Skip to main content
SpringerLink
Log in

Dihydromyricetin alleviates inflammatory bowel disease associated intestinal fibrosis by inducing autophagy through the PI3K/AKT/mTOR signaling pathway

  • Research
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Intestinal fibrosis is a common complication of inflammatory bowel disease and is characterized by tissue stiffening and luminal narrowing. Dihydromyricetin (DHM) can alleviate liver fibrosis and renal interstitial fibrosis by inducing autophagy. However, whether DHM can alleviate intestinal fibrosis remains unclear. This study is aimed at evaluating the role and mechanism of action of DHM in inflammatory bowel disease-associated intestinal fibrosis. Mice were administered dextran sulfate sodium (DSS) in drinking water to induce inflammatory bowel disease-associated intestinal fibrosis. HE staining, qPCR, and Western blotting were used to analyze colon inflammation. Masson’s trichrome staining, qPCR, Western blotting, and immunofluorescence staining were used to evaluate the severity of fibrosis. Transmission electron microscopy and Western blotting were used to assess the activation of autophagosomes. The human colonic fibroblast line CCD-18Co was cultured in the presence of TGF-β1 to develop a fibrotic phenotype. Immunofluorescence staining, Western blotting, and qPCR were used to assess the alteration of fibrosis markers and used to investigate whether DHM-induced autophagy was involved in the inactivation of CCD-18Co cells. Additionally, the role of the PI3K/AKT/mTOR pathway was investigated. DHM alleviated intestinal inflammation and inhibited the progression of intestinal fibrosis. Additionally, DHM induced the activation of autophagy, thereby alleviating intestinal fibrosis, and downregulated the PI3K/AKT/mTOR signaling pathway in vitro. Overall, this study demonstrated that DHM can inhibit the progression of intestinal fibrosis and activation of colonic fibroblasts by inducing autophagy through the PI3K/AKT/mTOR signaling pathway, thereby playing a preventive and therapeutic role in intestinal fibrosis.

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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The authors do not have permission to share data. The data pertaining to this study are included in the article.

References

  • Antar SA, Ashour NA, Marawan ME, Al-Karmalawy AA (2023) Fibrosis: types, effects, markers, mechanisms for disease progression, and its relation with oxidative stress, immunity, and inflammation. Int J Mol Sci 24:4004

  • Bamias G, Pizarro TT, Cominelli F (2022) Immunological regulation of intestinal fibrosis in inflammatory bowel disease. Inflamm Bowel Dis 28:337–349

    Article  PubMed  Google Scholar 

  • Chan WPW, Mourad F, Leong RW (2018) Crohn’s disease associated strictures. J Gastroenterol Hepatol 33:998–1008

    Article  PubMed  Google Scholar 

  • Chen J, Wang X, Xia T, Bi Y, Liu B, Fu J, Zhu R (2021) Molecular mechanisms and therapeutic implications of dihydromyricetin in liver disease. Biomed Pharmacother. 142:111927

    Article  PubMed  CAS  Google Scholar 

  • Chen L, Shi M, Lv C, Song Y, Wu Y, Liu S, Zheng Z, Lu X, Qin S (2021) Dihydromyricetin acts as a potential redox balance mediator in cancer chemoprevention. Mediators Inflamm 2021:6692579

    Article  PubMed  PubMed Central  Google Scholar 

  • Crespi M, Dulbecco P, De Ceglie A, Conio M (2020) Strictures in Crohn’s disease: from pathophysiology to treatment. Dig Dis Sci 65:1904–1916

    Article  PubMed  Google Scholar 

  • Cushing K, Higgins PDR (2021) Management of Crohn disease: a review. JAMA 325:69–80

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • D’Haens G, Rieder F, Feagan BG, Higgins PDR, Panés J, Maaser C, Rogler G, Löwenberg M, van der Voort R, Pinzani M et al (2022) Challenges in the pathophysiology, diagnosis, and management of intestinal fibrosis in inflammatory bowel disease. Gastroenterology 162:26–31

    Article  PubMed  CAS  Google Scholar 

  • Dong S, Zhu M, Wang K, Zhao X, Hu L, Jing W, Lu H, Wang S (2021) Dihydromyricetin improves DSS-induced colitis in mice via modulation of fecal-bacteria-related bile acid metabolism. Pharmacol Res. 171:105767

    Article  PubMed  CAS  Google Scholar 

  • Granato M, Rizzello C, Gilardini Montani MS, Cuomo L, Vitillo M, Santarelli R, Gonnella R, D’Orazi G, Faggioni A, Cirone M (2017) Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways. J Nutr Biochem 41:124–136

    Article  PubMed  CAS  Google Scholar 

  • Guo L, Zhang H, Yan X (2019) Protective effect of dihydromyricetin revents fatty liver through nuclear factor-κB/p53/B-cell lymphoma 2-associated X protein signaling pathways in a rat model. Mol Med Rep 19:1638–1644

    PubMed  CAS  Google Scholar 

  • Guo L, Tan K, Luo Q, Bai X (2020) Dihydromyricetin promotes autophagy and attenuates renal interstitial fibrosis by regulating miR-155-5p/PTEN signaling in diabetic nephropathy. Bosn J Basic Med Sci 20:372–380

    PubMed  PubMed Central  CAS  Google Scholar 

  • Hayashi Y, Nakase H (2022) The molecular mechanisms of intestinal inflammation and fibrosis in Crohn’s disease. Front Physiol. 13:845078

    Article  PubMed  PubMed Central  Google Scholar 

  • Klionsky DJ, Petroni G, Amaravadi RK, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cadwell K, Cecconi F, Choi AMK et al (2021) Autophagy in major human diseases. EMBO J. 40:e108863

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li Q, Cui Y, Xu B, Wang Y, Lv F, Li Z, Li H, Chen X, Peng X, Chen Y et al (2021) Main active components of Jiawei Gegen Qinlian decoction protects against ulcerative colitis under different dietary environments in a gut microbiota-dependent manner. Pharmacol Res. 170:105694

    Article  PubMed  CAS  Google Scholar 

  • Liu MW, Su MX, Tang DY, Hao L, Xun XH, Huang YQ (2019) Ligustrazin increases lung cell autophagy and ameliorates paraquat-induced pulmonary fibrosis by inhibiting PI3K/Akt/mTOR and hedgehog signalling via increasing miR-193a expression. BMC Pulm Med. 19:35

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu M, Guo H, Li Z, Zhang C, Zhang X, Cui Q, Tian J (2020) Molecular level insight into the benefit of myricetin and dihydromyricetin uptake in patients with Alzheimer’s diseases. Front Aging Neurosci. 12:601603

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu J, Lin H, Cao M, Lin T, Lin A, Xu W, Wang H, He J, Li Y, Tang H et al (2023) Shifts and importance of viable bacteria in treatment of DSS-induced ulcerative colitis mice with FMT. Front Cell Infect Microbiol. 13:1124256

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lucantoni F, Martínez-Cerezuela A, Gruevska A, Moragrega ÁB, Víctor VM, Esplugues JV, Blas-García A, Apostolova N (2021) Understanding the implication of autophagy in the activation of hepatic stellate cells in liver fibrosis: are we there yet? J Pathol 254:216–228

    Article  PubMed  Google Scholar 

  • Ni T, Lin N, Lu W, Sun Z, Lin H, Chi J, Guo H (2020) Dihydromyricetin prevents diabetic cardiomyopathy via miR-34a suppression by activating autophagy. Cardiovasc Drugs Ther 34:291–301

    Article  PubMed  CAS  Google Scholar 

  • Pakshir P, Noskovicova N, Lodyga M, Son DO, Schuster R, Goodwin A, Karvonen H, Hinz B (2020) The myofibroblast at a glance. J Cell Sci 133:jcs227900

  • Rezq S, Hassan R, Mahmoud MF (2021) Rimonabant ameliorates hepatic ischemia/reperfusion injury in rats: involvement of autophagy via modulating ERK- and PI3K/AKT-mTOR pathways. Int Immunopharmacol. 100:108140

    Article  PubMed  CAS  Google Scholar 

  • Richter FC, Friedrich M, Kampschulte N, Piletic K, Alsaleh G, Zummach R, Hecker J, Pohin M, Ilott N, Guschina I et al (2023) Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL-10. EMBO J. 42:e112202

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Saha K, Subramenium Ganapathy A, Wang A, Michael Morris N, Suchanec E, Ding W, Yochum G, Koltun W, Nighot M, Ma T et al (2023) Autophagy reduces the degradation and promotes membrane localization of occludin to enhance the intestinal epithelial tight junction barrier against paracellular macromolecule flux. J Crohns Colitis 17:433–449

    Article  PubMed  Google Scholar 

  • Shapiro JM, Subedi S, LeLeiko NS (2016) Inflammatory bowel disease. Pediatr Rev 37:337–347

    Article  PubMed  Google Scholar 

  • Sleiman J, El Ouali S, Qazi T, Cohen B, Steele SR, Baker ME, Rieder F (2021) Prevention and treatment of stricturing Crohn’s disease - perspectives and challenges. Expert Rev Gastroenterol Hepatol 15:401–411

    Article  PubMed  CAS  Google Scholar 

  • Song Q, Liu L, Yu J, Zhang J, Xu M, Sun L, Luo H, Feng Z, Meng G (2017) Dihydromyricetin attenuated Ang II induced cardiac fibroblasts proliferation related to inhibitory of oxidative stress. Eur J Pharmacol 807:159–167

    Article  PubMed  CAS  Google Scholar 

  • Su HY, Gupta V, Day AS, Gearry RB (2016) Rising incidence of inflammatory bowel disease in Canterbury. New Zealand Inflamm Bowel Dis 22:2238–2244

    Article  PubMed  Google Scholar 

  • Sun Y, Liu S, Yang S, Chen C, Yang Y, Lin M, Liu C, Wang W, Zhou X, Ai Q et al (2021) Mechanism of dihydromyricetin on inflammatory diseases. Front Pharmacol. 12:794563

    Article  PubMed  CAS  Google Scholar 

  • Vítek L, Tiribelli C (2020) Bilirubin, intestinal integrity, the microbiome, and inflammation. N Engl J Med 383:684–686

    Article  PubMed  Google Scholar 

  • Wang J, Lin S, Brown JM, van Wagoner D, Fiocchi C, Rieder F (2021) Novel mechanisms and clinical trial endpoints in intestinal fibrosis. Immunol Rev 302:211–227

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang X, Hu H, Hu B, Xia H, Cheng X, Zheng J, Zhang Z, Liu H (2023a) Dihydromyricetin inhibits hepatitis B virus replication by activating NF-κB, MAPKs, and autophagy in HepG2.2.15 cells. Mol Biol Rep 50:1403–1414

    Article  PubMed  CAS  Google Scholar 

  • Wang Z, Cao Z, Yue Z, Yang Z (2023) Research progress of dihydromyricetin in the treatment of diabetes mellitus. Front Endocrinol. 14:1216907

    Article  Google Scholar 

  • Wu X, Lin X, Tan J, Liu Z, He J, Hu F, Wang Y, Chen M, Liu F, Mao R (2023) Cellular and molecular mechanisms of intestinal fibrosis. Gut and Liver 17:360–374

    Article  PubMed  PubMed Central  Google Scholar 

  • Xia Y, Lu Y, Qian S, Zhang J, Gao Y, Wei Y, Heng W (2023) An efficient cocrystallization strategy for separation of dihydromyricetin from vine tea and enhanced its antibacterial activity for food preserving application. Food Chem. 426:136525

    Article  PubMed  CAS  Google Scholar 

  • Xiao T, Wei Y, Cui M, Li X, Ruan H, Zhang L, Bao J, Ren S, Gao D, Wang M et al (2021) Effect of dihydromyricetin on SARS-CoV-2 viral replication and pulmonary inflammation and fibrosis. Phytomedicine. 91:153704

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xiu AY, Ding Q, Li Z, Zhang CQ (2021) Doxazosin attenuates liver fibrosis by inhibiting autophagy in hepatic stellate cells via activation of the PI3K/Akt/mTOR signaling pathway. Drug Des Devel Ther 15:3643–3659

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang M, Zhang Q, Taha R, Abdelmotalab MI, Wen Q, Yuan Y, Zhao Y, Li Q, Liao C, Huang X et al (2022) Polysaccharide from Atractylodes macrocephala Koidz. ameliorates DSS-induced colitis in mice by regulating the Th17/Treg cell balance. Front Immunol. 13:1021695

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zeng C, Liu X, Xiong D, Zou K, Bai T (2022) Resolvin D1 prevents epithelial-to-mesenchymal transition and reduces collagen deposition by stimulating autophagy in intestinal fibrosis. Dig Dis Sci 67:4749–4759

    Article  PubMed  CAS  Google Scholar 

  • Zhang Q, Zhao Y, Zhang M, Zhang Y, Ji H, Shen L (2021) Recent advances in research on vine tea, a potential and functional herbal tea with dihydromyricetin and myricetin as major bioactive compounds. J Pharm Anal 11:555–563

    Article  PubMed  CAS  Google Scholar 

  • Zhou J, Jiang YY, Chen H, Wu YC, Zhang L (2020) Tanshinone I attenuates the malignant biological properties of ovarian cancer by inducing apoptosis and autophagy via the inactivation of PI3K/AKT/mTOR pathway. Cell Prolif. 53:e12739

    Article  PubMed  Google Scholar 

  • Zhou X, Yu L, Zhou M, Hou P, Yi L, Mi M (2021) Dihydromyricetin ameliorates liver fibrosis via inhibition of hepatic stellate cells by inducing autophagy and natural killer cell-mediated killing effect. Nutr Metab (Lond). 18:64

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to thank the Cuiying Platform of Lanzhou University Second Hospital for the experimental instruments and KetengEdit for linguistic assistance during the preparation of this manuscript.

Funding

This study was supported by the Gansu Province Health Industry Project (No. GSWSKY2017-01), Lanzhou Talent Innovation and Entrepreneurship Project (No. 2018-RC-76), and Gansu Provincial People’s Hospital Science and technology innovation platform fund project (No. ZX-62000001–2021-136).

Author information

Authors and Affiliations

  1. The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China

    XiaoChun Wang, XiaoLi Li, XueNi Ma & LuDan Zhang

  2. Department of Gastroenterology, Gansu Provincial Hospital, Lanzhou, 730000, China

    XiaoChun Wang

  3. Key Laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, 730000, China

    TiYun Han & DeKui Zhang

  4. Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, 730000, China

    DeKui Zhang

Authors
  1. XiaoChun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. XiaoLi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. XueNi Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. LuDan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. TiYun Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. DeKui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D K ZH and T Y H designed the study. X CH W performed the experiments, analyzed the data, and wrote the manuscript. L D ZH and X N M performed some animal experiments. X L L guided the execution of the experiment. X L L and X N M revised the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to DeKui Zhang.

Ethics declarations

Ethical approval

All procedures involving animals were approved by the Animal Care and Use Committee (No: D2021–173) of the Lanzhou University Second Hospital.

Competing interests

The authors declare no competing interests.

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 7382 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

Wang, X., Li, X., Ma, X. et al. Dihydromyricetin alleviates inflammatory bowel disease associated intestinal fibrosis by inducing autophagy through the PI3K/AKT/mTOR signaling pathway. Naunyn-Schmiedeberg's Arch Pharmacol (2023). https://doi.org/10.1007/s00210-023-02856-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00210-023-02856-0

Keywords

Search

Navigation