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- Bioactive Substances from Medicinal Plants for Metabolic DisordersPublication . Silva, Branca M.; Oliveira, Pedro F.; Alves, Marco G; Dias, Tânia R.Metabolic disorders, particularly Diabetes Mellitus (DM), are major causes of death worldwide. In fact, the world statistics for DM are alarming: this epidemic disease kills one person every six seconds, being the fourth cause of death. Besides the health issues, the costs associated with DM, and its co-morbidities, are massive and the pressure in National Health Care Systems is dramatically increasing. Patients with DM, particularly those with type 2 diabetes (T2D), are primarily advised to change their dietary habits and exercise regime. However, as the disease progresses and becomes more severe, conventional drugs are prescribed. Most of these patients need polypharmacological therapy and though progresses have been made, efforts are mandatory in a search for a “perfect” antidiabetic drug. [...]
- L-Theanine promotes cultured human Sertoli cells proliferation and modulates glucose metabolismPublication . Dias, T. R.; Bernardino, Raquel; Alves, Marco G; Silva, Joaquina; Barros, Alberto; Sousa, Mário; Casal, Susana; Silva, Branca M.; Oliveira, P.F.L-Theanine is the major free amino acid present in tea (Camellia sinensis L.). The effects of several tea constituents on male reproduction have been investigated, but L-theanine has been overlooked. Sertoli cells (SCs) are essential for the physical and nutritional support of germ cells. In this study, we aimed to investigate the ability of L-theanine to modulate important mechanisms of human SCs (hSCs) metabolism, mitochondrial function and oxidative profile, which are essential to prevent or counteract spermatogenesis disruption in several health conditions.
- 8-(3-phenylpropyl)-1,3,7-triethylxanthine is a synthetic caffeine substitute with stronger metabolic modulator activityPublication . Carrageta, David F; Dias, Tânia R.; Jarak, Ivana; Alves, Marco G; Oliveira, P.F.; Walt, Mietha Van Der; Terre'Blanche, Gisella; Monteiro, Mariana P.; Silva, Branca M.Caffeine is one of the most worldwide consumed methylxanthines. It is well-known for its thermogenic and cell metabolism modulating effects. Based on methylxanthines' chemical structure, 8-(3-phenylpropyl)-1,3,7-triethylxanthine (PTX) is a novel adenosine antagonist with higher receptor affinity than caffeine. Therefore, we hypothesized that PTX metabolic effects could be stronger than those of caffeine. For that purpose, murine 3T3-L1 cells were cultured in the presence of increasing doses of PTX or caffeine (0.1, 1, 10 and 100 μM) for 24 h. Cytotoxicity was evaluated by reduction of tetrazolium salt (MTT) and lactate dehydrogenase (LDH) release. Cell metabolites released to the culture medium were identified and quantified by proton nuclear magnetic resonance (1H NMR). Cellular oxidative profile was also evaluated. Our results showed that PTX displayed no signs of cytotoxicity at all studied concentrations. When compared with caffeine, PTX increased glucose, pyruvate, and glutamine consumption, as well as lactate, alanine, and acetate production. Additionally, PTX decreased protein oxidation, thus protecting against oxidative stress-induced damage. These results illustrate that PTX is a stronger and less cytotoxic caffeine substitute with potential applications as metabolic modulator and a good candidate for novel drug design.
- Androgens enhance the glycolytic metabolism and lactate export in prostate cancer cells by modulating the expression of GLUT1, GLUT3, PFK, LDH and MCT4 genesPublication . Vaz, Cátia; Marques, Ricardo; Alves, Marco G; Oliveira, P.F.; Cavaco, JE; Baptista, Cláudio; Socorro, SílviaPurpose The present study aims to investigate the role of androgens in controlling the glycolytic metabolism and lactate efflux in prostate cancer (PCa) cells. [...]
- Pharmacological potential of methylxanthines: Retrospective analysis and future expectationsPublication . Monteiro, João; Alves, Marco G; Oliveira, P.F.; Silva, Branca M.Methylated xanthines (methylxanthines) are available from a significant number of different botanical species. They are ordinarily included in daily diet, in many extremely common beverages and foods. Caffeine, theophylline and theobromine are the main methylxanthines available from natural sources. The supposedly relatively low toxicity of methylxanthines, combined with the many beneficial effects that have been attributed to these compounds through time, generated a justified attention and a very prolific ground for dedicated scientific reports. Methylxanthines have been widely used as therapeutical tools, in an intriguing range of medicinal scopes. In fact, methylxanthines have been/were medically used as Central Nervous System stimulants, bronchodilators, coronary dilators, diuretics and anti-cancer adjuvant treatments. Other than these applications, methylxanthines have also been hinted to hold other beneficial health effects, namely regarding neurodegenerative diseases, cardioprotection, diabetes and fertility. However, it seems now consensual that toxicity concerns related to methylxanthine consumption and/or therapeutic use should not be dismissed. Taking all the knowledge and expectations on the potential of methylxanthines into account, we propose a systematic look at the past and future of methylxanthine pharmacologic applications, discussing all the promise and anticipating possible constraints. Anyways, methylxanthines will still substantiate considerable meaningful research and discussion for years to come.
- Obesity, energy balance and spermatogenesisPublication . Oliveira, Pedro F.; Sousa, Mário; Silva, Branca M.; Monteiro, Mariana P; Alves, Marco GObesity has grown to pandemic proportions. It affects an increasing number of children, adolescents and young adults exposed to the silent comorbidities of this disorder for a longer period. Infertility has arisen as one important comorbidity associated with the energy dysfunction promoted by obesity. Spermatogenesis is a highly regulated process that is determined by specific energetic requirements. The reproductive potential of males relies on hormonal-dependent and -independent stimuli that control sperm quality. There are conflicting data concerning the impact of male overweight and obesity on sperm quality, as well as on the possible paternal-induced epigenetic trait inheritance of obesity. In addition, it remains a matter of debate whether massive weight loss induced by lifestyle interventions, drugs or bariatric surgery may or may not benefit obese men seeking fatherhood. Herein, we propose to discuss how energy balance may modulate hormonal signalling and sperm quality in overweight and obese men. We also discuss some molecular mechanisms that mediate obesity-related dysfunction in male reproductive system and how paternal obesity may lead to trait inheritance. Finally, we will discuss how lifestyle modifications and sustained weight loss, particularly the loss achieved by bariatric surgery, may revert some of the deleterious effects of obesity in men and their offspring.
- Metabolic dynamics of human Sertoli cells are differentially modulated by physiological and pharmacological concentrations of GLP-1Publication . Martins, Ana D.; Monteiro, Mariana P.; Silva, Branca M.; Barros, Alberto; Sousa, Mário; Carvalho, Rui A.; Oliveira, P.F.; Alves, Marco G.Obesity incidence has pandemic proportions and is expected to increase even further. Glucagon-like peptide-1 (GLP-1) based therapies are well-established pharmacological resources for obesity treatment. GLP-1 regulates energy and glucose homeostasis, which are also crucial for spermatogenesis. Herein, we studied the GLP-1 effects in human Sertoli cells (hSCs) metabolism and mitochondrial function. hSCs were cultured in absence or exposed to increasing doses of GLP-1 mimicking physiological post-prandial (0.01 nM) levels or equivalent to pharmacological levels (1 and 100 nM) used for obesity treatment. We identified GLP-1 receptor in hSCs. Consumption/production of extracellular metabolites were assessed, as well as protein levels or activities of glycolysis-related enzymes and transporters. Mitochondrial membrane potential and oxidative damage were evaluated. Glucose consumption decreased, while lactate production increased in hSCs exposed to 0.01 and 1 nM GLP-1. Though lactate dehydrogenase (LDH) protein decreased after exposure to 100 nM GLP-1 its activity increased in hSCs exposed to the same concentration of GLP-1. Mitochondrial membrane potential decreased in hSCs exposed to 100 nM of GLP-1, while formation of carbonyl groups was decreased in those cells. Those effects were followed by an increase in p-mammalian target of rapamycin (mTOR) Ser(2448). Overall, the lowest concentrations of GLP-1 increased the efficiency of glucose conversion to lactate, while GLP-1 concentration of 100 nM induces mTOR phosphorylation, decreases mitochondrial membrane potential and oxidative damage. GLP-1 regulates testicular energy homeostasis and pharmacological use of GLP-1 analogues could be valuable to counteract the negative impact of obesity in male reproductive function.
- Androgen-responsive and nonresponsive prostate cancer cells present a distinct glycolytic metabolism profilePublication . Vaz, Cátia Alexandra Vicente; Alves, Marco G.; Marques, Ricardo; Moreira, Paula I; Oliveira, P.F.; Baptista, Cláudio; Socorro, SílviaProstate cancer (PCa) progresses from an early stage, confined to prostate, to a more aggressive metastasized cancer related with loss of androgen responsiveness. Although, it has been recognized that PCa cells have unique metabolic features, their glycolytic profile in androgen-dependent and androgen-independent stages of disease is much less known. Hence, the main purpose of this study was to compare glucose metabolism in androgen-responsive (LNCaP) and androgen-nonresponsive (PC3) PCa cells. Cell culture medium was collected and differences in glucose consumption and, lactate and alanine production were measured using Proton Nuclear Magnetic Resonance ((1)H NMR) spectra analysis. The mRNA and protein expression of glucose transporters (GLUT1 and GLUT3), phosphofructokinase 1 (PFK1), lactate dehydrogenase (LDH) and monocarboxylate transporter (MCT4) were determined by real-time PCR and Western Blot, respectively. The obtained results demonstrate that androgen-responsive (LNCaP) and androgen-nonresponsive (PC3) cells consumed similar amounts of glucose, whereas PC3 cells present higher lactate production. This increase in lactate production was concomitant with higher levels of MCT4 protein, increased LDH activity and higher lactate/alanine ratio, also suggesting increased levels of oxidative stress in PC3 cells. However, protein levels of LDH, associated with lactate metabolism, and GLUT3, involved in glucose uptake, were decreased in PC3 comparatively with LNCaP. Androgen-responsive and nonresponsive PCa cells present distinct glycolytic metabolism profiles, which suggest that targeting LDH and MCT4 metabolic pathways may be an important step for the development of new diagnostic and therapeutic strategies in the different stages of PCa.
- The Action of Polyphenols in Diabetes Mellitus and Alzheimer's Disease: A Common Agent for Overlapping PathologiesPublication . Silveira, Ana C.; Dias, Jane; Santos, Vanessa M.; Oliveira, P.F.; Alves, Marco G; Rato, Luís; Silva, Branca M.Diabetes Mellitus (DM) and Alzheimer's disease (AD) are two prevalent diseases in modern societies, which are caused mainly by current lifestyle, aging and genetic alterations. It has already been demonstrated that these two diseases are associated, since individuals suffering from DM are prone to develop AD. Conversely, it is also known that individuals with AD are more susceptible to DM, namely type 2 diabetes (T2DM). Therefore, these two pathologies, although completely different in terms of symptomatology, end up sharing several mechanisms at the molecular level, with the most obvious being the increase of oxidative stress and inflammation. Polyphenols are natural compounds widely spread in fruits and vegetables whose dietary intake has been considered inversely proportional to the incidence of DM and AD. So, it is believed that this group of phytochemicals may have preventive and therapeutic potential, not only by reducing the risk and delaying the development of these pathologies, but also by improving brain's metabolic profile and cognitive function. The aim of this review is to understand the extent to which DM and AD are related pathologies, the degree of similarity and the relationship between them, to detail the molecular mechanisms by which polyphenols may exert a protective effect, such as antioxidant and anti-inflammatory effects, and highlight possible advantages of their use as common preventive and therapeutic alternatives.
- Implications of epigallocatechin-3-gallate in cultured human Sertoli cells glycolytic and oxidative profilePublication . Dias, Tânia R.; Alves, Marco G; Silva, Joaquina; Barros, Alberto; Sousa, Mário; Casal, Susana; Silva, Branca M.; Oliveira, Pedro F.Sertoli cells are crucial for the success of spermatogenesis, which is the biological process that ensures male fertility. These cells present high metabolic rates, being often subjected to high oxidative stress levels that, if uncontrolled, may compromise male fertility. Since the most abundant tea catechin, epigallocatechin-3-gallate (EGCG), has demonstrated a potent preventive activity against oxidative stress, we have evaluated its effect at concentrations of 5 and 50μM, on the metabolism, mitochondrial functionality and oxidative profile of human Sertoli cells (hSCs). While, the highest concentration of EGCG (50μM) increased glucose and pyruvate consumption, it decreased the conversion of pyruvate to alanine to sustain a regular lactate production. However, despite maintaining Krebs cycle functionality, EGCG (50μM) decreased mitochondrial membrane potential of hSCs, which could compromise the normal rates of ATP production. Interestingly, oxidative damages to proteins and lipids decreased in this experimental group, which may be valuable for the nutritional support of spermatogenesis.