Caesalpinia digyna root extract and bergenin alleviate myocardial infarction in rats by modulating oxidative stress, inflammation, and fibrotic pathways

Abstract

Objective: To evaluate the cardioprotective potential of Caesalpinia digyna root extract (CDRE) and its major bioactive constituent, bergenin, against isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Methods: CDRE was prepared via methanolic extraction and standardized using RP-HPLC. MI was induced in Sprague-Dawley rats by ISO administration. Animals were pretreated with the extract and bergenin prior to the ISO challenge. Cardioprotective effects were assessed by measuring serum cardiac biomarkers, evaluating myocardial hypertrophy, inflammation, and fibrosis, and determining the expression of Nrf2, FGF21, NF-κB p65, and brain natriuretic peptide. Results: Pretreatment with the CDRE and bergenin significantly attenuated ISO-induced MI, as evidenced by reduced creatine kinase-MB and lactate dehydrogenase levels and improved histopathological architecture. CDRE and bergenin markedly alleviated myocardial hypertrophy, inflammatory infiltration, and fibrotic changes. They also upregulated Nrf2 and FGF21 expression, and downregulated NF-κB p65 and brain natriuretic peptide expression. Conclusions: The findings demonstrate significant cardioprotective effects of CDRE and bergenin, by modulating oxidative stress, inflammation, and fibrotic pathways, validating its traditional use for the management of MI.

Keywords

Caesalpinia digyna / Bergenin / Isoproterenol / Myocardial infarction / Myocardial damage

References

[1] Gaidai O, Cao Y, Loginov S. Global cardiovascular diseases death rate prediction. Curr Probl Cardiol 2023; 48(5): 101622.

[2] Chong B, Jayabaskaran J, Jauhari SM, Chan SP, Goh R, Kueh MTW, et al. Global burden of cardiovascular diseases: Projections from 2025 to 2050. Eur J Prev Cardiol 2025; 32(11): 1001-1015.

[3] Welt FGP, Batchelor W, Spears JR, Penna C, Pagliaro P, Ibanez B, et al. Reperfusion injury in patients with acute myocardial infarction: JACC scientific statement. J Am Coll Cardiol 2024; 83(22): 2196-2213.

[4] Buja LM. Pathobiology of myocardial and cardiomyocyte injury in ischemic heart disease: Perspective from seventy years of cell injury research. Exp Mol Pathol 2024; 140: 104944.

[5] Li T, Wang N, Yi D, Xiao Y, Li X, Shao B, et al. ROS-mediated ferroptosis and pyroptosis in cardiomyocytes: An update. Life Sci 2025; 370: 123565.

[6] Abdel-Kareem MA, Osman A, Farage AE, Taha M, Abubakr S, Elshehawy Helal N, et al. The antioxidant, anti-inflammatory, and antiapoptotic effects of royal jelly against isoproterenol-induced myocardial infarction in experimental rats. Eur J Anat 2025; 29(5): 687-698.

[7] Mi X, Zhang Z, Cheng J, Xu Z, Zhu K, Ren Y. Cardioprotective effects of Schisantherin A against isoproterenol-induced acute myocardial infarction through amelioration of oxidative stress and inflammation via modulation of PI3K-AKT/Nrf2/ARE and TLR4/MAPK/NF-κB pathways in rats. BMC Complement Med Ther 2023; 23(1): 277.

[8] Khattak M, Khan IA, Shah N, Abdulsamad SA, Naeem AA, Shah AJ. Shikimic acid, a phenolic acid reverses isoproterenol-induced myocardial infarction in rat model. Phytomedicine Plus 2025; 5(2): 100788.

[9] Ponnian SMP, Stanely SP, Roy AJ. Cardioprotective effects of p-coumaric acid on tachycardia, inflammation, ion pump dysfunction, and electrolyte imbalance in isoproterenol-induced experimental myocardial infarction. J Biochem Mol Toxicol 2024; 38(3): e23668.

[10] Kumar R, Patel DK, Prasad SK, Laloo D, Krishnamurthy S, Hemalatha S. Type 2 antidiabetic activity of bergenin from the roots of Caesalpinia digyna Rottler. Fitoterapia 2012; 83(2): 395-401.

[11] Banerjee P, Maity S, Das T, Mazumder S. A double-blind randomized placebo-controlled clinical study to evaluate the efficacy and safety of a polyherbal formulation in geriatric age group: A phase IV clinical report. J Ethnopharmacol 2011; 134(2): 429.

[12] Bansal A. Cytoprotective and immunomodulatory properties of Geriforte, a herbomineral preparation, in lymphocytes. Phytomedicine 2001; 8(6): 438-444.

[13] Ibáñez B, Melero A, Montoro A, Merino-Torres JF, Soriano JM, San Onofre N. A narrative review of the herbal preparation of Ayurvedic, Traditional Chinese, and Kampo medicines applied as radioprotectors. Antioxidants 2023; 12(7): 1437.

[14] Fatema K, Haque MA, Sharna JF, Patwary MAM, Uddin MN, Kazi M, et al. Combined in vitro and computational studies on the antioxidant and anticancer effects of Caesalpinia digyna (Rottl.) fruit extracts. Nat Sci Rep 2025; 16(1): 193.

[15] Duan C, Qin H, Bi D, Gao Y, Xie H, Dai Q, et al. Caesalpinflavans D-F and caesalpinnone B, hybrid flavan-chalcones and normonoterpene-chalcone heterodimer from Caesalpinia digyna. Phytochemistry 2024; 217: 113925.

[16] Fatema K, Mia MAR, Nipun TS, Hossen SMM. Phytochemical profiling and pharmacological evaluation of methanolic leaf extract of C. digyna for cytotoxic, anti-inflammatory, antioxidant, antiarthritic, and analgesic activities. Food Sci Nutr 2024; 12(12): 10231-10241.

[17] Emon NU, Jahan I, Sayeed MA. Investigation of antinociceptive, anti-inflammatory and thrombolytic activity of Caesalpinia digyna (Rottl.) leaves by experimental and computational approaches. Adv Tradit Med 2020; 20(3): 451-459.

[18] Robbani S, Elya B, Iswandana R. Alpha-glucosidase and DPP-IV inhibitory activities of ethanol extract from Caesalpinia sappan, Andrographis paniculata, and Syzygium cumini. Pharmacogn J 2022; 14(3): 702-709.

[19] Karuna M, Ravindra Babu S. Antihypertensive and antioxidant activity of Caesalpinia digyna Rottler in L-NAME induced hypertensive rats. Indo Am J Pharm Res 2016; 6(1): 6800-6806.

[20] Ahmad T, Haq IU, Khan T, Mahnashi MH, Alasmary MY, Almedhesh SA, et al. Bergenin from Bergenia species produces a protective response against myocardial infarction in rats. Processes 2022; 10(7): 1403.

[21] Jia L, Yang S, Yin J, Feng O, Jia M, Wang Z. Bergenin alleviates myocardial ischemia/reperfusion injury via regulating SIRT1 through ferroptosis. J Inflamm Res 2025; 18: 5519-5531.

[22] Gupta K, Bagang N, Singh G, Laddi L. Rat model of isoproterenol-induced myocardial injury. Methods Mol Biol 2024; 2803: 123-136.

[23] Pham VA, Tran HT, Mai TP, Nguyen LH, Nguyen VH, Nguyen TH, et al. Myocardial infarction model induced by isoproterenol in rats and potential cardiovascular protective effect of a nattokinase-containing hard capsule. Phytomedicine Plus 2023; 3(3): 100472.

[24] Chen Y, Guo X, Zeng Y, Mo X, Hong S, He H, et al. Ferroptosis contributes to catecholamine-induced cardiotoxicity and pathological remodeling. Free Radic Biol Med 2023; 207: 227-238.

[25] Shaboodien S, Payne C, Parker M, Marais E, Johnson R, Maarman G. Cardioprotective effects of Rooibos (Aspalathus linearis) against isoproterenol-induced hypertrophy in H9c2 cardiomyoblasts: Enhancing antioxidative and mitochondrial function. South African J Bot 2025; 177: 211-224.

[26] Chisty TTE, Sarif S, Jahan I, Ismail IN, Chowdhury FI, Siddiqua S, et al. Protective effects of L-carnitine on isoprenaline-induced heart and kidney dysfunctions: Modulation of inflammation and oxidative stress-related gene expression in rats. Heliyon 2024; 10(3): e25057.

[27] Ibrahim RM, Muhammad MH, Soliman AEAE, Khairat EHM, Youssef HS. Cardioprotective impact of L-carnitine against isoprenaline-induced myocardial infarction by focusing on Nrf2/parkin-mediated mitophagy. Bull Egypt Soc Physiol Sci 2025; 45(1): 32-50.

[28] Mahmoud DSE, Kamel MA, El-Sayed IE, Binsuwaidan R, Elmongy EI, Razzaq MK, et al. Astaxanthin ameliorated isoproterenol induced myocardial infarction via improving the mitochondrial function and antioxidant activity in rats. J Biochem Mol Toxicol 2024; 38(8): e23804.

[29] Thangaiyan R, Arjunan S, Govindasamy K, Khan HA, Alhomida AS, Prasad NR. Galangin attenuates isoproterenol-induced inflammation and fibrosis in the cardiac tissue of albino Wistar rats. Front Pharmacol 2020; 11: 585163.

[30] Abukhalil MH, Hussein OE, Aladaileh SH, Althunibat OY, Al-Amarat W, Saghir SA, et al. Visnagin prevents isoproterenol-induced myocardial injury by attenuating oxidative stress and inflammation and upregulating Nrf2 signaling in rats. J Biochem Mol Toxicol 2021; 35(11): e22906.

[31] Althunibat OY, Abduh MS, Abukhalil MH, Aladaileh SH, Hanieh H, Mahmoud AM. Umbelliferone prevents isoproterenol-induced myocardial injury by upregulating Nrf2/HO-1 signaling, and attenuating oxidative stress, inflammation, and cell death in rats. Biomed Pharmacother 2022; 149: 112900.

[32] Qian K, Song L, Guo JM, Fu D, Shi J, Ma Y, et al. Baicalin improves isoproterenol-induced cardiac remodeling by regulating the Nrf2-dependent signaling pathway. BMC Cardiovasc Disord 2024; 24(1): 733.

[33] Ding J, Zhang S, Li Q, Xia B, Wu J, Lu X, et al. Geraniin attenuates isoproterenol-induced cardiac hypertrophy by inhibiting inflammation, oxidative stress and cellular apoptosis. Korean J Physiol Pharmacol 2025; 29(3): 307-319.

[34] Salimo ZM, Yakubu MN, da Silva EL, de Almeida ACG, Chaves YO, Costa EV, et al. Chemistry and pharmacology of bergenin or its derivatives: A promising molecule. Biomolecules 2023; 13(3): 403.

[35] Albadrani GM, BinMowyna MN, Bin-Jumah MN, El-Akabawy G, Aldera H, AL-Farga AM. Quercetin prevents myocardial infarction adverse remodeling in rats by attenuating TGF-β1/Smad3 signaling: Different mechanisms of action. Saudi J Biol Sci 2021; 28(5): 2772-2782.

[36] Nocchi E, Scalzo S, Rocha-Resende C, Almeida P, Parreira A, Miranda K, et al. The Mas agonist CGEN-856S prevents Ang II induced cardiomyocyte hypertrophy via nitric oxide production. Peptides 2024; 175: 171182.

[37] Qian L, Xu H, Yuan R, Yun W, Ma Y. Formononetin ameliorates isoproterenol induced cardiac fibrosis through improving mitochondrial dysfunction. Biomed Pharmacother 2024; 170: 116000.

[38] Sun X, Cao S, Mao C, Sun F, Zhang X, Song Y. Post-translational modifications of p65: State of the art. Front Cell Dev Biol 2024; 12: 1417502.

[39] Li Y, Ha T, Gao X, Kelley J, Williams DL, Browder IW, et al. NF-κB activation is required for the development of cardiac hypertrophy in vivo. Am J Physiol Heart Circ Physiol 2004; 287: H1712-H1720.

[40] Chen L, Gao M, Ong SB, Gong G. Functions of FGF21 and its role in cardiac hypertrophy. J Adv Res 2026; 79: 475-489.

[41] Li Y, Li D, Wang W, Li X, Li P, Zhang Y, et al. Effect of Danhong injection on prognosis and inflammatory factor expression in patients with acute coronary syndrome during the perioperative period of percutaneous coronary intervention: A systematic review and meta-analysis. Front Cardiovasc Med 2022; 9: 1029387.