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PubMed | University of Porto, Center For Reproductive Genetics Prof Alberto Barros and University of Beira Interior
Type: Journal Article | Journal: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | Year: 2016

Men with Klinefelter syndrome (KS) present severe hormonal dysregulation, particularly elevated serum estradiol concentration. Estrogens act through specific receptors and regulate testes development and spermatogenesis. Herein, we evaluated GPR30, ER, and ER mRNA expression in testis of KS men and men with 46XY karyotype by reverse transcriptase and quantitative PCR. ER transcripts are the most abundant in testicular tissue of 46XY men. Notably, testicular GPR30 transcription in KS men was approximately 12 times higher. Since GPR30 is essential to mediate estrogen effects over steroidogenesis, our data illustrate that GPR30 may underpin the testicular alterations observed in KS men.


PubMed | University of Porto, Center For Reproductive Genetics Prof Alberto Barros, University of Beira Interior, Centro Hospitalar Of Lisbon Central Chlc and University of Coimbra
Type: Journal Article | Journal: Cell and tissue research | Year: 2015

Diabetes mellitus (DM) is a metabolic disease that has grown to pandemic proportions. Recent reports have highlighted the effect of DM on male reproductive function. Here, we hypothesize that testicular metabolism is altered in type 1 diabetic (T1D) men seeking fertility treatment. We propose to determine some metabolic fingerprints in testicular biopsies of diabetic patients. For that, testicular tissue from five normal and five type 1 diabetic men was analyzed by high-resolution magic-angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy. mRNA and protein expression of glucose transporters and glycolysis-related enzymes were also evaluated. Our results show that testes from diabetic men presented decreased levels of lactate, alanine, citrate and creatine. The mRNA levels of glucose transporter1 (GLUT1) and phosphofructokinase1 (PFK1) were decreased in testes from diabetic men but only GLUT3 presented decreased mRNA and protein levels. Lactate dehydrogenase (LDH) and glutamate pyruvate transaminase (GPT) protein levels were also found to be decreased in testes from diabetic men. Overall, our results show that T1D alters glycolysis-related transporters and enzymes, compromising lactate content in the testes. Moreover, testicular creatine content was severely depressed in T1D men. Since lactate and creatine are essential for germ cells development and support, the data discussed here open new insights into the molecular mechanism by which DM promotes subfertility/infertility in human males.


Ferreira C.,University of Porto | Ferreira C.,Royal University | Sousa M.,University of Porto | Sousa M.,Center For Reproductive Genetics Prof Alberto Barros | And 5 more authors.
Current Pharmaceutical Design | Year: 2015

Male infertility has been increasing over the last decades being nowadays a pressing health problem. Diabetes mellitus (DM) can contribute directly or indirectly to male infertility due to an abnormal spermatogenesis, which results in a decreased sperm quality. Type 2 Diabetes mellitus (T2DM) is responsible for the vast majority of DM cases, being frequently treated with oral antidiabetic drugs. Metformin is the most cost-effective therapy for the treatment of T2DM. This biguanide is an oral insulin-sensitizing agent capable of increasing insulin sensitivity and decreasing plasma fasting insulin levels. The main metabolic action of this drug occurs in the liver. However, it has been shown that metformin acts on a variety of organs including the male reproductive system. With the rising numbers of diabetic individuals among younger populations, there is an increase in the consumption of metformin in individuals of this age group. As a result, it is important to discuss the role of metformin in male fertility. This review presents the most recent data available from studies on the effects of metformin on male reproductive system. Together with the discussion of these effects, their significance to male fertility is also debated. © 2015 Bentham Science Publishers.


Jesus T.T.,University of Porto | Jesus T.T.,University of Beira Interior | Oliveira P.F.,University of Porto | Oliveira P.F.,Institute of Health Research An Innovation | And 10 more authors.
Fertility and Sterility | Year: 2016

Objective To study the role of mammalian target of rapamycin (mTOR) in the regulation of human Sertoli cell (hSC) metabolism, mitochondrial activity, and oxidative stress. Design Experimental study. Setting University research center and private assisted reproductive technology centers. Patient(s) Six men with anejaculation (psychological, vascular, neurologic) and conserved spermatogenesis. Intervention(s) Testicular biopsies were used from patients under treatment for recovery of male gametes. Primary hSCs cultures were established from each biopsy and divided into a control group and one treated with rapamycin, the inhibitor of mTOR, for 24 hours. Main Outcome Measure(s) Cytotoxicity of hSCs to rapamycin was evaluated by sulforhodamine B assay. The glycolytic profile of hSCs was assessed by proton nuclear magnetic resonance and by studying protein expression of key glycolysis-related transporters and enzymes. Expression of mitochondrial complexes and citrate synthase activity were determined. Protein carbonylation, nitration, lipid peroxidation, and sulfhydryl protein group contents were quantified. The mTOR signaling pathway was studied. Result(s) Rapamycin increased glucose consumption by hSCs, maintaining lactate production. Alanine production by rapamycin-exposed hSCs was affected, resulting in an unbalanced intracellular redox state. Rapamycin-exposed hSCs had decreased expression of mitochondrial complex III and increased lipid peroxidation, whereas other oxidative stress markers were unaltered. Treatment of hSCs with rapamycin down-regulated phospho-mTOR (Ser-2448) levels, illustrating an effective partial inhibition of mTORC1. Protein levels of downstream signaling molecule p-4E-BP1 were not altered, suggesting that during treatment it became rephosphorylated. Conclusion(s) We show that mTOR regulates the nutritional support of spermatogenesis by hSCs and redox balance in these cells. © 2016 American Society for Reproductive Medicine.


Botelho M.C.,National Institute Of Health Dr Ricardo Jorge | Botelho M.C.,University of Porto | Alves H.,National Institute Of Health Dr Ricardo Jorge | Barros A.,Center For Reproductive Genetics Prof Alberto Barros | And 4 more authors.
Trends in Parasitology | Year: 2015

Schistosoma haematobium, a parasitic flatworm that infects more than 100 million people, mostly in the developing world, is the causative agent of urogenital schistosomiasis, and is associated with a high incidence of squamous cell carcinoma (SCC) of the bladder. Schistosomiasis haematobia also appears to negatively influence fertility, and is particularly associated with female infertility. Given that estrogens and estrogen receptors are key players in human reproduction, we speculate that schistosome estrogen-like molecules may contribute to infertility through hormonal imbalances. Here, we review recent findings on the role of estrogens and estrogen receptors on both carcinogenesis and infertility associated with urogenital schistosomiasis and discuss the basic hormonal mechanisms that might be common in cancer and infertility. © 2015 Elsevier Ltd.


Rato L.,University of Beira Interior | Alves M.G.,University of Beira Interior | Silva B.M.,University of Beira Interior | Sousa M.,University of Porto | And 2 more authors.
Current Medicinal Chemistry | Year: 2016

The current lifestyle of "western societies" is based on excessive consumption of high-energy diets and physical inactivity. Such behavior has pressured biological systems towards the development of metabolic diseases. This increased incidence of metabolic disorders is also accompanied by a decline in male reproductive health, particularly among young males. Male fertility is sensitive to metabolic dysfunctions, such as diabetes mellitus, which disrupt the link between energy metabolism and reproduction. Evidences showed that compromised sperm parameters induced by diabetes are associated with impaired testicular metabolism, suggesting that deficient testicular bioenergetics contributes to a decline in spermatogenesis. Energy metabolism is a well-coordinated process that involves a network of carbohydrate, lipid and protein metabolic pathways. This intricate process is an act of balance between mitochondria and nucleus, governed by metabolic sensors, such as sirtuins. The emerging role of sirtuins in the control of metabolism has been highlighted, specially in cancer metabolism. Little attention has been given to their role in non-cancerous cells that exhibit a "Warburg-like metabolism", such as Sertoli cells. Spermatogenesis is highly dependent on glycolytic metabolism, since the lactate produced by Sertoli cells is the major substrate of germ cells. The regulation of sirtuins in the glycolytic metabolism not only increases their physiological relevance to the testicular environment, but also suggests that these proteins may control male fertility. This review will discuss the recent findings in the role of sirtuins in testicular metabolism and will address the concept that sirtuins can be a potential target to counteract subfertility/infertility promoted by diabetes mellitus. © 2016 Bentham Science Publishers.


Almeida S.,University of Porto | Alves M.G.,University of Beira Interior | Sousa M.,University of Porto | Sousa M.,Center For Reproductive Genetics Prof Alberto Barros | And 2 more authors.
Neurotoxicity Research | Year: 2016

Life expectancy of most human populations has greatly increased as a result of factors including better hygiene, medical practice, and nutrition. Unfortunately, as humans age, they become more prone to suffer from neurodegenerative diseases and neurotoxicity. Polyphenols can be cheaply and easily obtained as part of a healthy diet. They present a wide range of biological activities, many of which have relevance for human health. Compelling evidence has shown that dietary phytochemicals, particularly polyphenols, have properties that may suppress neuroinflammation and prevent toxic and degenerative effects in the brain. The mechanisms by which polyphenols exert their action are not fully understood, but it is clear that they have a direct effect through their antioxidant activities. They have also been shown to modulate intracellular signaling cascades, including the PI3K–Akt, MAPK, Nrf2, and MEK pathways. Polyphenols also interact with a range of neurotransmitters, illustrating that these compounds can promote their health benefits in the brain through a direct, indirect, or complex action. We discuss whether polyphenols obtained from diet or food supplements are an effective strategy to prevent or treat neurodegeneration. We also discuss the safety, mechanisms of action, and the current and future relevance of polyphenols in clinical treatment of neurodegenerative diseases. As populations age, it is important to discuss the dietary strategies to avoid or counteract the effects of incurable neurodegenerative disorders, which already represent an enormous financial and emotional burden for health care systems, patients, and their families. © 2016 Springer Science+Business Media New York


PubMed | University of Porto, Center For Reproductive Genetics Prof Alberto Barros and University of Beira Interior
Type: Journal Article | Journal: Biology of the cell | Year: 2016

Infertile men often present deregulation of serum estrogen levels. Notably, high levels of estradiol (E2) are associated with low sperm production and quality. Sertoli cells (SCs) are responsible for spermatogenesis maintenance and are major targets for the hormonal signalling that regulates this complex process.In this study, we used primary cultures of human SCs and studied the localisation, expression and functionality of the Na(+) -dependent HCO3 (-) transporters by confocal microscopy, immunoblot, epifluorescence and voltage clamp after 24 h of exposure to E2 (100 nM). All studied transporters were identified in human SCs. In E2-treated human SCs, there was an increase in NBCn1, NBCe1 and NDCBE protein levels, as well as an increase in intracellular pH and a decrease in transcellular transport.We report an association between increased levels of E2 and the expression/function of Na(+) -dependent HCO3 (-) transporters in human SCs. Our results provide new evidence on the mechanisms by which E2 can regulate SCs physiology and consequently spermatogenesis. These mechanisms may have an influence on male reproductive potential and help to explain male infertility conditions associated with estrogen deregulation.Exposure to E2 increased human SCs intracellular pH. E2 is a modulator of ionic transcellular transport in human SCs.


PubMed | University of Aveiro, University of Porto, Abel Salazar Biomedical Sciences Institute, University of Beira Interior and 2 more.
Type: Journal Article | Journal: Fertility and sterility | Year: 2016

To study the role of mammalian target of rapamycin (mTOR) in the regulation of human Sertoli cell (hSC) metabolism, mitochondrial activity, and oxidative stress.Experimental study.University research center and private assisted reproductive technology centers.Six men with anejaculation (psychological, vascular, neurologic) and conserved spermatogenesis.Testicular biopsies were used from patients under treatment for recovery of male gametes. Primary hSCs cultures were established from each biopsy and divided into a control group and one treated with rapamycin, the inhibitor of mTOR, for 24hours.Cytotoxicity of hSCs to rapamycin was evaluated by sulforhodamine B assay. The glycolytic profile of hSCs was assessed by proton nuclear magnetic resonance and by studying protein expression of key glycolysis-related transporters and enzymes. Expression of mitochondrial complexes and citrate synthase activity were determined. Protein carbonylation, nitration, lipid peroxidation, and sulfhydryl protein group contents were quantified. The mTOR signaling pathway was studied.Rapamycin increased glucose consumption by hSCs, maintaining lactate production. Alanine production by rapamycin-exposed hSCs was affected, resulting in an unbalanced intracellular redox state. Rapamycin-exposed hSCs had decreased expression of mitochondrial complex III and increased lipid peroxidation, whereas other oxidative stress markers were unaltered. Treatment of hSCs with rapamycin down-regulated phospho-mTOR (Ser-2448) levels, illustrating an effective partial inhibition of mTORC1. Protein levels of downstream signaling molecule p-4E-BP1 were not altered, suggesting that during treatment it became rephosphorylated.We show that mTOR regulates the nutritional support of spermatogenesis by hSCs and redox balance in these cells.


PubMed | University of Porto, Center For Reproductive Genetics Prof Alberto Barros, University of Aveiro and Abel Salazar Biomedical Sciences Institute
Type: Journal Article | Journal: Zygote (Cambridge, England) | Year: 2015

Exposure to lead may cause changes in the male reproductive system. We evaluated the effect of lead chloride (PbCl2) in vitro on semen quality from 31 individuals. Samples were incubated at room temperature for two exposure times (4 h and 8 h) and with two concentrations of PbCl2 (15 g/ml or 30 g/ml). Results showed that PbCl2 significantly inhibited rapid progressive motility and caused an increase in the percentage of tail anomalies in both times and concentrations assessed, as well as a decrease in vitality in the group exposed to 30 g/ml PbCl2. A significant increase in immotile sperm was also observed between the group control and the groups submitted to lead. Total motility and DNA fragmentation also showed a significant decrease and increase, respectively, after 4 h of incubation in the group exposed to 30 g/ml and in both groups after 8 h of incubation. In conclusion, PbCl2 affected sperm parameters and DNA integrity, which are essential for male fertility.

Loading Center For Reproductive Genetics Prof Alberto Barros collaborators
Loading Center For Reproductive Genetics Prof Alberto Barros collaborators