Pathophysiology and management of testicular ischemia/reperfusion injury: Lessons from animal models.

Testicular torsion is a urological emergency that involves the twisting of the spermatic cord along its course. Compelling pieces of evidence have implicated oxidative stress-sensitive signaling in pathogenesis of testicular I/R injury. Although, surgical detorsion is the mainstay management; blockade of the pathways involved in the pathogenesis may improve the surgical outcome. Experimental studies using various testicular I/R models have been reported in a bid to explore the mechanisms associated with testicular I/R and evaluate the benefits of potential therapeutic measures; however, most are limited by their shortcomings. Thus, this review was intended to describe the details of the available testicular I/R models as well as their merits and drawbacks, the pathophysiological basis and consequences of testicular I/R, and the pharmacological agents that have being proposed to confer testicular benefits against testicular I/R. This provides an understanding of the pathophysiological events and available models used in studying testicular I/R. In addition, this research provides evidence-based molecules with therapeutic potentials as well as their mechanisms of action in testicular I/R.

Metabolic Derangement by Arsenic: a Review of the Mechanisms.

Studies have implicated arsenic exposure in various pathological conditions, including metabolic disorders, which have become a global phenomenon, affecting developed, developing, and under-developed nations. Despite the huge risks associated with arsenic exposure, humans remain constantly exposed to it, especially through the consumption of contaminated water and food. This present study provides an in-depth insight into the mechanistic pathways involved in the metabolic derangement by arsenic. Compelling pieces of evidence demonstrate that arsenic induces metabolic disorders via multiple pathways. Apart from the initiation of oxidative stress and inflammation, arsenic prevents the phosphorylation of Akt at Ser473 and Thr308, leading to the inhibition of PDK-1/Akt insulin signaling, thereby reducing GLUT4 translocation through the activation of Nrf2. Also, arsenic downregulates mitochondrial deacetylase Sirt3, decreasing the ability of its associated transcription factor, FOXO3a, to bind to the agents that support the genes for manganese superoxide dismutase and PPARg co-activator (PGC)-1a. In addition, arsenic activates MAPKs, modulates p53/ Bcl-2 signaling, suppresses Mdm-2 and PARP, activates NLRP3 inflammasome and caspase-mediated apoptosis, and induces ER stress, and ox-mtDNA-dependent mitophagy and autophagy. More so, arsenic alters lipid metabolism by decreasing the presence of 3-hydroxy-e-methylglutaryl-CoA synthase 1 and carnitine O-octanoyl transferase (Crot) and increasing the presence of fatty acid-binding protein-3 mRNA. Furthermore, arsenic promotes atherosclerosis by inducing endothelial damage. This cascade of pathophysiological events promotes metabolic derangement. Although the pieces of evidence provided by this study are convincing, future studies evaluating the involvement of other likely mechanisms are important. Also, epidemiological studies might be necessary for the translation of most of the findings in animal models to humans.

Sodium acetate abates lead-induced sexual dysfunction by upregulating testosterone-dependent eNOS/NO/cGMP signaling and activating Nrf2/HO-1 in male Wistar rat.

Oxidative stress has been linked with lead toxicity, including lead-induced sexual dysfunction. On the contrary, sodium acetate has been proven to exert antioxidant activity. However, the effect of sodium acetate on lead-induced sexual dysfunction has not been fully explored. This study investigated the effect of sodium acetate on lead-induced sexual dysfunction, exploring the involvement of testosterone, eNOS/NO/cGMP, and Nrf2/HO-1 signaling. Twenty male Wistar rats with similar weights were randomly assigned into four groups (n = 5 rats/group) after two weeks of acclimatization. Animals were vehicle-treated (0.5 ml/day of distilled water, per os), acetate-treated (200 mg/kg/day, per os), lead-treated (20 mg/kg/day, per os), or lead + acetate-treated. The results revealed that sodium acetate treatment attenuated lead-induced rise in penile lead, malondialdehyde and oxidized glutathione concentrations, and acetylcholinesterase activity. In addition, lead exposure prolonged mount, intromission, and ejaculation latency and reduced mount, intromission, and ejaculation frequency, as well as the motivation to mate and penile reflex, which were improved by acetate treatment. More so, acetate treatment ameliorated lead-induced reductions in absolute and relative penile weight, eNOS, NO, cGMP, luteinizing hormone, follicle-stimulating hormone, testosterone, dopamine, Nrf2, HO-1, and reduced glutathione concentrations, as well as glutathione reductase, glutathione peroxidase, glutathione-S-transferase, superoxide dismutase, and catalase activities. In conclusion, this study demonstrates that sodium acetate attenuated lead-induced sexual dysfunction by upregulating testosterone-dependent eNOS/NO/cGMP and Nrf2/HO-1 signaling. Despite the compelling data presented in this study, other possible associated mechanisms in the protective role of acetate should be explored.

Acetate Abates Arsenic-Induced Male Reproductive Toxicity by Suppressing HDAC and Uric Acid-Driven Oxido-inflammatory NFkB/iNOS/NO Response in Rats.

Arsenic is associated with male reproductive toxicity through histone deacetylation and oxido-inflammatory injury. Notwithstanding, short-chain fatty acids such as acetate exert anti-oxido-inflammatory activities and inhibit histone deacetylation. This study investigated the impact of acetate on arsenic-induced male reproductive toxicity. Forty eight adult male Wistar rats were allotted into any of these four groups (n = 12 rats per group): vehicle-treated, sodium acetate-treated, arsenic-exposed, and arsenic-exposed + sodium acetate-treated. The results revealed that arsenic exposure prolonged the latencies of mount, intromission, and ejaculation and reduced the frequencies of mount, intromission, and ejaculation, as well as mating and fertility indices, litter size and weight, anogenital distance, anogenital index, and survival rate in male F1 offspring at weaning. Also, arsenic reduced the circulating levels of gonadotropin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, and testosterone and testicular 3ß-hydroxysteroid dehydrogenase and 17ß-hydroxysteroid dehydrogenase activities. In addition, arsenic reduced the daily and total spermatid production, sperm count, motility, and viability but increased the percentage of sperm cells with abnormal morphology. Furthermore, arsenic increased testicular xanthine oxidase activity, uric acid, and malondialdehyde levels, and reduced glutathione content, superoxide dismutase and catalase activities, total antioxidant capacity, and Nrf2 level. More so, arsenic exposure increased testicular iNOS activity and nitric oxide (NO), TNF-α, IL-1ß, IL-6, and NFkB levels as well as Bax, caspase 9, and caspase 3 activities, and reduced Bcl-2. These findings were associated with arsenic-induced increase in testicular arsenic concentration, histone deacetylase activity, and reduced testicular weight. Histopathological examination revealed that arsenic also disrupted testicular histoarchitecture, which was accompanied by altered testicular planimetry and reduced spermatogenic cells. Notwithstanding, sodium acetate alleviated arsenic-induced sexual dysfunction as well as biochemical and histological alterations. These were accompanied acetate-driven downregulation of histone deacetylase (HDAC) activity. Succinctly, acetate attenuated arsenic-induced male reproductive toxicity by suppressing HDAC and uric acid-driven oxido-inflammatory NFkB/iNOS/NO response.

Zinc protects against lead-induced testicular damage via modulation of steroidogenic and xanthine oxidase/uric acid/caspase 3-mediated apoptotic signaling in male Wistar rats.

AIM: This study evaluated the effect of lead, with or without zinc co-administration, on steroidogenic and xanthine oxidase (XO)/uric acid (UA)/caspase 3-mediated apoptotic signaling in the testis. MATERIALS AND METHODS: Forty male Wistar rats were divided into four groups at random; vehicle-treated control, zinc-treated, lead-treated, and lead + zinc-treated groups. RESULTS: Lead exposure significantly lowered overall weight gain, testicular, epididymal, seminal vesicle, and prostate weights. Also, lead decreased sperm count, viability and motility but increased the fraction of sperm with aberrant morphology. In addition, lead caused a marked rise in the level of UA and XO activity but a decrease in nuclear factor erythroid 2-related factor 2 (Nrf2), reduced glutathione (GSH) as well as total antioxidant capacity (TAC) levels, and superoxide dismutase (SOD) and catalase activities. Furthermore, lead increased the testicular levels of nuclear factor kappa B (NFkB), interleukin-1beta (IL-1ß), and tumour necrotic factor-alpha (TNF-α), which were associated with an increase in testicular caspase 3 activity and DNA fragmentation as well as a decline in circulating gonadotropin releasing hormone (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and testicular 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and 17ß-hydroxysteroid dehydrogenase (17ß-HSD). These were associated with lead-induced degenerative changes in testicular tissues evidenced by shrunken seminiferous tubules, degeneration and sloughing of germ cells. Co-administration of zinc prevented lead-induced testicular injury by ameliorating oxidative stress, apoptosis, and inflammation through downregulation of XO/UA/caspase 3 pathway and upregulation of testicular 3ß-HSD/17ß-HSD. CONCLUSION: This study demonstrated that zinc protected against lead-induced testicular toxicity via the downregulation of XO/UA/caspase 3 signaling.

Zinc improves sexual and erectile function in HAART-treated rats via the upregulation of erectogenic enzymes and maintenance of redox balance.

PURPOSE: HAART has been shown to impair sexual function and penile erection via perturbation of penile redox balance, while zinc has been established to exert antioxidant activity. Therefore, this study focused on the role and associated molecular mechanism of zinc in HAART-induced sexual and erectile dysfunction. MATERIALS AND METHODS: Twenty male Wistar rats were randomly grouped into four (n = 5 rats per group); the control, zinc-treated, HAART-treated, and HAART + zinc-treated groups. Treatments were per os daily for eight weeks. RESULTS: Zinc co-administration significantly improved HAART-induced increase in the latencies of mount, intromission, and ejaculations. Zinc also attenuated HAART-induced reduction in the motivation to mate, penile reflex/erection, and frequencies of mount, intromission, and ejaculations. In addition, zinc co-treatment improved HAART-induced decline in penile NO and cGMP, dopamine, and serum testosterone. More so, zinc prevented HAART-induced rise in penile activities of monoamine oxidase, acetylcholinesterase, phosphodiesterase-5, and arginase. Furthermore, concomitant treatment with zinc ameliorated HAART-induced penile oxidative stress and inflammation. CONCLUSION: In conclusion, our present findings show that zinc improves sexual and erectile function in HAART-treated rats by upregulating erectogenic enzymes via the maintenance of penile redox balance.

Methanolic Moringa oleifera leaf extract protects against epithelial barrier damage and enteric bacterial translocation in intestinal I/R: Possible role of caspase 3.

Background: Activation of caspase 3 has been implicated in the pathogenesis of I/R injury in various organs, but there is a paucity of data on its role in IIRI. Also, no reports were found on the beneficial role of methanolic Moringa oleifera leaf extract (MMOLE) in IIRI. This study investigated the involvement of caspase 3 in IIRI, and the impact of MMOLE in IIRI. Methods: Male Wistar rats were randomized into five groups; the sham-operated group that was sham-operated and received 0.5 ml of distilled water for 7 days prior to sham surgery, and the IIRI, febuxostat (FEB) +IIRI, low dose MMOLE (LDMO)+IIRI, and high dose MMOLE (HDMO)+IIRI groups that underwent I/R and also received 0.5 ml of distilled water, 10 mg/kg of febuxostat, 200 mg/kg of MMOLE, and 400 mg/kg of MMOLE respectively for 7 days prior to I/R. Markers of hepatic function, oxidative stress, and inflammation as well as enteric bacterial translocation and histoarchitecture integrity of intestinal and hepatic tissues were evaluated. The bioactive components of MMOLE were also determined by GC-MS. Results: As revealed by GC-MS, the active bioactive components of MMOLE were thiosemicarbazone, hydrazine, 1,3-dioxolane, octanoic acid, 1,3-benzenediamine, 9-octadecenoic acid, oleic acid, nonadecanoic acid, 3-undecanone, phosphonic acid, and cyclopentanecarboxylic acid. MMOLE alleviated IIRI-induced rise in intestinal and hepatic injury markers, malondialdehyde, TNF-α, IL-6, and myeloperoxidase activities. MMOLE improved IIRI-induced suppression of reduced glutathione, thiol and non-thiol proteins, and superoxide dismutase, catalase and glutathione peroxidase activities. These were associated with suppression of IIRI-induced caspase 3 activity and bacterial translocation. Histopathological evaluation revealed that MMOLE attenuated IIRI-induced alterations in intestinal and hepatic histoarchitecture integrity. MMOLE also militated against increased absolute and relative intestinal and hepatic weight, intestinal and hepatic injuries, epithelial mucosal barrier dysfunction, and enteric bacterial translocation associated with IIRI by downregulating oxidative stress-mediated activation of caspase 3. Conclusion: IIRI is associated with a rise in caspase 3 activity. Also, MMOLE confers protection against IIRI, possibly due to its constituent bioactive molecules, especially hydrazine, 9-octadecenoic acid, 1,3-dioxolane, oleic acid, and nonadecanoic acid.

Glutamine restores testicular glutathione-dependent antioxidant defense and upregulates NO/cGMP signaling in sleep deprivation-induced reproductive dysfunction in rats.

Oxidative stress has been linked with sleep deprivation (SD)-induced pathological conditions and reproductive dysfunction. On the other hand, glutamine has been established to have antioxidant property. However, the impact of SD, with or without glutamine, on male reproductive function is yet to be elucidated. Thus, this study was designed to investigate the role of SD, with or without glutamine, on male reproductive function and possible associated mechanisms. Ten-week old male Wistar rats weighing 175.6 g± 0.42 were randomly assigned into vehicle that received per os (p.o.) distilled water, glutamine (1 g/kg; po), SD, and SD + glutamine that received treatments as glutamine and SD. Treatment/exposure lasted for 72 h. The results showed that SD led to reduced body weight, seminiferous luminal and epididymal sperm density, low sperm quality, increased testicular and epididymal malondialdehyde, uric acid, DNA fragmentation, and testicular injury markers. In addition, SD caused a reduction in reduced glutathione level and activities of superoxide dismutase, catalase, glucose-6-phosphate dehydrogenase, glutathione peroxidase, and glutathione-S-transferase. Also, SD increased tumor necrotic factor-α, interleukin-1ß, and nuclear factor-kappa B levels. Furthermore SD led to impaired libido and erectile dysfunction, and suppression of circulatory nitric oxide, gonadotropins and testosterone, and penile cGMP. However, glutamine attenuated the effects induced by SD. Taken together, the findings of this study demonstrate that SD induces reproductive dysfunction via glutathione-dependent defense depletion and down-regulation of NO/cGMP signaling, which was abolished by glutamine supplementation.

Contraceptive potential of Andrographis paniculata is via androgen suppression and not induction of oxidative stress in male Wistar rats.

Andrographis paniculata has been shown to be associated with male reproductive dysfunction, although the available data are scarce and inconsistent, and the associated mechanisms are elusive. Hormonal mechanism via hypothalamic-pituitary-testicular axis, and non-hormonal mechanism primarily through oxidative stress, are involved in the modulation of male reproductive function. We therefore, hypothesized that suppression of hypothalamic-pituitary-testicular axis and/or oxidative stress is involved in Andrographis paniculata-induced reproductive dysfunction. Male Wistar rats received either vehicle or Andrographis paniculata in varying doses of 250, 500, and 1000 mg/kg body weight daily for 8 weeks. Treatment with Andrographis paniculata led to reduced sperm count, motility, and viability. Andrographis paniculata treatment also resulted in distorted spermatogenesis and reduced serum testosterone. On the other hand, Andrographis paniculata led to reduction in the testicular content of malondialdehyde, nitric oxide, TNF-α, and IL-6, and testicular activities of xanthine oxidase and myeloperoxidase, but raised testicular levels of reduced glutathione content and enhanced activity of super oxide dismutase. However, body weight gain, and absolute and relative reproductive organ weights were similar across all the groups. These findings demonstrate that Andrographis paniculata induces reproductive toxicity via suppression of testosterone and not induction of oxidative stress. Therefore, Andrographis paniculata could be a potential and safe male contraceptive.

Omega-3 fatty acid rescues ischaemia/perfusion-induced testicular and sperm damage via modulation of lactate transport and xanthine oxidase/uric acid signaling.

This study aimed to explore the potential antioxidant, anti-inflammatory, and anti-apoptotic effects of omega 3 fatty acid (Ω-3) in a rat model of testicular torsion/detorsion (T/D). Under ketamine/xylazine anaesthesia, age-matched adult male Wistar rats of comparable weight underwent sham-operation or testicular torsion by fixing the left testis rotated at 720° for two and half hours. After detorsion, animals were treated with either olive oil as vehicle or Ω-3 subcutaneously for three days. On post-operative day 3, rats were culled and the ipsilateral and contralateral testes, as well as obtained blood samples, were analyzed. Our findings revealed that T/D led to significant poor weight gain, distorted gross anatomy, and cytoarchitecture of the testes, low sperm quality, redox imbalance, and inflammation of the ipsilateral and contralateral testes. This was accompanied by reduced circulatory testosterone, a decline in testicular lactate metabolism and transport, upregulation of xanthine oxidase/uric acid signaling, and increased testicular DNA fragmentation. Administration of Ω-3 attenuated T/D-induced damage to the testes and sperm cells with a significant rise in the level of serum testosterone. Enhancement of lactate transport and down-regulation of xanthine oxidase/uric acid signaling by Ω-3 may be beneficial in protecting against T/D-related oxido-inflammatory damage and male infertility.