Skip to main content
SpringerLink
Log in

Hepatoprotective effects of paeonol by suppressing hepatic stellate cell activation via inhibition of SMAD2/3 and STAT3 pathways

  • Research Article
  • Published:
Food Science and Biotechnology Aims and scope Submit manuscript

Abstract

Hepatic stellate cell (HSC) activation is a key event in extracellular matrix accumulation, causing hepatic fibrosis. Therefore, identifying chemicals that inhibit HSC activation is an important therapeutic strategy for hepatic fibrosis. The aim of this study was to investigate the therapeutic effects of paeonol on HSC activation. In LX-2 cells, paeonol inhibited the expression of collagen and decreased the expression of HSC activation markers. In mice with thioacetamide-induced liver fibrosis, paeonol treatment decreased the serum levels of aspartate aminotransferase and alanine transaminase and mRNA expression of α-smooth muscle actin, platelet-derived growth factor-β, and connective-tissue growth factor. Investigation of the underlying molecular mechanism of paeonol showed that paeonol inhibits the SMAD2/3 and STAT3 signaling pathways that are important for HSC activation. On the basis of these results, paeonol should be investigated and developed further for hepatic fibrosis treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Bataller R, Brenner DA. Liver fibrosis. Journal of Clinical Investigation. 115: 209-218 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carpino G, Morini S, Ginanni Corradini S, Franchitto A, Merli M, Siciliano M, Gentili F, Onetti Muda A, Berloco P, Rossi M, Attili AF, Gaudio E. Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation.Digestive and Liver Disease. 37: 349-356 (2005)

    Article  CAS  PubMed  Google Scholar 

  • Chakraborty D, Šumová B, Mallano T, Chen C-W, Distler A, Bergmann C, Ludolph I, Horch RE, Gelse K, Ramming A, Distler O, Schett G, Šenolt L, Distler JHW. Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis. Nature Communications. 8: 1130 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  • Cheng CS, Chen JX, Tang J, Geng YW, Zheng L, Lv LL, Chen LY, Chen Z. Paeonol inhibits pancreatic cancer cell migration and invasion through the inhibition of TGF-β1/Smad signaling and epithelial-mesenchymal-transition. Cancer Management and Research. 12: 641-651 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chou TC. Anti-inflammatory and analgesic effects of paeonol in carrageenan-evoked thermal hyperalgesia. British Journal of Pharmacology. 139: 1146-1152 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chun SC, Jee SY, Lee SG, Park SJ, Lee JR, Kim SC. Anti-inflammatory activity of the methanol extract of moutan cortex in LPS-activated Raw264.7 cells. Evid. Complementary and Alternative Medicine. 4: 327–333 (2007)

  • Chung JY, Chan MK, Li JS, Chan AS, Tang PC, Leung KT, To KF, Lan HY, Tang PM. TGF-β signaling: from tissue fibrosis to tumor microenvironment. International Journal of Molecular Sciences. 22: 7575 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dai M, Zhi X, Peng D, Liu Q. Inhibitory effect of paeonol on experimental atherosclerosis in quails. Zhongguo Zhong Yao Za Zhi. 24: 488–490, 512 (1999)

  • Dewidar B, Soukupova J, Fabregat I, Dooley S. TGF-β in hepatic stellate cell activation and liver fibrogenesis: updated. Current Pathobiology Reports. 3: 291-305 (2015)

    Article  Google Scholar 

  • Fabregat I, Caballero-Díaz D. Transforming growth factor-β-induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Frontiers in Oncology. 8: 357 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  • Ginès P, Castera L, Lammert F, Graupera I, Serra‐Burriel M, Allen AM, Wong VWS, Hartmann P, Thiele M, Caballeria L, De Knegt RJ, Grgurevic I, Augustin S, Tsochatzis EA, Schattenberg JM, Guha IN, Martini A, Morillas RM, Garcia‐Retortillo M, De Koning HJ, Fabrellas N, Pich J, Ma AT, Diaz MA, Roulot D, Newsome PN, Manns M, Kamath PS, Krag A. Population screening for liver fibrosis: toward early diagnosis and intervention for chronic liver diseases. Hepatology. 75: 219-228 (2022)

    Article  PubMed  Google Scholar 

  • Han CV, Bhat R. In vitro control of food-borne pathogenic bacteria by essential oils and solvent extracts of underutilized flower buds of Paeonia suffruticosa (Andr.). Industrial Crops and Products. 54: 203–208 (2014)

  • Hata A, Chen YG. TGF-β signaling from receptors to Smads. Cold Spring Harbor Perspectives in Biology. 8: a022061 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  • Hsieh CL, Cheng CY, Tsai TH, Lin IH, Liu CH, Chiang SY, Lin JG, Lao CJ, Tang NY. Paeonol reduced cerebral infarction involving the superoxide anion and microglia activation in ischemia-reperfusion injured rats. Journal of Ethnopharmacology. 106: 208-215 (2006)

    Article  CAS  PubMed  Google Scholar 

  • Hu HH, Chen DQ, Wang YN, Feng YL, Cao G, Vaziri ND, Zhao YY. New insights into TGF-β/Smad signaling in tissue fibrosis. Chemico-Biological Interactions. 292: 76-83 (2018)

    Article  CAS  PubMed  Google Scholar 

  • Hu S, Shen G, Zhao W, Wang F, Jiang X, Huang D. Paeonol, the main active principles of Paeonia moutan, ameliorates alcoholic steatohepatitis in mice. Journal of Ethnopharmacology. 128: 100-106 (2010)

    Article  CAS  PubMed  Google Scholar 

  • Kasembeli MM, Bharadwaj U, Robinson P, Tweardy DJ. Contribution of STAT3 to inflammatory and fibrotic diseases and prospects for its targeting for treatment. International Journal of Molecular Sciences. 19: 2299 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee SJ, Lee IS, Mar W. Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 activity by 1,2,3,4,6-penta-O-galloyl-beta-D-glucose in murine macrophage cells. Archives of Pharmacal Research. 26: 832-839 (2003)

    Article  CAS  PubMed  Google Scholar 

  • Liu F, Chen L, Rao H-Y, Teng X, Ren Y-Y, Lu Y-Q, Zhang W, Wu N, Liu F-F, Wei L. Automated evaluation of liver fibrosis in thioacetamide, carbon tetrachloride, and bile duct ligation rodent models using second-harmonic generation/two-photon excited fluorescence microscopy. Laboratory Investigation. 97: 84-92 (2017)

    Article  CAS  PubMed  Google Scholar 

  • Nagasawa H, Iwabuchi T, Inatomi H. Protection by tree-peony (Paeonia suffruticosa Andr) of obesity in (SLN x C3H/He) F1 obese mice. In Vivo. 5: 115-118 (1991)

    CAS  PubMed  Google Scholar 

  • Pan Y, Gao Z, Huang X-Y, Chen J-J, Geng C-A. Chemical and biological comparison of different parts of Paeonia suffruticosa (Mudan) based on LCMS-IT-TOF and multi-evaluation in vitro. Industrial Crops and Products. 144: 112028 (2020)

    Article  CAS  Google Scholar 

  • Park YJ, An H-T, Park J-S, Park O, Duh AJ, Kim K, Chung KH, Lee KC, Oh Y, Lee S. Tyrosine kinase inhibitor neratinib attenuates liver fibrosis by targeting activated hepatic stellate cells. Scientific Reports 10: 14756 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park YJ, Jeon MS, Lee S, Kim JK, Jang TS, Chung KH, Kim KH. Anti-fibrotic effects of brevilin A in hepatic fibrosis via inhibiting the STAT3 signaling pathway. Bioorganic & Medicinal Chemistry Letters. 41: 127989 (2021)

    Article  CAS  Google Scholar 

  • Park YJ, Kim DM, Jeong MH, Yu JS, So HM, Bang IJ, Kim HR, Kwon SH, Kim KH, Chung KH. (-)-Catechin-7-O-β-d-apiofuranoside inhibits hepatic stellate cell activation by suppressing the STAT3 signaling pathway. Cells. 9: 30 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  • Peng D, Fu M, Wang M, Wei Y, Wei X. Targeting TGF-β signal transduction for fibrosis and cancer therapy. Molecular Cancer. 21: 104 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pisani P, Parkin DM, Bray F, Ferlay J. Estimates of the worldwide mortality from 25 cancers in 1990. International Journal of Cancer. 83: 18-29 (1999)

    Article  CAS  PubMed  Google Scholar 

  • Senoo H, Yoshikawa K, Morii M, Miura M, Imai K, Mezaki Y. Hepatic stellate cell (vitamin A-storing cell) and its relative—past, present and future. Cell Biology International. 34: 1247-1272 (2010)

    Article  CAS  PubMed  Google Scholar 

  • Sun SW, Du J, Hwang E, Yi TH. Paernol extracted from Paeonia suffruticosa Andr. amealiorated UVB-induced skin photoaging via DLD/Nrf2/ARE and MAPK/AP-1 pathway. Phytotherapy Research. 32(9): 1741-1749 (2018)

  • Tang LY, Heller M, Meng Z, Yu LR, Tang Y, Zhou M, Zhang YE. Transforming growth factor-β (TGF-β) directly activates the JAK1-STAT3 axis to induce hepatic fibrosis in coordination with the SMAD pathway. Journal of Biological Chemistry. 292: 4302-4312 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nature Reviews Gastroenterology & Hepatology. 14: 397-411 (2017)

    Article  CAS  Google Scholar 

  • Wang H, Lafdil F, Kong X, Gao B. Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic target. International Journal of Biological Sciences. 7: 536-550 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Liu Q, He J, Li Y. Novel therapeutic targets in liver fibrosis. Frontiers in Molecular Biosciences. 8: 766855 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang YE. Non-Smad pathways in TGF-β signaling. Cell Research. 19: 128-139 (2009)

    Article  CAS  PubMed  Google Scholar 

  • Zhao J, Qi YF, Yu YR. STAT3: a key regulator in liver fibrosis. Annals of Hepatology. 21: 100224 (2021)

    Article  CAS  PubMed  Google Scholar 

  • Zhu S, Shirakawa A, Shi Y, Yu X, Tamura T, Shibahara N, Yoshimatsu K, Komatsu K. Impact of different post-harvest processing methods on the chemical compositions of peony root. Journal of Natural Medicines. 72: 757-767 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by Kyungsung University Research Grants in 2021.

Author information

Author notes

  1. Hye Kyung Kim and Yong Joo Park contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy, Kyungsung University, Busan, 48434, Republic of Korea

    Hye-Jin Jeong, Sooyeon Koo, Yeon-Ho Kang, Tae Won Kim, Hye Kyung Kim & Yong Joo Park

  2. Brain Busan 21 plus Research Project Group, Kyungsung University, Busan, Republic of Korea

    Tae Won Kim & Hye Kyung Kim

Authors
  1. Hye-Jin Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sooyeon Koo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yeon-Ho Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tae Won Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hye Kyung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yong Joo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hye Kyung Kim or Yong Joo Park.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 159 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jeong, HJ., Koo, S., Kang, YH. et al. Hepatoprotective effects of paeonol by suppressing hepatic stellate cell activation via inhibition of SMAD2/3 and STAT3 pathways. Food Sci Biotechnol (2023). https://doi.org/10.1007/s10068-023-01440-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10068-023-01440-9

Keywords

Search

Navigation