Effect of metabolic syndrome and individual components on colon cancer characteristics and prognosis

Metabolic syndrome (MS) is recognized as a risk factor for colon cancer (CC). However, whether the cluster of metabolic changes that define MS also influence CC prognosis remains unclear. Thus, our aim was to investigate whether the presence of MS or any of the MS individual components could provide prognostic information on tumor phenotype and survival outcomes. Clinical and pathological data from patients with CC (n = 300) who underwent surgical resection at a single tertiary hospital were retrospectively collected to evaluate presence of MS components and diagnostic criteria, CC phenotype and disease outcomes. Patients were allocated into two groups according to the presence or absence of MS (n = 85 MS vs n = 83 non-MS). The overall prevalence of MS individual components was 82.7% for increased waist-circumference (WC), 61.3% for high blood pressure (BP), 48.8% for low HDL-cholesterol, 39.9% for high fasting glucose, and 33.9% for hypertriglyceridemia. Patients in the MS group presented smaller tumors (p = 0.006) with lower T-stage (p = 0.002). High BP (p = 0.029) and hypertriglyceridemia (p = 0.044) were associated with a smaller tumor size, while low-HDL (p = 0.008) was associated with lower T-stage. After propensity score matching using age, tumor size and staging as covariates high-BP (p = 0.020) and WC (p = 0.003) were found to influence disease-free survival, but not overall survival. In conclusion, despite MS being an established risk factor for CC, our data does not support the hypothesis that MS components have a negative impact on disease extension or prognosis. Nevertheless, a protective role of BP and lipid lowering drugs cannot be excluded.info:eu-repo/semantics/publishedVersio

Obesity, energy balance and spermatogenesis

Obesity 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.info:eu-repo/semantics/publishedVersio

Adipose Tissue Epigenetic Profile in Obesity-Related Dysglycemia - A Systematic Review.

BackgroundObesity is a major risk factor for dysglycemic disorders, including type 2 diabetes (T2D). However, there is wide phenotypic variation in metabolic profiles. Tissue-specific epigenetic modifications could be partially accountable for the observed phenotypic variability.ScopeThe aim of this systematic review was to summarize the available data on epigenetic signatures in human adipose tissue (AT) that characterize overweight or obesity-related insulin resistance (IR) and dysglycemia states and to identify potential underlying mechanisms through the use of unbiased bioinformatics approaches.MethodsOriginal data published in the last decade concerning the comparison of epigenetic marks in human AT of individuals with metabolically unhealthy overweight/obesity (MUHO) versus normal weight individuals or individuals with metabolically healthy overweight/obesity (MHO) was assessed. Furthermore, association of these epigenetic marks with IR/dysglycemic traits, including T2D, was compiled.ResultsWe catalogued more than two thousand differentially methylated regions (DMRs; above the cut-off of 5%) in the AT of individuals with MUHO compared to individuals with MHO. These DNA methylation changes were less likely to occur around the promoter regions and were enriched at loci implicated in intracellular signaling (signal transduction mediated by small GTPases, ERK1/2 signaling and intracellular trafficking). We also identified a network of seven transcription factors that may play an important role in targeting DNA methylation changes to specific genes in the AT of subjects with MUHO, contributing to the pathogeny of obesity-related IR/T2D. Furthermore, we found differentially methylated CpG sites at 8 genes that were present in AT and whole blood, suggesting that DMRs in whole blood could be potentially used as accessible biomarkers of MUHO.ConclusionsThe overall evidence linking epigenetic alterations in key tissues such AT to metabolic complications in human obesity is still very limited, highlighting the need for further studies, particularly those focusing on epigenetic marks other than DNA methylation. Our initial analysis suggests that DNA methylation patterns can potentially discriminate between MUHO from MHO and provide new clues into why some people with obesity are less susceptible to dysglycemia. Identifying AT-specific epigenetic targets could also lead to novel approaches to modify the progression of individuals with obesity towards metabolic disease.Systematic review registrationPROSPERO, identifier CRD42021227237

Análise do efeito de nanopartículas de prata contra células aderidas e biofilmes de Candida albicans e Candida glabrata

O aumento na resistência dos biofilmes de Candida à terapia antifúngica convencional tem despertado o interesse no uso da prata como um agente antimicrobiano. Assim, o objetivo deste trabalho foi avaliar a eficácia antifúngica de nanopartículas de prata (NPs) contra células aderidas e biofilmes de Candida albicans e Candida glabrata. Métodos: NPs esféricas (5 nm) foram sintetizadas através da redução do nitrato de prata pelo citrato de sódio. Testes de mínima concentração inibitória (MCI) foram realizados para as duas espécies de Candida de acordo com o método da microdiluição. NPs foram aplicadas sobre células aderidas (2 hrs) e biofilmes (48 hrs), e após 24 horas de contato os biofilmes resultantes foram caracterizados através da contagem do número de unidades formadoras de colônias (UFCs) e quantificação da biomassa total. Resultados: Os valores de MCI para C. glabrata foram maiores (0,4 – 3,3 µg/mL) do que para C. albicans (0,4 – 1,6 µg/mL). NPs foram mais efetivas na redução da biomassa total quando aplicadas sobre células aderidas do que sobre biofilmes pré-formados. NPs também foram altamente efetivas na redução das UFCs quando aplicadas sobre as células aderidas de C. glabrata (~70%) e respectivos biofilmes (~50%). Para as cepas de C. albicans o efeito não foi tão notório, mas também existiu uma redução no número de UFCs. Conclusão: NPs apresentam potencial como agente antifúngico alternativo no controle de infecções por espécies de Candida

Lifestyle, metabolic disorders and male hypogonadism - a one-way ticket?

Hypogonadism is more frequent among men with common metabolic diseases, notably obesity and type 2 diabetes. Indeed, endocrine disruption caused by metabolic diseases can trigger the onset of hypogonadism, although the underlying molecular mechanisms are not entirely understood. Metabolic diseases are closely related to unhealthy lifestyle choices, such as dietary habits and sedentarism. Therefore, hypogonadism is part of a pathological triad gathering unhealthy lifestyle, metabolic disease and genetic background. Additionally, hypogonadism harbors the potential to aggravate underlying metabolic disorders, further sustaining the mechanisms leading to disease. To what extent does lifestyle intervention in men suffering from these metabolic disorders can prevent, improve or reverse hypogonadism, is still controversial. Moreover, recent evidence suggests that the metabolic status of the father is related to the risk of inter and transgenerational inheritance of hypogonadism. In this review, we will address the proposed mechanisms of disease, as well as currently available interventions for hypogonadism.publishe

Colon tumor CD31 expression is associated with higher disease-free survival in patients with metabolic syndrome

Metabolic syndrome (MS) is recognized as a risk factor for colon cancer (CC). However, how does the interplay between metabolic dysfunction caused by MS and its individual components affect CC microenvironment and prognosis remains unexplored. Angiogenesis and lymphangiogenesis are fundamental processes for tumor progression and dissemination, ensuring oxygen and nutrient delivery and supporting one of the most important pathways of tumor dissemination, contributing to metastasis. Thus, our aim was to evaluate whether the expression of molecular biomarkers involved in angiogenic and lymphangiogenic processes influenced CC clinicopathological features and prognosis in patients with MS. Clinical and pathological data of 300 patients submitted to CC surgical resection at a single tertiary hospital were retrospectively retrieved from hospital records. Tumor tissue microarrays of archived paraffin-embedded blocks were used to assess CD31, VEGF-A and D2–40 tissue expression by immunohistochemistry. The percentage of stained area was quantified by computerized morphometric analysis. No association between tissue expression of angiogenesis and lymphangiogenesis biomarkers and tumor clinical and pathological characteristics was found. However, in subgroup analysis of patients with MS, dysglycemia was associated with lower D2–40 expression (p = 0.007) and high waist-circumference was associated with higher D2–40 (p = 0.0029) and VEGF-A expression (p = 0.026). In an adjusted Cox proportional hazard model CD31 expression was significantly associated with greater disease-free survival (HR=0.62; 95% CI: 0.41–0.95, p = 0.028). No association was found between D2–40 and VEGF-A expression and CC prognosis. Our data reinforces previous reports that suggest the potential use of CD31 as a CC prognostic biomarker. Additionally, our data further supports the evidence for an interplay between metabolic dysfunction, tumor microenvironment, and vascularization pathways.info:eu-repo/semantics/publishedVersio

Metabolic dynamics of human Sertoli cells are differentially modulated by physiological and pharmacological concentrations of GLP-1

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.info:eu-repo/semantics/publishedVersio

Phase behaviour and miscibility studies of collagen/silk fibroin macromolecular system in dilute solutions and solid state

Miscibility is an important issue in biopolymer blends for analysis of the behavior of polymer pairs through the detection of phase separation and improvement of the mechanical and physical properties of the blend. This study presents the formulation of a stable and one-phase mixture of collagen and regenerated silk fibroin (RSF), with the highest miscibility ratio between these two macromolecules, through inducing electrostatic interactions, using salt ions. For this aim, a ternary phase diagram was experimentally built for the mixtures, based on observations of phase behavior of blend solutions with various ratios. The miscibility behavior of the blend solutions in the miscible zones of the phase diagram was confirmed quantitatively by viscosimetric measurements. Assessing the effects of biopolymer mixing ratio and salt ions, before and after dialysis of blend solutions, revealed the importance of ion-specific interactions in the formation of coacervate-based materials containing collagen and RSF blends that can be used in pharmaceutical, drug delivery, and biomedical applications. Moreover, the conformational change of silk fibroin from random coil to beta sheet, in solution and in the final solid films, was detected by circular dichroism (CD) and Fourier transform infrared spectroscopy (FTIR), respectively. Scanning electron microscopy (SEM) exhibited alterations of surface morphology for the biocomposite films with different ratios. Surface contact angle measurement illustrated different hydrophobic properties for the blended film surfaces. Differential scanning calorimetry (DSC) showed that the formation of the beta sheet structure of silk fibroin enhances the thermal stability of the final blend films. Therefore, the novel method presented in this study resulted in the formation of biocomposite films whose physico-chemical properties can be tuned by silk fibroin conformational changes by applying different component mixing ratios228sem informaçãosem informaçã

Diabetic and Elder Patients Experience Superior Cardiovascular Benefits After Gastric Bypass Induced Weight Loss

Background/Objetives: Obesity and obesity related co-morbidities are well-recognized risks for cardiovascular (CV) disease and mortality. Weight loss improves CV risk factors and the efficacy of bariatric surgery in decreasing CV mortality is now well-established. Our aim was to assess CV risk progression and occurrence of CV events in a cohort of patients that underwent Roux-en-Y gastric bypass (RYGB) for obesity treatment in a single academic public center.Subjects and Methods: Ten year CV risk was estimated using the Framingham Equation at baseline and 2 years after RYGB surgery in our patients cohort (n = 260). In the subgroup with a follow-up time longer than 4 years after surgery (n = 185; mean 5.4 ± 0.1 years), CV risk adjusted for the time length after RYGB was similarly estimated and the occurrence of CV events for outcome adjudication was monitored during the same time period by reviewing the hospital patients' record, the electronic national health system patient register and our center outpatient clinic records.Results: Ten year CV risk was significantly reduced 2 years after surgery when compared to baseline, with reductions of 1.65 ± 0.25% in the risk of CV disease. Patients with prior type 2 diabetes and aged 50 years or older experienced a significantly superior CV risk reduction, with diabetic patients experiencing a reduction of their 10–year CV disease risk of 3.58 ± 1.11% vs. a reduction of 1.31 ± 0.20% in non-diabetic patients and with the 10–year risk of CV disease dropping 3.41 ± 0.75% in patients older than 50 vs. a reduction of 0.99 ± 0.18 in patients up to 50 years. For the subgroup of patients with a longer follow-up time, baseline CV risk estimation predicted the occurrence of 6.08 ± 0.56 cardiovascular disease (CVD) events, 3.87 ± 0.39 coronary heart disease (CHD) events, 1.49 ± 0.22 myocardial infarctions (MI), 0.71 ± 0.09 strokes, 0. 28 ± 0.05 deaths from CHD and 0.35 ± 0.05 deaths from CVD. No CV events were adjudicated in this subgroup during follow-up.Conclusions: RYGB significantly improves CV risk and prevents the occurrence of CV events. For similar weight loss, diabetic and elder patients experience a superior CV risk improvement and may have additional CV benefits after bariatric surgery

Leptin modulates human Sertoli cells acetate production and glycolytic profile: a novel mechanism of obesity-induced male infertility?

AbstractHuman feeding behavior and lifestyle are gradually being altered, favoring the development of metabolic diseases, particularly type 2 diabetes and obesity. Leptin is produced by the adipose tissue acting as a satiety signal. Its levels have been positively correlated with fat mass and hyperleptinemia has been proposed to negatively affect male reproductive function. Nevertheless, the molecular mechanisms by which this hormone affects male fertility remain unknown. Herein, we hypothesize that leptin acts on human Sertoli cells (hSCs), the “nurse cells” of spermatogenesis, altering their metabolism. To test our hypothesis, hSCs were cultured without or with leptin (5, 25 and 50ng/mL). Leptin receptor was identified by qPCR and Western blot. Protein levels of glucose transporters (GLUT1, GLUT2 and GLUT3), phosphofructokinase, lactate dehydrogenase (LDH) and monocarboxylate transporter 4 (MCT4) were determined by Western Blot. LDH activity was assessed and metabolite production/consumption determined by proton nuclear magnetic resonance. Oxidative damage was evaluated by assessing lipid peroxidation, protein carbonilation and nitration. Our data shows that leptin receptor is expressed in hSCs. The concentration of leptin found in lean, healthy patients, upregulated GLUT2 protein levels and concentrations of leptin found in lean and obese patients increased LDH activity. Of note, all leptin concentrations decreased hSCs acetate production illustrating a novel mechanism for this hormone action. Moreover, our data shows that leptin does not induce or protect hSCs from oxidative damage. We report that this hormone modulates the nutritional support of spermatogenesis, illustrating a novel mechanism that may be linked to obesity-induced male infertility