Iranian Journal of Medical Sciences

Document Type : Original Article(s)


1 Department of Biochemistry and Genetics, School of Medicine, Arak University of Medical Sciences, Arak, Iran

2 Department of Biochemistry and Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

3 Department of Anatomy, School of Medicine, Arak University of Medical Sciences, Arak, Iran

4 Research Center and Molecular Medicine, Arak University of Medical Sciences, Arak, Iran

5 Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran



Background: Hyperglycemia-induced oxidative stress can damage the liver and lead to diabetes complications. Coenzyme Q10 (CoQ-10) reduces diabetes-related oxidative stress. However, its molecular mechanisms are still unclear. This study aimed to examine CoQ-10’s antioxidant capabilities against hyperglycemia-induced oxidative stress in the livers of diabetic rats, specifically targeting the Nrf2/Keap1/ARE signaling pathway.
Methods: This study was conducted between 2020-2021 at Arak University of Medical Sciences. A total of 30 male adult Wistar rats (8 weeks old) weighing 220-250 g were randomly assigned to five groups (n=6 in each group): control healthy, sesame oil (CoQ-10 solvent), CoQ-10 (10 mg/Kg), diabetic, and diabetic+CoQ-10. Liver oxidative stress indicators, including malondialdehyde, catalase, glutathione peroxidase, and glutathione, were estimated using the spectrophotometry method. Nrf2, Keap1, HO-1, and NQO1 gene expressions were measured using real-time PCR tests in the liver tissue. All treatments were conducted for 6 weeks. Statistical analysis was performed using SPSS software. One-way ANOVA followed by LSD’s or Tukey’s post hoc tests were used to compare the results of different groups. P<0.05 was considered statistically significant.
Results: The findings showed that induction of diabetes significantly increased Keap1 expression (2.1±0.9 folds, P=0.01), and significantly inhibited the mRNAs expression of Nrf2 (0.38±0.2 folds, P=0.009), HO-1 (0.27±0.1 folds, P=0.02), and NQO1 (0.26±0.1 folds P=0.01), compared with the healthy group. In the diabetic group, the activity of glutathione peroxidase, catalase enzymes, and glutathione levels was decreased with an increase in malondialdehyde level. CoQ-10 supplementation significantly up-regulated the expressions of Nrf2 (0.85±0.3, P=0.04), HO-1 (0.94±0.2, P=0.04), NQO1 (0.88±0.5, P=0.03) genes, and inhibited Keap1 expression (1.1±0.6, P=0.02). Furthermore, as compared to control diabetic rats, CoQ-10 ameliorated oxidative stress by decreasing malondialdehyde levels and increasing catalase, glutathione peroxidase activities, and glutathione levels in the liver tissues of the treated rats in the treatment group. 
Conclusion: The findings of this study revealed that CoQ-10 could increase the antioxidant capacity of the liver tissue in diabetic rats by modulating the Nrf2/Keap1/HO-1/NQO1 signaling pathway.


  1. Lima J, Moreira NCS, Sakamoto-Hojo ET. Mechanisms underlying the pathophysiology of type 2 diabetes: From risk factors to oxidative stress, metabolic dysfunction, and hyperglycemia. Mutat Res Genet Toxicol Environ Mutagen. 2022;874-875:503437. doi: 10.1016/j.mrgentox.2021.503437. PubMed PMID: 35151421.
  2. Malaekeh-Nikouei A, Shokri-Naei S, Karbasforoushan S, Bahari H, Baradaran Rahimi V, Heidari R, et al. Metformin beyond an anti-diabetic agent: A comprehensive and mechanistic review on its effects against natural and chemical toxins. Biomed Pharmacother. 2023;165:115263. doi: 10.1016/j.biopha.2023.115263. PubMed PMID: 37541178.
  3. Neha K, Haider MR, Pathak A, Yar MS. Medicinal prospects of antioxidants: A review. Eur J Med Chem. 2019;178:687-704. doi: 10.1016/j.ejmech.2019.06.010. PubMed PMID: 31228811.
  4. Hosseini SA, Zahrooni N, Ahmadzadeh A, Ahmadiangali K, Assarehzadegan MA. The Effect of CoQ(10) Supplementation on Quality of Life in Women with Breast Cancer Undergoing Tamoxifen Therapy: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial. Psychol Res Behav Manag. 2020;13:151-9. doi: 10.2147/PRBM.S241431. PubMed PMID: 32110123; PubMed Central PMCID: PMCPMC7039424.
  5. Maheshwari R, Balaraman R, Sen AK, Shukla D, Seth A. Effect of concomitant administration of coenzyme Q10 with sitagliptin on experimentally induced diabetic nephropathy in rats. Ren Fail. 2017;39:130-9. doi: 10.1080/0886022X.2016.1254659. PubMed PMID: 27841100; PubMed Central PMCID: PMCPMC6014506.
  6. Gutierrez-Mariscal FM, Arenas-de Larriva AP, Limia-Perez L, Romero-Cabrera JL, Yubero-Serrano EM, Lopez-Miranda J. Coenzyme Q(10) Supplementation for the Reduction of Oxidative Stress: Clinical Implications in the Treatment of Chronic Diseases. Int J Mol Sci. 2020;21. doi: 10.3390/ijms21217870. PubMed PMID: 33114148; PubMed Central PMCID: PMCPMC7660335.
  7. Zhang SY, Yang KL, Zeng LT, Wu XH, Huang HY. Effectiveness of Coenzyme Q10 Supplementation for Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Int J Endocrinol. 2018;2018:6484839. doi: 10.1155/2018/6484839. PubMed PMID: 30305810; PubMed Central PMCID: PMCPMC6165589.
  8. Wu X, Huang L, Liu J. Relationship between oxidative stress and nuclear factor-erythroid-2-related factor 2 signaling in diabetic cardiomyopathy (Review). Exp Ther Med. 2021;22:678. doi: 10.3892/etm.2021.10110. PubMed PMID: 33986843; PubMed Central PMCID: PMCPMC8111863.
  9. Duvigneau JC, Esterbauer H, Kozlov AV. Role of Heme Oxygenase as a Modulator of Heme-Mediated Pathways. Antioxidants (Basel). 2019;8. doi: 10.3390/antiox8100475. PubMed PMID: 31614577; PubMed Central PMCID: PMCPMC6827082.
  10. Ross D, Siegel D. Functions of NQO1 in Cellular Protection and CoQ(10) Metabolism and its Potential Role as a Redox Sensitive Molecular Switch. Front Physiol. 2017;8:595. doi: 10.3389/fphys.2017.00595. PubMed PMID: 28883796; PubMed Central PMCID: PMCPMC5573868.
  11. Jimenez-Osorio AS, Gonzalez-Reyes S, Pedraza-Chaverri J. Natural Nrf2 activators in diabetes. Clin Chim Acta. 2015;448:182-92. doi: 10.1016/j.cca.2015.07.009. PubMed PMID: 26165427.
  12. Nabavi SF, Barber AJ, Spagnuolo C, Russo GL, Daglia M, Nabavi SM, et al. Nrf2 as molecular target for polyphenols: A novel therapeutic strategy in diabetic retinopathy. Crit Rev Clin Lab Sci. 2016;53:293-312. doi: 10.3109/10408363.2015.1129530. PubMed PMID: 26926494.
  13. Rahmani AH, Alsahli MA, Khan AA, Almatroodi SA. Quercetin, a Plant Flavonol Attenuates Diabetic Complications, Renal Tissue Damage, Renal Oxidative Stress and Inflammation in Streptozotocin-Induced Diabetic Rats. Metabolites. 2023;13. doi: 10.3390/metabo13010130. PubMed PMID: 36677055; PubMed Central PMCID: PMCPMC9861508.
  14. Peter JS, Shalini M, Giridharan R, Basha KS, Lavinya UB, Evan Prince S. Administration of coenzyme Q10 to a diabetic rat model: changes in biochemical, antioxidant, and histopathological indicators. International Journal of Diabetes in Developing Countries. 2020;40:143-52. doi: 10.1007/s13410-019-00752-z.
  15. Samimi F, Baazm M, Eftekhar E, Rajabi S, Goodarzi MT, Jalali Mashayekhi F. Possible antioxidant mechanism of coenzyme Q10 in diabetes: impact on Sirt1/Nrf2 signaling pathways. Res Pharm Sci. 2019;14:524-33. doi: 10.4103/1735-5362.272561. PubMed PMID: 32038732; PubMed Central PMCID: PMCPMC6937743.
  16. Rezaei Vandchali N, Koolivand A, Ranjbar A, Zarei P, Fathi M, Malekafzali S, et al. Oxidative toxic stress and p53 level in healthy subjects occupationally exposed to outdoor air Pollution - a cross-sectional study in Iran. Ann Agric Environ Med. 2020;27:585-90. doi: 10.26444/aaem/126313. PubMed PMID: 33356065.
  17. Muller N, Scheld M, Voelz C, Gasterich N, Zhao W, Behrens V, et al. Lipocalin-2 Deficiency Diminishes Canonical NLRP3 Inflammasome Formation and IL-1beta Production in the Subacute Phase of Spinal Cord Injury. Int J Mol Sci. 2023;24. doi: 10.3390/ijms24108689. PubMed PMID: 37240031; PubMed Central PMCID: PMCPMC10218144.
  18. Charlton A, Garzarella J, Jandeleit-Dahm KAM, Jha JC. Oxidative Stress and Inflammation in Renal and Cardiovascular Complications of Diabetes. Biology (Basel). 2020;10. doi: 10.3390/biology10010018. PubMed PMID: 33396868; PubMed Central PMCID: PMCPMC7830433.
  19. Motamedrad M, Shokouhifar A, Hemmati M, Moossavi M. The regulatory effect of saffron stigma on the gene expression of the glucose metabolism key enzymes and stress proteins in streptozotocin-induced diabetic rats. Res Pharm Sci. 2019;14:255-62. doi: 10.4103/1735-5362.258494. PubMed PMID: 31160903; PubMed Central PMCID: PMCPMC6540927.
  20. Nahdi A, John A, Raza H. Elucidation of Molecular Mechanisms of Streptozotocin-Induced Oxidative Stress, Apoptosis, and Mitochondrial Dysfunction in Rin-5F Pancreatic beta-Cells. Oxid Med Cell Longev. 2017;2017:7054272. doi: 10.1155/2017/7054272. PubMed PMID: 28845214; PubMed Central PMCID: PMCPMC5563420.
  21. Motawi TK, Darwish HA, Hamed MA, El-Rigal NS, Aboul Naser AF. Coenzyme Q10 and niacin mitigate streptozotocin- induced diabetic encephalopathy in a rat model. Metab Brain Dis. 2017;32:1519-27. doi: 10.1007/s11011-017-0037-x. PubMed PMID: 28560538.
  22. Ghanbari M, Shokrzadeh Lamuki M, Sadeghimahalli F, Habibi E, Sayedi Moqadam MR. Oxidative stress in liver of streptozotocin-induced diabetic mice fed a high-fat diet: A treatment role of Artemisia annua L. Endocr Regul. 2023;57:242-51. doi: 10.2478/enr-2023-0027. PubMed PMID: 37823572.
  23. Ighodaro OM, Akinloye OA. First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): Their fundamental role in the entire antioxidant defence grid. Alexandria Journal of Medicine. 2018;54:287-93. doi: 10.1016/j.ajme.2017.09.001.
  24. Yen CH, Chu YJ, Lee BJ, Lin YC, Lin PT. Effect of liquid ubiquinol supplementation on glucose, lipids and antioxidant capacity in type 2 diabetes patients: a double-blind, randomised, placebo-controlled trial. Br J Nutr. 2018;120:57-63. doi: 10.1017/S0007114518001241. PubMed PMID: 29936921.
  25. Ulla A, Mohamed MK, Sikder B, Rahman AT, Sumi FA, Hossain M, et al. Coenzyme Q10 prevents oxidative stress and fibrosis in isoprenaline induced cardiac remodeling in aged rats. BMC Pharmacol Toxicol. 2017;18:29. doi: 10.1186/s40360-017-0136-7. PubMed PMID: 28427467; PubMed Central PMCID: PMCPMC5399319.
  26. Tian G, Sawashita J, Kubo H, Nishio SY, Hashimoto S, Suzuki N, et al. Ubiquinol-10 supplementation activates mitochondria functions to decelerate senescence in senescence-accelerated mice. Antioxid Redox Signal. 2014;20:2606-20. doi: 10.1089/ars.2013.5406. PubMed PMID: 24124769; PubMed Central PMCID: PMCPMC4025630.
  27. Bellezza I, Giambanco I, Minelli A, Donato R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res. 2018;1865:721-33. doi: 10.1016/j.bbamcr.2018.02.010. PubMed PMID: 29499228.
  28. Rabbani PS, Soares MA, Hameedi SG, Kadle RL, Mubasher A, Kowzun M, et al. Dysregulation of Nrf2/Keap1 Redox Pathway in Diabetes Affects Multipotency of Stromal Cells. Diabetes. 2019;68:141-55. doi: 10.2337/db18-0232. PubMed PMID: 30352880; PubMed Central PMCID: PMCPMC6302538.
  29. Dodson M, Redmann M, Rajasekaran NS, Darley-Usmar V, Zhang J. Correction: KEAP1-NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity. Biochem J. 2015;471:431. doi: 10.1042/BJ4710431. PubMed PMID: 26475451.
  30. Abdelsamia EM, Khaleel SA, Balah A, Abdel Baky NA. Curcumin augments the cardioprotective effect of metformin in an experimental model of type I diabetes mellitus; Impact of Nrf2/HO-1 and JAK/STAT pathways. Biomed Pharmacother. 2019;109:2136-44. doi: 10.1016/j.biopha.2018.11.064. PubMed PMID: 30551471.
  31. You L, Peng H, Liu J, Cai M, Wu H, Zhang Z, et al. Catalpol Protects ARPE-19 Cells against Oxidative Stress via Activation of the Keap1/Nrf2/ARE Pathway. Cells. 2021;10. doi: 10.3390/cells10102635. PubMed PMID: 34685615; PubMed Central PMCID: PMCPMC8534470.
  32. Ding Q, Sun B, Wang M, Li T, Li H, Han Q, et al. N-acetylcysteine alleviates oxidative stress and apoptosis and prevents skeletal muscle atrophy in type 1 diabetes mellitus through the NRF2/HO-1 pathway. Life Sci. 2023;329:121975. doi: 10.1016/j.lfs.2023.121975. PubMed PMID: 37495077.
  33. Sharath Babu GR, Anand T, Ilaiyaraja N, Khanum F, Gopalan N. Pelargonidin Modulates Keap1/Nrf2 Pathway Gene Expression and Ameliorates Citrinin-Induced Oxidative Stress in HepG2 Cells. Front Pharmacol. 2017;8:868. doi: 10.3389/fphar.2017.00868. PubMed PMID: 29230174; PubMed Central PMCID: PMCPMC5711834.
  34. Zhang L, Ma Q, Zhou Y. Strawberry Leaf Extract Treatment Alleviates Cognitive Impairment by Activating Nrf2/HO-1 Signaling in Rats With Streptozotocin-Induced Diabetes. Front Aging Neurosci. 2020;12:201. doi: 10.3389/fnagi.2020.00201. PubMed PMID: 32792939; PubMed Central PMCID: PMCPMC7390916.
  35. Bhakkiyalakshmi E, Sireesh D, Sakthivadivel M, Sivasubramanian S, Gunasekaran P, Ramkumar KM. Anti-hyperlipidemic and anti-peroxidative role of pterostilbene via Nrf2 signaling in experimental diabetes. Eur J Pharmacol. 2016;777:9-16. doi: 10.1016/j.ejphar.2016.02.054. PubMed PMID: 26921755.
  36. Liu YW, Liu XL, Kong L, Zhang MY, Chen YJ, Zhu X, et al. Neuroprotection of quercetin on central neurons against chronic high glucose through enhancement of Nrf2/ARE/glyoxalase-1 pathway mediated by phosphorylation regulation. Biomed Pharmacother. 2019;109:2145-54. doi: 10.1016/j.biopha.2018.11.066. PubMed PMID: 30551472.
  37. Choi HK, Pokharel YR, Lim SC, Han HK, Ryu CS, Kim SK, et al. Inhibition of liver fibrosis by solubilized coenzyme Q10: Role of Nrf2 activation in inhibiting transforming growth factor-beta1 expression. Toxicol Appl Pharmacol. 2009;240:377-84. doi: 10.1016/j.taap.2009.07.030. PubMed PMID: 19647758.
  38. Pala R, Orhan C, Tuzcu M, Sahin N, Ali S, Cinar V, et al. Coenzyme Q10 Supplementation Modulates NFkappaB and Nrf2 Pathways in Exercise Training. J Sports Sci Med. 2016;15:196-203. PubMed PMID: 26957943; PubMed Central PMCID: PMCPMC4763840.
  39. AO SY, A AF, Abdel Moneim AE, Metwally DM, El-Khadragy MF, Kassab RB. The Neuroprotective Role of Coenzyme Q10 Against Lead Acetate-Induced Neurotoxicity Is Mediated by Antioxidant, Anti-Inflammatory and Anti-Apoptotic Activities. Int J Environ Res Public Health. 2019;16. doi: 10.3390/ijerph16162895. PubMed PMID: 31412628; PubMed Central PMCID: PMCPMC6720293.