Protective Potential of Ginseng and/or Coenzyme Q10 on Doxorubicin-induced Testicular and Hepatic Toxicity in Rats

Authors

  • Suzan Khodir Department of Medical Physiology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt https://orcid.org/0000-0002-2535-9445
  • Aliaa Alafify Department of Anatomy and Embryology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt https://orcid.org/0000-0003-4675-0977
  • Essam Omar Department of Medical Physiology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt https://orcid.org/0000-0001-5065-6620
  • Marwa Al-Gholam Department of Anatomy and Embryology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt

DOI:

https://doi.org/10.3889/oamjms.2021.7063

Keywords:

Doxorubicin, Nuclear factor E2‐related factor 2, Caspase-3, Ginseng, Coenzyme Q10

Abstract

Introduction: Although doxorubicin (DOX) is a successful cancer chemotherapeutic, side effects limit the clinical utility of DOX-based therapy, including male infertility and hepatotoxicity.

Objective: To evaluate the testicular and hepatoprotective effect of ginseng and/or coenzyme Q10 (CoQ10) in rats exposed to DOX and the possible underlying mechanisms.

Materials and Methods:  Fifty adult male albino rats were divided into (10/group), control, DOX group, DOX/Gin group, DOX/CoQ10 group and DOX/Gin+CoQ10 group. Serum testosterone, serum liver enzymes, fasting serum cholesterol and triglyceride (TG), tissue malondialdehyde (MDA), tissue superoxide dismutase (SOD), serum tumor necrosis factor-alpha (TNF-α), serum interleukin 6, serum interleukin 10, nuclear factor E2‐related factor 2 (Nrf2) gene expression in liver and testis and organ indices were measured.  Histopathological and immunohistochemical assessments of apoptotic marker kaspase3 in testis and liver were also performed.

Results DOX-induced toxicity is associated with a significant decrease in serum testosterone, testis and liver index values, testicular and hepatic SOD,  testicular and hepatic Nrf2 gene expression and serum interleukin 10. However, there was a significant increase in serum liver enzymes, serum cholesterol and TG, testicular and hepatic MDA, serum TNF-α and serum interleukin 6 when compared with the control group. The combination of ginseng and CoQ10 resulted in significant improvement of DOX-induced changes when compared with other treated groups.

Conclusion: Ginseng and CoQ10 have valuable therapeutic effects on DOX-induced testicular and hepatic toxicity via up-regulation of Nrf2 gene expression, inhibition of apoptosis, anti-oxidant, anti-inflammatory and hypolipidemic effects.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Markham MJ, Wachter K, Agarwal N, Bertagnolli MM, Chang SM, Dale W, et al. Clinical cancer advances 2020: Annual report on progress against cancer from the American society of clinical oncology. J Clin Oncol. 2020;38(10):1081-101. https://doi.org/10.1200/jco.19.03141 PMid:32013670

Podyacheva EY, Kushnareva EA, Karpov AA, Toropova YG. Analysis of models of doxorubicin-induced cardiomyopathy in rats and mice. A modern view from the perspective of the pathophysiologist and the clinician. Front Pharmacol. 2021;3(12):670479. https://doi.org/10.3389/fphar.2021.670479 PMid:34149423

Afsar T, Razak S, Almajwal A. Effect of Acacia hydaspica R. Parker extract on lipid peroxidation, antioxidant status, liver function test and histopathology in doxorubicin treated rats. Lipids Health Dis. 2019;18(1):126. https://doi.org/10.1186/s12944-019-1051-2 PMid:31142345

Ujah GA, Nna VU, Suleiman JB, Eleazu C, Nwokocha C, Rebene JA, et al. Tert-butylhydroquinone attenuates doxorubicin-induced dysregulation of testicular cytoprotective and steroidogenic genes, and improves spermatogenesis in rats. Sci Rep 2021;11:5522. https://doi.org/10.1038/s41598-021-85026-7

Hinkley JM, Morton AB, Ichinoseki-Sekine N, Huertas AM, Smuder AJ. Exercise training prevents doxorubicin-induced mitochondrial dysfunction of the liver. Med Sci Sports Exerc. 2019;51(6):1106-15. https://doi.org/10.1249/mss.0000000000001887 PMid:30629044

Hozayen WG. Effect of hesperidin and rutin on doxorubicin induced testicular toxicity in male rats. Int J Food Nutr Sci. 2012;1:31-42.

Arunachalam S, Meeran MF, Azimullah S, Sharma C, Goyal SN, Ojha S. Nerolidol attenuates oxidative stress, inflammation, and apoptosis by modulating Nrf2/MAPK signaling pathways in doxorubicin-induced acute cardiotoxicity in rats. Antioxidants. 2021;10(6):984. https://doi.org/10.3390/antiox10060984

Boettler U, Volz N, Teller N, Haupt LM, Bakuradze T, Eisenbrand G, et al. Induction of antioxidative Nrf2 gene transcription by coffee in humans: Depending on genotype? Mol Biol Rep. 2012;39(6):7155‐62. https://doi.org/10.1007/s11033-012-1547-6 PMid:22314914

Das J, Ghosh J, Roy A, Sil PC. Mangiferin exerts hepatoprotective activity against D‐galactosamine induced acute toxicity and oxidative/nitrosative stress via Nrf2‐NFkappaB pathways. Toxicol Appl Pharmacol. 2012;260(1):35‐47. https://doi.org/10.1016/j.taap.2012.01.015 PMid:22310181

Wu S, Yue Y, Tian H, Li Z, Li X, He W, et al. Carthamus red from Carthamus tinctorius L. exerts antioxidant and hepatoprotective effect against CCl(4)‐induced liver damage in rats via the Nrf2 pathway. J Ethnopharmacol. 2013;148(2):570‐8. https://doi.org/10.1016/j.jep.2013.04.054 PMid:23684718

Abd El-Aziz TA, Mohamed RH, Pasha HF, Abdel-Aziz HR. Catechin protects against oxidative stress and inflammatory mediated cardiotoxicity in adriamycin-treated rats. Clin Exp Med. 2012;12(4):233-40. https://doi.org/10.1007/s10238-011-0165-2 PMid:22080234

Malekinejad H, Janbaz-Acyabar H, Razi M, Varasteh S. Preventive and protective effects of silymarin on doxorubicin-induced testicular damages correlate with changes in c-myc gene expression. Phytomedicine. 2012;19(12):1077-84. https://doi.org/10.1016/j.phymed.2012.06.011 PMid:22819302

Gray SL, Lackey BR, Boone WR. Effects of Panax ginseng, zearalenol, and estradiol on sperm function. J Ginseng Res. 2016;40(3):251-9. https://doi.org/10.1016/j.jgr.2015.08.004 PMid:27616901

Rahim SA. Role of Panax ginseng as an antioxidant and hepatoprotective after liver toxicity caused by flutamide in adult male rats. SRP 2020;11(6):449-58.

Huang YC, Chen CT, Chen SC, Lai PH, Liang HC, Chang Y, et al. A natural compound (ginsenoside Re) isolated from panax ginseng as a novel angiogenic agent for tissue regeneration. Pharm Res. 2005;22(4):636-46. https://doi.org/10.1007/s11095-005-2500-3 PMid:15846472

El-Demerdash FM, El-Magd MA, El-Sayed RA. Panax ginseng modulates oxidative stress, DNA damage, apoptosis, and inflammations induced by silicon dioxide nanoparticles in rats. Environ Toxicol. 2021;36(7):1362-74. https://doi.org/10.1002/tox.23132 PMid:33749107

Kwak YS, Kyung JS, Kim JS, Cho JY, Rhee MH. Antihyperlipidemic effects of red ginseng acidic polysaccharides from Korean red Ginseng. Biol Pharm Bull. 2010;33(3):468-72. https://doi.org/10.1248/bpb.33.468 PMid:20190411

Lamia SS, Emran T, Rikta JK, Chowdhury NI, Sarker M, Jain P, et al. Coenzyme Q10 and silymarin reduce CCl4-induced oxidative stress and liver and kidney injury in ovariectomized rats-implications for protective therapy in chronic liver and kidney diseases. Pathophysiology. 2021;28:50-63. https://doi.org/10.3390/pathophysiology28010005

Chen HH, Yeh TC, Cheng PW, Ho WY, Ho CY, Lai CC, et al. Antihypertensive potential of coenzyme Q10 via free radical scavenging and enhanced Akt-nNOS signaling in the nucleus Tractus solitarii in rats. Mol Nutr Food Res. 2019;63(6):e1801042. https://doi.org/10.1002/mnfr.201801042 PMid:30668894

Mohamed HA, Said RS. Coenzyme Q10 attenuates inflammation and fibrosis implicated in radiation enteropathy through suppression of NF-kB/TGF-β/MMP-9 pathways. Int Immunopharmacol. 2021;92:107347. https://doi.org/10.1016/j.intimp.2020.107347 PMid:33418245

Pala R, Orhan C, Tuzcu M, Sahin N, Ali S, Cinar V, et al. Coenzyme Q10 supplementation modulates NFκB and Nrf2 pathways in exer-cise training. J Sports Sci Med. 2016;15(1):196-203. PMid:26957943

El-Sheikh AA, Morsy MA, Mahmoud MM, Rifaai RA, Abdelrahman AM. Effect of coenzyme-Q10 on doxorubicin-induced nephrotoxicity in rats. Adv Pharmacol Sci. 2012;2012:981461. https://doi.org/10.1155/2012/981461 PMid:23346106

Omobowale TO, Oyagbemi AA, Ajufo UE, Adejumobi OA, Ola- Davies OE, Adedapo AA et al. Ameliorative effect of gallic acid in doxorubicin-induced hepatotoxicity in wistar rats through antioxidant defense system. J Diet Suppl. 2018;15(2):183-96. https://doi.org/10.1080/19390211.2017.1335822 PMid:28718673

Hafez MM, Hamed SS, El-Khadragy MF, Hassan ZK, Al Rejaie SS, Sayed-Ahmed MM et al. Effect of ginseng extract on the TGF-β1 signaling pathway in CCl4-induced liver fibrosis in rats. BMC Complement Altern Med. 2017;17(1):45. https://doi.org/10.1186/s12906-016-1507-0 PMid:28086769

Oda SS, Waheeb RS, El-Maddawy ZK. Potential efficacy of coenzyme Q10 against oxytetracycline-induced hepatorenal and reproductive toxicity in male rats. J Appl Pharm Sci. 2018;8(1):98-107. https://doi.org/10.7324/japs.2018.8115

Farsani BE, Karimi S, Mansouri E. Pravastatin attenuates testicular damage induced by doxorubicin a stereological and histopatological study. J Basic Clin Physiol Pharmacol. 2018;30(1):103-9. https://doi.org/10.1515/jbcpp-2018-0073 PMid:30530881

Dorak M. Real-time PCR. Clin Chem 2018;50:1680-2.

Bancroft JD, Layton C. The hematoxylin and eosin, connective and mesenchymal tissues with their stains. In: Suvarna SK, Layton C, Bancroft JD, editors. Bancroft’s Theory and Practice of Histological Techniques. 7th ed. Philadelphia, PA: Churchill Livingstone; 2013. p. 173-212. https://doi.org/10.1016/b978-0-7020-4226-3.00011-1

Badkoobeh P, Parivar K, Kalantar SM, Hosseini SD, Salabat A. Effect of nano-zinc oxide on doxorubicin induced oxidative stress and sperm disorders in adult male Wistar rats. Iran J Reprod Med. 2013;11(5):355-64. PMid:24639766

Hamadouche AN, Slimani M, Merad-Boudia B, Zaoui C. Reproductive toxicity of lead acetate in adult male rats. Am J Sci Res. 2009;3:38-50.

Barakat BM, Ahmed HI, Bahr HI, Elbahaie AM. Protective effect of boswellic acids against doxorubicin-induced hepatotoxicity: Impact on Nrf2/HO-1 defense pathway. Oxid Med Cell Longev. 2018;2018:8296451. https://doi.org/10.1155/2018/8296451 PMid:29541348

Neilan TG, Blake SL, Ichinose F, Raher MJ, Buys ES, Jassal DS, et al. Disruption of nitric oxide synthase 3 protects against the cardiac injury, dysfunction, and mortality induced by doxorubicin. Circulation. 2007;116(5):506-14. https://doi.org/10.1161/circulationaha.106.652339 PMid:17638931

Kopalli SR, Cha K, Lee S, Ryu J, Hwang S, Jeong M, et al. Pectinase-treated Panax ginseng protects against chronic intermittent heat stress-induced testicular damage by modulating hormonal and spermatogenesis-related molecular expression in rats. J Ginseng Res. 2017;41(4):578-88. https://doi.org/10.1016/j.jgr.2016.12.001 PMid:29021707

Hwang SY, Sohn SH, Wee JJ, Yang JB, Kyung JS, Kwak YS, et al. Panax ginseng improves senile testicular function in rats. J Ginseng Res. 2010;34:327-35. https://doi.org/10.5142/jgr.2010.34.4.327

Won YJ, Kim BK, Shin YK, Jung SH, Yoo SK, Hwang SY, et al. Pectinase-treated Panax ginseng extract (GINST) rescues testicular dysfunction in aged rats via redox-modulating proteins. Exp Gerontol. 2014;53:57-66. https://doi.org/10.1016/j.exger.2014.02.012 PMid:24594315

Kopalli SR, Hwang SY, Won YJ, Kim SW, Cha KM, Han CK, et al. Korean red ginseng extract rejuvenates testicular ineffectiveness and sperm maturation process in aged rats by regulating redox proteins and oxidative defense mechanisms. Exp Gerontol. 2015;69:94-102. https://doi.org/10.1016/j.exger.2015.05.004 PMid:25980653

Kitts DD, Wijewickreme AN, Hu C. Antioxidant properties of a north american ginseng extract. Mol Cell Biochem. 2000;203(1-2):1-10. PMid:10724326

Kim HJ, Chun YJ, Park JD, Kim SI, Roh JK, Jeong TC. Protection of rat liver microsomes against carbon tetrachloride-induced lipid peroxidation by red ginseng saponin through cytochrome P450 inhibition. Planta Med. 1997;63(5):415-8. https://doi.org/10.1055/s-2006-957724 PMid:9342944

Safarinejad MR, Safarinejad S, Shafiei N, Safarinejad S. Effects of the reduced form of coenzyme Q10 (ubiquinol) on semen parameters in men with idiopathic infertility: A double-blind, placebo controlled, randomized study. J Urol. 2012;188(2):526-31. https://doi.org/10.1016/j.juro.2013.01.086 PMid:22704112

Mustafa MN, El-Awdan SA, Hegazy GA, Abdel Jaleel GA. Prophylactic role of coenzyme Q10 and Cynara scolymus L on doxorubicin-induced toxicity in rats. Biochemical and immunohistochemical study. Indian J Pharmacol. 2015;47(6):649-56. https://doi.org/10.4103/0253-7613.169588 PMid:26729958

Geetha A, Catherine J, Sankar R, Devi CS. Lipids and lipoprotein profile in doxorubicin treated rats: Influence of alpha-tocopherol administration. Indian J Exp Biol. 1990;28(11):1071-4. PMid:2283173

Kim HJ, Lee SG, Chae IG, Kim MJ, Im NK, Yu MH, et al. Antioxidant effects of fermented red ginseng extracts in streptozotocin-induced diabetic rats. J Ginseng Res. 2011;35(2):129-37. https://doi.org/10.5142/jgr.2011.35.2.129 PMid:23717054

Kang MS, Yang HM, Kang JY, Ryou SH, Kang JS. Effect of coenzyme Q10 and Ardisia japonica Blume on plasma and liver lipids, platelet aggregation, and erythrocyte Na efflux channels in simvastatin-treated guinea pigs. Nutr Res Pract. 2012;6(5):414-20. https://doi.org/10.4162/nrp.2012.6.5.414 PMid:23198020

Abdel-Wahab MH, El-Mahdy MA, Abd-Ellah MF, Helal GK, Khalifa F, Hamadaa FM. Influence of pcoumaric acid on doxorubicin-induced oxidative stress in rat’s heart. Pharmacol Res. 2003;48(5):461-5. https://doi.org/10.1016/s1043-6618(03)00214-7 PMid:12967591

Yeh YC, Liu TJ, Wang LC, Lee HW, Ting CT. A standardized extract of Ginkgo biloba suppresses doxorubicin-induced oxidative stress and p53-mediated mitochondrial apoptosis in rat testes. Br J Pharmacol. 2009;156(1):48-61. https://doi.org/10.1111/j.1476-5381.2008.00042.x PMid:19133991

Ramesh T, Kim SW, Sung JH, Hwang SY, Sohn SH, Yoo SK, et al. Effect of fermented Panax ginseng extract (GINST) on oxidative stress and antioxidant activities in major organs of aged rats. Exp Gerontol. 2012;47(1):77-84. https://doi.org/10.1016/j.exger.2011.10.007 PMid:22075532

Lee JH, Sul D, Oh E, Jung W, Hwang KW, Hwang TS, et al. Panax ginseng effects on DNA damage, CYP1A1 expression and histopathological changes in testes of rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Food Chem Toxicol. 2007;45(11):2237-44. https://doi.org/10.1016/j.fct.2007.05.019 PMid:17624648

Kitts DD, Hu C. Efficacy and safety of ginseng. Public Health Nutr. 2000;3(4A):473-85. https://doi.org/10.1017/s1368980000000550 PMid:11276295

Saleh AA, Shahin MI, Kelada NA. Hepatoprotective effect of taurine and coenzyme Q10 and their combination against acrylamide-induced oxidative stress in rats. Trop J Pharm Res. 2017;16(8):1849-55. https://doi.org/10.4314/tjpr.v16i8.14

Laredj LN, Licitra F, Puccio HM. The molecular genetics of coenzyme Q biosynthesis in health and disease. Biochimie. 2014;100:78-87. https://doi.org/10.1016/j.biochi.2013.12.006 Mid:24355204

Sohet FM, Neyrinck AM, Pachikian BD, de Backer FC, Bindels LB, Niklowitz P, et al. Coenzyme Q10 supplementation lowers hepatic oxidative stress and inflammation associated with diet-induced obesity in mice. Biochem Pharmacol. 2009;78(11):1391-400. https://doi.org/10.1016/j.bcp.2009.07.008 PMid:19632207

Tsuneki H, Sekizaki N, Suzuki T, Kobayashi S, Wada T, Okamoto T, et al. Coenzyme Q10 prevents high glucose-induced oxidative stress in human umbilical vein endothelial cells. Eur J Pharmacol. 2007;566(1-3):1-10. https://doi.org/10.1016/j.ejphar.2007.03.006 PMid:17434478

Ma T, Kandhare AD, Mukherjee-Kandhare AA, Bodhankar S. Fisetin, a plant flavonoid ameliorates doxorubicin-induced cardiotoxicity in experimental rats: The decisive role of caspase-3, COXII, cTn-I, iNOs and TNF-α. Mol Biol Rep. 2019;46(1):105-18. https://doi.org/10.1007/s11033-018-4450-y PMid:30362071

Schmelzer C, Lindner I, Rimbach G, Niklowitz P, Menke T, Doring F. Functions of coenzyme Q10 in inflammation and gene expression. Biofactors. 2008;32(1-4):179-83. https://doi.org/10.1002/biof.5520320121 PMid:19096114

Schmelzer C, Lorenz G, Lindner I, Rimbach G, Niklowitz P, Menke T, et al. Effects of coenzyme Q10 on TNF-alpha secretion in human and murine monocytic cell lines. Biofactors. 2007;31:35-41. https://doi.org/10.1002/biof.5520310104 PMid:18806307

Martinez-Ruiz A, Lamas S. Signalling by NO-induced protein S-nitrosylation and S-glutathionylation: Convergences and divergences. Cardiovasc Res. 2007;75(2):220-8. https://doi.org/10.1016/j.cardiores.2007.03.016 PMid:17451659

Forman HJ, Davies KJ, Ursini F. How do nutritional antioxidants really work: Nucleophilic tone and parahormesis versus free radical scavenging in vivo. Free Radic Biol Med. 2014;66:24-35. https://doi.org/10.1016/j.freeradbiomed.2014.05.012 PMid:23747930

Finkel T. Signal transduction by reactive oxygen species. J Cell Biol 2011;194(1):7-15. PMid:21746850

Ning C, Gao X, Wang C, Huo X, Liu Z, Sun H, et al. Hepatoprotective effect of ginsenoside Rg1 from Panax ginsengon carbon tetrachloride‐induced acute liver injury by activating Nrf2 signaling pathway in mice. Environ Toxicol. 2018;33(10):1050-60. https://doi.org/10.1002/tox.22616 PMid:29964319

Tarry-Adkins JL, Fernandez-Twinn DS, IP, Neergheen V, CE, Martin-Gronert MS, et al. Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth. Am J Clin Nutr. 2016;103(2):579-88. https://doi.org/10.3945/ajcn.115.119834 PMid:26718412

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-beta-1 expression. Toxicol Appl Pharmacol. 2009;240:377-84. https://doi.org/10.1016/j.taap.2009.07.030 PMid:19647758

Zhang YY, Meng C, Zhang XM, Yuan CH, Wen MD, Chen Z, et al. Ophiopogonin D attenuates doxorubicin-induced autophagic cell death by relieving mitochondrial damage in vitro and in vivo. J Pharmacol Exp Ther. 2015;352(1):166-74. https://doi.org/10.1124/jpet.114.219261 PMid:25378375

Madonna E, Kamel F, Mohammad HMF, Maurice C, Hagras MM. Ginseng nanoparticles protect against methotrexate-induced testicular toxicity in rats. Egypt J Basic Clin Pharmacol. 2019;9:101397. https://doi.org/10.32527/2019/101397

Vasiliev AV, Martinova EA, Sharanova NV, Gapparov MM. Effects of coenzyme Q10 on rat liver cells under conditions of metabolic stress. Bull Exp Biol Med. 2011;150(4):416-9. https://doi.org/10.1007/s10517-011-1156-8 PMid:22268031

Downloads

Published

2021-11-12

How to Cite

1.
Khodir S, Alafify A, Omar E, Al-Gholam M. Protective Potential of Ginseng and/or Coenzyme Q10 on Doxorubicin-induced Testicular and Hepatic Toxicity in Rats. Open Access Maced J Med Sci [Internet]. 2021 Nov. 12 [cited 2026 Oct. 15];9(A):993-1005. Available from: https://oamjms.eu/index.php/mjms/article/view/7063

Issue

Section

Pathophysiology

Categories