Abstract
Cardiac failure accounts for many deaths worldwide. Increasing experimental evidence suggests that exposure to chemicals such as bisphenol-S (BPS) and diethyl phthalate (DEP) exacerbate cardiac injuries. Morin is a flavonoid with reported cardioprotective activity. This study evaluated the modulation of pathways relevant to cardiac endothelial function in rats exposed to BPS and DEP mixture (Mix). Thirty male albino rats were distributed across five groups (n = 6): control received dimethyl sulfoxide (DMSO) as vehicle, Mix dissolved in DMSO, Mix + morin (25 mg/kg), Mix + morin (50 mg/kg), and morin (50 mg/kg). After 21 days of oral exposure at 1 ml/kg bodyweight of the Mix and treatment with morin, the animals were sacrificed, and their hearts were excised for biochemical, histological, immunohistochemical, and gene expression analyses. Exposure to the Mix caused a significant increase in oxidative stress indices (H2O2, malondialdehyde, DNA fragmentation, and advanced oxidation protein products). Also, arginase, phosphodiesterase 5′, and the relative expression of TNF-α, interleukin-1β, Bax, androgen receptor, and vascular endothelial growth factor were markedly increased. In contrast, nitric oxide, reduced glutathione, interleukin-10 levels, superoxide dismutase, catalase, and glutathione peroxidase activities decreased significantly. Furthermore, p-NF-kB-p65 expression increased markedly in the Mix-exposed group. Morin treatment significantly reversed these perturbations in a dose-dependent manner in most instances. This study concludes that morin might offer a cardioprotective effect by enhancing the cardiac endothelial system and attenuating oxidative stress, inflammation, and apoptosis elicited by BPS and DEP co-exposure in male Wistar rats.
Similar content being viewed by others
Data Availability
Data that are not in the supplementary file are available on request.
References
Centre for Disease Control and Prevention (CDC). 2022. https://www.cdc.gov/heartdisease/facts.htm . Assessed 14th march 2022; 16:38 WAT.
Adegoke, O., N.A. Awolola, and J.N. Ajuluchukwu. 2018. Prevalence and pattern of cardiovascular-related causes of out-of-hospital deaths in Lagos, Nigeria. African Health Sciences 18: 942–949.
Mozaffarian, D., E.J. Benjamin, A.S. Go, D.K. Arnett, M.J. Blaha, M. Cushman, S.R. Das, S. De Ferranti, J.P. Després, H.J. Fullerton, and V.J. Howard. 2016. Heart disease and stroke statistics—2016 update: A report from the American Heart Association. Circulation 133 (4): e38–e360.
Savarese, G., and L.H. Lund. 2017. Global public health burden of heart failure. Cardiac failure review 3 (1): 7.
Gallagher, J., K. McDonald, M. Ledwidge, and C.J. Watson. 2018. Heart failure in sub-Saharan Africa. Cardiac failure review 4 (1): 21–24.
Perera, L., Y. Li, L.A. Coons, R. Houtman, R. van Beuningen, B. Goodwin, S.S. Auerbach, and C.T. Teng. 2017. Binding of bisphenol A, bisphenol AF, and bisphenol S on the androgen receptor: Coregulator recruitment and stimulation of potential interaction sites. Toxicology in Vitro 44: 287–302.
Tham, Y.K., B.C. Bernardo, J.Y. Ooi, K.L. Weeks, and J.R. McMullen. 2015. Pathophysiology of cardiac hypertrophy and heart failure: Signaling pathways and novel therapeutic targets. Archives of toxicology 89: 1401–1438.
Pradhan, A., P.E. Olsson, and J. Jass. 2018. Di (2-ethylhexyl) phthalate and diethyl phthalate disrupt lipid metabolism, reduce fecundity and shortens lifespan of Caenorhabditis elegans. Chemosphere 190: 375–382.
Ferguson, M., I. Lorenzen-Schmidt, and W.G. Pyle. 2019. Bisphenol S rapidly depresses heart function through estrogen receptor-β and decreases phospholamban phosphorylation in a sex-dependent manner. Scientific reports 9: 1–12.
Howard, G.J. 2014. Chemical alternatives assessment: The case of flame retardants. Chemosphere 116: 112–117.
Kirkley, A.G., and R.M. Sargis. 2014. Environmental endocrine disruption of energy metabolism and cardiovascular risk. Current diabetes reports 14: 1–15.
Inserte, J., and D. Garcia-Dorado. 2015. The cGMP/PKG pathway as a common mediator of cardioprotection: Translatability and mechanism. British Journal of Pharmacology 172: 1996–2009.
Inserte, J., V. Hernando, Ú. Vilardosa, E. Abad, M. Poncelas-Nozal, and D. Garcia-Dorado. 2013. Activation of cGMP/protein kinase G pathway in postconditioned myocardium depends on reduced oxidative stress and preserved endothelial nitric oxide synthase coupling. Journal of the American Heart Association 2: e005975.
Kim, N.H., and P.M. Kang. 2010. Apoptosis in cardiovascular diseases: Mechanism and clinical implications. Korean circulation journal 40: 299–305.
Senoner, T., and W. Dichtl. 2019. Oxidative stress in cardiovascular diseases: Still a therapeutic target? Nutrients 11: 2090–2097.
Pogula, B.K., M.K. Maharajan, D.R. Oddepalli, L. Boini, M. Arella, and D.Q. Sabarimuthu. 2012. Morin protects heart from beta-adrenergic-stimulated myocardial infarction: An electrocardiographic, biochemical, and histological study in rats. Journal of physiology and biochemistry 68: 433–446.
Verma, V.K., S. Malik, S.P. Narayanan, E. Mutneja, A.K. Sahu, J. Bhatia, and D.S. Arya. 2019. Role of MAPK/NF-κB pathway in cardioprotective effect of Morin in isoproterenol induced myocardial injury in rats. Molecular biology reports 46: 1139–1148.
Nair, P.S., and C.S. Devi. 2006. Efficacy of mangiferin on serum and heart tissue lipids in rats subjected to isoproterenol induced cardiotoxicity. Toxicology 228: 135–139.
Liu, S., N. Wu, J. Miao, Z. Huang, X. Li, P. Jia, Y. Guo, and D. Jia. 2018. Protective effect of morin on myocardial ischemia reperfusion injury in rats. International Journal of Molecular Medicine 42: 1379–1390.
Baralić, K., A. Buha Djordjevic, K. Živančević, E. Antonijević, M. Anđelković, D. Javorac, M. Ćurčić, Z. Bulat, B. Antonijević, and D. Đukić-Ćosić. 2020. Toxic effects of the mixture of phthalates and bisphenol a—subacute oral toxicity study in wistar rats. International journal of environmental research and public health 17: 746.
Percie du Sert, N., V. Hurst, A. Ahluwalia, S. Alam, M.T. Avey, M. Baker, W.J. Browne, A. Clark, I.C. Cuthill, U. Dirnagl, and M. Emerson. 2020. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. Journal of Cerebral Blood Flow & Metabolism 40: 1769–1777.
Catanese, M.C., and L.N. Vandenberg. 2017. Bisphenol S (BPS) alters maternal behavior and brain in mice exposed during pregnancy/lactation and their daughters. Endocrinology 158: 516–530.
Ahmadpour, D., S. Mhaouty-Kodja, and V. Grange-Messent. 2021. Disruption of the blood-brain barrier and its close environment following adult exposure to low doses of di (2-ethylhexyl) phthalate alone or in an environmental phthalate mixture in male mice. Chemosphere 282: 131013.
Ben-Azu, B., O. Emokpae, A.M. Ajayi, T.A. Jarikre, V. Orhode, A.O. Aderibigbe, S. Umukoro, and E.O. Iwalewa. 2020. Repeated psychosocial stress causes glutamic acid decarboxylase isoform-67, oxidative-Nox-2 changes and neuroinflammation in mice: Prevention by treatment with a neuroactive flavonoid, morin. Brain Research 1744: 146917.
Liu, J., L. Zhang, G. Lu, R. Jiang, Z. Yan, and Y. Li. 2021. Occurrence, toxicity and ecological risk of bisphenol A analogues in aquatic environment–a review. Ecotoxicology and Environmental Safety 208: 111481.
Choi, Y.A., Y.H. Yoon, K. Choi, M. Kwon, S.H. Goo, J.S. Cha, M.K. Choi, H.S. Lee, and I.S. Song. 2015. Enhanced oral bioavailability of morin administered in mixed micelle formulation with PluronicF127 and Tween80 in rats. Biological and Pharmaceutical Bulletin 38 (2): 208–217.
Blevins, J.E., B.G. Stanley, and R.D. Reidelberger. 2002. DMSO as a vehicle for central injections: Tests with feeding elicited by norepinephrine injected into the paraventricular nucleus. Pharmacology Biochemistry and Behavior. 71 (1–2): 277–282.
Oguntoye, C.O., and B.O. Oke. 2014. A comparison of xylazine/ketamine, diazepam/ketamine and acepromazine/ketamine anaesthesia in rabbit. Sokoto Journal of Veterinary Sciences. 12 (3): 21–25.
Beuge, J.A., and S.D. Aust. 1978. Estimation of serum malondialdehyde level. Methods in enzymology Hoffee Jones edt. By Hoffee PA and Jone ME. Academic Press, a Subsidinary of Harcoart Brace Jovanovich Publisher, New York.
Junglee, S., L. Urban, H. Sallanon, and F. Lopez-Lauri. 2014. Optimized assay for hydrogen peroxide determination in plant tissue using potassium iodide. American Journal of Analytical Chemistry 5: 730.
Witko-Sarsat, V., M. Friedlander, C. Capeillère-Blandin, T. Nguyen-Khoa, A.T. Nguyen, J. Zingraff, P. Jungers, and B. Descamps-Latscha. 1996. Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney international 49: 1304–1313.
Gercel-Taylor, C. 2005. Diphenylamine assay of DNA fragmentation for chemosensitivity testing. In Chemosensitivity: Volume II (79–82). Humana Press, Totowa, NJ.
Shangari, N., and P.J. O’Brien. 2006. Catalase activity assays. Current protocols in toxicology 27: 7–7.
Ellman, G.L. 1959. Tissue sulfhydryl groups. Archives of biochemistry and biophysics 82 (1): 70–77.
Rotruck, J.T., A.L. Pope, H.E. Ganther, A.B. Swanson, D.G. Hafeman, and W. Hoekstra. 1973. Selenium: Biochemical role as a component of glutathione peroxidase. Science 179: 588–590.
Marklund, S., and G. Marklund. 1974. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. European journal of biochemistry 47: 469–474.
Rao, M.N.A. 1997. Nitric oxide scavenging by curcuminoids. Journal of pharmacy and Pharmacology 49: 105–107.
Zhang, X., L. Shen, F. Li, D. Meng, and J. Sheng. 2013. Arginase induction by heat treatment contributes to amelioration of chilling injury and activation of antioxidant enzymes in tomato fruit. Postharvest Biology and Technology 79: 1–8.
Ademosun, A.O., A. Mohammed, G. Oboh, and O.F. Ajeigbe, 2022. Influence of lemon (Citrus limon) and lime (Citrus aurantifolia) juices on the erectogenic properties of sildenafil in rats with L‐NAME‐induced erectile dysfunction. Journal of Food Biochemistry p.e14074.
Ugbaja, R.N., A.S. James, E.I. Ugwor, A.J. Akamo, F.C. Thomas, and A.M. Kosoko. 2021. Lycopene suppresses palmitic acid-induced brain oxidative stress, hyperactivity of some neuro-signalling enzymes, and inflammation in female Wistar rat. Scientific reports 11: 1–13.
Ugbaja, R.N., K. Ogungbemi, A.S. James, A. Peter Folorunsho, S.O. Abolade, S.O. Ajamikoko, E.O. Atayese, and O.V. Adedeji. 2021. Chitosan from crabs (Scylla serrata) represses hyperlipidemia-induced hepato-renal dysfunctions in rats: Modulation of CD43 and p53 expression. Pathophysiology 28: 224–237.
Onuoha, N.O., N.O. Ogbusua, N.J. Uwaezuoke, and C.E. Ejike. 2017. Tigernut (Cyperus esculentus L) milk’reverses acetaminophen-induced hepatotoxicity in a murine model. Nutrafoods 16: 166–174.
Hall, J.M., and C.W. Greco. 2019. Perturbation of nuclear hormone receptors by endocrine disrupting chemicals: Mechanisms and pathological consequences of exposure. Cells 9: 13.
Song, Y., P. Xie, and Z. Cai. 2018. Metabolism of bisphenol S in mice after oral administration. Rapid Communications in Mass Spectrometry 32: 495–502.
Wang, H., Q. Yao, S. Zhu, G. Zhang, Z. Wang, Z. Li, R. Sun, C. Lu, C. Li, and J. Pu. 2014. The autopsy study of 553 cases of sudden cardiac death in Chinese adults. Heart and vessels 29: 486–495.
Liu, S.X., F.F. Hou, Z.J. Guo, R. Nagai, W.R. Zhang, Z.Q. Liu, Z.M. Zhou, M. Zhou, D. Xie, G.B. Wang, and X. Zhang. 2006. Advanced oxidation protein products accelerate atherosclerosis through promoting oxidative stress and inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology 26 (5): 1156–1162.
Amin, A., and A.A. Hamza. 2005. Oxidative stress mediates drug-induced hepatotoxicity in rats: A possible role of DNA fragmentation. Toxicology 208: 367–375.
Nagata, S. 2000. Apoptotic DNA fragmentation. Experimental cell research 256: 12–18.
Kok, L.D.S., Y.P. Wong, T.W. Wu, H.C. Chan, T.T. Kwok, and K.P. Fung. 2000. Morin hydrate: A potential antioxidant in minimizing the free-radicals-mediated damage to cardiovascular cells by anti-tumor drugs. Life sciences 67: 91–99.
Bresciani, G., I.B.M. da Cruz, and J. González-Gallego. 2015. Manganese superoxide dismutase and oxidative stress modulation. Advances in clinical chemistry 68: 87–130.
WenJun, L., G. JianPeng, W. GuanYing, Z. LuSheng, W. JinHua, and W. Jun. 2017. Oxidating stress and DNA damage of DEHP to soil earthworms. Acta Pedologica Sinica 54: 1170–1180.
Caselli, A., P. Cirri, A. Santi, and P. Paoli. 2016. Morin: A promising natural drug. Current medicinal chemistry 23: 774–791.
Pernow, J., and C. Jung. 2013. Arginase as a potential target in the treatment of cardiovascular disease: Reversal of arginine steal. Cardiovascular research 98: 334–343.
Lugnier, C. 2006. Cyclic nucleotide phosphodiesterase (PDE) superfamily: A new target for the development of specific therapeutic agents. Pharmacology & therapeutics 109: 366–398.
Oboh, G., A.A. Adebayo, A.O. Ademosun, and A.A. Boligon. 2017. In vitro inhibition of phosphodiesterase-5 and arginase activities from rat penile tissue by two Nigerian herbs (Hunteria umbellata and Anogeissus leiocarpus). Journal of basic and clinical physiology and pharmacology 28: 393–401.
Smiljic, S. 2017. The clinical significance of endocardial endothelial dysfunction. Medicina 53: 295–302.
Taguchi, K., I. Tano, N. Kaneko, T. Matsumoto, and T. Kobayashi. 2020. Plant polyphenols Morin and Quercetin rescue nitric oxide production in diabetic mouse aorta through distinct pathways. Biomedicine & Pharmacotherapy 129: 110463.
Liu, Q., Y. Chen, M. Auger-Messier, and J.D. Molkentin. 2012. Interaction between NFκB and NFAT coordinates cardiac hypertrophy and pathological remodeling. Circulation research 110: 1077–1086.
Braile, M., S. Marcella, L. Cristinziano, M.R. Galdiero, L. Modestino, A.L. Ferrara, G. Varricchi, G. Marone, and S. Loffredo. 2020. VEGF-A in cardiomyocytes and heart diseases. International Journal of Molecular Sciences 21: 5294.
Ramalingam, P., M.G. Poulos, E. Lazzari, M.C. Gutkin, D. Lopez, C.C. Kloss, M.J. Crowley, L. Katsnelson, A.G. Freire, M.B. Greenblatt, and C.Y. Park. 2020. Chronic activation of endothelial MAPK disrupts hematopoiesis via NFKB dependent inflammatory stress reversible by SCGF. Nature communications 11: 1–20.
Zhang, L., S. Altuwaijri, F. Deng, L. Chen, P. Lal, U.K. Bhanot, R. Korets, S. Wenske, H.G. Lilja, C. Chang, and H.I. Scher. 2009. NF-κB regulates androgen receptor expression and prostate cancer growth. The American journal of pathology 175: 489–499.
Jodynis-Liebert, J., and M. Kujawska. 2020. Biphasic dose-response induced by phytochemicals: Experimental evidence. Journal of Clinical Medicine 9 (3): 718.
Sotler, R., B. Poljšak, R. Dahmane, T. Jukić, D. Pavan Jukić, C. Rotim, P. Trebše, and A. Starc, 2019. Prooxidant activities of antioxidants and their impact on health. Acta clinica Croatica 58 (4): 726–736.
Acknowledgements
We acknowledge the efforts of the laboratory staffs of the Department of Biochemistry, Federal University of Agriculture, Abeokuta.
Author information
Authors and Affiliations
Contributions
ASJ and EIU prepared the manuscript and did formal analyses, and collected the data; OEE conceptualized the study; OAD and RNU supervised the study and provided resources; CAM sourced for resources and cured data; CUO and OAA got methodology; BCO, RFF, and AMO did the project. All the authors read the manuscript.
Corresponding author
Ethics declarations
Ethical Approval
Ethical approval was obtained from the Departmental Ethical Committee, Federal University of Agriculture, Abeokuta (approval number: FUNAAB/CBS/BCH/SP/2725–21).
Consent for Publication
All authors have read the manuscript and authorize its publication.
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.
Rights and permissions
Springer Nature or its licensor 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.
About this article
Cite this article
James, A.S., Eteng, O.E., Dosumu, O.A. et al. Morin Augmented Myocardial eNOS/cGMP/PKG Signaling Pathway and Abated Oxidative and Inflammo-apoptotic Responses in Diethyl Phthalate and Bisphenol-S Co-Exposed Male Albino Rats. Inflammation 46, 175–189 (2023). https://doi.org/10.1007/s10753-022-01720-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10753-022-01720-2