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Pedro Ferreira Alves Oliveira,1 André Bonadias Gadelha,2 Rafael Gauche,2 Flávio Macedo Lahud Paiva,2 Martim Bottaro,2 Lauro C Vianna,2 Ricardo Moreno Lima2 1Department of Physical Education, Instituto Federal de Brasília, 2College of Physical Education, University of Brasília, Brasília, DF, Brazil Purpose: To examine the effects of resistance training (RT) on metabolic syndrome-related phenotypes in postmenopausal women. Patients and methods: Twenty-two postmenopausal women (65.0±4.2 years) underwent 12 weeks of whole body progressive training with intensity prescribed based on rating of perceived exertion. Dominant knee extension strength was assessed using an isokinetic dynamometer before and after the intervention. Moreover, all volunteers had blood samples collected for lipid profile, glycemic control, and C-reactive protein analyses. Waist circumference and arterial blood pressure were also measured at baseline and after the training period. Student’s t-tests for paired samples and repeated measures ANOVA were used to compare dependent variables, and statistical significance was set at P

Diets leading to caloric overload are linked to metabolic disorders and reproductive function impairment. Metabolic and hormonal abnormalities stand out as defining features of metabolic disorders, and substantially affect the functionality of the testis. Metabolic disorders induce testicular metabolic dysfunction, chronic inflammation and oxidative stress. The disruption of gastrointestinal, pancreatic, adipose tissue and testicular hormonal regulation induced by metabolic disorders can also contribute to a state of compromised fertility. In this Review, we will delve into the effects of high-fat diets and metabolic disorders on testicular metabolism and spermatogenesis, which are crucial elements for male reproductive function. Moreover, metabolic disorders have been shown to influence the epigenome of male gametes and might have a potential role in transmitting phenotype traits across generations. However, the existing evidence strongly underscores the unmet need to understand the mechanisms responsible for transgenerational paternal inheritance of male reproductive function impairment related to metabolic disorders. This knowledge could be useful for developing targeted interventions to prevent, counteract, and most of all break the perpetuation chain of male reproductive dysfunction associated with metabolic disorders across generations., (© 2024. Springer Nature Limited.)

Mitoxantrone (MTX) is a therapeutic agent used in the treatment of solid tumors and multiple sclerosis, recognized for its cardiotoxicity, with underlying molecular mechanisms not fully disclosed. The cardiotoxicity is influenced by risk factors, including age. Our study intended to assess the molecular effect of MTX on the cardiac muscle of old male CD-1 mice. Mice aged 19 months received a total cumulative dose of 4.5 mg/kg of MTX (MTX group) or saline solution (CTRL group). Two months post treatment, blood was collected, animals sacrificed, and the heart removed. MTX caused structural cardiac changes, which were accompanied by extracellular matrix remodeling, as indicated by the increased ratio between matrix metallopeptidase 2 and metalloproteinase inhibitor 2. At the metabolic level, decreased glycerol levels were found, together with a trend towards increased content of the electron transfer flavoprotein dehydrogenase. In contrast, lower glycolysis, given by the decreased content of glucose transporter GLUT4 and phosphofructokinase, seemed to occur. The findings suggest higher reliance on fatty acids oxidation, despite no major remodeling occurring at the mitochondrial level. Furthermore, the levels of glutamine and other amino acids (although to a lesser extent) were decreased, which aligns with decreased content of the E3 ubiquitin-protein ligase Atrogin-1, suggesting a decrease in proteolysis. As far as we know, this was the first study made in old mice with a clinically relevant dose of MTX, evaluating its long-term cardiac effects. Even two months after MTX exposure, changes in metabolic fingerprint occurred, highlighting enduring cardiac effects that may require clinical vigilance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Infertility is a major health issue, affecting 15% of reproductive-age couples with male factors contributing to 50% of cases. Asthenozoospermia (AS), or low sperm motility, is a common cause of male infertility with complex aetiology, involving genetic and metabolic alterations, inflammation and oxidative stress. However, the molecular mechanisms behind low motility are unclear. In this study, we used a metabolomics approach to identify metabolic biomarkers and pathways involved in sperm motility., Methods: We compared the metabolome and lipidome of spermatozoa of men with normozoospermia (n = 44) and AS (n = 22) using untargeted LC-MS and the metabolome of seminal fluid using 1 H-NMR. Additionally, we evaluated the seminal fluid redox status to assess the oxidative stress in the ejaculate., Results: We identified 112 metabolites and 209 lipids in spermatozoa and 27 metabolites in the seminal fluid of normozoospermic and asthenozoospermic men. PCA analysis of the spermatozoa's metabolomics and lipidomics data showed a clear separation between groups. Spermatozoa of asthenozoospermic men presented lower levels of several amino acids, and increased levels of energetic substrates and lysophospholipids. However, the metabolome and redox status of the seminal fluid was not altered inAS., Conclusions: Our results indicate impaired metabolic pathways associated with redox homeostasis and amino acid, energy and lipid metabolism in AS. Taken together, these findings suggest that the metabolome and lipidome of human spermatozoa are key factors influencing their motility and that oxidative stress exposure during spermatogenesis or sperm maturation may be in the aetiology of decreased motility in AS., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: Sperm-borne microRNAs play a pivotal role in influencing essential cellular processes during fertilization, impacting the quality of embryo development. Dysregulated microRNA profiles have been associated with compromised embryonic development and increased incidences of pregnancy loss., Objective: This study aimed to investigate the potential associations between the abundance of miR-34c-5p and miR-191-3p in human spermatozoa with sperm quality, as well as with embryo quality and metabolic performance during in vitro development., Materials and Methods: Thirteen couples who underwent a total of 13 cycles participated in this study. The sperm quality was assessed using conventional methods following World Health Organization guidelines. Quantitative polymerase chain reaction was employed to measure microRNA abundance in spermatozoa. Embryos were categorized as good, lagging, or bad based on morphokinetic evaluation. Evaluation of embryo metabolic performance involved tracking changes in specific metabolites within the cultured media using nuclear magnetic resonance spectroscopy. Statistical analysis was conducted to explore the correlation between microRNA abundance in human spermatozoa and all other collected data., Results: Our findings revealed a negative correlation between the abundance of miR-34c-5p (but not miR-191-3p) and total sperm motility, potentially mediated by the modulation of key signaling pathways. Additionally, higher levels of miR-34c-5p in spermatozoa were strongly associated with the consumption or release of key metabolites by developing embryos, particularly those linked with lipid and glucose metabolism, suggesting enhanced metabolic performance, while miR-191-3p was mostly associated with glucose consumption. Concurrently, only miR-34c-5p content in spermatozoa correlated with higher embryo quality., Discussion and Conclusion: This study provides evidence suggesting that the abundance of miR-34c-5p in spermatozoa is correlated not only with total sperm motility but also with markers of embryo developmental competence, highlighting the potential significance of this sperm microRNA content as a biomarker in assisted reproduction., (© 2024 American Society of Andrology and European Academy of Andrology.)

Sepsis-associated encephalopathy, which manifests in severe cognitive and depressive symptoms, is directly linked to neuroinflammation. Our study investigates the efficacy of 25H-NBOMe, a phenethylamine, in alleviating these symptoms, potentially offering an innovative treatment for post-sepsis depression. Wistar rats, weighing between 250-300 g, were subjected to cecal ligation and puncture (CLP) surgery to induce sepsis. Depressive-like behaviors were assessed using the forced swim test (FST) on either day 7 or 14 post-surgery, to establish the presence of depressive symptoms. The impact of 25H-NBOMe treatment was then evaluated, focusing on the head-twitch response (HTR), performance in the FST, and GFAP expression in the prefrontal cortex. Treatment with 25H-NBOMe resulted in significant behavioral changes, demonstrated by decreased immobility and increased swimming times in the FST, along with a rise in the HTR. These outcomes indicate a reduction in depressive-like symptoms post-sepsis and the psychoactive effects of the compound. Furthermore, a notable decrease in GFAP expression in the study highlights the compound's impact on mitigating sepsis-induced astrogliosis. This study demonstrates the effectiveness of 25H-NBOMe, a psychedelic in the phenethylamine class, in treating post-sepsis depression and reducing astrogliosis. However, the psychedelic nature of 25H-NBOMe calls for further investigation into similar compounds with less psychoactive impact, crucial for advancing treatment options for neuropsychiatric symptoms following sepsis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Oxidative stress and mitochondrial dysfunction are important elements for the pathophysiology of preeclampsia (PE), a multisystemic hypertensive syndrome of pregnancy, characterized by endothelial dysfunction and responsible for a large part of maternal and fetal morbidity and mortality worldwide. Researchers have dedicated their efforts to unraveling the intricate ways in which certain molecules influence both energy metabolism and oxidative stress. Exploring established methodologies from existing literature, shows that these investigations predominantly focus on the placenta, identified as a pivotal source that drives the changes observed in the disease. In this review, we discuss the role of oxidative stress in pathophysiology of PE, as well as metabolic/endothelial dysfunction. We further discuss the use of seahorse analyzers to study real-time bioenergetics of endothelial cells. Although the benefits are clear, few studies have presented results using this method to assess mitochondrial metabolism in these cells. We performed a search on MEDLINE/PubMed using the terms "Seahorse assay and endothelial dysfunction in HUVEC" as well as "Seahorse assay and preeclampsia". From our research, we selected 16 original peer-review papers for discussion. Notably, the first search retrieved studies involving Human Umbilical Vein Endothelial Cells (HUVECs) but none investigating bioenergetics in PE while the second search retrieved studies exploring the technique in PE but none of the studies used HUVECs. Additional studies are required to investigate real-time mitochondrial bioenergetics in PE. Clearly, there is a need for more complete studies to examine the nuances of mitochondrial bioenergetics, focusing on the contributions of HUVECs in the context of PE., Competing Interests: Declaration of competing interest The authors declare there are no financial or non-financial interests that are directly or indirectly related to the work submitted for peer review., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Lung branching morphogenesis relies on intricate epithelial-mesenchymal interactions and signaling networks. Still, the interplay between signaling and energy metabolism in shaping embryonic lung development remains unexplored. Retinoic acid (RA) signaling influences lung proximal-distal patterning and branching morphogenesis, but its role as a metabolic modulator is unknown. Hence, this study investigates how RA signaling affects the metabolic profile of lung branching. We performed ex vivo lung explant culture of embryonic chicken lungs treated with DMSO, 1 µM RA, or 10 µM BMS493. Extracellular metabolite consumption/production was evaluated by using 1 H-NMR spectroscopy. Mitochondrial respiration and biogenesis were also analyzed. Proliferation was assessed using an EdU-based assay. The expression of crucial metabolic/signaling components was examined through Western blot, qPCR, and in situ hybridization. RA signaling stimulation redirects glucose towards pyruvate and succinate production rather than to alanine or lactate. Inhibition of RA signaling reduces lung branching, resulting in a cystic-like phenotype while promoting mitochondrial function. Here, RA signaling emerges as a regulator of tissue proliferation and lactate dehydrogenase expression. Furthermore, RA governs fatty acid metabolism through an AMPK-dependent mechanism. These findings underscore RA's pivotal role in shaping lung metabolism during branching morphogenesis, contributing to our understanding of lung development and cystic-related lung disorders.

Atrazine (ATZ), a widely used herbicide with potent endocrine-disrupting properties, has been implicated in hormonal disturbances and fertility issues. Sertoli cells (SCs) play a crucial role in providing mechanical and nutritional support of spermatogenesis. Herein, we aimed to study the effects of environmentally relevant ATZ concentrations on the nutritional support of spermatogenesis provided by SCs. For that, mouse SCs (TM4) were exposed to increasing ATZ concentrations (in μg/L: 0.3, 3, 30, 300, or 3000). After 24 h, cellular proliferation and metabolic activity were assessed. Mitochondrial activity and endogenous reactive oxygen species (ROS) production were evaluated using JC-1 and CM-H 2 DCFDA probes, respectively. We also analyzed protein levels of lactate dehydrogenase (LDH) using Western Blot and live cells glycolytic function through Seahorse XF Glycolysis Stress Test Kit. ATZ exposure decreased the activity of oxidoreductases in SCs, suggesting a decreased metabolic activity. Although ATZ is reported to induce oxidative stress, we did not observe alterations in mitochondrial membrane potential and ROS production across all tested concentrations. When we evaluated the glycolytic function of SCs, we observed that ATZ significantly impaired glycolysis and the glycolytic capacity at all tested concentrations. These results were supported by the decreased expression of LDH in SCs. Overall, our findings suggest that ATZ impairs the glycolytic function of SCs through LDH downregulation. Since lactate is the preferential energetic substrate for germ cells, exposure to ATZ may detrimentally impact the nutritional support crucial for spermatogenesis, hinting for a relationship between ATZ exposure and male infertility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

The health benefits of exercise training in a cancer setting are increasingly acknowledged; however, the underlying molecular mechanisms remain poorly understood. It has been suggested that extracellular vesicles (EVs) released from contracting skeletal muscles play a key role in mediating the systemic benefits of exercise by transporting bioactive molecules, including myokines. Nevertheless, skeletal muscle-derived vesicles account for only about 5% of plasma EVs, with the immune cells making the largest contribution. Moreover, it remains unclear whether the contribution of skeletal muscle-derived EVs increases after physical exercise or how muscle contraction modulates the secretory activity of other tissues and thus influences the content and profile of circulating EVs. Furthermore, the destination of EVs after exercise is unknown, and it depends on their molecular composition, particularly adhesion proteins. The cargo of EVs is influenced by the training program, with acute training sessions having a greater impact than chronic adaptations. Indeed, there are numerous questions regarding the role of EVs in mediating the effects of exercise, the clarification of which is critical for tailoring exercise training prescriptions and designing exercise mimetics for patients unable to engage in exercise programs. This review critically analyzes the current knowledge on the effects of exercise on the content and molecular composition of circulating EVs and their impact on cancer progression., (© 2024. The Author(s).)

Even though in silico drug ligand-based methods have been successful in predicting interactions with known target proteins, they struggle with new, unassessed targets. To address this challenge, we propose an approach that integrates structural data from AlphaFold 2 predicted protein structures into machine learning models. Our method extracts 3D structural protein fingerprints and combines them with ligand structural data to train a single machine learning model. This model captures the relationship between ligand properties and the unique structural features of various target proteins, enabling predictions for never before tested molecules and protein targets. To assess our model, we used a dataset of 144 Human G-protein Coupled Receptors (GPCRs) with over 140,000 measured inhibition constants (K i ) values. Results strongly suggest that our approach performs as well as state-of-the-art ligand-based methods. In a second modeling approach that used 129 targets for training and a separate test set of 15 different protein targets, our model correctly predicted interactions for 73% of targets, with explained variances exceeding 0.50 in 22% of cases. Our findings further verified that the usage of experimentally determined protein structures produced models that were statistically indistinct from the Alphafold synthetic structures. This study presents a proteo-chemometric drug screening approach that uses a simple and scalable method for extracting protein structural information for usage in machine learning models capable of predicting protein-molecule interactions even for orphan targets., (© 2024. The Author(s).)

Objective: Summarize the evidence on drug therapies for obstructive sleep apnea., Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. PubMed, Embase, Scopus, Web of Science, SciELO, LILACS, Scopus, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched on February 17th, 2023. A search strategy retrieved randomized clinical trials comparing the Apnea-Hypopnea Index (AHI) in pharmacotherapies. Studies were selected and data was extracted by two authors independently. The risk of bias was assessed using the Cochrane Risk of Bias tool. RevMan 5.4. was used for data synthesis., Results: 4930 articles were obtained, 68 met inclusion criteria, and 29 studies (involving 11 drugs) were combined in a meta-analysis. Atomoxetine plus oxybutynin vs placebo in AHI mean difference of -7.71 (-10.59, -4.83) [Fixed, 95 % CI, I2 = 50 %, overall effect: Z = 5.25, p < 0.001]. Donepezil vs placebo in AHI mean difference of -8.56 (-15.78, -1.33) [Fixed, 95 % CI, I2 = 21 %, overall effect: Z = 2.32, p = 0.02]. Sodium oxybate vs placebo in AHI mean difference of -5.50 (-9.28, -1.73) [Fixed, 95 % CI, I2 = 32 %, overall effect: Z = 2.86, p = 0.004]. Trazodone vs placebo in AHI mean difference of -12.75 (-21.30, -4.19) [Fixed, 95 % CI, I2 = 0 %, overall effect: Z = 2.92, p = 0.003]., Conclusion: The combination of noradrenergic and antimuscarinic drugs shows promising results. Identifying endotypes may be the key to future drug therapies for obstructive sleep apnea. Moreover, studies with longer follow-up assessing the safety and sustained effects of these treatments are needed., Prospero Registration Number: CRD42022362639., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

In Brief: Mitochondrial uncoupling proteins (UCPs) regulate mitochondrial activity and reactive oxygen species production through the transport of protons and metabolites. This study identified the expression of UCPs in human Sertoli cells, which proved to be modulators of their mitochondrial activity., Abstract: Mitochondrial uncoupling proteins (UCPs) are mitochondrial channels responsible for the transport of protons and small molecular substrates across the inner mitochondrial membrane. Altered UCP expression or function is commonly associated with mitochondrial dysfunction and increased oxidative stress, which are both known causes of male infertility. However, UCP expression and function in the human testis remain to be characterized. This study aimed to assess the UCP homologs (UCP1-6) expression and function in primary cultures of human Sertoli cells (hSCs). We identified the mRNA expression of all UCP homologs (UCP1-6) and protein expression of UCP1, UCP2, and UCP3 in hSCs. UCP inhibition by genipin for 24 h decreased hSCs proliferation without causing cytotoxicity (n = 6). Surprisingly, the prolonged UCP inhibition for 24 h decreased mitochondrial membrane potential, oxygen consumption rate (OCR), and endogenous reactive oxygen species (ROS) production. The metabolism of hSCs was also affected as UCP inhibition shifted their metabolism toward an increased pyruvate consumption. Taken together, these findings demonstrate that UCPs play a role as regulators of the mitochondrial function in hSCs, emphasizing their potential as targets in the study of male (in)fertility.

Purpose: The advent of proteomics provides new opportunities to investigate the molecular mechanisms underlying male infertility. The selection of relevant targets based on a single analysis is not always feasible, due to the growing number of proteomic studies with conflicting results. Thus, this study aimed to systematically review investigations comparing the sperm proteome of normozoospermic and infertile men to define a panel of proteins with the potential to be used to evaluate sperm quality., Materials and Methods: A literature search was conducted on PubMed, Web of Science, and Scopus databases following the PRISMA guidelines. To identify proteins systematically reported, first the studies were divided by condition into four groups (asthenozoospermia, low motility, unexplained infertility, and infertility related to risk factors) and then, all studies were analysed simultaneously (poor sperm quality). To gain molecular insights regarding identified proteins, additional searches were performed within the Human Protein Atlas, Mouse Genome Informatics, UniProt, and PubMed databases., Results: Thirty-two studies were included and divided into 4 sub-analysis groups. A total of 2752 proteins were collected, of which 38, 1, 3 and 2 were indicated as potential markers for asthenozoospermia, low motility, unexplained infertility and infertility related to risk factors, respectively, and 58 for poor sperm quality. Among the identified proteins, ACR, ACRBP, ACRV1, ACTL9, AKAP4, ATG3, CCT2, CFAP276, CFAP52, FAM209A, GGH, HPRT1, LYZL4, PRDX6, PRSS37, REEP6, ROPN1B, SPACA3, SOD1, SPEM1, SPESP1, SPINK2, TEKT5, and ZPBP were highlighted due to their roles in male reproductive tissues, association with infertility phenotypes or participation in specific biological functions in spermatozoa., Conclusions: Sperm proteomics allows the identification of protein markers with the potential to overcome limitations in male infertility diagnosis and to understand changes in sperm function at the molecular level. This study provides a reliable list of systematically reported proteins that could be potential targets for further basic and clinical studies., Competing Interests: The authors have nothing to disclose., (Copyright © 2024 Korean Society for Sexual Medicine and Andrology.)

Embryo quality evaluation during in vitro development is a crucial factor for the success of assisted reproductive technologies (ARTs). However, the subjectivity inherent in the morphological evaluation by embryologists can introduce inconsistencies that impact the optimal embryo choice for transfer. To provide a more comprehensive evaluation of embryo quality, we undertook the integration of embryo metabolomics alongside standardized morphokinetic classification. The culture medium of 55 embryos (derived from 21 couples undergoing ICSI) was collected at two timepoints (days 3 and 5). Samples were split into Good (n = 29), Lagging (n = 19), and Bad (n = 10) according to embryo morphokinetic evaluation. Embryo metabolic performance was assessed by monitoring the variation in specific metabolites (pyruvate, lactate, alanine, glutamine, acetate, formate) using 1 H-NMR. Adjusted metabolite differentials were observed during the first 3 days of culture and found to be discriminative of embryo quality at the end of day 5. Pyruvate, alanine, glutamine, and acetate were major contributors to this discrimination. Good and Lagging embryos were found to export and accumulate pyruvate and glutamine in the first 3 days of culture, while Bad embryos consumed them. This suggests that Bad embryos have less active metabolic activity than Good and Lagging embryos, and these two metabolites are putative biomarkers for embryo quality. This study provides a more comprehensive evaluation of embryo quality and can lead to improvements in ARTs by enabling the selection of the best embryos. By combining morphological assessment and metabolomics, the selection of high-quality embryos with the potential to result in successful pregnancies may become more accurate and consistent.

Leydig cells (LCs) play a pivotal role in male fertility, producing testosterone. Chromium (III) picolinate (CrPic 3 ), a contentious supplement with antidiabetic and antioxidant properties, raises concerns regarding male fertility. Using a rodent LC line, we investigated the cytotoxicity of increasing CrPic 3 doses. An insulin resistance (IR) model was established using palmitate (PA), and LCs were further exposed to CrPic 3 to assess its antioxidant/antidiabetic activities. An exometabolome analysis was performed using 1 H-NMR. Mitochondrial function and oxidative stress were evaluated via immunoblot. Steroidogenesis was assessed by quantifying androstenedione through ELISA. Our results uncover the toxic effects of CrPic 3 on LCs even at low doses under IR conditions. Furthermore, even under these IR conditions, CrPic 3 fails to enhance glucose consumption but restores the expression of mitochondrial complexes CII and CIII, alleviating oxidative stress in LCs. While baseline androgen production remained unaffected, CrPic 3 promoted androstenedione production in LCs in the presence of PA, suggesting that it promotes cholesterol conversion into androgenic intermediates in this context. This study highlights the need for caution with CrPic 3 even at lower doses. It provides valuable insights into the intricate factors influencing LCs metabolism and antioxidant defenses, shedding light on potential benefits and risks of CrPic 3 , particularly in IR conditions.

In recent years, the treatment of advanced non-small cell lung cancer (NSCLC) has suffered a variety of alterations. Chemotherapy (CTX), immunotherapy (IT) and tyrosine kinase inhibitors (TKI) have shown remarkable results. However, not all patients with NSCLC respond to these drug treatments or receive durable benefits. In this framework, metabolomics has been applied to improve the diagnosis, treatment, and prognosis of lung cancer and particularly lung adenocarcinoma (AdC). In our study, metabolomics was used to analyze plasma samples from 18 patients with AdC treated with CTX or IT via 1 H-NMR spectroscopy. Relevant clinical information was gathered, and several biochemical parameters were also evaluated throughout the treatments. During the follow-up of patients undergoing CTX or IT, imaging control is recommended in order to assess the effectiveness of the therapy. This evaluation is usually performed every three treatments. Based on this procedure, all the samples were collected before the beginning of the treatment and after three and six treatments. The identified and quantified metabolites in the analyzed plasma samples were the following: isoleucine, valine, alanine, acetate, lactate, glucose, tyrosine, and formate. Multivariate/univariate statistical analyses were performed. Our data are in accordance with previous published results, suggesting that the plasma glucose levels of patients under CTX become higher throughout the course of treatment, which we hypothesize could be related to the tumor response to the therapy. It was also found that alanine levels become lower during treatment with CTX regimens, a fact that could be associated with frailty. NMR spectra of long responders' profiles also showed similar results. Based on the results of the study, metabolomics can represent a potential option for future studies, in order to facilitate patient selection and the monitoring of therapy efficacy in treated patients with AdC. Further studies are needed to improve the prospective identification of predictive markers, particularly glucose and alanine levels, as well as confer guidance to NSCLC treatment and patient stratification, thus avoiding ineffective therapeutic strategies.

In recent decades, the escalating prevalence of metabolic disorders, notably obesity and being overweight, has emerged as a pressing concern in public health. Projections for the future indicate a continual upward trajectory in obesity rates, primarily attributable to unhealthy dietary patterns and sedentary lifestyles. The ramifications of obesity extend beyond its visible manifestations, intricately weaving a web of hormonal dysregulation, chronic inflammation, and oxidative stress. This nexus of factors holds particular significance in the context of carcinogenesis, notably in the case of prostate cancer (PCa), which is a pervasive malignancy and a leading cause of mortality among men. A compelling hypothesis arises from the perspective of transgenerational inheritance, wherein genetic and epigenetic imprints associated with obesity may wield influence over the development of PCa. This review proposes a comprehensive exploration of the nuanced mechanisms through which obesity disrupts prostate homeostasis and serves as a catalyst for PCa initiation. Additionally, it delves into the intriguing interplay between the transgenerational transmission of both obesity-related traits and the predisposition to PCa. Drawing insights from a spectrum of sources, ranging from in vitro and animal model research to human studies, this review endeavors to discuss the intricate connections between obesity and PCa. However, the landscape remains partially obscured as the current state of knowledge unveils only fragments of the complex mechanisms linking these phenomena. As research advances, unraveling the associated factors and underlying mechanisms promises to unveil novel avenues for understanding and potentially mitigating the nexus between obesity and the development of PCa.

Background: The concept of the inheritance of acquired traits, a foundational principle of Lamarck's evolutionary theory, has garnered renewed attention in recent years. Evidence for this phenomenon remained limited for decades but gained prominence with the Överkalix cohort study in 2002. This study revealed a link between cardiovascular disease incidence and the food availability experienced by individuals' grandparents during their slow growth periods, reigniting interest in the inheritance of acquired traits, particularly in the context of non-communicable diseases. This scientometric analysis and systematic review comprehensively explores the current landscape of paternally transmitted acquired metabolic traits., Results: Utilizing Scopus Advanced search and meticulous screening, we included mammalian studies that document the inheritance or modification of metabolic traits in subsequent generations of unexposed descendants. Our inclusive criteria encompass intergenerational and transgenerational studies, as well as multigenerational exposures. Predominantly, this field has been driven by a select group of researchers, potentially shaping the design and focus of existing studies. Consequently, the literature primarily comprises transgenerational rodent investigations into the effects of ancestral exposure to environmental pollutants on sperm DNA methylation. The complexity and volume of data often lead to multiple or redundant publications. This practice, while understandable, may obscure the true extent of the impact of ancestral exposures on the health of non-exposed descendants. In addition to DNA methylation, studies have illuminated the role of sperm RNAs and histone marks in paternally acquired metabolic disorders, expanding our understanding of the mechanisms underlying epigenetic inheritance., Conclusions: This review serves as a comprehensive resource, shedding light on the current state of research in this critical area of science, and underscores the need for continued exploration to uncover the full spectrum of paternally mediated metabolic inheritance., (© 2023. The Author(s).)

Diabetic nephropathy (DN) and insulin resistance (IR) in kidney cells are considered main causes for end-stage renal failure. However, it is unclear how IR affects early stages of the disease. Here, we investigate the impact of mild (11 mM) and severe (22 mM) hyperglycemia, with and without induced IR, on cellular metabolism and mitochondrial bioenergetics in a human kidney cell line (HK-2). IR in HK-2 cells was induced with palmitic acid and cellular cytotoxicity was studied. We evaluated the impact of mild and severe hyperglycemia with and without IR on the metabolic secretome of the cells, their live-cell mitochondria function, mitochondrial membrane potential, and mitochondrial complex activities. Furthermore, we measured fatty acid oxidation and lipid accumulation. Cells cultured under mild hyperglycemic conditions exhibited increased mitochondrial bioenergetic parameters, such as basal respiration, ATP-linked production, maximal respiration capacity, and spare respiration capacity. However, these parameters decreased when cells were cultured under higher glucose concentrations when IR was induced. Our data suggests that progression from mild to severe hyperglycemia induces a metabolic shift, where gluconeogenic amino acids play a crucial role in supplying the energy requirements of HK-2. To our knowledge, this is the first study to evaluate the progression from mild to severe hyperglycemia allied to IR in human kidney cells. This work highlights that this progression leads to mitochondrial dysfunction and alters the metabolic profile of kidney cells. These results identify possible targets for early intervention in DN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This study aimed at evaluating the potential of Copaifera lucens , specifically its oleoresin (CLO), extract (CECL), and the compound ent -polyalthic acid (PA), in combating caries and toxoplasmosis, while also assessing its toxicity. The study involved multiple assessments, including determining the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against cariogenic bacteria. CLO and PA exhibited MIC and MBC values ranging from 25 to 50 μg/mL, whereas CECL showed values equal to or exceeding 400 μg/mL. PA also displayed antibiofilm activity with minimum inhibitory concentration of biofilm (MICB 50 ) values spanning from 62.5 to 1000 μg/mL. Moreover, PA effectively hindered the intracellular proliferation of Toxoplasma gondii at 64 μg/mL, even after 24 h without treatment. Toxicological evaluations included in vitro tests on V79 cells, where concentrations ranged from 78.1 to 1250 μg/mL of PA reduced colony formation. Additionally, using the Caenorhabditis elegans model, the lethal concentration (LC 50 ) of PA was determined as 1000 μg/mL after 48 h of incubation. Notably, no significant differences in micronucleus induction and the NDI were observed in cultures treated with 10, 20, or 40 μg/mL of CLO. These findings underscore the safety profile of CLO and PA, highlighting their potential as alternative treatments for caries and toxoplasmosis.

L-Carnitine, a natural antioxidant found in mammals, plays a crucial role in the transport of long-chain fatty acids across the inner mitochondrial membrane. It is used as a nutritional supplement by professional athletes, improving performance and post-exercise recovery. Additionally, its therapeutic applications, including those in male infertility, have been investigated, as it may act as a defense mechanism against the excessive production of reactive oxygen species (ROS) in the testis, a process that can lead to sperm damage. This effect is achieved by enhancing the expression and activity of enzymes with antioxidant properties. Nevertheless, the mechanisms underlying the benefits of L-Carnitine remain unknown. This review aims to consolidate the current knowledge about the potential benefits of L-Carnitine and its role in male (in)fertility. Considering in vitro studies with Sertoli cells, pre-clinical studies, and investigations involving infertile men, a comprehensive understanding of the effects of L-Carnitine has been established. In vitro studies suggest that L-Carnitine has a direct influence on somatic Sertoli cells, improving the development of germ cells. Overall, evidence supports that L-Carnitine can positively impact male fertility, even at a relatively low dose of 2 g/day. This supplementation enhances sperm parameters, regulates hormone levels, reduces ROS levels, and subsequently improves fertility rates. However, further research is needed to elucidate the underlying mechanisms and establish optimal doses. In conclusion, the role of L-Carnitine in the field of male reproductive health is highlighted, with the potential to improve sperm quality and fertility.

Low testosterone (T) levels are a major cause of male infertility, as this hormone is crucial for several processes throughout the entire male reproductive tract. Leydig cells (LC) produce T through testicular steroidogenesis. Disrupted LC function can hinder steroid production and fertility. Among the factors that affect steroidogenesis, endocrine-disrupting chemicals (EDCs) raise concerns, as they disturb hormonal signaling. Chromium is classified as an EDC, and its main forms are hexavalent (Cr(VI)) and trivalent chromium (Cr(III)). While Cr(III) is controversially regarded as an essential metal, its compound Cr(III) picolinate (CrPic 3 ) is used as a nutritional supplement due to its antidiabetic and antioxidant properties. This review aims to identify the possible effects of CrPic 3 on testicular steroidogenesis and thus, on male fertility. The detriments caused by CrPic 3 in LC include the inhibition of enzymes involved in steroidogenesis, and, as in other cells, the induction of mutagenesis and apoptosis. Remarkably, CrPic 3 impacts male fertility through the alteration of reactive oxygen species (ROS), T levels, and sperm parameters (sperm motility and abnormal sperm count). However, gaps and inconsistencies exist in the literature concerning its effects on male fertility. Thus, further research is imperative to comprehend the underlying mechanisms of CrPic 3 in the physiological processes relevant to male fertility, ensuring the supplement's safety for use by men.

Osmoregulation plays a vital role in sperm function, encompassing spermatogenesis, maturation, and fertilization. Aquaglyceroporins, a subclass of aquaporins (AQPs), facilitate the transport of water and glycerol across the sperm membrane, with glycerol serving as an important substrate for sperm bioenergetics. This study aimed to elucidate the significance of AQP-mediated glycerol permeability in sperm motility. The presence and localization of AQP3 and AQP7 in human sperm were assessed using immunofluorescence. Subsequently, the glycerol permeability of spermatozoa obtained from normozoospermic individuals ( n = 30) was measured, using stopped-flow light scattering, after incubation with specific aquaporin inhibitors targeting AQP3 (DFP00173), AQP7 (Z433927330), or general aquaglyceroporin (phloretin). Sperm from asthenozoospermic men ( n = 30) were utilized to evaluate the AQP7-mediated glycerol permeability, and to compare it with that of normozoospermic men. Furthermore, hypermotile capacitated sperm cells were examined, to determine the AQP7 expression and membrane glycerol permeability. AQP3 was predominantly observed in the tail region, while AQP7 was present in the head, midpiece, and tail of human sperm. Our findings indicate that AQP7 plays a key role in glycerol permeability, as the inhibition of AQP7 resulted in a 55% decrease in glycerol diffusion across the sperm membrane. Importantly, this glycerol permeability impairment was evident in spermatozoa from asthenozoospermic individuals, suggesting the dysregulation of AQP7-mediated glycerol transport, despite similar AQP7 levels. Conversely, the AQP7 expression increased in capacitated sperm, compared to non-capacitated sperm. Hence, AQP7-mediated permeability may serve as a valuable indicator of sperm motility, and be crucial in sperm function.

Introduction: Fertility rates in developing countries have declined over the past decades, and the trend of delayed fatherhood is rising as societies develop. The reasons behind the decline in male fertility with advancing age remain mysterious, making it a compelling and crucial area for further research. However, the limited number of studies dedicated to unraveling this enigma poses a challenge. Thus, our objective is to illuminate some of the upregulated and downregulated mechanisms in the male testis during the aging process., Areas Covered: Herein, we present a critical overview of the studies addressing the alterations of testicular proteome through the aging process, starting from sexually matured young males to end-of-life-expectancy aged males. The comparative studies of the proteomic testicular profile of men with and without spermatogenic impairment are also discussed and key proteins and pathways involved are highlighted., Expert Opinion: The difficulty of making age-comparative studies, especially of advanced-age study subjects, makes this topic of study quite challenging. Another topic worth mentioning is the heterogeneous nature and vast cellular composition of testicular tissue, which makes proteome data interpretation tricky. The cell type sorting and comorbidities testing in the testicular tissue of the studied subjects would help mitigate these problems.

Mitochondria are pivotal to cellular homeostasis, performing vital functions such as bioenergetics, biosynthesis, and cell signalling. Proper maintenance of these processes is crucial to prevent disease development and ensure optimal cell function. Mitochondrial dynamics, including fission, fusion, biogenesis, mitophagy, and apoptosis, maintain mitochondrial quality control, which is essential for overall cell health. In male reproduction, mitochondria play a pivotal role in germ cell development and any defects in mitochondrial quality can have serious consequences on male fertility. Reactive oxygen species (ROS) also play a crucial role in sperm capacitation, but excessive ROS levels can trigger oxidative damage. Any imbalance between ROS and sperm quality control, caused by non-communicable diseases or environmental factors, can lead to an increase in oxidative stress, cell damage, and apoptosis, which in turn affect sperm concentration, quality, and motility. Therefore, assessing mitochondrial functionality and quality control is essential to gain valuable insights into male infertility. In sum, proper mitochondrial functionality is essential for overall health, and particularly important for male fertility. The assessment of mitochondrial functionality and quality control can provide crucial information for the study and management of male infertility and may lead to the development of new strategies for its management.

The modulation of inflammatory elements, cell differentiation and proliferation by vitamin D and the role of probiotics in the intestinal microbiota and immunogenic response have sparked interest in the application of both in chemotherapeutics and chemoprevention of colorectal tumors., Aims: The present study aimed to investigate the effects of isolated and/or combined treatment of vitamin D3 and probiotics on colorectal carcinogenesis., Main Methods: Pre-neoplastic lesions were induced with 1,2-dimethylhydrazine in the colon of Wistar rats, which were treated with probiotics and/or vitamin D in three different approaches (simultaneous, pre-, and post-treatment). We investigated the frequency of aberrant crypt foci (ACF) and aberrant crypt (AC) in the distal colon, fecal microbiome composition, gene and protein expression through immunohistochemical and RT-PCR assays, and general toxicity through water consumption and weight gain monitoring., Key Findings: Results confirm the systemic safety of treatments, and show a protective effect of vitamin D and probiotics in all approaches studied, as well as in combined treatments, with predominance of different bacterial phyla compared to controls. Treated groups show different levels of Nrf2, GST, COX2, iNOS, β-catenin and PCNA expression., Significance: These experimental conditions explore the combination of vitamin D and probiotics supplementation at low doses over pathways involved in distinct stages of colorectal carcinogenesis, with results supporting its application in prevention and long-term strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Visceral adipose tissue (VAT) metabolic fingerprints differ according to body mass index (BMI) and glycemic status. Glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon are gut-associated hormones that play an important role in regulating energy and glucose homeostasis, although their metabolic actions in VAT are still poorly characterized. Our aim was to assess whether GLP-1, GIP and glucagon influence the VAT metabolite profile. To achieve this goal, VAT harvested during elective surgical procedures from individuals ( N = 19) with different BMIs and glycemic statuses was stimulated with GLP-1, GIP or glucagon, and culture media was analyzed using proton nuclear magnetic resonance. In the VAT of individuals with obesity and prediabetes, GLP-1 shifted its metabolic profile by increasing alanine and lactate production while also decreasing isoleucine consumption, whereas GIP and glucagon decreased lactate and alanine production and increased pyruvate consumption. In summary, GLP-1, GIP and glucagon were shown to distinctively modulate the VAT metabolic profile depending on the subject's BMI and glycemic status. In VAT from patients with obesity and prediabetes, these hormones induced metabolic shifts toward gluconeogenesis suppression and oxidative phosphorylation enhancement, suggesting an overall improvement in AT mitochondrial function.

Mitochondrial uncoupling proteins (UCPs) are central in the regulation of mitochondrial activity and reactive oxygen species (ROS) production. High oxidative stress is a major cause of male infertility; however, UCPs expression and function in human spermatozoa are still unknown. Herein, we aimed to assess the expression and function of the different homologs (UCP1-6) in human spermatozoa. For this purpose, we screened for the mRNA expression of all UCP homologs. Protein expression and immunolocalization of UCP1, UCP2, and UCP3 were also assessed. Highly motile spermatozoa were isolated from human normozoospermic seminal samples (n = 16) and incubated with genipin, an inhibitor of UCPs (0, 0.5, 5, and 50 µM) for 3 h at 37 °C. Viability and total motility were assessed. Mitochondrial membrane potential and ROS production were evaluated. Media were collected and the metabolic profile and antioxidant potential were analyzed by 1 H-NMR and FRAP, respectively. The expression of all UCP homologs ( UCP1-6 ) mRNA by human spermatozoa is herein reported for the first time. UCP1-3 are predominant at the head equatorial segment, whereas UCP1 and UCP2 are also expressed at the spermatozoa midpiece, where mitochondria are located. The inhibition of UCPs by 50 µM genipin, resulting in the UCP3 inhibition, did not compromise sperm cell viability but resulted in irreversible total motility loss that persisted despite washing or incubation with theophylline, a cAMP activator. These effects were associated with decreased mitochondrial membrane potential and lactate production. No differences concerning UCP3 expression, however, were observed in spermatozoa from normozoospermic versus asthenozoospermic men (n = 6). The inhibition of UCPs did not increase ROS production, possibly due to the decreased mitochondrial activity and genipin antioxidant properties. In sum, UCPs are major regulators of human spermatozoa motility and metabolism. The discovery and characterization of UCPs' role in human spermatozoa can shed new light on spermatozoa ROS-related pathways and bioenergetics physiology.

Infertility is becoming a chronic and emerging problem in the world. There is a resistant stigma that this health condition is mostly due to the female, although the literature supports that the responsibility for the onset of infertility is equally shared between both sexes in more or less equal proportions. Nevertheless, male sex hormones, particularly testosterone (T), are key players in male-related infertility. Indeed, hypogonadism, which is also characterized by changes in T levels, is one of the most common causes of male infertility and its incidence has been interconnected to the increased prevalence of metabolic diseases. Recent data also highlight the role of aquaporin (AQP)-mediated water and solute diffusion and the metabolic homeostasis in testicular cells suggesting a strong correlation between AQPs function, metabolism of testicular cells, and infertility. Indeed, recent studies showed that both metabolic and sexual hormone concentrations can change the expression pattern and function of AQPs. Herein, we review up-to-date information on the involvement of AQP-mediated function and permeability in men with metabolic syndrome and testosterone deficit, highlighting the putative mechanisms that show an interaction between sex hormones, AQPs, and metabolic syndrome that may contribute to male infertility.

Research Question: Does sirtuin-1 (SIRT1) have a role in the human spermatozoa capacitation process?, Design: Human spermatozoa were incubated for 6 h in a capacitating medium in presence or absence of the specific SIRT1 activator, YK 3-237. Several sperm parameters were determined by flow cytometry: viability, acrosome reaction and mitochondria membrane status. Sperm motility was determined objectively by computer-assisted semen analysis. Sperm capacitation status was evaluated by the extent of protein tyrosine phosphorylation and by the percentage of spermatozoa with the acrosome reacted by a calcium ionophore challenge., Results: SIRT1 was detected in the connecting piece of human spermatozoa where a lysine acetylation pattern was mainly found along the sperm tail. SIRT1 activation accelerates the occurrence of a phenotype associated with human sperm capacitation, with no differences seen in the lysine acetylation pattern. After 1 h of co-incubation of YK 3-237 with human spermatozoa, tyrosine phosphorylation levels were comparable to control levels after 6 h of incubation in capacitating conditions. In addition, the activator improved sperm responsiveness to a Ca 2+ ionophore (A23187) challenge determined by an increase in acrosome-reacted spermatozoa (P = 0.025). Importantly, sperm viability and mitochondrial activity-related parameters assessed by flow cytometry were not affected by YK 3-237., Conclusion: YK 3-237 induces capacitation-related events in human spermatozoa such an increase of tyrosine phosphorylation levels and acrosome-reacted spermatozoa after the ionophore challenge. Together, these results show that YK 3-237 affects human spermatozoa capacitation-related events by a mechanism independent of protein lysine acetylation but dependent on bicarbonate and calcium., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Male fertility relies on the ability of spermatozoa to fertilize the egg in the female reproductive tract (FRT). Spermatozoa acquire activated motility during epididymal maturation; however, to be capable of fertilization, they must achieve hyperactivated motility in the FRT. Extensive research found that three protein phosphatases (PPs) are crucial to sperm motility regulation, the sperm-specific protein phosphatase type 1 (PP1) isoform gamma 2 (PP1γ2), protein phosphatase type 2A (PP2A) and protein phosphatase type 2B (PP2B). Studies have reported that PP activity decreases during epididymal maturation, whereas protein kinase activity increases, which appears to be a requirement for motility acquisition. An interplay between these PPs has been extensively investigated; however, many specific interactions and some inconsistencies remain to be elucidated. The study of PPs significantly advanced following the identification of naturally occurring toxins, including calyculin A, okadaic acid, cyclosporin, endothall and deltamethrin, which are powerful and specific PP inhibitors. This review aims to overview the protein phosphorylation-dependent biochemical pathways underlying sperm motility acquisition and hyperactivation, followed by a discussion of the PP inhibitors that allowed advances in the current knowledge of these pathways. Since male infertility cases still attain alarming numbers, additional research on the topic is required, particularly using other PP inhibitors.

Ageing is the time-dependent gradual decline of the functional characteristics in an organism. It has been shown that it results in the loss of reproductive health and fertility. The age-dependent decline of fertility is a potential issue as the parenthood age is increasing in Western countries, mostly due to socioeconomic factors. In comparison to women, for whom the consequences of ageing are well documented and general awareness of the population is extensively raised, the effects of ageing for male fertility and the consequences of advanced paternal age for the offspring have not been widely studied. Studies with humans are welcome but it is hard to implement relevant experimental approaches to unveil the molecular mechanisms by which ageing affects male reproductive potential. Animal models have thus been extensively used. These models are advantageous due to their reduced costs, general easy maintenance in laboratory facilities, rigorous manipulation tools, short lifespan, known genetic backgrounds, and reduced ethical constraints. Herein, we discuss animal models for the study of male reproductive ageing. The most well-known and studied reproductive ageing models are rodents and non-human primates. The data collected from these models, particularly studies on testicular ageing, steroidogenesis, and genetic and epigenetic changes in spermatogenesis are detailed. Notably, some species challenge the currently accepted ageing theories and the concept of senescence itself, which renders them interesting animal models for the study of male reproductive ageing., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2022 Wiley-VCH GmbH.)

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that is crucial for fluid homeodynamics throughout the male reproductive tract. Previous evidence shed light on a potential molecular partnership between this channel and aquaporins (AQPs). Herein, we explore the role of CFTR on AQPs-mediated glycerol permeability in mouse Sertoli cells (mSCs). We were able to identify the expression of CFTR, AQP3, AQP7, and AQP9 in mSCs by RT-PCR, Western blot, and immunofluorescence techniques. Cells were then treated with CFTRinh-172, a specific CFTR inhibitor, and its glycerol permeability was evaluated by stopped-flow light scattering. We observed that CFTR inhibition decreased glycerol permeability in mSCs by 30.6% when compared to the control group. A DUOLINK proximity ligation assay was used to evaluate the endogenous protein-protein interactions between CFTR and the various aquaglyceroporins we identified. We positively detected that CFTR is in close proximity with AQP3, AQP7, and AQP9 and that, through a possible physical interaction, CFTR can modulate AQP-mediated glycerol permeability in mSCs. As glycerol is essential for the control of the blood-testis barrier and elevated concentration in testis results in the disruption of spermatogenesis, we suggest that the malfunction of CFTR and the consequent alteration in glycerol permeability is a potential link between male infertility and cystic fibrosis., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The renewal of the natural resources is one of the most concerning aspects of modern farming. In animal production, there are many barriers breeders and researchers have to overcome to develop new practices to improve reproductive potential and hasten sexual maturation of the commercially viable species, while maintaining meat quality and sustainability. With the utilization of molecular biology techniques, there have been relevant advances in the knowledge of spermatogenesis, especially in mammals, resulting in new possibilities to control male fertility and the selection of desirable characteristics. Most of these discoveries have not been implemented in animal production. In this review, recent studies are highlighted on the molecular pathways involved in spermatogenesis in the context of animal production. There is also exploration of the interaction between environmental factors and spermatogenesis and how this knowledge may revolutionize animal production techniques. Furthermore, new insights are described about the inheritance of desired characteristics in mammals and there is a review of nefarious actions of pollutants, nutrition, and metabolism on reproductive potential in subsequent generations. Even though there are these advances in knowledge base, results from recent studies indicate there are previously unrecognized environmental effects on spermatogenesis. The molecular mechanisms underlying this interaction are not well understood. Research in spermatogenesis, therefore, remains pivotal as a pillar of animal production sustainability., Competing Interests: Declarations of interest None to declare., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim : Calorie restriction (CR) diets and glucagon-Like Peptide-1 (GLP-1) analogs are known to alter energy homeostasis with the potential to affect the expression of obesity-related genes (ORGs). We hypothesized that CR and GLP-1 administration can alter ORGs expression in spermatozoa and testes, as well as the sperm parameters implicated in male fertility. Materials and Methods: Six-week-old adult male Wistar rats (n = 16) were divided into three groups, submitted either to CR (n = 6, fed with 30% less chow diet than the control rats), GLP-1 administration (n = 5, 3.5 pmol/min/kg intraperitoneal) for 28 days, or used as controls (n = 5, fed ad libitum). Selected ORGs expression, namely the fat mass and obesity-associated ( FTO ), melanocortin-4 receptor ( MC4R ), glucosamine-6-phosphate deaminase 2 ( GNPDA2 ), and transmembrane protein 18 ( TMEM18 ) were evaluated in testes and spermatozoa by a quantitative polymerase chain reaction (qPCR). Results: CR resulted in lower body weight gain and insulin resistance, but a higher percentage of sperm head defects. GLP-1 administration, despite showing no influence on body weight or glucose homeostasis, resulted in a lower percentage of sperm head defects. CR and GLP-1 administration were associated with a higher expression of all ORGs in the testes. Under CR conditions, the genes FTO and TMEM18 expression in the testes and the MC4R and TMEM18 transcripts abundance in sperm were positively correlated with the spermatozoa oxidative status. The abundance of FTO and TMEM18 in the spermatozoa of rats under CR were positively correlated with sperm concentration, while the testes' TMEM18 expression was also positively correlated with sperm vitality and negatively correlated with insulin resistance. Testes GNPDA2 expression was negatively correlated with sperm head defects. Conclusions: CR and GLP-1 administration results in higher ORGs expression in testes, and these were correlated with several alterations in sperm fertility parameters.

Aims: Brief episodes of sublethal hypoxia reprogram brain response to face possible subsequent lethal stimuli by triggering adaptive and prosurvival events-a phenomenon denominated hypoxic preconditioning (HP). To date, the potential therapeutic implications of HP to forestall sporadic Alzheimer's disease (sAD) pathology remain unexplored. Using a well-established protocol of HP and focusing on hippocampus as a first brain region affected in AD, this study was undertaken to investigate the potential protective effects of HP in a sAD rat model induced by the intracerebroventricular (icv) administration of streptozotocin (STZ) and to uncover the mitochondrial adaptations underlying this nonpharmacological strategy. Results: HP prevented the memory and learning deficits as well as tau pathology in the icvSTZ rat model. HP also attenuated icvSTZ-related reactive astrogliosis, as noted by increased glial fibrillary acidic protein immunoreactivity and myo-inositol levels. Notably, HP abrogated the icvSTZ-related impaired energy metabolism and oxidative damage. Particularly, HP averted increased lactate, glutamate, and succinate levels, and decreased mitochondrial respiratory chain function and mitochondrial DNA content. Concerning mitochondrial adaptations underlying HP-triggered tolerance to icvSTZ, preconditioned hippocampal mitochondria displayed an enhanced complex II-energized mitochondrial respiration, which resulted from a coordinated interaction between mitochondrial biogenesis and fusion-fission. Mitochondrial biogenesis was stimulated immediately after HP, whereas in a latter phase mitochondrial fusion-fission events are modulated favoring the generation of elongated mitochondria. Innovation and Conclusion: Overall, these results demonstrate for the first time that HP prevents the sAD-like phenotype, in part, by targeting mitochondria emerging as a preventive strategy in the context of AD. Antioxid. Redox Signal . 37, 739-757.