Cisplatin (CIS) is used in the treatment of cancer, but its nonspecific systemic actions lead to toxic effects on other parts of the body. This study investigated the severity of CIS toxicity by increasing its dose over a constant time period. Sprague Dawley rats were divided into five treatment groups and control group with CIS (2, 4, 6, 8, and 10 mg/kg) administered intraperitoneally for 5 days. The body and organs were weighed, epididymal sperm was counted, and sperm motility and sperm apoptosis were evaluated. Blood samples were evaluated for complete blood count, reactive oxygen and nitrogen species, malondialdehyde levels, and total testosterone. The testicular tissue was examined for steroidogenic acute regulatory protein and endoplasmic reticulum stress protein. Epididymal sperm was collected for CatSper Western blot. The toxic effects of different doses of CIS on the testis and kidney were compared histologically. The weights of body, testis, epididymis, prostate, seminal vesicle, and kidney; sperm count; sperm motility; steroidogenic acute regulatory protein level; and epididymal sperm count were significantly lower in the CIS-treated groups than in the control group. In contrast, sperm apoptosis, plasma reactive oxygen and nitrogen species, and malondialdehyde, testosterone, red blood cell, hematocrit, hemoglobin, and endoplasmic reticulum stress protein levels all increased. Though CIS effectively treats cancer, at an increased dose it is toxic and life-threatening to the genitourinary system and other parts of the body.

Endoplasmic reticulum (ER) stress, defined as prolonged disturbances in protein folding and accumulation of unfolded proteins in the ER. Perturbation of the ER, such as distribution of oxidative stress, iron imbalance, Ca2+ leakage, protein overload, and hypoxia, can cause ER stress. The cell reacts to ER stress by activating protective pathways, called the unfolded protein response (UPR), which is comprised of cellular mechanisms aimed for maintaining cellular homeostasis or, in case of excessively severe stress, at the initiation of cellular apoptosis. The three UPR signaling pathways from the ER stress sensors are initiated by activating transcription factor 6, inositol requiring enzyme 1, and protein kinase RNA-activated-like ER kinase. A number of physiological and pathological conditions, environmental toxicants and variety of pharmacological agents showed disruption of proper ER functions and thereby cause ER stress in male reproductive organ in rat model. The present review summarizes the existing data concerning the molecular and biological mechanism of ER stress in male reproduction and male infertility. ER stress initiated cell death pathway has been related to several diseases, including hypoxia, heath disease, diabetes, and Parkinson's disease. Although there is not enough evidence to prove the relationship between ER stress and male infertility in human, most studies in this review found that ER stress was correlated with male reproduction and infertility in animal models. The ER stress could be novel signaling pathway of regulating male reproductive cellular apoptosis. Infertility might be a result of disturbing the ER stress response during the process of male reproduction.

Schisandra chinensis Baillon (SC) has been utilized for its antioxidants and anti-inflammatory activities in a broad variety of medical applications. However; SC uses for improving fertility in males and related disorders with proper scientific validation remain obscure. The present study aimed to investigate the effects of SC on varicocele (VC)-induced testicular dysfunction and the potential molecular mechanism associated with VC-induced germ cell apoptosis. The male Sprague–Dawley rats were equally divided into four groups consisting of 10 rats in a normal control group (CTR), a control group administered SC 200 mg/kg (SC 200), a varicocele-induced control group (VC), and a varicocele-induced group administered SC 200 mg/kg (VC + SC 200). Rats were administrated 200 mg/kg SC once daily for 28 days after induction of varicocele rats and sham controls. At the end of the treatment period, body and reproductive organ weight, sperm parameters, histopathological damages, proinflammatory cytokines, apoptosis markers, biomarkers of oxidative stress, endoplasmic reticulum (ER) stress, and steroidogenic acute regulatory protein (StAR) were evaluated. The effects of SC extract on human sperm motility were also analyzed. SC treatment reduces VC-induced testicular dysfunction by significantly increasing testicular weight, sperm count and sperm motility, serum testosterone level, Johnsen score, spermatogenic cell density, testicular superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase level, and steroidogenic acute regulatory protein (StAR) level. Furthermore, the effects of SC on malondialdehyde (MDA) level, reactive oxygen species (ROS)/reactive nitrogen species (RNS) level, apoptotic index, serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, Glucose-regulated protein-78 (Grp 78), phosphorylated c-Jun-N-terminal kinase (p-JNK), phosphorylated inositol-requiring transmembrane kinase/endoribonuclease 1α (p-IRE1α), cleaved caspase 3, and Bax:Bcl2 in VC-induced rats were significantly decreased. Treatment with SC extracts also increased sperm motility in human sperm. Our findings suggest that the SC ameliorate testicular dysfunction in VC-induced rats via crosstalk between oxidative stress, ER stress, and mitochondrial-mediated testicular germ cell apoptosis signaling pathways. SC promotes spermatogenesis by upregulating abnormal sex hormones and decreasing proinflammatory cytokines (interleukin-6; TNF-α).

Background: Monotropein, astragalin, and spiraeoside (MAS) are active compounds extracted from medicinal herbs; monotropein from Morinda officinalis How (Rubiaceae), astragalin (kaempferol 3-O-glucoside) from Cuscuta chinensis Lamark (Convolvulaceae) and spiraeoside from the outer scales of Allium cepa L. (Liliceae) in a ratio of 6.69:0.41:3.61. Monotropein, astragalin, and spiraeoside are well-known antioxidants, anti-inflammatory, and antinociceptive agents. The current investigation aims to study the molecular mechanism of varicocele-induced male infertility and the underlying pharmacological mechanisms of MAS. Methods: Four groups were included: control (CTR), MAS 200 group (MAS 200 mg/kg), varicocele group (VC), and VC + MAS 200 group (MAS 200 mg/kg). Sprague-Dawley (SD) rats were treated with 200 mg/kg MAS or vehicle once daily for 28 days. The possible signaling mechanism and effects of MAS were measured via histological staining, immunohistochemistry, western blot, and biochemical assays. Results: Parameters such as sperm motility and count, Johnsen’s scores, spermatogenic cell density, serum testosterone, testicular superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and expression of the steroidogenic acute regulatory protein (StAR) improved significantly in the VC + MAS 200 group compared with the VC group. MAS treatment of varicocele-induced group significantly decreased the levels of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as testicular interleukin-6 (IL6), tumor necrosis factor-α (TNF-α), ROS/RNS, and malondialdehyde (MDA). It also decreased the apoptotic index and reduced the expression of endoplasmic reticulum (ER) protein levels (Grp78, p-IRE1α, and p-JNK) and apoptotic markers such as cleaved caspase-3 and Bax/Bcl2 ratio. Conclusion: This study suggests that the crosstalk between oxidative stress, ER stress, and mitochondrial pathway mediates varicocele-induced testicular germ cell apoptosis. MAS promotes spermatogenesis in varicocele-induced SD rat, probably by decreasing cytokines (IL-6, TNF-α) levels, regulating abnormal sex hormones, and decreasing oxidative stress, ER stress, and apoptosis.

Study Type – Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Avanafil is a potent selective phosphodiesterase type 5 (PDE5) inhibitor newly developed for treating erectile dysfunction (ED). Preclinical and clinical phase I studies showed that avanafil had enhanced selectivity, faster onset of action and a favourable side‐effect profile relative to currently available PDE5 inhibitors. As the result of phase III clinical trial for the efficacy and safety of avanafil treatment (100 and 200 mg), taken as needed over a period of 12 weeks, in Korean patients with ED, avanafil is an effective and well‐tolerated therapy for ED of broad‐spectrum aetiology and severity. OBJECTIVE: To evaluate the efficacy and safety of avanafil, a new potent selective phosphodiesterase type 5 (PDE5) inhibitor, in patients with erectile dysfunction (ED). PATIENTS AND METHODS: The present study was a multicentre, randomized, double‐blind, placebo‐controlled, fix‐dosed phase three clinical trial involving 200 patients with ED. The subjects were treated with placebo or avanafil (100 or 200 mg) for 12 weeks and were asked to complete the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment Questionnaire (GAQ). The primary outcome variable was the change from baseline for IIEF erectile function domain (EFD) score. The secondary outcome variables were SEP Q2 and Q3, the shift to normal rate (EFD ≥ 26), and response to the GAQ. RESULTS: Compared with placebo, patients who took 100 or 200 mg of avanafil had significantly improved IIEF‐EFD score. There were similar results when comparing Q2 and Q3 in the SEP diary and the GAQ. Flushing was the most common treatment‐related adverse event. Most adverse events were transient and mild or moderate in severity. CONCLUSION: Avanafil is an effective and well‐tolerated therapy for ED of broad‐spectrum aetiology and severity.

To elucidate the changes that occur in the blood-testis barrier (BTB) during varicocele, we examined changes in claudin-11 (Cldn11), an element of the BTB, steroidogenesis, and proinflammatory cytokines in a model of varicocele rat testes.Male rats with experimentally-induced varicocele were sacrificed 4 weeks after operation. Testicular histology and blood testosterone concentrations were examined, and the expression of tight junctions, steroidogenic enzymes, apoptosis and immune cell markers, and proinflammatory cytokines in the testes were evaluated using RT-PCR, Western blotting, and immunohistochemistry.Weight and Johnsen scores of varicocele testes were lower than those of normal testes. mRNA expression of Bad and Bax increased, whereas Bcl-xl and Bcl2 mRNA decreased in the varicocele testes compared to the controls. Although blood testosterone was not changed, Leydig cell 3βHsd immunoreactivity, testicular 3βHsd6 and 17βHsd3 mRNA were significantly decreased in the varicocele testes. Cldn11 mRNA and protein levels in the varicocele testes were higher than those of normal testes together with an altered expression of Ocln, Zo1, and N-cadherin mRNA. Cldn11 immunoreactivity appeared as wavy strands at the periphery of the seminiferous epithelium in normal testes, but was frequently found in the Sertoli cell cytoplasm in the varicocele testes. In the varicocele testes Tnfα, Il1α, Il6, Cd45, Cd3g, and Cd3d mRNA were increased.An increase in proinflammatory cytokines might be responsible for deregulation of Cldn11 in the Sertoli cells in varicocele testis, leading to alterations in the permeability of the BTB and immunological barriers to normal spermatogenesis.