Cardiotoxicity caused by acrylamide in rats can be alleviated as a result of suppression of oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis by morin treatment

Document Type : Original Article

Authors

1 İstanbul Atlas University, Faculty of Medicine, Department of Emergency Medicine, İstanbul, Turkey

2 Atatürk University, Faculty of Veterinary Medicine, Department of Biochemistry, Erzurum, Turkey

3 Atatürk University, Vocational School of Health Services, Department of Medical Laboratory Techniques, Erzurum, Turkey

4 Atatürk University, Horasan Vocational College, Department of Animal Science, Erzurum, Turkey

5 Aksaray University, Faculty of Medicine, Department of Cardiology, Aksaray, Turkey

6 Final Inernational University, Vocational School of Health Services, Cyprus, Turkey

10.22038/ijbms.2024.81490.17634

Abstract

Objective(s): The present study investigated whether morin has a protective effect against ACR-induced cardiac toxicity.
Materials and Methods: In this study, oxidative stress, inflammation, endoplasmic reticulum stress (ERS), and apoptosis markers in heart tissues were analyzed by different methods after ACR (38.27 mg/kg) and morin (50 or 100 mg/kg) oral administration for ten days to Sprague Dawley rats.
Results: The data obtained showed that ACR induced lipid peroxidation by decreasing superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) enzyme activities, glutathione (GSH) levels and nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone 1 (NQO1), glutamate-cysteine ligase modifier subunit (GCLM), and glutamate-cysteine ligase catalytic subunit (GCLC) gene expressions. On the other hand, these markers approached the control group levels after morin treatment. Moreover, morin suppressed ACR-induced inflammatory genes. Morin down-regulated the related genes by reducing the ERS, exacerbated after ACR administration. In addition, it was observed that B-cell lymphoma-2 (Bcl-2) associated X protein (Bax), caspase-3, and apoptotic peptidase activating factor 1 (apaf-1) expressions, elevated by ACR in the heart tissue, were suppressed after morin administration. Moreover, Bcl-2 expression was triggered by morin treatment. Thus, morin suppressed ACR-induced apoptosis. 
Conclusion: Taken together, morin may protect against ACR-induced cardiac injury by suppressing oxidative stress, inflammation, ERS, and apoptosis.

Keywords

Main Subjects

References

1.Farouk SM, Gad FA, Almeer R, Abdel-Daim MM, Emam MA. Exploring the possible neuroprotective and antioxidant potency of lycopene against acrylamide-induced neurotoxicity in rats’ brain. Biomed Pharmacother 2021; 138:111458-111469.
2.Huang M, Jiao J, Wang J, Xia Z, Zhang Y. Characterization of acrylamide-induced oxidative stress and cardiovascular toxicity in zebrafish embryos. J Hazard Mater 2018; 347: 451-460.
3.Cengiz M, Ayhanci A, Akkemik E, Şahin İK, Gür F, Bayrakdar A, et al. The role of Bax/Bcl-2 and Nrf2-Keap-1 signaling pathways in mediating the protective effect of boric acid on acrylamide-induced acute liver injury in rats. Life Sci 2022; 307:120864.
4.Huang M, Zhu F, Jiao J, Wang J, Zhang Y. Exposure to acrylamide disrupts cardiomyocyte interactions during ventricular morphogenesis in zebrafish embryos. Sci Total Environ 2019; 656: 1337-1345.
5.Elsawy H, Alzahrani AM, Alfwuaires M, Sedky A, El-Trass EE, Mahmoud O, et al. Analysis of silymarin-modulating effects against acrylamide-induced cerebellar damage in male rats: Biochemical and pathological markers. J Chem Neuroanat 2021; 115: 101964.
6.Wang A, Chen X, Wu S, Jia W, Jiao J, Zhang Y. Unraveling the serum metabolomic profile of acrylamide-induced cardiovascular toxicity. J Agric Food Chem 2021; 69: 12012-12020.
7. Huang M, Jiao J, Wang J, Xia Z, Zhang Y. Exposure to acrylamide induces cardiac developmental toxicity in zebrafish during cardiogenesis. Environ Pollut 2018; 234: 656-666.
8. Yardim A, Kandemir FM, Ozdemir S, Kucukler S, Comakli S, Gur C, et al. Quercetin provides protection against the peripheral nerve damage caused by vincristine in rats by suppressing caspase 3, NF-κB, ATF-6 pathways and activating Nrf2, Akt pathways. Neurotoxicology 2020; 81: 137-146.
9. Kucukler S, Benzer F, Yildirim S, Gur C, Kandemir FM, Bengu AS, et al. Protective effects of chrysin against oxidative stress and inflammation induced by lead acetate in rat kidneys: a biochemical and histopathological approach. Biol Trace Elem Res 2021; 199: 1501-1514.
10. Ileriturk M, Kandemir O, Kandemir FM. Evaluation of protective effects of quercetin against cypermethrin‐induced lung toxicity in rats via oxidative stress, inflammation, apoptosis, autophagy, and endoplasmic reticulum stress pathway. Environ Toxicol 2022; 37: 2639-2650.
11. Gur C, Kandemir FM, Caglayan C, Satıcı E. Chemopreventive effects of hesperidin against paclitaxel-induced hepatotoxicity and nephrotoxicity via amendment of Nrf2/HO-1 and caspase-3/Bax/Bcl-2 signaling pathways. Chem Biol Interact 2022; 365: 110073.
12. Celik H, Kucukler S, Ozdemir S, Comakli S, Gur C, Kandemir FM, et al. Lycopene protects against central and peripheral neuropathy by inhibiting oxaliplatin-induced ATF-6 pathway, apoptosis, inflammation and oxidative stress in brains and sciatic tissues of rats. Neurotoxicology 2020; 80: 29-40.
13. Yesildag K, Gur C, Ileriturk M, Kandemir FM. Evaluation of oxidative stress, inflammation, apoptosis, oxidative DNA damage and metalloproteinases in the lungs of rats treated with cadmium and carvacrol. Mol Biol Rep 2022; 49: 1201-1211.
14. Kandemir FM, Caglayan C, Aksu EH, Yildirim S, Kucukler S, Gur C, et al. Protective effect of rutin on mercuric chloride‐induced reproductive damage in male rats. Andrologia 2020; 52:e13524.
15. Gür C, Kandemir Ö, Kandemir FM. Evaluation of the effects of chrysin on diclofenac-ınduced cardiotoxicity in rats by the markers of oxidative stress, endoplasmic reticulum stress and apoptosis. Kocatepe Vet J 2022; 15: 151-160.
16. Cakmak F, Kucukler S, Gur C, Comakli S, Ileriturk M, Kandemir FM. Morin provides therapeutic effect by attenuating oxidative stress, inflammation, endoplasmic reticulum stress, autophagy, apoptosis, and oxidative DNA damage in testicular toxicity caused by ifosfamide in rats. Iran J Basic Med Sci 2023; 26: 1227-1236.
17. Kapoor R, Kakkar P. Protective role of morin, a flavonoid, against high glucose induced oxidative stress mediated apoptosis in primary rat hepatocytes. PLoS One 2012; 7: e41663-41673.
18. Kızıl HE, Caglayan C, Darendelioğlu E, Ayna A, Gür C, Kandemir FM, et al. Morin ameliorates methotrexate-induced hepatotoxicity via targeting Nrf2/HO-1 and Bax/Bcl2/Caspase-3 signaling pathways. Mol Biol Rep 2023; 50: 3479-3488.
19. KV A, Madhana RM, Kasala ER, Samudrala PK, Lahkar M, Gogoi R. Morin hydrate mitigates cisplatin‐induced renal and hepatic injury by impeding oxidative/nitrosative stress and inflammation in mice. J Biochem Mol Toxicol 2016; 30: 571-579.
20. Annie L, Nicy V, Rempuia V, Marak CC, Gurusubramanian G, Roy VK. Morin mitigates cadmium‐induced testicular impairment by stimulating testosterone secretion and germ cell proliferation in mice. J Biochem Mol Toxicol 2023; 37: e23400.
21. Thangarajan S, Vedagiri A, Somasundaram S, Sakthimanogaran R, Murugesan M. Neuroprotective effect of morin on lead acetate-induced apoptosis by preventing cytochrome c translocation via regulation of Bax/Bcl-2 ratio. Neurotoxicol Teratol 2018; 66: 35-45.
22. Uthra C, Shrivastava S, Jaswal A, Sinha N, Reshi MS, Shukla S. Therapeutic potential of quercetin against acrylamide induced toxicity in rats. Biomed Pharmacother 2017; 86: 705-714.
23. Çelik H, Kucukler S, Çomaklı S, Özdemir S, Caglayan C, Yardım A, et al. Morin attenuates ifosfamide-induced neurotoxicity in rats via suppression of oxidative stress, neuroinflammation and neuronal apoptosis. Neurotoxicology 2020; 76: 126-137.
24. Placer ZA, Cushman LL, Johnson BC. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem 1966; 16: 359-364.
25. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem 1988; 34: 497-500.
26. Aebi H. Catalase in vitro. Methods Enzymol 1984: 105: 121-126.
27. Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 1976; 71: 952-958.
28. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 1968; 25: 192-205.
29. Lowry OH. Protein measurement with the Folin phenol reagent. J biol Chem 1951; 193: 265-275.
30. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 2001; 25:402-408.
31. Gao H, Xue Y, Wu L, Huo J, Pang Y, Chen J, et al. Protective effect of Lycium ruthenicum polyphenols on oxidative stress against acrylamide induced liver injury in rats. Molecules 2022; 27: 4100-4113.
32. Gur C, Kandemir O, Kandemir FM. Investigation of the effects of hesperidin administration on abamectin‐induced testicular toxicity in rats through oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, autophagy, and JAK2/STAT3 pathways. Environ Toxicol 2022; 37: 401-412.
33. Varışlı B, Caglayan C, Kandemir FM, Gür C, Ayna A, Genç A, et al. Chrysin mitigates diclofenac-induced hepatotoxicity by modulating oxidative stress, apoptosis, autophagy and endoplasmic reticulum stress in rats. Mol Biol Rep 2023; 50: 433-442.
34.  Gur C, Kandemir FM. Molecular and biochemical investigation of the protective effects of rutin against liver and kidney toxicity caused by malathion administration in a rat model. Environ Toxicol 2022; 38: 555-565.
35. Hong Y, Nan B, Wu X, Yan H, Yuan Y. Allicin alleviates acrylamide-induced oxidative stress in BRL-3A cells. Life sci 2019; 231: 116550.
36. Angsutararux P, Luanpitpong S, Issaragrisil S. Chemotherapy-induced cardiotoxicity: Overview of the roles of oxidative stress. Oxid Med Cell Longev 2015; 2015: 1-13.
37. Abdel-Wahab BA, Metwally ME. Clozapine-induced cardiotoxicity: Role of oxidative stress, tumour necrosis factor alpha and NF-κβ. Cardiovas Toxicol 2015; 15: 355-365.
38. Semis HS, Gur C, Ileriturk M, Kandemir FM, Kaynar O. Evaluation of therapeutic effects of quercetin against Achilles tendinopathy in rats via oxidative stress, inflammation, apoptosis, autophagy, and metalloproteinases. Am J Sports Med 2022; 50: 486-498.
39. Semis HS, Gur C, Ileriturk M, Kaynar O, Kandemir FM. Investigation of the anti-inflammatory effects of caffeic acid phenethyl ester in a model of λ-Carrageenan–induced paw edema in rats. Hum Exp Toxicol 2021; 40: S721-S738.
40. Yardim A, Gur C, Comakli S, Ozdemir S, Kucukler S, Celik H, et al. Investigation of the effects of berberine on bortezomib-induced sciatic nerve and spinal cord damage in rats through pathways involved in oxidative stress and neuro-inflammation. Neurotoxicology 2022; 89: 127-139.
41. Yıldız MO, Çelik H, Caglayan C, Kandemir FM, Gür C, Bayav İ, et al. Neuromodulatory effects of hesperidin against sodium fluoride-induced neurotoxicity in rats: Involvement of neuroinflammation, endoplasmic reticulum stress, apoptosis and autophagy. Neurotoxicology 2022; 90: 197-204.
42. Sharma B, Chaube U, Patel BM. Beneficial effect of silymarin in pressure overload induced experimental cardiac hypertrophy. Cardiovasc Toxicol 2019; 19: 23-35.
43. Koosha F, Sheikhzadeh P. Investigating radioprotective effect of hesperidin/diosmin compound against 99mTc-MIBI-induced cardiotoxicity: Animal Study. Cardiovasc Toxicol 2022; 22: 646-654.
44. James AS, Eteng OE, Dosumu OA, Moses CA, Ogbonna CU, Adeleye OA, 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 2023; 46: 175-189.
45. Wang LF, Su SW, Wang L, Zhang GQ, Zhang R, Niu YJ, et al. Tert-butylhydroquinone ameliorates doxorubicin-induced cardiotoxicity by activating Nrf2 and inducing the expression of its target genes. Am J Transl Res 2015; 7: 1724-1735.
46. Oh GS, Kim HJ, Choi JH, Shen A, Choe SK, Karna A, et al. Pharmacological activation of NQO1 increases NAD+ levels and attenuates cisplatin-mediated acute kidney injury in mice. Kidney Internat 2014; 85: 547-560.
47. Li L, Sun HY, Liu W, Zhao HY, Shao Ml. Silymarin protects against acrylamide-induced neurotoxicity via Nrf2 signalling in PC12 cells. Food Chem Toxicol 2017; 102: 93-101.
48. Li J, Ichikawa T, Villacorta L, Janicki JS, Brower GL, Yamamoto M, et al. Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arterioscler Thromb Vasc Biol 2009; 29: 1843-1850.
49. Arab HH, Saad MA, El-Sahar AE, Al-Shorbagy MY. Mechanistic perspective of morin protection against ketoprofen-induced gastric mucosal injury: Targeting HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways. Arch Biochem Biophys 2020; 693: 108552.
50. Sheibani M, Azizi Y, Shayan M, Nezamoleslami S, Eslami F, Farjoo MH, et al. Doxorubicin-induced cardiotoxicity: An overview on pre-clinical therapeutic approaches. Cardiovasc Toxicol 2022; 22: 292-310.
51. Ibrahim Fouad G, Ahmed KA. Curcumin ameliorates doxorubicin-induced cardiotoxicity and hepatotoxicity via suppressing oxidative stress and modulating iNOS, NF-κB, and TNF-α in rats. Cardiovasc Toxicol 2022; 22: 152-166.
52. Cinar I, Yayla M, Tavaci T, Toktay E, Ugan RA, Bayram P, et al. In vivo and in vitro cardioprotective effect of gossypin against isoproterenol-induced myocardial infarction injury. Cardiovasc Toxicol 2022; 22: 52-62.
53. Soliman MM, Alotaibi SS, Sayed S, Hassan MM, Althobaiti F, Aldhahrani A, et al. The protective impact of salsola imbricata leaf extract from taif against acrylamide-induced hepatic inflammation and oxidative damage: The role of antioxidants, cytokines, and apoptosis-associated genes. Front Vet Sci 2022; 8: 1661-1673.
54. Lyn-Cook Jr LE, Tareke E, Word B, Starlard-Davenport A, Lyn-Cook BD, Hammons GJ. Food contaminant acrylamide increases expression of Cox-2 and nitric oxide synthase in breast epithelial cells. Toxicol Ind Health 2011; 27:11-18.
55. Varışlı B, Caglayan C, Kandemir FM, Gür C, Bayav I, Genç A. The impact of Nrf2/HO-1, caspase-3/Bax/Bcl2 and ATF6/IRE1/PERK/GRP78 signaling pathways in the ameliorative effects of morin against methotrexate-induced testicular toxicity in rats. Mol Biol Rep 2022; 49: 9641-9649.
56. Caglayan C, Kandemir FM, Ayna A, Gür C, Küçükler S, Darendelioğlu E. Neuroprotective effects of 18β-glycyrrhetinic acid against bisphenol A-induced neurotoxicity in rats: Involvement of neuronal apoptosis, endoplasmic reticulum stress and JAK1/STAT1 signaling pathway. Metab Brain Dis 2022; 37: 1931-1940.
57. Altyar AE, Kensara OA, Sayed AA, Aleya L, Almutairi MH, Zaazouee MS, et al. Acute aflatoxin B1-induced hepatic and cardiac oxidative damage in rats: Ameliorative effects of morin. Heliyon 2023; 9: e21837-21836.
58. Hong Z, Minghua W, Bo N, Chaoyue Y, Haiyang Y, Haiqing Y, et al. Rosmarinic acid attenuates acrylamide-induced apoptosis of BRL-3A cells by inhibiting oxidative stress and endoplasmic reticulum stress. Food Chem Toxicol 2021; 151: 112156.
59. Refaie MM, Shehata S, Ibrahim RA, Bayoumi A, Abdel-Gaber SA. Dose-dependent cardioprotective effect of hemin in doxorubicin-induced cardiotoxicity via Nrf-2/HO-1 and TLR-5/NF-κB/TNF-α signaling pathways. Cardiovasc Toxicol 2021; 21: 1033-1044.
60. Abdulkareem Aljumaily SA, Demir M, Elbe H, Yigitturk G, Bicer Y, Altinoz E. Antioxidant, anti-inflammatory, and anti-apoptotic effects of crocin against doxorubicin-induced myocardial toxicity in rats. Environ Sci Pollut Res 2021; 28: 65802-65813.
61. Tabeshpour J, Mehri S, Abnous K, Hosseinzadeh H. Role of oxidative stress, MAPKinase and apoptosis pathways in the protective effects of thymoquinone against acrylamide-induced central nervous system toxicity in rat. Neurochem Res 2020; 45: 254-267.
62. Mehri S, Abnous K, Mousavi SH, Shariaty VM, Hosseinzadeh H. Neuroprotective effect of crocin on acrylamide-induced cytotoxicity in PC12 cells. Cell Mol Neurobiol 2012; 32: 227-235.
63. Kianfar M, Nezami A, Mehri S, Hosseinzadeh H, Hayes AW, Karimi G. The protective effect of fasudil against acrylamide-induced cytotoxicity in PC12 cells. Drug Chem Toxicol 2020; 43: 595-601.
64. Christidi E, Brunham LR. Regulated cell death pathways in doxorubicin-induced cardiotoxicity. Cell Death Dis 2021; 12: 1-15.
65. Shyma R, Mini S. Neuroprotective effect of Morin via TrkB/Akt pathway against diabetes mediated oxidative stress and apoptosis in neuronal cells. Toxicol Mech Methods 2022; 32: 695-704.
66. Kim BS, Park IH, Lee A, Kim HJ, Lim YH, Shin JH. Sacubitril/valsartan reduces endoplasmic reticulum stress in a rat model of doxorubicin-induced cardiotoxicity. Arch Toxicol 2022; 96: 1065-1074.
67. Chen R, Sun G, Yang L, Wang J, Sun X. Salvianolic acid B protects against doxorubicin induced cardiac dysfunction via inhibition of ER stress mediated cardiomyocyte apoptosis. Toxicol Res 2016; 5: 1335-1345.
68. Kandemir FM, Ileriturk M, Gur C. Rutin protects rat liver and kidney from sodium valproate-induce damage by attenuating oxidative stress, ER stress, inflammation, apoptosis and autophagy. Mol Biol Rep 2022; 49: 6063–6074.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 3
March 2025
Pages 376-384

Files

Share

How to cite

Statistics