Current Understanding of Human Polymorphism in Selenoprotein Genes: A Review of Its Significance as a Risk Biomarker.

Selenium has been proven to influence several biological functions, showing to be an essential micronutrient. The functional studies demonstrated the benefits of a balanced selenium diet and how its deficiency is associated with diverse diseases, especially cancer and viral diseases. Selenium is an antioxidant, protecting the cells from damage, enhancing the immune system response, preventing cardiovascular diseases, and decreasing inflammation. Selenium can be found in its inorganic and organic forms, and its main form in the cells is the selenocysteine incorporated into selenoproteins. Twenty-five selenoproteins are currently known in the human genome: glutathione peroxidases, iodothyronine deiodinases, thioredoxin reductases, selenophosphate synthetase, and other selenoproteins. These proteins lead to the transport of selenium in the tissues, protect against oxidative damage, contribute to the stress of the endoplasmic reticulum, and control inflammation. Due to these functions, there has been growing interest in the influence of polymorphisms in selenoproteins in the last two decades. Selenoproteins' gene polymorphisms may influence protein structure and selenium concentration in plasma and its absorption and even impact the development and progression of certain diseases. This review aims to elucidate the role of selenoproteins and understand how their gene polymorphisms can influence the balance of physiological conditions. In this polymorphism review, we focused on the PubMed database, with only articles published in English between 2003 and 2023. The keywords used were "selenoprotein" and "polymorphism". Articles that did not approach the theme subject were excluded. Selenium and selenoproteins still have a long way to go in molecular studies, and several works demonstrated the importance of their polymorphisms as a risk biomarker for some diseases, especially cardiovascular and thyroid diseases, diabetes, and cancer.

Predictors of Trypanosoma cruzi PCR positivity in patients with chronic Chagas disease.

BACKGROUND: A positive Trypanosoma cruzi polymerase chain reaction (PCR) is associated with a worse prognosis in patients with chronic Chagas disease (CD). OBJECTIVES: To study the association of clinical, electrocardiographic, and echocardiographic characteristics and biomarker blood levels with positive T. cruzi PCR in chronic CD. METHODS: This is a single-centre observational cross-sectional study. Positive T. cruzi PCR association with clinical, electrocardiographic, and echocardiographic characteristics, and biomarker blood levels were studied by logistic regression analysis. p values < 0.05 were considered significant. FINDINGS: Among 333 patients with chronic CD (56.4% men; 62 ± 10 years), T. cruzi PCR was positive in 41.1%. Stepwise multivariate logistic regression showed an independent association between positive T. cruzi PCR and diabetes mellitus {odds ratio (OR) 0.53 [95% confidence interval (CI) 0.30-0.93]; p = 0.03}, right bundle branch block [OR 1.78 (95% CI 1.09-2.89); p = 0.02], and history of trypanocidal treatment [OR 0.13 (95% CI 0.04-0.38); p = 0.0002]. Among patients with a history of trypanocidal treatment (n = 39), only four (10%) patients had a positive T. cruzi PCR. MAIN CONCLUSIONS: Among several studied parameters, only diabetes mellitus, right bundle branch block, and history of trypanocidal treatment showed an independent association with positive T. cruzi PCR. History of trypanocidal treatment was a strong protective factor against a positive T. cruzi PCR.

Transforming growth factor-ß as a therapeutic target for the cardiac damage of Chagas disease.

Transforming growth factor beta (TGF-ß) is deeply involved on the pathogenesis of Chagas disease. Our group has been investigating the participation of this pleiotropic cytokine in different aspects of Chagas disease over the last 20 years. Important observations have been made, such as: (i) the ability of Trypanosoma cruzi in activating latent TGF-ß; (ii) the potential involvement of TGF-ß pathway on T. cruzi invasion of host cells; (iii) association of TGF-ß with parasite intracellular replication; (iv) cardiac fibrosis development and maintenance; (v) disruption of Connexin-43 plaque structures and (vi) inflammation and immune response. In this perspective article we intend to discuss the advances of the potential use of new therapies targeting TGF-ß to treat the cardiac alterations of Chagas disease-affected patients.

Increased angiogenesis parallels cardiac tissue remodelling in experimental acute Trypanosoma cruzi infection.

BACKGROUND: Angiogenesis has been implicated in tissue injury in several noninfectious diseases, but its role in Chagas disease (CD) physiopathology is unclear. OBJECTIVES: The present study aimed to investigate the effect of Trypanosoma cruzi infection on cardiac angiogenesis during the acute phase of experimental CD. METHODS: The signalling pathway involved in blood vessel formation and cardiac remodelling was evaluated in Swiss Webster mice infected with the Y strain of T. cruzi. The levels of molecules involved in the regulation of angiogenesis, such as vascular endothelial growth factor-A (VEGF-A), Flk-1, phosphorylated extracellular-signal-regulated protein kinase (pERK), hypoxia-inducible factor-1α (HIF-1α), CD31, α-smooth muscle actin (α-SMA) and also the blood vessel growth were analysed during T. cruzi infection. Hearts were analysed using conventional histopathology, immunohistochemistry and western blotting. FINDINGS: In this study, our data demonstrate that T. cruzi acute infection in mice induces exacerbated angiogenesis in the heart and parallels cardiac remodelling. In comparison with noninfected controls, the cardiac tissue of T. cruzi-infected mice presented higher levels of (i) HIF-1α, VEGF-A, Flk-1 and pERK; (ii) angiogenesis; (iii) α-SMA+ cells in the tissue; and (iv) collagen -1 deposition around blood vessels and infiltrating throughout the myocardium. MAIN CONCLUSIONS: We observed cardiac angiogenesis during acute experimental T. cruzi infection parallels cardiac inflammation and remodelling.

Impact of pharmaceutical care on the quality of life of patients with heart failure due to chronic Chagas disease: Randomized clinical trial.

AIMS: Chronic Chagas disease (ChD) has high morbimortality and loss in quality of life due to heart failure (HF). Pharmaceutical care (PC) optimizes clinical treatment and can improve quality of life in HF. We evaluated if PC improves quality of life of patients with ChD and HF. METHODS: Single-blinded, randomized, controlled trial that assigned adult patients with ChD and HF (81 patients; 61 ± 11 years; 48% male) to PC (n = 40) or standard care (n = 41). Quality of life according to SF-36 and Minnesota living with HF questionnaires, incidence of drug-related problems (DRPs), and adherence to medical treatment were determined at baseline and at every 3 months for 1 year. Intention-to-treat analyses were performed by mixed linear model to verify the treatment effect on the changes of these variables throughout the intervention period. RESULTS: Relative changes from baseline to 1 year of follow-up of the domains physical functioning (+16.6 vs -8.5; P < .001), role-physical (+34.0 vs +5.2; P = .01), general health (+19.4 vs -6.1; P < .001), vitality (+11.5 vs. -5.8; P = .003), social functioning (+7.5 vs -13.3; P = .002), and mental health (+9.0 vs -3.7; P = .006) of the SF-36 questionnaire and the Minnesota living with HF questionnaire score (-12.7 vs +4.8; P < .001) were superior in the PC group than in the standard care group. Adherence to medical treatment increased as early as after 3 months of follow-up and DRPs incidence decreased after 6 months of follow-up only in the PC group. CONCLUSIONS: Patients with ChD and HF who received PC presented improved quality of life, decrease in DRP frequency, and increase in medication adherence.

Unveiling Lovastatin's Anti-Inflammatory Potential in Mouse's Brain during Acute Trypanosoma cruzi Infection.

Neurological commitment is a neglected manifestation of Chagas disease (CD). Meningoencephalitis mainly affects children and immunosuppressed patients, while stroke can occur with or without cardiac compromise. One of the possible causes of stroke development is microvascular commitment. Our group previously described that experimental Trypanossoma cruzi acute infection leads to cerebral microvasculopathy. This condition is characterized by decreased capillary density, increased leukocyte rolling and adhesion, and endothelial dysfunction. CD was discovered 114 years ago, and until today, only two drugs have been available for clinical treatment: benznidazole and nifurtimox. Both present a high cure rate for the acute phase (80%) and small cure rate for the chronic phase (20%). In addition, the high occurrence of side-effects, without proper medical follow-up, can result in treatment abandonment. Therefore, the search for new therapeutic schemes is necessary. Statins are drugs already used in the clinic that have several pleiotropic effects including endothelial function improvement, anti-inflammatory action, as well as trypanocidal effects, making them a potential alternative treatment for brain microvasculopathy in CD. Here, we investigate the effect of lovastatin (LOV) on brain microvasculopathy and inflammatory parameters. Swiss Webster mice were intraperitoneally inoculated with the Y strain of T. cruzi. Treatment with lovastatin (20 mg/kg/day) was initiated 24 h after the infection and continued for 14 consecutive days. We observed that LOV treatment did not affect parasitemia, brain microcirculation alterations, or the reduction in cerebral blood flow caused by T. cruzi infection. Also, LOV did not prevent the increased number of CD3+ cells and eNOS levels in the T. cruzi-infected brain. No alterations were observed on VCAM-1 and MCP-1 expressions, neither caused by infection nor LOV treatment. However, LOV prevented the increase in F4/80+ cells and ICAM-1 levels in the brain caused by acute infection with T. cruzi. These results suggest an anti-inflammatory activity of LOV, but more studies are needed to elucidate the role of LOV in CD acute infection.

Spheroid Model of Mammary Tumor Cells: Epithelial-Mesenchymal Transition and Doxorubicin Response.

Breast cancer is the most prevalent cancer among women worldwide. Therapeutic strategies to control tumors and metastasis are still challenging. Three-dimensional (3D) spheroid-type systems more accurately replicate the features of tumors in vivo, working as a better platform for performing therapeutic response analysis. This work aimed to characterize the epithelial-mesenchymal transition and doxorubicin (dox) response in a mammary tumor spheroid (MTS) model. We evaluated the doxorubicin treatment effect on MCF-7 spheroid diameter, cell viability, death, migration and proteins involved in the epithelial-mesenchymal transition (EMT) process. Spheroids were also produced from tumors formed from 4T1 and 67NR cell lines. MTSs mimicked avascular tumor characteristics, exhibited adherens junction proteins and independently produced their own extracellular matrix. Our spheroid model supports the 3D culturing of cells isolated from mice mammary tumors. Through the migration assay, we verified a reduction in E-cadherin expression and an increase in vimentin expression as the cells became more distant from spheroids. Dox promoted cytotoxicity in MTSs and inhibited cell migration and the EMT process. These results suggest, for the first time, that this model reproduces aspects of the EMT process and describes the potential of dox in inhibiting the metastatic process, which can be further explored.

Clinical trials for Chagas disease: etiological and pathophysiological treatment.

Chagas disease (CD) is caused by the flagellate protozoan Trypanosoma cruzi. It is endemic in Latin America. Nowadays around 6 million people are affected worldwide, and 75 million are still at risk. CD has two evolutive phases, acute and chronic. The acute phase is mostly asymptomatic, or presenting unspecific symptoms which makes it hard to diagnose. At the chronic phase, patients can stay in the indeterminate form or develop cardiac and/or digestive manifestations. The two trypanocide drugs available for the treatment of CD are benznidazole (BZ) and nifurtimox (NFX), introduced in the clinic more than five decades ago. WHO recommends treatment for patients at the acute phase, at risk of congenital infection, for immunosuppressed patients and children with chronic infection. A high cure rate is seen at the CD acute phase but better treatment schemes still need to be investigated for the chronic phase. There are some limitations within the use of the trypanocide drugs, with side effects occurring in about 40% of the patients, that can lead patients to interrupt treatment. In addition, patients with advanced heart problems should not be treated with BZ. This is a neglected disease, discovered 114 years ago that still has no drug effective for their chronic phase. Multiple social economic and cultural barriers influence CD research. The high cost of the development of new drugs, in addition to the low economical return, results in the lack of investment. More economic support is required from governments and pharmaceutical companies on the development of more research for CD treatment. Two approaches stand out: repositioning and combination of drugs, witch drastically decrease the cost of this process, when compared to the development of a new drug. Here we discuss the progress of the clinical trials for the etiological and pathophysiological treatment for CD. In summary, more studies are needed to propose a new drug for CD. Therefore, BZ is still the best option for CD. The trials in course should clarify more about new treatment regimens, but it is already possible to indicate that dosage and time of treatment need to be adjusted.

Vascular Growth Factor Inhibition with Bevacizumab Improves Cardiac Electrical Alterations and Fibrosis in Experimental Acute Chagas Disease.

Chagas disease (CD) caused by Trypanosoma cruzi is a neglected illness and a major reason for cardiomyopathy in endemic areas. The existing therapy generally involves trypanocidal agents and therapies that control cardiac alterations. However, there is no treatment for the progressive cardiac remodeling that is characterized by inflammation, microvasculopathy and extensive fibrosis. Thus, the search for new therapeutic strategies aiming to inhibit the progression of cardiac injury and failure is necessary. Vascular Endothelial Growth Factor A (VEGF-A) is the most potent regulator of vasculogenesis and angiogenesis and has been implicated in inducing exacerbated angiogenesis and fibrosis in chronic inflammatory diseases. Since cardiac microvasculopathy in CD is also characterized by exacerbated angiogenesis, we investigated the effect of inhibition of the VEGF signaling pathway using a monoclonal antibody (bevacizumab) on cardiac remodeling and function. Swiss Webster mice were infected with Y strain, and cardiac morphological and molecular analyses were performed. We found that bevacizumab significantly increased survival, reduced inflammation, improved cardiac electrical function, diminished angiogenesis, decreased myofibroblasts in cardiac tissue and restored collagen levels. This work shows that VEGF is involved in cardiac microvasculopathy and fibrosis in CD and the inhibition of this factor could be a potential therapeutic strategy for CD.

The perceptions of Brazilian postgraduate students about the impact of COVID-19 on their well-being and academic performance.

This study aimed at identifying the perceptions of Brazilian postgraduate students from all over the country on the impacts of the COVID-19 pandemic on their academic trajectories. Data from 5985 postgraduate students were collected in the end of 2020, through a 37-item questionnaire, including multiple-choice questions, through Google Forms. The questions were divided into blocks with different proposals: personal profile, academic profile, issues related to COVID-19 infection, and issues related to mental health. Our analysis showed that 51.43% were master's degree students; 43.02% were doctorate and 5.55% were specialization students, mostly attending Biological, Health, and Human Sciences post-graduation courses (18.13%, 17.91%, and 17.38%, respectively) of different Brazilian educational institutions, including public (e.g., UFRJ) and private (e.g., PUC) federal universities as well as research institutions (e.g., Fiocruz) from all five regions of Brazil (north, south, southeast, northeast, and center Midwest). Most of them were academically impacted by the COVID-19 pandemic, which also involved psychological aspects such as high levels of anxiety and depression. The results showed readjustments of research projects, and academic activities, which in some particular research fields led to the successful completion through the remote activities. However, efforts are still needed by graduate programs in order to allow greater flexibility in academic activities to fulfill all previous planning and chronograms, in addition to implementing ongoing projects to support students' mental health.