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1.
Biology (Basel) ; 13(9)2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39336148

RESUMO

Exposure to pesticides, poses a significant threat to male fertility by compromising crucial cells involved in spermatogenesis. Aminocarb, is a widely used carbamate insecticide, although its detrimental effects on the male reproductive system, especially on sustentacular Sertoli cells, pivotal for spermatogenesis, remains poorly understood. In this study, we investigated the effects of escalating concentrations of aminocarb on a mouse Sertoli cell line, TM4. Assessments included cytotoxic analysis, mitochondrial biogenesis and membrane potential, expression of apoptotic proteins, caspase-3 activity, and oxidative stress evaluation. Our findings revealed a dose-dependent reduction in the proliferation and viability of TM4 cells following exposure to increasing concentrations of aminocarb. Notably, exposure to 5 µM of aminocarb induced depolarization of mitochondria membrane potential, and a significant decrease in the ratio of phosphorylated eIF2α to total eIF2α, suggesting heightened endoplasmic reticulum stress via the activation of the eIF2α pathway. Moreover, the same aminocarb concentration was demonstrated to increase both caspase-3 protein levels and activity, indicating an apoptotic induction. Collectively, our results demonstrate that aminocarb serves as an apoptotic inducer for mouse sustentacular Sertoli cells in vitro, suggesting its potential to modulate independent pathways of the apoptotic cascade. These findings underscore the deleterious impact of aminocarb on spermatogenic performance and male fertility, highlighting the urgent need for further investigation into its mechanisms of action and mitigation strategies to safeguard male fertility.

2.
Pharmaceutics ; 16(9)2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39339236

RESUMO

Protein phosphatase 1 (PP1) complexes have emerged as promising targets for anticancer therapies. The ability of peptides to mimic PP1-docking motifs, and so modulate interactions with regulatory factors, has enabled the creation of highly selective modulators of PP1-dependent cellular processes that promote tumor growth. The major objective of this study was to develop a novel bioactive cell-penetrating peptide (bioportide), which, by mimicking the PP1-binding motif of caveolin-1 (CAV1), would regulate PP1 activity, to hinder prostate cancer (PCa) progression. The designed bioportide, herein designated CAVPENET, and a scrambled homologue, were synthesized using microwave-assisted solid-phase methodologies and evaluated using PCa cell lines. Our findings indicate that CAVPENET successfully entered PCa cells to influence both viability and migration. This tumor suppressor activity of CAVPENET was attributed to inhibition of AKT signaling, a consequence of increased PP1γ activity. This led to the suppression of glycolytic metabolism and alteration in lipid metabolism, collectively representing the primary mechanism responsible for the anticancer properties of CAVPENET. Our results underscore the potential of the designed peptide as a novel therapy for PCa patients, setting the stage for further testing in more advanced models to fully realize its therapeutic promise.

3.
J Cell Physiol ; : e31422, 2024 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-39324358

RESUMO

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic adenosine monophosphate (cAMP)-regulated chloride and bicarbonate ion channel found in many human cells. Its unique biochemical characteristics and role as a member of the adenosine triphosphate (ATP)-binding cassette transporters superfamily are pivotal for the transport of several substrates across cellular membranes. CFTR is known to interact, physically and functionally, with several other cellular proteins. Hence, its properties are essential for moving various substances across cell membranes and ensuring correct cell functioning. Genetic mutations or environmental factors may disrupt CFTR's function resulting in different possible phenotypes due to gene variations that affect not only CFTR's function, localization, and processing within cells, but also those of its interactors. This has been reported as an underlying cause of various diseases, including cystic fibrosis. The severe clinical implications of cystic fibrosis have driven intense research into the role of CFTR in lung function but its significance to fertility, particularly in men, has been comparatively understudied. However, ongoing and more recent research into CFTR and its interacting proteins in the testis or specific testicular cells is beginning to shed light on this field. Herein, we provide a comprehensive and up-to-date overview of the CFTR, its interactome, and its crucial role in male reproduction, highlighting recent discoveries and advancements in understanding the molecular mechanisms involved. The comprehension of these complex interactions may pave the way for potential therapeutic approaches to improve fertility of men suffering from alterations in the function of CFTR.

4.
Andrology ; 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39044679

RESUMO

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.

5.
Eur J Clin Invest ; : e14289, 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39046266

RESUMO

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 1H-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.

6.
Int J Mol Sci ; 25(9)2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38732272

RESUMO

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 1H-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.


Assuntos
Metabolismo Energético , Pulmão , Morfogênese , Transdução de Sinais , Tretinoína , Animais , Tretinoína/metabolismo , Tretinoína/farmacologia , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/embriologia , Metabolismo Energético/efeitos dos fármacos , Morfogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Embrião de Galinha , Proliferação de Células/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Galinhas
7.
Vascul Pharmacol ; 155: 107372, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38583694

RESUMO

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.


Assuntos
Metabolismo Energético , Células Endoteliais da Veia Umbilical Humana , Mitocôndrias , Estresse Oxidativo , Pré-Eclâmpsia , Humanos , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/patologia , Gravidez , Feminino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Animais , Valor Preditivo dos Testes
9.
Toxicol Appl Pharmacol ; 486: 116929, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38608961

RESUMO

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-H2DCFDA 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.


Assuntos
Atrazina , Regulação para Baixo , Glicólise , Herbicidas , L-Lactato Desidrogenase , Espécies Reativas de Oxigênio , Células de Sertoli , Animais , Masculino , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Atrazina/toxicidade , Camundongos , Glicólise/efeitos dos fármacos , Herbicidas/toxicidade , L-Lactato Desidrogenase/metabolismo , Regulação para Baixo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Estresse Oxidativo/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo
10.
Nat Rev Urol ; 21(8): 477-494, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38528255

RESUMO

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.


Assuntos
Doenças Metabólicas , Espermatogênese , Testículo , Masculino , Humanos , Espermatogênese/fisiologia , Testículo/metabolismo , Doenças Metabólicas/metabolismo , Doenças Metabólicas/fisiopatologia , Doenças Metabólicas/etiologia , Animais , Infertilidade Masculina/metabolismo , Infertilidade Masculina/etiologia , Infertilidade Masculina/fisiopatologia , Dieta Hiperlipídica/efeitos adversos
11.
Iran J Basic Med Sci ; 27(1): 3-11, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38164482

RESUMO

The impact of diabetes on various organs failure including testis has been highlighted during the last decades. If on one hand diabetes-induced hyperglycemia has a key role in induced damages; on the other hand, glucose deprivation plays a key role in inducing male infertility. Indeed, glucose metabolism during spermatogenesis has been highlighted due to post-meiotic germ cells drastic dependence on glucose-derived metabolites, especially lactate. In fact, hyperglycemia-induced spermatogenesis arrest has been demonstrated in various studies. Moreover, various sperm maturation processes related to sperm function such as motility are directly depending on glucose metabolism in Sertoli cells. It has been demonstrated that diabetes-induced hyperglycemia adversely impacts sperm morphology, motility and DNA integrity, leading to infertility. However, fertility quality is another important factor to be considered. Diabetes-induced hyperglycemia is not only impacting sperm functions, but also affecting sperm epigenome. DNA packing process and epigenetics modifications occur during spermatogenesis process, determining next generation genetic quality transmitted through sperm. Critical damages may occur due to under- or downregulation of key proteins during spermatogenesis. Consequently, unpacked DNA is more exposed to oxidative stress, leading to intensive DNA damages. Moreover, epigenetic dysregulation occurred during spermatogenesis may impact embryo quality and be transmitted to next generations, increasing offspring genetic issues. Herein we discuss the mechanisms by which diabetes-induced hyperglycemia can affect epigenetic modifications and DNA packaging and methylation during spermatogenesis thus promoting long-lasting effects to the next generation.

12.
Reproduction ; 167(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38019967

RESUMO

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.


Assuntos
Canais Iônicos , Prótons , Humanos , Masculino , Proteínas de Desacoplamento Mitocondrial , Canais Iônicos/genética , Canais Iônicos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células de Sertoli/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Testículo/metabolismo
13.
Nutrients ; 15(23)2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-38068717

RESUMO

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.


Assuntos
Epigênese Genética , Neoplasias da Próstata , Masculino , Animais , Humanos , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/genética , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/genética , Próstata/metabolismo , Suscetibilidade a Doenças
14.
Metabolites ; 13(12)2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38132862

RESUMO

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 1H-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.

15.
Obes Surg ; 33(12): 3988-3998, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37910328

RESUMO

PURPOSE: Remission of type 2 diabetes (T2D) can be achieved by many, but not all, people following bariatric/metabolic surgery. The mechanisms underlying T2D remission remain incompletely understood. This observational study aimed to identify novel weight-loss independent clinical, metabolic and genetic factors that associate with T2D remission using comprehensive phenotyping. MATERIALS AND METHODS: Ten patients without T2D remission (non-remitters) were matched to 10 patients with T2D remission (remitters) for age, sex, type of surgery, body weight, BMI, post-operative weight loss, duration from surgery and duration of T2D. Detailed body composition assessed using magnetic resonance imaging, gut hormones, serum metabolomics, insulin sensitivity, and genetic risk scores for T2D and anthropometric traits were assessed. RESULTS: Remitters had significantly greater ß-cell function and circulating acyl ghrelin levels, but lower visceral adipose tissue (VAT): subcutaneous adipose tissue (SAT) ratio than non-remitters. Branched-chain amino acids (BCAAs) and VLDL particle size were the most discriminant metabolites between groups. A significant positive correlation between, VAT area, VAT:SAT ratio and circulating levels of BCAAs was observed, whereas a significant negative correlation between BCAAs and ß-cell function was revealed. CONCLUSION: We highlight a potentially novel relationship between VAT and BCAAs, which may play a role in glucoregulatory control. Improvement in ß-cell function, and the role ghrelin plays in its recovery, is likely another key factor influencing T2D remission post-surgery. These findings suggest that adjunctive approaches that target VAT loss and restoration of BCAA metabolism might achieve higher rates of long-term T2D remission post-surgery.


Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Obesidade Mórbida , Humanos , Grelina , Obesidade Mórbida/cirurgia , Resultado do Tratamento , Redução de Peso , Biomarcadores
16.
Antioxidants (Basel) ; 12(11)2023 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-38001763

RESUMO

The association between obstructive sleep apnea (OSA) and metabolic disorders is well-established; however, the underlying mechanisms that elucidate this relationship remain incompletely understood. Since the liver is a major organ in the maintenance of metabolic homeostasis, we hypothesize that liver dysfunction plays a crucial role in the pathogenesis of metabolic dysfunction associated with obstructive sleep apnea (OSA). Herein, we explored the underlying mechanisms of this association within the liver. Experiments were performed in male Wistar rats fed with a control or high fat (HF) diet (60% lipid-rich) for 12 weeks. Half of the groups were exposed to chronic intermittent hypoxia (CIH) (30 hypoxic (5% O2) cycles, 8 h/day) that mimics OSA, in the last 15 days. Insulin sensitivity and glucose tolerance were assessed. Liver samples were collected for evaluation of lipid deposition, insulin signaling, glucose homeostasis, hypoxia, oxidative stress, antioxidant defenses, mitochondrial biogenesis and inflammation. Both the CIH and HF diet induced dysmetabolism, a state not aggravated in animals submitted to HF plus CIH. CIH aggravates hepatic lipid deposition in obese animals. Hypoxia-inducible factors levels were altered by these stimuli. CIH decreased the levels of oxidative phosphorylation complexes in both groups and the levels of SOD-1. The HF diet reduced mitochondrial density and hepatic antioxidant capacity. The CIH and HF diet produced alterations in cysteine-related thiols and pro-inflammatory markers. The results obtained suggest that hepatic mitochondrial dysfunction and oxidative stress, leading to inflammation, may be significant factors contributing to the development of dysmetabolism associated with OSA.

17.
BMC Biol ; 21(1): 255, 2023 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-37953286

RESUMO

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.


Assuntos
Epigênese Genética , Herança Paterna , Humanos , Animais , Masculino , Estudos de Coortes , Sêmen , Metilação de DNA , Mamíferos
18.
Expert Rev Proteomics ; 20(12): 331-343, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37878493

RESUMO

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.


Assuntos
Infertilidade Masculina , Testículo , Masculino , Humanos , Idoso , Proteoma/genética , Proteômica , Espermatogênese/genética , Infertilidade Masculina/genética
19.
Cells ; 12(17)2023 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-37681855

RESUMO

Molecular subtype (MS) is one of the most used classifications of breast cancer (BC). Four MSs are widely accepted according to receptor expression of estrogen, progesterone, and HER2. The impact of adipose tissue on BC MS metabolic impairment is still unclear. The present work aims to elucidate the metabolic alterations in breast cancer cell lines representing different MSs subjected to adipocyte associated factors. Preadipocytes isolated from human subcutaneous adipose tissue were differentiated into mature adipocytes. MS representative cell lines were exposed to mature adipocyte secretome. Extracellular medium was collected for metabolomics and RNA was extracted to evaluate enzymatic expression by RT-PCR. Adipocyte secretome exposure resulted in a decrease in the Warburg effect rate and an increase in cholesterol release. HER2+ cell lines (BT-474 and SK-BR-3) exhibited a similar metabolic pattern, in contrast to luminal A (MCF-7) and triple negative (TN) (MDA-MB-231), both presenting identical metabolisms. Anaplerosis was found in luminal A and TN representative cells, whereas cataplerotic reactions were likely to occur in HER2+ cell lines. Our results indicate that adipocyte secretome affects the central metabolism distinctly in each BC MS representative cell line.


Assuntos
Neoplasias , Secretoma , Humanos , Células MCF-7 , Adipócitos , Tecido Adiposo , Estrogênios
20.
J Clin Med ; 12(18)2023 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-37762736

RESUMO

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.

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