Next Article in Journal
A Consolidated Understanding of the Contribution of Redox Dysregulation in the Development of Hearing Impairment
Previous Article in Journal
Assessment of the Antioxidant and Hypolipidemic Properties of Salicornia europaea for the Prevention of TAFLD in Rats
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Antioxidants
Volume 13
Issue 5
10.3390/antiox13050597
antioxidants-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Bioactive Compounds Protect Mammalian Reproductive Cells from Xenobiotics and Heat Stress-Induced Oxidative Distress via Nrf2 Signaling Activation: A Narrative Review

by
Muhammad Zahoor Khan
1,*,
Adnan Khan
2,
Bingjian Huang
1,
Ren Wei
1,
Xiyan Kou
1,
Xinrui Wang
1,
Wenting Chen
1,
Liangliang Li
1,
Muhammad Zahoor
3 and
Changfa Wang
1,*
1
Liaocheng Research Institute of Donkey High-Efficiency Breeding and Ecological Feeding, Liaocheng University, Liaocheng 522000, China
2
Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 511464, China
3
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Sognsvannsveien, 90372 Oslo, Norway
*
Authors to whom correspondence should be addressed.
Antioxidants 2024, 13(5), 597; https://doi.org/10.3390/antiox13050597
Submission received: 3 April 2024 / Revised: 8 May 2024 / Accepted: 10 May 2024 / Published: 13 May 2024
(This article belongs to the Special Issue Novel Antioxidants for Animal Nutrition—2nd Edition)
Browse Figure
Versions Notes

Abstract

:
Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body’s antioxidant defenses. It poses a significant threat to the physiological function of reproductive cells. Factors such as xenobiotics and heat can worsen this stress, leading to cellular damage and apoptosis, ultimately decreasing reproductive efficiency. The nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathway plays a crucial role in defending against oxidative stress and protecting reproductive cells via enhancing antioxidant responses. Dysregulation of Nrf2 signaling has been associated with infertility and suboptimal reproductive performance in mammals. Recent advancements in therapeutic interventions have underscored the critical role of Nrf2 in mitigating oxidative damage and restoring the functional integrity of reproductive cells. In this narrative review, we delineate the harmful effects of heat and xenobiotic-induced oxidative stress on reproductive cells and explain how Nrf2 signaling provides protection against these challenges. Recent studies have shown that activating the Nrf2 signaling pathway using various bioactive compounds can ameliorate heat stress and xenobiotic-induced oxidative distress and apoptosis in mammalian reproductive cells. By comprehensively analyzing the existing literature, we propose Nrf2 as a key therapeutic target for mitigating oxidative damage and apoptosis in reproductive cells caused by exposure to xenobiotic exposure and heat stress. Additionally, based on the synthesis of these findings, we discuss the potential of therapies focused on the Nrf2 signaling pathway to improve mammalian reproductive efficiency.

1. Introduction

External environmental stressors such as high temperatures and exposure to xenobiotics significantly contribute to the initiation of oxidative stress and apoptosis processes, which have a negative impact on the functionality of reproductive cells [1,2,3,4]. Normally, an organism’s intrinsic antioxidant mechanisms are able to counteract the harmful effects of reactive oxygen species (ROS) overproduction, thus maintaining cellular integrity [5]. However, when there is chronic and excessive ROS generation, oxidative stress occurs, resulting in cellular damage and disruption of normal physiological processes [6]. To mitigate these effects, the use of external antioxidants is recommended to improve cellular antioxidant capacity and influence important biochemical pathways, including the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. This intervention aims to protect mammalian reproductive cells from oxidative damage and apoptosis [2,7,8,9].
The Nrf2 protein serves as a vital transcription factor essential for preserving the integrity of redox signaling when cells face oxidative stress [10,11]. As a member of the cap’n’collar basic leucine zipper transcription factor family, Nrf2 plays a vital role in coordinating antioxidant and detoxification responses by upregulating downstream genes [12,13,14]. Under normal conditions, Nrf2 predominantly resides in the cytoplasm, forming a complex with its inhibitory partner, Kelch-like ECH-associated protein 1 (Keap1). However, in the presence of elevated levels of ROS, this complex dissociates, allowing Nrf2 to translocate from the cytoplasm into the nucleus [2,15,16]. Once activated, Nrf2 binds to the antioxidant response element (ARE) sequence, starting the transcription of genes involved in antioxidant defenses to counteract ROS-induced damage [9,17,18,19]. Recent research suggests that p62 competes with Keap1 for binding to the Nrf2 site, disrupting their association, releasing ubiquitinated Nrf2, and subsequently activating the Nrf2–antioxidant systems [20,21].
The role of Nrf2 signaling in safeguarding the reproductive cells/organs against oxidative stress has been extensively studied [22,23,24]. It has been well documented that supplementation of bioactive compounds protects reproductive cells from oxidative stress induced by heat stress and environmental toxicants, via regulation of Nrf2 signaling [25]. Nrf2 has demonstrated protective effects on bovine granulosa cells against H2O2-induced oxidative stress [26]. Additionally, research by Sun et al. [27] illustrated that supplementation of melatonin safeguarded cryopreserved ovarian tissues from oxidative stress and apoptosis through the Nrf2/HO-1 signaling pathway. They observed an elevation in Nrf2 levels following melatonin administration, leading to the regulation of antioxidant genes [glutathione peroxidase (GSH-Px), catalase (CAT), superoxide dismutase (SOD), and heme oxygenase 1 (HO-1)] and a reduction in malondialdehyde (MDA) content [27]. Antioxidant responses, including autophagy and Nrf2 activation, are triggered in response to heat stress-induced apoptosis [9,21]. Alterations in autophagy dynamics play a crucial role in regulating the protective function of the Nrf2 signaling pathway in the testes. This protection involves the suppression of MDA levels and the promotion of an antioxidant status that shields the testes from the detrimental effects of heat stress [28,29,30]. Notably, inhibition of Nrf2 leads to decreased cell viability, increased MDA levels, and Sertoli cell death [11]. Consistently, studies have shown that exposure to heavy metals such as aluminum results in downregulated Nrf2 expression, increased oxidative stress, and toxicity, negatively impacting male reproductive function [31].
Nrf2 regulates several critical antioxidant genes, such as CAT, heme oxygenase 1 (HMOX1), peroxiredoxin 1 (PRDX1), SOD1, and thioredoxin 1 (TXN1). These genes collectively enhance antioxidant activity, thereby mitigating oxidative stress in mouse testis cells and safeguarding germ cells and Leydig cells from oxidative damage [30,32]. Recent research has revealed that heat stress-induced ROS overproduction suppresses the expression of antioxidant genes (SOD, CAT, quinone oxidoreductase 1 (NQO1), and GSH-Px) in uterine tissue [33]. In Sertoli cells, heightened ROS levels due to heat stress elevate MDA levels and reduce antioxidant enzyme levels [34]. Additionally, heat stress increases the expression of apoptotic markers such as Fas, FasL, caspase 3, and caspase 9 in mouse Sertoli cells [34]. Consequently, the Keap1/Nrf2 signaling pathway is significantly associated with the protective effects observed in mouse uterine tissue, characterized by increased levels of antioxidant genes [33].
Moreover, oxidative stress affects various crucial signaling pathways, including the Nrf2/Keap1 signaling axis in the testes [24]. Recent studies emphasize Nrf2’s protective role in shielding mouse Sertoli cells from heat-induced oxidative stress through the Nrf2/Keap1 signaling pathway [11]. Similarly, another investigation demonstrated that Nrf2 significantly reduces caspase 3 levels, consequently decreasing cell death induced by heat stress treatment in Sertoli cells [29]. Under conditions of severe heat stress, heightened expression of Keap1 and Nrf2 facilitates the regulation of genes associated with antioxidants through forming complexes with antioxidant regulated elements (ARE), thus establishing a defensive mechanism against heat stress within bovine endometrial epithelial cells [35]. These findings collectively underscore the critical role of Nrf2 in alleviating oxidative stress and apoptosis in various cellular contexts, particularly under heat stress conditions.
Overall, Nrf2 plays a significant role in regulating the physiology and pathology of reproductive cells via modulating cellular resistance to oxidative stress and apoptosis induced through various factors such as chemicals, environmental toxicants, and heat stress [20]. However, it is notable that several compounds act as both activators and inhibitors of testicular Nrf2. Nrf2 activators potentially hold therapeutic promise in preventing and treating testicular dysfunction, while Nrf2 inhibitors may contribute to dysfunction within testicular components. Activators of Nrf2 confer cellular protection against oxidative damage by stimulating Nrf2-related signaling pathways, facilitating its translocation into the nucleus, and enhancing Nrf2 function and expression, thereby upregulating downstream antioxidant gene expression. Conversely, Nrf2 inhibitors exacerbate oxidative stress by interfering with the Nrf2 signaling pathway. Therefore, this narrative review aims to investigate the impact of xenobiotics and heat stress-induced oxidative distress and apoptosis on the physiology of reproductive cells, while also addressing the protective role of activating the Nrf2 signaling pathway against oxidative stress and apoptosis in mammalian reproductive cells via supplementation of bioactive compounds.

2. Methodology

This study’s methodology entailed a comprehensive literature review, primarily focusing on scholarly articles published between 2018 and April 2024. Additionally, select publications dating back to 2013 were also incorporated, specifically those addressing the role of Nrf2 signaling in mitigating oxidative stress and apoptosis induced by heat stress in mammalian reproductive cells. The literature search was conducted using esteemed academic databases, including Google Scholar, Web of Science, X-MOL, and PubMed. The selection of literature was guided by a set of predetermined keywords: “Oxidative Stress”, “Apoptosis”, “Mammalian Reproductive Cells”, “Nrf2 Signaling”, “Xenobiotics”, “Heat Stress”, and “Bioactive Compounds Regulating Nrf2 Signaling”. To ensure the credibility and relevance of the sourced information, only articles published in English and indexed in Science Citation Index (SCI) Journals were considered for this review. In addition, book chapters and articles published in non-English languages were excluded from this review to maintain a focused and high-quality dataset for analysis.

3. Administration of Bioactive Compounds Protects Mammalian Reproductive Cells against Xenobiotic and Heat Stress-Induced Oxidative Stress through Nrf2 Signaling Activation

The regulation of Nrf2 is intricately managed through its interaction with Keap1. In a state of equilibrium, Keap1 confines Nrf2 within the cytoplasm, maintaining it at minimal levels. This confinement is achieved through the binding of Keap1 to Nrf2 at its C-terminal region, which triggers the ubiquitination of Nrf2. The ubiquitination process, facilitated by the Keap1–Cullin3–RING box protein complex, leads to the subsequent degradation of Nrf2 by the 26S proteasome [29]. During episodes of oxidative distress caused by heat stress or xenobiotics, the increased expression of Keap1 inhibits the translocation of Nrf2 to the nucleus [3,27,33], consequently reducing the antioxidant response (Figure 1B). Conversely, supplementation with bioactive compounds has been observed to downregulate Keap1 expression, resulting in increased Nrf2 levels and subsequent elevation of downstream antioxidant response genes, such as NAD(P)H quinone dehydrogenase 1 (NQO1), HO-1, SOD1, CAT, and GPx (Figure 1A) [30,36]. Consistently, the pivotal role of Nrf2 in antioxidant defense has been well documented, highlighting its importance in combating oxidative stress and mitigating cellular damage [37,38]. In addition, the therapeutic potential of modulating Nrf2 signaling via administration of bioactive compounds to alleviate oxidative stress has garnered considerable attention in the recent literature [11,14,39,40,41,42,43,44]. Furthermore, the Nrf2 signaling cascade, in conjunction with other protective mechanisms, is crucial in preserving the integrity of mammalian reproductive cells against oxidative stress. This safeguarding is essential for maintaining reproductive health and function.

4. Bioactive Compound Supplementation to Combat Xenobiotic-Induced Oxidative Stress and Apoptosis in Reproductive Cells via Activation of the Nrf2 Signaling Pathway

Xenobiotic agents have been identified as initiators of ROS generation, subsequently inducing oxidative stress [45]. This oxidative milieu has been implicated in impairing the integrity of key reproductive cells, including Sertoli cells, spermatogonial cells, and granulosa cells, potentially underpinning reduced reproductive efficiency and health [46,47,48,49]. The perturbation is manifested through mechanisms such as increased DNA fragmentation in spermatozoa, disruption of mitochondrial membrane lipids in sperm, and compromised functionality of granulosa cells. In response, a spectrum of therapeutic interventions has been explored to fortify reproductive cells against xenobiotic-induced oxidative insult, specifically through the modulation of the Nrf2 signaling cascade [50]. To combat xenobiotic-induced oxidative stress and apoptosis in reproductive cells, several exogenous bioactive compounds with antioxidant properties have been given to animals. These operate via regulating Nrf2 signaling in reproductive cells and consequently ameliorate oxidative damage. Notably, Ji et al. [51] elucidated the ameliorative effects of salidroside on oxidative stress and apoptosis in dihydrotestosterone-challenged human granulosa cells via the AMP-activated protein kinase (AMPK)/Nrf2 pathway, marked by upregulation of Nrf2, HO-1, and NQO1. In a similar way, sulforaphane has been shown to confer protection to bovine granulosa cells against H2O2-induced oxidative stress through Nrf2 pathway activation, enhancing antioxidant defenses including SOD, CAT, NQO1, and HO-1, thereby mitigating oxidative stress and apoptosis [26,52].
Further investigations have revealed that lycopene counteracts dihydrotestosterone-induced oxidative stress in human granulosa cells by activating the Nrf2 signaling pathway [53], while anthocyanins have been reported to safeguard testicular tissue from cadmium-induced oxidative harm through Nrf2 signaling mediation, also revitalizing the activity of key antioxidant enzymes [3]. Targeting the Nrf2/HO-1 axis, carvacrol administration in rats has shown promise in alleviating oxidative stress and apoptosis, evidenced by modulated expression of Bcl-2, Nrf2, CAT, GPx, and HO-1 and reduced MDA and Bax levels in testicular tissue [54]. Another study highlighted sitagliptin’s efficacy in attenuating cadmium-induced oxidative stress and toxicity in rats via the Nrf2/HO-1 pathway, resulting in improved testicular health markers [55]. Complementary to these findings, treatments with Artemisia judaica extract, ellagic acid, and cardamonin significantly curtailed oxidative stress and apoptosis in diabetic rat testes, underscoring the therapeutic potential of these agents in modulating oxidative balance [56,57,58]. Vitamin D3 has also been recognized for its capacity to mitigate lead-induced oxidative stress and toxicity in rat testes through Nrf2 signaling pathway regulation [59].
In the realm of granulosa cell protection, sulforaphane’s role in enhancing the antioxidant response, thereby shielding the cells from oxidative stress-induced damage, has been reaffirmed [60]. Additionally, vitamin E supplementation has emerged as a viable strategy in bolstering bovine granulosa cell resilience against oxidative stress and apoptosis, facilitated by Nrf2 pathway activation [61]. The deleterious impact of methotrexate on testicular tissue underscores the need for protective agents, with apocynin showing efficacy in safeguarding the testis through Nrf2 signaling pathway activation [62]. Furthermore, the role of deubiquitination in mitigating testicular oxidative stress injury induced by di-n-butylphthalate via the Keap1/Nrf2 signaling pathway has been explored [63]. The emerging concern of diminished ovarian reserve (DOR) in reproductive-aged women, associated with inflammation, has been addressed through studies demonstrating the beneficial effects of moxibustion in modulating the Nrf2/HO-1/nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) anti-inflammatory pathway, thereby offering therapeutic insights into DOR management [64]. Collectively, these insights underscore the pivotal role of the Nrf2 signaling pathway in countering the oxidative challenges posed by xenobiotics to mammalian reproductive cells, as encapsulated in Table 1.

5. Bioactive Compound Supplementation to Combat Heat Stress Induced Oxidative Stress and Apoptosis in Mammalian Reproductive Cells via Activation of the Nrf2 Signaling Pathway

Exposure to high temperature has been linked to the activation of cell death and oxidative stress responses within reproductive cells. This phenomenon is supported by a study conducted by Sammad et al. [137], wherein bovine granulosa cells exposed to a thermal stress of 43 °C for 2 h showed a decrease in Nrf2 signaling, resulting in increased apoptosis and oxidative stress markers. Consistently, another study found that heat treatment increased ROS production in granulosa cells with silenced HO-1 and Nrf2 genes [138]. However, granulosa cells with overexpressed HO-1 and Nrf2 genes demonstrated significant resistance, including increased antioxidant response and anti-apoptotic activities [138]. Sertoli cells, which play a vital role in supporting the development of germ cells, rely on normal glucose metabolism for effective spermatogenesis. Melatonin has emerged as a potential therapeutic agent for mitigating the negative effects of heat stress on spermatogenesis. Research by Deng et al. [139] revealed that melatonin reduced heat-induced oxidative stress and apoptotic pathways by activating the KEAP1/Nrf2 signaling axis, thereby enhancing antioxidant defenses. In a parallel finding, He et al. [11] demonstrated the protective role of the Nrf2 signaling pathway against heat stress-induced oxidative challenges in Sertoli cells. Inhibition of the Nrf2 signaling pathway was associated with increased cellular apoptosis, reduced viability, and higher levels of intracellular ROS production. Additionally, melatonin, as reported by Sun et al. [27], upregulated the expression of heat-shock protein 90 (HSP90) through the melatonin receptor 1B (MTNR1B), which stabilized hypoxia-inducible factor-1α (HIF-1α). This activation of HIF-1α signaling promoted glycolysis, enhanced the pentose phosphate pathway, and improved cell viability.
In the domain of uterine physiology, Li et al. [33] observed that heat stress compromised normal uterine function by downregulating Nrf2 expression and its downstream antioxidant genes while upregulating the MDA level. The administration of baicalin significantly improved antioxidant responses and restored normal uterine function. Similarly, Alemu et al. [32] reported downregulated expression of Nrf2 and its target antioxidant genes (SOD, CAT) in bovine granulosa cells exposed to heat stress, resulting in reduced cell proliferation and increased cell death. Conversely, Li et al. [29] reported an increase in Nrf2 expression after scrotal heat treatment in mouse testes, suggesting a time-dependent response of the Nrf2-antioxidant system to heat stress. Moreover, Li et al. [21] demonstrated that heat stress induced autophagy in mice, activating the Nrf2 signaling pathway as a protective response to oxidative stress, safeguarding testicular tissue from damage. Furthermore, comprehensive research indicates that bioactive compounds given to animals can mitigate oxidative stress and cell death caused by heat stress, while also enhancing the antioxidant response through the regulation of Nrf2 signaling pathways [32,139,140,141,142,143].
The collective body of evidence highlights the crucial role of Nrf2 signaling in counteracting oxidative stress caused by heat exposure in mammalian reproductive cells, as summarized in Table 2. These findings emphasize the importance of Nrf2 signaling pathways in the cellular defense mechanism against heat stress-induced reproductive dysfunction.

6. Limitations and Future Recommendations

Based on the existing literature, it has been established that most of the evidence presented to date has been derived from in vitro studies and animal models. The absence of clinical trials limits the direct applicability of these findings to reproductive health and, therefore, the therapeutic use of bioactive compounds in clinical settings. Thus, to validate the therapeutic potential of Nrf2 signaling pathway activation in improving reproductive health, clinical trials are needed. These studies should assess the safety, efficacy, and optimal dosing of bioactive compounds in human populations. In addition, the existing review has presented only the protective roles of Nrf2 signaling pathway activation, and it may underrepresent the potential negative effects of prolonged or excessive Nrf2 signaling pathway stimulation, such as possible interference with normal cellular functions or promotion of tumorigenesis in certain contexts. Investigating the long-term effects of chronic Nrf2 signaling pathway mediation on reproductive health is crucial. More detailed mechanistic studies are necessary to better understand how Nrf2 interacts with other cellular pathways under stress conditions. Such studies could lead to the development of more targeted therapies that minimize side effects while enhancing therapeutic efficacy.

7. Conclusions

Overall, this review provides compelling evidence that the Nrf2 signaling pathway plays a crucial role in safeguarding mammalian reproductive cells from oxidative stress and apoptosis induced by heat stress and xenobiotic exposure. Through the activation of antioxidant defense genes, the Nrf2 signaling pathway mitigates the harmful effects of heat stress and xenobiotic-induced oxidative stress and apoptosis, thereby preserving the functionality and viability of reproductive cells. Furthermore, the review highlights the pivotal bioactive compounds capable of alleviating oxidative distress caused by heat stress and xenobiotics, safeguarding mammalian reproductive cells from oxidative damage through the activation of the Nrf2 signaling pathway. These findings underscore the importance of Nrf2 in maintaining cellular homeostasis under environmental stressors, highlighting its potential as a therapeutic target for enhancing reproductive health. The intricate regulation of Nrf2 through its interaction with Keap1 and subsequent activation in response to oxidative stress illustrates a sophisticated cellular mechanism for combating cellular damage and maintaining reproductive integrity. Future studies should explore the development of targeted therapies that enhance the Nrf2 signaling pathway, offering new avenues for protecting reproductive health against environmental stressors. Additionally, investigating the long-term effects of Nrf2 modulation on reproductive function could provide deeper insights into its therapeutic potential.

Author Contributions

Conceptualization, methodology, supervision, writing—original draft, project administration: M.Z.K. and C.W.; formal analysis and interpretation, software: M.Z.K. and A.K.; data curation, validation, writing—review and editing: M.Z.K., A.K., B.H., W.C., X.K., R.W., X.W., L.L., M.Z. and C.W.; resources and funding: C.W. All authors have read and agreed to the published version of the manuscript.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by the National Key R&D Program of China (grant number 2022YFD1600103), The Shandong Province Modern Agricultural Technology System Donkey Industrial Innovation Team (grant no. SDAIT-27), Livestock and Poultry Breeding Industry Project of the Ministry of Agriculture and Rural Affairs (grant number 19211162), The National Natural Science Foundation of China (grant no. 31671287), The Open Project of Liaocheng University Animal Husbandry Discipline (grant no. 319312101-14), The Open Project of Shandong Collaborative Innovation Center for Donkey Industry Technology (grant no. 3193308), Research on Donkey Pregnancy Improvement (grant no. K20LC0901) and Liaocheng University scientific research fund (grant no. 318052025).

Data Availability Statement

All the data are available in the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Zhang, S.X.; Wang, D.L.; Qi, J.J.; Yang, Y.W.; Sun, H.; Sun, B.X.; Liang, S. Chlorogenic Acid Ameliorates the Heat Stress-Induced Impairment of Porcine Sertoli Cells by Suppressing Oxidative Stress and Apoptosis. Theriogenology 2024, 214, 148–156. [Google Scholar] [CrossRef] [PubMed]
  2. Khan, M.Z.; Khan, A.; Chen, W.; Chai, W.; Wang, C. Advancements in Genetic Biomarkers and Exogenous Antioxidant Supplementation for Safeguarding Mammalian Cells against Heat-Induced Oxidative Stress and Apoptosis. Antioxidants 2024, 13, 258. [Google Scholar] [CrossRef] [PubMed]
  3. Dong, M.; Lu, J.; Xue, H.; Lou, Y.; Li, S.; Liu, T.; Ding, Z.; Chen, X. Anthocyanins from Lycium ruthenicum Murray Mitigate Cadmium-Induced Oxidative Stress and Testicular Toxicity by Activating the Keap1/Nrf2 Signaling Pathway. Pharmaceuticals 2024, 17, 322. [Google Scholar] [CrossRef] [PubMed]
  4. Arafa, E.S.; Hassanein, E.H.; Ibrahim, N.A.; Buabeid, M.A.; Mohamed, W.R. Involvement of Nrf2-PPAR-γ Signaling in Coenzyme Q10 Protecting Effect Against Methotrexate-Induced Testicular Oxidative Damage. Int. Immunopharmacol. 2024, 129, 111566. [Google Scholar] [CrossRef] [PubMed]
  5. Ribeiro, J.C.; Braga, P.C.; Martins, A.D.; Silva, B.M.; Alves, M.G.; Oliveira, P.F. Antioxidants Present in Reproductive Tract Fluids and Their Relevance for Fertility. Antioxidants 2021, 10, 1441. [Google Scholar] [CrossRef] [PubMed]
  6. Khan, A.; Dou, J.; Wang, Y.; Jiang, X.; Khan, M.Z.; Luo, H.; Usman, T.; Zhu, H. Evaluation of Heat Stress Effects on Cellular and Transcriptional Adaptation of Bovine Granulosa Cells. J. Anim. Sci. Biotechnol. 2020, 11, 25. [Google Scholar] [CrossRef] [PubMed]
  7. Saini, S.; Selokar, N.L.; Singh, M.K. Curcumin Supplementation Ameliorates Heat Stress and Affects Early Embryonic Development. Anim. Reprod. Update 2024, 4, 21–28. [Google Scholar]
  8. Samir, H.; Samir, M.; Radwan, F.; Mandour, A.S.; El-Sherbiny, H.R.; Ahmed, A.E.; Al Syaad, K.M.; Al-Saeed, F.A.; Watanabe, G. Effect of Pre-Treatment of Melatonin on Superovulation Response, Circulatory Hormones, and miRNAs in Goats During Environmental Heat Stress Conditions. Vet. Res. Commun. 2024, 48, 459–474. [Google Scholar] [CrossRef] [PubMed]
  9. Signorini, C.; Saso, L.; Ghareghomi, S.; Telkoparan-Akillilar, P.; Collodel, G.; Moretti, E. Redox Homeostasis and Nrf2-Regulated Mechanisms Are Relevant to Male Infertility. Antioxidants 2024, 13, 193. [Google Scholar] [CrossRef]
  10. Bonay, M. Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease. Antioxidants 2024, 13, 262. [Google Scholar] [CrossRef]
  11. He, C.; Sun, J.; Yang, D.; He, W.; Wang, J.; Qin, D.; Zhang, H.; Cai, H.; Liu, Y.; Li, N.; et al. Nrf2 activation mediates the protection of mouse Sertoli Cells damage under acute heat stress conditions. Theriogenology 2022, 177, 183–194. [Google Scholar] [CrossRef] [PubMed]
  12. Cui, W.; Li, B.; Bai, Y.; Miao, X.; Chen, Q.; Sun, W.; Tan, Y.; Luo, P.; Zhang, C.; Zheng, S.; et al. Potential role for Nrf2 activation in the therapeutic effect of MG132 on diabetic nephropathy in OVE26 diabetic mice. Am. J. Physiol. Endocrinol. Metab. 2013, 304, E87–E99. [Google Scholar] [CrossRef] [PubMed]
  13. Díaz, M.; Valdés-Baizabal, C.; de Pablo, D.P.; Marin, R. Age-Dependent Changes in Nrf2/Keap1 and Target Antioxidant Protein Expression Correlate to Lipoxidative Adducts, and Are Modulated by Dietary N-3 LCPUFA in the Hippocampus of Mice. Antioxidants 2024, 13, 206. [Google Scholar] [CrossRef] [PubMed]
  14. El Kebbaj, R.; Bouchab, H.; Tahri-Joutey, M.; Rabbaa, S.; Limami, Y.; Nasser, B.; Egbujor, M.C.; Tucci, P.; Andreoletti, P.; Saso, L.; et al. The Potential Role of Major Argan Oil Compounds as Nrf2 Regulators and Their Antioxidant Effects. Antioxidants 2024, 13, 344. [Google Scholar] [CrossRef] [PubMed]
  15. Suzuki, T.; Takahashi, J.; Yamamoto, M. Molecular Basis of the KEAP1-NRF2 Signaling Pathway. Mol. Cells 2023, 46, 133–141. [Google Scholar] [CrossRef] [PubMed]
  16. Ucar, B.I.; Ucar, G.; Saha, S.; Buttari, B.; Profumo, E.; Saso, L. Pharmacological Protection Against Ischemia-Reperfusion Injury by Regulating the Nrf2-Keap1-ARE Signaling Pathway. Antioxidants 2021, 10, 823. [Google Scholar] [CrossRef]
  17. Xi, C.; Palani, C.; Takezaki, M.; Shi, H.; Horuzsko, A.; Pace, B.S.; Zhu, X. Simvastatin-Mediated Nrf2 Activation Induces Fetal Hemoglobin and Antioxidant Enzyme Expression to Ameliorate the Phenotype of Sickle Cell Disease. Antioxidants 2024, 13, 337. [Google Scholar] [CrossRef]
  18. Chakkittukandiyil, A.; Sajini, D.V.; Karuppaiah, A.; Selvaraj, D. The Principal Molecular Mechanisms Behind the Activation of Keap1/Nrf2/ARE Pathway Leading to Neuroprotective Action in Parkinson’s Disease. Neurochem. Int. 2022, 156, 105325. [Google Scholar] [CrossRef]
  19. Ulasov, A.V.; Rosenkranz, A.A.; Georgiev, G.P.; Sobolev, A.S. Nrf2/Keap1/ARE Signaling: Towards Specific Regulation. Life Sci. 2022, 291, 120111. [Google Scholar] [CrossRef]
  20. Rotimi, D.E.; Ojo, O.A.; Olaolu, T.D.; Adeyemi, O.S. Exploring Nrf2 as a Therapeutic Target in Testicular Dysfunction. Cell Tissue Res. 2022, 390, 23–33. [Google Scholar] [CrossRef]
  21. Li, Z.; Li, Y.; Zhou, X.; Dai, P.; Li, C. Autophagy Involved in the Activation of the Nrf2-Antioxidant System in Testes of Heat-Exposed Mice. J. Thermal Biol. 2018, 71, 142–152. [Google Scholar] [CrossRef] [PubMed]
  22. Ding, X.; Ge, B.; Wang, M.; Zhou, H.; Sang, R.; Yu, Y.; Xu, L.; Zhang, X. Inonotus obliquus Polysaccharide Ameliorates Impaired Reproductive Function Caused by Toxoplasma gondii Infection in Male Mice via Regulating Nrf2-PI3K/AKT Pathway. Int. J. Biol. Macromol. 2020, 151, 449–458. [Google Scholar] [CrossRef] [PubMed]
  23. Farkhondeh, T.; Folgado, S.L.; Pourbagher-Shahri, A.M.; Ashrafizadeh, M.; Samarghandian, S. The Therapeutic Effect of Resveratrol: Focusing on the Nrf2 Signaling Pathway. Biomed. Pharmacother. 2020, 127, 110234. [Google Scholar] [CrossRef]
  24. Feng, J.; He, Y.; Shen, Y.; Zhang, G.; Ma, S.; Zhao, X.; Zhang, Y. Protective Effects of Nuclear Factor Erythroid 2-Related Factor on Oxidative Stress and Apoptosis in the Testis of Mice Before Adulthood. Theriogenology 2020, 148, 112–121. [Google Scholar] [CrossRef] [PubMed]
  25. Vašková, J.; Klepcová, Z.; Špaková, I.; Urdzík, P.; Štofilová, J.; Bertková, I.; Kľoc, M.; Rabajdová, M. The Importance of Natural Antioxidants in Female Reproduction. Antioxidants 2023, 12, 907. [Google Scholar] [CrossRef] [PubMed]
  26. Taqi, M.O.; Saeed-Zidane, M.; Gebremedhn, S.; Salilew-Wondim, D.; Tholen, E.; Neuhoff, C.; Hoelker, M.; Schellander, K.; Tesfaye, D. NRF2-Mediated Signaling is a Master Regulator of Transcription Factors in Bovine Granulosa Cells Under Oxidative Stress Condition. Cell Tissue Res. 2021, 385, 769–783. [Google Scholar] [CrossRef]
  27. Sun, T.C.; Liu, X.C.; Yang, S.H.; Song, L.L.; Zhou, S.J.; Deng, S.L.; Tian, L.; Cheng, L.Y. Melatonin Inhibits Oxidative Stress and Apoptosis in Cryopreserved Ovarian Tissues via Nrf2/HO-1 Signaling Pathway. Front. Mol. Biosci. 2020, 7, 163. [Google Scholar] [CrossRef] [PubMed]
  28. Li, Y.; Cao, Y.; Wang, F.; Li, C. Scrotal heat induced the Nrf2-driven antioxidant response during oxidative stress and apoptosis in the mouse testis. Acta Histochem. 2014, 116, 883–890. [Google Scholar] [CrossRef] [PubMed]
  29. Li, Y.; Cao, Y.; Wang, F.; Pu, S.; Zhang, Y.; Li, C. Tert-butylhydroquinone attenuates scrotal heat-induced dam-age by regulating Nrf2-antioxidant system in the mouse testis. Gen. Comp. Endocrinol. 2014, 208, 12–20. [Google Scholar] [CrossRef]
  30. Li, Y.; Huang, Y.; Piao, Y.; Nagaoka, K.; Watanabe, G.; Taya, K.; Li, C.M. 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. 2013, 11, 23. [Google Scholar] [CrossRef]
  31. Ali, F.E.; Badran, K.S.; Baraka, M.A.; Althagafy, H.S.; Hassanein, E.H. Mechanism and impact of heavy met-al-aluminum (Al) toxicity on male reproduction: Therapeutic approaches with some phytochemicals. Life Sci. 2024, 340, 122461. [Google Scholar] [CrossRef] [PubMed]
  32. Alemu, T.W.; Pandey, H.O.; Wondim, D.S.; Gebremedhn, S.; Neuhof, C.; Tholen, E.; Holker, M.; Schellander, K.; Tesfaye, D. Oxidative and endoplasmic reticulum stress defense mechanisms of bovine granulosa cells exposed to heat stress. Theriogenology 2018, 110, 130–141. [Google Scholar] [CrossRef] [PubMed]
  33. Li, H.; Cong, X.; Yu, W.; Jiang, Z.; Fu, K.; Cao, R.; Tian, W.; Feng, Y. Baicalin inhibits oxidative injures of mouse uterine tissue induced by acute heat stress through activating the Keap1/Nrf2 signaling pathway. Res. Vet. Sci. 2022, 152, 717–725. [Google Scholar] [CrossRef] [PubMed]
  34. Sui, J.; Feng, Y.; Li, H.; Cao, R.; Tian, W.; Jiang, Z. Baicalin protects mouse testis from injury induced by heat stress. J. Therm. Biol. 2019, 82, 63–69. [Google Scholar] [CrossRef] [PubMed]
  35. Murata, H.; Kunii, H.; Kusama, K.; Sakurai, T.; Bai, H.; Kawahara, M.; Takahashi, M. Heat stress induces oxidative stress and activates the KEAP1-NFE2L2-ARE pathway in bovine endometrial epithelial cells. Biol. Reprod. 2021, 105, 1114–1125. [Google Scholar] [CrossRef] [PubMed]
  36. Hammad, M.; Raftari, M.; Cesário, R.; Salma, R.; Godoy, P.; Emami, S.N.; Haghdoost, S. Roles of oxidative stress and Nrf2 signaling in pathogenic and non-pathogenic cells: A possible general mechanism of resistance to therapy. Antioxidants 2023, 12, 1371. [Google Scholar] [CrossRef]
  37. Yin, C.; Bi, Q.; Chen, W.; Wang, C.; Castiglioni, B.; Li, Y.; Sun, W.; Pi, Y.; Bontempo, V.; Li, X.; et al. Fucoidan Supplementation Improves Antioxidant Capacity via Regulating the Keap1/Nrf2 Signaling Pathway and Mitochondrial Function in Low-Weaning Weight Piglets. Antioxidants 2024, 13, 407. [Google Scholar] [CrossRef] [PubMed]
  38. Ngo, V.; Duennwald, M.L. Nrf2 and oxidative stress: A general overview of mechanisms and implications in human disease. Antioxidants 2022, 11, 2345. [Google Scholar] [CrossRef] [PubMed]
  39. Glanzner, W.G.; da Silva Sousa, L.R.; Gutierrez, K.; de Macedo, M.P.; Currin, L.; Perecin, F.; Bordignon, V. NRF2 attenuation aggravates detrimental consequences of metabolic stress on cultured porcine parthenote embryos. Sci. Rep. 2024, 14, 2973. [Google Scholar] [CrossRef]
  40. Li, Y.; Cai, L.; Bi, Q.; Sun, W.; Pi, Y.; Jiang, X.; Li, X. Genistein Alleviates Intestinal Oxidative Stress by Activating the Nrf2 Signaling Pathway in IPEC-J2 Cells. Vet. Sci. 2024, 11, 154. [Google Scholar] [CrossRef]
  41. Xiong, L.; Azad, M.A.; Liu, Y.; Zhang, W.; Zhu, Q.; Hu, C.; You, J.; Kong, X. Intrauterine Growth Restriction Affects Colonic Barrier Function via Regulating the Nrf2/Keap1 and TLR4-NF-κB/ERK Pathways and Altering Colonic Microbiome and Metabolome Homeostasis in Growing–Finishing Pigs. Antioxidants 2024, 13, 283. [Google Scholar] [CrossRef] [PubMed]
  42. Zheng, S.L.; Wang, Y.M.; Chi, C.F.; Wang, B. Chemical Characterization of Honeysuckle Polyphenols and Their Alleviating Function on Ultraviolet B-Damaged HaCaT Cells by Modulating the Nrf2/NF-κB Signaling Pathways. Antioxidants 2024, 13, 294. [Google Scholar] [CrossRef] [PubMed]
  43. Yuan, M.; Fu, H.; Mo, Q.; Wang, S.; Wang, C.; Wang, D.; Zhang, J.; Li, M. Protective Mechanism of Rosa roxburghii Tratt Fermentation Broth against Ultraviolet-A-Induced Photoaging of Human Embryonic Skin Fibroblasts. Antioxidants 2024, 13, 382. [Google Scholar] [CrossRef] [PubMed]
  44. Thiruvengadam, M.; Venkidasamy, B.; Subramanian, U.; Samynathan, R.; Ali Shariati, M.; Rebezov, M.; Girish, S.; Thangavel, S.; Dhanapal, A.R.; Fedoseeva, N.; et al. Bioactive Compounds in Oxidative Stress-Mediated Diseases: Targeting the NRF2/ARE Signaling Pathway and Epigenetic Regulation. Antioxidants 2021, 10, 1859. [Google Scholar] [CrossRef] [PubMed]
  45. Buha, A.; Baralić, K.; Djukic-Cosic, D.; Bulat, Z.; Tinkov, A.; Panieri, E.; Saso, L. The role of toxic metals and metalloids in Nrf2 signaling. Antioxidants 2021, 10, 630. [Google Scholar] [CrossRef] [PubMed]
  46. El-Din, M.A.; Ghareeb, A.E.; El-Garawani, I.M.; El-Rahman, H.A. Induction of apoptosis, oxidative stress, hormonal, and histological alterations in the reproductive system of thiamethoxam-exposed female rats. Environ. Sci. Pollut. Res. 2023, 30, 77917–77930. [Google Scholar] [CrossRef] [PubMed]
  47. Deluao, J.C.; Winstanley, Y.; Robker, R.L.; Pacella-Ince, L.; Gonzalez, M.B.; McPherson, N.O. Oxidative stress and reproductive function: Reactive oxygen species in the mammalian pre-implantation embryo. Reproduction 2022, 164, F95–F108. [Google Scholar] [CrossRef] [PubMed]
  48. Jiang, X.; Xing, X.; Zhang, Y.; Zhang, C.; Wu, Y.; Chen, Y.; Meng, R.; Jia, H.; Cheng, Y.; Zhang, Y.; et al. Lead exposure activates the Nrf2/Keap1 pathway, aggravates oxidative stress, and induces reproductive damage in female mice. Ecotoxicol. Environ. Saf. 2021, 207, 111231. [Google Scholar] [CrossRef] [PubMed]
  49. Meli, R.; Monnolo, A.; Annunziata, C.; Pirozzi, C.; Ferrante, M.C. Oxidative stress and BPA toxicity: An antioxidant approach for male and female reproductive dysfunction. Antioxidants 2020, 9, 405. [Google Scholar] [CrossRef]
  50. Chung, J.Y.; Chen, H.; Zirkin, B. Sirt1 and Nrf2: Regulation of Leydig cell oxidant/antioxidant intracellular environment and steroid formation. Biol. Reprod. 2021, 105, 1307–1316. [Google Scholar] [CrossRef]
  51. Ji, R.; Jia, F.Y.; Chen, X.; Wang, Z.H.; Jin, W.Y.; Yang, J. Salidroside alleviates oxidative stress and apoptosis via AMPK/Nrf2 pathway in DHT-induced human granulosa cell line KGN. Arch. Biochem. Biophys. 2022, 715, 109094. [Google Scholar] [CrossRef] [PubMed]
  52. Sohel, M.M.; Amin, A.; Prastowo, S.; Linares-Otoya, L.; Hoelker, M.; Schellander, K.; Tesfaye, D. Sulforaphane protects granulosa cells against oxidative stress via activation of NRF2-ARE pathway. Cell Tissue Res. 2018, 374, 629–641. [Google Scholar] [CrossRef] [PubMed]
  53. Chen, Y.; Zhao, M.; Li, X.; Liu, Y.; Shang, Y. Lycopene mitigates DHT-induced apoptosis and oxidative stress in human granulosa cell line KGN by regulating the Nrf2 pathway. Mol. Cell Toxicol. 2024, 1–11. [Google Scholar] [CrossRef]
  54. Arkali, G.; Aksakal, M.; Kaya, Ş.Ö. Protective effects of carvacrol against diabetes-induced reproductive damage in male rats: Modulation of Nrf2/HO-1 signalling pathway and inhibition of Nf-kB-mediated testicular apoptosis and inflammation. Andrologia 2021, 53, e13899. [Google Scholar] [CrossRef] [PubMed]
  55. Arab, H.H.; Gad, A.M.; Reda, E.; Yahia, R.; Eid, A.H. Activation of autophagy by sitagliptin attenuates cadmium-induced testicular impairment in rats: Targeting AMPK/mTOR and Nrf2/HO-1 pathways. Life Sci. 2021, 269, 119031. [Google Scholar] [CrossRef] [PubMed]
  56. ALTamimi, J.Z.; AlFaris, N.A.; Aljabryn, D.H.; Alagal, R.I.; Alshammari, G.M.; Aldera, H.; Alqahtani, S.; Yahya, M.A. Ellagic acid improved diabetes mellitus-induced testicular damage and sperm abnormalities by activation of Nrf2. Saudi J. Biol. Sci. 2021, 28, 4300–4310. [Google Scholar] [CrossRef] [PubMed]
  57. Saeedan, A.S.; Soliman, G.A.; Abdel-Rahman, R.F.; Abd-Elsalam, R.M.; Ogaly, H.A.; Foudah, A.I.; Abdel-Kader, M.S. Artemisia judaica L. diminishes diabetes-induced reproductive dysfunction in male rats via activation of Nrf2/HO-1-mediated antioxidant responses. Saudi J. Biol. Sci. 2021, 28, 1713–1722. [Google Scholar] [CrossRef] [PubMed]
  58. Samir, S.M.; Elalfy, M.; El Nashar, E.M.; Alghamdi, M.A.; Hamza, E.; Serria, M.S.; Elhadidy, M.G. Cardamonin exerts a protective effect against autophagy and apoptosis in the testicles of diabetic male rats through the expression of Nrf2 via p62-mediated Keap-1 degradation. Korean J. Physiol. Pharmacol. 2021, 25, 341. [Google Scholar] [CrossRef]
  59. Abbaszadeh, S.; Yadegari, P.; Imani, A.; Taghdir, M. Vitamin D3 protects against lead-induced testicular toxicity by modulating Nrf2 and NF-κB genes expression in rat. Reprod. Toxicol. 2021, 103, 36–45. [Google Scholar] [CrossRef]
  60. Esfandyari, S.; Aleyasin, A.; Noroozi, Z.; Taheri, M.; Khodarahmian, M.; Eslami, M.; Rashidi, Z.; Amidi, F. The protective effect of sulforaphane against oxidative stress through activation of NRF2/ARE pathway in human granulosa cells. Cell J. 2021, 23, 692. [Google Scholar]
  61. Wang, M.; Li, Y.; Gao, Y.; Li, Q.; Cao, Y.; Shen, Y.; Chen, P.; Yan, J.; Li, J. Vitamin E regulates bovine granulosa cell apoptosis via NRF2-mediated defence mechanism by activating PI3K/AKT and ERK1/2 signalling pathways. Reprod. Domest. Anim. 2021, 56, 1066–1084. [Google Scholar] [CrossRef]
  62. Sayed, A.M.; Hassanein, E.H.; Ali, F.E.; Omar, Z.M.; Rashwan, E.K.; Mohammedsaleh, Z.M.; Abd El-Ghafar, O.A. Regulation of Keap-1/Nrf2/AKT and iNOS/NF-κB/TLR4 signals by apocynin abrogated methotrexate-induced testicular toxicity: Mechanistic insights and computational pharmacological analysis. Life Sci. 2021, 284, 119911. [Google Scholar] [CrossRef]
  63. Zhang, L.; Gao, X.; Qin, Z.; Shi, X.; Xu, K.; Wang, S.; Tang, M.; Wang, W.; Gao, S.; Zuo, L.; et al. USP15 Participates in DBP-Induced Testicular Oxidative Stress Injury through Regulating the Keap1/Nrf2 Signaling Pathway. Sci. Total Environ. 2021, 783, 146898. [Google Scholar] [CrossRef] [PubMed]
  64. Lu, G.; Wang, Q.; Xie, Z.J.; Liang, S.J.; Li, H.X.; Shi, L.; Li, Q.; Shen, J.; Cheng, J.; Shen, M.H. Moxibustion Ameliorates Ovarian Reserve in Rats by Mediating Nrf2/HO-1/NLRP3 Anti-Inflammatory Pathway. Evid. Based Complement. Alternat. Med. 2021, 2021, 1. [Google Scholar] [CrossRef]
  65. Liang, S.; Yin, Y.; Zhang, Z.; Fang, Y.; Lu, G.; Li, H.; Yin, Y.; Shen, M. Moxibustion Prevents Tripterygium Glycoside-Induced Oligoasthenoteratozoospermia in Rats via Reduced Oxidative Stress and Modulation of the Nrf2/HO-1 Signaling Pathway. Aging 2024, 16, 2141. [Google Scholar] [CrossRef] [PubMed]
  66. Demir, S.; Mentese, A.; Usta, Z.T.; Alemdar, N.T.; Demir, E.A.; Aliyazicioglu, Y. Alpha-Pinene Neutralizes Cisplatin-Induced Reproductive Toxicity in Male Rats through Activation of Nrf2 Pathway. Int. Urol. Nephrol. 2024, 56, 527–537. [Google Scholar] [CrossRef] [PubMed]
  67. Demir, E.A. Syringic Acid Alleviates Cisplatin-Induced Ovarian Injury through Modulating Endoplasmic Reticulum Stress, Inflammation and Nrf2 Pathway. J. Trace Elem. Med. Biol. 2024, 82, 127356. [Google Scholar] [CrossRef]
  68. Lu, C.S.; Wu, C.Y.; Wang, Y.H.; Hu, Q.Q.; Sun, R.Y.; Pan, M.J.; Lu, X.Y.; Zhu, T.; Luo, S.; Yang, H.J.; et al. The Protective Effects of Icariin against Testicular Dysfunction in Type 1 Diabetic Mice via AMPK-Mediated Nrf2 Activation and NF-κB p65 Inhibition. Phytomedicine 2024, 123, 155217. [Google Scholar] [CrossRef] [PubMed]
  69. Abdelmonem, M.; Ali, S.O.; Al-Mokaddem, A.K.; Ghaiad, H.R. Ameliorating Diabetes-Induced Testicular Dysfunction by Modulating PKC/Nrf2/Bcl-2 Signaling: Protective Role of Sulbutiamine. BioFactors 2024. [Google Scholar] [CrossRef]
  70. Akaras, N.; Gür, C.; Caglayan, C.; Kandemir, F.M. Protective Effects of Naringin against Oxaliplatin-Induced Testicular Damage in Rats: Involvement of Oxidative Stress, Inflammation, Endoplasmic Reticulum Stress, Apoptosis, and Histopathology. Iran. J. Basic Med. Sci. 2024, 27, 466. [Google Scholar]
  71. Ajibare, A.J.; Akintoye, O.O.; Folawiyo, M.A.; Babalola, K.T.; Omotuyi, O.I.; Oladun, B.T.; Aransiola, K.T.; Odetayo, A.F.; Olayaki, L.A. Therapeutic Potential of Virgin Coconut Oil in Mitigating Sodium Benzoate-Model of Male Infertility: Role of Nrf2/Hmox-1/NF-kB Signaling Pathway. Iran. J. Basic Med. Sci. 2024, 27, 543. [Google Scholar] [PubMed]
  72. Oyovwi, O.M.; Ben-Azu, B.; Tesi, E.P.; Emojevwe, V.; Rotu, R.A.; Moke, G.E.; Umukoro, E.; Asiwe, J.N.; Nwangwa, K.E. Possible Mechanisms Involved in the Protective Effect of Lutein against Cyclosporine-Induced Testicular Damage in Rats. Heliyon 2024, 10, 3. [Google Scholar] [CrossRef]
  73. Wei, L.; Li, S.; Ma, Y.; Ye, S.; Yuan, Y.; Zeng, Y.; Raza, T.; Xiao, F. Curcumin Attenuates Diphenyl Phosphate-Induced Apoptosis in GC-2spd (ts) Cells through Activated Autophagy via the Nrf2/P53 Pathway. Environ. Toxicol. 2024, 39, 2032–2042. [Google Scholar] [CrossRef] [PubMed]
  74. Demir, E.A.; Mentese, A.; Yilmaz, Z.S.; Alemdar, N.T.; Demir, S.; Aliyazicioglu, Y. Evaluation of the Therapeutic Effects of Arbutin on Cisplatin-Induced Ovarian Toxicity in Rats through Endoplasmic Reticulum Stress and Nrf2 Pathway. Reprod. Biol. 2023, 23, 100824. [Google Scholar] [CrossRef]
  75. Xi, H.; Hu, Z.; Han, S.; Liu, X.; Wang, L.; Hu, J. FSH-Inhibited Autophagy Protects Against Oxidative Stress in Goat Sertoli Cells through p62-Nrf2 Pathway. Theriogenology 2023, 195, 103–114. [Google Scholar] [CrossRef]
  76. Xu, B.; He, T.; Yang, H.; Dai, W.; Liu, L.; Ma, X.; Ma, J.; Yang, G.; Si, R.; Du, X.; et al. Activation of the p62-Keap1-Nrf2 Pathway Protects against Oxidative Stress and Excessive Autophagy in Ovarian Granulosa Cells to Attenuate DEHP-Induced Ovarian Impairment in Mice. Ecotoxicol. Environ. Saf. 2023, 265, 115534. [Google Scholar] [CrossRef]
  77. Mancuso, F.; Arato, I.; Bellucci, C.; Eugeni, E.; Stabile, A.M.; Pistilli, A.; Brancorsini, S.; Gaggia, F.; Calvitti, M.; Baroni, T.; et al. Zinc Restores Functionality in Porcine Prepubertal Sertoli Cells Exposed to Subtoxic Cadmium Concentration via Regulating the Nrf2 Signaling Pathway. Front. Endocrinol. 2023, 14, 962519. [Google Scholar] [CrossRef] [PubMed]
  78. Qin, Z.; Song, J.; Huang, J.; Jiang, S.; Zhang, G.; Huang, M.; Huang, Z.; Jin, J. Mitigation of Triptolide-Induced Testicular Sertoli Cell Damage by Melatonin via Regulating the Crosstalk Between SIRT1 and NRF2. Phytomedicine 2023, 118, 154945. [Google Scholar] [CrossRef]
  79. Somade, O.T.; Ajiboye, B.O.; Osukoya, O.A.; Jarikre, T.A.; Oyinloye, B.E. Syringic Acid Ameliorates Testicular Oxidative Stress via the Conservation of Endogenous Antioxidant Markers and Inhibition of the Activated Nrf2-Keap1-NQO1-HO1 Signaling in Methyl Cellosolve-Administered Rats. Pharmacol. Res.-Mod. Chin. Med. 2023, 6, 100207. [Google Scholar] [CrossRef]
  80. Akanji, O.D.; Hassanzadeh, G.; Malekzadeh, M.; Khanmohammadi, N.; Khanezad, M.; Sadeghiani, G.; Rastegar, T. Pentoxifylline Promotes Spermatogenesis via Upregulation of the Nrf2-ARE Signalling Pathway in a Mouse Model of Germ-Cell Apoptosis Induced by Testicular Torsion–Detorsion. Reprod. Fertil. Dev. 2023, 35, 423–432. [Google Scholar] [CrossRef]
  81. Shati, A.A.; Khalil, M.A. Acylated Ghrelin Suppresses Doxorubicin-Induced Testicular Damage and Improves Sperm Parameters in Rats via Activation of Nrf2 and Mammalian Target of Rapamycin. J. Cancer Res. Ther. 2023, 19, 1194–1205. [Google Scholar] [CrossRef] [PubMed]
  82. AlTamimi, J.Z.; AlFaris, N.A.; Alshammari, G.M.; Alagal, R.I.; Aljabryn, D.H.; Yahya, M.A. Esculeoside A Alleviates Reproductive Toxicity in Streptozotocin-Diabetic Rats’s Model by Activating Nrf2 Signaling. Saudi J. Biol. Sci. 2023, 30, 103780. [Google Scholar] [CrossRef] [PubMed]
  83. Adeyi, O.E.; Somade, O.T.; James, A.S.; Adeyi, A.O.; Ogbonna-Eze, S.N.; Salako, O.Q.; Makinde, T.V.; Ajadi, O.M.; Nosiru, S.A. Ferulic Acid Mitigates 2-Methoxyethanol-Induced Testicular Oxidative Stress via Combined Downregulation of FoxO1, PTEN, and Modulation of Nrf2-Hmox1-NQO1 Signaling Pathway in Rats. Pharmacol. Res.-Mod. Chin. Med. 2023, 7, 100257. [Google Scholar] [CrossRef]
  84. Gür, F.; Cengiz, M.; Gür, B.; Cengiz, O.; Sarıcıçek, O.; Ayhancı, A. Therapeutic Role of Boron on Acrylamide-Induced Nephrotoxicity, Cardiotoxicity, Neurotoxicity, and Testicular Toxicity in Rats: Effects on Nrf2/Keap-1 Signaling Pathway and Oxidative Stress. J. Trace Elem. Med. Biol. 2023, 80, 127274. [Google Scholar] [CrossRef] [PubMed]
  85. Akarsu, S.A.; Gür, C.; İleritürk, M.; Akaras, N.; Küçükler, S.; Kandemir, F.M. Effect of Syringic Acid on Oxidative Stress, Autophagy, Apoptosis, Inflammation Pathways Against Testicular Damage Induced by Lead Acetate. J. Trace Elem. Med. Biol. 2023, 80, 127315. [Google Scholar] [CrossRef] [PubMed]
  86. Guan, F.; Zhang, S.; Fan, L.; Sun, Y.; Ma, Y.; Cao, C.; Zhang, Y.; He, M.; Du, H. Kunling Wan Improves Oocyte Quality by Regulating the PKC/Keap1/Nrf2 Pathway to Inhibit Oxidative Damage Caused by Repeated Controlled Ovarian Hyperstimulation. J. Ethnopharmacol. 2023, 301, 115777. [Google Scholar] [CrossRef] [PubMed]
  87. Cai, M.; Wang, J.; Sun, H.; Guo, Q.; Zhang, C.; Yao, H.; Zhao, C.; Jia, Y.; Zhu, H. Resveratrol Attenuates Hydrogen Peroxide-Induced Injury of Rat Ovarian Granulosa-Lutein Cells by Resisting Oxidative Stress via the SIRT1/Nrf2/ARE Signaling Pathway. Curr. Pharm. Des. 2023, 29, 947–956. [Google Scholar] [CrossRef] [PubMed]
  88. Qian, Z.; Li, C.; Zhao, W.; He, Z.; Xue, M.; Wang, S.; Cheng, X.; Ma, R.; Ge, X. Chronic Oral Exposure to Short Chain Chlorinated Paraffins Induced Testicular Toxicity by Promoting NRF2-Mediated Oxidative Stress. Toxicol. Lett. 2023, 376, 1–12. [Google Scholar] [CrossRef] [PubMed]
  89. Niu, C.; Jiang, D.; Guo, Y.; Wang, Z.; Sun, Q.; Wang, X.; Ling, W.; An, X.; Ji, C.; Li, S.; et al. Spermidine Suppresses Oxidative Stress and Ferroptosis by Nrf2/HO-1/GPX4 and Akt/FHC/ACSL4 Pathway to Alleviate Ovarian Damage. Life Sci. 2023, 332, 122109. [Google Scholar] [CrossRef]
  90. Liu, M.; Zhou, X.; Wang, X.J.; Wang, Y.S.; Yang, S.J.; Ding, Z.M.; Zhang, S.X.; Zhang, L.D.; Duan, Z.Q.; Liang, A.X.; et al. Curcumin Alleviates Bisphenol AF-Induced Oxidative Stress and Apoptosis in Caprine Endometrial Epithelial Cells via the Nrf2 Signaling Pathway. Environ. Toxicol. 2023, 38, 2904–2914. [Google Scholar] [CrossRef]
  91. Feng, Z.; Wang, T.; Sun, Y.; Chen, S.; Hao, H.; Du, W.; Zou, H.; Yu, D.; Zhu, H.; Pang, Y. Sulforaphane Suppresses Paraquat-Induced Oxidative Damage in Bovine In Vitro-Matured Oocytes through Nrf2 Transduction Pathway. Ecotoxicol. Environ. Saf. 2023, 254, 114747. [Google Scholar] [CrossRef] [PubMed]
  92. Arab, H.H.; Fikry, E.M.; Alsufyani, S.E.; Ashour, A.M.; El-Sheikh, A.A.; Darwish, H.W.; Al-Hossaini, A.M.; Saad, M.A.; Al-Shorbagy, M.Y.; Eid, A.H. Stimulation of Autophagy by Dapagliflozin Mitigates Cadmium-Induced Testicular Dysfunction in Rats: The Role of AMPK/mTOR and SIRT1/Nrf2/HO-1 Pathways. Pharmaceuticals 2023, 16, 1006. [Google Scholar] [CrossRef] [PubMed]
  93. Odetayo, A.F.; Adeyemi, W.J. Omega-3 Fatty Acid Ameliorates Bisphenol F-Induced Testicular Toxicity by Modulating Nrf2/NFkB Pathway and Apoptotic Signaling. Front. Endocrinol. 2023, 14, 1256154. [Google Scholar] [CrossRef] [PubMed]
  94. Liang, Y.; Lu, J.; Yi, W.; Cai, M.; Shi, W.; Li, B.; Zhang, Z.; Jiang, F. 1α, 25-Dihydroxyvitamin D3 Supplementation Alleviates Perfluorooctanesulfonate Acid-Induced Reproductive Injury in Male Mice: Modulation of Nrf2 Mediated Oxidative Stress Response. Environ. Toxicol. 2023, 38, 322–331. [Google Scholar] [CrossRef] [PubMed]
  95. Habiba, E.S.; Harby, S.A.; El-Sayed, N.S.; Omar, E.M.; Bakr, B.A.; Augustyniak, M.; El-Samad, L.M.; Hassan, M.A. Sericin and Melatonin Mitigate Diethylnitrosamine-Instigated Testicular Impairment in Mice: Implications of Oxidative Stress, Spermatogenesis, Steroidogenesis, and Modulation of Nrf2/WT1/SF-1 Signaling Pathways. Life Sci. 2023, 334, 122220. [Google Scholar] [CrossRef] [PubMed]
  96. Huang, W.; Cao, Z.; Cui, Y.; Huo, S.; Shao, B.; Song, M.; Cheng, P.; Li, Y. Lycopene Ameliorates Aflatoxin B1-Induced Testicular Lesion by Attenuating Oxidative Stress and Mitochondrial Damage with Nrf2 Activation in Mice. Ecotoxicol. Environ. Saf. 2023, 256, 114846. [Google Scholar] [CrossRef] [PubMed]
  97. Heidarizadi, S.; Rashidi, Z.; Jalili, C.; Mansouri, K.; Rashidi, I.; Mahaki, B.; Gholami, M. Melatonin Protects Mouse Type A Spermatogonial Stem Cells against Oxidative Stress via The Mitochondrial Thioredoxin System. Cell J. 2023, 25, 741. [Google Scholar] [PubMed]
  98. Sarawi, W.S.; Alhusaini, A.M.; Fadda, L.M.; Alomar, H.A.; Albaker, A.B.; Alghibiwi, H.K.; Aljrboa, A.S.; Alotaibi, A.M.; Hasan, I.H.; Mahmoud, A.M. Nano-Curcumin Prevents Copper Reproductive Toxicity by Attenuating Oxidative Stress and Inflammation and Improving Nrf2/HO-1 Signaling and Pituitary-Gonadal Axis in Male Rats. Toxics 2022, 10, 356. [Google Scholar] [CrossRef] [PubMed]
  99. Bakr, A.G.; Hassanein, E.H.; Ali, F.E.; El-Shoura, E.A. Combined Apocynin and Carvedilol Protect against Cadmium-Induced Testicular Damage via Modulation of Inflammatory Response and Redox-Sensitive Pathways. Life Sci. 2022, 311, 121152. [Google Scholar] [CrossRef]
  100. Bartolini, D.; Arato, I.; Mancuso, F.; Giustarini, D.; Bellucci, C.; Vacca, C.; Aglietti, M.C.; Stabile, A.M.; Rossi, R.; Cruciani, G.; et al. Melatonin Modulates Nrf2 Activity to Protect Porcine Pre-Pubertal Sertoli Cells from the Abnormal H2O2 Generation and Reductive Stress Effects of Cadmium. J. Pineal Res. 2022, 73, e12806. [Google Scholar] [CrossRef]
  101. Fan, L.; Guan, F.; Ma, Y.; Zhang, Y.; Li, L.; Sun, Y.; Cao, C.; Du, H.; He, M. N-Acetylcysteine Improves Oocyte Quality through Modulating the Nrf2 Signaling Pathway to Ameliorate Oxidative Stress Caused by Repeated Controlled Ovarian Hyperstimulation. Reprod. Fertil. Dev. 2022, 34, 736–750. [Google Scholar] [CrossRef] [PubMed]
  102. Zhang, J.; Fang, Y.; Tang, D.; Xu, X.; Zhu, X.; Wu, S.; Yu, H.; Cheng, H.; Luo, T.; Shen, Q.; et al. Activation of MT1/MT2 to Protect Testes and Leydig Cells against Cisplatin-Induced Oxidative Stress through the SIRT1/Nrf2 Signaling Pathway. Cells 2022, 11, 1690. [Google Scholar] [CrossRef] [PubMed]
  103. Lin, X.; Zhu, L.; Gao, X.; Kong, L.; Huang, Y.; Zhao, H.; Chen, Y.; Wen, L.; Li, R.; Wu, J.; et al. Ameliorative Effect of Betulinic Acid against Zearalenone Exposure Triggers Testicular Dysfunction and Oxidative Stress in Mice via p38/ERK MAPK Inhibition and Nrf2-Mediated Antioxidant Defense Activation. Ecotoxicol. Environ. Saf. 2022, 238, 113561. [Google Scholar] [CrossRef]
  104. Yan, R.; Wang, H.; Zhu, J.; Wang, T.; Nepovimova, E.; Long, M.; Li, P.; Kuca, K.; Wu, W. Procyanidins Inhibit Zearalenone-Induced Apoptosis and Oxidative Stress of Porcine Testis Cells through Activation of Nrf2 Signaling Pathway. Food Chem. Toxicol. 2022, 165, 113061. [Google Scholar] [CrossRef]
  105. Chen, H.; Chen, J.; Shi, X.; Li, L.; Xu, S. Naringenin Protects Swine Testis Cells from Bisphenol A-Induced Apoptosis via Keap1/Nrf2 Signaling Pathway. BioFactors 2022, 48, 190–203. [Google Scholar] [CrossRef] [PubMed]
  106. Hemati, U.; Moshajari, M.; Jalali Mashayekhi, F.; Bayat, M.; Moslemi, A.; Baazm, M. The Effect of Curcumin on NRF2/Keap1 Signalling Pathway in the Epididymis of Mouse Experimental Cryptorchidism. Andrologia 2022, 54, e14532. [Google Scholar] [CrossRef]
  107. Ouyang, H.; Zhu, H.; Li, J.; Chen, L.; Zhang, R.; Fu, Q.; Li, X.; Cao, C. Fumonisin B1 Promotes Germ Cells Apoptosis Associated with Oxidative Stress-Related Nrf2 Signaling in Mice Testes. Chem.-Biol. Interact. 2022, 363, 110009. [Google Scholar] [CrossRef] [PubMed]
  108. Chen, Z.; Zuo, Z.; Chen, K.; Yang, Z.; Wang, F.; Fang, J.; Cui, H.; Guo, H.; Ouyang, P.; Chen, Z.; et al. Activated Nrf-2 Pathway by Vitamin E to Attenuate Testicular Injuries of Rats with Sub-Chronic Cadmium Exposure. Biol. Trace Elem. Res. 2022, 200, 1722–1735. [Google Scholar] [CrossRef] [PubMed]
  109. Wang, Y.; Li, J.; Gu, J.; He, W.; Ma, B.; Fan, H. Hyperoside, A Natural Flavonoid Compound, Attenuates Triptolide-Induced Testicular Damage by Activating the Keap1-Nrf2 and SIRT1-PGC1α Signalling Pathway. J. Pharm. Pharmacol. 2022, 74, 985–995. [Google Scholar] [CrossRef]
  110. Shahidi, M.; Moradi, A.; Dayati, P. Zingerone Attenuates Zearalenone-Induced Steroidogenesis Impairment and Apoptosis in TM3 Leydig Cell Line. Toxicon 2022, 211, 50–60. [Google Scholar] [CrossRef]
  111. Abdelzaher, W.Y.; Mostafa-Hedeab, G.; Sayed AboBakr Ali, A.H.; Fawzy, M.A.; Ahmed, A.F.; Bahaa El-deen, M.A.; Welson, N.N.; Aly Labib, D.A. Idebenone Regulates Sirt1/Nrf2/TNF-α Pathway with Inhibition of Oxidative Stress, Inflammation, and Apoptosis in Testicular Torsion/Detorsion in Juvenile Rats. Hum. Exp. Toxicol. 2022, 41, 09603271221102515. [Google Scholar] [CrossRef] [PubMed]
  112. Ukwenya, V.O.; Aderemi, A.S.; Alese, O.M.; Augustine, O.A. Caffeic Acid Abrogates Amyloidosis, Hypospermatogenesis and Cell Membrane Alterations in the Testes and Epididymis of Fructose-Diabetic Rats by Upregulating Steroidogenesis, PCNA and Nrf2 Expression. Tissue Cell 2022, 79, 101912. [Google Scholar] [CrossRef] [PubMed]
  113. Adeniran, S.O.; Zheng, P.; Feng, R.; Adegoke, E.O.; Huang, F.; Ma, M.; Wang, Z.; Ifarajimi, O.O.; Li, X.; Zhang, G. The Antioxidant Role of Selenium via GPx1 and GPx4 in LPS-Induced Oxidative Stress in Bovine Endometrial Cells. Biol. Trace Elem. Res. 2022, 200, 1140–1155. [Google Scholar] [CrossRef] [PubMed]
  114. Cao, L.; Zhao, J.; Ma, L.; Chen, J.; Xu, J.; Rahman, S.U.; Feng, S.; Li, Y.; Wu, J.; Wang, X. Lycopene Attenuates Zearalenone-Induced Oxidative Damage of Piglet Sertoli Cells through the Nuclear Factor Erythroid-2 Related Factor 2 Signaling Pathway. Ecotoxicol. Environ. Saf. 2021, 225, 112737. [Google Scholar] [CrossRef]
  115. Li, G.; Zhang, P.; Ma, Z. Qiangjing Tablets Regulate Apoptosis and Oxidative Stress via Keap/Nrf2 Pathway to Improve Reproductive Function in Asthenospermia Rats. Front. Pharmacol. 2021, 12, 714892. [Google Scholar] [CrossRef] [PubMed]
  116. Jia, L.I.; Yu-Hang, C.H.; Jia-Yu, X.U.; Jiang-Ying, L.I.; Jia-Cheng, F.U.; Xiu-Ping, C.A.; Huang, J.; Zheng, Y.H. Effects of Chitooligosaccharide-Zinc on the Ovarian Function of Mice with Premature Ovarian Failure via the SESN2/NRF2 Signaling Pathway. Chin. J. Nat. Med. 2021, 19, 721–731. [Google Scholar]
  117. Al-Megrin, W.A.; Alomar, S.; Alkhuriji, A.F.; Metwally, D.M.; Mohamed, S.K.; Kassab, R.B.; Abdel Moneim, A.E.; El-Khadragy, M.F. Luteolin Protects against Testicular Injury Induced by Lead Acetate by Activating the Nrf2/HO-1 Pathway. IUBMB Life 2020, 72, 1787–1798. [Google Scholar] [CrossRef] [PubMed]
  118. Yuan, L.; Li, Q.; Bai, D.; Shang, X.; Hu, F.; Chen, Z.; An, T.; Chen, Y.; Zhang, X. La2O3 Nanoparticles Induce Reproductive Toxicity Mediated by the Nrf-2/ARE Signaling Pathway in Kunming Mice. Int. J. Nanomed. 2020, 15, 3415–3431. [Google Scholar] [CrossRef] [PubMed]
  119. Kassab, R.B.; Lokman, M.S.; Daabo, H.M.; Gaber, D.A.; Habotta, O.A.; Hafez, M.M.; Zhery, A.S.; Moneim, A.E.; Fouda, M.S. Ferulic Acid Influences Nrf2 Activation to Restore Testicular Tissue from Cadmium-Induced Oxidative Challenge, Inflammation, and Apoptosis in Rats. J. Food Biochem. 2020, 44, e13505. [Google Scholar] [CrossRef]
  120. Abdel-Wahab, B.A.; Alkahtani, S.A.; Elagab, E.A. 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. 2020, 96, 165–174. [Google Scholar] [CrossRef]
  121. Khadrawy, O.; Gebremedhn, S.; Salilew-Wondim, D.; Rings, F.; Neuhoff, C.; Hoelker, M.; Schellander, K.; Tesfaye, D. Quercetin Supports Bovine Preimplantation Embryo Development under Oxidative Stress Condition via Activation of the Nrf2 Signalling Pathway. Reprod. Domest. Anim. 2020, 55, 1275–1285. [Google Scholar] [CrossRef] [PubMed]
  122. Güvenç, M.; Cellat, M.; Gökçek, İ.; Arkalı, G.; Uyar, A.; Tekeli, İ.O.; Yavaş, İ. Tyrosol Prevents AlCl3 Induced Male Reproductive Damage by Suppressing Apoptosis and Activating the Nrf-2/HO-1 Pathway. Andrologia 2020, 52, e13499. [Google Scholar] [CrossRef] [PubMed]
  123. Chen, S.; Yang, S.; Wang, M.; Chen, J.; Huang, S.; Wei, Z.; Cheng, Z.; Wang, H.; Long, M.; Li, P. Curcumin Inhibits Zearalenone-Induced Apoptosis and Oxidative Stress in Leydig Cells via Modulation of the PTEN/Nrf2/Bip Signaling Pathway. Food Chem. Toxicol. 2020, 141, 111385. [Google Scholar] [CrossRef] [PubMed]
  124. Yang, S.H.; Li, P.; Yu, L.H.; Li, L.; Long, M.; Liu, M.D.; He, J.B. Sulforaphane Protects against Cadmium-Induced Oxidative Damage in Mouse Leydig Cells by Activating Nrf2/ARE Signaling Pathway. Int. J. Mol. Sci. 2019, 20, 630. [Google Scholar] [CrossRef] [PubMed]
  125. Renu, K.; Gopalakrishnan, A.V. Deciphering the Molecular Mechanism during Doxorubicin-Mediated Oxidative Stress, Apoptosis through Nrf2 and PGC-1α in a Rat Testicular Milieu. Reprod. Biol. 2019, 19, 22–37. [Google Scholar] [CrossRef] [PubMed]
  126. Zhao, Y.; Li, M.Z.; Shen, Y.; Lin, J.; Wang, H.R.; Talukder, M.; Li, J.L. Lycopene Prevents DEHP-Induced Leydig Cell Damage with the Nrf2 Antioxidant Signaling Pathway in Mice. J. Agric. Food Chem. 2019, 68, 2031–2040. [Google Scholar] [CrossRef] [PubMed]
  127. Hu, Y.; Wang, Y.; Yan, T.; Feng, D.; Ba, Y.; Zhang, H.; Zhu, J.; Cheng, X.; Cui, L.; Huang, H. N-Acetylcysteine Alleviates Fluoride-Induced Testicular Apoptosis by Modulating IRE1α/JNK Signaling and Nuclear Nrf2 Activation. Reprod. Toxicol. 2019, 84, 98–107. [Google Scholar] [CrossRef]
  128. Yang, S.H.; He, J.B.; Yu, L.H.; Li, L.; Long, M.; Liu, M.D.; Li, P. Protective Role of Curcumin in Cadmium-Induced Testicular Injury in Mice by Attenuating Oxidative Stress via Nrf2/ARE Pathway. Environ. Sci. Pollut. Res. 2019, 26, 34575–34583. [Google Scholar] [CrossRef]
  129. Shi, X.; Fu, L. 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. Devel. Ther. 2019, 13, 2811–2824. [Google Scholar] [CrossRef]
  130. Yang, S.H.; Yu, L.H.; Li, L.; Guo, Y.; Zhang, Y.; Long, M.; Li, P.; He, J.B. Protective Mechanism of Sulforaphane on Cadmium-Induced Sertoli Cell Injury in Mice Testis via Nrf2/ARE Signaling Pathway. Molecules 2018, 23, 1774. [Google Scholar] [CrossRef]
  131. He, L.; Li, P.; Yu, L.H.; Li, L.; Zhang, Y.; Guo, Y.; Long, M.; He, J.B.; Yang, S.H. Protective Effects of Proanthocyanidins against Cadmium-Induced Testicular Injury through the Modification of Nrf2-Keap1 Signal Path in Rats. Environ. Toxicol. Pharmacol. 2018, 57, 1–8. [Google Scholar] [CrossRef]
  132. Chen, X.; Song, Q.L.; Li, Z.H.; Ji, R.; Wang, J.Y.; Cao, M.L.; Mu, X.F.; Zhang, Y.; Guo, D.Y.; Yang, J. Pterostilbene Ameliorates Oxidative Damage and Ferroptosis in Human Ovarian Granulosa Cells by Regulating the Nrf2/HO-1 Pathway. Arch. Biochem. Biophys. 2023, 738, 109561. [Google Scholar] [CrossRef] [PubMed]
  133. Taheri, M.; Roudbari, N.H.; Amidi, F.; Parivar, K. Investigating the Effect of Sulforaphane on AMPK/AKT/NRF2 Pathway in Human Granulosa-Lutein Cells under H2O2-Induced Oxidative Stress. Eur. J. Obstet. Gynecol. Reprod. Biol. 2022, 276, 125–133. [Google Scholar] [CrossRef] [PubMed]
  134. Ma, Y.; Hao, G.; Lin, X.; Zhao, Z.; Yang, A.; Cao, Y.; Zhang, S.; Fan, L.; Geng, J.; Zhang, Y.; et al. Morroniside Protects Human Granulosa Cells against H2O2-Induced Oxidative Damage by Regulating the Nrf2 and MAPK Signaling Pathways. Evid. Based Complement. Alternat. Med. 2022, 2022, 8099724. [Google Scholar] [CrossRef] [PubMed]
  135. Afzali, A.; Amidi, F.; Koruji, M.; Nazari, H.; Gilani, M.A.; Sanjbad, A.S. Astaxanthin Relieves Busulfan-Induced Oxidative Apoptosis in Cultured Human Spermatogonial Stem Cells by Activating the Nrf-2/HO-1 Pathway. Reprod. Sci. 2022, 29, 374–394. [Google Scholar] [CrossRef] [PubMed]
  136. Taheri, M.; Roudbari, N.H.; Amidi, F.; Parivar, K. The Protective Effect of Sulforaphane against Oxidative Stress in Granulosa Cells of Patients with Polycystic Ovary Syndrome (PCOS) through Activation of AMPK/AKT/NRF2 Signaling Pathway. Reprod. Biol. 2021, 21, 100563. [Google Scholar] [CrossRef] [PubMed]
  137. Sammad, A.; Luo, H.; Hu, L.; Zhu, H.; Wang, Y. Transcriptome Reveals Granulosa Cells Coping through Redox, Inflammatory and Metabolic Mechanisms under Acute Heat Stress. Cells 2022, 11, 1443. [Google Scholar] [CrossRef] [PubMed]
  138. Wang, Y.; Yang, C.; Nahla Abdalla Hassan, E.; Li, C.; Yang, F.; Wang, G.; Li, L. HO-1 Reduces Heat Stress-Induced Apoptosis in Bovine Granulosa Cells by Suppressing Oxidative Stress. Aging 2019, 11, 5535. [Google Scholar] [CrossRef] [PubMed]
  139. Deng, C.C.; Zhang, J.P.; Huo, Y.N.; Xue, H.Y.; Wang, W.; Zhang, J.J.; Wang, X.Z. Melatonin Alleviates the Heat Stress-Induced Impairment of Sertoli Cells by Reprogramming Glucose Metabolism. J. Pineal Res. 2022, 73, e12819. [Google Scholar] [CrossRef]
  140. Toosinia, S.; Davoodian, N.; Arabi, M.; Kadivar, A. Ameliorating Effect of Sodium Selenite on Developmental and Molecular Response of Bovine Cumulus-Oocyte Complexes Matured In vitro Under Heat Stress Condition. Biol. Trace Elem. Res. 2024, 202, 161–174. [Google Scholar] [CrossRef]
  141. Ho, K.T.; Homma, K.; Takanari, J.; Bai, H.; Kawahara, M.; Nguyen, K.T.; Takahashi, M. Standardized Extract of Asparagus officinalis Stem Improves HSP70-Mediated Redox Balance and Cell Functions in Bovine Cumulus-Granulosa Cells. Sci. Rep. 2021, 11, 18175. [Google Scholar] [CrossRef] [PubMed]
  142. Badr, G.; Abdel-Tawab, H.S.; Ramadan, N.K.; Ahmed, S.F.; Mahmoud, M.H. Protective Effects of Camel Whey Protein against Scrotal Heat-Mediated Damage and Infertility in the Mouse Testis through YAP/Nrf2 and PPAR-Gamma Signaling Pathways. Mol. Reprod. Dev. 2018, 85, 505–518. [Google Scholar] [CrossRef] [PubMed]
  143. Kumar, S.S.; Manna, K.; Das, A. Tender Coconut Water Attenuates Heat Stress-Induced Testicular Damage through Modulation of the NF-κB and Nrf2 Pathways. Food Funct. 2018, 9, 5463–5479. [Google Scholar] [CrossRef] [PubMed]
Antioxidants 13 00597 g001
Figure 1. The role of Nrf2 signaling in mitigating heat stress and xenobiotic-induced oxidative distress and apoptosis. (A) Exogenous supplementation of bioactive compounds with antioxidant ability activates the Nrf2/KEAP1 signaling pathway. This activation leads to NRF2 translocation to the nucleus and heterodimerization with sMaf proteins. Subsequently, there is binding with ARE to activate antioxidant genes (SOD, CAT, NQO1, HO1, and GPx). The activation of these antioxidant genes enhances the antioxidant response by suppressing oxidative stress and apoptosis induced via heat stress and xenobiotics. (B) Oxidative stress induced by xenobiotics/heat stress increases the level of KEAP1 and inhibits the translocation of NRF2 to the nucleus, leading to oxidative damage and apoptosis of reproductive cells. Note: Blunt arrows (Antioxidants 13 00597 i001) indicate inhibition and sharp arrows (→) indicate stimulation.
Figure 1. The role of Nrf2 signaling in mitigating heat stress and xenobiotic-induced oxidative distress and apoptosis. (A) Exogenous supplementation of bioactive compounds with antioxidant ability activates the Nrf2/KEAP1 signaling pathway. This activation leads to NRF2 translocation to the nucleus and heterodimerization with sMaf proteins. Subsequently, there is binding with ARE to activate antioxidant genes (SOD, CAT, NQO1, HO1, and GPx). The activation of these antioxidant genes enhances the antioxidant response by suppressing oxidative stress and apoptosis induced via heat stress and xenobiotics. (B) Oxidative stress induced by xenobiotics/heat stress increases the level of KEAP1 and inhibits the translocation of NRF2 to the nucleus, leading to oxidative damage and apoptosis of reproductive cells. Note: Blunt arrows (Antioxidants 13 00597 i001) indicate inhibition and sharp arrows (→) indicate stimulation.
Antioxidants 13 00597 g001
Table 1. Summary of studies targeting bioactive compound supplementation to combat xenobiotic-induced oxidative stress and apoptosis in reproductive cells via activation of the Nrf2 signaling pathway.
Table 1. Summary of studies targeting bioactive compound supplementation to combat xenobiotic-induced oxidative stress and apoptosis in reproductive cells via activation of the Nrf2 signaling pathway.
Xenobiotic-Induced Oxidative Stress/ApoptosisTherapeutic Agent Target PathwayOutcomesSpeciesReferences
Oxidative stress caused by cadmium (Cd)Anthocyanins (Extract of Lycium ruthenicum Murray plant)Keap1/Nrf2 Signaling Pathway
✧
Mitigated damage to sperm cells, alleviated oxidative stress, and protected testes from toxicity.
Mouse[3]
Methotrexate-induced oxidative stressCoenzyme Q10 (CoQ10)Nrf2/PPAR-γ signaling pathway
✧
Prevented testicular damage and testicular toxicity, primarily via its anti-inflammatory, anti-oxidant, and anti-apoptotic effects.
Rat[4]
Tripterygium glycoside-induced oxidative stressMoxibustionNrf2/HO-1 signaling pathway
✧
Prevented oligoasthenoteratozoospermia.
Rat[65]
✧
Enhances the antioxidant response (increasing T-AOC and T-SOD) and alleviated oxidative stress (decreased MDA) in testes.
Cisplatin-induced oxidative stress and toxicityAlpha-pinene (monoterpene)Nrf2 signaling pathway
✧
Enhanced the level of Nrf2 in testicular tissue.
Rat[66]
Syringic acid
✧
Ameliorated oxidative stress and apoptosis and protected testicular tissue from toxicity.
[67]
Type 1 diabetes-induced testicular dysfunctionIcariinNrf2 pathway
✧
Enhanced testicular antioxidant capacity by elevating levels of Nrf2.
Mice[68]
✧
Improved testicular function.
Streptozotocin-induced diabetes mellitus, oxidative stress. and apoptosisSulbutiamineNrf2 signaling pathway
✧
Enhanced antioxidant capacity via elevated expression of NRF2, reduced apoptosis via inhibiting levels of Bax and caspase-3, and improved the expression of Bcl-2.
Mouse[69]
✧
Improved testicular weight, testosterone level, sperm number, and motility.
Oxaliplatin-induced toxicity and oxidative stressNaringinNrf2 signaling pathway
✧
Enhanced the antioxidant response via upregulating the expression of Nrf2 followed by elevated levels of SOD, HO-1, NQO1, and GPx.
Rat[70]
✧
Inhibited oxaliplatin-induced oxidative stress and toxicity, caspase-3, Bax, and Apaf-1 and increased Bcl2 in OXL-induced testicular toxicity.
✧
Protected testicular tissue from the toxic effect of oxaliplatin.
Sodium benzoate-induced toxicity and oxidative stressVirgin coconut oilNrf2 signaling pathway
✧
Increased the expression of Nrf2, CAT, and GPx.
Rat[71]
✧
Relieved oxidative stress and toxicity caused by sodium benzoate.
✧
Improved sperm numbers and motility.
Cyclosporin-induced oxidative stressLuteinNrf2/HO-1 signaling pathway
✧
Promoted antioxidant response (upregulated the expression of Nrf2, CAT, GPx, SOD, HO-1) and apoptosis (increased the level of Bcl2)
Rat[72]
Diphenyl phosphate (DPhP)-induced apoptosis and reproductive toxicityCurcuminNrf2/P53 signaling pathway
✧
Prevented apoptosis through regulating autophagy via activation of the Nrf2/P53 pathway in mouse spermatocytes.
Mouse[73]
✧
Also reduced the risk of reproductive toxicity.
Cisplatin-induced oxidative stress and toxicityArbutinNrf2 signaling pathway
✧
Increased expression of Nrf2.
Rat[74]
✧
Prevented oxidative stress, toxicity, and endoplasmic reticulum stress.
✧
Protected ovarian injury caused by cisplatin.
H2O2-induced oxidative stress and autophagyFollicle-stimulating hormone (FSH)p62/Nrf2 signaling pathway
✧
Protected Sertoli cells from injury via inhibiting oxidative stress and autophagy.
Goat[75]
Oxidative stress and autophagy caused by Di-(2-ethylhexyl) phthalate (DEHP) N/Ap62/Keap1/Nrf2 signaling pathway
✧
Protected GCs from oxidative stress and excessive autophagy.
Mouse[76]
Cadmium-induced oxidative stress and toxicityZincNrf2 signaling pathway
✧
Restored the normal function of porcine prepubertal Sertoli cells caused by cadmium toxicity.
pig[77]
✧
Enhanced the antioxidant response (upregulated Nrf2, SOD, HO-1, and GPx expression) in Sertoli cells.
Triptolide-induced dysfunction of testicular Sertoli cells, oxidativity, and toxicityMelatoninSIRT1/Nrf2 Signaling Pathway
✧
SIRT1 and Nrf2 expression levels were enhanced.
Mouse[78]
✧
Oxidative stress was relieved and prevented, restoring the normal function of testes.
Methyl cellosolve-induced oxidative stressSyringic acidNrf2-Keap1-NQO1-HO1 signaling pathway
✧
Enhanced antioxidant response via elevating levels of Nrf2, NQO1, HO1, SOD, CAT, and GPx in testes.
Rat[79]
✧
Also decreased the expression of MDA
Torsion–detorsion-induced apoptosisPentoxifyllineNrf2/ARE signaling pathway
✧
Pentoxifylline promoted spermatogenesis.
Mouse[80]
✧
Prevented testicular apoptosis by enhancing Bcl2 and decreasing caspase-3 and Bax expression levels.
Doxorubicin-induced oxidative stressAcylated ghrelinNrf2/ARE signaling pathway
✧
Enhanced the expression of Nrf2, GSH, and SOD.
Rat[81]
✧
Decrease MDA level.
✧
Elevated antioxidant response.
✧
Improved sperm parameters.
✧
Prevented doxorubicin-induced testicular damage.
Streptozotocin-induced testicular damage and oxidative stressEsculeoside ANrf2-signaling pathway
✧
Enhanced HO-1, SOD, and GSH expression levels.
Rat[82]
✧
Decreased the level of MDA;
✧
Elevated the level of antioxidant response;
✧
Improved total sperm count, motility, and survival, reduced head and tail sperm abnormalities, increased circulatory concentrations of follicular stimulating hormone (FSH), testosterone, and luteinizing hormone (LH), and stimulated the testicular expression of several steroidogenic enzymes (StAR, CYP11A1, CYP17A1, 3β-HSD1);
✧
Protected testes from oxidative damage caused by streptozotocin.
2-methoxyethanol-induced testicular oxidative stressFerulic acidNrf2/Hmox1/NQO1 signaling pathway
✧
Enhanced the expression of Nrf2, GSH, SOD, Hmox1, and NQO1;
Rat[83]
✧
Suppressed the level of MDA;
✧
Prevented oxidative stress and damage to testes.
Acrylamide-induced testicular toxicity and oxidative stressBoronNrf2/Keap-1 signaling pathway
✧
Elevated the levels of Nrf2, GSH, SOD, Keap-1 and reduced the expression of MDA;
Rat[84]
✧
Promoted the antioxidant response;
✧
Protected the testes from toxicity and oxidative damage.
Lead acetate-induced oxidative stressSyringic acidNrf2 signaling pathway
✧
Improved the expression levels of SOD, GSH, GPx, CAT, Nrf2, and NQO1;
Rat[85]
✧
Elevated the level of Bcl2 and reduced the expression of Bax and caspase-3
H2O2-induced oxidative stressKunling Wan (Chinese traditional medicine)Keap1/Nrf2 signaling pathway
✧
Inhibited oxidative stress and enhanced antioxidant response. Prevented mitochondrial damage;
Mouse[86]
✧
Improved oocyte quality.
H2O2-induced oxidative stressResveratrolSIRT1/Nrf2/ARE signaling Pathway
✧
Enhance the antioxidant response (increasing T-AOC and T-SOD) and alleviate oxidative stress (decreased MDA).
Rat[87]
✧
Suppressed the level of anti-apoptosis protein Bcl-2 and improved the level of pro-apoptosis protein Bax;
✧
Prevented ovarian granulosa–lutein cell injury and apoptosis.
Chlorinated paraffin-induced oxidative stressResveratrolNrf2 signaling pathway
✧
Prevented testicular toxicity by inhibiting oxidative stress.
Mouse[88]
3-nitropropionic acid-induced oxidative stress and toxicitySpermidineNrf2/HO-1/GPX4 Signaling Pathway
✧
Prevented apoptosis and oxidative stress and alleviated damage in GCs and ovarian cells.
Mouse and Pig[89]
Bisphenol AF oxidative stress and apoptosisCurcuminNrf2 signaling pathway
✧
Suppressed intracellular ROS production, discouraged cell apoptosis, downregulated the expression of Bax and cytochrome c, and upregulated the expression of Bcl-2. Reduced the level of MDA;
Goat[90]
✧
Enhanced the levels of GSH-Px and SOD;
✧
Improved antioxidant response and prevented damage to caprine endometrial epithelial cells.
Paraquat-induced oxidative stressSulforaphaneKeap1/Nrf2 signaling pathway
✧
Inhibited apoptosis via downregulating Bax and caspase-3 expression;
Cow[91]
✧
Enhanced antioxidant response via elevating levels of T-SOD and GSH contents;
✧
Protected bovine oocytes from cytotoxicity and damage.
Cadmium-induced oxidative stress and testicular dysfunctionDapagliflozinSIRT1/Nrf2/HO-1 signaling pathway
✧
Elevated levels of GPx, Nrf2, and SOD and enhanced antioxidant response;
Rat[92]
✧
Decreased expression of Bax, increased Bcl2, and prevented apoptosis;
✧
Improved testicular function.
Bisphenol F-induced testicular toxicityOmega-3 fatty acidNrf2/NF-kB signaling pathway
✧
Reversed inflammatory changes, enhanced antioxidant response, and prevented testis toxicity.
Rat[93]
Perfluorooctanesulfonate acid-induced oxidative stress and reproductive injury1α,25-dihydroxyvitamin D3Nrf2 signaling pathway
✧
Promoted antioxidant response via elevating levels of HO-1, Nrf2, NQO1, and SOD2.
Mouse[94]
Diethylnitrosamine-induced testicular damageSericin and melatoninNrf2 signaling pathways
✧
Increased expression of Nrf2, SOD, CAT and GPx;
Mouse[95]
✧
Enhanced antioxidant capacity;
✧
Restored the normal function of testes, which had been impaired by diethylnitrosamine.
Aflatoxin B1-induced oxidative stressLycopeneNrf2 signaling pathways
✧
Protected testes from aflatoxin B1-induced toxicity and oxidative stress.
Mouse[96]
H2O2-induced oxidative stressMelatoninNrf2 signaling pathway
✧
Reduced the level of MDA and increased the expression of Nrf2, SOD, and Sirt3;
Mouse[97]
✧
Protected Sertoli cells from oxidative stress and prevented infertility.
Copper-induced toxicity and oxidative stressNano-CurcuminNrf2/HO-1 signaling pathway
✧
Nano-curcumin and curcumin protected testicular tissue from oxidative injury, enhanced the circulating FSH, LH, and testosterone, and elevated testicular steroidogenesis-linked genes and AR. N-nano-curcumin and curcumin inhibited testicular MDA, NO, NF-κB, iNOS, TNF-α, Bax, and caspase-3 and promoted Bcl-2, Nrf2, and the antioxidants genes including GSH, HO-1, SOD, and CAT
Rat[98]
Cadmium-induced oxidative stress and injuryZinc Nrf2 signaling pathway
✧
Elevated the expression of SOD, HO-1, and GSHPx in Sertoli cells;
Pig[99]
✧
Protected Sertoli cells from Cd-induced oxidative damage.
Cadmium-induced oxidative stressMelatoninNrf2 signaling pathway
✧
Antioxidant response was enhanced;
Pig[100]
✧
Prevented cytotoxicity of Sertoli cells.
H2O2-induced oxidative stressN-acetyl-cysteineNrf2 signaling pathway
✧
Prevented oxidative stress damage to mouse ovaries.
Mouse[101]
Cisplatin-induced apoptosis and oxidative stressMelatoninSIRT1/Nrf2 signaling
✧
Prevented oxidative damage to Leydig and Sertoli cells in the testes.
Mouse[102]
Zearalenone-induced toxicity and oxidative stressBetulinic acidNrf2-signaling pathway
✧
Protected testes from zearalenone-induced oxidative stress and toxicity.
Mouse[103]
Zearalenone-induced apoptosis and oxidative stressProcyanidinsNrf2 signaling pathway
✧
Enhanced antioxidant response and prevented apoptosis;
Pig[104]
✧
Protection of swine testicles from oxidative damage.
Bisphenol A-induced oxidative stressNaringeninKeap1/Nrf2 signaling pathway
✧
Enhanced antioxidant response (enhanced SOD, GPx, and CAT expressions);
Pig[105]
✧
Protected swine testes from oxidative damage and cytotoxicity.
N/ACurcuminNrf2/Keap1 signaling pathway
✧
Enhanced the expression of Nrf2, NQO1, HO1, and Keap1 genes.
Mouse[106]
✧
Prevent cryptorchidism complications
Fumonisin-induced oxidative stressN/ANrf2 signaling pathway
✧
Increased ROS level, reduced expression of MDA, disrupted the Keap1-Nrf2 pathway, and compromised the antioxidant system of the testes.
Mouse[107]
Cadmium-induced oxidative stress and toxicityVitamin ENrf2 signaling pathway
✧
Reduced expression of MDA and enhanced activities of T-AOC, GSH, CAT, SOD, and GSH-Px;
Rat[108]
✧
Enhanced antioxidant response and prevented oxidative damage to testes;
✧
Elevated rate of normal sperm, increased sperm count, motility, and viability.
Triptolide-induced oxidative stress and apoptosisHyperosideKeap1-Nrf2 signaling pathway
✧
Upregulated the expressions of Nrf2, SOD and GPx, and decreased caspase-3;
Mouse[109]
✧
Prevented testicular atrophy and injury.
Zearalenone-induced oxidative stress and impaired steroidogenesisZingeroneNrf2 signaling pathway
✧
Enhanced antioxidant response by upregulating Nrf2 expression in Leydig cells.
Mouse[110]
✧
Improved steroidogenesis.
Testicular torsion/detorsion-induced injury enhancing inflammation, suppression of Nrf2 siganling, and oxidative stressIdebenoneNrf2 signaling pathway
✧
Decreased the levels of MDA and caspase-3 and enhanced the expression of Nrf2;
Mouse[111]
✧
Relieved apoptosis and inflammation and improved antioxidant response;
✧
Protected testes from testicular torsion injury.
Fructose–streptozotocin-impaired steroidogenesis and spermatogenesisCaffeic acidNrf2 signaling pathway
✧
Enhanced Nrf2 expression and restored the normal process of steroidogenesis and spermatogenesis in testes of mice.
Mouse[112]
LPS-induced oxidative stress in bovine endometrial cellsSeleniumNrf2/HO-1 signaling pathway
✧
Enhanced the levels of Nrf2 and GPx;
Cow[113]
✧
Relieved oxidative stress and prevented endometritis.
Zearalenone-induced oxidative damageLycopeneNrf2 signaling pathway
✧
Enhanced the antioxidant response genes (increased expressions of GPx, Nrf2, HO1, and SOD).
Pig[114]
N/AQiangjing TabletsNrf2 signaling pathway
✧
Enhanced sperm motility, concentration, and viability, which was linked significantly increased levels of HO-1, Keap1, P-Nrf2, estradiol, and testosterone, along with increasing the activity of SOD, GSH-Px, and GSH and suppressing MDA content, luteinizing hormone, and vimentin levels.
Mouse[115]
✧
Protected spermatogenic cells to upregulate male sex hormone, improved sperm quality and reproductive function in asthenozoospermia rats via activating the Keap/Nrf2 signaling pathway.
N/AChitooligosaccharide-zincSESN2/Nrf2 signaling pathway
✧
Prevented premature ovarian failure and enhanced ovarian and follicular development via activation of the SESN2/Nrf2 signaling pathway;
Mouse[116]
✧
SOD, Nrf2, and SESN2 expression levels were upregulated following improved antioxidant response.
Lead-induced oxidative stress and apoptosisLuteolinNrf2/HO-1 signaling pathway
✧
Prevented testicular tissue injury by relieving apoptosis (decreased Bax and caspase 3) and enhanced antioxidant response via elevated expressions of GPx, Nrf2, HO-1, NQO1 in testicular tissue.
Rat[117]
La2O3 nanoparticle-induced oxidative stress apoptosis and toxicityN/ANrf2/HO-1 signaling pathway
✧
Prevented the translocation of Nrf2 to the nucleus;
Mouse[118]
✧
Enhanced apoptosis and oxidative and testicular tissue injury.
Cadmium-induced oxidative stress and apoptosisFerulic acidNrf2 signaling pathway
✧
Upregulated the expressions of Nrf2, SOD, CAT, and GPx;
Rat[119]
✧
Improved antioxidant response and protected testicular injury.
Cisplatin-induced oxidative stress and apoptosisTadalafilNrf2/HO-1 signaling pathway
✧
Promoted the antioxidant response (Nrf2 and HO-1) and inhibited apoptosis (decreased Bax and enhanced Bcl2 expression).
Rat[120]
✧
Prevented testicular oxidative damage and toxicity in rats.
N/AQuercetinNrf2 signaling pathway
✧
Enhanced antioxidant response via upregulating the expression of Nrf2, NQO1, PRDX1, CAT, and SOD1;
Cow [121]
✧
Protected preimplantation embryos against oxidative stress and improved embryo viability via activation of the Nrf2 signaling pathway.
Aluminium chloride-induced oxidative stress and apoptosisTyrosolNrf2/HO-1 signaling pathway
✧
Protected testicular toxicity and oxidative damage and improved sperm motility by upregulating GSH, CAT, Nrf2, HO-1, and bcl-2 expression and downregulating caspase-3 and MDA levels.
Rat[122]
Zearalenone-induced apoptosis and oxidative stress.CurcuminNrf2 signaling pathway
✧
Protected Leydig cells from oxidative stress and apoptosis via regulation of the Nrf2 signaling pathway;
Mouse[123]
✧
Enhanced the antioxidant response (Increased Nrf2, HO-1, SOD, GSH, and GSH-Px expressions, and reduced MDA level) and relieved apoptosis (enhanced Bcl-2 and reduced Bax levels).
Cadmium-induced oxidative stress and apoptosisSulforaphaneNrf2/ARE signaling pathway
✧
Protected Leydig cells from oxidative stress and apoptosis via regulation of the Nrf2 signaling pathway.
Mouse[124]
✧
Enhanced the antioxidant response (Nrf2, GSH-Px, HO-1, γ-GCS, and NQO1 expression, reduced MDA level) and relieved apoptosis;
✧
Protected testicular tissue toxicity.
Doxorubicin-induced oxidative stress and toxicityN/ANrf2 signaling pathway
✧
Suppressed the level of Nrf2, enhanced apoptosis (decreased caspase 3 and Bcl2 levels) and oxidative stress;
Mouse[125]
✧
Caused testicular tissue toxicity and injury.
di(2-ethylhexyl) phthalate (DEHP)-induced oxidative stress and Leydig cell damageLycopeneNrf2 signaling pathway
✧
Elevated level of Nrf2 and its antioxidant linked genes (HO-1, NQO1);
Mouse[126]
✧
Prevented oxidative stress and Leydig cell injury in mice.
Fluoride-induced testicular apoptosisN-acetylcysteineNrf2 signaling pathway
✧
Improved the antioxidant response and alleviated apoptosis via activation of the Nrf2 pathway;
Mouse[127]
✧
Protected testis tissue from oxidative damage.
Cadmium-induced testicular injury and oxidative stressCurcumin Nrf2/ARE signaling pathway
✧
Upregulated the expression levels of T-SOD, GSH-Px, GSH, Nrf2, and γ-GCS and reduced the level of MDA in testicular tissue;
Mouse[128]
✧
Prevented testicular injury.
Cadmium-induced testicular injury and oxidative stressPiceatannolNrf2 signaling pathway
✧
Piceatannol inhibited oxidative stress via upregulation of antioxidant genes (Nrf2, HO1, γGCS, GPx, and NQO1).
Rat[129]
Cd-induced oxidative stress and apoptosisSulforaphane Nrf2/ARE signaling pathway
✧
Upregulated the expression of antioxidant linked genes (Nrf2, T-SOD, HO-1, NQO1, GSH-Px, and γ-GCS);
Mouse[130]
proanthocyanidins
✧
Protective against oxidative damage and apoptosis caused by Cd in Sertoli cells.
[131]
Dihydrotestosterone-induced oxidative stressSalidrosideNrf2 signaling pathway
✧
Suppressed apoptosis and oxidative stress;
✧
Protected human granulosa cell from oxidative stress.
 [51]
H2O2-induced oxidative damage and ferroptosis PterostilbeneNrf2/HO-1 signaling pathway
✧
Inhibited oxidative damage and ferroptosis in human ovarian granulosa cells via Nrf2/HO-1 signaling pathway.
 [132]
H2O2-induced oxidative stressSulforaphaneAMPK/AKT/NRF2 signaling pathway
✧
Suppressed apoptosis and oxidative stress;
✧
Increased the expression of AMPK, AKT, and NRF2;
✧
Protected human granulosa–lutein cells from the injury of oxidative stress.
 [133]
H2O2-induced oxidative stressMorronisideNrf2 signaling pathway
✧
Improved antioxidant response (increased expression of Nrf2, SOD, and NQO1 and decreased level of MDA);
✧
Prevented apoptosis;
✧
Improved quality of oocytes;
✧
Protected ovarian granulosa cells from oxidative stress and apoptosis.
Human[134]
Busulfan-induced oxidative stress and apoptosisAstaxanthinNrf2/HO-1 signaling pathway
✧
Relieved oxidative stress by enhancing antioxidant response (increased expression of Nrf2, HO-1, and SOD) and reduced apoptosis genes (decreased levels of CASP9, CASP3, Bax and suppressed the BCL2 content) in human spermatogonial stem cells.
[135]
Polycystic ovary syndrome (PCOS)-induced oxidative stressSulforaphaneNrf2 signaling pathway
✧
Protected granulosa cells from PCOS-induced oxidative stress;
✧
Activated Nrf2 signaling to enhance the antioxidant response.
 [136]
Total antioxidant capacity (T-AOC); total superoxide dismutase (T-SOD); malondialdehyde (MDA); granulosa cells (GCs); nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE); heme oxygenase-1 (HO-1); glutathione peroxidase (GSH-Px); quinone oxidoreductase 1 (NQO1); sirtuin 3 (Sirt3); androgen receptor (AR); kelch-like ECH-associated protein 1 (KEAP1); peroxiredoxin 1 (PRDX1); γ-glutamylcysteine synthetase (γ-GCS); Tumour Necrosis Factor alpha (TNF-α); steroidogenic acute regulatory protein (StAR); cytochrome P450 family 11 subfamily A member 1 (CYP11A1); human 3 beta-hydroxysteroid dehydrogenase deficiency (3β-HSD1); nitric oxide (NO); inducible nitric oxide synthase (iNOS), nuclear factor-κB (NF-κB).
Table 2. Summary of studies investigation supplementation with bioactive compounds to combat heat stress-induced oxidative distress and apoptosis in mammalian reproductive cells via activation of the Nrf2 signaling pathway.
Table 2. Summary of studies investigation supplementation with bioactive compounds to combat heat stress-induced oxidative distress and apoptosis in mammalian reproductive cells via activation of the Nrf2 signaling pathway.
Causative Agent of Oxidative Stress/ApoptosisTherapeutic Agent Target PathwayOutcomesSpeciesReferences
Heat stress-induced oxidative stressN/ANrf2 signaling pathway
✧
Treatment with 41 °C for 24 h significantly downregulated the levels of CAT, SOD, and Nrf2 gene expression;
✧
Upregulated the level apoptosis by regulating BAX and caspase-3 in bovine granulosa cells;
✧
Heat-induced oxidative stress compromised cell proliferation and apoptosis.
Cow[32]
Heat stress-induced oxidative stress and uterine injuriesBaicalinKeap1/Nrf2 signaling pathway
✧
Enhanced the levels of antioxidant genes (SOD, CAT, GSH-Px) and decreased the level of MDA;
✧
Inhibited the expression of caspase-3 and caspase-9 in mouse uterine cells;
✧
Protected mouse uterine cells from heat stress-induced oxidative injures and apoptosis.
Mouse[33]
Heat stress-induced oxidative stress in bovine endometrial cellsN/AKeap1/Nrf2 signaling pathway
✧
Activated Nrf2 further regulated antioxidant-linked genes to balance the oxidative stress.
Cow[35]
Heat stress-induced oxidative stress and apoptosisMelatoninKeap1/Nrf2 signaling pathway
✧
Alleviated oxidative stress and apoptosis via activating Keap1/Nrf2 signaling in Sertoli cells.
Mouse[139]
Heat stress-induced oxidative stressSeleniumNrf2 signaling pathway
✧
Upregulated GPX-4, SOD, and CAT and downregulated MDA.
Cow[140]
Heat stress-induced oxidative stress and toxicityAsparagus officinalis stemNrf2 signaling pathway
✧
Enhanced the levels of HSP70, Nrf2, Keap1, and HSF1 in bovine cumulus–granulosa cells;
✧
Protected bovine cumulus–granulosa cells from oxidative damage and toxicity.
Cow[141]
Scrotal heat-mediated damage and infertilityCamel whey proteinNrf2 signaling pathway
✧
Camel milk significantly upregulated the expression of Nrf2 and BCL2, which were downregulated in Leydig cells through scrotal heating.
Mouse[142]
Heat stress-induced inflammation and oxidative stressTender coconut waterNF-κB/Nrf2 signaling pathway
✧
Prevented testicular damage and enhanced the antioxidant response.
Mouse[143]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Khan, M.Z.; Khan, A.; Huang, B.; Wei, R.; Kou, X.; Wang, X.; Chen, W.; Li, L.; Zahoor, M.; Wang, C. Bioactive Compounds Protect Mammalian Reproductive Cells from Xenobiotics and Heat Stress-Induced Oxidative Distress via Nrf2 Signaling Activation: A Narrative Review. Antioxidants 2024, 13, 597. https://doi.org/10.3390/antiox13050597

AMA Style

Khan MZ, Khan A, Huang B, Wei R, Kou X, Wang X, Chen W, Li L, Zahoor M, Wang C. Bioactive Compounds Protect Mammalian Reproductive Cells from Xenobiotics and Heat Stress-Induced Oxidative Distress via Nrf2 Signaling Activation: A Narrative Review. Antioxidants. 2024; 13(5):597. https://doi.org/10.3390/antiox13050597

Chicago/Turabian Style

Khan, Muhammad Zahoor, Adnan Khan, Bingjian Huang, Ren Wei, Xiyan Kou, Xinrui Wang, Wenting Chen, Liangliang Li, Muhammad Zahoor, and Changfa Wang. 2024. "Bioactive Compounds Protect Mammalian Reproductive Cells from Xenobiotics and Heat Stress-Induced Oxidative Distress via Nrf2 Signaling Activation: A Narrative Review" Antioxidants 13, no. 5: 597. https://doi.org/10.3390/antiox13050597

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop