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.

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.

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.

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.

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.

Trypanosoma cruzi activates mouse cardiac fibroblasts in vitro leading to fibroblast-myofibroblast transition and increase in expression of extracellular matrix proteins.

BACKGROUND: Cardiac fibrosis is a consequence of chronic chagasic cardiomyopathy (CCC). In other cardiovascular diseases, the protagonist role of fibroblasts in cardiac fibrosis is well established. However, the role of cardiac fibroblasts (CFs) in fibrosis during the CCC is not clear. Here, our aim was to investigate the effect of Trypanosoma cruzi, the etiological agent of Chagas disease on CFs activation. METHODS: Cardiac fibroblasts were purified from primary cultures of mouse embryo cardiac cells. After two passages, cells were infected with T. cruzi (Y strain) and analyzed at different times for determination of infectivity, activation and production of extracellular matrix components (fibronectin, laminin and collagen IV) by immunofluorescence and western blot. RESULTS: At second passage, cultures were enriched in CFs (95% of fibroblasts and 5% of cardiomyocytes), as revealed by presence of alpha-smooth muscle actin (α-SMA) and discoidin domain receptor 2 (DDR2) and absence of sarcomeric tropomyosin (ST) protein expression. Trypanosoma cruzi infection induced fibroblast-myofibroblast transition, with increased expression of α-SMA after 6 and 24 h post-infection (hpi). Fibronectin was increased at 6, 24 and 48 hpi, laminin was increased at 6 and 24 hpi and collagen IV was increased at 6 hpi. CONCLUSIONS: Our results showed that T. cruzi activates CFs, inducing activation and exacerbates ECM production. Furthermore, our data raise the possibility of the involvement of CFs in heart fibrosis during Chagas disease.