SpringerLink
Log in

Exploring Nrf2 as a therapeutic target in testicular dysfunction

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Testicular dysfunction, a major contributory factor to infertility, has received a lot of attention over the recent years. Several studies have linked abnormal sperm function and morphology with an enhanced generation of reactive oxygen species (ROS) and oxidative stress. The nuclear factor erythroid-derived 2 (Nrf2) is a transcriptional response to cellular stresses (intrinsic or extrinsic) that regulates the oxidative status, mitochondrial dysfunction, inflammation, and proteostasis. In this review, the therapeutic role of Nrf2 was explored. To do so, scientific data were retrieved from databases such as Elsevier, Wiley, Web of Science, Springer, PubMed, Taylor and Francis, and Google Scholar using search terms such as “Nrf2” and “testis,” “sperm,” “testicular function,” and “testosterone.” It has been noted that Nrf2 influences the physiology and pathology of testicular dysfunction, especially in the spermatogenic process, by regulating cellular resistance to oxidative stress, inflammation, and environmental toxicants. However, numerous compounds serve as activators and inhibitors of testicular Nrf2. Nrf2 activators might play a therapeutic role in the prevention and treatment of testicular dysfunction, while molecules that inhibit Nrf2 might induce dysfunction in testis components. Nrf2 activators protect cells against oxidative damage and activate Nrf2/KEAP1 signaling which promotes its movement to the nucleus, and increased Nrf2 function and expression, along with their downstream antioxidant gene. Nrf2 inhibitors facilitate oxidative stress via interfering with the Nrf2 signal pathway. The Nrf2 activation could serve as a promising therapeutic target for testicular dysfunction. This review explored the effect of Nrf2 on testicular function while highlighting potential activators and inhibitors of Nrf2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

Not applicable.

References

  • Abdel-Wahab BA, Alkahtani SA, Elagab EA (2020) Tadalafil alleviates cisplatin-induced reproductive toxicity through the activation of the Nrf2/HO-1 pathway and the inhibition of oxidative stress and apoptosis in male rats. Reprod Toxicol 96:165–174

    Article  CAS  PubMed  Google Scholar 

  • Alotaibi MF, Al-Joufi F, Abou Seif HS, Alzoghaibi MA, Djouhri L, Ahmeda AF, Mahmoud AM (2020) Umbelliferone inhibits spermatogenic defects and testicular injury in lead-intoxicated rats by suppressing oxidative stress and inflammation, and improving Nrf2/HO-1 signaling. Drug Des Dev Ther 14:4003

    Article  CAS  Google Scholar 

  • Amara I, Salah A, Timoumi R, Annabi E, Scuto M, Trovato A, Neffati F, Calabrese V, Abid-Essefi S (2020) Effect of di (2-ethylhexyl) phthalate on Nrf2-regulated glutathione homeostasis in mouse kidney. Cell Stress Chaperones 25:919–928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arab HH, Ashour AM, Alqarni AM, Arafa E-SA, Kabel AM (2021) Camel milk mitigates cyclosporine-induced renal damage in rats: targeting p38/ERK/JNK MAPKs, NF-κB, and matrix metalloproteinases. Biology 10:442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arora PK, Srivastava A, Singh VP (2014) Bacterial degradation of nitrophenols and their derivatives. J Hazard Mater 266:42–59

    Article  CAS  PubMed  Google Scholar 

  • Belhadj Slimen I, Najar T, Ghram A, Dabbebi H, Ben Mrad M, Abdrabbah M (2014) Reactive oxygen species, heat stress and oxidative-induced mitochondrial damage. A Review International Journal of Hyperthermia 30:513–523

    Article  CAS  Google Scholar 

  • Bhakkiyalakshmi E, Sireesh D, Rajaguru P, Paulmurugan R, Ramkumar KM (2015) The emerging role of redox-sensitive Nrf2–Keap1 pathway in diabetes. Pharmacol Res 91:104–114

    Article  CAS  PubMed  Google Scholar 

  • Bieniek JM, Drabovich AP, Lo KC (2016) Seminal biomarkers for the evaluation of male infertility. Asian J Androl 18:426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bryan HK, Olayanju A, Goldring CE, Park BK (2013) The Nrf2 cell defence pathway: Keap1-dependent and-independent mechanisms of regulation. Biochem Pharmacol 85:705–717

    Article  CAS  PubMed  Google Scholar 

  • Chen S, Zhu Y, Liu Z, Gao Z, Li B, Zhang D, Zhang Z, Jiang X, Liu Z, Meng L (2015) Grape seed proanthocyanidin extract ameliorates diabetic bladder dysfunction via the activation of the Nrf2 pathway. PLoS ONE 10:e0126457

    Article  PubMed  PubMed Central  Google Scholar 

  • Chian S, Thapa R, Chi Z, Wang XJ, Tang X (2014) Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo. Biochem Biophys Res Commun 447:602–608

    Article  PubMed  Google Scholar 

  • Chun Li Y, Cheng Hao J, Shang B, Zhao C, Juan Wang L, lin Yang K, Zhou He X, Gian Tian Q, Liang Wang Z, Ling **g H (2021) Neuroprotective effects of aucubin on hydrogen peroxide-induced toxicity in human neuroblastoma SH-SY5Y cells via the Nrf2/HO-1 pathway. Phytomedicine 87:153577

  • Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP, Rumsey WL, Attucks OC, Franklin S, Levonen A-L, Kensler TW (2019) Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov 18:295–317

    Article  CAS  PubMed  Google Scholar 

  • Dutta S, Majzoub A, Agarwal A (2019) Oxidative stress and sperm function: a systematic review on evaluation and management. Arab J Urol 17:87–97

    Article  PubMed  PubMed Central  Google Scholar 

  • Ebokaiwe AP, Osawe S, Griffin S, Keck CM, Olusanya O, Ehiri RC (2020) Loranthus micranthus nanoparticles abates streptozotocin-instigated testicular dysfunction in Wistar rats: involvement of glucose metabolism enzymes, oxido-inflammatory stress, steroidogenic enzymes/protein and Nrf2 pathway. Andrologia 52:e13749

    Article  CAS  PubMed  Google Scholar 

  • Eugenio-Pérez D, Medina-Fernández LY, Saldivar-Anaya JA, Molina-Jijón E, Pedraza-Chaverri J (2016) Role of dietary antioxidant agents in chronic kidney. Free Radicals Dis 1:331

    Google Scholar 

  • Feng D, Huang H, Yang Y, Yan T, ** Y, Cheng X, Cui L (2015) Ameliorative effects of N-acetylcysteine on fluoride-induced oxidative stress and DNA damage in male rats’ testis. Mutat Res/gen Toxicol Environ Mutagen 792:35–45

    Article  CAS  Google Scholar 

  • Guerrero-Beltrán CE, Calderón-Oliver M, Pedraza-Chaverri J, Chirino YI (2012) Protective effect of sulforaphane against oxidative stress: recent advances. Exp Toxicol Pathol 64:503–508

    Article  PubMed  Google Scholar 

  • Guo Y, Sun J, Li T, Zhang Q, Bu S, Wang Q, Lai D (2017) Melatonin ameliorates restraint stress-induced oxidative stress and apoptosis in testicular cells via NF-κB/iNOS and Nrf2/HO-1 signaling pathway. Sci Rep 7:1–13

    Google Scholar 

  • Hayes JD, Dinkova-Kostova AT (2014) The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 39:199–218

    Article  CAS  PubMed  Google Scholar 

  • He L, Li P, Yu L-H, Li L, Zhang Y, Guo Y, Long M, He J-B, Yang S-H (2018) Protective effects of proanthocyanidins against cadmium-induced testicular injury through the modification of Nrf2-Keap1 signal path in rats. Environ Toxicol Pharmacol 57:1–8

    Article  CAS  PubMed  Google Scholar 

  • Hu Y, Wang Y, Yan T, Feng D, Ba Y, Zhang H, Zhu J, Cheng X, Cui L, Huang H (2019) N-acetylcysteine alleviates fluoride-induced testicular apoptosis by modulating IRE1α/JNK signaling and nuclear Nrf2 activation. Reprod Toxicol 84:98–107

    Article  CAS  PubMed  Google Scholar 

  • Ishitsuka Y, Ogawa T, Roop D (2020) The KEAP1/NRF2 signaling pathway in keratinization. Antioxidants 9:751

    Article  CAS  PubMed Central  Google Scholar 

  • Jannatifar R, Parivar K, Roodbari NH, Nasr-Esfahani MH (2020) The effect of N-acetyl-cysteine on NRF2 antioxidant gene expression in asthenoteratozoospermia men: a clinical trial study. Int J Fertil Steril 14:171

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang X, Bai Y, Zhang Z, **n Y, Cai L (2014) Protection by sulforaphane from type 1 diabetes-induced testicular apoptosis is associated with the up-regulation of Nrf2 expression and function. Toxicol Appl Pharmacol 279:198–210

    Article  CAS  PubMed  Google Scholar 

  • Kabel AM, Salama SA, Alghorabi AA, Estfanous RS (2020) Amelioration of cyclosporine-induced testicular toxicity by carvedilol and/or alpha-lipoic acid: role of TGF-β1, the proinflammatory cytokines, Nrf2/HO-1 pathway and apoptosis. Clin Exp Pharmacol Physiol 47:1169–1181

    Article  CAS  PubMed  Google Scholar 

  • Karna KK, Soni KK, You JH, Choi NY, Kim HK, Kim CY, Lee SW, Shin YS, Park JK (2020) MOTILIPERM ameliorates immobilization stress-induced testicular dysfunction via inhibition of oxidative stress and modulation of the Nrf2/HO-1 pathway in SD rats. Int J Mol Sci 21:4750

    Article  CAS  PubMed Central  Google Scholar 

  • Kayode OT, Rotimi DE, Olaolu TD, Adeyemi OS (2020) Ketogenic diet improves and restores redox status and biochemical indices in monosodium glutamate-induced rat testicular toxicity. Biomed Pharmacother 127:110227

    Article  CAS  PubMed  Google Scholar 

  • Keum Y-S, Choi BY (2014) Molecular and chemical regulation of the Keap1-Nrf2 signaling pathway. Molecules 19:10074–10089

    Article  PubMed  PubMed Central  Google Scholar 

  • Khan AR, Awan FR (2014) Metals in the pathogenesis of type 2 diabetes. J Diabetes Metab Disord 13:1–6

    Article  Google Scholar 

  • Kitamura H, Motohashi H (2018) NRF2 addiction in cancer cells. Cancer Sci 109:900–911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krajka-Kuźniak V, Paluszczak J, Baer-Dubowska W (2017) The Nrf2-ARE signaling pathway: an update on its regulation and possible role in cancer prevention and treatment. Pharmacol Rep 69:393–402

    Article  PubMed  Google Scholar 

  • Kumar H, Kim I-S, More SV, Kim B-W, Choi D-K (2014) Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases. Nat Prod Rep 31:109–139

    Article  CAS  PubMed  Google Scholar 

  • Le X, Luo P, Gu Y, Tao Y, Liu H (2015) Interventional effects of squid ink polysaccharides on cyclophosphamide-associated testicular damage in mice. Bratisl Lek Listy 116:334–339

    CAS  PubMed  Google Scholar 

  • Li J, Li Y, Pan S, Zhang L, He L, Niu Y (2019) Paeonol attenuates ligation-induced periodontitis in rats by inhibiting osteoclastogenesis via regulating Nrf2/NF-κB/NFATc1 signaling pathway. Biochimie 156:129–137

    Article  CAS  PubMed  Google Scholar 

  • Li S, Xu S, Niu Q, Ding Y, Pang L, Ma R, **g M, Wang K, Ma X, Feng G (2016) Lutein alleviates arsenic-induced reproductive toxicity in male mice via Nrf2 signaling. Hum Exp Toxicol 35:491–500

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Cao Y, Wang F, Li C (2014) Scrotal heat induced the Nrf2-driven antioxidant response during oxidative stress and apoptosis in the mouse testis. Acta Histochem 116:883–890

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Huang Y, Piao Y, Nagaoka K, Watanabe G, Taya K, Li C (2013) Protective effects of nuclear factor erythroid 2-related factor 2 on whole body heat stress-induced oxidative damage in the mouse testis. Reprod Biol Endocrinol 11:1–10

    Article  Google Scholar 

  • Liu C, Wang X, Shulaev V, Dixon RA (2016) A role for leucoanthocyanidin reductase in the extension of proanthocyanidins. Nature Plants 2:1–7

    Article  CAS  Google Scholar 

  • Liu T, Li N, Zhu J, Yu G, Guo K, Zhou L, Zheng D, Qu X, Huang J, Chen X (2014) Effects of di-(2-ethylhexyl) phthalate on the hypothalamus-pituitary-ovarian axis in adult female rats. Reprod Toxicol 46:141–147

    Article  CAS  PubMed  Google Scholar 

  • Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J (2016) Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 73:3221–3247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo Q, Li Y, Huang C, Cheng D, Ma W, **a Y, Liu W, Chen Z (2019) Soy isoflavones improve the spermatogenic defects in diet-induced obesity rats through Nrf2/HO-1 pathway. Molecules 24:2966

    Article  CAS  PubMed Central  Google Scholar 

  • Ma B, Zhang J, Zhu Z, Bao X, Zhang M, Ren C, Zhang Q (2019a) Aucubin, a natural iridoid glucoside, attenuates oxidative stress-induced testis injury by inhibiting JNK and CHOP activation via Nrf2 up-regulation. Phytomedicine 64:153057

    Article  CAS  PubMed  Google Scholar 

  • Ma B, Zhang J, Zhu Z, Zhao A, Zhou Y, Ying H, Zhang Q (2019b) Luteolin ameliorates testis injury and blood–testis barrier disruption through the Nrf2 signaling pathway and by upregulating Cx43. Mol Nutr Food Res 63:1800843

    Article  Google Scholar 

  • Ma B, Zhu Z, Zhang J, Ren C, Zhang Q (2020) Aucubin alleviates diabetic nephropathy by inhibiting NF-κB activation and inducing SIRT1/SIRT3-FOXO3a signaling pathway in high-fat diet/streptozotocin-induced diabetic mice. J Function Foods 64:103702

    Article  CAS  Google Scholar 

  • Manayi A, Abdollahi M, Raman T, Nabavi SF, Habtemariam S, Daglia M, Nabavi SM (2016) Lutein and cataract: from bench to bedside. Crit Rev Biotechnol 36:829–839

    Article  CAS  PubMed  Google Scholar 

  • Maremanda KP, Khan S, Jena G (2014) Zinc protects cyclophosphamide-induced testicular damage in rat: involvement of metallothionein, tesmin and Nrf2. Biochem Biophys Res Commun 445:591–596

    Article  CAS  PubMed  Google Scholar 

  • Maremanda KP, Khan S, Jena G (2016) Role of zinc supplementation in testicular and epididymal damages in diabetic rat: involvement of Nrf2, SOD1, and GPX5. Biol Trace Elem Res 173:452–464

    Article  CAS  PubMed  Google Scholar 

  • Mercantepe T, Unal D, Tümkaya L, Yazici ZA (2018) Protective effects of amifostine, curcumin and caffeic acid phenethyl ester against cisplatin-induced testis tissue damage in rats. Exp Ther Med 15:3404–3412

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mi Y, Tu L, Wang H, Zeng W, Zhang C (2013) Supplementation with quercetin attenuates 4-nitrophenol-induced testicular toxicity in adult male mice. Anat Rec 296:1650–1657

    Article  CAS  Google Scholar 

  • Mohamed MZ, Morsy MA, Mohamed HH, Hafez HM (2020) Paeonol protects against testicular ischaemia-reperfusion injury in rats through inhibition of oxidative stress and inflammation. Andrologia 52:e13599

    Article  CAS  PubMed  Google Scholar 

  • Moon EJ, Giaccia A (2015) Dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment. Free Radical Biol Med 79:292–299

    Article  CAS  Google Scholar 

  • Moreno-Fernandez J, Alférez MJ, López-Aliaga I, Diaz-Castro J (2019) Protective effects of fermented goat milk on genomic stability, oxidative stress and inflammatory signalling in testis during anaemia recovery. Sci Rep 9:1–11

    Google Scholar 

  • Ojo OA, Ajiboye B, Fadaka A, Taro P, Shariati MA (2017) Nrf2-Keap1 activation, a promising strategy in the prevention of cancer. Free Radacals Antioxid 7:1–7

    CAS  Google Scholar 

  • Olaolu D, Rotimi DE, Olaolu AP (2018) Effect of alcohol infusion of Cissus populnea root on testicular function and serum hormone of male Wistar rats. Asian Pacific J Reproduct 7:117–122

    Article  CAS  Google Scholar 

  • Pallesen JS, Tran KT, Bach A (2018) Non-covalent small-molecule Kelch-like ECH-associated protein 1–nuclear factor erythroid 2-related factor 2 (Keap1–Nrf2) inhibitors and their potential for targeting central nervous system diseases. J Med Chem 61:8088–8103

    Article  CAS  PubMed  Google Scholar 

  • Qin Z, Tang J, Han P, Jiang X, Yang C, Li R, Tang M, Shen B, Wang W, Qin C (2017) Protective effects of sulforaphane on di-n-butylphthalate-induced testicular oxidative stress injury in male mice offsprings via activating Nrf2/ARE pathway. Oncotarget 8:82956

    Article  PubMed  PubMed Central  Google Scholar 

  • Rajput SA, Sun L, Zhang N-Y, Khalil MM, Ling Z, Chong L, Wang S, Rajput IR, Bloch DM, Khan FA (2019) Grape seed proanthocyanidin extract alleviates aflatoxinB1-induced immunotoxicity and oxidative stress via modulation of NF-κB and Nrf2 signaling pathways in broilers. Toxins 11:23

    Article  CAS  PubMed Central  Google Scholar 

  • Renu K, Gopalakrishnan AV (2019) Deciphering the molecular mechanism during doxorubicin-mediated oxidative stress, apoptosis through Nrf2 and PGC-1α in a rat testicular milieu. Reprod Biol 19:22–37

    Article  PubMed  Google Scholar 

  • Rössler OG, Thiel G (2017) Specificity of stress-responsive transcription factors Nrf2, ATF4, and AP-1. J Cell Biochem 118:127–140

    Article  PubMed  Google Scholar 

  • Sabeti P, Pourmasumi S, Rahiminia T, Akyash F, Talebi AR (2016) Etiologies of sperm oxidative stress. Int J Reproduct Biomed 14:231

    CAS  Google Scholar 

  • Saha S, Buttari B, Panieri E, Profumo E, Saso L (2020) An overview of Nrf2 signaling pathway and its role in inflammation. Molecules 25:5474

    Article  CAS  PubMed Central  Google Scholar 

  • Sengupta P, Nwagha U, Dutta S, Krajewska-Kulak E, Izuka E (2017) Evidence for decreasing sperm count in African population from 1965 to 2015. Afr Health Sci 17:418–427

    Article  PubMed  PubMed Central  Google Scholar 

  • Shahat A, Rizzoto G, Kastelic J (2020) Amelioration of heat stress-induced damage to testes and sperm quality. Theriogenology 158:84–96

    Article  CAS  PubMed  Google Scholar 

  • Shi X, Fu L (2019) Piceatannol inhibits oxidative stress through modification of Nrf2-signaling pathway in testes and attenuates spermatogenesis and steroidogenesis in rats exposed to cadmium during adulthood. Drug Des Dev Ther 13:2811

    Article  CAS  Google Scholar 

  • Sihvola V, Levonen A-L (2017) Keap1 as the redox sensor of the antioxidant response. Arch Biochem Biophys 617:94–100

    Article  CAS  PubMed  Google Scholar 

  • Sinha D, Biswas J, Bishayee A (2013) Nrf2-mediated redox signaling in arsenic carcinogenesis: a review. Arch Toxicol 87:383–396

    Article  CAS  PubMed  Google Scholar 

  • Soni KK, Zhang LT, Choi BR, Karna KK, You JH, Shin YS, Lee SW, Kim CY, Zhao C, Chae H-J (2018) Protective effect of MOTILIPERM in varicocele-induced oxidative injury in rat testis by activating phosphorylated inositol requiring kinase 1α (p-IRE1α) and phosphorylated c-Jun N-terminal kinase (p-JNK) pathways. Pharm Biol 56:94–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sumathy VJH (2016) Identification of Lyc Studies. Int J Curnt Tren Pharm Res 4:351–354

    Google Scholar 

  • Sun C, Liu X, Di C, Wang Z, Mi X, Liu Y, Zhao Q, Mao A, Chen W, Gan L (2017) MitoQ regulates autophagy by inducing a pseudo-mitochondrial membrane potential. Autophagy 13:730–738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun Y, **u C, Liu W, Tao Y, Wang J, Qu Y (2016) Grape seed proanthocyanidin extract protects the retina against early diabetic injury by activating the Nrf2 pathway. Exp Ther Med 11:1253–1258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang X, Wu S, Shen L, Wei Y, Cao X, Wang Y, Long C, Zhou Y, Li D, Huang F (2018) Di-(2-ethylhexyl) phthalate (DEHP)-induced testicular toxicity through Nrf2-mediated Notch1 signaling pathway in Sprague-Dawley rats. Environ Toxicol 33:720–728

    Article  CAS  PubMed  Google Scholar 

  • Tonelli C, Chio IIC, Tuveson DA (2018) Transcriptional regulation by Nrf2. Antioxid Redox Signal 29:1727–1745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tong Y-H, Zhang B, Fan Y, Lin N-M (2015) Keap1-Nrf2 pathway: a promising target towards lung cancer prevention and therapeutics. Chronic Dis Translation Med 1:175–186

    Article  Google Scholar 

  • Uddin MS, Al Mamun A, Jakaria M, Thangapandiyan S, Ahmad J, Rahman MA, Mathew B, Abdel-Daim MM, Aleya L (2020) Emerging promise of sulforaphane-mediated Nrf2 signaling cascade against neurological disorders. Sci Total Environ 707:135624

    Article  CAS  PubMed  Google Scholar 

  • Wajda A, Łapczuk J, Grabowska M, Słojewski M, Laszczyńska M, Urasińska E, Droździk M (2016) Nuclear factor E2-related factor-2 (Nrf2) expression and regulation in male reproductive tract. Pharmacol Rep 68:101–108

    Article  CAS  PubMed  Google Scholar 

  • Wang S-n, **e G-p, Qin C-h, Chen Y-r, Zhang K-r, Li X, Wu Q, Dong W-q, Yang J, Yu B (2015) Aucubin prevents interleukin-1 beta induced inflammation and cartilage matrix degradation via inhibition of NF-κB signaling pathway in rat articular chondrocytes. Int Immunopharmacol 24:408–415

    Article  PubMed  Google Scholar 

  • Wang Y, Chen F, Liang M, Chen S, Zhu Y, Zou Z, Shi B (2018) Grape seed proanthocyanidin extract attenuates varicocele-induced testicular oxidative injury in rats by activating the Nrf2-antioxidant system. Mol Med Rep 17:1799–1806

    CAS  PubMed  Google Scholar 

  • Wang Y, Zhang Z, Guo W, Sun W, Miao X, Wu H, Cong X, Wintergerst KA, Kong X, Cai L (2014) Sulforaphane reduction of testicular apoptotic cell death in diabetic mice is associated with the upregulation of Nrf2 expression and function. Am J Physiol-Endocrinol Metab 307:E14–E23

    Article  CAS  PubMed  Google Scholar 

  • Wu S, Lu H, Bai Y (2019) Nrf2 in cancers: a double-edged sword. Cancer Med 8:2252–2267

    Article  PubMed  PubMed Central  Google Scholar 

  • **ao L, Xu X, Zhang F, Wang M, Xu Y, Tang D, Wang J, Qin Y, Liu Y, Tang C (2017) The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1. Redox Biol 11:297–311

    Article  CAS  PubMed  Google Scholar 

  • Xu C, Wu A, Zhu H, Fang H, Xu L, Ye J, Shen J (2013) Melatonin is involved in the apoptosis and necrosis of pancreatic cancer cell line SW-1990 via modulating of Bcl-2/Bax balance. Biomed Pharmacother 67:133–139

    Article  CAS  PubMed  Google Scholar 

  • Yalcin H, Çapar TD (2017) Bioactive compounds of fruits and vegetables. Minimally Processed Refrigerated Fruits and Vegetables. Springer, pp 723–745

  • Yamamoto M, Kensler TW, Motohashi H (2018) The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev 98:1169–1203

    Article  CAS  PubMed  Google Scholar 

  • Yang ZhuJ, Luo X, Li F, Cong L, Wang Y, Sun Y (2019a) Melatonin attenuates cadmium-induced ovulatory dysfunction by suppressing endoplasmic reticulum stress and cell apoptosis. Reprod Biol Endocrinol 17:1–8

    Article  Google Scholar 

  • Yang L, Palliyaguru DL, Kensler TW (2016) Frugal chemoprevention: targeting Nrf2 with foods rich in sulforaphane. Sem Oncol 43. Elsevier, pp 146–153

  • Yang S-H, He J-B, Yu L-H, Li L, Long M, Liu M-D, Li P (2019b) Protective role of curcumin in cadmium-induced testicular injury in mice by attenuating oxidative stress via Nrf2/ARE pathway. Environ Sci Pollut Res 26:34575–34583

    Article  CAS  Google Scholar 

  • Yang S-H, Yu L-H, Li L, Guo Y, Zhang Y, Long M, Li P, He J-B (2018) Protective mechanism of sulforaphane on cadmium-induced Sertoli cell injury in mice testis via Nrf2/ARE signaling pathway. Molecules 23:1774

    Article  PubMed Central  Google Scholar 

  • Zang H, Mathew RO, Cui T (2020) The dark side of Nrf2 in the heart. Front Physiol 11:722

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Cao Y, Wang F, Song M, Rui X, Li Y, Li C (2016) 4-Nitrophenol induces activation of Nrf2 antioxidant pathway and apoptosis of the germ cells in rat testes. Environ Sci Pollut Res 23:13035–13046

    Article  CAS  Google Scholar 

  • Zhang Y, Piao Y, Li Y, Song M, Tang P, Li C (2013) 4-Nitrophenol induces Leydig cells hyperplasia, which may contribute to the differential modulation of the androgen receptor and estrogen receptor-α and-β expression in male rat testes. Toxicol Lett 223:228–235

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Li M-Z, Shen Y, Lin J, Wang H-R, Talukder M, Li J-L (2019) Lycopene prevents DEHP-induced Leydig cell damage with the Nrf2 antioxidant signaling pathway in mice. J Agric Food Chem 68:2031–2040

    Article  Google Scholar 

  • Zhao Y, Li M-Z, Talukder M, Luo Y, Shen Y, Wang H-R, Li J-L (2020) Effect of mitochondrial quality control on the lycopene antagonizing DEHP-induced mitophagy in spermatogenic cells. Food Funct 11:5815–5826

    Article  CAS  PubMed  Google Scholar 

  • Zong S, Pu Y, Li S, Xu B, Zhang Y, Zhang T, Wang B (2018) Beneficial anti-inflammatory effect of paeonol self-microemulsion-loaded colon-specific capsules on experimental ulcerative colitis rats. Artif Cells Nanomed Biotechnol 46:324–335

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. SDG 03 Group – Good Health & Well-being, Landmark University, Kwara State, Omu-Aran, 251101, Nigeria

    Damilare E. Rotimi, Tomilola D. Olaolu & Oluyomi S. Adeyemi

  2. Department of Biochemistry, Medicinal Biochemistry, Nanomedicine & Toxicology Laboratory, Landmark University, PMB 1001, Omu-Aran, 251101, Nigeria

    Damilare E. Rotimi, Oluwafemi A. Ojo, Tomilola D. Olaolu & Oluyomi S. Adeyemi

  3. Department of Biochemistry, Bowen University, Iwo, Nigeria

    Oluwafemi A. Ojo

Authors
  1. Damilare E. Rotimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oluwafemi A. Ojo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomilola D. Olaolu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Oluyomi S. Adeyemi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RDE conceived and designed the study; RDE, OTD, OAO, and AOS collaborated in the discussion of the results. All authors wrote the manuscript and provided administrative support and critically revised the manuscript. All the authors have and approved the final manuscript.

Corresponding author

Correspondence to Damilare E. Rotimi.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rotimi, D.E., Ojo, O.A., Olaolu, T.D. et al. Exploring Nrf2 as a therapeutic target in testicular dysfunction. Cell Tissue Res 390, 23–33 (2022). https://doi.org/10.1007/s00441-022-03664-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-022-03664-3

Keywords

Search

Navigation