injury induced by D-galactosamine. Korean J Environ Biol. 2018. 36: 498-506. https://doi.org/10.11626/KJEB.2018.36.4.498
  33. Piek A, Koonen DPY, Schouten EM, et al. Pharmacological myeloperoxidase (MPO) inhibition in an obese/hypertensive mouse model attenuates obesity and liver damage, but not cardiac remodeling. Sci Rep. 2019. 9: 18765. https://doi.org/10.1038/s41598-019-55263-y
  34. Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radical Biol Med. 1999. 26: 1231-1237. https://doi.org/10.1016/S0891-5849(98)00315-3
  35. Robinson SM, Mann DA. Role of nuclear factor kappaB in liver health and disease. Clin Sci (Lond). 2010. 118: 691-705. https://doi.org/10.1042/CS20090549
  36. Singleton VL, Rossi JA. Colorimetry of total phenolics with phosphomolybdic-phosphotungstic acid reagents. Am J Enol Vitic. 1965. 16: 144-158.
  37. Trefts E, Gannon M, Wasserman DH. The liver. Curr Biol. 2017. 27: R1147-R1151. https://doi.org/10.1016/j.cub.2017.09.019
  38. Wu CT, Deng JS, Huang WC, Shieh PC, Chung MI, Huang GJ. Salvianolic acid C against acetaminophen-induced acute liver injury by attenuating inflammation, oxidative stress, and apoptosis through inhibition of the Keap1/Nrf2/HO-1 Signaling. Oxid Med Cell Longev. 2019. 2019: 9056845. https://doi.org/10.1155/2019/9056845
  39. Xu L, Yu Y, Sang R, Li J, Ge B, Zhang X. Protective effects of taraxasterol against ethanol-induced liver injury by regulating CYP2E1/Nrf2/HO-1 and NF-κB signaling pathways in mice. Oxid Med Cell Longev. 2018. 2018: 8284107. https://doi.org/10.1155/2018/8284107
  40. Yoon YC, Fang Z, Lee JE, et al. Selonsertib inhibits liver fibrosis via downregulation of ASK1/ MAPK Pathway of hepatic stellate cells. Biomol Ther (Seoul). 2020. 28: 527-536. https://doi.org/10.4062/biomolther.2020.016