In vivo exposure to a new 2-cyano-2-p-nitrophenyl-N-benzylthioamide decreases doxorubicin-triggered structural damages in the mature testis.

The use of doxorubicin (DOX) in clinical practice continues to be challenged by its severe toxicity. DOX cytotoxic activity is not only directed against malignant tumours, given that the treatment will damage healthy tissues as well leading to irreversible injuries. This study aimed to address the in vivo effects of DOX and its co-administration with a new analog of thioamide; thiocyanoacetamide (TA) on the germinal epithelium. Thus, male rats received either intravenous injection (iv) of 0.03 mg/kg of body weight/week, 0.9% NaCl and were regarded as the control group (CTR), treated with DOX (3.7 mg/kg/week iv), TA [10 mg/kg/day intragastrically (ig)] or a co-supplementation of DOX and TA. After 50 days, the left testes were dissected and used for toluidine blue, periodic acid-Schiff (PAS) staining (to evaluate the change in polysaccharides/glycoproteins content), and transmission electron microscopy (TEM) (to assess the morphological damages). To estimate the impact of the test compounds on mitochondrial biogenesis, the expression of NAD-dependent deacetylase sirtuin-3 (SIRT-3) and proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were evaluated by immunofluorescence. Apoptotic cells were observed using Hoechst 33324 fluorescent staining. Data showed testicular injuries in the DOX-treated group, manifested by a significant decrease in total germ cell (GC) number, alteration of Sertoli cell (SC) nucleolus, anchoring junction, along with modifications of the basement membrane (BM) regularity and increase in apoptotic cell count. Mitochondrial aspect and SIRT-3 and PGC-1α expression in the testis were unaffected by the DOX. Co-therapy increased GC number, decreased apoptotic cell count, and restored the BM and anchoring junction regular aspects. This study provides novel insights into understanding DOX-mediated impairment in rats' testis and might offer some basis for the emerging new alternative therapeutic schemes in male patients undergoing chemotherapy.

White Tea Intake Abrogates Markers of Streptozotocin-Induced Prediabetes Oxidative Stress in Rat Lungs'.

Prediabetes (PrDM) is a prodromal stage of diabetes mellitus (DM) with an increasing prevalence worldwide. During DM progression, individuals gradually develop complications in various organs. However, lungs are suggested to be affected later than other organs, such as the eyes, heart or brain. In this work, we studied the effects of PrDM on male Wistar rats' lungs and whether the regular consumption of white tea (WTEA) for 2 months contributes to the improvement of the antioxidant profile of this tissue, namely through improved activity of the first line defense antioxidant enzymes, the total antioxidant capacity and the damages caused in proteins, lipids and histone H2A. Our data shows that PrDM induced a decrease in lung superoxide dismutase and glutathione peroxidase activities and histone H2A levels and an increase in protein nitration and lipid peroxidation. Remarkably, the regular WTEA intake improved lung antioxidant enzymes activity and total antioxidant capacity and re-established the values of protein nitration, lipid peroxidation and histone H2A. Overall, this is the first time that lung is reported as a major target for PrDM. Moreover, it is also the first report showing that WTEA possesses relevant chemical properties against PrDM-induced lung dysfunction.

Utility of Antioxidants in the Treatment of Male Infertility: Clinical Guidelines Based on a Systematic Review and Analysis of Evidence.

It is widely accepted that oxidative stress plays an important role in the pathophysiology of male infertility and that antioxidants could have a significant role in the treatment of male infertility. The main objectives of this study are: 1) to systematically review the current evidence for the utility of antioxidants in the treatment of male infertility; and 2) propose evidence-based clinical guidelines for the use of antioxidants in the treatment of male infertility. A systematic review of the available clinical evidence was performed, with articles published on Scopus being manually screened. Data extracted included the type of antioxidant used, the clinical conditions under investigation, the evaluation of semen parameters and reproductive outcomes. The adherence to the Cambridge Quality Checklist, Cochrane Risk of Bias for randomized controlled trials (RCTs), CONSORT guidelines and JADAD score were analyzed for each included study. Further, we provided a Strength Weakness Opportunity Threat (SWOT) analysis to analyze the current and future value of antioxidants in male infertility. Of the 1,978 articles identified, 97 articles were included in the study. Of these, 52 (53.6%) were uncontrolled (open label), 12 (12.4%) unblinded RCTs, and 33 (34.0%) blinded RCTs, whereas 44 (45.4%) articles tested individual antioxidants, 31 (32.0%) a combination of several products in variable dosages, and 22 (22.6%) registered antioxidant products. Based on the published evidence, we 1) critically examined the necessity of additional double-blind, randomized, placebo-controlled trials, and 2) proposed updated evidence-based clinical guidelines for antioxidant therapy in male infertility. The current systematic review on antioxidants and male infertility clearly shows that antioxidant supplementation improves semen parameters. In addition, it provides the indications for antioxidant treatment in specific clinical conditions, including varicocele, unexplained and idiopathic male infertility, as well as in cases of altered semen quality.

An online educational model in andrology for student training in the art of scientific writing in the COVID-19 pandemic.

In 2020, the COVID-19 pandemic led to the suspension of the annual Summer Internship at the American Center for Reproductive Medicine (ACRM). To transit it into an online format, an inaugural 6-week 2020 ACRM Online Mentorship Program was developed focusing on five core pillars of andrology research: scientific writing, scientific methodology, plagiarism understanding, soft skills development and mentee basic andrology knowledge. This study aims to determine mentee developmental outcomes based on student surveys and discuss these within the context of the relevant teaching and learning methodology. The mentorship was structured around scientific writing projects established by the team using a student-centred approach, with one-on-one expert mentorship through weekly formative assessments. Furthermore, weekly online meetings were conducted, including expert lectures, formative assessments and social engagement. Data were collected through final assessments and mentee surveys on mentorship outcomes. Results show that mentees (n = 28) reported a significant (p < .0001) improvement in all criteria related to the five core pillars. These results illustrate that the aims of the online mentorship program were achieved through a unique and adaptive online educational model and that our model has demonstrated its effectiveness as an innovative structured educational experience through the COVID-19 crisis.

Discordance between human sperm quality and telomere length following differential gradient separation/swim-up.

BACKGROUND: Strong evidence has suggested an important role of telomeres in meiosis, fertilization, and embryo development. PURPOSE: To determine if sperm telomere length (STL) in sperm purified by differential gradient centrifugation followed by swim-up (selected STL) is correlated with sperm quality and clinical outcomes. METHODS: Relative selected STL was assessed by quantitative polymerase chain reaction (Q-PCR) in 78 consecutive assisted reproductive technology (ART) treatments during 2017. Statistical analyses were performed in the totality of patients, and in normozoospermic and non-normozoospermic patients. These included correlations between selected STL and sperm quality parameters, embryological parameters (multivariable linear regression), and clinical parameters (multivariable logistic regression). RESULTS: No significant correlations were found between selected STL and sperm quality in the total population. However, selected STL was significantly correlated with total sperm count (r = 0.361; P = 0.039) and sperm DNA fragmentation-post-acrosomal region pattern (r = - 0.464; P = 0.030) in normozoospermic patients. No relation was observed between selected STL and clinical outcomes in any clinical group. CONCLUSIONS: As the correlations observed in normozoospermic patients were not representative of the whole heterogeneous population, differences in the sperm characteristics of the study population may lead to discrepant results when evaluating the association of STL with sperm quality. Since the total population selected STL was not related with sperm quality and with clinical outcomes, results do not support the use of selected STL measurement to evaluate the reproductive potential of the male patient or to predict the success rates of ART treatments.

mTOR Signaling Pathway Regulates Sperm Quality in Older Men.

Understanding how age affects fertility becomes increasingly relevant as couples delay childbearing toward later stages of their lives. While the influence of maternal age on fertility is well established, the impact of paternal age is poorly characterized. Thus, this study aimed to understand the molecular mechanisms responsible for age-dependent decline in spermatozoa quality. To attain it, we evaluated the impact of male age on the activity of signaling proteins in two distinct spermatozoa populations: total spermatozoa fraction and highly motile/viable fraction. In older men, we observed an inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) in the highly viable spermatozoa population. On the contrary, when considering the entire spermatozoa population (including defective/immotile/apoptotic cells) our findings support an active mTORC1 signaling pathway in older men. Additionally, total spermatozoa fractions of older men presented increased levels of apoptotic/stress markers (e.g., cellular tumor antigen p53-TP53) and mitogen-activated protein kinases (MAPKs) activity. Moreover, we established that the levels of most signaling proteins analyzed were consistently and significantly altered in men more than 27 years of age. This study was the first to associate the mTOR signaling pathway with the age impact on spermatozoa quality. Additionally, we constructed a network of the sperm proteins associated with male aging, identifying TP53 as a central player in spermatozoa aging.

The Action of Polyphenols in Diabetes Mellitus and Alzheimer's Disease: A Common Agent for Overlapping Pathologies.

Diabetes Mellitus (DM) and Alzheimer's disease (AD) are two prevalent diseases in modern societies, which are caused mainly by current lifestyle, aging and genetic alterations. It has already been demonstrated that these two diseases are associated, since individuals suffering from DM are prone to develop AD. Conversely, it is also known that individuals with AD are more susceptible to DM, namely type 2 diabetes (T2DM). Therefore, these two pathologies, although completely different in terms of symptomatology, end up sharing several mechanisms at the molecular level, with the most obvious being the increase of oxidative stress and inflammation. Polyphenols are natural compounds widely spread in fruits and vegetables whose dietary intake has been considered inversely proportional to the incidence of DM and AD. So, it is believed that this group of phytochemicals may have preventive and therapeutic potential, not only by reducing the risk and delaying the development of these pathologies, but also by improving brain's metabolic profile and cognitive function. The aim of this review is to understand the extent to which DM and AD are related pathologies, the degree of similarity and the relationship between them, to detail the molecular mechanisms by which polyphenols may exert a protective effect, such as antioxidant and anti-inflammatory effects, and highlight possible advantages of their use as common preventive and therapeutic alternatives.

Metabolic fingerprints in testicular biopsies from type 1 diabetic patients.

Diabetes mellitus (DM) is a metabolic disease that has grown to pandemic proportions. Recent reports have highlighted the effect of DM on male reproductive function. Here, we hypothesize that testicular metabolism is altered in type 1 diabetic (T1D) men seeking fertility treatment. We propose to determine some metabolic fingerprints in testicular biopsies of diabetic patients. For that, testicular tissue from five normal and five type 1 diabetic men was analyzed by high-resolution magic-angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy. mRNA and protein expression of glucose transporters and glycolysis-related enzymes were also evaluated. Our results show that testes from diabetic men presented decreased levels of lactate, alanine, citrate and creatine. The mRNA levels of glucose transporter 1 (GLUT1) and phosphofructokinase 1 (PFK1) were decreased in testes from diabetic men but only GLUT3 presented decreased mRNA and protein levels. Lactate dehydrogenase (LDH) and glutamate pyruvate transaminase (GPT) protein levels were also found to be decreased in testes from diabetic men. Overall, our results show that T1D alters glycolysis-related transporters and enzymes, compromising lactate content in the testes. Moreover, testicular creatine content was severely depressed in T1D men. Since lactate and creatine are essential for germ cells development and support, the data discussed here open new insights into the molecular mechanism by which DM promotes subfertility/infertility in human males.

Regucalcin, a calcium-binding protein with a role in male reproduction?

Regucalcin (RGN) is a calcium (Ca(2+))-binding protein which plays an important role in the regulation of Ca(2+) homeostasis and has been shown to catalyse an important step in L-ascorbic acid biosynthesis. It is encoded by an X-linked gene and differs from other Ca(2+)-binding proteins by lacking the typical EF-hand Ca(2+)-binding domain. RGN controls intracellular Ca(2+) concentration by regulating the activity of membrane Ca(2+) pumps. Moreover, RGN has been indicated to regulate the activity of numerous enzymes and to act in the regulation of cell proliferation and apoptosis. The importance of Ca(2+) homeostasis in spermatogenesis has been demonstrated by several studies, and its disruption has been shown to cause reversible male infertility. Recently, the expression of RGN in male reproductive tissues has been described and its localization in all testicular cell types was demonstrated. In addition, RGN expression is regulated by androgens, a class of steroid hormones recognized as male germ cell survival factors and of uttermost importance for spermatogenesis. Altogether, available information suggests the hypothesis that RGN might play a role in spermatogenesis, directly or as a mediator of androgen action. This review discusses this hypothesis presenting novel data about RGN expression in human testis.

Apoptosis-inhibitor Aven is downregulated in defective spermatogenesis and a novel estrogen target gene in mammalian testis.

OBJECTIVE: To study the expression and localization of Aven in rat and human testis from azoospermic patients with different etiologies and its regulation by estrogens. DESIGN: Experimental study. SETTING: University research center and private IVF clinic. PATIENT(S): Six men with obstructive azoospermia, five with hypospermatogenesis, and six with Sertoli cell-only syndrome; male Wistar rats. INTERVENTION(S): Testicular biopsies and rat seminiferous tubules (SeT) cultured in the presence or absence of 17ß-estradiol (E(2)). MAIN OUTCOME MEASURE(S): Testicular cell localization of Aven protein was analyzed by immunohistochemistry. Expression levels of Aven in testicular biopsies and cultured SeT, in the presence or absence of 17ß-estradiol, were determined by quantitative reverse transcription-polymerase chain reaction and Western blot. RESULT(S): Aven is expressed in Sertoli cells, spermatocytes, and spermatogonia of both rat and human testis. Aven is underexpressed in the testis of men with nonobstructive azoospermia, and its expression levels correlate with severity of spermatogenic status. Aven expression is regulated by E(2) in rat SeT cultured ex vivo. CONCLUSION(S): The results suggest that deregulation of the expression of the apoptosis inhibitor Aven may be related to male factor infertility. Moreover, Aven is an estrogen target gene and may be involved in the mechanism of testicular apoptosis control by estrogens.