Penile erection and cardiovascular function: effects and pathophysiology.

Penile erection (PE) is a hemodynamic event that results from a neuroendocrine process, and it is influenced by the cardiovascular status of the patient. However, it may also modulate an individual's cardiovascular events. The present study provides the mechanisms involved in the association of PE and cardiovascular function. Erection upsurges the cardiac rate, blood pressure, and oxygen uptake. Sex-enhancing strategies, such as phosphodiesterase inhibitors, alprostadil, and testosterone also promote vasodilatation and cardiac performance, thus preventing myocardial infarction. More so, drugs that are used in the treatment of hypertensive heart diseases (such as angiotensin system inhibitors and ß-blockers) facilitate vasodilatation and PE. These associations have been linked with nitric oxide- and testosterone-dependent enhancing effects on the vascular endothelium. In addition, impaired cardiovascular function may negatively impact PE; therefore, impaired PE may be a pointer to cardiovascular pathology. Hence, evaluation of the cardiovascular status of an individual with erectile dysfunction (ED) is essential. Also, employing strategies that are used in maintaining optimal cardiac function may be useful in the management of ED.

Sodium acetate ameliorates doxorubicin-induced cardiac injury via upregulation of Nrf2/HO-1 signaling and downregulation of NFkB-mediated apoptotic signaling in Wistar rats.

Despite the effectiveness of doxorubicin (DOX) in the management of a wide range of cancers, a major challenge is its cardio-toxic effect. Oxidative stress, inflammation, and apoptosis are major pathways for the cardiotoxic effect of DOX. On the other hand, acetate reportedly exerts antioxidant, anti-inflammatory, and anti-apoptotic activities. This particular research assessed the impact of acetate on cardiotoxicity induced by DOX. Mechanistically, acetate dramatically inhibited DOX-induced upregulation of xanthine oxidase and uric acid pathway as well as downregulation of Nrf2/HO-1 signaling and its upstream proteins (reduced glutathione peroxidase, superoxide dismutase, glutathione-S-transferase, glutathione, and catalase, glutathione reductase). In addition, acetate markedly attenuated DOX-driven rise inTNF-α, NFkB IL-6 and IL-1ß expression, and myeloperoxidase activity. Furthermore, acetate significantly ameliorated DOX-led suppression of Bcl-2 and Ca2+-ATPase activity and upregulation of Bax, caspase 3, and caspase 9 actions. Improved body weight, heart structural integrity, and cardiac function as depicted by cardiac injury markers convoyed these cascades of events. Summarily, the present study demonstrated that acetate protects against DOX-induced cardiotoxicity by upregulating Nrf2/HO-1 signaling and downregulating NFkB-mediated activation of Bax/Bcl-2 and caspase signaling.

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 attenuates cyclophosphamide-induced cardiac injury via inhibition of NF-kB signaling and suppression of caspase 3-dependent apoptosis in Wistar rats.

AIM: The goal of the current study was to examine the potential therapeutic effects of sodium acetate on cardiac toxicities caused by cyclophosphamide in Wistar rats. The possible involvement of NF-kB/caspase 3 signaling was also explored. MAIN METHODS: Thirty-two male Wistar rats were divided into four groups at random. (n = 8). The control animals received 0.5 mL of distilled water orally for 14 days, the acetate-treated group received 200 mg/kg/day of sodium acetate orally for 14 consecutive days, and cyclophosphamide-treated rats received 150 mg/kg /day of cyclophosphamide i.p. on day 8, while cyclophosphamide + acetate group received sodium acetate and cyclophosphamide as earlier stated. KEY FINDINGS: Results showed that cyclophosphamide-induced cardiotoxicity, which manifested as a marked drop in body and cardiac weights as well as cardiac weight/tibial length, increased levels of troponin, C-reactive protein, lactate, and creatinine kinase, and lactate dehydrogenase activities in the plasma and cardiac tissue. Histopathological examination also revealed toxic cardiac histopathological changes. These alterations were associated with a significant increase in xanthine oxidase and myeloperoxidase activities, uric acid, malondialdehyde, TNF-α, IL-1ß, NFkB, DNA fragmentation, and caspase 3 and caspase 9 activities in addition to a marked decline in Nrf2 and GSH levels, and SOD and catalase activities in the cardiac tissue. Acetate co-administration significantly attenuated cyclophosphamide cardiotoxicity by its antioxidant effect, preventing NFkB activation and caspase 9/caspase 3 signalings. SIGNIFICANCE: This study shows that acetate co-administration may have cardio-protective effects against cyclophosphamide-induced cardiotoxicity by inhibiting NF-kB signaling and suppressing caspase-3-dependent apoptosis.

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.

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.

Impact of hypoxia on male reproductive functions.

Male reproductive functions, which include testicular steroidogenesis, spermatogenesis, and sexual/erectile functions are key in male fertility, but may be adversely altered by several factors, including hypoxia. This review demonstrates the impact of hypoxia on male reproductive functions. Acute exposure to hypoxia promotes testosterone production via stimulation of autophagy and upregulation of steroidogenic enzymes and voltage-gated L-type calcium channel, nonetheless, chronic exposure to hypoxia impairs steroidogenesis via suppression of the hypothalamic-pituitary-testicular axis. Also, hypoxia distorts spermatogenesis and reduces sperm count, motility, and normal forms via upregulation of VEGF and oxidative stress-sensitive signaling. Furthermore, hypoxia induces sexual and erectile dysfunction via a testosterone-dependent downregulation of NO/cGMP signaling and upregulation of PGE1/TGFß1-driven penile endothelial dysfunction. Notably, hypoxia programs male sexual function and spermatogenesis/sperm quality via feminization and demasculinization of males and oxidative stress-mediated alteration in sperm DNA methylation. Since oxidative stress plays a central role in hypoxia-induced male reproductive dysfunction, studies exploring the effects of antioxidants and upregulation of transcription of antioxidants on hypoxia-induced male reproductive dysfunction are recommended.

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.

Atorvastatin-mediated downregulation of VCAM-1 and XO/UA/caspase 3 signaling averts oxidative damage and apoptosis induced by ovarian ischaemia/reperfusion injury.

BACKGROUND: Oxidative damage is critical in the pathogenesis of ovarian ischaemia/reperfusion (I/R) injury, and statins have been reported to exert antioxidant activity. However, the role of VCAM-1 and xanthine oxidase (XO)/uric acid (UA) in ovarian I/R injury is not known. Also, whether or not atorvastatin exerts antioxidant activity like other statins is unclear. OBJECTIVES: This study investigated the involvement of VCAM-1 and XO/UA in ovarian I/R injury and the likely protective role of atorvastatin. METHODS: Forty female Wistar rats were randomized into sham-operated, ischaemia, ischaemia/reperfusion (I/R), ischaemia and atorvastatin, and I/R and atorvastatin. RESULTS: In comparison with the sham-operated group, atorvastatin blunted ischaemia and I/R-induced distortion of ovarian histoarchitecture and follicular degeneration. Also, atorvastatin alleviated ischaemia and I/R-induced rise in XO, UA, and malondialdehyde, which was accompanied by inhibition of ischaemia and I/R-induced reductions in reduced glutathione level, enzymatic antioxidant activities and increase in myeloperoxidase activity and TNF-α and IL-6 levels by atorvastatin treatment. Additionally, atorvastatin blocked ischaemia and I/R-induced increase in VCAM-1 expression, caspase 3 activity, 8-hydroxydeoxyguanosine level and ovarian DNA fragmentation index. CONCLUSION: For the first time, this study revealed that atorvastatin-mediated downregulation of VCAM-1 and XO/UA/caspase 3 signaling averts oxidative injury, inflammation, and apoptosis induced by ovarian ischaemia/reperfusion injury.

Zinc normalizes hepatic lipid handling via modulation of ADA/XO/UA pathway and caspase 3 signaling in highly active antiretroviral therapy-treated Wistar rats.

BACKGROUND: Although highly active antiretroviral therapy (HAART) is effective in the management of HIV, it has been reported to induce hepatic injury and non-alcoholic fatty liver (NAFLD). However, there is a lack of data on the roles of the adenosine deaminase (ADA)/xanthine oxidase (XO)/uric acid (UA) pathway and caspase 3 signaling in HAART-induced NAFLD. Also, whether or not zinc confers protection against HAART-induced NAFLD is not known. AIM: This study evaluated the involvement of the ADA/XO/UA pathway and caspase 3 signaling in HAART-induced hepatic lipid accumulation. It also evaluated the possible protective effect of zinc in HAART-induced hepatic lipid accumulation and injury. METHODS: Thirty two male Wistar rats (n = 8/group) were assigned into four groups namely; vehicle-treated (p.o), zinc-treated (3 mg/kg/day of elemental zinc; p.o), HAART-treated (a cocktail of 52.9 mg/kg of Efavirenz, 26.48 mg/kg of Lamivudine, and 26.48 mg/kg of Tenofovir; p.o), and HAART + zinc-treated groups. The treatment lasted for 8 weeks. RESULTS: HAART administration led to increased body weight and hepatic weight, but unaltered hepatic organo-somatic index. HAART exposure also resulted in impaired glucose homeostasis, evidenced by increased fasting blood glucose, hyperinsulinemia, and insulin resistance (IR), increased plasma and hepatic cholesterol and triglycerides, and impaired hepatic function as depicted by elevated hepatic injury markers and reduced glycogen synthase activity and glycogen content. These findings were accompanied by increased plasma and hepatic ADA and XO activities, UA and malondialdehyde levels, inflammatory markers, and caspase 3 activities. However, HAART suppressed plasma and hepatic antioxidant defenses. Furthermore, HAART distorted hepatic histoarchitecture and reduced hepatic sinusoidal diameter. Co-administration of zinc with HAART normalized HAART-induced alterations. CONCLUSIONS: These findings showed that downregulation of the ADA/XO/UA pathway and caspase 3 signalings may rescue the liver from HAART-induced lipid accumulation and injury.

Impact of COVID 19 on erectile function.

Purpose: COVID-19, a novel infection, presented with several complications, including socioeconomical and reproductive health challenges such as erectile dysfunction (ED). The present review summarizes the available shreds of evidence on the impact of COVID-19 on ED.Materials and methods: All published peer-reviewed articles from the onset of the COVID-19 outbreak to date, relating to ED, were reviewed. Results: Available pieces of evidence that ED is a consequence of COVID-19 are convincing. COVID-19 and ED share common risk factors such as disruption of vascular integrity, cardiovascular disease (CVD), cytokine storm, diabetes, obesity, and chronic kidney disease (CKD). COVID-19 also induces impaired pulmonary haemodynamics, increased ang II, testicular damage and low serum testosterone, and reduced arginine-dependent NO bioavailability that promotes reactive oxygen species (ROS) generation and endothelial dysfunction, resulting in ED. In addition, COVID-19 triggers psychological/mental stress and suppresses testosterone-dependent dopamine concentration, which contributes to incident ED.Conclusions: In conclusion, COVID-19 exerts a detrimental effect on male reproductive function, including erectile function. This involves a cascade of events from multiple pathways. As the pandemic dwindles, identifying the long-term effects of COVID-19-induced ED, and proffering adequate and effective measures in militating against COVID-19-induced ED remains pertinent.

Glutamine prevents upregulation of NF-kB signaling and caspase 3 activation in ischaemia/reperfusion-induced testicular damage: An animal model.

AIM: Testicular ischaemia/reperfusion (I/R) injury is a major consequence of testicular torsion with possible attendant risk of male infertility. Glutamine, on the other hand, is a known antioxidant with anti-inflammatory potential. The present study evaluated whether or not glutamine would improve I/R-induced testicular injury in torsion/detorsion (T/D). The possible associated mechanisms were also investigated. METHODS: Wistar rats were randomly allotted into four groups (n = 10); sham-operated, glutamine-treated, T/D, and T/D + glutamine. Testicular torsion was induced and reperfusion established after two and a half hour under ketamine/xylazine anaethesia. Glutamine was administered one hour before reperfusion and continued daily for 3 days. At the end of the study, animals were euthanized, blood samples obtained, epididymal sperm suspension collected, and the testes harvested for biochemical and histopathological assays using established methods. RESULTS: Glutamine prevented T/D-driven I/R-induced reduced sperm quality, impaired testicular histoarchitecture, and suppressed circulating testosterone. Also, glutamine abated I/R-induced oxidative stress (evidenced by reduced hydrogen peroxide and MDA generation and enhanced concentrations and activities of antioxidants), inflammation (evidenced by suppression of TNF-α and IL-1ß), and apoptosis (evidenced by reduced DNA fragmentation) by down-regulating NF-kB and caspase 3 activity. CONCLUSION: For the first time, this study demonstrated that glutamine administration improved testicular I/R injury in T/D rat model by maintaining testicular redox balance, and testicular integrity and function via inhibition of I/R-induced upregulation of NF-kB signaling and caspase 3 activation.

Suppression of glutathione system and upregulation of caspase 3-dependent apoptosis mediate rohypnol-induced gastric injury.

Objectives: This study investigated the impact of rohypnol on gastric tissue integrity.Methods: Forty male Wistar rats were randomized into control, low dose rohypnol-treated, high dose rohypnol-treated, low dose rohypnol-treated recovery and high dose rohypnol-treated recovery groups.Results: Rohypnol caused significant rise in gastric malondialdehyde (MDA), oxidized glutathione (GSSG), nitric oxide (NO), tumour necrotic factor-α (TNF-α), and interleukin-6 (IL-6) levels. Also, rohypnol caused reductions in gastric reduced glutathione (GSH) (as well as GSH/GSSG), and activities of superoxide dismutase (SOD), catalase, glutathione-S-transferase (GST), glutathione peroxidase (GPx), cyclo-oxygenase (COX-2). Furthermore, rohypnol upregulated caspase 3 activity and induced gastric DNA damage, evident by a rise in 8-hydroxydeoxyguanosine (8-OHdG) and DNA fragmentation index (DFI) in gastric tissue. These alterations were coupled with reduced gastric weight and distorted gastric cytoarchitecture. Cessation of rohypnol caused a significant but not complete reversal of rohypnol-induced gastric damage.Conclusion: This study revealed that rohypnol induced gastric injury by suppressing glutathione content and COX-2 activity, and upregulating caspase 3-dependent apoptosis, which was partly reversed by rohypnol withdrawal.

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.

Codeine alters female reproductive function by targeting ovarian steroidogenesis and folliculogenesis via the induction of oxidative stress, inflammation, and apoptosis.

The rise in the abuse of codeine raises concerns about its impact on the health of users, and little has appeared on its effect on the female reproductive function. Therefore, this study evaluated the impact of codeine on female reproductive function. We administered codeine at low (2 mg/kg) and high (5 mg/kg) doses to female animals prior to mating for 8 weeks. In comparison with a vehicle-treated group, we then assessed the impact of codeine on body weight gain and ovarian weight, female sexual behaviour, ovarian steroidogenesis, and folliculogenesis. The role of oxidative stress, inflammation, and apoptosis were also evaluated. Codeine at either dose elicited a profound deficit in the absolute and relative ovarian weight, indicative of ovarian toxicity. Also, codeine induced female sexual dysfunction, and suppressed ovarian steroidogenesis and folliculogenesis, with degeneration of the ovarian cytoarchitecture and follicles. The effects of codeine were associated with a rise in ovarian hydroxyl radical generation and oxidative stress, evident by an increase in ovarian malondialdehyde, a reduction in reduced glutathione, and a decline in the activities of ovarian enzymatic antioxidants. In addition, codeine triggered an increase in the ovarian concentration of inflammatory cytokines, TNF-α and IL-1ß, and myeloperoxidase activity. Furthermore, codeine caused an increase in 8-hydroxydeoxyguanosine (8OHdG), ovarian DNA fragmentation, and caspase-3 activity, suggestive of genotoxicity and apoptosis respectively. The current study provides some of the first evidence for the adverse effects of prolong codeine use on female sexual function, ovarian steroidogenesis, and folliculogenesis. It also emphasizes the reproductive health consequences of drug abuse.

Upregulation of Uric Acid Production and Caspase 3 Signalling Mediates Rohypnol-Induced Cardiorenal Damage.

The global prevalence of illicit drug use is on the increase with attendant complications like cardiorenal collapse. One such substance of abuse is rohypnol. Despite its ban in most countries, it remains a popular substance of abuse. Whether or not rohypnol induces cardiorenal injury and the associated mechanism is yet to be elucidated. Therefore, the present study investigated the effect of rohypnol on cardiorenal integrity and functions, and glucolipid metabolism. Forty-eight male Wistar rats randomized into six groups (n = 8/group) received (per os) vehicle, low-dose (2 mg/kg) and high-dose (4 mg/kg) rohypnol once daily for twenty eight days, with or without a cessation period. Data revealed that rohypnol exposure irreversibly caused insulin resistance, hyperglycaemia, and dyslipidaemia. This was accompanied by reduced cardiorenal mass and impaired cardiorenal cytoarchitecture and function. Furthermore, rohypnol treatment promoted oxidative stress, inflammation, genotoxicity, and decreased cardiorenal activities of Na+-K+-ATPase, Ca2+-ATPase, and Mg2+-ATPase. These alterations were associated with enhanced uric acid generation and caspase 3 activity in the cardiorenal complex. Thus, this study reveals that rohypnol exposure triggers cardiorenal toxicity with incident insulin resistance, glucolipid and cardiorenal proton pump dysregulation, altered redox state, and inflammation via enhancement of uric acid generation and caspase 3-dependent mechanism.

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.