Next Article in Journal
Hydroxy Selenomethionine Alleviates Hepatic Lipid Metabolism Disorder of Pigs Induced by Dietary Oxidative Stress via Relieving the Endoplasmic Reticulum Stress
Next Article in Special Issue
Antioxidant Activity, Metal Chelating Ability and DNA Protective Effect of the Hydroethanolic Extracts of Crocus sativus Stigmas, Tepals and Leaves
Previous Article in Journal
Assessment of Lipid Peroxidation in Alzheimer’s Disease Differential Diagnosis and Prognosis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Antioxidants
Volume 11
Issue 3
10.3390/antiox11030548
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

COVID-19, Oxidative Stress and Male Reproduction: Possible Role of Antioxidants

by
Pallav Sengupta
1,2,†,
Sulagna Dutta
2,3,†,
Shubhadeep Roychoudhury
4,*,
Urban John Arnold D’Souza
5,6,
Kadirvel Govindasamy
7 and
Adriana Kolesarova
8
1
Physiology Unit, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom 42610, Selangor, Malaysia
2
School of Medical Sciences, Bharath Institute of Higher Education and Research (BIHER), Chennai 600126, India
3
Department of Oral Biology and Biomedical Sciences, Faculty of Dentistry, MAHSA University, Jenjarom 42610, Selangor, Malaysia
4
Department of Life Science and Bioinformatics, Assam University, Silchar 788011, India
5
Father Muller Medical College, Mangalore 575025, India
6
Father Muller College of Allied Health Sciences, Kankanady, Mangalore 575002, India
7
Animal Production Division, ICAR Research Complex for NEH Region, Indian Council of Agricultural Research, Umiam 793103, India
8
Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, 94976 Nitra, Slovakia
*
Author to whom correspondence should be addressed.
†
These authors have contributed equally to this work.
Antioxidants 2022, 11(3), 548; https://doi.org/10.3390/antiox11030548
Submission received: 18 February 2022 / Revised: 10 March 2022 / Accepted: 12 March 2022 / Published: 14 March 2022
(This article belongs to the Special Issue Cellular and DNA Damage in Oxidative Stress Conditions: Cytoprotective and Genoprotective Potential of Antioxidant Molecules)
Browse Figures
Versions Notes

Abstract

:
Coronavirus disease 2019 (COVID-19) involves a complex pathogenesis and with the evolving novel variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the long-term impacts of the unceasing COVID-19 pandemic are mostly uncertain. Evidence indicates deleterious impact of this disease upon male reproductive health. It is concerning that COVID-19 may contribute to the already global declining trend of male fertility. The adverse impacts of COVID-19 on male reproduction may primarily be attributed to the induction of systemic inflammatory responses and oxidative stress (OS), which operate as a vicious loop. Bringing the systemic inflammation to a halt is critical for ‘putting out’ the ‘cytokine storm’ induced by excessive reactive oxygen species (ROS) generation. The possibility of OS playing a prime role in COVID-19-mediated male reproductive dysfunctions has led to the advocacy of antioxidant therapy. An array of antioxidant defense medications has shown to be effective in experimental and clinical studies of COVID-19. The present review thus discusses the possibilities as to whether antioxidant drugs would contribute to combating the SARS-CoV-2 infection-induced male reproductive disruptions, thereby aiming at kindling research ideas that are needed for identification and treatment of COVID-19-mediated male reproductive impairments.

1. Introduction

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), first identified in December 2019 in Wuhan city of China [1], causes the coronavirus disease-2019 (COVID-19). Attributable to its inordinate transmissibility, World Health Organization (WHO) has labelled it as a global ‘pandemic’ on 11 March 2020 [2]. Various hypotheses have already been put forth to explain its pathogenesis. It has been observed that men are more vulnerable to COVID-19 compared to women [3]. Thus, it is essential to focus on the possible mechanisms of COVID-19-mediated impairment of men’s health as well as fertility. There is hardly any more confusion regarding the fact that the virus may enter the testes [4,5,6], presumably due to the infection-mediated inflammatory response disrupting the blood-testes barrier. Furthermore, testicular immunological privilege and the local presence of regulatory T cells may aid viral persistence in this tissue [7]. Li et al. recently reported SARS-CoV-2 presence in semen samples in six individuals, two of whom were recovering from COVID-19. This discovery reopened debates about male genital tract infection, viral shedding in sperm, and prospects of reproductive therapies for COVID-19 patients [5]. The testes of deceased COVID-19 patients showed testicular congestion, interstitial oedema, exudation of red blood cells, and T-lymphocyte (CD3+) and macrophage infiltration. Both the testis and epididymides showed elevated inflammatory responses. The same study found elevated ACE2 expression in the Leydig cells of males who died with COVID-19 [8]. The increase in apoptotic cells inside seminiferous tubules of deceased COVID-19 patients suggests SARS-CoV-2-mediated spermatogenic disruptions. Moreover, the influence of the viral infection on semen quality and endocrine dys-homeostasis is also known. According to Ma et al. [9], COVID-19 patients had higher circulating levels of LH and lower testosterone: LH ratio, indicating impaired Leydig cell activity. Following infection, Koç and Keserolu [10] found a decrease in circulating testosterone levels, which Cinislioglu et al. [11] linked to the severity of the disease. The findings for semen quality are more varied. A substantial influence of COVID-19 infection on semen quality has been reported, including semen volume, total sperm motility, progressive motility, and sperm morphology [10,12,13].
It is noteworthy that the general mode of actions of any respiratory viral infections (that include inflammatory responses, cytokine production, host cell apoptosis, and subsequently a chain of systemic pathophysiological processes) may be attributed to compromised antioxidant actions and the induction of oxidative stress (OS) [14]. Antioxidant treatments for COVID-19 show promising results; thus, it will be interesting to explore the scope of further research on the possibilities of these antioxidants to ameliorate both COVID-19 and the disease-induced male reproductive dysfunctions.

2. COVID-19 and Male Infertility: Oxidative Stress (OS)–Inflammation Vicious Cycle

Oxidative stress occurs via a disrupted prooxidant–antioxidant balance that shifts towards prooxidant over-production [15]. Oxidative stress and inflammation are interlinked phenomena [14]. SARS-CoV-induced OS is mediated via various pathways. The virus evokes innate immune responses [14] triggering inflammation and excessive production of reactive oxygen species (ROS), eventually leading to OS [14]. A systemic ‘cytokine storm’ further elicits inflammatory responses leading to severe tissue injury [16].
The testicular microenvironment maintains immune homeostasis, where local innate immune responses are counteracted by an immune suppressive system [17]. Severe systemic inflammation via blood-borne dissemination of pathogens or via secondary inflammation, may adversely affect male reproductive functions [18,19].
The high expressions of angiotensin-converting enzyme 2 (ACE-2) receptors in the testicular cells may indicate direct viral invasion in these cells [20]. Viral infections may act via specific host pattern recognition receptors (PRRs) [21]. Toll-like receptors (TLRs) are the best-characterized PRRs that can recognize viral proteins, nucleic acids, and oxidized macrophage phospholipids caused by high ROS levels [21,22]. Interestingly, Sertoli cells, Leydig cells, and spermatogonial cells express different TLRs [22]. Activations of TLRs may trigger myeloid differentiation primary response 88 (MYD88) and mitogen activated protein kinase (MAPK) pathways, activating the transcription factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NFkβ), and interferon regulatory factor 3 (IRF3). This, in turn, upregulates transcription of inflammatory gene subsets including Sertoli cell immunoregulatory activin A [18]. The inflammatory mediators induce infiltration of activated leukocytes exaggerating generation of ROS and inducing testicular OS (Figure 1).
As SARS-CoV-2 shares a 79% nucleotide resemblance to SARS-CoV, it may utilize a similar primary immune-evasive strategy as reported for SARS-CoV [23]. SARS-CoV-induced OS leads to high release of macrophage-derived oxidized phospholipids [24], which can trigger cytokine overproduction and amplify the host inflammatory response via oxidant sensitive inflammatory pathways [24]. NF-kβ plays a central role in SARS-CoV infections [24]. It has binding sites in the promoter region of genes related to apoptotic elements and pro-inflammatory mediators. SARS-CoV 3CLpro (a viral protease) causes a significant increase in ROS production, which in turn, activates NF-kβ-mediated cell apoptosis [21]. SARS-CoV acts through MAPK pathway that may act through Bax oligomerization to activate mitochondrial apoptotic pathways [24]. Peripheral blood mononuclear cells (PBMC) of SARS-CoV infected patients showed upregulation of inflammatory genes in response to OS [21], which also suggests that SARS-CoV infection triggers the vitiating loop of inflammation and OS. Moreover, this virus can potentially cause orchitis which may also induce OS. Finally, SARS-CoV-2 infection inflicts psychological stress that again paves the way for OS [25].
Secondary inflammation of SARS-CoV-2 may also affect testicular functions. Sertoli cells are sensitive to endogenous inflammatory mediators, most notably interleukin (IL)-1A, IL1B, tumor necrosis factor-α (TNF-α), nitric oxide, transforming growth factor B3 (TGF B3) and type 1 and type 2 interferons [18]. These molecules may extend their effects on Sertoli cells as well as mediate intercellular communication within the seminiferous epithelium [21]. Consequently, the presence of viral components or ligands of TLRs, increased levels of inflammatory cytokines within the testis, or reaching the testis via blood in case of progressive systemic inflammation, may severely impair testicular functions [26].
SARS-CoV-2-mediated disruption in male reproduction is also related to androgen synthesis. There are conflicting findings indicating that SARS-CoV-2 infection in males results in acute stage hypogonadism [27], which is associated with increased levels of pro-inflammatory cytokines, mainly IL-1β, IL-6, and TNF-α [26]. Inflammation-induced OS may also influence the endocrine regulation of male reproductive functions including steroidogenesis [28].

3. COVID-19, Oxidative Stress (OS) and Male Infertility: Role of Antioxidants

In order to reduce the threat of SARS-CoV-2 infection and/or to be utilized as an adjuvant treatment in the case of severe COVID-19 forms, several therapeutic measures involving antioxidant(s) have been investigated or proposed (Figure 2).

3.1. Vitamin C

Given the intricate involvement of oxidant sensitive mechanisms in COVID-19-mediated male infertility, OS-targeted therapies may possibly lead to effective amelioration [29,30]. Early use of high-dose vitamin C may be beneficial in reversing these adverse effects. Vitamin C has been shown to benefit critical care management since it is a major component of the cellular antioxidant system [31,32]. A clinical study involving 146 patients with sepsis showed that intravenous high-dose vitamin C may be an effective treatment regime [33]. Vitamin C and sulforaphane have been shown to decrease OS-induced acute inflammatory lung injury [34].
Vitamin C is a key antioxidant in the testis and is particularly effective in neutralizing ROS and reducing sperm agglutination. It contributes electrons to redox systems, inhibits lipid peroxidation, recycles vitamin E, and protects DNA from peroxide radical damage [35] all of which can help preserve testicular cells from OS and also help reduce sperm DNA fragmentation (SDF). Additionally, it has been demonstrated that it increases serum testosterone levels in animals exposed to OS [36,37,38]. Thus, incorporating vitamin C in the therapy regimens of COVID-19 may benefit males with primary hypogonadism. In China, high-dose intravenous vitamin C was found to be beneficial in the treatment of 50 patients with moderate to severe COVID-19. An expert panel of National Institutes of Health has demonstrated that vitamin C dosage of 1.5 g/kg body weight is safe [39]. Given that high-dose vitamin C is regarded as safe, healthcare providers should benefit from these scientific and clinical observations. For COVID-19 male patients, well-designed clinical trials are required to investigate the efficacy of vitamin C therapy combined with standard treatment for resolving the systemic viral infection together with restoring male reproductive functions.

3.2. N-Acetyl Cysteine (NAC)

As a powerful antioxidant biomolecule, N-acetyl cysteine (NAC) may be used to combat the generation of ROS and, more significantly, the ‘cytokine storm’ that occurs in COVID-19 [40,41]. Similar to SARS-CoV, SARS-CoV-2 is thought to cause an immune response involving pro-inflammatory cytokines such as IL-1, IL-2, IL-4, TNFα, and IFNs. SARS-CoV infection inhibits type-I IFNs by inhibiting STAT1, antagonizing IFN. In SARS-CoV-2 infection, a cytokine storm causes delayed IFN response. N-acetyl cysteine may boost TLR-7 and mitochondrial antiviral signal protein signal cascades, restoring SARS-CoV-2-mediated type-I IFN production [40]. NF-κβ is a mediator of SARS-CoV-2 pathogenesis playing a central role in triggering a cytokine storm. However, in an in vitro influenza A and B model, NAC inhibited NF-κβ activation [42], replenishing thiol pools and the ROS scavenging mechanism. Decreased GSH levels and increased ROS production aid the progression of inflammatory diseases. A recent study reported an elevated ROS/GSH ratio in patients with severe COVID-19 infection compared to mild forms [43]. Since secondary immune responses elicited by systemic inflammation and OS may cause male reproductive dysfunction in COVID-19 patients [44], anti-inflammatory and antioxidant characteristics of NAC may protect the tissues from the oxidative damage.
Oral, intravenous, or inhaled NAC in patients with mild COVID-19 symptoms has been used as a less expensive clinical treatment. Clinical trials are carried out to find the safety and effectiveness of combination-treatment for ventilated COVID-19 patients by an FDA-approved drug, nebulized heparin-NAC by evaluation of pulmonary functions [45]. Another recent trial found that COVID-19 patients taking 6 g NAC intravenously daily had improved treatment outcomes [46,47]. Additionally, oral NAC (600 mg/day) could also prevent SARS-CoV-2 in people who are constantly exposed to the virus.
Thus, NAC is a potent COVID-19 therapeutic drug whose possible effectiveness in ameliorating COVID-19-mediated male reproductive impairment is an important research area to explore. It has been reported that NAC supplementation can improve sperm parameters and oxidative/antioxidant state in infertile men [48,49]. Due to its free sulfhydryl group, NAC reduces sulphide bonds in the cross-linked glycoprotein matrix in mucus. Owing to its ability to cleave viral disulfide bonds [50], NAC may also help inhibit SARS-CoV-2 invasion into testicular cells. In addition to being a potent anti-inflammatory and antioxidant, NAC maintains the thiol pool, which in turn regulates the redox state as it is an important substrate for glutathione synthesis [51,52]. The anti-inflammatory and antioxidant effects of NAC may contribute to preserving male reproductive functions from COVID-19 mediated damages.

3.3. Melatonin

Melatonin does not have direct anti-viral effects [53], but owing to its anti-inflammatory, antioxidant, and immune boosting properties [54,55], it can contribute to the treatment of SARS-CoV-2 infection. In addition, melatonin is a potent inhibitor of calmodulin, which is a critical intracellular component for the maintenance of ACE-2 on the cell membrane [56]. The multifunctional pineal hormone, melatonin, has been shown to reduce the symptoms of viral infections in some instances. After infecting mice with a virus (e.g., encephalitis), researchers found that using melatonin lowered the viral load in their blood and brain and reduced the severity of paralysis and death [57]. Recent studies using respiratory syncytial virus models found that melatonin was effective in decreasing acute lung oxidative injury, as well as pro-inflammatory cytokine production and inflammatory cell recruitment. These data, together with those previously presented by Reiter et al., provided evidence in favor of the use of melatonin in the treatment of viral infections including COVID-19 [53]. According to recent research, patients with obesity and diabetes, who are at high risk of severe inflammation and OS following infection with SARS-CoV-2, may benefit from the use of melatonin [58]. Moreover, it has been posited that children may not suffer from COVID-19 as much as their grandparents, as melatonin diminishes with age [59]. Melatonin influences male reproduction in three major ways. First, it modulates GnRH and LH secretion. Second, it controls testosterone biosynthesis and maturation of testes. Third, as an effective lipophilic and hydrophilic free radical scavenger, it protects against toxicants and inflammation [60,61,62]. Thus, melatonin is a potentially endogenous molecule to be studied extensively for its role in COVID-19 mediated male reproductive disruptions.

3.4. Selenium (Se)

Selenium (Se) deficiency may impact COVID-19 severity. A study conducted including 17 Chinese cities showed a positive correlation between COVID-19 prevalence and endogenous Se concentration, and Se insufficiency was linked to an elevated COVID-19 mortality risk [63]. Evidence suggests that the micronutrients zinc, Se, and vitamin D might be involved in the course and outcome of COVID-19 disease, but the number of studies undertaken in this area still remains inadequate. However, it was hypothesized that nutritional supplement(s) given during the early phases of infection may boost the host’s resistance to the infections [64]. The ebselen organoselenium compound reduces the activities of hydroperoxide- and peroxynitrite thereby mimicking the enzymes, glutathione peroxidase and peroxiredoxin. Ebselen forms a selenosulfide bond by reacting with several protein thiols, and this is attributed to its pleiotropic characteristics, mainly, antibacterial, antiviral, and anti-inflammatory. The main protease (Mpro) of SARS-CoV-2 is a potential drug target, and among over 10,000 compounds that have been screened to identify the specific potent Mpro inhibitor, ebselen has emerged as one of the potent Mpro inhibitors [65,66]. In humans or other animals, the prime role of Se attributes to its antioxidant actions through Se-dependent enzyme glutathione peroxidase (GPx1). The GPx1 system protects the cells from OS mediated peroxidative damage to the membranes and organelles. Moreover, through this mechanism of action of Se, it has been found to improve semen parameters in infertile men and also increases pregnancy rates [67,68]. The connection between the GPx1 detoxifying system and the primary protease (Mpro) of SARS-CoV-2 also represents a unique molecular target for COVID-19 [69]. Considering the beneficial impacts of Se on male fertility as well as on COVID-19 via similar mechanisms, it may be deemed that Se is a potential research candidate to be explored for male reproductive restoration in COVID-19-infected men.

3.5. Nrf-2 Activators and Flavonoids

S-protein of SARS-CoV-2 binds ACE2 receptors for its cellular entry followed by downregulation of endogenous anti-viral mechanism, activation of NF-κβ pathways, and production of pro-apoptotic proteins and ROS [70]. The nuclear factor erythroid 2-related factor-2 (Nrf2) is one of the main components mediating cellular oxidant resistance. To minimize the adverse effects of oxidant exposure, Nrf2 regulates the expression of numerous antioxidant response element (ARE)-dependent genes. Thus, Nrf2 activators have been conjectured to suppress the impacts of SARS-CoV-2 infection [70]. Nrf2-activators include curcumin, gingerol, capsaicin, epigallocatechin gallate (EGCG), genistein, lycopene, resveratrol, diallyl sulphide, phenethyl ester, indole-3-carbinol, and sulphoraphane. On the other hand, the synthetic Nrf2 activator PB125® was found to downregulate 36 genes encoding cytokines such as IL-6, IL-1β, TNFα, and cell adhesion molecules as well as a group of IFN-induced genes [71]. Curcumin, a natural Nrf2 activator with minimal toxicity and antioxidant, and anti-inflammatory properties, has been proposed as a therapeutic agent for viral pneumonia and ALI/ARDS. By stimulating polymorphonulcear leukocytes’ (PMNs) apoptosis and neutralizing ROS, curcumin protects against inflammation and OS [72]. The antioxidant epigallocatechin-3-gallate (EGCG), found in green tea leaves, has been advocated as a supplement therapy for COVID-19 patients. Most of EGCG’s advantages come from its anti-fibrotic activity and ability to downregulate various inflammatory mediators [73]. The thiols glutathione (GSH) and NAC are also Nrf2 activators [74].
These compounds acting as Nrf-2 activators and flavonoids, owing to their anti-inflammatory, antioxidant, anti-apoptotic, and antiviral activities, are suitable candidates for nullifying impairing effects of oxidants on semen quality. The flavonoids, naringin, rutin, catechin, kaempferol, and quercetin were found to be ameliorative of sperm oxidative damage [75]. These may, therefore, be beneficial in the prevention or reduction of COVID-19 severity as well as its impacts on male reproduction.

3.6. Drugs

Antioxidant characteristics may be found in COVID-19 therapy drugs. Hydroxychloroquine is an old malaria drug now used to treat autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus (SLE). Although hydroxychloroquine has several protective benefits, including antioxidant mechanisms [76], the same drug has been shown to exhibit oxidative characteristics due to a reduction in GSH levels [77]. Its antioxidant, immunomodulatory, and antiviral actions have been recommended in the 6th and 7th versions of Clinical Practice Guideline on COVID-19 in China [78]. Although paracetamol is used in COVID-19, it has been suggested to employ NAC as an adjuvant treatment, maybe in combination with other medications, at high intravenous dosages similar to those used as an antidote to paracetamol intoxication [77]. It is worth noting that paracetamol, which is the chosen medicine for symptomatic and domiciliary therapy of COVID-19 in its early stages, can deplete GSH, especially in individuals with a greater COVID-19 risk, raising the chance of severe COVID-19 forms [79]. In the case of extended administration of high dosages of this antipyretic and analgesic drug, it would be necessary to determine if NAC supplementation should be used regardless of COVID-19 [79]. It has been reported that excess dosages of paracetamol appear to alter semen quality, notably sperm morphology, and hence its capacity to fertilize. Paracetamol may have this impact on sperm quality by limiting testosterone synthesis, generating OS, inducing germ cell apoptosis, and lowering prostaglandins and nitric oxide production. It will be critical to carry out more studies, particularly clinical research, to corroborate these findings [80]. Moreover, given the ameliorating impacts of NAC on male fertility (as previously discussed), it may be assumed that in the treatment of COVID-19, if NAC is combined with the conventional paracetamol therapy, it may prevent adverse impacts of paracetamol upon semen quality and overall male reproductive health.

4. Conclusions

Oxidative stress is a prominent pathogenic mechanism in both chronic degenerative and infectious diseases. Oxidation, systemic inflammation, and immune response deficiency are all linked with COVID-19, that may adversely impact male fertility. Given the concerning global declining trend in male fertility, it is important to gauge the impact of the COVID-19 pandemic and its treatment regime on male reproductive health. The article has precisely discussed the use of several antioxidants in the treatment of COVID-19 and their possible roles in the amelioration of COVID-19-mediated disruptions in male fertility. There are few potential candidates, such as the vitamin C, NAC, flavonoids, and melatonin as well as Se, which should be essentially studied further for their abilities to address both COVID-19 and its impacts upon male reproductive functions.

Author Contributions

Conceptualization, data curation, and writing—original draft preparation, P.S., S.D., and S.R.; writing—review and editing, U.J.A.D., K.G. and A.K. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the Ministry of Education, Science, Research and Sport of the Slovak Republic (project KEGA 033SPU-4/2021).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Guan, W.J.; Ni, Z.Y.; Hu, Y.; Liang, W.H.; Ou, C.Q.; He, J.X.; Liu, L.; Shan, H.; Lei, C.l.; Hui, D.S. Clinical characteristics of coronavirus disease 2019 in China. N. Eng. J. Med. 2020, 382, 1708–1720. [Google Scholar] [CrossRef] [PubMed]
  2. World Health Organization. Naming the Coronavirus Disease (COVID-19) and the Virus that Causes It. Available online: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(COVID-2019)-and-the-virus-that-causes-it (accessed on 17 February 2022).
  3. Jordan, R.E.; Adab, P.; Cheng, K. COVID-19: Risk factors for severe disease and death. BMJ 2020, 26, 368. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Poma, A.M.; Bonuccelli, D.; Giannini, R.; Macerola, E.; Vignali, P.; Ugolini, C.; Torregrossa, L.; Proietti, A.; Pistello, M.; Basolo, A.; et al. COVID-19 autopsy cases: Detection of virus in endocrine tissues. J. Endocrinol. Investig. 2022, 45, 209–214. [Google Scholar] [CrossRef] [PubMed]
  5. Li, D.; Jin, M.; Bao, P.; Zhao, W.; Zhang, S. Clinical characteristics and results of semen tests among men with coronavirus disease 2019. JAMA Net Open 2020, 3, 08292. [Google Scholar] [CrossRef]
  6. Song, C.; Wang, Y.; Li, W.; Hu, B.; Chen, G.; Xia, P.; Wang, W.; Li, C.; Hu, Z.; Yang, X. Detection of 2019 novel coronavirus in semen and testicular biopsy specimen of COVID-19 patients. MedRxiv 2020, 103, 4–6. [Google Scholar] [CrossRef]
  7. Gong, J.; Zeng, Q.; Yu, D.; Duan, Y.G. T lymphocytes and testicular immunity: A new insight into immune regulation in testes. Int. J. Mol. Sci. 2020, 22, 57. [Google Scholar] [CrossRef]
  8. Li, H.; Xiao, X.; Zhang, J.; Zafar, M.I.; Wu, C.; Long, Y.; Lu, W.; Pan, F.; Meng, T.; Zhao, K.; et al. Impaired spermatogenesis in COVID-19 patients. EClinicalMedicine 2020, 28, 100604. [Google Scholar] [CrossRef]
  9. Ma, L.; Xie, W.; Li, D.; Shi, L.; Ye, G.; Mao, Y.; Xiong, Y.; Sun, H.; Zheng, F.; Chen, Z.; et al. Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients. J. Med. Virol. 2021, 93, 456–462. [Google Scholar] [CrossRef]
  10. Koç, E.; Keseroğlu, B.B. Does COVID-19 worsen the semen parameters? Early results of a tertiary healthcare center. Urol. Int. 2021, 105, 743–748. [Google Scholar] [CrossRef]
  11. Cinislioglu, A.E.; Cinislioglu, N.; Demirdogen, S.O.; Sam, E.; Akkas, F.; Altay, M.S.; Utlu, M.; Sen, I.A.; Yildirim, F.; Kartal, S.; et al. The relationship of serum testosterone levels with the clinical course and prognosis of COVID-19 disease in male patients: A prospective study. Andrology 2022, 10, 24–33. [Google Scholar] [CrossRef]
  12. Temiz, M.Z.; Dincer, M.M.; Hacibey, I.; Yazar, R.O.; Celik, C.; Kucuk, S.H.; Alkurt, G.; Doganay, L.; Yuruk, E.; Muslumanoglu, A.Y. Investigation of SARS-CoV-2 in semen samples and the effects of COVID-19 on male sexual health by using semen analysis and serum male hormone profile: A cross-sectional, pilot study. Andrologia 2021, 53, 13912. [Google Scholar] [CrossRef] [PubMed]
  13. Gacci, M.; Coppi, M.; Baldi, E.; Sebastianelli, A.; Zaccaro, C.; Morselli, S.; Pecoraro, A.; Manera, A.; Nicoletti, R.; Liaci, A.; et al. Semen impairment and occurrence of SARS-CoV-2 virus in semen after recovery from COVID-19. Hum. Reprod. 2021, 36, 1520–1529. [Google Scholar] [CrossRef] [PubMed]
  14. Delgado-Roche, L.; Mesta, F. Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Arch. Med. Res. 2020, 51, 384–387. [Google Scholar] [CrossRef] [PubMed]
  15. Bisht, S.; Faiq, M.; Tolahunase, M.; Dada, R. Oxidative stress and male infertility. Nat. Rev. Urol. 2017, 14, 470. [Google Scholar] [CrossRef] [PubMed]
  16. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X. Clinical features of patients infected with 2019 novel coronavirus in wuhan, China. Lancet 2020, 395, 497–506. [Google Scholar] [CrossRef] [Green Version]
  17. Dutta, S.; Sandhu, N.; Sengupta, P.; Alves, M.G.; Henkel, R.; Agarwal, A. Somatic-Immune Cells Crosstalk in-the-Making of Testicular Immune Privilege. 2021. Available online: https://link.springer.com/article/10.1007/s43032-021-00721-0 (accessed on 17 February 2022).
  18. Schuppe, H.-C.; Meinhardt, A. Immune privilege and inflammation of the testis. In Immunology of Gametes and Embryo Implantation; Karger Publishers: Basel, Switzerland, 2005; Volume 88, pp. 1–14. [Google Scholar]
  19. Dutta, S.; Sengupta, P.; Chhikara, B.S. Reproductive inflammatory mediators and male infertility. Chem. Biol. Lett. 2020, 7, 73–74. [Google Scholar]
  20. Fan, C.; Li, K.; Ding, Y.; Lu, W.L.; Wang, J. Ace2 expression in kidney and testis may cause kidney and testis damage after 2019-ncov infection. Front. Med. 2020, 7, 563893. [Google Scholar] [CrossRef]
  21. Hedger, M.P. Immunophysiology and pathology of inflammation in the testis and epididymis. J. Androl. 2011, 32, 625–640. [Google Scholar] [CrossRef]
  22. Dutta, S.; Sengupta, P.; Hassan, M.F.; Biswas, A. Role of toll-like receptors in the reproductive tract inflammation and male infertility. Chem. Biol. Lett. 2020, 7, 113–123. [Google Scholar]
  23. Ren, L.L.; Wang, Y.M.; Wu, Z.Q.; Xiang, Z.C.; Guo, L.; Xu, T.; Jiang, Y.Z.; Xiong, Y.; Li, Y.J.; Li, X.W. Identification of a novel coronavirus causing severe pneumonia in human: A descriptive study. Chin. Med. J. 2020, 133, 1015–1024. [Google Scholar] [CrossRef]
  24. Merad, M.; Martin, J.C. Pathological inflammation in patients with COVID-19: A key role for monocytes and macrophages. Nat. Rev. Immunol. 2020, 20, 355–362. [Google Scholar] [CrossRef] [PubMed]
  25. Dutta, S.; Majzoub, A.; Agarwal, A. Oxidative stress and sperm function: A systematic review on evaluation and management. Arab. J. Urol. 2019, 17, 87–97. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Sengupta, P.; Dutta, S.; Alahmar, A.T.; D’souza, U.J.A. Reproductive tract infection, inflammation and male infertility. Chem. Biol. Lett. 2020, 7, 75–84. [Google Scholar]
  27. Ma, L.; Xie, W.; Li, D.; Shi, L.; Mao, Y.; Xiong, Y.; Zhang, Y.; Zhang, M. Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study. MedRxiv 2020. [Google Scholar] [CrossRef] [Green Version]
  28. Darbandi, M.; Darbandi, S.; Agarwal, A.; Sengupta, P.; Durairajanayagam, D.; Henkel, R.; Sadeghi, M.R. Reactive oxygen species and male reproductive hormones. Reprod. Biol. Endocrinol. 2018, 16, 1–14. [Google Scholar] [CrossRef] [Green Version]
  29. Moghimi, N.; Farsani, B.E.; Ghadipasha, M.; Mahmoudiasl, G.-R.; Piryaei, A.; Aliaghaei, A.; Abdi, S.; Abbaszadeh, H.-A.; Abdollahifar, M.-A.; Forozesh, M. COVID-19 disrupts spermatogenesis through the oxidative stress pathway following induction of apoptosis. Apoptosis 2021, 26, 415–430. [Google Scholar] [CrossRef]
  30. Izuka, E.; Menuba, I.; Sengupta, P.; Dutta, S.; Nwagha, U. Antioxidants, anti-inflammatory drugs and antibiotics in the treatment of reproductive tract infections and their association with male infertility. Chem. Biol. Lett. 2020, 7, 156–165. [Google Scholar]
  31. Liu, Q.; Gao, Y.; Ci, X. Role of nrf2 and its activators in respiratory diseases. Oxidat. Med. Cell. Longev. 2019, 2019, 7090534. [Google Scholar] [CrossRef] [Green Version]
  32. Nabzdyk, C.S.; Bittner, E.A. Vitamin C in the critically ill-indications and controversies. World J. Crit. Care Med. 2018, 7, 52. [Google Scholar] [CrossRef]
  33. Li, J. Evidence is stronger than you think: A meta-analysis of vitamin c use in patients with sepsis. Crit. Care 2018, 22, 1–4. [Google Scholar] [CrossRef] [Green Version]
  34. Patel, V.; Dial, K.; Wu, J.; Gauthier, A.G.; Wu, W.; Lin, M.; Espey, M.G.; Thomas, D.D.; Ashby, C.R.; Mantell, L.L. Dietary antioxidants significantly attenuate hyperoxia-induced acute inflammatory lung injury by enhancing macrophage function via reducing the accumulation of airway hmgb1. Int. J. Mol. Sci. 2020, 21, 977. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Angulo, C.; Maldonado, R.; Pulgar, E.; Mancilla, H.; Córdova, A.; Villarroel, F.; Castro, M.A.; Concha, I.I. Vitamin C and oxidative stress in the seminiferous epithelium. Biol. Res. 2011, 44, 169–180. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Sönmez, M.; Türk, G.; Yüce, A. The effect of ascorbic acid supplementation on sperm quality, lipid peroxidation and testosterone levels of male wistar rats. Theriogenology 2005, 63, 2063–2072. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Ayinde, O.C.; Ogunnowo, S.; Ogedegbe, R.A. Influence of vitamin c and vitamin e on testicular zinc content and testicular toxicity in lead exposed albino rats. BMC Pharm. Toxicol 2012, 13, 17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Behairy, A.; El-Sharkawy, N.I.; Saber, T.M.; Soliman, M.M.; Metwally, M.M.M.; Abd El-Rahman, G.I.; Abd-Elhakim, Y.M.; El Deib, M.M. The modulatory role of vitamin C in boldenone undecylenate induced testicular oxidative damage and androgen receptor dysregulation in adult male rats. Antioxidants 2020, 9, 1053. [Google Scholar] [CrossRef]
  39. National Cancer Institute. High-Dose Vitamin C (pdq®)–Health Professional Version. Available online: https://www.cancer.gov/about-cancer/treatment/cam/hp/vitamin-c-pdq (accessed on 17 February 2022).
  40. McCarty, M.F.; DiNicolantonio, J.J. Nutraceuticals have potential for boosting the type 1 interferon response to rna viruses including influenza and coronavirus. Prog. Card. Dis. 2020, 63, 383. [Google Scholar] [CrossRef]
  41. Sengupta, P.; Dutta, S.; Slama, P.; Roychoudhury, S. COVID-19, oxidative stress, and male reproductive dysfunctions: Is vitamin c a potential remedy? Physiol. Res. 2022, 71, 19. [Google Scholar]
  42. Mata, M.; Morcillo, E.; Gimeno, C.; Cortijo, J. N-acetyl-l-cysteine (NAC) inhibit mucin synthesis and pro-inflammatory mediators in alveolar type ii epithelial cells infected with influenza virus a and b and with respiratory syncytial virus (rsv). Biochem. Pharm. 2011, 82, 548–555. [Google Scholar] [CrossRef] [Green Version]
  43. Polonikov, A. Endogenous deficiency of glutathione as the most likely cause of serious manifestations and death in COVID-19 patients. ACS Infect. Dis. 2020, 6, 1558–1562. [Google Scholar] [CrossRef]
  44. Sengupta, P.; Dutta, S. COVID-19 and hypogonadism: Secondary immune responses rule-over endocrine mechanisms. Hum. Fertil. 2021, 1–6. [Google Scholar] [CrossRef]
  45. Wright, J.H.; Caudill, R. Remote treatment delivery in response to the COVID-19 pandemic. Psychother. Psychosom. 2020, 89, 1. [Google Scholar] [CrossRef] [PubMed]
  46. Jorge-Aarón, R.-M.; Rosa-Ester, M.-P. N-acetylcysteine as a potential treatment for novel coronavirus disease 2019. Fut. Micobiol. 2020, 15, 959–962. [Google Scholar] [CrossRef] [PubMed]
  47. Memorial Sloan Kettering Cancer Center. A Study of N-Acetylcysteine in Patients with COVID-19 Infection; Clinical Trial Identifier: NCT04374461. Available online: https://clinicaltrials.gov/ct2/show/NCT04374461 (accessed on 17 February 2022).
  48. Jannatifar, R.; Parivar, K.; Roodbari, N.H.; Nasr-Esfahani, M.H. Effects of n-acetyl-cysteine supplementation on sperm quality, chromatin integrity and level of oxidative stress in infertile men. Reprod. Biol. Endocrinol. 2019, 17, 24. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Comhaire, F.H.; Christophe, A.B.; Zalata, A.A.; Dhooge, W.S.; Mahmoud, A.M.; Depuydt, C.E. The effects of combined conventional treatment, oral antioxidants and essential fatty acids on sperm biology in subfertile men. Prostaglandins Leukot. Essent. Fat. Acids 2000, 63, 159–165. [Google Scholar] [CrossRef] [PubMed]
  50. Schoeman, D.; Fielding, B.C. Coronavirus envelope protein: Current knowledge. Virol. J. 2019, 16, 69. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Aldini, G.; Altomare, A.; Baron, G.; Vistoli, G.; Carini, M.; Borsani, L.; Sergio, F. N-acetylcysteine as an antioxidant and disulphide breaking agent: The reasons why. Free Rad. Res. 2018, 52, 751–762. [Google Scholar] [CrossRef]
  52. Semenovich, D.S.; Plotnikov, E.Y.; Titko, O.V.; Lukiyenko, E.P.; Kanunnikova, N.P. Effects of Panthenol and N-Acetylcysteine on Changes in the Redox State of Brain Mitochondria under Oxidative Stress In Vitro. Antioxidants. 2021, 10, 1699. [Google Scholar] [CrossRef]
  53. Reiter, R.J.; Ma, Q.; Sharma, R. Treatment of ebola and other infectious diseases: Melatonin “goes viral”. Melatonin Res. 2020, 3, 43–57. [Google Scholar] [CrossRef]
  54. Junaid, A.; Tang, H.; Van Reeuwijk, A.; Abouleila, Y.; Wuelfroth, P.; Van Duinen, V.; Stam, W.; Van Zonneveld, A.J.; Hankemeier, T.; Mashaghi, A. Ebola hemorrhagic shock syndrome-on-a-chip. IScience 2020, 23, 100765. [Google Scholar] [CrossRef] [Green Version]
  55. Boga, J.A.; Coto-Montes, A.; Rosales-Corral, S.A.; Tan, D.X.; Reiter, R.J. Beneficial actions of melatonin in the management of viral infections: A new use for this ”molecular handyman”? Rev. Med. Virol. 2012, 22, 323–338. [Google Scholar] [CrossRef]
  56. Feitosa, E.L.; Júnior, F.; Nery Neto, J.A.O.; Matos, L.F.L.; Moura, M.H.S.; Rosales, T.O.; De Freitas, G.B.L. COVID-19: Rational discovery of the therapeutic potential of melatonin as a SARS-CoV-2 main protease inhibitor. Int. J. Med. Sci. 2020, 17, 2133–2146. [Google Scholar] [CrossRef] [PubMed]
  57. Ben-Nathan, D.; Maestroni, G.; Lustig, S.; Conti, A. Protective effects of melatonin in mice infected with encephalitis viruses. Arch. Virol. 1995, 140, 223–230. [Google Scholar] [CrossRef] [PubMed]
  58. El-Missiry, M.A.; El-Missiry, Z.M.A.; Othman, A.I. Melatonin is a potential adjuvant to improve clinical outcomes in individuals with obesity and diabetes with coexistence of COVID-19. Eur. J. Pharmacol. 2020, 882, 173329. [Google Scholar] [CrossRef]
  59. Shneider, A.; Kudriavtsev, A.; Vakhrusheva, A. Can melatonin reduce the severity of COVID-19 pandemic? Int. Rev. Immunol. 2020, 39, 153–162. [Google Scholar] [CrossRef]
  60. Li, C.; Zhou, X. Melatonin and male reproduction. Clin. Chim. Acta. 2015, 446, 175–180. [Google Scholar] [CrossRef] [PubMed]
  61. Riviere, E.; Rossi, S.P.; Tavalieri, Y.E.; Muñoz de Toro, M.M.; Ponzio, R.; Puigdomenech, E.; Levalle, O.; Martinez, G.; Terradas, C.; Calandra, R.S.; et al. Melatonin daily oral supplementation attenuates inflammation and oxidative stress in testes of men with altered spermatogenesis of unknown aetiology. Mol. Cell. Endocrinol. 2020, 515, 110889. [Google Scholar] [CrossRef]
  62. Deng, S.L.; Zhang, B.L.; Reiter, R.J.; Liu, Y.X. Melatonin ameliorates inflammation and oxidative stress by suppressing the p38mapk signaling pathway in lps-induced sheep orchitis. Antioxidants 2020, 9, 1277. [Google Scholar] [CrossRef]
  63. Zhang, J.; Taylor, E.W.; Bennett, K.; Saad, R.; Rayman, M.P. Association between regional selenium status and reported outcome of COVID-19 cases in china. Am. J. Clin. Nutr. 2020, 111, 1297–1299. [Google Scholar] [CrossRef]
  64. Alexander, J.; Tinkov, A.; Strand, T.A.; Alehagen, U.; Skalny, A.; Aaseth, J. Early nutritional interventions with zinc, selenium and vitamin d for raising anti-viral resistance against progressive COVID-19. Nutrients 2020, 12, 2358. [Google Scholar] [CrossRef]
  65. Sies, H.; Parnham, M.J. Potential therapeutic use of ebselen for COVID-19 and other respiratory viral infections. Free Rad. Biol. Med. 2020, 156, 107–112. [Google Scholar] [CrossRef]
  66. Jin, Z.; Du, X.; Xu, Y.; Deng, Y.; Liu, M.; Zhao, Y.; Zhang, B.; Li, X.; Zhang, L.; Peng, C.; et al. Structure of mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 2020, 582, 289–293. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Moslemi, M.K.; Tavanbakhsh, S. Selenium-vitamin E supplementation in infertile men: Effects on semen parameters and pregnancy rate. Int. J. Gen. Med. 2011, 4, 99–104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Mazjin, M.A.; Salehi, Z.; Mashayekhi, F.; Bahadori, M. Evaluation of gpx1 pro198leu polymorphism in idiopathic male infertility. Molekul. Biol. 2016, 50, 89–93. [Google Scholar] [CrossRef]
  69. Seale, L.A.; Torres, D.J.; Berry, M.J.; Pitts, M.W. A role for selenium-dependent gpx1 in SARS-CoV-2 virulence. Am. J. Clin. Nutr. 2020, 112, 447–448. [Google Scholar] [CrossRef]
  70. Hassan, S.M.; Jawad, M.J.; Ahjel, S.W.; Singh, R.B.; Singh, J.; Awad, S.M.; Hadi, N.R. The nrf2 activator (dmf) and COVID-19: Is there a possible role? Med. Arch. 2020, 74, 134–138. [Google Scholar] [CrossRef]
  71. McCord, J.M.; Hybertson, B.M.; Cota-Gomez, A.; Geraci, K.P.; Gao, B. Nrf2 activator pb125(®) as a potential therapeutic agent against COVID-19. Antioxidants 2020, 9, 518. [Google Scholar] [CrossRef]
  72. Liu, Z.; Ying, Y. The inhibitory effect of curcumin on virus-induced cytokine storm and its potential use in the associated severe pneumonia. Front. Cell Dev. Biol. 2020, 8, 479. [Google Scholar] [CrossRef]
  73. Menegazzi, M.; Campagnari, R.; Bertoldi, M.; Crupi, R.; Di Paola, R.; Cuzzocrea, S. Protective effect of epigallocatechin-3-gallate (egcg) in diseases with uncontrolled immune activation: Could such a scenario be helpful to counteract COVID-19? Int. J. Mol. Sci. 2020, 21, 5171. [Google Scholar] [CrossRef]
  74. Mendonca, P.; Soliman, K.F.A. Flavonoids activation of the transcription factor nrf2 as a hypothesis approach for the prevention and modulation of SARS-CoV-2 infection severity. Antioxidants 2020, 9, 659. [Google Scholar] [CrossRef]
  75. Jamalan, M.; Ghaffari, M.A.; Hoseinzadeh, P.; Hashemitabar, M.; Zeinali, M. Human sperm quality and metal toxicants: Protective effects of some flavonoids on male reproductive function. Int. J. Fert. Steril. 2016, 10, 215–223. [Google Scholar]
  76. Pahan, P.; Pahan, K. Smooth or risky revisit of an old malaria drug for COVID-19? J. Neuroimm. Pharmacol. 2020, 15, 174–180. [Google Scholar] [CrossRef] [PubMed]
  77. Ibrahim, H.; Perl, A.; Smith, D.; Lewis, T.; Kon, Z.; Goldenberg, R.; Yarta, K.; Staniloae, C.; Williams, M. Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous n-acetylcysteine. Clin. Immunol. 2020, 219, 108544. [Google Scholar] [CrossRef] [PubMed]
  78. Zhong, L.L.D.; Lam, W.C.; Yang, W.; Chan, K.W.; Sze, S.C.W.; Miao, J.; Yung, K.K.L.; Bian, Z.; Wong, V.T. Potential targets for treatment of coronavirus disease 2019 (COVID-19): A review of qing-fei-pai-du-tang and its major herbs. Am. J. Chin. Med. 2020, 48, 1051–1071. [Google Scholar] [CrossRef] [PubMed]
  79. Sestili, P.; Fimognari, C. Paracetamol use in COVID-19: Friend or enemy? Preprints 2020, 2020, 202080186. [Google Scholar]
  80. Banihani, S.A. Effect of paracetamol on semen quality. Andrologia 2018, 50, 12874. [Google Scholar] [CrossRef] [PubMed]
Antioxidants 11 00548 g001 550
Figure 1. Mechanisms of SARS-CoV-2-mediated oxidative stress and male reproductive disruptions (A–D) and the roles of antioxidants in mitigating the damaging actions (E).
Figure 1. Mechanisms of SARS-CoV-2-mediated oxidative stress and male reproductive disruptions (A–D) and the roles of antioxidants in mitigating the damaging actions (E).
Antioxidants 11 00548 g001
Antioxidants 11 00548 g002 550
Figure 2. Most common antioxidants used in the management of SARS-CoV-2 infection.
Figure 2. Most common antioxidants used in the management of SARS-CoV-2 infection.
Antioxidants 11 00548 g002
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Sengupta, P.; Dutta, S.; Roychoudhury, S.; D’Souza, U.J.A.; Govindasamy, K.; Kolesarova, A. COVID-19, Oxidative Stress and Male Reproduction: Possible Role of Antioxidants. Antioxidants 2022, 11, 548. https://doi.org/10.3390/antiox11030548

AMA Style

Sengupta P, Dutta S, Roychoudhury S, D’Souza UJA, Govindasamy K, Kolesarova A. COVID-19, Oxidative Stress and Male Reproduction: Possible Role of Antioxidants. Antioxidants. 2022; 11(3):548. https://doi.org/10.3390/antiox11030548

Chicago/Turabian Style

Sengupta, Pallav, Sulagna Dutta, Shubhadeep Roychoudhury, Urban John Arnold D’Souza, Kadirvel Govindasamy, and Adriana Kolesarova. 2022. "COVID-19, Oxidative Stress and Male Reproduction: Possible Role of Antioxidants" Antioxidants 11, no. 3: 548. https://doi.org/10.3390/antiox11030548

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