Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Protective effect of fisetin against subchronic chlorpyrifos-induced toxicity on oxidative stress biomarkers and neurobehavioral parameters in adult male albino mice

  • Akpa, Amaka Rosita (Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, Ahmadu Bello University) ;
  • Ayo, Joseph Olusegun (Department of Veterinary Physiology, Faculty of Veterinary Medicine, Ahmadu Bello University) ;
  • Mika'il, Hudu Garba (Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Abuja) ;
  • Zakari, Friday Ocheja (Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Jos)
  • Received : 2019.12.08
  • Accepted : 2020.05.25
  • Published : 2021.04.15
⟨ Previous Next ⟩

Abstract

Chlorpyrifos (CPF), a chlorinated organophosphate insecticide that is widely used in agriculture and public health, has neurotoxic effects in animals. In addition to acetylcholinesterase inhibition, CPF has been shown to induce alterations such as oxidative stress and lipid peroxidation. Fisetin is a dietary flavonol that protects the brain tissue against oxidative stress by modulating the activity of antioxidant enzymes. This study was designed to investigate the protective role of fisetin against brain oxidative damages and neurobehavioral parameters induced by subchronic oral exposure to CPF in albino mice. Adult albino mice (males, n=32, weighing 20~25 g) were assigned randomly into 4 groups and treated accordingly for 7 weeks as follows: Group 1(S/OIL): served as the control group and were given 2 ml/kg of soya oil; Group 2 (CPF): received CPF (6.6 mg/kg; 1/5th of the LD50); Group 3 (FIS): fisetin (15 mg/kg) and Group 4 (FIS+CPF): received fisetin at 15 mg/kg, followed by CPF (6.6 mg/kg) 30 min later. Co-treatment with FIS+CPF mitigated the increase in brain malondialdehyde concentration (0.28±0.02 nmol/mg) and orchestrated the increase in the activities of catalase (81.35±7.26 µ/mg), superoxide dismutase (93.03±6.63 IU/mL), glutathione peroxidase (68.76±3.554 nmol/mL) and acetylcholinesterase (11.59±0.72 nmol/min/mL) when compared to the CPF group. The result showed that deficits in motor strength and excitability scores induced by subchronic CPF were mitigated by fisetin administration. It was concluded that fisetin has a protective potential in mitigating against oxidative stress and damages in the brain tissues, induced by subchronic exposure to CPF in adult male albino mice.

Keywords

Acknowledgement

The authors thank the technical staff of the Department of Veterinary Pharmacology and Toxicology, Ahmadu Bello University, Zaria, Nigeria, for their support.

References

  1. Adhami VM, Syed DN, Khan N, Mukhtar H (2012) Dietary flavonoid fisetin: A novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management. Biochem Pharmacol 84:1277-1281 https://doi.org/10.1016/j.bcp.2012.07.012
  2. Jayakumar M, Subramanian P (2013) Chronotherapeutic influence of fisetin on ammonium chloride-induced hyperammonemic rats. Biol Rhythm Res 44:577-588 https://doi.org/10.1080/09291016.2012.730890
  3. Syed DN, Adhami VM, Khan N, Khan MI, Mukhtar H (2016) Exploring the molecular targets of dietary flavonoid fisetin in cancer. Semin Cancer Biol 40-41:130-140 https://doi.org/10.1016/j.semcancer.2016.04.003
  4. Khan N, Syed DN, Ahmad N, Mukhtar H (2013) Fisetin: a dietary antioxidant for health promotion. Antioxid Redox Signal 19:151-162 https://doi.org/10.1089/ars.2012.4901
  5. Wang TH, Wang SY, Wang XD, Jiang HQ, Yang YQ, Wang Y, Feng HL (2018) Fisetin exerts antioxidant and neuroprotective effects in multiple mutant hSOD1 models of amyotrophic lateral sclerosis by activating ERK. Neuroscience 379:152-166 https://doi.org/10.1016/j.neuroscience.2018.03.008
  6. Hussain T, Al-Attas OS, Alamery S, Ahmed M, Odeibat HA, Alrokayan S (2019) The plant flavonoid, fisetin alleviates cigarette smoke-induced oxidative stress, and inflammation in Wistar rat lungs. J Food Biochem 43:e12962
  7. Zheng LT, Ock J, Kwon BM, Suk K (2008) Suppressive effects of flavonoid fisetin on lipopolysaccharide-induced microglial activation and neurotoxicity. Int J Immunopharmacol 8:484-494 https://doi.org/10.1016/j.intimp.2007.12.012
  8. Zhou CH, Wang CX, Xie GB, Wu LY, Wei YX, Wang Q, Shi JX (2015) Fisetin alleviates early brain injury following experimental subarachnoid hemorrhage in rats possibly by suppressing TLR 4/NF-κB signaling pathway. Brain Res 1629:250-259 https://doi.org/10.1016/j.brainres.2015.10.016
  9. Maher P (2017) Protective effects of fisetin and other berry flavonoids in Parkinson's disease. Food Funct 8:3033-3042 https://doi.org/10.1039/C7FO00809K
  10. Zhang L, Wang H, Zhou Y, Zhu Y, Fei M (2018) Fisetin alleviates oxidative stress after traumatic brain injury via the nrf2-are pathway. Neurochem Int 118:304-313 https://doi.org/10.1016/j.neuint.2018.05.011
  11. Chuang JY, Chang PC, Shen YC, Lin C, Tsai CF, Chen JH, Yeh WL, Wu LH, Lin HY, Liu YS, Lu DY (2014) Regulatory effects of fisetin on microglial activation. Molecules 19:8820-8839 https://doi.org/10.3390/molecules19078820
  12. Subramanian P, Jayskumar M, Singaravel M, Kumar D, Basu P, Jayapalan JJ, Hashim OH (2015) Fisetin a dietary flavonoid, attenuates hyperammonemia and improves circadian locomotor deficits, redox balance and astrocytic markers in rats. J Funct Foods 12:409-419 https://doi.org/10.1016/j.jff.2014.11.025
  13. Ravichandran N, Suresh G, Ramesh B, Siva GV (2011) Fisetin, a novel flavonol attenuates benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice. Food Chem Toxicol 49:1141-1147 https://doi.org/10.1016/j.fct.2011.02.005
  14. Prakash D, Gopinath K, Sudhandiran G (2013) Fisetin enhances behavioural performances and attenuates reactive gliosis and inflammation during aluminum chloride-induced neurotoxicity. Neuromol Med 15:192-208 https://doi.org/10.1007/s12017-012-8210-1
  15. Tirelli V, Catone T, Turco Di Consiglio E, Testai E, De Angelis I (2007) Biochemical effects of chlorpyrifos and deltamethrin on altered antioxidative defense mechanisms and lipid peroxidation in rat liver. Cell Biochem Funct 26:119-124 https://doi.org/10.1002/cbf.1411
  16. Lovasi GS, Quinn JW, Rauh VA, Perera FP, Andrews HF, Garfinkel R, Rundle A (2011) Chlorpyrifos exposure and urban residential environment characteristics as determinants of early childhood neurodevelopment. Am J Public Health 101:63-70 https://doi.org/10.2105/AJPH.2009.168419
  17. Kwong TC (2002) Organophosphate pesticides: biochemistry and clinical toxicology. Ther Drug Monit 24:144-149 https://doi.org/10.1097/00007691-200202000-00022
  18. Marks AR, Harley K, Bradman A, Kogut K, Barr DB, Johnson C, Calderon N, Eskenazi B (2010) Organophosphate pesticide exposure and attention in young Mexican American children: the Chamacos study. Environ Health Perspect 118:1768-1788 https://doi.org/10.1289/ehp.1002056
  19. Timofeeva OA, Sanders D, Seeman K, Yamg L, Hermanson D, Regenbogen S, Agoos S, Kallepalli A, Rastogi A, Braddy D, Wells C, Perraut C, Sielder F, Slotkin TA, Levin ED (2008) Persistent behavioural alterations in rats neonatally exposed to low doses of the organophosphate pesticide, parathion. Brain Res Bull 77:404-411 https://doi.org/10.1016/j.brainresbull.2008.08.019
  20. Ogueji OE, Usman IB, Jehu A (2013) Investigation of acute toxicity of chlorpyrifos-ethyl on Clarias gariepinus-(Burchell, 1822) using some behavioral indices. Int J Basic Appl Sci 2:176-183
  21. Saunders M, Magnanti B, Carriera SC, Yang A, Alamo-Hernandez U, Riojas-Rodriguez H, Calamandrei G, Koppe JG, Von Krauss MK, Keune H, Bartonova A (2012) Chlorpyrifos and neurodevelopmental effects; a literature review and expert elicitation on research and policy. Environ Health 11:5-14 https://doi.org/10.1186/1476-069X-11-5
  22. Slotkin TA, Sielder FJ (2005) The alterations in CNS serotogenic mechanisms caused by neonatal chlorpyrifos exposure are permanent. Dev Brain Res 158:115-119 https://doi.org/10.1016/j.devbrainres.2005.06.008
  23. Lee JE, Park JH, Jang SJ, Koh HC (2014) Rosiglitazone inhibits chlorpyrifos-induced apoptosis via modulation of the oxidative stress and inflammatory response in SH-SY5Y cells. Toxicol Appl Pharmacol 278:159-171 https://doi.org/10.1016/j.taap.2014.04.021
  24. Xu MY, Wang P, Sun YJ, Yang L, Wu YJ (2017) Joint toxicity of chlorpyrifos and cadmium on the oxidative stress and mitochondrial damage in neuronal cells. Food Chem Toxicol 103:246-252 https://doi.org/10.1016/j.fct.2017.03.013
  25. Jokanovic M (2018) Neurotoxic effects of organophosphorus pesticides and possible association with neurodegenerative diseases in man: a review. Toxicology 410:125-131 https://doi.org/10.1016/j.tox.2018.09.009
  26. Thomsen M, Sorensen G, Dencker D (2018) Physiological roles of CNS muscarinic receptors gained from knockout mice. Neuropharmacology 136:411-420 https://doi.org/10.1016/j.neuropharm.2017.09.011
  27. Uzun FG, Demir F, Kalender S, Bas H, Kalender Y (2010) Protective effect of catechin and quercetin on chlorpyrifos-induced lung toxicity in male rats. Food Chem Toxicol 48:1714-1720 https://doi.org/10.1016/j.fct.2010.03.051
  28. Ambali SF, Ayo JO (2012) Vitamin C attenuates chronic chlorpyrifos-induced alteration of neurobehavioral parameters in Wistar rats. Toxicol Int 19:144-152 https://doi.org/10.4103/0971-6580.97211
  29. El-Demerdash FM, Nasr HM (2014) Antioxidant effect of selenium on lipid peroxidation, hyperlipidemia and biochemical parameters in rats exposed to diazinon. J Trace Elem Med Biol 28:89-93 https://doi.org/10.1016/j.jtemb.2013.10.001
  30. Uchendu C, Ambali SF, Ayo JO, Esievo KAN (2018) Chronic co-exposure to chlorpyrifos and deltamethrin pesticides induces alterations in serum lipids and oxidative stress in Wistar rats: mitigating role of alpha-lipoic acid. Environ Sci Pollut Res 25:19605-19611 https://doi.org/10.1007/s11356-018-2185-x
  31. Galal AA, Ramadan RA, Metwally MM, El-Sheikh SM (2019) Protective effect of N-acetylcysteine on fenitrothion-induced toxicity: the antioxidant status and metabolizing enzymes expression in rats. Ecotoxicol Environ Saf 171:502-510 https://doi.org/10.1016/j.ecoenv.2019.01.004
  32. National Research Council (1996) Guide for the care and use of laboratory animals. Academic Press, Washington
  33. Lorke D (1983) A new approach to practical acute toxicity testing. Arch Toxicol 54:275-287 https://doi.org/10.1007/BF01234480
  34. Abou-Donia MB, Goldstein LB, Jones KH, Abdel-Rahman AA, Damodaran TV, Dechkovskaia AM (2001) Locomotor and sensorimotor performance deficit in rats following exposure to pyridostigmine bromide, DEET and permethrin alone and in combination. Toxicol Sci 60:305-314 https://doi.org/10.1093/toxsci/60.2.305
  35. Nonato LF, Rocha-Vieira E, Tossige-Gomes R, Soares AA, Soares BA, Freitas DA, Leite HR (2016) Swimming training attenuates oxidative damage and increases enzymatic but not non-enzymatic antioxidant defenses in the rat brain. Brazil J Med Biol Res 49:1-5. https://doi.org/10.1590/1414-431X20165310
  36. Draper HH, Hadley M (1990) Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 186:421-431 https://doi.org/10.1016/0076-6879(90)86135-I
  37. Yavuz TN, Delibao B, YaldArAm I, Altuntao O, CandAr A, Cora N, Karahan E, Kutsal A (2004) Vascular wall damage in rats induced by methidathion and ameliorating effect of vitamins E and C. Arch Toxicol 78:655-659 https://doi.org/10.1007/s00204-004-0593-9
  38. Flohe L, Gunzler WA (1984) Assays of glutathione peroxidase. Methods Enzymol 105:114-120 https://doi.org/10.1016/S0076-6879(84)05015-1
  39. Martin JP Jr, Dailey M, Sugarman E (1987) Negative and positive assays of superoxide dismutase based on hematoxylin autoxidation. Arch Biochem Biophys 255:329-336 https://doi.org/10.1016/0003-9861(87)90400-0
  40. Beers RF, Sizer IW (1952) A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem 195:133-140 https://doi.org/10.1016/S0021-9258(19)50881-X
  41. Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88-95 https://doi.org/10.1016/0006-2952(61)90145-9
  42. Ambali S, Akanbi D, Igbokwe N, Shittu M, Kawu M, Ayo J (2007) Evaluation of subchronic chlorpyrifos poisoning on hematological and serum biochemical changes in mice and protective effect of vitamin C. J Toxicol Sci 32:111-120 https://doi.org/10.2131/jts.32.111
  43. Ezzi L, Salah IB, Haouas Z, Sakly A, Grissa I, Chakroun S, Kerkeni E, Hassine M, Mehdi M, Cheikh HB (2016) Histopathological and genotoxic effects of chlorpyrifos in rats. Environ Sci Pollut Res 23:4859-4867. https://doi.org/10.1007/s11356-015-5722-x
  44. Goel A, Dani V, Dhawan DK (2005) Protective effects of zinc on lipid peroxidation, antioxidant enzymes and hepatic histoarchitecture in chlorpyrifos-induced toxicity. Chem Biol Interact 156:131-140 https://doi.org/10.1016/j.cbi.2005.08.004
  45. Shittu M, Ayo JO, Ambali SF, Fatihu MY, Onyeanusi BI, Kawu MU (2012) Chronic chlorpyrifos-induced oxidative changes in the testes and pituitary gland of Wistar rats: ameliorative effects of vitamin C. Pestic Biochem Physiol 102:79-85 https://doi.org/10.1016/j.pestbp.2011.10.014
  46. Tuzmen N, Candan N, Kaya E (2007) The evaluation of altered antioxidative defence mechanism and acetylcholinesterase activity in rat brain exposed to chlorpyrifos, deltamethrin, and their combination. Toxicol Mech Method 17:535-540 https://doi.org/10.1080/15376510701380463
  47. Ambali SF, Idris SB, Onukak C, Shittu M, Ayo JO (2010) Ameliorative effect of vitamins C on short-term sensorimotor and cognitive changes induced by acute chlorpyrifos exposure in Wistar rats. Toxicol Ind Health 26:547-558 https://doi.org/10.1177/0748233710373086
  48. Afaf AE, Hanan AT (2010) Chlorpyrifos (from different sources): Effect on testicular biochemistry of male albino rats. J Am Sci 6:251-261
  49. Parran DK, Magnin G, Li W, Jortner BS, Ehrich M (2005) Chlorpyrifos alters functional integrity and structure of an in vitro bbb model: co-cultures of bovine endothelial cells and neonatal rat astrocytes. Neurotoxicology 26:77-88 https://doi.org/10.1016/j.neuro.2004.07.003
  50. Halliwell B, Gutteridge JMC (2001) Free radicals in biology and medicine. Clarendon Press Inc, Oxford
  51. Gultekin F, Karakoyun I, Sutcu R, Savik E, Cesur G, Orhan H (2007) Chlorpyrifos increases the levels of hippocampal NMDA receptor subunits NR2A and NR2B in juvenile and adult rats. Int J Neurosci 117:47-62 https://doi.org/10.1080/00207450500535719
  52. Ronika S, Poonam G, Jain SK (2011) In vitro antioxidant effect of vitamin E on oxidative stress induced due to pesticides in rat erythrocytes. Toxicol Int 18:73-76 https://doi.org/10.4103/0971-6580.75871
  53. Maurya BK, Trigun SK (2015) Fisetin modulates antioxidant enzymes and inflammatory factors to inhibit aflatoxin-B1 induced hepatocellular carcinoma in rats. Oxid Med Cell Long 40:185-196
  54. Brajesh K, Surendra K (2016) Fisetin modulates antioxidant enzymes and inflammatory factors to inhibit aflatoxin B1 induced hepatocellular carcinoma in rats. Oxid Med Cell Long 16:1-9
  55. Sahu BD, Kalvala AK, Koneru M, Kumar JM, Kuncha M, Rachamalla SS, Sistla R (2014) Ameliorative effect of fisetin on cisplatin-induced nephrotoxicity in rats via modulation of NF-κB activation and antioxidant defence. PLoS ONE 9:e105070 https://doi.org/10.1371/journal.pone.0105070
  56. Chiruta C, Schubert D, Dargusch R, Maher P (2012) Chemical modification of the multitarget neuroprotective compound fisetin. J Med Chem 55:378-389 https://doi.org/10.1021/jm2012563
  57. Altuntas I, Delibas N, Sutcu R (2002) The effects of organophosphate insecticide methidathion on lipid peroxidation and anti-oxidant enzymes in rat erythrocytes: role of vitamins E and C. Hum Exp Toxicol 21:681-685 https://doi.org/10.1191/0960327102ht304oa
  58. Mansour SA, Mossa ATH (2009) Lipid peroxidation and oxidative stress in rat erythrocytes induced by chlorpyrifos and the protective effect of zinc. Pest Biochem Physiol 93:34-39 https://doi.org/10.1016/j.pestbp.2008.09.004
  59. Heikal TM, El-Sherbiny M, Hassan SA, Arafa A, Ghanem HZ (2012) Antioxidant effect of selenium on hepatotoxicity induced by chlorpyrifos in male rats. Int J Pharm Pharm Sci 4:603-609
  60. Koneru M, Sahu BD, Kumar JM, Kuncha M, Kadari A, Kilari EK, Sistla R (2016) Fisetin protects liver from binge alcohol-induced toxicity by mechanisms including inhibition of matrix metalloproteinases (MMPs) and oxidative stress. J Funct Foods 22:588-601 https://doi.org/10.1016/j.jff.2016.02.019
  61. Bousova I, Skalova L (2012) Inhibition and induction of glutathione S-transferases by flavonoids: possible pharmacological and toxicological consequences. Drug Metab Rev 44:267-286 https://doi.org/10.3109/03602532.2012.713969
  62. Gupta SC, Tyagi AK, Deshmukh-Taskar P, Hinojosa M, Prasad S, Aggarwal BB (2014) Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols. Arch Biochem Biophys 559:91-99 https://doi.org/10.1016/j.abb.2014.06.006
  63. Naghma K, Deeba N, Nihal A, Hassan M (2013) Fisetin a dietary antioxidant for health promotion. Antioxid Redox Signal 19:151-162 https://doi.org/10.1089/ars.2012.4901
  64. Naseer AB, Raina R, Pawan K, Verma M, Sultana S, Prawez N, Ahmad Nisara R, Pura S, Jammu I (2013) Toxic effects of fluoride and chlorpyrifos on antioxidant parameters in rats: protective effects of vitamins C and E. Fluoride 46:73-79
  65. Chen C, Yao L, Cui J, Liu B (2018) Fisetin protects against intracerebral hemorrhage-induced neuroinflammation in aged mice. Cerebrovasc Dis 45:154-161 https://doi.org/10.1159/000488117
  66. Nguyen T, Hakan B, Jenny L, Nguyen V, Micjael T (2016) Effects of sequential applications of Bassa 50 EC (fenbucarb) and Vita shield 40EC (chlorpyrifos ethyl) on acetylcholinesterase activity in climbing perch (Anabas testudinus) cultured in rice fields in the Mekong Delta. Vietnam Bull Environ Contam Toxicol 97:98-104 https://doi.org/10.1007/s00128-016-1796-5
  67. Brocardo PS, Assini F, Franco JL, Pandolfo P, Muller YM, Takahashi RN (2007) Zinc attenuates malathion-induced depressant-like behavior and confers neuroprotection in the rat brain. Toxicol Sci 97:140-148 https://doi.org/10.1093/toxsci/kfm024
  68. Shou L, Bei Y, Song Y, Wang L, Ai L, Yan Q, He W (2019) Nrf2 mediates the protective effect of edaravone after chlorpyrifos-induced nervous system toxicity. Environ Toxicol 34:626-633 https://doi.org/10.1002/tox.22728
  69. Youdim KA, Shukitt-Hale B, Joseph JA (2004) Flavonoids and the brain: interactions at the blood-brain barrier and their physiological effects on the nervous system. Free Rad Biol Med 37:1683-1693 https://doi.org/10.1016/j.freeradbiomed.2004.08.002
  70. Rossi L, Mazzitelli S, Arciello M, Capo CR, Rotilio G (2008) Benefits from dietary polyphenols for brain aging and Alzheimer's disease. Neurochem Res 33:2390-2400 https://doi.org/10.1007/s11064-008-9696-7
  71. Katalinic M, Rusak G, Barovic JD, Sinko G, Jelic D, Antolovic R, Kovarik Z (2010) Structural aspects of flavonoids as inhibitors of human butyrylcholinesterase. Eur J Med Chem 45:186-192 https://doi.org/10.1016/j.ejmech.2009.09.041
  72. Khan H, Amin S, Kamal MA, Patel S (2018) Flavonoids as acetylcholinesterase inhibitors: current therapeutic standing and future prospects. Biomed Pharmacother 101:860-870 https://doi.org/10.1016/j.biopha.2018.03.007
  73. Terry AV Jr, Stone JD, Buccafusco JJ, Sickles DW, Sood A, Prendergast MA (2003) Repeated exposures to subthreshold doses of chlorpyrifos in rats: hippocampal damage, impaired axonal transport, and deficits in spatial learning. J Pharmacol Exp Ther 305:375-384 https://doi.org/10.1124/jpet.102.041897
  74. Miranda J, McConnell R, Wesseling C, Cuadra R, Delgado E, Torres E, Lundberg I (2004) Muscular strength and vibration thresholds during two years after acute poisoning with organophosphate insecticides. Occup Environ Med 61:e4
  75. Steenland K, Jenkins B, Ames RG, O'Malley M, Chrislip D, Russo J (1994) Chronic neurological sequelae to organophosphate pesticide poisoning. Am J Public Health 84:731-736 https://doi.org/10.2105/AJPH.84.5.731
  76. Steenland K, Dick RB, Howell RJ, Chrislip DW, Hines CJ, Reid TM (2000) Neurologic function among termiticide applicators exposed to chlorpyrifos. Environ Health Perspect 108:293-300 https://doi.org/10.1289/ehp.00108293
  77. Yu ZW, Quinn PJ (1994) Dimethyl sulphoxide: a review of its applications in cell biology. Biosci Rep 14:259-281 https://doi.org/10.1007/BF01199051

Cited by

  1. Pterostilbene Alleviates Chlorpyrifos-Induced Damage During Porcine Oocyte Maturation vol.9, 2021, https://doi.org/10.3389/fcell.2021.803181
  2. Neuroprotective Effect of Fisetin Against the Cerebral Ischemia-Reperfusion Damage via Suppression of Oxidative Stress and Inflammatory Parameters vol.44, pp.4, 2021, https://doi.org/10.1007/s10753-021-01434-x
  3. Potential Protective Effect of Vitamin C on Qunalphos-Induced Cardiac Toxicity: Histological and Tissue Biomarker Assay vol.10, pp.1, 2021, https://doi.org/10.3390/biomedicines10010039