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Angelica dahurica extract and its effective component bergapten alleviated hepatic fibrosis by activating FXR signaling pathway

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Abstract

Angelica dahurica (A. dahurica) has a wide range of pharmacological effects, including analgesic, anti-inflammatory and hepatoprotective effects. In this study, we investigated the effect of A. dahurica extract (AD) and its effective component bergapten (BG) on hepatic fibrosis and potential mechanisms. Hepatic fibrosis was induced by intraperitoneal injection with carbon tetrachloride (CCl4) for 1 week, and mice were administrated with AD or BG by gavage for 1 week before CCl4 injection. Hepatic stellate cells (HSCs) were stimulated by transforming growth factor-β (TGF-β) and cultured with AD, BG, GW4064 (FXR agonist) or Guggulsterone (FXR inhibitor). In CCl4-induced mice, AD significantly decreased serum aminotransferase, reduced excess accumulation of extracellular matrix (ECM), inhibited caspase-1 and IL-1β, and increased FXR expressions. In activated HSCs, AD suppressed the expressions of α-SMA, collagen I, and TIMP-1/MMP-13 ratio and inflammatory factors, functioning as FXR agonist. In CCl4-induced mice, BG significantly improved serum transaminase and histopathological changes, reduced ECM excessive deposition, inflammatory response, and activated FXR expression. BG increased FXR expression and inhibited α-SMA and IL-1β expressions in activated HSCs, functioning as GW4064. FXR deficiency significantly attenuated the decreasing effect of BG on α-SMA and IL-1β expressions in LX-2 cells. In conclusion, AD could regulate hepatic fibrosis by regulating ECM excessive deposition and inflammation. Activating FXR signaling by BG might be the potential mechanism of AD against hepatic fibrosis.

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References

  1. Kisseleva T, Brenner D (2021) Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol 18:151–166

    Article  PubMed  Google Scholar 

  2. Mu M, Zuo S, Wu RM, Deng KS, Lu S, Zhu JJ, Zou G, Yang J, Cheng ML, Zhao XK (2018) Ferulic acid attenuates liver fibrosis and hepatic stellate cell activation via inhibition of TGF-β/Smad signaling pathway. Drug Des Devel Ther 12:4107–4115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. He X, Chen J, Mu Y, Zhang H, Chen G, Liu P, Liu W (2020) The effects of inhibiting the activation of hepatic stellate cells by lignan components from the fruits of Schisandra chinensis and the mechanism of schisanhenol. J Nat Med 74:513–524

    Article  CAS  PubMed  Google Scholar 

  4. Liu X, Xu J, Brenner DA, Kisseleva T (2013) Reversibility of liver fibrosis and inactivation of fibrogenic myofibroblasts. Curr Pathobiol Rep 1:209–214

    Article  PubMed  PubMed Central  Google Scholar 

  5. Seki E, Brenner DA (2015) Recent advancement of molecular mechanisms of liver fibrosis. J Hepatobiliary Pancreat Sci 22:512–518

    Article  PubMed  PubMed Central  Google Scholar 

  6. Parola M, Pinzani M (2019) Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med 65:37–55

    Article  CAS  PubMed  Google Scholar 

  7. Yang D, Li L, Qian S, Liu L (2018) Evodiamine ameliorates liver fibrosis in rats via TGF-β1/Smad signaling pathway. J Nat Med 72:145–154

    Article  CAS  PubMed  Google Scholar 

  8. Gan C, Cai Q, Tang C, Gao J (2022) Inflammasomes and pyroptosis of liver cells in liver fibrosis. Front Immunol 13:896473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tsuchida T, Friedman SL (2017) Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 14:397–411

    Article  CAS  PubMed  Google Scholar 

  10. Dewidar B, Meyer C, Dooley S, Meindl-Beinker AN (2019) TGF-β in hepatic stellate cell activation and liver fibrogenesis-updated. Cells 8:1419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dooley S, ten Dijke P (2019) TGF-β in progression of liver disease. Cell Tissue Res 347:245–256

    Article  Google Scholar 

  12. Xu A, Li Y, Zhao W, Hou F, Li X, Sun L, Chen W, Yang A, Wu S, Zhang B, Yao J, Wang H, Huang J (2018) PHP14 regulates hepatic stellate cells migration in liver fibrosis via mediating TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway. J Mol Med (Berl) 96:119–133

    Article  CAS  PubMed  Google Scholar 

  13. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, Oshima K, Morita H, Hattori M, Honda K, Ishikawa Y, Hara E, Ohtani N (2018) Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499:97–101

    Article  ADS  Google Scholar 

  14. Wang XX, Xie C, Libby AE, Ranjit S, Levi J, Myakala K, Bhasin K, Jones BA, Orlicky DJ, Takahashi S, Dvornikov A, Kleiner DE, Hewitt SM, Adorini L, Kopp JB, Krausz KW, Rosenberg A, McManaman JL, Robertson CE, Ir D, Frank DN, Luo Y, Gonzalez FJ, Gratton E, Levi M (2022) The role of FXR and TGR5 in reversing and preventing progression of Western diet-induced hepatic steatosis, inflammation, and fibrosis in mice. J Biol Chem 298:102530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu Y, Binz J, Numerick MJ, Dennis S, Luo G, Desai B, MacKenzie KI, Mansfield TA, Kliewer SA, Goodwin B, Jones SA (2003) Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest 112:1678–1687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tian SY, Chen SM, Pan CX, Li Y (2022) FXR: structures, biology, and drug development for NASH and fibrosis diseases. Acta Pharmacol Sin 43:1120–1132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Halilbasic E, Fuchs C, Traussnigg S, Trauner M (2022) Farnesoid X receptor agonists and other bile acid signaling strategies for treatment of liver disease. Dig Dis 34:580–588

    Article  Google Scholar 

  18. Han X, Cui ZY, Song J, Piao HQ, Lian LH, Hou LS, Wang G, Zheng S, Dong XX, Nan JX, Wu YL (2019) Acanthoic acid modulates lipogenesis in nonalcoholic fatty liver disease via FXR/LXRs-dependent manner. Chem Biol Interact 311:108794

    Article  CAS  PubMed  Google Scholar 

  19. Zhao H, Feng YL, Wang M, Wang JJ, Liu T, Yu J (2022) The Angelica dahurica: a review of traditional uses. Phytochemistry and Pharmacology Front Pharmacol 13:896637

    Article  CAS  PubMed  Google Scholar 

  20. Liang WH, Chang TW, Charng YC (2018) Effects of drying methods on contents of bioactive compounds and antioxidant activities of Angelica dahurica. Food Sci Biotechnol 27:1085–1092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liang Y, Xie L, Liu K, Cao Y, Dai X, Wang X, Lu J, Zhang X, Li X (2021) Bergapten: a review of its pharmacology, pharmacokinetics, and toxicity. Phytother Res 35:6131–6147

    Article  CAS  PubMed  Google Scholar 

  22. Quetglas-Llabrés MM, Quispe C, Herrera-Bravo J, Catarino MD, Pereira OR, Cardoso SM, Dua K, Chellappan DK, Pabreja K, Satija S, Mehta M, Sureda A, Martorell M, Satmbekova D, Yeskaliyeva B, Sharifi-Rad J, Rasool N, Butnariu M, Bagiu IC, Bagiu RV, Calina D, Cho WC (2022) Pharmacological properties of bergapten: mechanistic and therapeutic aspects. Oxid Med Cell Longev 2022:8615242

    Article  PubMed  PubMed Central  Google Scholar 

  23. Liu WX, Jia FL, He YY, Zhang BX (2012) Protective effects of 5-methoxypsoralen against acetaminophen-induced hepatotoxicity in mice. World J Gastroenterol 18:2197–2202

    Article  PubMed  PubMed Central  Google Scholar 

  24. Wan P, Hengfan NI, Dale G, Yun D, Manyun D (2023) Farnesoid X receptor regulators from natural products and their biological function. J Tradit Chin Med 43:618–626

    PubMed  Google Scholar 

  25. Caligiuri A, Gentilini A, Pastore M, Gitto S, Marra F (2021) Cellular and molecular mechanisms underlying liver fibrosis regression. Cells 10(10):2759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dong S, Chen QL, Song YN, Sun Y, Wei B, Li XY, Hu YY, Liu P, Su SB (2016) Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis. J Toxicol Sci 41:561–572

    Article  CAS  PubMed  Google Scholar 

  27. Kong D, Zhang F, Zhang Z, Lu Y, Zheng S (2013) Clearance of activated stellate cells for hepatic fibrosis regression: molecular basis and translational potential. Biomed Pharmacother 67:246–250

    Article  CAS  PubMed  Google Scholar 

  28. Wree A, Holtmann TM, Inzaugarat ME, Feldstein AE (2019) Novel drivers of the inflammatory response in liver injury and fibrosis. Semin Liver Dis 39:275–282

    Article  CAS  PubMed  Google Scholar 

  29. Gong J, Yang F, Yang Q, Tang X, Shu F, Xu L, Wang Z, Yang L (2020) Sweroside ameliorated carbon tetrachloride (CCl4)-induced liver fibrosis through FXR-miR-29a signaling pathway. J Nat Med 74:17–25

    Article  CAS  PubMed  Google Scholar 

  30. Namisaki T, Kaji K, Shimozato N, Kaya D, Ozutsumi T, Tsuji Y, Fujinaga Y, Kitagawa K, Furukawa M, Sato S, Sawada Y, Nishimura N, Takaya H, Okura Y, Seki K, Kawaratani H, Moriya K, Noguchi R, Asada K, Akahane T, Mitoro A, Yoshiji H (2022) Effect of combined farnesoid X receptor agonist and angiotensin II type 1 receptor blocker on ongoing hepatic fibrosis. Indian J Gastroenterol 41:169–180

    Article  PubMed  Google Scholar 

  31. Song J, Cui ZY, Lian LH, Han X, Hou LS, Wang G, Gao L, Zhu Y, Jiang YC, Dou JY, Hu ZH, Zhao YQ, Nan JX, Wu YL (2020) 20S-Protopanaxatriol ameliorates hepatic fibrosis, potentially involving FXR-mediated inflammatory signaling cascades. J Agric Food 68:8195–8204

    Article  CAS  Google Scholar 

  32. Verbeke L, Mannaerts I, Schierwagen R, Govaere O, Klein S, Vander Elst I, Windmolders P, Farre R, Wenes M, Mazzone M, Nevens F, van Grunsven LA, Trebicka J, Laleman W (2016) FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep 6:33453

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are indebted to all individuals who participated in or helped with the study.

Funding

The work was supported by National Natural Science Foundation of China, 81973555, and Science and Technology Department grant funded by the Jilin government of China, YDZJ202101ZYTS106.

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Author notes

  1. Chong Gao and Zhong-He Hu have contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China

    Chong Gao, Zhong-He Hu, Zhen-Yu Cui, Yu-Chen Jiang, Jia-Yi Dou, Zhao-Xu Li, Li-Hua Lian, Ji-Xing Nan & Yan-Ling Wu

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  1. Chong Gao
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  2. Zhong-He Hu
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Contributions

JXN and YLW designed the study and supervised the experiments. CG, ZHH, ZYC, YCJ, and JYD performed the experiments. CG, ZHH, and ZXL analyzed the data. GC and YLW wrote the manuscript. YLW, JYC, JYD, and LHL revised the manuscript. All authors have read and approved the manuscript.

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Correspondence to Ji-Xing Nan or Yan-Ling Wu.

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Gao, C., Hu, ZH., Cui, ZY. et al. Angelica dahurica extract and its effective component bergapten alleviated hepatic fibrosis by activating FXR signaling pathway. J Nat Med 78, 427–438 (2024). https://doi.org/10.1007/s11418-024-01780-8

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