1. Introduction

In mammals, adult testicles participate in the biosynthesis and secretion of sex steroid hormones and the production of testicular fluid and spermatozoa, crucial for male fertility [1]. The production of male gametes is a complex, dynamic, and continuous process that occurs inside the seminiferous tubules (SeT), the functional unit of the testis [1,2].

Several factors have been shown to affect the normal progression of spermatogenesis. Oxidative stress is one of the most harmful factors and a major cause of male infertility, with relevant damaging effects on the development of germ cells and sperm function [3]. The endogenous cellular antioxidant defense system protects the cells against reactive oxygen species (ROS). When ROS production exceeds the capacity of the endogenous cellular antioxidant defense system, oxidative stress occurs [4]. ROS actions will disturb the structure and function of the sperm membrane and DNA, declining the normal sperm parameters as well as the capacity to fertilize the oocyte [5,6]. In addition, it is well established that increased levels of ROS are associated with an inflammatory response, which may be triggered by several conditions, such as varicocele, tobacco, alcohol, and metabolic syndromes [7]. Finally, the testis is very sensitive to exogenous agents, such as several pharmacological treatments [8].

For centuries, humans have used natural products in folk medicine. The use of these natural products has increased in recent decades and have been gradually introduced into the pharmaceutical market [9]. Several studies have demonstrated that certain natural products and derivatives might play a protective role against the damaging effects [10,11]. Moreover, many natural products have already been described as being useful for the treatment of male disorders such as sexual impotence [12,13].

This review provides an overview of relevant bioactive compounds, such as curcumin, ellagic acid, vitamin C, and vitamin E (Table 1), and natural products that contain bioactive compounds in their composition, such as garlic, ginger, grape, green tea, microalgae and algae, and propolis (Table 2). All of them have been identified as protective agents and/or have beneficial effects on animal models for male reproductive function due to their biological activity. This review mainly focuses on reports of animal experiments because due to the high complexity of the male reproductive system, they are more realistic models.

2. Bioactive Compounds

2.1. Curcumin

Curcumin or [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadi-ene-3,5-dione] is a bioactive substance that is present in the rhizome of the turmeric plant (Curcuma longa) and is the major constituent of turmeric powder [14-16]. It has been used in Asian folk medicine for several purposes and is also described in Hindu texts [17]. It presents a wide range of pharmacological and biological activities such as antioxidant [18]. The phenolic-OH group present in curcumin and β diketone derivatives can react with ROS and are powerful radical scavengers [19,20]. Curcumin can also reduce lipid peroxidation and oxidative DNA damage and regulates glutathione (GSH) levels [20,21].

In the testis, it has been shown that curcumin acts as a protective factor against oxidative stress-inducers such as cadmium preventing histopathological damage [20,22]. Additionally, curcumin increases the levels of GSH, glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) [20,22]; testosterone levels, transcription factor NF-E2-related factor 2 (Nrf2), and γ-glutamylcysteine synthetase [22]; catalase (CAT) and total thiols levels [20]; and decreased malondialdehyde (MDA) and hydrogen peroxide content [20,22]. Considering sperm parameters increased sperm motility and concentration and decreased the morphologic defects of sperm compared to cadmium chloride alone [22].

Other events/incidents inducing testicular damage may include chronic variable stress, scrotal heat stress, ischemia–reperfusion injury, and ageing. Curcumin also seems to improve histopathological testicular changes in these situations [15,16,38] by increasing the Johnson’s Testicular Score [14,16], germinal epithelium height [14], the number of germ cell layers, and the mean of the SeT diameter [16]. Additionally, curcumin seems to decrease the number of apoptotic cells in the SeT [15] and oxidative stress, as indicated by the diminished MDA levels [16,23] among other beneficial effects. In Table 1, it is summarized the beneficial effects in male reproductive system.

2.2. Ellagic Acid

Ellagic acid (2,3,7,8-tetrahydroxy [1]-benzopyrano [5,4,3-cde] [1] benzopyran-5,10-dione) is a phenolic compound found in several fruits, nuts, and seeds [24]. Recently, phenolic compounds have been receiving a great deal of attention due to their potential health benefits in the prevention and treatment of certain human diseases [25]. Its antioxidant activity is due to its ability to scavenge free radicals[26], and ellagic acid contains four hydroxyl groups and two lactone groups, in which it is known that hydroxyl group can increase antioxidant activity [27]. Additionally, ellagic acid can modulate cellular antioxidant enzyme systems [28].

Several studies have used ellagic acid as a protective factor against several compounds that induce-reproductive damage, such as phthalates, arsenic, and polychlorinated biphenyl (Aroclor 1254), which are environmental pollutants that are present in a wide variety of daily products. Quite a few studies have shown that ellagic acid avoids histopathologic damage [29-31], preventing the decrease of SeT diameter, germinal cell layer thickness [29,31], and the Johnsen’s testicular score [31]. Additionally, it increases the levels of antioxidant defense, GSH [29-31], SOD [29,31], and CAT [30,31], total antioxidant capacity (TAC) [30], and GSH-Px [31] and decreased TBARS levels [29,31] as well as MDA and protein carbonyl (PC) content [30]. Ellagic acid improves sperm parameters [30,31], functional membrane integrity, mitochondrial membrane potential, and sperm kinematics (progressive motility, rapid and fast progressive motility) [30]. Additionally, arsenic up-regulates the Ppargc1a (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha) gene and down-regulates the Nrf2 and StAR (steroidogenic acute regulatory protein) genes [30]. Ppargc1a is a gene that is related to energy metabolism and mitochondrial biogenesis, which is upregulated in response to cell stress. Nrf2 is a regulator of the antioxidant defense system, and low expression of this gene is related to decreased TAC in the testes and increased sperm abnormalities. StAR is a gene that regulates steroid hormone synthesis, and low StAR expression of is linked with low testosterone production and sperm quality [30]. These variations were prevented with ellagic acid treatment, demonstrating the protective effect of ellagic acid against the toxic effects of arsenic-induced toxicity [30]. In Table 1, it is summarized the beneficial effects in male reproductive system.

2.3. Vitamin C

Vitamin C or ascorbic acid is a water-soluble vitamin found in berries, citrus fruits, green leafy vegetables, tomatoes, and potatoes [32]. The antioxidant properties of Vitamin C are due to its ability to scavenge reactive oxygen and nitrogen species and its ability to regenerate other small antioxidant molecules [33].

Several studies have shown the beneficial effects of vitamin C administration against the reproductive toxicity of environmental pollutants such as aluminum, mercury, carbon tetrachloride, and lead. The effects of vitamin C against aluminum chloride toxicity include ameliorated histopathological and sperm parameters, namely counts, concentration, morphology, and motility (increased fast progressive motility and decreased slow progressive motility). Additionally, vitamin C increased SOD activity while decreasing NO activity [34]. Vitamin C co-administration against mercuric chloride toxicity improved histopathological findings, daily sperm production parameters, and final body weight compared to the group treated for mercuric chloride only. Moreover, it increased the total protein, high-density lipoprotein (HDL) cholesterol, testosterone and the antioxidant enzymes peroxidase, and GST. On the other hand, decreased levels of low-density lipoprotein (LDL) cholesterol and lipid peroxidation (ROS and TBARS levels) were observed [35]. Additionally, vitamin C treatment against carbon tetrachloride toxicity improved the histopathological findings in testis sperm parameters (motility, counts and morphology). It increased FSH and LH hormone levels and the expression of antioxidant enzymes, CAT, and SOD. Additionally, vitamin C decreased GSH-Px expression and TBARS levels compared to the carbon tetrachloride group [36]. Finally, vitamin C treatment can recover histopathological parameters to the control levels [37]. In Table 1, it is summarized the beneficial effects in male reproductive system.

2.4. Vitamin E

Vitamin E is a lipo-soluble vitamin that is obtained exclusively through the diet [38] and is widely present in olive and sunflower oils, avocados, green leafy vegetables, nuts, soybeans, and wheat [39]. Vitamin E presents eight different isoforms that include alpha, beta, gamma, and delta-tocopherol and alpha, beta, gamma, and delta-tocotrienol [39].

The main biological activity of vitamin E is its antioxidant properties [40]. Several studies that have used vitamin E supplementation against environmental pollutants such as arsenic, para-nonylphenol, and 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) have shown the beneficial effects of vitamin E, mainly in terms of several histological parameters [41,42]. Vitamin E also increases the epididymal sperm number [41], the number of spermatogonia A, spermatogonia B, spermatocytes, spermatids and Sertoli cells [42], and daily sperm production [43]. Vitamin E treatment has been used against TCDD-induced toxicity; has been shown to increase body, testis, epididymis, seminal vesicles, and ventral prostate weights; antioxidant enzymes (SOD, CAT, GSH-R,x and GSH-Px); and has been shown to decrease hydrogen peroxide generation and TBARS levels [43].

Moreover, vitamin E seems capable of improving the effect of some drugs that can induce reproductive toxicity in males. Vitamin E counteracted the damage associated with methotrexate, improving histopathological parameters, increasing SOD levels, and decreasing MDA levels [44]. Increasing evidence of the beneficial actions of vitamin E against several diseases prompted have its use as a dietary supplement. In Table 1, it is summarized the beneficial effects in male reproductive system.

Table 1. Bioactive compounds with beneficial effects in male reproductive system.

3. Natural Products with Bioactive Compounds

3.1. Garlic

Garlic has been used as a therapeutic and medicinal agent in several cultures for centuries, specifically in Egyptian Cordex Ebers and in ancient Greece, Rome, India, China, and Japan [45,46]. Garlic a substantial amount of evidence has shown that some of the compounds present in garlic have antioxidant properties with radical-scavenging functions and antioxidant enzyme modulation [47,48].

Several garlic preparations, such as raw garlic homogenate, garlic powder, aged garlic extract, and garlic oil have been used in scientific studies to determine the effects of garlic. These may explain the diversity of the results concerning the effect of garlic in the male reproductive system. For example, Oi et al. used garlic powder to evaluate its effect on testosterone production in rats on a casein-based diet, a high protein level diet [49]. After 28 days of supplementation, the testosterone levels were increased in the rats fed 40 and 25% casein diets, indicating that garlic enhanced testosterone production in high protein level diets [49].

On the other hand, the effect of garlic extract on sperm characteristics and testicular oxidative damage after cadmium exposure showed that garlic extract improved epididymal sperm parameters (concentration, motility and counts) and reduced the number of abnormal sperm. It increased GSH, SOD, CAT, and alkaline phosphate (ALP) and decreased MDA and GST levels, improving antioxidant status after cadmium exposure [50]. Concerning other environmental contaminants, Furan is a contaminant found in a wide variety of foods that have been heat-treated via thermal degradation that can induce damage in the testis. Garlic oil has been shown to ameliorate the effect of furan on histopathological alterations and the reduction of testosterone levels. Garlic oil also increased SOD, CAT, and GSH levels and decreased the MDA, CYP2E1, and caspase-3 levels [51]. In Table 2, it is summarized the beneficial effects in male reproductive system.

3.2. Ginger

Ginger or Zingiber officinale is a grayish-white rhizome with pale brown rings that is used worldwide as a cooking spice and can be used as a powder or fresh root [52]. For generations, it has been used as a medicinal plant to treat several medical conditions [53], including disorders of the male reproductive system [54]. In medieval Persia, medical texts such as Qanoonfel-teb (The Canon) by Ebn-e-Sina (980–1037) described ginger as a very effective herb for erectile dysfunction [55]. In Western Uganda, men drink ginger tea to treat sexual impotence and erectile dysfunction [56]. Additionally, hot ginger remedies are used to increase sexual energy and semen volume [54].

In terms of biological activity, ginger presents among other antioxidant activity [57]. The main bioactive compounds present in ginger are gingerdiol, gingerol, shogaols, zingerone, and zingibrene, which are responsible for the antioxidant activity of ginger [58] and properties of free radical scavenging, inhibition of lipid peroxidation, and DNA protection [59].

In the testis, ginger is a protective factor against oxidative stress-inducers, such as carbon tetrachloride, an industrial chemical that, when it is decomposed, creates sulfite salts (e.g., sodium metabisulfite). These sulfite salts are used as preservatives and disinfectants in foods and pharmaceutical agents, as they release sulfur dioxide that can cause oxidative stress. Ginger treatment in the presence of carbon tetrachloride or sodium metabisulfite improved histopathological findings [60] and prevented the toxic effects in the SeT, epididymal tissue [53], and in the sperm parameters (morphology and motility) [60]. Additionally, ginger increased the enzymes GHS-Px, [53,60], TAC, SOD, and CAT [53]; GSH-Rx levels; and testosterone [60] and decreased MDA levels [53,60].

Several metabolic syndromes can induce damage in the testis, such as high-fructose diet-induced metabolic syndrome. Fructose is a carbohydrate that is widely used as a food additive because of its sweetness. However, it is one of the main factors that is responsible for the progression to metabolic syndrome, leading to oxidative stress [61]. In rats fed with a high-fructose diet, ginger decreased the total body weight but increased testicular weight. Additionally, it improved histopathological findings, increasing the epithelial height and SeT perimeter and proliferative cell nuclear antigen (PCNA) and Beclin 1 immunoreactivity. PCNA is considered to be a proliferation marker that can be used to analyse spermatogenesis, and Becilin 1 is a protein involved in autophagic pathways and is considered to be an important regulatory mechanism in spermatogenesis and steroidogenesis [61]. The increased immunoreactivity of PCNA and Beclin 1 indicate an improvement in spermatogenesis and steroidogenesis in the presence of ginger treatment. Ginger increased the FSH, LH, testosterone, HDL, and SOD levels and decreased the triglycerides, LDL, MDA, and serum levels of glucose, insulin as well as the subsequent diminution of the homeostasis model assessment for insulin resistance (HOMA-IR) [61]. In Table 2, it is summarized the beneficial effects in male reproductive system.

3.3. Grape

Grape (Vitis vinifera) is one of the most farmed and largely produced fruits in the world [62] and has a history of use in Europe for traditional treatments [63].Grape seed extract presents several biological activities, namely antioxidant [64] effects. Its capacity to scavenge oxidants and free radicals is due to the presence of the phenolic compounds, especially the pro-anthocyanidins [65], which present a higher antioxidant capacity than vitamin C or E [66].

Several studies have identified grape seed extract, grape seed pro-anthocyanidin extract, and grape juice concentrate as protective factors against cadmium toxicity. Grape seed extract and grape seed pro-anthocyanidin extract improved histopathological findings [67-70], increasing the diameter and normal SeT [67,70], testicular weight [67], and Johnsen’s mean testicular biopsy score and decreasing the apoptotic index [70]. It was also observed to increase PCNA immunoreactivity [67] and total antioxidant status (TAS) [68] in the enzymes of the antioxidant defense system and genes associated with steroidogenesis and Ki-67 expression [69], and it decreased MDA levels [68,69] and the immunoreactivity of the apoptotic regulator Bax [69]. Grape juice concentrate treatment against cadmium toxicity demonstrated that co-administration restored the testis, epididymis, and ventral prostate weight [71] to normal levels, ameliorating tissue architecture [125,136,137], epididymis epithelium height (caput and cauda regions) [72] and improving sperm parameters such as production, counts, transit time [72], and morphology [71]. Additionally, it increased testosterone and GSH levels and decreased cadmium accumulation, MDA levels [72], and SOD and mitochondrial SOD activity [71].

Grape seed extract can also protect the testis against the toxic effects of drugs such as dexamethasone, an immunosuppressive and anti-inflammatory glucocorticoid drug [73]. Using two doses (200 or 400 mg/kg body weight) of grape seed extract administrated with dexamethasone, it was possible to observe histopathological improvement, especially at a dose of 400 mg/kg, which increased body, testis weight, and serum testosterone. It also increased thyroid hormones, (free T3, T4 and thyroid-stimulating hormone); antioxidant defenses (CAT and GSH); total protein content; acid phosphatase (ACP), a specific marker for spermatogenesis; and glucose-6-phosphate dehydrogenase (G-6-PDH). Thyroid hormones are essential in the regulation of the reproductive system, and G-6-PDH is associated with GSH synthesis that when decreased can indicate testicular degeneration [73].

Additionally, grape seed extract seems to attenuate the effects of ethanol by increasing the weight of the testis, epididymis and accessory sex organs, sperm parameters (counts, motility, and morphology), testosterone, and GSH levels and decreasing the MDA levels in the testis [74]. In Table 2, it is summarized the beneficial effects in male reproductive system.

3.4. Green Tea

Green tea (Camellia sinensis) is one of the oldest and most popular drinks worldwide [75]. It has several biological characteristics and health benefits such as antioxidant [76] effects. Phenolic compounds are potent antioxidants with the ability to scavenge oxygen, hydroxyl, and anion superoxide radicals and have metal chelating functions [77,78].

Green tea consumption is a common practice that is well accepted by modern society, and its beneficial effects are well recognized in our day to day lives. During a 52-day study period, the administration of green tea extract (2 and 5%) in male Wistar rats resulted in the body and reproductive organs weight remaining unchanged compared to control group. Liver weight also remained unchanged, but decreased levels of AST and ALT were observed, suggesting hepatoprotective properties. The testosterone level was similar to the control group as was the weight of the testosterone-dependent organs. Normal histological sections (except an increase in diameter of SeT) were observed between the green tea consumption group and control group. Concerning sperm parameters, green tea increased sperm concentration and viability, but the sperm motility and velocity functions remain similar to the control. However, a significant increase in spontaneous acrosome reactions was observed. Finally, the antioxidant defenses (CAT, GSH, MDA, and SOD levels) remain unchanged, indicating the safety of green tea consumption and a balance of the oxidative stress status of the tissues [79].

Several studies identify green tea as a protective factor against environmental pollutants that are widely used in industry and that can induce oxidative damage. These includes para-nonylphenol, deltamethrin (a synthetic insecticide), cadmium, and nicotine (a volatile alkaloid that is the primary toxic component of cigarette smoking). Green tea extract ameliorated histopathologic damage [77,80-83] by increasing the SeT diameter [77,82], epithelium height, Johnson’s score [77], and the volume of the SeT and testis [80]. Additionally, green tea extract increased testis, body, and reproductive organ weight [159,161,162]. In terms of the sperm parameters (concentration, motility, viability, morphology, production and counts), green tea extract co-administration with these environmental pollutants seemed to induce a beneficial effect [77,80-83]. Green tea extract increased testosterone levels [156,161,162] and antioxidant defenses (SOD, CAT, and GSH) [82,83], and decreased caspase-3 [77,82] and cholesterol levels [82]. Regarding the lipid peroxidation, green tea extract decreased MDA [156,159,160] and TBARS levels [83] compared to the environmental pollutants groups. In Table 2, it is summarized the beneficial effects in male reproductive system.

3.5. Microalgae and Algae

Microalgae are a natural source of various bioactive compounds, such as phycobilins, carotenoids, PUFA, polysaccharides, sterols, and vitamins, which have many applications from animal feed to human nutrition [84]. PUFA are abundant in microalgae, and they are one of the major compounds responsible for its bioactivities [85]. Therefore, their effects on male infertility have been explored because oxidative stress is a major contributor to defective spermatogenesis [86]. Moreover, elevated oxidative stress within semen is also associated with infection/inflammation of the male reproductive system, which compromises sperm quality [87]. After several studies indicating its safety and beneficial effects for human health, namely antitoxic, antigenotoxic, antioxidant effects, and reporting no reproductive and teratogenic toxicity, the microalgae Chlorella vulgaris and Spirulina platensis were classified as Generally Regarded as Safe (GRAS) substances by the United States Food and Drug Administration (FDA) [88,89]. Additionally, some studies have reported the protective properties of C. vulgaris against various noxious stimuli [90-92], and it has been suggested that C. vulgaris might be helpful in diseases where the maintenance of antioxidant status is crucial [91].

In deltamethrin-intoxicated rats, C. vulgaris administered orally for 8 weeks was able to re-establish the serum testosterone concentration, sperm counts, sperm viability, sperm motility, and sperm abnormalities as well as the testicular levels of SOD and CAT antioxidant enzymes and the lipid peroxidation marker MDA to levels similar to the control group [93]. More recently, Eissa et al., demonstrated that pre- and co-treatment with C. vulgaris was helpful against sodium nitrite-induced reproductive dysfunction via the partial prevention of negative changes in sperm quality, serum testosterone and FSH levels, testicular oxidant/antioxidant balance, and testicular histological architecture [94].

Although fewer works that compare the effects of microalgae are available, some algae also seem to have garnered interest in terms of reproductive purposes. Such is the case of Halopteris scoparia, a brown alga that is generally consumed as a salad in Far East countries, which ha sbeen reported to protect against cadmium chloride-induced testicular damage in mice [95]. In another study, fucoxanthin extract from brown algae Laminaria japonica ameliorated male reproductive function in diabetic rats by (i) decreasing the glucose level, (ii) restoring sperm motility, (iii) reducing sperm abnormalities, (iv) enhancing enzymatic antioxidant activity, (v) reducing proinflammatory cytokine levels, and (vi) recovering LH and testosterone levels [96]. Indeed, fucoxanthin is a natural agent with the potential to be considered an anti-diabetic candidate and a functional food to improve male fertility affected by diabetes mellitus [96]. Furthermore, fucoxanthin extract from brown algae Sargassum glaucescens increased sperm count, decreased sperm abnormalities, and improved the morphology of SeT as well as improved testosterone levels in hamsters treated with the chemotherapeutic drug cisplatin [97]. In Table 2, it is summarized the beneficial effects in male reproductive system.

3.6. Propolis

Propolis or bee glue is a natural resinous mixture produced by honeybees that is used to seal holes in their honeycombs, smooth out the internal walls, and protect the entrance against intruders [98].

Propolis is a complex mixture of several compounds derived from plants and is processed by the salivary enzymes of bees [99], and for this reason, propolis content can vary depending on the plant source used by the bees [100]. Due to this variability, propolis can have more than 300 compounds with pharmacological activity, [98,101].

In fact, it has been used in folk medicine [102], and no side effects have been described after propolis administration in humans and mice [103]. Several biological activities with pharmaceutical interest have been described for propolis, such as antioxidant [103,104]

Phenolic compounds, such as flavonoids, are the main bioactive components responsible for the biological activity of propolis, specifically antioxidant activity. Additionally, propolis antioxidant activity includes the capacity to activate antioxidant enzymes such as CAT [105] and SOD [106]. Moreover, propolis can inhibit the generation of superoxide anions and can reverse the consumption of glutathione, an enzyme with radical scavenging activity [107,108].

In testis, several studies have described the use of propolis as a protective factor against many different oxidative stress inducers, showing significant improvements in male fertility [109]. In addition, it has been found to have a protective role against oxidative stress-inducers such as copper, cadmium, and aluminum in the reproductive tissues of rats [191,199,205]. Propolis co-treatment improved histopathological changes [191,199,205] by decreasing the number of apoptotic cells [100] and degenerative changes in the tubular epithelium [110] and increasing Johnsen’s testicular score [100]. Additionally, propolis coadministration induced an increase in CAT and GSH levels [100,107], SOD

[100], testosterone, 17-ketosteroid reductase, and GST levels [107], and it decreased MDA [100,110] and TBARS levels [107] and immunoreactivity of testicular HIF-1α [110]. In terms of sperm parameters, propolis co-treatment increased sperm concentration and motility and decreased abnormal sperm [100,107] and sperm death [107]. Finally, it also increased the weight of the testis [107,110] and epididymis [107].

Diabetes mellitus has been associated with male infertility [111]. Propolis may regulate the testicular and epididymal oxidative stress levels in induced-streptozotocin diabetic rats. Improved histopathologic changes have been found, namely increased SeT diameter and seminiferous epithelial height and decreased germ cells loss and epididymal epithelial height. Propolis co-administration increased the weight of the testes, epididymis, prostate, and seminal vesicles. Additionally, it demonstrated an increase of Nrf2, SOD, CAT, GSH-Px, GSH-Rx, GST, and TAC levels, and it decreased NO and TBARS levels, supporting the antioxidant properties of propolis. Concerning the pro-inflammatory mediators and apoptosis-related genes, propolis increased the protein levels of NF-kB, tumour necrosis factor-α, interleukin (IL)-1β, and IL-10 and decreased testicular levels of Bax/Bcl-2 ratio, p53, caspase-8, caspase-9, and caspase-3 [111], demonstrating the anti-inflammatory and anti-apoptotic properties of propolis. Recently, it has also been shown that propolis treatment in diabetic rats ameliorated sperm parameters (counts, motility, viability and morphology) and diminished non-motile spermatozoa and sperm DNA fragmentation. Additionally, it improved steroidogenesis through the increase of testosterone levels, StAR, CYP11A1, CYP17A1, 3β-HSD, and 17β-HSD. Relative to the metabolic pathways, propolis increased glucose transporter 3 (GLUT3), MCT2, MCT4, and decreased LDH, intra-testicular glucose, and lactate levels [112]. In Table 2, it is summarized the beneficial effects in male reproductive system.

Table 2. Bioactive compounds present in natural products with beneficial effects in male reproductive system.

4. Conclusions and Future Perspectives

Various studies in animal models have demonstrated the beneficial effects of distinct natural compounds and bioactive compounds on male fertility when administered in isolation or in the presence of a noxious stimulus. They could suppress oxidative stress, inflammation, and damaging drug effects and also counteracted pathology-associated alterations. Several of compounds have already been described as having high antioxidant and anti-inflammatory properties, indicating the possibility of beneficial effects on the male reproductive system. However, the mechanisms that lead to these beneficial effects need further understanding. The presented outcomes using animal models highlighted the usefulness of these natural agents in the protection of male animal fertility against damaging factors.

Supplementary Materials: The following are available online at https://www.mdpi.com/article/10.3390/biochem1030011/s1. Supplementary Table: Bioactive compound, Present in, and Chemical structures.

Author Contributions: Conceptualization, S.C. and C.J.M.; writing—original draft preparation, R.V.L.M. and A.M.S.S.; writing—review and editing, A.P.D., S.S., S.C. and C.J.M. All authors have read and agreed to the published version of the manuscript.

Funding: This work was supported by FEDER funds through the POCI-COMPETE 2020—Operational Programme Competitiveness and Internationalisation in Axis I—Strengthening research, technological development and innovation (Project No. 007491; Project No 029114), and National Funds by FCT-Foundation for Science and Technology (Project UID/Multi/00709/2020). R.V.L.M. wasfunded by BID/ICI-FC/CICS/Santander Universidades—UBI/2021. A.M.S.S. was funded by PhD Fellowship (SFRH/BD/145197/2019).

Conflicts of Interest: The authors declare no conflict of interest.

References:

1. Hess, R.A.; de Franca, L.R. Spermatogenesis and Cycle of the Seminiferous Epithelium. In Molecular Mechanisms in Spermatogenesis; Cheng, C.Y., Ed.; Springer: New York, NY, USA, 2008; pp. 1–15.
2. Clermont, Y. Kinetics of spermatogenesis in mammals: Seminiferous epithelium cycle and spermatogonial renewal. Rev. 1972, 52, 198–236.
3. Correia, S.; Vaz, C.V.; Silva, A.M.; Cavaco, J.E.; Socorro, S. Regucalcin counteracts tert-butyl hydroperoxide and cadmium-induced oxidative stress in rat testis. Appl. Toxicol. 2017, 37, 159–166.
4. Cocuzza, M.; Athayde, K.S.; Agarwal, A.; Pagani, R.; Sikka, S.C.; Lucon, A.M.; Srougi, M.; Hallak, J. Impact of clinical varicocele and testis size on seminal reactive oxygen species levels in a fertile population: A prospective controlled study. Steril. 2008, 90, 1103–1108.
5. Fatemi, N.; Sanati, M.H.; Jamali Zavarehei, M.; Ayat, H.; Esmaeili, V.; Golkar-Narenji, A.; Zarabi, M.; Gourabi, H. Effect of tertiary-butyl hydroperoxide (TBHP)-induced oxidative stress on mice sperm quality and testis histopathology. Andrologia 2013, 45, 232–239.
6. Kaur, P.; Kaur, G.; Bansal, M.P. Tertiary-butyl hydroperoxide induced oxidative stress and male reproductive activity in mice: Role of transcription factor NF-kappaB and testicular antioxidant enzymes. Toxicol. 2006, 22, 479–484.
7. Agarwal, A.; Rana, M.; Qiu, E.; AlBunni, H.; Bui, A.D.; Henkel, R. Role of oxidative stress, infection and inflammation in male infertility. Andrologia 2018, 50, e13126.
8. Semet, M.; Paci, M.; Saïas-Magnan, J.; Metzler-Guillemain, C.; Boissier, R.; Lejeune, H.; Perrin, J. The impact of drugs on male fertility: A review. Andrology 2017, 5, 640–663.
9. Dias, T.R.; Alves, M.G.; Oliveira, P.F.; Silva, B.M. Natural products as modulators of spermatogenesis: The search for a male contraceptive. Mol. Pharmacol. 2014, 7, 154–166.
10. Jia, Z.; Anandh Babu, P.V.; Chen, W. Natural Products Targeting on Oxidative Stress and Inflammation: Mechanisms, Therapies, and Safety Assessment. Med. Cell. Longev. 2018, 2018, 6576093.
11. Amin, A.; Hamza, A.A.; Kambal, A.; Daoud, S. Herbal extracts counteract cisplatin-mediated cell death in rat testis. Asian J. Androl. 2008, 10, 291–297.
12. Mbongue, G.Y.; Kamtchouing, P.; Dimo, T. Effects of the aqueous extract of dry seeds of Aframomum melegueta on some parameters of the reproductive function of mature male rats. Andrologia 2012, 44, 53–58.
13. Soliman, G.A.; Donia Ael, R.; Awaad, A.S.; Alqasoumi, S.I.; Yusufoglu, H. Effect of Emex spinosa, Leptadenia pyrotechnica, Haloxylon salicornicum and Ochradenus baccatus extracts on the reproductive organs of adult male rats. Biol. 2012, 50, 105–112.
14. Murato˘ glu, S.; Akarca Dizakar, O.S. The protective role of melatonin and curcumin in the testis of young and aged rats. Andrologia 2019, 51, e13203.
15. Mohamadpour, M.; Noorafshan, A.; Karbalay-Doust, S.; Talaei-Khozani, T.; Aliabadi, E. Protective effects of curcumin cotreatment in rats with establishing chronic variable stress on testis and reproductive hormones. J. Reprod. Biomed. 2017, 15,447–452.
16. Wei, S.M.; Yan, Z.Z.; Zhou, J. Curcumin attenuates ischemia-reperfusion injury in rat testis. Steril. 2009, 91, 271–277.
17. Ammon, H.P.;Wahl, M.A. Pharmacology of Curcuma longa. Planta Med. 1991, 57, 1–7.
18. Maheshwari, R.K.; Singh, A.K.; Gaddipati, J.; Srimal, R.C. Multiple biological activities of curcumin: A short review. Life Sci. 2006, 78, 2081–2087.
19. Mercantepe, T.; Unal, D.; Tümkaya, L.; Yazici, Z.A. Protective effects of amifostine, curcumin and caffeic acid phenethyl ester against cisplatin-induced testis tissue damage in rats. Ther. Med. 2018, 15, 3404–3412.
20. Momeni, H.R.; Eskandari, N. Curcumin protects the testis against cadmium-induced histopathological damages and oxidative stress in mice. Exp. Toxicol. 2020, 39, 653–661.
21. Desai, K.R.; Rajput, D.K.; Patel, P.B.; Highland, H.N. Ameliorative Effects of Curcumin on Artesunate-Induced Subchronic Toxicity in Testis of Swiss Albino Male Mice. Dose-Response 2015, 13, 1559325815592393.
22. 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. Sci. Pollut. Res. 2019, 26, 34575–34583.
23. Lin, C.; Shin, D.G.; Park, S.G.; Chu, S.B.; Gwon, L.W.; Lee, J.G.; Yon, J.M.; Baek, I.J.; Nam, S.Y. Curcumin dose-dependently improves spermatogenic disorders induced by scrotal heat stress in mice. Food Funct. 2015, 6, 3770–3777.
24. Landete, J.M. Ellagitannins, ellagic acid and their derived metabolites: A review about source, metabolism, functions and health. Food Res. Int. 2011, 44, 1150–1160.
25. Abdul-Hamid, M.; Abdella, E.M.; Galaly, S.R.; Ahmed, R.H. Protective effect of ellagic acid against cyclosporine A-induced histopathological, ultrastructural changes, oxidative stress, and cytogenotoxicity in albino rats. Pathol. 2016, 40, 205–221.
26. Dalvi, L.T.; Moreira, D.C.; Andrade, R., Jr.; Ginani, J.; Alonso, A.; Hermes-Lima, M. Ellagic acid inhibits iron-mediated free radical formation. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2017, 173, 910–917.
27. Pari, L.; Sivasankari, R. Effect of ellagic acid on cyclosporine A-induced oxidative damage in the liver of rats. Clin. Pharmacol. 2008, 22, 395–401.
28. Vattem, D.A.; Shetty, K. Biological functionality of ellagic acid: A review. Food Biochem. 2005, 29, 234–266.
29. Baçsak Türkmen, N.; Ayhan, ˙I.; Ta¸slıdere, A.; Aydın, M.; Çiftçi, O. Investigation of protective effect of ellagic acid in phthalatesinduced reproductive damage. Drug Chem. Toxicol. 2020, 1–14.
30. Guvvala, P.R.; Ravindra, J.P.; Selvaraju, S.; Arangasamy, A.; Venkata, K.M. Ellagic and ferulic acids protect arsenic-induced male reproductive toxicity via regulating Nfe2l2, Ppargc1a and StAR expressions in testis. Toxicology 2019, 413, 1–12.
31. Ateçsçsahin, A.; Türk, G.; Yilmaz, S.; Sönmez, M.; Sakin, F.; Ceribasi, A.O. Modulatory effects of lycopene and ellagic acid on reproductive dysfunction induced by polychlorinated biphenyl (Aroclor 1254) in male rats. Basic Clin. Pharmacol. Toxicol. 2010, 106, 479–489.
32. Abdullah, M.; Jamil, R.T.; Attia, F.N. Vitamin C (Ascorbic Acid) StatPearls 2021. Available online: https://www.ncbi.nlm.nih.gov/books/NBK499877/ (accessed on 18 March 2019).
33. Carr, A.; Frei, B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J. 1999, 13, 1007–1024.
34. Akinola, B.K.; Olawuyi, T.S.; Ukwenya, V.O.; Daniel, L.D.; Faleye, B.C. Protective effects of aloe vera gel (Aloe baberdensis Miller) on aluminum chloride-induced reproductive toxicity in male Wistar rats. JBRA Assist. Reprod. 2021, 25, 193–201.
35. Jahan, S.; Azad, T.; Ayub, A.; Ullah, A.; Afsar, T.; Almajwal, A.; Razak, S. Ameliorating potency of Chenopodium album Linn. And vitamin C against mercuric chloride-induced oxidative stress in testes of Sprague Dawley rats. Environ. Health Prev. Med. 2019, 24, 62.
36. Rahmouni, F.; Daoud, S.; Rebai, T. Teucrium polium attenuates carbon tetrachloride-induced toxicity in the male reproductive system of rats. Andrologia 2019, 51, e13182.
37. El Shafai, A.; Zohdy, N.; El Mulla, K.; Hassan, M.; Morad, N. Light and electron microscopic study of the toxic effect of prolonged lead exposure on the seminiferous tubules of albino rats and the possible protective effect of ascorbic acid. Food Chem. Toxicol. 2011, 49, 734–743.
38. Salama, A.F.; Kasem, S.M.; Tousson, E.; Elsisy, M.K. Protective role of L-carnitine and vitamin E on the testis of atherosclerotic rats. Ind. Health 2015, 31, 467–474.
39. Medina, J.; Gupta, V. Vitamin E. StatPearls 2021. Available online: https://www.ncbi.nlm.nih.gov/books/NBK557737/ (accessed on 18 March 2019).
40. Colombo, M.L. An update on vitamin E, tocopherol and tocotrienol-perspectives. Molecules 2010, 15, 2103–2113.
41. Momeni, H.R.; Oryan, S.; Eskandari, N. Effect of vitamin E on sperm number and testis histopathology of sodium arsenite-treated rats. Biol. 2012, 12, 171–181.
42. Mehranjani, M.S.; Noorafshan, A.; Momeni, H.R.; Abnosi, M.H.; Mahmoodi, M.; Anvari, M.; Hoseini, S.M. Stereological study of the effects of vitamin E on testis structure in rats treated with para-nonylphenol. Asian J. Androl. 2009, 11, 508–516.
43. Latchoumycandane, C.; Mathur, P.P. Effects of vitamin E on reactive oxygen species-mediated 2,3,7,8-tetrachlorodi-benzo-p-dioxin toxicity in rat testis. J. Appl. Toxicol. 2002, 22, 345–351.
44. Yüncü, M.; Bükücü, N.; Bayat, N.; Sencar, L.; Tarakçio˘ glu, M. The effect of vitamin E and L-carnitine against methotrexate-induced injury in rat testis. J. Med. Sci. 2015, 45, 517–525.
45. Hammami, I.; El May, M.V. Impact of garlic feeding (Allium sativum) on male fertility. Andrologia 2013, 45, 217–224.
46. Rivlin, R.S. Historical perspective on the use of garlic. J. Nutr. 2001, 131, 951s–954s.
47. Park, J.H.; Park, Y.K.; Park, E. Antioxidative and antigenotoxic effects of garlic (Allium sativum L.) prepared by different processing methods. Plant Foods Hum. Nutr. 2009, 64, 244–249.
48. Srinivasan, K. Antioxidant potential of spices and their active constituents. Rev. Food Sci. Nutr. 2014, 54, 352–372.
49. Oi, Y.; Imafuku, M.; Shishido, C.; Kominato, Y.; Nishimura, S.; Iwai, K. Garlic supplementation increases testicular testosterone and decreases plasma corticosterone in rats fed a high protein diet. Nutr. 2001, 131, 2150–2156.
50. Ola-Mudathir, K.F.; Suru, S.M.; Fafunso, M.A.; Obioha, U.E.; Faremi, T.Y. Protective roles of onion and garlic extracts on cadmiuminduced changes in sperm characteristics and testicular oxidative damage in rats. Food Chem. Toxicol. 2008, 46, 3604–3611.
51. El-Akabawy, G.; El-Sherif, N.M. Protective role of garlic oil against oxidative damage induced by furan exposure from weaning through adulthood in adult rat testis. Acta Histochem. 2016, 118, 456–463.
52. Zahedi, A.; Fathiazad, F.; Khaki, A.; Ahmadnejad, B. Protective effect of ginger on gentamicin-induced apoptosis in testis of rats. Pharm. Bull. 2012, 2, 197–200.
53. Mazani, M.; Ojarudi, M.; Banaei, S. The protective effect of cinnamon and ginger hydro-alcoholic extract on carbon tetrachlorideinduced testicular damage in rats. Andrologia 2020, 52, e13651.
54. Khodaie, L.; Sadeghpoor, O. Ginger from ancient times to the new outlook. Jundishapur J. Nat. Pharm. Prod. 2015, 10, e18402.
55. Khaleghi Ghadiri, M.; Gorji, A. Natural remedies for impotence in medieval Persia. Int. J. Impot. Res. 2004, 16, 80–83.
56. Kamatenesi-Mugisha, M.; Oryem-Origa, H. Traditional herbal remedies used in the management of sexual impotence and erectile dysfunction in western Uganda. Health Sci. 2005, 5, 40–49.
57. Ghasemzadeh, A.; Jaafar, H.Z.; Rahmat, A. Antioxidant activities, total phenolics and flavonoids content in two varieties of Malaysia young ginger (Zingiber officinale Roscoe). Molecules 2010, 15, 4324–4333.
58. Sakr, S.; Badawy, G. Effect of ginger (Zingiber officinale R.) on metiram-inhibited spermatogenesis and induced apoptosis in albino mice. Appl. Pharm. Sci. 2011, 1, 131–136.
59. Akbari, A.; Nasiri, K.; Heydari, M.; Mosavat, S.H.; Iraji, A. The Protective Effect of Hydroalcoholic Extract of Zingiber officinale Roscoe (Ginger) on Ethanol-Induced Reproductive Toxicity in Male Rats. Evid. Based Complement. Altern. Med. 2017, 22, 609–617.
60. Afkhami Fathabad, A.; Shekarforoush, S.; Hoseini, M.; Ebrahimi, Z. Attenuation of Sulfite-Induced Testicular Injury in Rats by Zingiber officinale Roscoe. J. Diet. Suppl. 2018, 15, 398–409.
61. El-Mehi, A.E.; Faried, M.A. Effect of high-fructose diet-induced metabolic syndrome on the pituitary-gonadal axis from adolescence through adulthood in male albino rats and the possible protective role of ginger extract. A biochemical, histological and immunohistochemical study. Folia Morphol. 2020, 79, 690–708.
62. Hassan, H.A.; El-Kholy, W.M.; Nour, S.E. Proanthocyanidin as a cytogenetic protective agent against adverse effects of plant growth regulators supplementation in rats. Cytotechnology 2014, 66, 585–596.
63. Gupta, M.; Dey, S.; Marbaniang, D.; Pal, P.; Ray, S.; Mazumder, B. Grape seed extract: Having a potential health benefits. J. Food Sci. Technol. 2020, 57, 1205–1215.
64. Bagchi, D.; Garg, A.; Krohn, R.L.; Bagchi, M.; Tran, M.X.; Stohs, S.J. Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro. Commun. Mol. Pathol. Pharmacol. 1997, 95, 179–189.
65. Maffei Facino, R.; Carini, M.; Aldini, G.; Bombardelli, E.; Morazzoni, P.; Morelli, R. Free radicals scavenging action and antienzyme activities of procyanidines from Vitis vinifera. A mechanism for their capillary protective action. Arzneimittel-Forschung 1994, 44, 592–601.
66. Shi, J.; Yu, J.; Pohorly, J.E.; Kakuda, Y. Polyphenolics in grape seeds-biochemistry and functionality. Med. Food 2003, 6, 291–299.
67. Morsi, A.A.; Shawky, L.M.; El Bana, E.A. The potential gonadoprotective effects of grape seed extract against the histopathological alterations elicited in an animal model of cadmium-induced testicular toxicity. Folia Morphol. 2020, 79, 767–776.
68. Evcimen, M.; Aslan, R.; Gulay, M.S. Protective effects of polydatin and grape seed extract in rats exposed to cadmium. Drug Chem. Toxicol. 2020, 43, 225–233.
69. Alkhedaide, A.; Alshehri, Z.S.; Sabry, A.; Abdel-Ghaffar, T.; Soliman, M.M.; Attia, H. Protective effect of grape seed extract against cadmium-induced testicular dysfunction. Med. Rep. 2016, 13, 3101–3109.
70. Sönmez, M.F.; Tascioglu, S. Protective effects of grape seed extract on cadmium-induced testicular damage, apoptosis, and endothelial nitric oxide synthases expression in rats. Ind. Health 2016, 32, 1486–1494.
71. Pires, V.C.; Gollücke, A.P.; Ribeiro, D.A.; Lungato, L.; D’Almeida, V.; Aguiar, O., Jr. Grape juice concentrate protects reproductive parameters of male rats against cadmium-induced damage: A chronic assay. J. Nutr. 2013, 110, 2020–2029.
72. Lamas, C.A.; Gollücke, A.P.; Dolder, H. Grape juice concentrate (G8000®) intake mitigates testicular morphological and ultrastructural damage following cadmium intoxication. J. Exp. Pathol. 2015, 96, 301–310.
73. Hasona, N.A. Grape seed extract attenuates dexamethasone-induced testicular and thyroid dysfunction in male albino rats. Andrologia 2018, 50, e13002.
74. El-Ashmawy, I.M.; Saleh, A.; Salama, O.M. Effects of marjoram volatile oil and grape seed extract on ethanol toxicity in male rats. Basic Clin. Pharmacol. Toxicol. 2007, 101, 320–327.
75. Musial, C.; Kuban-Jankowska, A.; Gorska-Ponikowska, M. Beneficial Properties of Green Tea Catechins. J. Mol. Sci. 2020, 21, 1744.
76. Osada, K.; Takahashi, M.; Hoshina, S.; Nakamura, M.; Nakamura, S.; Sugano, M. Tea catechins inhibit cholesterol oxidation accompanying oxidation of low density lipoprotein in vitro. Biochem. Physiol. C Toxicol. Pharmacol. 2001, 128, 153–164.
77. Bagherpour, H.; Karimpour Malekshah, A.; Talebpour Amiri, F.; Azadbakht, M. Protective effect of green tea extract on the deltamethrin-induced toxicity in mice testis: An experimental study. J. Reprod. Biomed. 2019, 17, 337–348.
78. Soussi, A.; Gaubin, Y.; Beau, B.; Murat, J.C.; Soleilhavoup, J.P.; Croute, F.; El Feki, A. Stress proteins (Hsp72/73, Grp94) expression pattern in rat organs following metavanadate administration. Effect of green tea drinking. Food Chem. Toxicol. 2006, 44, 1031–1037.
79. Opuwari, C.; Monsees, T. Green tea consumption increases sperm concentration and viability in male rats and is safe for reproductive, liver and kidney health. Rep. 2020, 10, 15269.
80. Azizi, P.; Soleimani Mehranjani, M. The effect of green tea extract on the sperm parameters and histological changes of testis in rats exposed to para-nonylphenol. J. Reprod. Biomed. 2019, 17, 717–726.
81. Mahmoudi, R.; Azizi, A.; Abedini, S.; Hemayatkhah Jahromi, V.; Abidi, H.; Jafari Barmak, M. Green tea improves rat sperm quality and reduced cadmium chloride damage effect in spermatogenesis cycle. J. Med. Life 2018, 11, 371–380.
82. Abdelrazek, H.M.; Helmy, S.A.; Elsayed, D.H.; Ebaid, H.M.; Mohamed, R.M. Ameliorating effects of green tea extract on cadmium induced reproductive injury in male Wistar rats with respect to androgen receptors and caspase-3. Biol. 2016, 16, 300–308.
83. Mosbah, R.; Yousef, M.I.; Mantovani, A. Nicotine-induced reproductive toxicity, oxidative damage, histological changes and haematotoxicity in male rats: The protective effects of green tea extract. Toxicol. Pathol. 2015, 67, 253–259.
84. Saha, S.K.; McHugh, E.; Murray, P.; Walsh, D.J. Microalgae as a source of nutraceuticals. In Phycotoxins; Wiley-Blackwell: Hackensack, NJ, USA, 2015; pp. 255–291.
85. Plaza, M.; Herrero, M.; Cifuentes, A.; Ibáñez, E. Innovative natural functional ingredients from microalgae. Agric. Food Chem. 2009, 57, 7159–7170.
86. Aitken, R.J.; Curry, B.J. Redox regulation of human sperm function: From the physiological control of sperm capacitation to the etiology of infertility and DNA damage in the germ line. Redox Signal. 2011, 14, 367–381.
87. Tremellen, K. Oxidative stress and male infertility—A clinical perspective. Reprod. Update 2008, 14, 243–258.
88. S. Food and Drug Administration. Re: GRAS Exemption Claim for Chlorella Vulgaris as an Ingredient in Foods. Available online: https://www.isditwelgezond.nl/wp-content/uploads/2017/04/ucm277773.pdf (accessed on 18 March 2019).
89. S. Food and Drug Administration. Re: GRAS Exemption Claim for Spirulina Platensis as an Ingredient in Foods. Available online: http://sdlbl.in/wp-content/uploads/2014/09/FDA-United-States.pdf (accessed on 18 March 2019).
90. Vecina, J.F.; Oliveira, A.G.; Araujo, T.G.; Baggio, S.R.; Torello, C.O.; Saad, M.J.; Queiroz, M.L. Chlorella modulates insulin signaling pathway and prevents high-fat diet-induced insulin resistance in mice. Life Sci. 2014, 95, 45–52.
91. Li, L.; Li, W.; Kim, Y.H.; Lee, Y.W. Chlorella vulgaris extract ameliorates carbon tetrachloride-induced acute hepatic injury in mice. Toxicol. Pathol. 2013, 65, 73–80.
92. Saberbaghi, T.; Abbasian, F.; Mohd Yusof, Y.A.; Makpol, S. Modulation of Cell Cycle Profile by Chlorella vulgaris Prevents Replicative Senescence of Human Diploid Fibroblasts. Based Complement. Altern. Med. 2013, 2013, 780504.
93. Osama, E.; Galal, A.A.A.; Abdalla, H.; El-Sheikh, S.M.A. Chlorella vulgaris ameliorates testicular toxicity induced by deltamethrin in male rats via modulating oxidative stress. Andrologia 2019, 51, e13214.
94. Eissa, M.M.; Ahmed, M.M. Methanolic extract of Chlorella vulgaris protects against sodium nitrite-induced reproductive toxicity in male rats. Andrologia 2020, 52, e13811.
95. Güner, Ö.; Güner, A.; Yava¸so˘ glu, A.; Karabay Yava¸so˘ glu, N.Ü.; Kavlak, O. Ameliorative effect of edible Halopteris scoparia against cadmium-induced reproductive toxicity in male mice: A biochemical and histopathologic study. Andrologia 2020, 52, e13591.
96. Kong, Z.L.; Sudirman, S. Fucoxanthin-Rich Brown Algae Extract Improves Male Reproductive Function on Streptozotocin-Nicotinamide-Induced Diabetic Rat Model. J. Mol. Sci. 2019, 20, 4485.
97. Wang, P.T.; Sudirman, S.; Hsieh, M.C.; Hu, J.Y.; Kong, Z.L. Oral supplementation of fucoxanthin-rich brown algae extract ameliorates cisplatin-induced testicular damage in hamsters. Pharmacother. 2020, 125, 109992.
98. Burdock, G.A. Review of the biological properties and toxicity of bee propolis (propolis). Food Chem. Toxicol. 1998, 36, 347–363.
99. Zabaiou, N.; Fouache, A.; Trousson, A.; Baron, S.; Zellagui, A.; Lahouel, M.; Lobaccaro, J.A. Biological properties of propolis extracts: Something new from an ancient product. Phys. Lipids 2017, 207, 214–222.
100. Seven, I.; Tatli Seven, P. Bee glue (propolis) improves reproductive organs, sperm quality and histological changes and antioxidant parameters of testis tissues in rats exposed to excess copper. Andrologia 2020, 52, e13540.
101. Collodel, G.; Moretti, E.; Del Vecchio, M.T.; Biagi, M.; Cardinali, R.; Mazzi, L.; Brecchia, G.; Maranesi, M.; Manca, D.; Castellini, C. Effect of chocolate and Propolfenol on rabbit spermatogenesis and sperm quality following bacterial lipopolysaccharide treatment. Biol. Reprod. Med. 2014, 60, 217–226.
102. Khalil, M.L. Biological activity of bee propolis in health and disease. Asian Pac. J. Cancer Prev. 2006, 7, 22–31.
103. Sforcin, J.M. Biological Properties and Therapeutic Applications of Propolis. Res. 2016, 30, 894–905.
104. Nna, V.U.; Abu Bakar, A.B.; Md Lazin, M.; Mohamed, M. Antioxidant, anti-inflammatory and synergistic anti-hyperglycemic effects of Malaysian propolis and metformin in streptozotocin-induced diabetic rats. Food Chem. Toxicol. 2018, 120, 305–320.
105. Sobocanec, S.; Sverko, V.; Balog, T.; Sari´c, A.; Rusak, G.; Liki´c, S.; Kusi´c, B.; Katalini´c, V.; Radi´c, S.; Marotti, T. Oxidant/antioxidant properties of Croatian native propolis. Agric. Food Chem. 2006, 54, 8018–8026.
106. Jasprica, I.; Mornar, A.; Debeljak, Z.; Smolci´c-Bubalo, A.; Medi´c-Sari´c, M.; Mayer, L.; Romi´c, Z.; Bu´can, K.; Balog, T.; Sobocanec, S.; et al. In vivo study of propolis supplementation effects on antioxidative status and red blood cells. Ethnopharmacol. 2007, 110, 548–554.
107. Yousef, M.I.; Salama, A.F. Propolis protection from reproductive toxicity caused by aluminium chloride in male rats. Food Chem. Toxicol. 2009, 47, 1168–1175.
108. Castaldo, S.; Capasso, F. Propolis, an old remedy used in modern medicine. Fitoterapia 2002, 73 (Suppl. 1), S1–S6.
109. Capucho, C.; Sette, R.; de Souza Predes, F.; de Castro Monteiro, J.; Pigoso, A.A.; Barbieri, R.; Dolder, M.A.; Severi-Aguiar, G.D. Green Brazilian propolis effects on sperm count and epididymis morphology and oxidative stress. Food Chem. Toxicol. 2012, 50, 3956–3962.
110. Çilenk, K.T.; Öztürk, ˙I.; Sönmez, M.F. Ameliorative effect of propolis on the cadmium-induced reproductive toxicity in male albino rats. Mol. Pathol. 2016, 101, 207–213.
111. Nna, V.U.; Abu Bakar, A.B.; Ahmad, A.; Eleazu, C.O.; Mohamed, M. Oxidative Stress, NF-B-Mediated Inflammation and Apoptosis in the Testes of Streptozotocin-Induced Diabetic Rats: Combined Protective Effects of Malaysian Propolis and Metformin. Antioxidants 2019, 8, 465.
112. Nna, V.U.; Bakar, A.B.A.; Ahmad, A.; Umar, U.Z.; Suleiman, J.B.; Zakaria, Z.; Othman, Z.A.; Mohamed, M. Malaysian propolis and metformin mitigate subfertility in streptozotocin-induced diabetic male rats by targeting steroidogenesis, testicular lactate transport, spermatogenesis and mating behavior. Andrologia 2020, 8, 731–746.

This entry is adapted from the peer-reviewed paper 10.3390/biochem1030011