Article

Trans-resveratrol relaxes the corpus cavernosum ex vivo and enhances testosterone levels and sperm quality in vivo

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Abstract

We examined the effects of trans-resveratrol on male reproductive functions; ex-vivo penile erection and in-vivo sperm counts and quality. For the ex-vivo study, the relaxation effects of resveratrol on isolated New Zealand white rabbit corpus cavernosum, precontracted by phenylephrine (5x10(-5) M) were measured. The in-vivo study measured reproductive organ weights, blood testosterone levels, testicular histopathology, sperm counts, as well as the epididymal sperm motility and deformity of male ICR mice given an oral dose of resveratrol (50 mg/ kg) for 28 days. Resveratrol elicited a concentration-dependent relaxing effect on corpus cavernosum, leading to a median effective concentration (EC50) of 0.29 mg/mL. Repeated treatment with resveratrol (50 mg/kg) did not cause an increase in body weight, reproductive organ weight or testicular microscopic findings; however, resveratrol did elicit an increase in blood testosterone concentration, testicular sperm counts and epididymal sperm motility by 51.6%, 15.8% and 23.3%, respectively, without influence on sperm deformity. In conclusion, we propose that resveratrol has a positive effect on male reproductive function by triggering a penile erection, as well as enhancing blood testosterone levels, testicular sperm counts, and epididymal sperm motility.

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... RVT has phytotherapeutic potential with antioxidant, calorie-restricting, anti-aging, cardioprotective effects [7]. Recent studies showed RVT can induce vasorelaxant effect in penile tissue [8][9][10] and appears to have beneficial effects in ED induced by hypertension, hypercholesterolemia, and diabetes [8,11,12]. Although RVT has been shown to induce relaxation of mice corpus cavernosum (MCC) independent of the NO pathway [13], the exact mechanism remains unknown. ...
... RVT has phytotherapeutic potential with antioxidant, calorie-restricting, anti-aging, cardioprotective effects [7]. Recent studies showed RVT can induce vasorelaxant effect in penile tissue [8][9][10] and appears to have beneficial effects in ED induced by hypertension, hypercholesterolemia, and diabetes [8,11,12]. Although RVT has been shown to induce relaxation of mice corpus cavernosum (MCC) independent of the NO pathway [13], the exact mechanism remains unknown. ...
... Although RVT activates eNOS and restores impaired relaxation to NO in aorta [19,28,29], in line with our studies, a recent paper also found ACh-induced relaxation was not increased by RVT in MCC [13]. This may be due to tissuespecific effect of RVT on eNOS activation as suggested by Muller and colleagues, since L-NAME inhibited RVT-induced relaxation in aorta but not in pulmonary artery [30] or due to prevailing pathological condition as RVT restores impaired ACh-induced relaxation in hypercholesterolemic rabbit corpus cavernosum [8,11,12] or spontaneous hypertensive rat aorta [31]. ...
Article
Introduction. Resveratrol (RVT) found in red wine protects against erectile dysfunction and relaxes penile tissue (corpus cavernosum) via a nitric oxide (NO) independent pathway. However, the mechanism remains to be elucidated. Hydrogen sulfide (H2S) is a potent vasodilator and neuromodulator generated in corpus cavernosum. Aims. We investigated whether RVT caused the relaxation of mice corpus cavernosum (MCC) through H2S. Methods. H2S formation is measured by methylene blue assay and vascular reactivity experiments have been performed by DMT strip myograph in CD1 MCC strips. Main Outcome Measures. Endothelial NO synthase (eNOS) inhibitor Nω-Nitro-L-arginine (L-NNA, 0.1 mM) or H2S inhibitor aminooxyacetic acid (AOAA, 2 mM) which inhibits both cystathionine-β-synthase (CBS) and cystathionine-gamma-lyase (CSE) enzyme or combination of AOAA with PAG (CSE inhibitor) has been used in the presence/absence of RVT (0.1 mM, 30 min) to elucidate the role of NO or H2S pathways on the effects of RVT in MCC. Concentration-dependent relaxations to RVT, L-cysteine, sodium hydrogen sulfide (NaHS) and acetylcholine (ACh) were studied. Results. Exposure of murine corpus cavernosum to RVT increased both basal and L-cysteine-stimulated H2S formation. Both of these effects were reversed by AOAA but not by L-NNA. RVT caused concentration-dependent relaxation of MCC and that RVT-induced relaxation was significantly inhibited by AOAA or AOAA + PAG but not by L-NNA. L-cysteine caused concentration-dependent relaxations, which are inhibited by AOAA or AOAA + PAG significantly. Incubation of MCC with RVT significantly increased L-cysteine-induced relaxation, and this effect was inhibited by AOAA + PAG. However, RVT did not alter the effect of exogenous H2S (NaHS) or ACh-induced relaxations. Conclusions. These results demonstrate that RVT-induced relaxation is at least partly dependent on H2S formation and acts independent of eNOS pathway. In phosphodiesterase 5 inhibitor (PDE-5i) nonresponder population, combination therapy with RVT may reverse erectile dysfunction via stimulating endogenous H2S formation.
... Recent studies in animals as well as humans demonstrate that resveratrol, a natural polyphenolic compound, has positive effects on the hypothalamic-pituitary-gonad axis, blood testosterone levels, sperm production and sperm motility [172,173]. Furthermore, resveratrol may decrease germ cell apoptosis [174,175]. At the same time, Mojica-Villegas et al. [138] and Shin et al. [173] showed that resveratrol has the capacity to inhibit mitochondrial ROS production, disruption of membrane potential and permeability transition, thereby protecting the key intracellular organelle against the oxidative stress promoted by FeAA. ...
... Furthermore, resveratrol may decrease germ cell apoptosis [174,175]. At the same time, Mojica-Villegas et al. [138] and Shin et al. [173] showed that resveratrol has the capacity to inhibit mitochondrial ROS production, disruption of membrane potential and permeability transition, thereby protecting the key intracellular organelle against the oxidative stress promoted by FeAA. Moreover, resveratrol has a cytoprotective effect against iron-related oxidative burst, as illustrated by the inhibition of apoptosis and alterations in apoptotic markers [173]. ...
... At the same time, Mojica-Villegas et al. [138] and Shin et al. [173] showed that resveratrol has the capacity to inhibit mitochondrial ROS production, disruption of membrane potential and permeability transition, thereby protecting the key intracellular organelle against the oxidative stress promoted by FeAA. Moreover, resveratrol has a cytoprotective effect against iron-related oxidative burst, as illustrated by the inhibition of apoptosis and alterations in apoptotic markers [173]. ...
Article
Iron and copper are essential trace nutrients playing important roles in general health and fertility. However, both elements are highly toxic when accumulating in large quanti-ties. Their direct or indirect impact on the structure and func-tion of male gonads and gametes is not completely understood yet. Excess or deficiency of either element may lead to defec-tive spermatogenesis, reduced libido, and oxidative damage to the testicular tissue and spermatozoa, ultimately leading to fertility impairment. This review will detail the complex in-formation currently available on the dual roles iron and copper play in male reproduction.
... The beneficial effects of RES have been referred to its capability to act as a chemopreventive (Wolter et al. 2004), antiinflammatory (Donnelly et al. 2004), and a potent antioxidant agent (Cai et al. 2003). In healthy rodents, RES has a good impact on most semen parameters, sperm production, testosterone levels, and penile erection in control or stress conditions (Juan et al. 2005;Shin et al. 2008;Eleawa et al. 2014). In an experiment performed on animal models of cadmium chloride-induced reproductive toxicity, RES protected rat's testis and restored steroidogenesis and reproductive function via an antioxidant potential and inhibition of apoptosis (Eleawa et al. 2014). ...
... Such increase in testicular weights in Cis-treated rats after RES therapy suggest a protective role of RES on testicular structural proteins (Rajkumar and Srinivasan, 1991) and could be related to increased testosterone levels and synthesis (as discussed before), enhanced spermatogenesis and sperm production, and/or lowered germ cell apoptosis (Katoh et al. 2002;Prahalathan et al. 2004;Pandya et al. 2012). Interestingly, sperm count and motility were significantly increased in control rats treated with RES ( Figure 2A,B), which is in accordance with some previous reports (Juan et al. 2005;Shin et al. 2008;Eleawa et al. 2014). ...
... Third, Cis can directly act as an activator of various stress-signaling pathways within the cell at the levels of the cell membrane, cytoplasm, and nucleus to induce apoptosis (Boulikas et al. 2003;Wang and Lippard 2005). Fourth, RES is a potent scavenger of hydroxyl, superoxide, and metal-induced radicals that was shown to successfully prevent and ameliorate Cis and other reproductive toxic agents-induced testicular and other damage and alterations in sperm parameter in laboratory animals (Amin et al. 2012;Juan et al. 2005;Ateşşahin et al. 2006;Shin et al. 2008;Ilbey et al. 2009;Rezvanfar et al. 2013;Eleawa et al. 2014;Keshtmand et al. 2014;Waseem et al. 2015;Eid et al. 2016;Singh et al. 2017). ROS can induce lipid peroxidation and rapid loss of ATP, both of which lead to decrease sperm motility, axonemal damage, morphologic defects, and apoptosis (Sharma and Agarwal 1996; Sikka et al. 1996). ...
Article
This study aimed to investigate the protective role of resveratrol (RES) against cisplatin (Cis)-induced testicular damage and reproductive dysfunction in rats and to examine the underlying mechanisms of protection including its effect on endoplasmic reticulum (ER) stress, P53, extracellular signal-regulated kinase (ERK)-1/2, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and Protein kinase B (Akt) signaling. Eight-week-old Rats were divided into four groups (n = 12 each) of 1) control group: received normal saline (i.p.) as vehicle for 45 days, 2) RES-treated group: received RES (20 mg/kg, i.p) for 45 days, 3) Cis-treated group: received Cis (3 mg/kg) for 3 days and then continued on normal saline, and 4) Cis + RES-treated group: received Cis for the first 3 days and then continued on RES for the next 45 days. Serum sex hormones levels, sperm parameters, and levels of testicular antioxidant potential and inflammatory mediators were assessed in all rats. In addition, activation of ER stress, P53, ERK1/2, JNK, and Akt and markers of apoptosis were evaluated in rats’ testis. Cis lowered sperm count and motility and increased sperm morphological abnormalities. Testis of Cis-treated rats had low expression of antioxidant enzymes including SOD, CAT, and GPx and decreased the level of GSH. Concomitantly, Cis upregulated levels of cleaved caspase-3, P53, calpain-1/cleaved caspase-12, p-ERK1/2, and p-SAPK/p-JNK. However, RES administration post-Cis administration restored all sperm parameters and prevented testicular apoptosis mediated by inhibition of all above-mentioned apoptotic pathways. Moreover, RES enhanced testosterone, FSH, and LH levels and upregulated p-Akt/p-Bad levels in both control and Cis-treated rats. In conclusion, RES protects against Cis-induced testicular damage and reproductive dysfunction via improving testosterone levels, increasing sperm count, reducing testicular apoptosis via an antioxidant potential, inhibition of ER stress, P53, ERK1/2, JNK, and activation of Akt. Abbreviations: RES: resveratrol, Cis: cisplatin; ER: endoplasmic reticulum; ERK1/2: extracellular signal-regulated kinase1/2; SAPK/JNK: stress-activated protein kinase/c-Jun N-terminal kinase; Akt: protein kinase B; HPG axis: hypothalamic-pituitary-gonadal axis; PUFAs: polyunsaturated fatty acids; FSH: Follicular stimulating hormone; LH: Luteinizing hormone; PBS: phosphate buffered saline; GSH: reduced glutathione; GSSG: glutathione disulfide; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; GRx: glutathione reductase; SOD: superoxide dismutase; CAT: catalase; 4HNE: 4-hydroxynonenal.
... However, in another study, although antioxidants led to a decrease in DNA fragmentation, the authors also reported an increase in sperm decondensation which they felt might interfere with sperm preimplantation [16]. [19][20][21], including reversing the process of testicular damage, increasing testicular weight, causing seminiferous epithelium differentiation, and restoring the physiological process of spermatogenesis [22]. Yet, despite the encouraging animal studies and known safety profile, resveratrol has not been studies for its ability to improve oligoasthenozoospermia in patients. ...
... In this study we found that supplementation with hydrogen sulfide prodrug resulted in increased sperm motility both pre-and postcapacitation, in contrast to previously published studies, such as that conducted by Donnelly et al, which reported that supplementation with antioxidants did not improve sperm motility in vitro. This difference can be attributed to the fact that this study used ascorbic acid and α-tocopherol as antioxidants [21]. It is known that even though the hydrogen sulfide prodrug species are less known and studied, their antioxidant effect is much greater than ascorbic acid and α-tocopherol; therefore it is feasible that in our study, besides the fact that it was performed in vivo, we also obtained satisfactory results with regard to motility. ...
Article
Full-text available
Objective: To determine whether subjects suffering from oligoasthenozoospermia would benefit from antioxidant treatment with resveratrol, a natural-occurring polyphenol, and hydrogen sulfide. Methods: A randomized controlled clinical trial involving 54 men with Oligoasthenozoospermia. We randomly assigned resveratrol (n=18), SG 1002 (n=18), and placebo (n=18) for 75 days. Sperm analysis was performed after treatment. Statistical analysis was made with chi square test. Results: When compared to the placebo treated group, SG1002 treatment led to an increase in sperm concentration (11.18 × 106 vs. 17.01 × 106, P < 0.05), sperm motility (10.06 × 106 vs. 20.06 × 106, P
... Resveratrol (RES) (3,5,4'-trihydroxystilbene) is a natural phytoalexin that is found particularly in red wine and peanuts. [1] There are two RES forms ie. ...
... [1,3] In recent years, several in vivo and in vitro studies have suggested that RES protects the spermatocytes against lipid peroxidation as well as increases testicular sperm count and sperm motility. [4] RES has also been reported to increase the sperm production and to decrease germ cell apoptosis. [5] Furthermore, it is well known that RES is protective against environmental toxins. ...
Article
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Objective: The aim of the present study was to investigate the possible beneficial effects of resveratrol in mice subjected to vinyl cyclohexene dieposide (VCD) -induced testicular toxicity. Material and methods: A total of thirty- six Swiss albino male mice aged 28-days were used in the present study. The study was composed of two stages where mice which received or did not receive VCD (320 mg/kg/day) were administered resveratrol. The animals were assigned into control and resveratrol-treated groups in the first stage and into groups of VCD- and VCD+resveratrol-treated groups in the second stage. At the end of the experiments, relative testicular weight (TW/BW) and dry/wet weight of testis (TDW/TWW) were calculated. Histological analysis by hematoxylin and eosin (H&E) staining and immunohistochemical staining by BAX and Bcl-2 were performed. Serum testosterone, LH and FSH levels were measured by a commercially available ELISA kit. Results: Resveratrol caused a dose-dependent increase in TW/BW and decrease in TDW/TWW (p<0.05). Resveratrol at a dose of 20 mg/kg resulted in an improvement in testosterone, LH and FSH levels in mice with VCD-induced testicular toxicity (p<0.001). Resveratrol also improved apoptotic index and epithelial cell height of testicular seminipherous tubuli significantly after VCD exposure (p<0.001). Conclusion: Results of the present study suggest that resveratrol can be used as a protective and/or therapeutic agent particularly for cases with male infertility caused by testicular toxicity.
... The right testis and epididymis of each rat were homogenized at 8,000 rpm for 2 minutes and sonicated at 4°C for 3 minutes to obtain homogenization-resistant sperm heads. The number of sperm heads was counted with a hemacytometer [17][18] . ...
... The left epididymis was dissected into a Petri dish containing M-199 media and incubated at 37°C for 10 minutes. After removing tissue debris, an aliquot of sperm was loaded on a slide glass and sperm motility was examined under a light microscope [17][18] . Separately, an aliquot of sperm was stained with the same volume of 1% eosin, smeared on a slide glass, and examined for deformity of sperm. ...
Article
Full-text available
Since estrogenic pollutants and phytoestrogens can cause the disorder of the reproductive system, the effects of a soybean milk product (Vegemil<sup>®</sup> containing 162 ppm isoflavones) on the feto-neonatal development, including male reproductive function, were investigated. Pregnant rats were fed the soybean milk (5% or 100% in drinking water) from gestational day (GD) 6 to parturition or to post-natal day (PND) 56. Specifically, the rats were divided into 4 groups: the control group (drinking water), the GD5% group (5% soybean milk during only the GD period), the GD-PND5% group (5% soybean milk during the GD and PND periods), and the GD-PND100% group (100% soybean milk instead of water during the GD and PND periods). During the gestational, lactational, and developmental periods, the reproductive and developmental parameters of dams and offspring were observed. Feeding soybean milk did not affect the birth and physical development of both male and female offspring. At PND57, the weights of the testes and epididymides of F1 males significantly increased by feeding a high concentration of the soybean milk (GD-PND100%). In addition, feeding of the soybean milk during both the GD and PND periods (GD-PND5% and GD-PND100%) enhanced the sperm counts and motility. The results indicate that soybean milk is safe for embryos, fetuses, and offspring, and improves the post-generational development of male reproductive function.
... [18] With respect to male reproduction, animal studies have suggested that RES stimulates and protects rabbit and murine spermatocytes and spermatozoa against LPO. [19,20] It has also been shown to reduce apoptosis in germinal cells, [20] and to protect them against environmental toxins. [21] Moreover it has been demonstrated that RES administration enhances spermatogenesis by stimulating the hypothalamic-pituitary-gonadal axis without exhibiting adverse effects. ...
... [22] Moreover RES supplementation may trigger penile erection and enhance blood testosterone levels, testicular sperm count and epididymal sperm motility. [19] This preliminary body of evidence emphasizes on a significant potential of RES in providing a possible protection to the male reproductive system. Therefore, the aim of the present study was to explore the in vitro antioxidant activity of RES against oxidative stress induced in bovine spermatozoa by exposure to ferrous ascorbate. ...
Article
Full-text available
Resveratrol (RES) is a natural polyphenol and phytoestrogen exhibiting cardioprotective, anticancer, antibacterial and vasorelaxing properties. It is also a powerful reactive oxygen species (ROS) scavenger and chelating agent. This study was designed to determine the efficiency of RES to reverse the ROS-mediated impairment of the motility, viability and intracellular antioxidant profile of bovine spermatozoa. Spermatozoa were washed out of fresh bovine semen, suspended in 2.9% sodium citrate and subjected to RES treatment (5, 10, 25 and 50 μmol L−1) in the presence or absence of a pro-oxidant, i.e., ferrous ascorbate (FeAA; 150 μmol L−1 FeSO4 and 750 μmol L−1 ascorbic acid) during a 6-h in vitro culture. Spermatozoa motion parameters were assessed using the SpermVision computer-aided sperm analysis (CASA) system. Cell viability was examined with the metabolic activity (MTT) assay, and the nitroblue-tetrazolium (NBT) test was applied to quantify the intracellular superoxide formation. Cell lysates were prepared at the end of the in vitro experiments in order to investigate the intracellular activity of superoxide dismutase (SOD), catalase (CAT), as well as the concentrations of glutathione (GSH) and malondialdehyde (MDA). FeAA treatment led to a reduced sperm motility (P P P P P P P P P −1 RES and P −1 RES; P −1 RES proving to be the most effective RES concentration. Our results suggest that RES possesses significant antioxidant properties that may prevent the deleterious effects caused by ROS to spermatozoa, and preserve the fertilization potential of male reproductive cells.
... Regarding male fertility, recent in vivo studies in animal models demonstrated that RES administration enhances sperm production in rats by stimulating the hypothalamic-pituitary-gonadal axis without inducing adverse effects [22]. RES has a positive effect by triggering penile erection and by enhancing blood testosterone levels, testicular sperm count and epididymal sperm motility, as demonstrated in rabbits [23]. A protective effect of RES against oxidative damage but not against the loss of motility induced by the cryopreservation of human semen has recently been observed as well [24]. ...
... The dose selected for CdCl 2 was based on previous dose-response studies that showed the maximum testicular damage and poorest semen quality occur at this dose [26]. Similarly, the dose selected for RES was based on previous studies that showed beneficial effects of RES on semen parameters at this dose and the safety of this dose [21][22][23][24][25]. ...
Article
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This study was performed to investigate the protective and therapeutic effects of resveratrol (RES) against CdCl2-induced toxicity in rat testes. Seven experimental groups of adult male rats were formulated as follows: A) controls+NS, B) control+vehicle (saline solution of hydroxypropyl cyclodextrin), C) RES treated, D) CdCl2+NS, E) CdCl2+vehicle, F) RES followed by CdCl2 and M) CdCl2 followed by RES. At the end of the protocol, serum levels of FSH, LH and testosterone were measured in all groups, and testicular levels of TBARS and superoxide dismutase (SOD) activity were measured. Epididymal semen analysis was performed, and testicular expression of Bcl-2, p53 and Bax was assessed by RT-PCR. Also, histopathological changes of the testes were examined microscopically. Administration of RES before or after cadmium chloride in rats improved semen parameters including count, motility, daily sperm production and morphology, increased serum concentrations of gonadotropins and testosterone, decreased testicular lipid peroxidation and increased SOD activity. RES not only attenuated cadmium chloride-induced testicular histopathology but was also able to protect against the onset of cadmium chloride testicular toxicity. Cadmium chloride downregulated the anti-apoptotic gene Bcl2 and upregulated the expression of pro-apoptotic genes p53 and Bax. Resveratrol protected against and partially reversed cadmium chloride testicular toxicity via upregulation of Bcl2 and downregulation of p53 and Bax gene expression. The antioxidant activity of RES protects against cadmium chloride testicular toxicity and partially reverses its effect via upregulation of BCl2 and downregulation of p53 and Bax expression.
... It is widely consumed in the Mediterranean diet in the form of peanuts, grapes and wine [8]. Assays with in vivo experimental models have shown a positive RVT-induced effect on male reproduction, reported as the enhancement of testosterone levels, motility and sperm count [13]. Moreover, it has recently been shown that in vivo treatment with RVT prevents oxidative stress in testes of hyperthyroid rats [30] and rats treated with a chemotherapy drug [31]. ...
... The daily intake of RVT in the Mediterranean diet is approximately 0.02 mg/kg, assuming that red wine is the main dietary source and the average concentration of trans-RVT in wine is 5 mg/L [32,33]. Recent in vivo studies have shown that repeated doses of RVT at 10 mg/kg, 20 mg/kg and 50 mg/kg, being 500, 1000, 2500 times higher than the aforementioned average consumption, respectively, provides a sufficiently large safety margin [34] and protects testes and spermatogenesis against oxidative stress [13,30,31]. Unfortunately, RVT concentrations in testes of animals receiving chronic treatment with this polyphenol are unknown. ...
Article
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Resveratrol (RVT) is a polyphenolic compound found mainly in the grape and attributed with various pharmacological properties, among them their antioxidant activity. In the present study, we assess the antioxidant activity of resveratrol on oxidative damage induced by ferrous iron/ascorbate (100 µM/150 µM) in sperm of CD1+ mice. We evaluated several parameters in spermatozoa treated with or without resveratrol: (i) sperm quality analysis; (ii) mitochondrial transmembrane potential (Δѱm); (iii) ROS generation; (iv) superoxide dismutase (SOD) activity; (v) glutathione peroxidase (GPX) activity; (vi) lipid peroxidation; (vii) and in vitro fertilization (IVF) capability. Spermatozoa treated with RVT (15 µg/mL) before ferrous iron/ascorbate treatment exhibited: a significant increase in motility (8-fold), a significant increase in viability (2-fold), a significant increase in Δѱm (1.15-fold), accompanied with a significant decrease in the generation of ROS (4.96-fold), a significant decrease in GPX activity (1.32-fold), and a significant decrease in lipid peroxidation concentration (10.29-fold) relative to spermatozoa treated with ferrous iron/ascorbate; however, no changes in SOD activity were observed. Finally, spermatozoa treated with RVT before ferrous iron/ascorbate treatment showed a significant increase in oocyte fertilization (1.2-fold), relative to spermatozoa treated with ferrous iron/ascorbate. These results suggest that RVT possesses antioxidant properties that may prevent the deleterious effects produced by oxidative damage on spermatozoa, resulting in the maintenance of fertility.
... • A powerful scavenger of singlet oxygen, peroxyl and hydroxyl radicals in the hydrophilic environment, but loses an ability to scavenge lipophilic radicals and cannot break the radical chain propagation within lipid membranes [149] Resveratrol (3,5,4′-Trihydroxystilbene) • A polyphenol that belongs to the stilbene family and is found in grapes, berries, pistachios, plums, peanuts and wines [150]. • A free radical scavenger and a potent antioxidant, promotes the activities of a variety of antioxidant enzymes and increases the antioxidant capacity [150] • Copper and iron chelator preventing the Fenton reaction [151] • Stimulates and protects spermatocytes and spermatozoa against LPO, reduces apoptosis of germinal cells [152] and protects against environmental toxins [153] • Enhances spermatogenesis by stimulating the hypothalamic-pituitary-gonadal axis without adverse efects, triggers penile erection and enhances blood testosterone levels, testicular sperm count and epididymal sperm motility [151,152] Lycopene (ψ,ψ-Carotene) • One of over 600 carotenoids found in nature, present in tomatoes, watermelons and pink grapefruits [154]. • A highly unsaturated straight chain hydrocarbon with a total of 13 double bonds, 11 of which are conjugated making the molecule to be twice as potent singlet oxygen quencher as ß-carotene and 10 times more active in comparison to α-tocopherol [154]. ...
... • A powerful scavenger of singlet oxygen, peroxyl and hydroxyl radicals in the hydrophilic environment, but loses an ability to scavenge lipophilic radicals and cannot break the radical chain propagation within lipid membranes [149] Resveratrol (3,5,4′-Trihydroxystilbene) • A polyphenol that belongs to the stilbene family and is found in grapes, berries, pistachios, plums, peanuts and wines [150]. • A free radical scavenger and a potent antioxidant, promotes the activities of a variety of antioxidant enzymes and increases the antioxidant capacity [150] • Copper and iron chelator preventing the Fenton reaction [151] • Stimulates and protects spermatocytes and spermatozoa against LPO, reduces apoptosis of germinal cells [152] and protects against environmental toxins [153] • Enhances spermatogenesis by stimulating the hypothalamic-pituitary-gonadal axis without adverse efects, triggers penile erection and enhances blood testosterone levels, testicular sperm count and epididymal sperm motility [151,152] Lycopene (ψ,ψ-Carotene) • One of over 600 carotenoids found in nature, present in tomatoes, watermelons and pink grapefruits [154]. • A highly unsaturated straight chain hydrocarbon with a total of 13 double bonds, 11 of which are conjugated making the molecule to be twice as potent singlet oxygen quencher as ß-carotene and 10 times more active in comparison to α-tocopherol [154]. ...
... 28 It inhibits lipid peroxidation (LPO) of spermatocytes and increases sperm motility, viability and enhances sperm production in vivo. 29 Moreover, it decreases germ cell apoptosis in mice and rats and shows protective effects against testicular toxicity induced by many anticancer drugs and environmental toxins. 28,[30][31][32] The present study provides the first toxicological efficacy data of a short-term toxicity study induced by Sulfx at two selected doses (79.5 and 205 mg/kg body weight) on the testis of adult male rats after daily oral administration. ...
... The dose of RES was selected based on reports from previous studies that showed safety and ameliorative effects of RES against testicular damage. 27,29 The LD50 of Sulfx is reported to be 1405 mg/kg body weight in male rats. 34 A previous study demonstrated that the low observable adverse effect level (LOAEL) for sulfoxaflor was reported to be 79.4 mg/kg bw/d in a 28-day dietary rat study. ...
Article
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This work was designed to explore the protective role of resveratrol (RES) against sulfoxaflor (Sulfx)-induced reproductive toxicity in adult male rats. The animals were divided into six groups: Control group, Sulfx treated groups (79.5 and 205 mg/kg/ day), RES treated group (20 mg/kg/day), RES + Sulfx treated groups (20 mg/kg Res + 79.5 or 205 mg/kg Sulfx) orally for 28 consecutive days. Testicular samples were collected from all groups at the end of the treatment period. Tissue supernatants were isolated for oxidative stress and cellular energy parameters; tissue samples were prepared for histopathological examination. In addition, caspase-3 activity was calculated to assess spermatogenesis. Finally, DNA laddering assay was performed to detect DNA fragmentation as a hallmark of apoptosis. Our results showed that Sulfx treatment induced a significant increase in testicular levels of MDA, NOx, GSSG and reduced GSH level and cellular energy parameters in a dose-dependent manner compared to the control group. The results were confirmed by histopathological study which showed pathological changes in Sulfx treated groups. A significant increase in caspase 3 and DNA fragmentation was also observed. However, concomitant administration of RES to Sulfx-treated rats showed significant modulation against Sulfx-induced reproductive toxicity and attenuated the biochemical, apoptotic and histopathological changes. In conclusion, our results suggest that exposure to Sulfx at the two selected doses induces testicular toxicity and these effects can be ameliorated by supplementation of RES. K E Y W O R D S apoptosis, oxidative stress, sulfoxaflor, resveratrol, testicular toxicity
... Chez les rongeurs, l'ingestion de metformine (durant 4 ou 8 semaines) n'induit pas de modification du nombre moyen de spermatozoïdes, ni de la motilité ou du pourcentage de spermatozoïdes anormaux (Attia et al., 2009). Au contraire, l'ingestion de resveratrol, un autre activateur de l'AMPK, pendant 28 jours, entraîne une augmentation de la testostérone (+52%), du nombre de spermatozoïdes (+16%) et de leur motilité (+23%) (Shin et al., 2008). ...
... Recently, several studies have shown that resveratrol exerts protective effects on acute nephrotoxicity in rats (24)(25)(26)(27) and mice (28) by suppressing the inflammatory processes and by inhibiting lipid peroxidation. Moreover, resveratrol has a positive effect on male reproductive function by triggering penile erection, as well as enhancing blood testosterone levels, testicular sperm counts, and epididymal sperm motility (29). ...
... Different studies have reported that RES acts as a direct FR scavenger as well as indirectly as a metal-chelation agent preventing the Fenton reaction (Baur and Sinclair, 2010). In vivo and in vitro studies have reported that RES stimulates and protects rabbit and murine spermatocytes and spermatozoa against LPO (Revel et al., 2001;Shin et al., 2008). It has also been shown to reduce apoptosis in germinal cells (Revel et al., 2001), and to protect them against environmental toxins (Jiang et al., 2009). ...
... Los mecanismos anticancerígenos propuestos para el RESV incluyen: a) inhibición de las actividades ribonucleótido reductasa (Fontecave, Lepoivre, Elleingand, Gerez & Guittet, 1998), DNA polimerasa (Sun, Cunningham & Gantt, 1998), proteínquinasa C (Stewart et al., 1999) o ciclooxigenasa-2 (Martín, Villegas, La Casa & de la Lastra, 2004); b) inhibición de la proliferación celular (Sauer, Wartenberg & Hescheler, 2001) y de la carcinogénesis inducida por radicales libres (Jang et al., 1997); y c) la inducción de la apoptosis (Martín et al., 2004). También se han reportado efectos del resveratrol en la reproducción masculina (Shin et al., 2008). ...
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The present review analyzes the antioxidant role of resveratrol in the animal health regarding oxidative stress. The term stress was coined by Hans Selye, who discovered the stimuli that could provoke this condition. The above mentioned author defined stress as “the action of nervous and emotional stimuli provoked by the environment on the nervous, endocrine, circulatory and digestive systems of an animal, producing measurable changes in the functional levels of these systems”. Stress can be classified as physical, psychological and physiological. Independently of the type of stress or stressor agent, the organism response is the same: there is an increase of sympathetic and adrenomedullary hypothalamus-pituitary-adrenal activity. Oxidative stress is an imbalance between the production of reactivate oxygen species (ROS) and the antioxidant defense systems, enzymatic or not, due to lack of vitamins and minerals, inflammatory processes, deficiency of the immune system, situations of intense exercise and environmental factors that prevent the organism from controlling the chain reaction of the ROS. This imbalance intervenes in the lipid peroxidation of the membranes and cellular organelles and in the peroxidation of nucleic acids. The grape polyphenolic antioxidants such as resveratrol are in the skin, especially in the epidermal cells and in the seeds, being its concentration low in pulp. The quantity and quality of grape polyphenols depend mainly on the variety of the grapevine, the climate, the area and the cultivation practices. Resveratrol has drawn a great interest in the scientific community due to the wide scope of its biological effects.
... ↑ICP/MAP in aged mice and neurogenic relaxation in obese rat CC Johnson et al., 2011;Sanchez et al., 2012 Arginase inhibitors ABH and BEC ↑Neurogenic and ICP/MAP in aged rats/mice and endothelial relaxation in aged/diabetic mice CC Bivalacqua et al., 2001;Toque et al., 2011;Segal et al., 2012 NADPH oxidase inhibitor apocynin ↑ICP/MAP in hypertensive/diabetic rats/hypercholesterolaemic mice and endothelium-dependent relaxation in aged rat CC. Jin et al., 2008a;Musicki et al., 2010;Li et al., 2012;Silva et al., 2013 Pharmacological NOS activator resveratrol ↑ICP/MAP in diabetic rats and endothelial relaxation in hypercholesterolaemic rabbit and healthy rat CC. Shin et al., 2008;Soner et al., 2010;Fukuhara et al., 2011;Yu et al., 2013 NO-releasing agents NaNO2 ↑ICP/MAP in healthy and diabetic rats and endothelial relaxation in hypercholesterolaemic rabbit CC. Shukla et al., 2005;Lasker et al., 2010b;Soni et al., 2013 Gene therapies eNOS/PnNOS/EC-SOD/ iNOS/PKG1α/VEGF gene and angiopoietin-1 ↑ICP/MAP in aged/ diabetic rat and in healthy /diabetic rat CC. ...
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The ability to get and keep an erection is important to men for several reasons and the inability is called as erectile dysfunction (ED). ED started to be accepted as an early indicator for systemic endothelial dysfunction and subsequent of cardiovascular diseases. The role of nitric oxide (NO) in endothelial relaxation and erectile function is well accepted. The discovery of NO as small signaling gasotransmitter led to the investigation of the role of other endogenously derived gases, carbon monoxide (CO) and hydrogen sulfide (H2 S) in physiological and pathophysiological conditions. The role of NO and CO in sexual function and dysfunction has been investigated more extensively and recently the involvement of H2 S in erectile function has also been confirmed. In this review, we focused on the role of these 3 sister gasotransmitters in the physiology, pharmacology and pathophysiology of sexual function in man, specifically erectile function. We also reviewed the role of soluble guanylyl cyclase /cyclic GMP pathway as a common target of these gasotransmitters. Several studies proposed alternative therapies targeting different mechanisms in addition to phosphodiesterase-5 inhibition for ED treatment, since some patients do not respond to these drugs. This review highlights complementary and possible coordinated roles for these mediators and treatments targeting these gasotransmitters in erectile function/ED.
... The biochemical properties of resveratrol (3,4,5 trihydroxytrans-stilbene) -bioflavonoids and natural phytoalexin were investigated and substantiated in clinical settings. [13][14][15][16][17][18]. Their anti-inflammatory, disagreggative, antioxidant activity have been proved, which proves the feasibility of its practical application in the food industry as a dried vegetable concentrates of fruits and berries, where the aforementioned bioflavonoid is present [19,20]. ...
Article
It is suggested to perfect technology of production of emulsive foodstuffs, as most consumed by all groups of population of Ukraine, by introduction to compounding of secondary wastes of exit-juice production and vine making as dry concentrates. Such method of enriching of foodstuffs will allow to bring down the deficit of necessary micro- and macronutrients, biologically active substances, and also to bring down indexes on the number of peroxide in the process of storage of low-caloric sauces due to being of natural antioxidants in powdered plant and vegetable material. Experiments were conducted for determination of micro- and macroelement composition and content of sum of polyphenolic substances samples of powdered plant and vegetable material. Samples with the optimal above-mentioned indexes were revealed and samples for the next stage of researches were chosen. The data plan experiment on the effect of temperature and time storage of powdered vegetable raw materials in the amount polyphenols (% wt) in samples of powdered vegetable raw materials used in the suggested corrections storage term low-calorie sauces based on secondary products of juice and wine manufacturing in recipes and calculations in compounding on productions.It was substantiated the choice of grape skin powder as bioactive addition in the emulsive foodstuffs for health improvment purposes, as a sample that has optimal indexes for micro- and macronutrients composition and maintenance of natural antioxidants of polyphenolic nature.
... The use of chemotherapeutics is known to cause acute toxic effects in multiorgan systems (Kim and Chung ,1999) ( Shin, et al., 2008)There are lots of known and unknown causes for infertility. One of the most common sources of infertility is chemotherapy. ...
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Sperm abnormality toxicity due to Methotrex in male rat rats
... It belongs to a class of polyphenolic compounds called stilbenes (Soleas et al. 1997). The in vivo and in vitro studies have shown that RES predominantly protects spermatocytes against lipid peroxidation, increases testicular sperm numbers and decrease sperm motility (Shin et al. 2008). Resveratrol increased the expression of P450 aromatase, LH-R and StAR genes in rat ovarian granulosa cells, suggesting its possible role in steroidogenesis and luteinization processes (Morita et al. 2012). ...
Article
The steroidogenic acute regulatory protein (StAR) plays a key role in transferring cholesterol across the inner mitochondrial membrane. In this study, the StAR gene was isolated from the gonads of Clarias batrachus. The gene has an open reading frame of 857 bp and encodes 285 amino acids with a predicted molecular weight of 32 kDa. The signalP analysis predicted that StAR would be a non-secreted protein that lacks a signal peptide. The subcellular localization demonstrated that the presence of the StAR protein was higher in mitochondria (41.8%), followed by the nuclear region (37.1%) and cytoplasm (11.1%). The StAR protein was found to interact highly with cyp11a1, followed by the cytochrome P450 family 11 proteins and the START5 domain. The homology modelling revealed that the protein has 4 helices and twisted U-shaped 10 beta sheets numbered from αA to αD and β1 to β10, respectively. Molecular modelling analysis showed that resveratrol and eurycomanone has high binding affinity with the StAR protein. The C. batrachus StAR transcript was found to be expressed exclusively in the gonads, kidney, and liver. These results overall lay a solid foundation for understanding the structure of StAR protein in fish. The identification of 3D structures and binding sites will help in designing a structure-based drug of StAR agonists for the treatment of impaired steroidogenesis. © 2017 The Genetics Society of Korea and Springer-Science and Media
... It belongs to a class of polyphenolic compounds called stilbenes (Soleas et al. 1997). The in vivo and in vitro studies have shown that RES predominantly protects spermatocytes against lipid peroxidation, increases testicular sperm numbers and decrease sperm motility (Shin et al. 2008). Resveratrol increased the expression of P450 aromatase, LH-R and StAR genes in rat ovarian granulosa cells, suggesting its possible role in steroidogenesis and luteinization processes (Morita et al. 2012). ...
Article
The steroidogenic acute regulatory protein (StAR) plays a key role in transferring cholesterol across the inner mitochondrial membrane. In this study, the StAR gene was isolated from the gonads of Clarias batrachus. The gene has an open reading frame of 857 bp and encodes 285 amino acids with a predicted molecular weight of 32 kDa. The signalP analysis predicted that StAR would be a non-secreted protein that lacks a signal peptide. The subcellular localization demonstrated that the presence of the StAR protein was higher in mitochondria (41.8%), followed by the nuclear region (37.1%) and cytoplasm (11.1%). The StAR protein was found to interact highly with cyp11a1, followed by the cytochrome P450 family 11 proteins and the START5 domain. The homology modelling revealed that the protein has 4 helices and twisted U-shaped 10 beta sheets numbered from αA to αD and β1 to β10, respectively. Molecular modelling analysis showed that resveratrol and eurycomanone has high binding affinity with the StAR protein. The C. batrachus StAR transcript was found to be expressed exclusively in the gonads, kidney, and liver. These results overall lay a solid foundation for understanding the structure of StAR protein in fish. The identification of 3D structures and binding sites will help in designing a structure-based drug of StAR agonists for the treatment of impaired steroidogenesis.
... Recent studies in animal models have demonstrated that resveratrol has a positive effect on the hypothalamic-pituitary-gonad axis, as well as blood testosterone levels, sperm production, and sperm motility [21,22]. Furthermore, resveratrol may decrease germ cell apoptosis [18,23]. ...
Article
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Background: It is known that a multitude of factors may lead to male factor infertility, but still, in the majority of cases, the cause remains largely idiopathic, reflecting poor understanding of the basic process of spermatogenesis and the mechanisms involved. Resveratrol is a polyphenol compound that displays several cellular aspects mainly associated with SIRT1-pathway activation and promotion of mitochondrial enhancer activities. In several animal models, resveratrol has shown positive effects on mitochondria and membrane potential. This could explain effects on sperm concentration and motility. The aim of this study is to evaluate the effects on the semen parameters of GENANTE®, a multivitamin supplement containing 150 mg of resveratrol/day, in patients with idiopathic infertility. Methods: This was a prospective single center clinical study. Twenty patients took a multivitamin supplement based on 150 mg of resveratrol (GENANTE®), in the form of an oral tablet every 12 h, and were followed up at 1, 3, and 6 months after treatment. Pre- and post-treatment evaluation included history, clinical examination, semen analysis, hormonal determinations, and scrotal and prostatic ultrasound. Results: Our preliminary pilot study demonstrated that the multivitamin supplement based on resveratrol improves sperm motility (48.3% ± 13.8 vs. 59.0% ± 12.8, p = 0.0001) and concentration (22.6×106/mL ± 9.5 vs. 25.7×106/mL ± 8.1, p = 0.0001) after 3 and 6 months of treatment in men with idiopathic infertility. Conclusion: Our data suggest that targeting the metabolic and energetic pathways involved in spermatogenesis and mitochondrial activity could lead to potential effects and counteract subfertility/infertility in men through a mitochondria dynamics mechanism. Trial registration number: ClinicalTrials.gov registration identifier: NCT03864198, registered on 1 January 2019.
... The use of chemotherapeutics is known to cause acute toxic effects in multiorgan systems (Kim and Chung ,1999) ( Shin, et al., 2008)There are lots of known and unknown causes for infertility. One of the most common sources of infertility is chemotherapy. ...
... Animal studies using Resveratrol have reported its antitumor, antidepressant and antidiabetic effects (8)(9)(10). In vivo study showed that Resveratrol can improve sperm count and sperm quality, improve testosterone levels and also prevent sperm DNA damage resulting from cryopreservation in humans (11). ...
Article
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Background Cisplatin is a potent antineoplastic agent for many cancers but causes several levels of gonadal damage. Ovarian toxicity is a major concern of young cancer patients undergoing chemotherapy. Objective This study sought to examine the effect of Cisplatin and Resveratrol supplementation on ovarian function in Sprague-Dawley rats. Materials and Methods In this experimental study, 45 cyclic Sprague-Dawley rats with an average weight of 160 gr were divided into 9 groups (n=5/group). Group 1 was used as control and received distilled water. Groups 2 and 9 received Cisplatin only. Groups 3, 4, and 5 received different doses of Resveratrol after a single dose of Cisplatin. Groups 6, 7, and 8 received Resveratrol before Cisplatin. At sacrifice, the ovary was analyzed for histopathology, biochemical indices of oxidation and hormonal assay. Results Relative and absolute organ weights were notably increased (p=0.001, 0.01) in the prophylactic groups relative to the groups that received Resveratrol after Cisplatin. Also, glutathione, superoxide dismutase and catalase were significantly increased (p=0.047, 0.01, 0.023) in a dose-dependent manner when compared to Cisplatin group only. Malondialdehyde decreased significantly (p=0.001) in the groups that received high dose Resveratrol compared with the control and Cisplatin alone groups. Although oestrogen showed no significant difference within the groups (p=0.48), Resveratrol significantly increased progesterone, follicle stimulating hormone and luteinizing hormone levels (p=0.007, 0.001, 0.006) at high doses when compared with Cisplatin alone groups. Ovarian histoarchitecture was best preserved in the prophylactic groups in a dose-dependent manner. Conclusion Resveratrol supplementation confers protection and preserves ovarian follicles from Cisplatin toxicity in Sprague-Dawley rats.
... Along with the neuroprotective and cardioprotective impacts of resveratrol, it also exhibits powerful anti-inflammatory and cytoprotective impacts preventing the tumour cell proliferation and inhibiting or postponing the onset of chronic diseases (Baur & Sinclair, 2006). It has been determined that sperm quality and output are enhanced by resveratrol in mice (Shin et al., 2008). Resveratrol has been identified to be the main active compound of stilbene phytoalexins, and it is believed to have beneficial impacts on health (Frèmont, 2000), due to its scavenger capacities against ROS, in particular. ...
... Thus, while the discordant viewpoints on the reproductive/gonadal research topic will certainly continue in reference to soy/isoflavonoid exposure, and is most likely dependent on the animal model/strain tested, dosage administered and compound(s) examined, the present data are more in line with the actions of the polyphenolic molecule, resveratrol that appears to have positive benefits on sperm quality and spermatogenesis (even after testicular injury) (Jiang, Peng, Luo, Li, & Lin, 2008;Shin et al., 2008). ...
... 20 Resveratrol elicited a concentration-dependent relaxing effect on the corpus cavernosum and an increase in blood testosterone concentration in a rabbit model. 26 Resveratrol might be an effective treatment in the prevention of atherosclerotic changes in the corpus cavernosum of hypercholesterolemic rabbits. 27 The intracellular cGMP level was elevated by resveratrol treatment in human corpus cavernosal smooth muscle cells. ...
Article
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Introduction: Phosphodiesterase type 5 inhibitors (PDE5i) are first-line therapy for most men with erectile dysfunction (ED). If ineffective, vacuum erection devices, intracavernous injections, and penile prosthesis implantation are suitable as second- or third-line therapies. However, very few patients select these therapies. It is critically important to improve erectile function with oral administration of effective agents. Administration of L-citrulline or transresveratrol in animal experiments has been reported to improve erectile function, but few such experiments have been performed on humans with ED. Aim: We aimed to investigate the efficacy of combination therapy of L-citrulline and transresveratrol in patients with ED despite their use of PDE5i. Methods: In this randomized, double-blind, placebo-controlled crossover pilot study, men with ED (Sexual Health Inventory for Men [SHIM] score below 16) despite on-demand use of PDE5i received a placebo for 1 month or the active treatment (L-citrulline 800 mg/day and transresveratrol 300 mg/day) for another month. Patients continued on-demand use of PDE5i. Main outcome measure: The SHIM score, Erection Hardness Score (EHS), Aging Male Symptoms Scale-sexual domain (AMS-SD), and adverse events were examined. Results: 20 patients ages 29-78 years were enrolled, and after 6 men withdrew, 13 concluded the study without adverse events. Mean SHIM score for the active treatment increased significantly (10.96 ± 1.21) compared with baseline (8.32 ± 1.21) and placebo (8.31 ± 1.23) (both P < .05). Mean EHS score for the active treatment (2.56 ± 0.26) also increased from baseline (2.31 ± 0.26), but not significantly (P = .79). Mean AMS-SD score was not significantly different in either group. Conclusion: To our knowledge, this is the first study to show that combination therapy of L-citrulline and transresveratrol is effective for ED treatment in men with added on-demand use of PDE5i. This combination supplement may be added if PDE5i is insufficient. Shirai M, Hiramatsu I, Aoki Y, et al. Oral L-citrulline and Transresveratrol Supplementation Improves Erectile Function in Men With Phosphodiesterase 5 Inhibitors: A Randomized, Double-Blind, Placebo-Controlled Crossover Pilot Study. Sex Med 2018;XX:XXX-XXX.
... This seems to be possible thanks to its capacity to pass through the blood-testis barrier, imparting its protective effects in the testis [81]. Resveratrol administration was shown to: (1) decrease germ cell apoptosis [82,83], (2) trigger penile erection [82,83], (3) enhance serum testosterone concentration [82,83], and (4) improve sperm quality and epididymal sperm number [84]. These different actions of resveratrol on the male reproductive system resulted from a direct stimulation of the hypothalamic-pituitary-gonadal axis, with no adverse effects on testes [73]. ...
Article
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Resveratrol is one of the most investigated natural polyphenolic compounds and is contained in more than 70 types of plants and in red wine. The widespread interest in this polyphenol derives from its antioxidant, anti-inflammatory and anti-aging properties. Several studies have established that resveratrol regulates animal reproduction. However, the mechanisms of action and the potential therapeutic effects are still unclear. This review aims to clarify the role of resveratrol in male and female reproductive functions, with a focus on animals of veterinary interest. In females, resveratrol has been considered as a phytoestrogen due to its capacity to modulate ovarian function and steroidogenesis via sirtuins, SIRT1 in particular. Resveratrol has also been used to enhance aged oocyte quality and as a gametes cryo-protectant with mainly antioxidant and anti-apoptotic effects. In males, resveratrol enhances testes function and spermatogenesis through activation of the AMPK pathway. Furthermore, resveratrol has been supplemented to semen extenders, improving the preservation of sperm quality. In conclusion, resveratrol has potentially beneficial effects for ameliorating ovarian and testes function.
... Supplementation of RSV (10 mg/ kg/day for 28 days) to nicotine-treated Wistar rats reversed contractile activity of the bladder and corpus cavernosum strips impairments (Toklu 2010). Other reports have shown that RSV downregulated the expression of PDE5, p53 and FOXO3a, which regulate apoptosis and oxidative stress and contrarily increased blood testosterone level, expression of nNOS, eNOS, cavernous cyclic guanosine monophosphate (cGMP) and SIRT1, an activator of mitochondrial biogenesis and thus, restored erectile function in experimental animals with diabetes (Bai and An 2015;Sener et al. 2018;Shin et al. 2008;Wen Yu et al. 2013). As we have described above, physiological diseases are closely linked to mitochondrial dysfunction. ...
Article
Plants produce a number of biological active substances with healthy benefits. Resveratrol (3,5,4′-trihydroxystilbene), a polyphenol produced by plants has been associated with many health beneficial properties, including its ability to induce mitochondrial biogenesis and fight against health problems such as obesity, inflammation, heart diseases, cancers among others. Mitochondrial dysfunction is recognized as central to the pathogenesis and development of many diseases. Thus the present review describes how resveratrol (RSV) may counteract physiological and age-related diseases/disorders through its effect on mitochondrial biogenesis and function. In addition, we discuss the chemistry, main sources, and the doses of RSV shown in previous studies to be efficient for the prevention and treatment of different diseases. Through its ability to improve mitochondrial dysfunction, RSV can be used in the prevention and/or treatment of human physiological diseases. However, more research for optimal dose in a human scale is still relevant. This review brings new hope to the therapy of physiological diseases as it will provide useful future perspectives for the planning of clinical studies on RSV and mitochondrial dysfunction-related diseases.
... Administration of metformin to rodents (for 4 or 8 weeks) does not affect the mean sperm count or motility, or percentage of abnormal sperm. In contrast, the ingestion of resveratrol, another AMPK activator, for 28 days results in increases to all of testosterone levels, sperm count and motility (Shin et al., 2008). In rat primary Sertoli cells, AMPK activation by AICAR or adenosine increases lactate production implicating AMPK in the modulation of the nutritional function of Sertoli cells (Galardo et al., 2007Galardo et al., 2010. ...
... Resveratrol (3, 4, 5 trihydroxystilben) is a high-concentration phytoalexin that occurs naturally; and is found in berries, nuts, and medicinal plants; and in grape skin and red wine, in particular [8]. In addition, supplementation with resveratrol can cause an erection of the penis and increase levels of blood testosterone, sperm count, and epididymal sperm motility [10]. Additionally, it has been shown that spermatogenesis is enhanced by stimulating the hypothalamic-pituitary-gonadal axis with resveratrol, with no unfavorable effects [11]. ...
Article
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We evaluated immobilization stress and resveratrol supplementation in immature male mice at 30 days of age for 15 consecutive days. Fifty Swiss mice were divided into five groups (10 mice each): Controls, restraint stress (RS), restraint stress + vehicle (RS + V), RS + 2 mg/kg, and RS + 20 mg/kg. We determined results on the basis of hematoxylin and eosin (H&E), “Periodic acid-Schiff” staining, and TUNEL assay. The results indicated that immobilization stress significantly decreased body weight, testis weight, and water/food intake compared to the control; while resveratrol ameliorated these effects. The quantitative histologic evaluation of the seminiferous tubule diameter, luminal diameter, area of seminiferous tubules, area of tubule lumen, epithelial height, Leydig cell number, and the width of the tunica albuginea were similarly decreased after exposure to RS. These parameters recovered back to normal in the RS + 2 mg/kg group. The development of spermatogenesis was significantly delayed in the RS, RS + V, and RS + 20 mg groups based upon our evaluation score system. However, we observed no significant differences in the RS + 2 mg group compared with the control group. The number of TUNEL-positive cells also significantly decreased in the RS + 2 mg/kg group. In conclusion, we found that the administration of 2 mg/kg was an effective dose against immobilization stress in mice.
... Resveratrol can affect the secretion of steroid hormones. For example, Shin et al. (27) reported that trans-resveratrol supplementation increased the testosterone levels in mice. Others reported that resveratrol also significantly increased natural testosterone production due to being both a selective estrogen receptor modulator (28,29) and an aromatase inhibitor (30). ...
Article
To analyze the potential beneficial effects and mechanisms of action of resveratrol on the maturation of bovine oocytes that were incubated in different concentrations of resveratrol (0.1, 1.0, or 10.0 μM) as germinal vesicle-stage oocytes. In vitro prospective study. University research laboratory. Animal models for human studies. In vitro culture in the presence of various concentrations of the antioxidant resveratrol. Parameters of hormone levels, oocyte nuclear maturation, cumulus expansion, levels of intracellular glutathione and reactive oxygen species, embryonic cleavage, blastocyst formation, gene expression associated with mature bovine oocytes and cumulus cells, and level of sirtuin 1 gene expression. Resveratrol statistically significantly increased progesterone secretion and decreased estradiol-17β secretion by cumulus cells. The elevated levels of progesterone activated the Mos/MEK/p42 mitogen-activated protein kinase (MAPK) cascade in the oocytes. At a concentration of 1.0 μM, resveratrol statistically significantly improved cumulus expansion, polar body formation, the (hatched) blastocyst rate, and the mean number of cells/blastocysts. Meanwhile, resveratrol statistically significantly reduced the level of reactive oxygen species (ROS) and increased the level of glutathione (GSH). For the first time, the expression of the sirtuin-1 gene was identified in granulosa cells, cumulus cells, oocytes, and blastocysts. Further studies revealed that resveratrol promoted sirtuin-1 gene expression. Resveratrol promoted bovine oocyte maturation and subsequent post-in vitro fertilization embryonic development by inducing progesterone secretion and an antioxidant effect, probably in a manner dependent on sirtuin-1.
... Resveratrol is a polyphenol with antioxidant activity that was found in the peanuts, grapes and red wine (Collodel et al., 2011). It was shown that its administration has a positive effect on sperm production and motility in animal models Shin et al., 2008). Its protective effect against DNA fragmentation induced by a cryopreservation procedure of human spermatozoa has recently been observed . ...
Conference Paper
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Freezing and thawing procedures of human spermatozoa trigger the excessive production of reaction oxygen species (ROS) that cause damage to spermatozoa. Resveratrol, a natural polyphenol, produced from several plants is being envisioned as a valuable antioxidant that prevents DNA damage. The aim of this study was to analyze the effect of resveratrol supplementation into cryopreservation medium on the motility and DNA fragmentation of human spermatozoa after freezing-thawing procedure. Semen was collected from 26 normozoospermic (N) patients. All samples were cryopreserved in nitrogen vapour after ten minutes incubation. After one week samples were thawed and sperm motion was measured. Using the Sperm Chromatin Structure Assay (SCSA), the number of DNA fragmented sperm, expressed as DNA fragmentation index (DFI) was evaluated in each sample. The addition of 0.01 mM resveratrol into cryopreservation medium have lead to better motility in 81% of the studied patients. The number of progressive spermatozoa in the samples with resveratrol was significantly higher compared with the control semen samples measured after the thawing procedure (25.45 ± 12.65 vs. 15.75 ± 9.65, respectively). The impact of resveratrol on DNA fragmentation of investigated spermatozoa was relatively small and led to insignificant change in the DFI. However, in 63% of the patients the addition of resveratrol had a positive effect and resulted in lower DFI in comparison with the control semen samples. In conclusion, the supplementation of 0.01 mM resveratrol significantly improves the post-thawed human spermatozoa progressive motility and decreases the level of DNA fragmentation.
Article
Busulfan (Bus), is an alkylating agent widely used in chemotherapy which has been proven to possess toxic side effects on testicles. This study was carried out to compare the probable treatment effects of resveratrol (Res) or/and l-carnitine (Lca), as strong antioxidants, on the testicular tissue as well as on the level of sex hormones in busulfan-induced azoospermic rat models. A total of 78 adult male rats, were divided into six different experimental groups including: 1) Control; 2) Lca + Res; 3) BUS; 4) Bus + Lca; 5) BUS + Res and 6) Bus + Lca + Res. Busulfan was intraperitoneally administered in a single dose (10 mg/kg b.w), while resveratrol (20 mg/kg b.w/day) and l-carnitine (200 mg/kg b.w/day) were orally administered by gavage during 48 consecutive days to the rats. At the end of the experiment in all groups the level of LH, FSH, and testosterone were biochemically analyzed by ELISA and the testicular tissue evaluated histologically using stereological technique. Results showed that Lca or/and Res, increased the body and testis weight, the volume of the testis, interstitial tissue, germinal epithelium, and seminiferous tubule, the number of the different cells of germinal epithelium and the level of testosterone. On the other hand, Lca, Res and their combination decreased the concentration of LH and FSH compared to the group treated with Bus. In conclusion, these results suggested that l-carnitine or/and resveratrol treatment significantly attenuated busulfan -induced changes of the rat reproductive system led to the recovery of both testis and sperm parameters. However, co-administration of L-ca and Res was more effective than their individual treatment. This combination may alleviate the side effects of alkylating drugs, such as busulfan and may be beneficial for spermatogenesis.
Article
The present study aimed to evaluate the effect of trans-Resveratrol on spermatogenesis. Male Kunming suckling mice (10 days old) were surgically rendered cryptorchid and subcutaneously injected with trans-Resveratrol at doses of 5, 10, 20, and 40 µg/g/day as groups I, II, III, and IV, respectively, for 35 days. Animals in the control group received 10 µL/mouse/day of olive oil. Serum estradiol, testosterone, FSH, and LH levels were measured on day 45. Tissue analysis and sperm morphological abnormalities analysis were done. Results showed that in the control group and group I only spermatogonia and primary spermatocytes were present, whereas spermatogenesis was totally restored in groups II, III, and IV. Sperm counts in groups III and IV were remarkably higher than the control group (P < 0.05). The morphological abnormalities in resveratrol-treated groups were higher than the mature mice. Serum estradiol levels in the resveratrol-treated groups were not significantly different from the control group, but were lower than the mature mice (P < 0.05). There was no significant difference in serum testosterone levels between the resveratrol-treated groups and mature mice, but the levels in the resveratrol-treated groups was significantly lower than the control group (P < 0.05). No significant influence of trans-Resveratrol was observed on serum FSH levels in all cryptorchid mice. Serum LH levels in groups I, II, and III were higher than the control group. These results indicate that trans-Resveratrol restores spermatogenesis in cryptorchid mice. In addition, proteomic analysis between the 20 μg/g/day resveratrol-treated group and the control group was carried out, and five kinds of proteins (BAF250, ZFP261, CHD1L, RBBP9, and SOHLH2) were identified. The expression of SOHLH2 increased, while that of BAF250, ZFP261, CHD1L, and RBBP9 decreased in the 20 µg/g/day resveratrol-treated group, indicating that SOHLH2 may contribute to testicular germ cell differentiation.
Article
This study aimed to observe the possible protective effects of resveratrol (RSV) against the damage of di-n-butyl phthalate (DBP) on the testis. The study was conducted in 6 groups of rats with 6 animals in each group aged 20 days. The groups include group 1: control group; group 2: solvent (carboxymethylcellulose (CMC), 10 ml/kg); group 3: 500 mg/kg/day DBP; group 4: 500 mg/kg/day DBP + 20 mg/kg/day RSV; group 5: 1000 mg/kg/day DBP; and group 6: 1000 mg/kg/day DBP + 20 mg/kg/day RSV. Groups were treated by gavage for 30 days. Indirect immunohistochemical staining was performed with c-kit, AT1, and ER-α antibodies. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) method was used for apoptosis. It was found in the DBP-applied groups the C-kit immunostaining, which is parallel to increasing dose, decreased in comparison with the control. C-kit reactivity was similar to that of the control group in the group applied with 500 mg/kg/day + RSV; however, the reactivity was not same in the 1000 mg/kg/day DBP-applied group. It was observed that the reactivity of AT1 increased in the DBP-applied groups. RSV reversed these changes with its protective effects. While there was not much difference between the groups in terms of estrogen receptor reactivity, it was observed that the high dose of DBP reduced the level of estrogen receptor and the resveratrol was not at enough levels in all doses. In TUNEL analysis, high doses of DBP increased the apoptosis in all types of cells; nevertheless, the resveratrol application decreased the apoptosis in the low-level DBP dose. In the statistical analysis, while the length of epithelium and the diameter of seminiferous tubules decreased for all the other groups, it reverted to its original state in the RSV-applied groups. In conclusion, DBP (with increasing dose) administration caused cycle and hormonal changes in testis, resveratrol were recovered the cyclic changes but in hormonal changes, RSV is efficient too but inadequate.
Article
To investigate the effect of resveratrol (RES) on methotrexate (MTX)-induced testicular damage. RES (10mg/kg/day) was given for 8days orally and MTX (20mg/kg i.p.) was given at day 4 of the experiment, with or without RES in rat. MTX decreased serum testosterone, induced histopathological testicular damage, and increased testicular tumor necrosis factor-α level and expression of nuclear factor-κB and cyclooxygenase-2. In MTX/RES group, significant reversal of these parameters was noticed, compared to MTX group. Testicular expression of multidrug resistance protein (Mrp) 3 was three- and five-folds higher in RES- and MTX/RES-treated groups, respectively. In vitro, using prostate cancer cells, each of MTX and RES alone induced cytotoxicity with IC50 0.18±0.08 and 20.5±3.6μM, respectively. RES also significantly enhanced cytotoxicity of MTX. Thus, RES has dual beneficial effects, as it promotes MTX tumor cytotoxicity, while protecting the testes, probably via up-regulation of testicular Mrp3 as a novel mechanism. Copyright © 2014 Elsevier Inc. All rights reserved.
Article
Present study analyzed the effect of naringenin, a bioflavonoid, on male reproductive function in adult mouse, after intra-peritoneal treatment with varying concentrations of naringenin (2, 8 and 20mg/kg b.wt.) for two weeks. Naringenin increased the generation of reactive oxygen species and lipid peroxidation in the testis with concomitant decrease in sperm count and motility in a dose dependent manner. Activities of antioxidant enzymes catalase, superoxide dismutase, glutathione peroxidase and levels of reduced glutathione were found to be decreased in a dose dependent manner. Also, the levels of oxidized glutathione were increased leading to a shift in redox ratio. Naringenin treatment also led to a dose dependent increase in the mRNA expression of c-jun, c-fos and NF-κB. The testicular histomorphology was also altered dose dependently. Additionally, the number of apoptotic germ cells increased with increasing doses of naringenin as evident from acridine orange/ethidium bromide co-staining and JC-1 staining. In conclusion, our study reveals that naringenin despite being a potent antioxidant with numerous important biological functions may also act as pro-oxidant, thus causing damaging effects in the testicular tissue.
Article
This study was performed to investigate the protective and therapeutic effects of resveratrol (RES) against Aluminium chloride (ALCl3-induced toxicity in rat testes. Six experimental groups of adult male rats were formulated as follows: (A) controls + NS, (B) control + vehicle (saline solution of hydroxypropyl cyclodextrin), (C) RES treated, (D) CdCl2 + NS, (E) CdCl2 + vehicle and (F) ALCl3 + RES treated. At the end of the protocol, serum levels of FSH, LH and testosterone were measured in all groups, and testicular levels of TBARS Glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity were measured. Epididymal semen analysis was performed, and testicular expression of, p53 and Bax was assessed by RT-PCR. Also, the histopathological changes of the testes were examined microscopically. Administration of RES concomitantly with ALCl3 in rats improved semen parameters including count, motility, daily sperm production and morphology, increased serum concentrations of gonadotropins and testosterone, decreased testicular lipid peroxidation and increased SOD and GPx activities. RES not only attenuated ALCl3-induced testicular histopathology but was also able to protect against the onset of cadmium chloride testicular toxicity. ALCl3 upregulated the expression of pro-apoptotic genes p53 and Bax. Resveratrol completely reversed ALCl3 testicular toxicity via down regulation of p53 and Bax gene expression. The data of the current study clearly demonstrates antiapoptotic and antioxidant protective effects of RSE against ALCl3 induced testicular damage.
Article
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The aim of this study was to assess the dose- and time dependent in vitro effects of resveratrol (RES), a natural polyphenol and phytoalexin with potential antiviral, anti-inflammatory and antioxidant properties on bovine spermatozoa during five different time periods (0h, 2h, 6h, 12h and 24h). Semen samples were collected from 20 adult breeding bulls, and diluted in physiological saline solution containing 0.5% DMSO together with 0, 1, 5, 10, 50, 100 and 200 μM/L RES. Spermatozoa motility was examined using the Sperm VisionTM and CASA (Computer Assisted Semen Analyzer) system. Cell viability was measured using the metabolic activity MTT assay, the nitroblue-tetrazolium (NBT) test was used to assess the intracellular superoxide formation. The initial CASA analysis showed no significant changes in the spermatozoa motion parameters, however a motion-promoting effect of 10 and 50 μM/L RES became significant after 2h (P
Article
As physical exercise has been shown to negatively affect sperm morphology, this study was undertaken to assess the effect of a 3-min forced swimming protocol during 50 days, with and without administration of antioxidants [N-acetylcysteine (NAC) and trans-resveratrol], on sperm morphology in CD-1 mice. Forty-four 13-week-old CD-1 mice were randomly allocated to four different groups: mice not submitted to exercise, control group (CG), mice submitted to swimming without administration of antioxidants (EX), mice submitted to swimming that received trans-resveratrol supplementation [exercise group (EX)+Resv] and mice submitted to swimming exercise that received NAC supplementation (EX+NAC). The EX showed 30.5% of spermatozoa with normal morphology, showing significant differences with regard to the CG, which showed 58.5%. The groups receiving antioxidant supplements showed significantly higher percentages of spermatozoa with normal morphology in comparison with the EX group (EX+Resv: 64.1%, EX+NAC: 48.2%). The imposed model of forced swimming caused alterations in sperm morphology. The antioxidants employed seem to be suitable antioxidants for avoiding exercise-associated sperm morphology anomalies in prolonged forced swimming exercise. Trans-resveratrol has proven to be more efficient for this purpose. © 2015 Blackwell Verlag GmbH.
Article
Trans-Resveratrol is a polyphenol found in a variety of plants, including many food items such as grapes, wine and peanuts. Classified as a phytoalexin, resveratrol is produced in response to fungal attack and certain types of stress, including trauma and UV irradiation ....
Thesis
Although diabetes is known to induce male infertility, effective protective strategies to restore gonadal functions are at large. In this study, we investigated the modulatory effects of Resveratrol on diabetes-induced alterations in poly (ADP-ribose) polymerase (PARP) signaling in testicular cells. Adult male Wistar rats (N=6-8) were randomly divided into a) control; b) Resveratrol-treated (5 mg/kg; ip); c) Streptozotocin-induced diabetes; and d) Resveratrol-treated diabetic groups. The Resveratrol and the Resveratrol-treated diabetic groups received the drug (5 mg/kg; ip) starting from day 22-42. All animals were killed on day 42 after the confirmation of diabetes. Resveratrol exacerbated diabetes-induced decreases in body weight gain but did not modulate blood glucose levels either in normal rats or in diabetic rats suggesting the lack protective effects. Resveratrol recovered the diabetes-induced decreases in testis weight, sperm count and motility indicating enhanced spermatogenesis, seminiferous epithelial regeneration and inhibition of cell death. Resveratrol inhibited oxidative stress and the genesis of morphologically abnormal sperm in diabetic rats. Resveratrol inhibited the S-phase of the cell cycle, which led to decreases in DNA synthesis in normal germ cells, but in diabetic rats, the drug restored the DNA synthesis and mitigated DNA base oxidation. However, Resveratrol was unable to completely alleviate the DNA damaging effects of diabetes in germ cells. Diabetes-induced oxidative stress up-regulated total PARP, but down-regulated PARP1 via caspase-3-mediated cleavage. Diabetes with or without Resveratrol did not induce apoptosis inducing factor (AIF) nuclear translocation. These results indicate that diabetes does not induce parthanatos in testis. Although PARP signaling was present in most germ cell types, the primary spermatocytes were the most vulnerable group of cells in the testis possibly due to their duplicated DNA content. In addition, the Sertoli cells, Leydig cells and intra-testicular microvessels also expressed PARP pathway related proteins. In conclusion, the results suggest that Resveratrol supplementation is useful to minimize sperm abnormality, DNA damage and to modulate PARP signaling in diabetic rat testes. In addition, diabetes with or without Resveratrol does not induce parthanatos of testicular cells. It may be ideal to supplement Resveratrol to diabetic patients to recover testicular functions although further studies in humans are needed in this regard.
Article
Resveratrol is a natural grape-derived polyphenol with potent antioxidant properties that protect spermatozoa against lipid peroxidation (LPO) by eradicating free radicals. The objectives of this study were to 1) appraise the effects of Resveratrol in extender on post-thaw quality parameters, antioxidant enzymes, adenosine triphosphate (ATP), DNA fragmentation, LPO and 2) fertilizing capability of buffalo spermatozoa. Semen was collected from four fertility proven bulls with artificial vagina thrice, evaluated initially and diluted in five different extenders containing Resveratrol (T4 = 100 μM, T3 = 50 μM, T2 = 20 μM, T1 = 10 μM), and control (no Resveratrol), and evaluated after post-dilution and post-thawing stage of cryopreservation. Analysis of variance revealed that, there was no difference (P > 0.05) in any parameters due to treatments at post-dilution. At post-thawing. Sperm progressive motility (%), plasma membrane integrity (%), mitochondrial membrane potential (%) and ATP levels (nmol/10⁶) were found higher in semen samples cryopreserved in T3 and 4 than control. Sperm supravital plasma membrane integrity (%) and viable/acrosome integrity were higher in T4 than control and T1. Furthermore, sperm catalase (U/mL), glutathione peroxidase (μM) and superoxide dismutase (U/mL) concentrations were found significantly higher in Resveratrol treated groups compared to control. Conversely, DNA fragmentation (%) and LPO (μM/mL) were significantly decreased in semen samples cryopreserved in T4 in comparison to the control. Fertilizing capability was found higher in T4 as compared to control (%, 77.33 vs. 57.41, P < 0.05). It is concluded that the addition of Resveratrol in extender ameliorates quality parameters, antioxidant enzymes levels and fertilizing capability, and alleviate DNA fragmentation and LPO in buffalo spermatozoa during cryopreservation.
Article
Finasteride is commonly used in the management of alopecia and nodular prostatic hyperplasia. It was reported to have a harmful effect on spermatogenesis with subsequent infertility. Thus, this research was to determine the ameliorative effect of resveratrol against testicular damage caused by finasteride. Forty adult male rats were randomly divided into four main groups: group I acted as the control, group II was administrated resveratrol 20 mg/kg/day, group III was administrated finasteride 5 mg/kg/day, and group IV was administrated finasteride and resveratrol as in the previous groups. Finasteride induced a significant decrement in the testosterone and dihydrotestosterone levels. The level of malondialdehyde significantly increased, while the levels of glutathione peroxidase, superoxide dismutase, and catalase significantly decreased in the finasteride-administrated rats. Variable histopathological alterations in the testes were revealed in the form of irregular seminiferous tubules. Some seminiferous tubules appeared with degenerated germinal epithelium. Others showed detachment of their germinal epithelium. Congested blood vessels and homogeneous acidophilic substance in-between tubules were also detected. A significant decrement in PCNA positive cells and a significant increment in Bax expression were demonstrated. Ultrastructural examination showed Sertoli cells with rarefied cytoplasm. Vacuolated cytoplasm, shrunken nuclei, and dilated perinuclear spaces were also revealed in the spermatogonia, primary spermatocytes, and early spermatids. On the contrary, few changes were noticed in rats received resveratrol concomitant with finasteride. This study indicated that resveratrol exerted a potent ameliorative effect against testicular injury caused by finasteride.
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Resveratrol has gained importance as a naturally available medicine for the prevention of inflammatory and neurodegenerative diseases. In addition to its antioxidant properties, resveratrol also plays a significant role in neuronal differentiation through activation of SIRT1 and SIRT3. However, the receptor-mediated intracellular signal induced by resveratrol is yet to be determined. The mode of action of resveratrol presumably involves transcriptional regulation of the NF-κB family of proteins. It may also interact with the nuclear hormone receptor family, which includes estrogen receptors and vitamin D receptors in the brain. We found that resveratrol-enriched grape extract prevents paraquat-induced damage of hippocampal neurons and has the least effect on hippocampal cell damage. In this review article, we discuss the perspectives on therapeutic efficacy of resveratrol and its mode of action in neuronal cell growth and differentiation following brain inflammation and neurodegeneration.
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Concern about the effect of environmental changes on male reproductive health has grown in recent years to become a major preoccupation in some developed countries. A possible decline in human sperm concentration was suggested in the early seventies following studies in the US. In 1992 a meta-analysis of 61 articles published by Carlsen et al. concluded that the mean sperm count of healthy men had declined by 1% per year over the previous 50 years. From 1995 and onwards, some retrospective, longitudinal analyses of the sperm count of fertile or infertile men contradicted this while others did not. The demonstration of a geographical variation in sperm concentration, between and within countries or regions, appears to be less controversial. The amplitude of the difference observed cannot only be explained by methodological or confounding factors, and must to some extent be attributed to ethnic, genetic or environmental factors. As many of the published studies suffer from imprecision regarding the description of population characteristics and confounding factors, and were not designed with controlled and standardised methodology, the debate remains open. Prospective studies in well-defined cohorts of men in various populations are required to evaluate the potential effect of external factors on male reproductive health. These studies should not be limited to the analysis of sperm concentration, as this may not be the best biomarker of testis function and human fertility.
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trans-Resveratrol was reported to have health benefits including anticarcinogenic effects and protection against cardiovascular disease. One of the mechanisms by which it exerts its action is through modulating the estrogen response systems. Because estrogen is involved in male reproductive biology, we investigated the effect of trans-resveratrol on testis and spermatogenesis. Adult male rats were divided into 2 groups. The treated group was administered by gavage 20 mg/(kg . d) of trans-resveratrol suspended in 10 g/L of carboxymethylcellulose for 90 d, whereas the control group received only carboxymethylcellulose during the same period. The relative weight of testes did not differ between the groups. However, the diameter of the seminiferous tubules was significantly reduced from 437.5 +/- 0.1 mum in the controls to 310.9 +/- 0.1 mum in the resveratrol-treated rats. This decrease was accompanied by a significant increase in tubular density, from 3.20 +/- 0.18 in controls to 6.58 +/- 0.18 tubules/mm(2) in the treated group. Moreover, sperm counts were significantly greater in the resveratrol-treated rats (24.8 +/- 3.30 x 10(7)) than in the control group (14.1 +/- 0.80 x 10(7)), but sperm quality did not differ. Serum concentrations of gonadotrophins and testosterone were significantly higher in the resveratrol-treated group. We identified a novel activity of trans-resveratrol. The daily oral administration of this phytochemical to adult male rats enhanced sperm production by stimulating the hypothalamic-pituitary-gonadal axis, without inducing adverse effects.
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The mammalian testis serves two main functions: production of spermatozoa and synthesis of steroids; among them estrogens are the end products obtained from the irreversible transformation of androgens by a microsomal enzymatic complex named aromatase. The aromatase is encoded by a single gene (cyp19) in humans which contains 18 exons, 9 of them being translated. In rats, the aromatase activity is mainly located in Sertoli cells of immature rats and then in Leydig cells of adult rats. We have demonstrated that germ cells represent an important source of estrogens: the amount of P450arom transcript is 3-fold higher in pachytene spermatocytes compared to gonocytes or round spermatids; conversely, aromatase activity is more intense in haploid cells. Male germ cells of mice, bank voles, bears, and monkeys express aromatase. In humans, we have shown the presence of a biologically active aromatase and of estrogen receptors (alpha and ss) in ejaculated spermatozoa and in immature germ cells in addition to Leydig cells. Moreover, we have demonstrated that the amount of P450arom transcripts is 30% lower in immotile than in motile spermatozoa. Alterations of spermatogenesis in terms of number and motility of spermatozoa have been described in men genetically deficient in aromatase. These last observations, together with our data showing a significant decrease of aromatase in immotile spermatozoa, suggest that aromatase could be involved in the acquisition of sperm motility. Thus, taking into account the widespread localization of aromatase and estrogen receptors in testicular cells, it is obvious that, besides gonadotrophins and androgens, estrogens produced locally should be considered to be physiologically relevant hormones involved in the regulation of spermatogenesis and spermiogenesis.
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We investigated the effects of fermentation filtrates from Rubus coreanus on the function of the male reproductive system. We performed an ex vivo study to determine if the candidate compounds relax isolated New Zealand white rabbit corpus cavernosum, which were precontracted by phenylephrine (5 x 10(-5) M). The results reveal that the filtrates of the reddish-purple (FRRC) and green (FGRC) R. coreanus exerted concentration-dependent relaxing effects, leading to median effective concentrations of 4.53 mg/mL and >10 mg/mL, respectively. For the in vivo study, male ICR mice were orally administered FRRC or FGRC (100 or 500 mg/kg) for 28 days, and the reproductive organ weights, serum testosterone level, cauda epididymal sperm counts, and motility were analyzed. Both the FRRC and FGRC had no significant effect on the reproductive organ weights; however, FRRC (100 or 500 mg/kg) enhanced testosterone levels and especially sperm counts at the higher dose (500 mg/kg). In comparison, FGRC increased hormone levels and sperm counts at a relatively low dose (100 mg/kg). In summary, it is proposed that the crude fermentation filtrates of ripe R. coreanus have positive effects on the function of the male reproductive system by triggering a penile erection, enhancing serum testosterone levels, and increasing epididymal sperm counts.
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Erection of the penis results from increase in blood flow into the corpora. The blood flows through the corpus spongiosum and glans which increase in volume, whereas the blood becomes trapped in the corpus cavernosum which becomes rigid as the pressure increases. The protrusion of the penis may be aided by relaxation of the retractor penis muscle. The major erectile fibres lie in the pelvic nerve and anti-erectile fibres in the sacral sympathetic outflow. The hypogastric nerves may contain both nerve types but there is considerable species and individual variation. The neurotransmitters mediating erection have yet to be determined. There is some evidence that acetylcholine is involved in the increase in blood flow through the corpus spongiosum but not in the corpus cavernosum. Vasoactive intestinal peptide may also have a role. It is possible that these and other substances interact to control the complete process. Erection is inhibited by noradrenaline released from sympathetic nerves, and this acts mainly on alpha-1 adrenoceptors within the penis and on the retractor penis muscle. During tumescence blood flows into the sinusoids from the helicine arterioles which supply them. The sinusoids become dilated due to relaxation of smooth muscle within the trabeculae. Blood may also be redirected from anastomoses between the dorsal arteries and corpus spongiosum through other helicine arterioles supplying the sinusoids of the corpus cavernosum. The significance of polsters (smooth muscle projections into the blood vessel lumen) remains controversial. Occlusion of venous drainage from the corpora cavernosa is both passive (due to increased corpus cavernosum pressure) and active. Relaxation of trabecular smooth muscle may also modify blood flow through the corpora cavernosa.
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Zona-free hamster oocytes were used to evaluate the penetrating capacity of spermatozoa recovered from the caput, corpus and cauda segments of 5 human epididymides. The ability of spermatozoa to bind tightly to oocytes increased in spermatozoa from successive segments. However, only spermatozoa recovered from the cauda epididymidis were able to penetrate the oocytes (26%). These results suggest that, in man, a gradual process of sperm maturation occurs in the epididymis, as has been observed in numerous other species of mammals.
1. Both resveratrol and quercetin dose-dependently inhibited the contractile response to noradrenaline (NA) in isolated endothelium-intact rat aorta. This inhibitory effect on vascular contraction was blocked by pretreatment of the blood vessel with the nitric oxide (NO) synthase inhibitor, L-NNA (1 microM). 2. Quercetin at a concentration > 1 x 10(-5) M, and resveratrol at > 3 x 10(-5) M, caused relaxation of the phenylephrine (PE) precontracted endothelium-intact aorta, and L-NNA, at 1 x 10(-6) M, reversed the relaxation. 3. At higher concentrations, > 6 x 10(-5) M, resveratrol and quercetin also relaxed the endothelium-denuded aortic rings. However, this effect could not be reversed by the NO inhibitor. 4. It is concluded that resveratrol and quercetin exert both indirect and direct vasodilator effects on the blood vessel by nitric oxide-mediated and non-NO-mediated mechanisms, respectively.
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The phytochemical resveratrol, which is found in grapes and wine, has been reported to have a variety of anti-inflammatory, anti-platelet, and anti-carcinogenic effects. Based on its structural similarity to diethylstilbestrol, a synthetic estrogen, we examined whether resveratrol might be a phytoestrogen. At concentrations (approximately 3-10 microM) comparable to those required for its other biological effects, resveratrol inhibited the binding of labeled estradiol to the estrogen receptor and it activated transcription of estrogen-responsive reporter genes transfected into human breast cancer cells. This transcriptional activation was estrogen receptor-dependent, required an estrogen response element in the reporter gene, and was inhibited by specific estrogen antagonists. In some cell types (e.g., MCF-7 cells), resveratrol functioned as a superagonist (i.e., produced a greater maximal transcriptional response than estradiol) whereas in others it produced activation equal to or less than that of estradiol. Resveratrol also increased the expression of native estrogen-regulated genes, and it stimulated the proliferation of estrogen-dependent T47D breast cancer cells. We conclude that resveratrol is a phytoestrogen and that it exhibits variable degrees of estrogen receptor agonism in different test systems. The estrogenic actions of resveratrol broaden the spectrum of its biological actions and may be relevant to the reported cardiovascular benefits of drinking wine.
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Estrogens have been found to reduce the incidence of cardiovascular disease that has been ascribed in part to an increased expression and/or activity of the vasoprotective endothelial NO synthase (NOS III). Some reports have shown that the level of expression of this constitutive enzyme can be upregulated by estrogens. The current study investigates the molecular mechanism of the NOS III upregulation in human endothelial EA.hy 926 cells. Incubation of EA.hy 926 cells with 17beta-estradiol or the more stable 17alpha-ethinyl estradiol enhanced NOS III mRNA and protein expression up to 1.8-fold, without changing the stability of the NOS III mRNA. There was no enhancement of NOS III mRNA after incubation of EA.hy 926 cells with testosterone, progesterone, or dihydrocortisol or when 17alpha-ethinyl estradiol was added together with the estrogen antagonist RU58668, indicating a specific estrogenic response. Nuclear run-on assays indicated that the increase in NOS III mRNA is the result of an estrogen-induced enhancement of NOS III gene transcription. In transient transfection experiments using a 1.6 kb human NOS III promoter fragment (which contains no bona fide estrogen-responsive element, ERE), basal promoter activity was enhanced 1.7-fold by 17alpha-ethinyl estradiol. In electrophoretic mobility shift assays, nuclear extracts from estrogen-incubated EA.hy 926 cells showed no enhanced binding activity either for the ERE-like motif in the human NOS III promoter or for transcription factor GATA. However, binding of transcription factor Sp1 (which is essential for the activity of the human NOS III promoter) was significantly enhanced by estrogens. These data suggest that the estrogen stimulation of the NOS III promoter could be mediated in part by an increased activity of transcription factor Sp1.
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We estimated the incidence of erectile dysfunction in men 40 to 69 years old at study entry during an average 8.8-year followup, and determined how risk varied with age, socioeconomic status and medical conditions. Data from a randomly sampled population based longitudinal study of Massachusetts men were analyzed. A total of 1,709 men completed the baseline interview during 1987 to 1989 and 1,156 survivors completed followup from 1995 to 1997. The analysis sample consisted of 847 men without erectile dysfunction at baseline and with complete followup information. Erectile dysfunction was assessed by discriminant analysis of 13 questions from a self-administered sexual function questionnaire and a single global self-rating question. The crude incidence rate for erectile dysfunction was 25.9 cases per 1,000 man-years (95% confidence interval [CI] 22.5 to 29.9). The annual incidence rate increased with each decade of age and was 12.4 cases per 1,000 man-years (95% CI 9.0 to 16.9), 29.8 (24.0 to 37.0) and 46.4 (36.9 to 58.4) for men 40 to 49, 50 to 59 and 60 to 69 years old, respectively. The age adjusted risk of erectile dysfunction was higher for men with lower education, diabetes, heart disease and hypertension. Population projections for men 40 to 69 years old suggest that 17,781 new cases of erectile dysfunction in Massachusetts and 617,715 in the United States (white males only) are expected annually. Although prevalence estimates and cross-sectional correlates of erectile dysfunction have recently been established, incidence estimates were lacking. Incidence is necessary to assess risk, and plan treatment and prevention strategies. The risk of erectile dysfunction was about 26 cases per 1,000 men annually, and increased with age, lower education, diabetes, heart disease and hypertension.
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Studies confirm that male sperm counts are declining, and environmental factors, such as pesticides, exogenous estrogens, and heavy metals may negatively impact spermatogenesis. A number of nutritional therapies have been shown to improve sperm counts and sperm motility, including carnitine, arginine, zinc, selenium, and vitamin B-12. Numerous antioxidants have also proven beneficial in treating male infertility, such as vitamin C, vitamin E, glutathione, and coenzyme Q10. Acupuncture, as well as specific botanical medicines, have been documented in several studies as having a positive effect on sperm parameters. A multi-faceted therapeutic approach to improving male fertility involves identifying harmful environmental and occupational risk factors, while correcting underlying nutritional imbalances to encourage optimal sperm production and function.
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Sildenafil has had a revolutionary impact on the medical, societal, and economic aspects of erectile dysfunction. The author reviews the clinical trial and field experience with respect to the efficacy and safety of this drug. It is clear that early in the new millenium, erectile dysfunction will not only be effectively treated, it may even be prevented.
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This review is designed to help the reproductive endocrinologist integrate his or her professional activity with those of other disciplines including urology, radiology, neurology, and psychology in order to successfully manage all of the inseparable aspects of male sexual and reproductive functioning. Significant advances in the field of male sexual physiology and pathophysiology and new methods of investigation and treatment of male sexual disorders are outlined. The review synthesizes available data on the following: norms of sexual organs, aging and sexuality, role of central and peripheral neurochemicals in each stage of the sexual cycle, role of corporeal smooth muscles in the hemodynamic control of erection and detumescence, influence of psychological factors, drugs, and disease on all aspects of sexual functioning, and use of nocturnal penile tumescence monitoring, imaging investigations, and neurophysiologic studies in the diagnostic workup of males with sexual dysfunction. Clinical algorithms are presented where appropriate. Extensive discussions on newly developed strategies in psychological and behavioral counseling, drug therapy, tissue engineering, nonsurgical devices, and surgical treatments for all forms of sexual disorders are also provided. Lastly, the effect of sexual dysfunction and its treatment on quality of life in affected men is addressed, along with recommendations for future research endeavors.
Article
Concern about the effect of environmental changes on male reproductive health has grown in recent years to become a major preoccupation in some developed countries. A possible decline in human sperm concentration was suggested in the early seventies following studies in the US. In 1992 a meta-analysis of 61 articles published by Carlsen et al. concluded that the mean sperm count of healthy men had declined by 1% per year over the previous 50 years. From 1995 and onwards, some retrospective, longitudinal analyses of the sperm count of fertile or infertile men contradicted this while others did not. The demonstration of a geographical variation in sperm concentration, between and within countries or regions, appears to be less controversial. The amplitude of the difference observed cannot only be explained by methodological or confounding factors, and must to some extent be attributed to ethnic, genetic or environmental factors. As many of the published studies suffer from imprecision regarding the description of population characteristics and confounding factors, and were not designed with controlled and standardised methodology, the debate remains open. Prospective studies in well-defined cohorts of men in various populations are required to evaluate the potential effect of external factors on male reproductive health. These studies should not be limited to the analysis of sperm concentration, as this may not be the best biomarker of testis function and human fertility.
Article
Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents, but also by visual, olfactory, and imaginary stimuli. The reflex involves both autonomic and somatic efferents and is modulated by supraspinal influences. Several central transmitters involved in the erectile control have been identified. Dopamine, acetylcholine, nitric oxide (NO), and peptides, such as oxytocin and adrenocorticotropic/alpha-melanocyte-stimulating hormone, seem to have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory. Peripherally, the balance between contractant and relaxant factors controls the degree of contraction of the smooth muscle of the corpora cavernosa and determines the functional state of the penis. Noradrenaline contracts both corpus cavernosum and penile vessels via stimulation of alpha(1)-adrenoceptors. Neurogenic NO is considered the most important factor for relaxation of penile vessels and corpus cavernosum. The role of other mediators released from nerves or endothelium has not been definitely established. Erectile dysfunction (ED) may be due to inability of penile smooth muscles to relax. This inability can have multiple causes. However, patients with ED respond well to the pharmacological treatments that are currently available. The drugs used are able to substitute, partially or completely, the malfunctioning endogenous mechanisms that control penile erection. Most drugs have a direct action on penile tissue facilitating penile smooth muscle relaxation, including prostaglandin E(1), NO donors, phosphodiesterase inhibitors, and alpha-adrenoceptor antagonists. Dopamine receptors in central nervous centers participating in the initiation of erection have been targeted for the treatment of ED. Apomorphine, administered sublingually, is the first of such drugs.
Article
Resveratrol is a phytoestrogen naturally found in grapes and is a major constituent of wine thought to exert both cardioprotective and chemopreventive activities. Recent studies show that this bioflavonoid binds to and activates gene transcription via the estrogen receptor (ER) subtypes ERalpha and ERbeta. Previous studies have focused primarily on the in vitro effects of resveratrol (RES) in estrogen-sensitive tissues or in carcinogenic cell lines, while frequently neglecting to document its potential effects in animal models with intact neuroendocrine systems. However, the present studies were designed to systematically characterize the in vivo effects of RES on reproductive physiology and behavior in adult female rats. In gonadally intact females, RES consumption reduced body weight, disrupted estrous cyclicity, and induced ovarian hypertrophy. However, in ovariectomized females RES (10-1000 microg) injections did not appear to mimic 17 beta-estradiol benzoate (EB)-induced behavioral responses and had no lasting effects on subsequent estrogen sensitivity or sociosexual behavior. The present studies support recent in vitro findings that RES differs from other phytoestrogens by acting as a possible mixed agonist/antagonist, depending on the availability of specific ER isoforms localized in the reproductive tract and brain of the female rat.
Article
Although endothelial nitric oxide synthase (eNOS) is a constitutively expressed enzyme, its expression is regulated by a number of biophysical, biochemical, and hormonal stimuli, both under physiological conditions and in pathology. This review summarizes the recent findings in this field. Shear stress, growth factors (such as transforming growth factor-beta, fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor), hormones (such as estrogens, insulin, angiotensin II, and endothelin 1), and other compounds (such as lysophosphatidylcholine) upregulate eNOS expression. On the other hand, the cytokine tumor necrosis factor-alpha and bacterial lipopolysaccharide downregulate the expression of this enzyme. The growth status of cells, the actin cytoskeleton, and NO itself are also important regulators of eNOS expression. Both transcriptional and posttranscriptional mechanisms are involved in the expressional regulation of eNOS. Different signaling pathways are involved in the regulation of eNOS promoter activity and eNOS mRNA stability. Changes in eNOS expression and activity under pathophysiological conditions and the pharmacological modulation of eNOS expression are subject of a subsequent brief review (part 2) to be published in the next issue of this journal.
Article
We report that NaON=N(O)-X-N(O)=NONa (1), where X is para-disubstituted benzene, hydrolyzes to 2 mol of nitric oxide (NO) with concurrent production of 1 mol of p-benzoquinone dioxime at physiological pH. The reaction is acid catalyzed, with a rate that slows as the substrate concentration is increased. The results demonstrate that a carbon-bound diazeniumdiolate can be quantitatively hydrolyzed to produce NO as the only gaseous nitrogen-containing product. The data also suggest that N-N bond cleavage is the rate-determining step in NO release, since C-N cleavage followed by dissociation of O=N-N=O to two NO molecules cannot be operative in this case. The finding that this oxime can absorb NO in organic media and regenerate it quantitatively at physiological pHs extends the potential pharmacological implications of the carbon-bound diazeniumdiolates.
Article
Estrogens can upregulate endothelial nitric oxide synthase (eNOS) in human endothelial cells by increasing eNOS promoter activity and enhancing the binding activity of the transcription factor Sp1. Resveratrol, a polyphenolic phytoalexin found in grapes and wine, has been reported to act as an agonist at the estrogen receptor. Therefore, we tested the effect of this putative phytoestrogen on eNOS expression in human endothelial cells. Incubation of human umbilical vein endothelial cells (HUVEC) and HUVEC-derived EA.hy 926 cells with resveratrol for 24 to 72 hours upregulated eNOS mRNA expression in a time- and concentration-dependent manner (up to 2.8-fold). eNOS protein expression and eNOS-derived NO production were also increased after long-term incubation with resveratrol. Resveratrol increased the activity of the eNOS promoter (3.5-kb fragment) in a concentration-dependent fashion, with the essential trans-stimulated sequence being located in the proximal 263 bp of the promoter sequence. In addition, eNOS mRNA was stabilized by resveratrol. The effect of resveratrol on eNOS expression was not modified by the estrogen receptor antagonists ICI 182780 and RU 58668. In electrophoretic mobility shift assays, nuclear extracts from resveratrol-incubated EA.hy 926 cells showed no enhanced binding activity of the eNOS promoter-relevant transcription factors Sp1, GATA, PEA3, YY1, or Elf-1. In addition to its long-term effects on eNOS expression, resveratrol also enhanced the production of bioactive NO in the short-term (after a 2-minute incubation). In concert with other effects, the stimulation of eNOS expression and activity may contribute to the cardiovascular protective effects attributed to resveratrol.
Article
Clinical studies have demonstrated that sildenafil citrate (Viagra) is an effective and well-tolerated oral treatment for erectile dysfunction. Despite its established safety profile, concern about its cardiovascular safety persists among some physicians and the general public. This concern has stemmed primarily from sporadic reports of adverse events published in the literature and sensationalized by the media. However, the only absolute contraindication for sildenafil is concurrent use of nitrates. Because sildenafil has been on the market for 4 years and under clinical investigation for even longer, we can now evaluate its long-term safety in men who have been taking the drug for several years. We review this issue from 3 perspectives. First, we reassess the overall safety profile of sildenafil by reviewing the initial controlled clinical trials and open-label studies. We present new data from patients who have been exposed to sildenafil for up to 4.5 years. We also evaluate the results from independent postmarketing studies. Second, we review the cardiovascular-specific results from the clinical trials, long-term extension, and postmarketing studies. Lastly, we review the specific effects on the visual system based on findings from studies conducted during drug development and post marketing.
Article
Serum testosterone levels decline gradually and progressively with aging in men. Many manifestations associated with aging in men, including muscle atrophy and weakness, osteoporosis, reduced sexual functioning, and increased fat mass, are similar to changes associated with testosterone deficiency in young men. These similarities suggest that testosterone supplementation may prevent or reverse the effects of aging. A MEDLINE search was performed to identify studies of testosterone supplementation therapy in older men. A structured, qualitative review was performed of placebo-controlled trials that included men aged 60 and older and evaluated one or more physical, cognitive, affective, functional, or quality-of-life outcomes. Studies focusing on patients with severe systemic diseases and hormone deficiencies related to specific diseases were excluded.
Article
The study tested the effect of red wine on endothelial-type nitric oxide synthase (eNOS) expression and eNOS activity in human endothelial cells. Endothelial-type nitric oxide (NO) synthase exerts vasoprotective effects. Moderate alcohol consumption has been associated with a reduction of cardiovascular disease, and red wine seems to offer more benefits than any other type of drink. However, the molecular basis of this protective effect is unclear. Human endothelial cells were treated with red wine, and eNOS messenger ribonucleic acid (mRNA) expression was measured by RNase protection assay, eNOS protein expression by Western blotting, and eNOS activity by RFL-6 reporter cell assay. The eNOS promoter activity was analyzed in transfected endothelial cells; binding activities of relevant transcription factors were determined by electrophoretic mobility shift assay. Incubation of endothelial cells with red wines from France upregulated eNOS mRNA and protein expression. In contrast, red wines from Germany showed little or no effect on eNOS expression. No significant difference in eNOS mRNA expression could be detected between "en barrique" (matured in oak barrels) and "non-barrique" (matured in steel tanks)-produced French red wines. Endothelial cells treated with French red wines produced up to three times more bioactive NO than did control cells. French red wines increased the activity of the eNOS promoter, with the essential trans-stimulated sequence being located in the proximal 326 bp of the promoter sequence. The eNOS mRNA stability was also increased by red wine. The increase in eNOS expression and activity brought about by red wines from France (and probably other locations) may contribute to the beneficial effects of this beverage on the cardiovascular system.
Article
Proper functioning of the mammalian testis is dependent upon an array of hormonal messengers acting through endocrine, paracrine, and autocrine pathways. Within the testis, the primary messengers are the gonadotrophins, follicle stimulating hormone and luteinizing hormone, and the androgens. Abundant evidence indicates that the role of the gonadotrophins is to maintain proper functioning of testicular somatic cells. It is the androgens, primarily testosterone, which act through the somatic cells to regulate germ cell differentiation. Despite extensive research in this area, little is known about the cell-specific requirements for androgens and even less is understood about the downstream effectors of androgen signalling. However, recent work using cell-specific ablation of androgen receptor function has demonstrated a clear requirement for androgen signalling at multiple, discrete time points during spermatogenesis. These models also provide useful tools for identifying the targets of androgen receptor activity. The purpose of this review is to provide a brief overview of recent advances in our understanding of hormonal regulation of spermatogenesis, with an emphasis on the role of testosterone within the testis, and to pose important questions for future research in this field.
Article
Epidemiologic studies suggest that low to moderate consumption of red wine is inversely associated with the risk of coronary heart disease; the protection is in part attributed to grape-derived polyphenols, notably trans-resveratrol, present in red wine. It is not clear whether the cardioprotective effects of resveratrol can be reproduced by standardized grape extracts (SGE). In the present studies, we determined, using cultured human aortic smooth muscle cells (HASMC), growth and specific gene responses to resveratrol and SGE provided by the California Table Grape Commission. Suppression of HASMC proliferation by resveratrol was accompanied by a dose-dependent increase in the expression of tumor suppressor gene p53 and heat shock protein HSP27. Using resveratrol affinity chromatography and biochemical fractionation procedures, we showed by immunoblot analysis that treatment of HASMC with resveratrol increased the expression of quinone reductase I and II, and also altered their subcellular distribution. Growth of HASMC was significantly inhibited by 70% ethanolic SGE; however, gene expression patterns in various cellular compartments elicited in response to SGE were substantially different from those observed in resveratrol-treated cells. Further, SGE also differed from resveratrol in not being able to induce relaxation of rat carotid arterial rings. These results indicate that distinct mechanisms are involved in the regulation of HASMC growth and gene expression by SGE and resveratrol.
Article
This study was carried out to monitor the effect of oral supplementation of vitamin C on various semen parameters in oligospermic, infertile, otherwise healthy individuals. Various semen parameters, including sperm motility, sperm count, and sperm morphology, were studied before and after the vitamin C treatment. A total of 13 infertile patients were included. Their ages ranged between 25 and 35 years. They had no genital infection or varicocele. Physical examination and other routine laboratory investigations were normal. General semen analysis revealed oligozoospermia (mean sperm count was 14.3 +/- 7.38 x 10(6) sperms/mL, mean sperm with normal morphology was 43 +/- 7.87%, and mean sperm motility was 31.2 +/- 9.61%). Testicular biopsy was not done. These patients received in an open trial of 1,000 mg of vitamin C twice daily for a maximum of 2 months. Results showed that the mean sperm count was increased to 32.8 +/- 10.3 x 10(6) sperms/mL (P < .001) after 2 months of vitamin C intake. The mean sperm motility was increased significantly to 60.1 +/- 8.47% (P < .001), and mean sperms with normal morphology increased significantly to 66.7 +/- 4.77% (P < .001). This study showed that vitamin C supplementation in infertile men might improve sperm count, sperm motility, and sperm morphology and might have a place as an additional supplement to improve the semen quality towards conception.
Representative findings of the sperms, showing normal feature (upper left), folded tail (upper right), abnormal head angle and shape (lower left) and tail detachment
  • Fig
Fig. 3. Representative findings of the sperms, showing normal feature (upper left), folded tail (upper right), abnormal head angle and shape (lower left) and tail detachment (lower right)
Resveratrol, a polyphenolic compound found in grapes and wine, is a agonist for the estrogen receptor
  • B D Gehm
  • J M Mcandrews
  • P Y Chien
  • B. D. Gehm
Gehm, B. D., McAndrews, J. M., Chien, P. Y., and Jameson, J. L., Resveratrol, a polyphenolic compound found in grapes and wine, is a agonist for the estrogen receptor. Proc. Natl. Acad. Sci. USA, 94, 14138-14143 (1997).
Regulation of proliferation and gene expression in cultured human aortic smooth muscle cells by resveratrol and standardized grape extracts
  • Z Wang
  • Y Chen
  • N Lavinsky
  • T Hsieh
  • Z Ungvari
  • J M Wu
Wang, Z., Chen, Y., Lavinsky, N., Hsieh, T., Ungvari, Z., and Wu, J. M., Regulation of proliferation and gene expression in cultured human aortic smooth muscle cells by resveratrol and standardized grape extracts. Biochem. Biophys. Res. Commun., 346, 367-376 (2006).
Physiological mechanisms regulating the expression of endothelial-type NO synthase
  • H Li
  • T Wallerath
  • U Förstermann
  • H. Li