Planta Med 2023; 89(03): 254-261
DOI: 10.1055/a-1939-7417
Biological and Pharmacological Activity
Original Papers

Berberine Regulates GPX4 to Inhibit Ferroptosis of Islet β Cells

Lei Bao‡
Department of Endocrinology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, Jiangsu Province, China
,
Yixuan Jin‡
Department of Endocrinology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, Jiangsu Province, China
,
Jiani Han
Department of Endocrinology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, Jiangsu Province, China
,
Wanqiu Wang
Department of Endocrinology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, Jiangsu Province, China
,
Lingling Qian
Department of Endocrinology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, Jiangsu Province, China
,
Weiming Wu 
Department of Endocrinology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, Jiangsu Province, China
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Abstract

Ferroptosis, as a kind of non-apoptotic cell death, is involved in the pathogenesis of type 1 diabetes mellitus (T1DM). Islet B cells mainly produce insulin that is used to treat diabetes. Berberine (BBR) can ameliorate type 2 diabetes and insulin resistance in many ways. However, a few clues concerning the mechanism of BBR regulating ferroptosis of islet β cells in T1DM have been detected so far. We measured the effects of BBR and GPX4 on islet β cell viability and proliferation by MTT and colony formation assays. Western blot and qRT-PCR were utilized to examine GPX4 expression in islet β cells with distinct treatments. The influence of BBR and GPX4 on ferroptosis of islet β cells was investigated by evaluating the content of Fe2+ and reactive oxygen species (ROS) in cells. The mechanism of BBR targeting GPX4 to inhibit ferroptosis of islet β cells was further revealed by the rescue experiment. Our results showed that BBR and overexpression of GPX4 could notably accelerate cell viability and the proliferative abilities of islet β cells. Moreover, BBR stimulated GPX4 expression to reduce the content of Fe2+ and ROS, thereby repressing the ferroptosis of islet β cells, which functioned similarly as ferroptosis inhibitor Fer-1. In conclusion, BBR suppressed ferroptosis of islet β cells via promoting GPX4 expression, providing new insights into the mechanism of BBR for islet β cells.

Key words

berberine - GPX4 - type I diabetes mellitus - islet β cells - ferroptosis

Supporting Information

    Fig. 1S: BBR acting on RSL3 promotes islet β-cell proliferation and inhibits islet β-cell ferroptosis.

  • Supporting Information


Publication History

Received: 25 February 2022

Accepted after revision: 15 August 2022

Article published online:
09 November 2022

© 2022. Thieme. All rights reserved.

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  • References

  • 1 Ogurtsova K, da Rocha Fernandes JD, Huang Y, Linnenkamp U, Guariguata L, Cho NH, Cavan D, Shaw JE, Makaroff LE. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract 2017; 128: 40-50
    CrossrefPubMedGoogle Scholar
  • 2 Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014; 103: 137-149
    CrossrefPubMedGoogle Scholar
  • 3 Norris JM, Johnson RK, Stene LC. Type 1 diabetes-early life origins and changing epidemiology. Lancet Diabetes Endocrinol 2020; 8: 226-238
    CrossrefPubMedGoogle Scholar
  • 4 American Diabetes Association. (2) Classification and diagnosis of diabetes. Diabetes Care 2015; 38: S8-S16
    CrossrefPubMedGoogle Scholar
  • 5 Weng J, Zhou Z, Guo L, Zhu D, Ji L, Luo X, Mu Y, Jia W. T1D China Study Group. Incidence of type 1 diabetes in China, 2010–13: Population based study. BMJ 2018; 360: j5295
    CrossrefPubMedGoogle Scholar
  • 6 Cerna M. Epigenetic regulation in etiology of type 1 diabetes mellitus. Int J Mol Sci 2019; 21: 36
    CrossrefPubMedGoogle Scholar
  • 7 Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapy of type 1 diabetes. Exp Clin Endocrinol Diabetes 2019; 127: S27-S38
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Anderson MS, Bluestone JA. The NOD mouse: A model of immune dysregulation. Annu Rev Immunol 2005; 23: 447-485
    CrossrefPubMedGoogle Scholar
  • 9 Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 2010; 464: 1293-1300
    CrossrefPubMedGoogle Scholar
  • 10 Vauzelle-Kervroedan F, Delcourt C, Forhan A, Jougla E, Hatton F, Papoz L. Analysis of mortality in French diabetic patients from death certificates: A comparative study. Diabetes Metab 1999; 25: 404-411
    PubMedGoogle Scholar
  • 11 Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: The Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 2003; 290: 2159-2167
    CrossrefPubMedGoogle Scholar
  • 12 Maahs DM, Rewers M. Editorial: Mortality and renal disease in type 1 diabetes mellitus–progress made, more to be done. J Clin Endocrinol Metab 2006; 91: 3757-3759
    CrossrefPubMedGoogle Scholar
  • 13 Pang B, Zhao LH, Zhou Q, Zhao TY, Wang H, Gu CJ, Tong XL. Application of berberine on treating type 2 diabetes mellitus. Int J Endocrinol 2015; 2015: 905749
    CrossrefPubMedGoogle Scholar
  • 14 Li WL, Zheng HC, Bukuru J, De Kimpe N. Natural medicines used in the traditional Chinese medical system for therapy of diabetes mellitus. J Ethnopharmacol 2004; 92: 1-21
    CrossrefPubMedGoogle Scholar
  • 15 El-Kaissi S, Sherbeeni S. Pharmacological management of type 2 diabetes mellitus: An update. Curr Diabetes Rev 2011; 7: 392-405
    CrossrefPubMedGoogle Scholar
  • 16 Baska A, Leis K, Galazka P. Berberine in the treatment of diabetes mellitus: A review. Endocr Metab Immune Disord Drug Targets 2021; 21: 1379-1386
    CrossrefPubMedGoogle Scholar
  • 17 Li W, Li D, Kuang H, Feng X, Ai W, Wang Y, Shi S, Chen J, Fan R. Berberine increases glucose uptake and intracellular ROS levels by promoting Sirtuin 3 ubiquitination. Biomed Pharmacother 2020; 121: 109563
    CrossrefPubMedGoogle Scholar
  • 18 Qin X, Jiang M, Zhao Y, Gong J, Su H, Yuan F, Fang K, Yuan X, Yu X, Dong H, Lu F. Berberine protects against diabetic kidney disease via promoting PGC-1alpha-regulated mitochondrial energy homeostasis. Br J Pharmacol 2020; 177: 3646-3661
    CrossrefPubMedGoogle Scholar
  • 19 Yao Y, Chen H, Yan L, Wang W, Wang D. Berberine alleviates type 2 diabetic symptoms by altering gut microbiota and reducing aromatic amino acids. Biomed Pharmacother 2020; 131: 110669
    CrossrefPubMedGoogle Scholar
  • 20 Hou Y, Cai S, Yu S, Lin H. Metformin induces ferroptosis by targeting miR-324-3p/GPX4 axis in breast cancer. Acta Biochim Biophys Sin (Shanghai) 2021; 53: 333-341
    CrossrefPubMedGoogle Scholar
  • 21 Zhou B, Liu J, Kang R, Klionsky DJ, Kroemer G, Tang D. Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol 2020; 66: 89-100
    CrossrefPubMedGoogle Scholar
  • 22 Liu J, Cheng C, Jiao J, Huang W, Huang J, Sun J, Shao J. MircoRNA-129-5p suppresses the development of glioma by targeting HOXC10. Pathol Res Pract 2020; 216: 152868
    CrossrefPubMedGoogle Scholar
  • 23 Geng N, Shi BJ, Li SL, Zhong ZY, Li YC, Xua WL, Zhou H, Cai JH. Knockdown of ferroportin accelerates erastin-induced ferroptosis in neuroblastoma cells. Eur Rev Med Pharmacol Sci 2018; 22: 3826-3836
    PubMedGoogle Scholar
  • 24 Shintoku R, Takigawa Y, Yamada K, Kubota C, Yoshimoto Y, Takeuchi T, Koshiishi I, Torii S. Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3. Cancer Sci 2017; 108: 2187-2194
    CrossrefPubMedGoogle Scholar
  • 25 Lu B, Chen XB, Hong YC, Zhu H, He QJ, Yang B, Ying MD, Cao J. Identification of PRDX6 as a regulator of ferroptosis. Acta Pharmacol Sin 2019; 40: 1334-1342
    CrossrefPubMedGoogle Scholar
  • 26 Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison 3rd B, Stockwell BR. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012; 149: 1060-1072
    CrossrefPubMedGoogle Scholar
  • 27 Liu P, Feng Y, Li H, Chen X, Wang G, Xu S, Li Y, Zhao L. Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis. Cell Mol Biol Lett 2020; 25: 10
    CrossrefPubMedGoogle Scholar
  • 28 Li D, Jiang C, Mei G, Zhao Y, Chen L, Liu J, Tang Y, Gao C, Yao P. Quercetin alleviates ferroptosis of pancreatic β cells in type 2 diabetes. Nutrients 2020; 12: 2954
    CrossrefPubMedGoogle Scholar
  • 29 El-Mokhtar MA, Elsherbiny NM, Sayed D, Raafat DM, Askar E, Hussein A, Abdel-Malek MAY, Shalaby AM. Altered regulatory B cell subsets in children with type 1 diabetes mellitus. J Immunol Res 2020; 2020: 8935694
    PubMedGoogle Scholar
  • 30 Stiner R, Alexander M, Liu G, Liao W, Liu Y, Yu J, Pone EJ, Zhao W, Lakey JRT. Transplantation of stem cells from umbilical cord blood as therapy for type I diabetes. Cell Tissue Res 2019; 378: 155-162
    CrossrefPubMedGoogle Scholar
  • 31 Suadoni MT, Atherton I. Berberine for the treatment of hypertension: A systematic review. Complement Ther Clin Pract 2021; 42: 101287
    CrossrefPubMedGoogle Scholar
  • 32 Feng X, Sureda A, Jafari S, Memariani Z, Tewari D, Annunziata G, Barrea L, Hassan STS, Šmejkal K, Malaník M, Sychrová A, Barreca D, Ziberna L, Mahomoodally MF, Zengin G, Xu S, Nabavi SM, Shen AZ. Berberine in cardiovascular and metabolic diseases: From mechanisms to therapeutics. Theranostics 2019; 9: 1923-1951
    CrossrefPubMedGoogle Scholar
  • 33 Memon MA, Khan RN, Riaz S, Ain QU, Ahmed M, Kumar N. Methylglyoxal and insulin resistance in berberine-treated type 2 diabetic patients. J Res Med Sci 2018; 23: 110
    CrossrefPubMedGoogle Scholar
  • 34 Chueh WH, Lin JY. Berberine, an isoquinoline alkaloid in herbal plants, protects pancreatic islets and serum lipids in nonobese diabetic mice. J Agric Food Chem 2011; 59: 8021-8027
    CrossrefPubMedGoogle Scholar
  • 35 Chueh WH, Lin JY. Protective effect of berberine on serum glucose levels in non-obese diabetic mice. Int Immunopharmacol 2012; 12: 534-538
    CrossrefPubMedGoogle Scholar
  • 36 Cui G, Qin X, Zhang Y, Gong Z, Ge B, Zang YQ. Berberine differentially modulates the activities of ERK, p38 MAPK, and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic mice. J Biol Chem 2009; 284: 28420-28429
    CrossrefPubMedGoogle Scholar
  • 37 Ko BS, Choi SB, Park SK, Jang JS, Kim YE, Park S. Insulin sensitizing and insulinotropic action of berberine from Cortidis rhizoma. Biol Pharm Bull 2005; 28: 1431-1437
    CrossrefPubMedGoogle Scholar
  • 38 Wu YS, Li ZM, Chen YT, Dai SJ, Zhou XJ, Yang YX, Lou JS, Ji LT, Bao YT, Xuan L, Lin LN, Li CY. Berberine improves inflammatory responses of diabetes mellitus in zucker diabetic fatty rats and insulin-resistant HepG2 cells through the PPM1B pathway. J Immunol Res 2020; 2020: 2141508
    PubMedGoogle Scholar
  • 39 Krümmel B, Plötz T, Jörns A, Lenzen S, Mehmeti I. The central role of glutathione peroxidase 4 in the regulation of ferroptosis and its implications for pro-inflammatory cytokine-mediated beta-cell death. Biochim Biophys Acta Mol Basis Dis 2021; 1867: 166114
    CrossrefPubMedGoogle Scholar
  • 40 Lv X, Zhao Y, Yang X, Han H, Ge Y, Zhang M, Zhang H, Zhang M, Chen L. Berberine potentiates insulin secretion and prevents β-cell dysfunction through the miR-204/SIRT1 signaling pathway. Front Pharmacol 2021; 12: 720866
    CrossrefPubMedGoogle Scholar