Glutamine-mediated Modulation of XO/uric acid/NF-kB Signaling Pathway Ameliorates Intestinal I/R-induced Bacterial Translocation and Cardiorenal Inflammatory Injury.

This study explored the effect of intestinal ischaemia/reperfusion (I/R) on cardiorenal tissues. The involvement of xanthine oxidase/uric acid/NF-kB signaling in intestinal I/R was also investigated. In addition, the possible protective effect of glutamine was also evaluated. Twenty-four male Wistar rats were acclimatized and then randomly assigned to four groups (n = 6); sham-operated, glutamine-treated rats (GLUT), I/R, and I/R + GLUT. The sham-operated rats were sham-operated and received 0.5 mL of distilled water, GLUT rats were sham-operated and had 1 g/kg b.w. of glutamine, I/R animals had an intestinal I/R procedure and received 0.5 mL of distilled water, and the I/R + GLUT rats had an intestinal I/R procedure and also received 1 g/kg b.w. of glutamine. Treatments were daily and per os. Glutamine attenuated intestinal I/R-induced rise in intestinal and cardiorenal activities of creatinine kinase and lactate dehydrogenase and lactate level. More so, glutamine alleviated I/R-induced rise in malondialdehyde, xanthine oxidase, uric acid, myeloperoxidase, NF-kB, TNF-α, IL-1ß, caspase 3 activity, and DNA fragmentation. Furthermore, glutamine suppressed I/R-induced decline in GSH levels and SOD and catalase activities. Moreover, glutamine improved intestinal, cardiac, and renal histology in animals subjected to intestinal I/R.

Gut microbiota-gonadal axis: the impact of gut microbiota on reproductive functions.

The influence of gut microbiota on physiological processes is rapidly gaining attention globally. Despite being under-studied, there are available data demonstrating a gut microbiota-gonadal cross-talk, and the importance of this axis in reproduction. This study reviews the impacts of gut microbiota on reproduction. In addition, the possible mechanisms by which gut microbiota modulates male and female reproduction are presented. Databases, including Embase, Google scholar, Pubmed/Medline, Scopus, and Web of Science, were explored using relevant key words. Findings showed that gut microbiota promotes gonadal functions by modulating the circulating levels of steroid sex hormones, insulin sensitivity, immune system, and gonadal microbiota. Gut microbiota also alters ROS generation and the activation of cytokine accumulation. In conclusion, available data demonstrate the existence of a gut microbiota-gonadal axis, and role of this axis on gonadal functions. However, majority of the data were compelling evidences from animal studies with a great dearth of human data. Therefore, human studies validating the reports of experimental studies using animal models are important.

Glutamine Alleviates I/R-Induced Intestinal Injury and Dysmotility Via the Downregulation of Xanthine Oxidase/Uric Acid Signaling and Lactate Generation in Wistar Rats.

INTRODUCTION: Disruption of intestinal histoarchitecture and intestinal dysmotility is critical to intestinal ischemia/reperfusion (IR) injury and xanthine oxidase (XO)/uric acid (UA) signaling and increased lactate generation have been reported to play a role. More so, glutamine treatment has been demonstrated to inhibit XO/UA signaling. However, the role of glutamine in intestinal IR injury-induced intestinal dysmotility and the associated mechanisms of action are unclear. Therefore, this study was to investigate the mechanisms underlying the role of glutamine in intestinal IR injury. METHODS: Forty male Wistar rats were acclimatized for two weeks and then randomized into four groups. The sham-operated, glutamine-treated, intestinal IR, and IR + glutamine groups. RESULTS: Glutamine therapy attenuated the IR-induced increase in intestinal weight, disruption of intestinal histoarchitecture, and intestinal dysmotility. In addition, glutamine ameliorated IR-induced intestinal oxidative stress (increased malondialdehyde, reduced glutathione and superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and glucose-6-phosphate dehydrogenase activities), inflammation (increased TNF-α and IL-1ß), and apoptosis (increased caspase three activity). These events were accompanied by glutamine alleviation of IR-induced upregulation of intestinal nuclear factor kappa B, XO/UA, and lactate generation. CONCLUSIONS: In conclusion, XO/UA signaling and lactate levels are key factors in IR-induced intestinal injury and dysmotility, and glutamine-mediated XO/UA/lactate modulation may attenuate IR-induced intestinal injury and dysmotility.

Histopathological evaluation of infertility: Lessons from laboratory rodents.

Infertility is a growing challenge globally with emerging risk factors. There are effective laboratory tests to evaluate infertility in humans, nevertheless, some measures, especially histopathological evaluations, are invasive due to the pain inflicted when accessing the reproductive organs and obtaining samples; hence, their relevance may be limited in humans. However, these histopathological evaluations provide essential information on the etiopathogenesis of infertility and the likely mechanisms of action of potential therapeutic candidates. Also, non-invasive methods are available, such as the assay of testosterone in the blood and semen analysis, both of which are predictors of testicular functions. This review provides detailed information on the available histopathological investigations of infertility, such as qualitative and quantitative histopathological assessments of gonadal tissues, specific cell counts, and sperm morphology characterization, with a focus on the procedures, interpretation, and pathophysiological basis. Data from the literature revealed that histopathological examinations of the reproductive organs, as well as spermatozoa, are useful in understanding the pathogenesis of incident infertility. Histopathological evaluation may range from basic hematoxylin and eosin stains to some special stains. Also, histopathological findings (such as spermatogenic cells and planimetric variables, like seminiferous tubule diameter and theca cell and corpus luteum thickness) may be quantified and analyzed for comparison. Some skill is required for these investigations, which may be a limiting factor; however, they are important tools in translational medicine.

L-Arginine abrogates maternal and pre-pubertal codeine exposure-induced impaired spermatogenesis and sperm quality by modulating the levels of mRNA encoding spermatogenic genes.

Introduction: Although, codeine has been demonstrated to lower sperm quality; the effects of maternal and prepubertal codeine exposure on male offspring is yet to be reported. In addition, the effect of arginine on codeine-induced decline in sperm quality has not been explored. This study investigated the impact of maternal and prepubertal codeine exposure on spermatogenesis and sperm quality in F1 male Wistar rats to study the effect that codeine may have during recreational use in humans. Also, the effect of arginine supplementation on codeine-induced alteration in spermatogenesis and sperm quality was evaluated. Methods: Female rats were treated with either 0.5 ml distilled water or codeine orally for eight weeks, and then mated with male rats (female:male, 2:1). The F1 male offsprings of both cohorts were weaned at 3 weeks old and administered distilled water, codeine, arginine, or codeine with arginine orally for eight weeks. Results: Prepubertal codeine exposure in rats whose dams (female parents) were exposed to codeine delayed puberty and reduced the weight at puberty. Prepubertal codeine exposure exacerbated maternal codeine exposure-induced reduced total and daily spermatid production, sperm count, sperm motility, and normal sperm form, as well as impaired sperm plasma membrane integrity and increased not intact acrosome and damaged sperm DNA integrity. These perturbations were accompanied by a decrease in mRNA levels encoding spermatogenic genes, testicular testosterone and androgen receptor (AR) concentrations, and upregulation of sperm 8-hydroxydeoxyguanosine (8OHdG). Prepubertal arginine supplementation mitigated codeine-induced alterations. Discussion: This study provides novel experimental evidence that maternal and prepubertal codeine exposure reprogramed spermatogenesis and sperm quality of male FI generation by decreasing mRNA levels encoding spermatogenic genes and AR via oxidative stress-mediated signaling, which was abrogated by prepubertal arginine supplementation.

Psychoactive drugs and male fertility: impacts and mechanisms.

Although psychoactive drugs have their therapeutic values, they have been implicated in the pathogenesis of male infertility. This study highlights psychoactive drugs reported to impair male fertility, their impacts, and associated mechanisms. Published data from scholarly peer-reviewed journals were used for the present study. Papers were assessed through AJOL, DOAJ, Google Scholar, PubMed/PubMed Central, and Scopus using Medical Subjects Heading (MeSH) indexes and relevant keywords. Psychoactive drugs negatively affect male reproductive functions, including sexual urge, androgen synthesis, spermatogenesis, and sperm quality. These drugs directly induce testicular toxicity by promoting ROS-dependent testicular and sperm oxidative damage, inflammation, and apoptosis, and they also suppress the hypothalamic-pituitary-testicular axis. This results in the suppression of circulating androgen, impaired spermatogenesis, and reduced sperm quality. In conclusion, psychoactive drug abuse not only harms male sexual and erectile function as well as testicular functions, viz., testosterone concentration, spermatogenesis, and sperm quality, but it also alters testicular histoarchitecture through a cascade of events via multiple pathways. Therefore, offering adequate and effective measures against psychoactive drug-induced male infertility remains pertinent.

Zinc improves sexual performance and erectile function by preventing penile oxidative injury and upregulating circulating testosterone in lead-exposed rats.

AIM: The present study evaluated the effect of lead exposure with and without zinc therapy on male sexual and erectile function. METHODS: Twenty male Wistar rats were randomly assigned into four groups; the control, zinc-treated, lead-exposed, lead + zinc-treated groups. Administrations were per os daily for 28 days. RESULTS: Zinc co-administration significantly improved absolute and relative penile weights and the latencies and frequencies of mount, intromission, and ejaculation in lead-exposed rats. Also, zinc ameliorated lead-induced reductions in motivation to mate and penile reflex/erection. These findings were accompanied by attenuation of lead-induced suppression of circulating nitric oxide (NO), penile cyclic guanosine monophosphate (cGMP), dopamine, serum luteinizing hormone, follicle-stimulating hormone, and testosterone. In addition, zinc alleviated lead-induced upregulation of penile activities of acetylcholinesterase and xanthine oxidase (XO), and uric acid (UA) and malondialdehyde (MDA) levels. Furthermore, zinc ameliorated the lead-induced decline in penile nuclear factor erythroid 2-related factor 2 (Nrf2) and reduced glutathione (GSH) levels, and catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) activities. CONCLUSION: This study revealed that co-administration of zinc improves lead-induced sexual and erectile dysfunction by suppressing XO/UA-driven oxidative stress and upregulating testosterone via Nrf2-mediated signaling.

Progress in research on the reproductive function in the sand rat (Psammomys obesus): A review.

The Fat Sand Rat (Psammomys obesus, P. obesus) is a diurnal herbivore and phytophage, with seasonal reproductive behavior. The sexually active phase lasts from autumn to early spring and the sexually inactive phase from late spring to summer. In the past years, P. obesus has gained much attention as an animal model in biological and clinical research. It is a suitable model for diet-induced insulin resistance, non-insulin-dependent diabetes mellitus and obesity studies. In addition, the seasonal reproduction of P. obesus is gaining more and more attention. The current paper aims to review and sum up the progress in the understanding of the reproductive anatomo-histo-physiology of Psammomys obesus, in order to facilitate future research in this area and to expose further perspectives for researchers.

L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling.

BACKGROUND: Although codeine has been reported to enhance sexual activity by improving penile reflexes, it has been shown to impair fertility indices. Also, codeine impairs ovarian steroidogenesis and folliculogenesis. Nonetheless, whether or not codeine exerts an epigenetic effect remains unclear. On the other hand, arginine has been speculated to enhance penile reflexes by upregulating NO/cGMP Signaling. AIM: The study evaluated the effect of maternal codeine exposure and prepubertal codeine and arginine treatments on F1 male sexual function and fertility indices, as well as the outcome of F2 progenies. In addition, the epigenetic programming mechanism was also explored. METHODS: Forty three-week-old female rats were randomized into two groups (n = 20 rats/group); the control that received 0.5 ml of distilled water and the codeine-treated that received 5 mg/kg of codeine via gavage for eight weeks. Afterward, the female rats were paired for mating with sexually mature male rats. Rats were maintained on their pre-pregnancy treatments throughout pregnancy and lactation. FI progenies from each cohort (control and codeine-treated cohorts) were weaned at three weeks and randomized into four groups; the control, codeine-treated, L-arginine-treated (300mg/kg), and codeine + L-arginine-treated (n = 10 rats/group). Administration commenced a week post-weaning and lasted for eight weeks via gavage. KEY FINDINGS: Maternal codeine exposure did not alter body weight, but significantly reduced anogenital distance and anogenital index of F1 male offspring. Also, maternal codeine delayed preputial membrane separation, impaired male sexual competence, and penile reflexes of F1 male offsprings. These were associated with reduced dopamine, gonadotropins, and testosterone levels as well as suppressed expression of androgen receptor mRNA. In addition, maternal codeine downregulated NO/cGMP signaling, impaired fertility indices, and reduced the litter size, weight, and survival of F2 progenies. These alterations were observed to be aggravated by prepubertal codeine exposure but improved by prepubertal arginine treatment. SIGNIFICANCE: In conclusion, codeine programmed sexual dysfunction by suppressing the levels of dopamine and testosterone, as well as repressing the expression of androgen receptor mRNA. In addition, codeine-induced epigenetic reprogramming was expressed in the F2 offsprings as reduced litter size and weight, and survival rate. Notably, these observations were worsened by prepubertal codeine exposure, but dampened by prepubertal arginine treatment.

Restoration of Hepatic and Intestinal Integrity by Phyllanthus amarus Is Dependent on Bax/Caspase 3 Modulation in Intestinal Ischemia-/Reperfusion-Induced Injury.

Ethnopharmacological relevance: Oxidative stress is a key player in intestinal ischemia/reperfusion (I/R) injury (IIRI) with a tendency to trigger systemic inflammatory response, resulting in progressive distal organ injury. To date, the role of Bax/caspase 3 signaling in IIRI has not been reported. Furthermore, the discovery of a safe and effective drug remains pertinent in improving the outcome of IIRI. Therefore, this study investigated the role of Bax/caspase 3 signaling in intestinal I/R-induced intestinal and hepatic injury. In addition, the protective effect and possible associated mechanism of action of methanolic Phyllanthus amarus leaf extract (PA) against intestinal I/R-induced intestinal and hepatic injury were evaluated. Materials and methods: Fifty male Wistar rats were randomized into five groups (n = 10). The sham-operated group was received 0.5 mL of distilled water for seven days prior to the sham surgery, while the IIRI, febuxostat (FEB) + IIRI, low-dose PA (LDPA) + IIRI, and high-dose PA (HDPA) + IIRI groups underwent the I/R procedure. In addition to the procedure, IIRI, FEB + IIRI, LDPA + IIRI, and HDPA + IIRI received 0.5 mL of distilled water, 10 mg/kg of febuxostat, 200 mg/kg of PA, and 400 mg/kg of PA, respectively, for seven days prior to the I/R procedure. Results: Administration of methanolic Phyllanthus amarus leaf extracts attenuated the intestinal I/R-induced rise in intestinal and hepatic injury markers, malondialdehyde, nitric oxide, TNF-α, IL-6, and myeloperoxidase activities. In addition, Phyllanthus amarus ameliorated I/R-induced suppression of reduced glutathione, thiol and non-thiol proteins, and superoxide dismutase, catalase, and glutathione peroxidase activities in intestinal and hepatic tissues. These were coupled with the suppression of I/R-induced bacterial translocation, downregulation of I/R-induced activation of Bax/caspase 3 signaling, and improvement of I/R-induced distortion of intestinal and hepatic histoarchitecture by Phyllanthus amarus. Conclusion: Methanolic Phyllanthus amarus leaf extract protects against intestinal and hepatic injuries associated with intestinal I/R by suppressing oxidative-stress-mediated activation of Bax/caspase 3 signaling. The beneficial effects of Phyllanthus amarus may be ascribed to its constituent bioactive molecules, especially tannins, anthocyanin, alkaloids, and phenolics.

Irisin, Energy Homeostasis and Male Reproduction.

Irisin is a novel skeletal muscle- and adipose tissue-secreted peptide. It is conventionally regarded as an adipomyokine and is a cleaved fragment of Fibronectin type III domain-containing protein 5 (FNDC5). It is involved in the browning of white adipose tissue, glucose tolerance, and reversing of metabolic disruptions. Fertility is closely linked to energy metabolism and the endocrine function of the adipose tissue. Moreover, there is established association between obesity and male infertility. Irisin bears strong therapeutic promise in obesity and its associated disorders, as well as shown to improve male reproductive functions. Thus, irisin is a molecule of great interest in exploring the amelioration of metabolic syndrome or obesity-induced male infertility. In this review we aim to enumerate the most significant aspects of irisin actions and discuss its involvement in energy homeostasis and male reproduction. Though current and future research on irisin is very promiscuous, a number of clarifications are still needed to reveal its full potential as a significant medicinal target in several human diseases including male infertility.

HAART and anti-Koch's impair sexual competence, sperm quality and offspring quality when used singly and in combination in male Wistar rats.

This study investigated the impact of the administration of HAART and anti-Koch's, singly and in combination, on sexual competence and birth statistics. Adult male Wistar rats were randomised into distilled water-treated control, HAART-treated, anti-Koch's-treated and HAART + anti-Koch's-treated groups. The 56-day oral treatment led to impaired sexual competence evident by significantly reduced motivation to mate, prolonged latencies of mount, intromissions, ejaculations and post-ejaculatory interval, as well as reduced frequencies of mount, intromissions and ejaculations. This was accompanied by significant reductions in penile erection reflex and penile grooming. HAART and anti-Koch's, when administered singly or in combination, also led to significant reductions in the circulatory follicle-stimulating hormone, luteinizing hormone, testosterone and intratesticular testosterone, but a significant rise in prolactin. Also, HAART and/or anti-Koch's significantly reduced sperm count, sperm motility, sperm viability and spermatozoa with normal morphology. Furthermore, HAART and anti-Koch's, separately or in combination, significantly lowered fertility capacity, litter size and litter weight and offspring survival. The deleterious effects of these drugs were more pronounced when combined. Findings of the present study revealed that HAART and/or anti-Koch's impair sexual competence via a testosterone-dependent hyperprolactinemia-mediated mechanism. These events are associated with reduced fertility capacity, poor sperm quality and lowered offspring survival.

Rohypnol-induced sexual dysfunction is via suppression of hypothalamic-pituitary-testicular axis: An experimental study in rats.

Sexual activity is an essential part of reproductive functions and needed for the maintenance of fertility. Drugs, particularly substances of abuse, impair male reproductive function either by interrupting hormonal functions or through the nonhormonal pathways. This study evaluated the impact of Rohypnol use in sexual behaviour. Materials and methods: Thirty adult male Wistar rats of comparable weights (180-200 g) were randomly allocated into three groups, the control and low-dose and high-dose Rohypnol-treated groups. The control group received 0.5 ml of distilled water, while the low- and high-dose Rohypnol-treated groups received 2 mg/kg b.w and 4 mg/kg b.w of Rohypnol via oral lavage once daily for 28 days. Rohypnol significantly increased mount latency, intromission latency, ejaculation latency and post-ejaculatory interval, as well as lowered mount frequency, intromission frequency and ejaculation frequency. Rohypnol-induced sexual dysfunction was found to be associated with significant suppression of circulatory follicle-stimulating hormone, luteinising hormone, testosterone and oestrogen. The present study reveals that Rohypnol induces sexual dysfunction through suppression of hypothalamic-pituitary-testicular axis. It also implicates Rohypnol as a potential candidate for drug-induced infertility.

The physiology of male reproduction: Impact of drugs and their abuse on male fertility.

Male factor accounts for about 30-50% of infertility. A common cause of male infertility is drug abuse; either illicit or prolonged use of prescribed drugs. This study provides a review of the physiology of the hypothalamic-pituitary-gonadal axis and recent literature on drugs that have been linked to male infertility and the associated mechanisms. Relevant peer-reviewed papers were assessed online using PubMed/PubMed Central, Scopus, AJOL, Google Scholar and DOAJ databases using Medical Subjects Headings (MeSH) indexes and relevant key word searches. Although drugs are beneficial when used at therapeutic levels, the abuse leads to impairment of hypothalamic-pituitary-gonadal functions, increased sperm DNA fragmentation and apoptosis, and reduced sperm quality. A good knowledge of the physiology of the hypothalamic-pituitary-gonadal axis and the influence of drugs on male fertility will guide healthcare providers in managing cases of infertility.

Codeine-induced sperm DNA damage is mediated predominantly by oxidative stress rather than apoptosis.

ABSTRACTBackground: Opioids have been implicated to induce infertility. Although codeine remains the most used opioid for recreational purpose, no study has documented its effect on sperm quality. Elucidating the effect of codeine on sperm cells and the associated mechanisms may provide an insight into preventing drug-induced sperm damage. Twenty-one New Zealand white rabbits were randomized into three groups; control and codeine-treated. The codeine-treated groups received either 4 or 10mg/kg b.w of codeine for six weeks.Results: Codeine treatment led to significant decrease in sperm count, motility, viability, normal morphology, and sperm membrane integrity. This was associated with significant rise in sperm DNA fragmentation, oxidative damage, and caspase 3 activity. The percentage of sperm DNA fragmentation correlates positively with 8-hydroxy-2'-deoxyguanosine, a biomarker of oxidative DNA damage, and caspase 3 activity, a biomarker of apoptosis. The observed correlation was stronger between sperm DNA fragmentation and oxidative DNA damage than sperm DNA fragmentation and caspase 3 activity.Conclusion: This study revealed that chronic codeine exposure causes sperm DNA fragmentation and poor sperm quality primarily via oxidative stress rather than activation of caspase 3-dependent apoptosis. Findings of the present study may explain drug-induced male factor infertility, particularly, those associated with opioid use.

Staging of the estrous cycle and induction of estrus in experimental rodents: an update.

BACKGROUND: Determination of the phases of the estrous cycle and induction of estrus (heat) in experimental animals remains useful, especially in reproductive function research. MAIN BODY OF THE ABSTRACT: This review provides a detailed description and discusses extensively the variations observed in different phases of the estrous cycle in laboratory animals using rats and mice as examples. It also illustrates how these phases can be determined and how to induce estrus 'heat' when required. The phases of the estrous cycle can be determined using various methods such as visual assessment, vaginal smear/cytology, histology of female reproductive organs (vagina, uterus and ovaries), vaginal wall impedance assessment and determination of urine biochemical parameters. Female animals can be artificially brought to estrus phase 'heat' to make them receptive to male counterparts. CONCLUSION: Determination of the length and phases of the estrous cycle and induction of estrus are useful in teaching and research and evaluating the effects of drugs/chemicals on the reproductive functions.