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Drug discovery for multifactorial diseases like metabolic dysfunction-associated steatotic liver disease (MASLD) remains challenging due to inadequate models and untargeted drug screenings. We combined stem-cell-based modeling with computational drug predictions identifying flavin pathways as therapeutic targets in MASLD. For disease stage-specific discovery, we established a MASLD testing model, compounding metabolic triggers to intensify mitochondrial crisis. In vitro injuries included adipo- and myokines, immune cell co-culture, and genomic risk factors. Benchmarking experiments revealed similarities with advanced human MASLD. To query therapeutic compounds, protein-protein-interaction networks, weighted gene co-expression, and knowledge graph-based analyses independently predicted flavin adenine dinucleotide (FAD) as an anti-MASLD factor. Dysregulated flavoproteomes in vitro and in vivo–in pediatric and adult MASLD patients– supported our flavin network-focused strategy. We established therapeutic FAD concentrations to mitigate metabolic injury and fibro-inflammation in human multicellular liver organoids and other assays. We enhanced therapeutic FAD effects through genetic mitochondrial biogenic augmentation and identified orally available flavo-active compounds—including Aspirin—restoring mitochondrial respiration. Our study demonstrates how integrating stem cell-derived disease modeling with computed drug predictions can expedite therapeutic discovery.

Flaviviruses include virus species that are major public health threats worldwide. To determine the immunity landscape of these viruses, seroprevalence studies are often performed using IgG ELISA, which is a simple and rapid alternative to the virus neutralization test. In this review, we aim to describe the trends in flavivirus IgG ELISA-based serosurveys. A systematic literature review using six databases was performed to collate cohort and cross-sectional studies performed on the general population. A total of 204 studies were included in this review. The results show that most studies were performed on dengue virus (DENV), whereas Japanese Encephalitis Virus (JEV) was the least studied. For geographic distribution, serosurveys followed known disease prevalence. Temporally, the number of serosurveys increased after outbreaks and epidemics except for JEV, for which studies were performed to demonstrate the effectiveness of vaccination campaigns. Commercial kits were more commonly used than in-house assays for DENV, West Nile Virus (WNV), and Zika virus (ZIKV). Overall, most studies employed an indirect ELISA format, and the choice of antigens varied per virus. This review shows that flavivirus epidemiology is related to the regional and temporal distribution of serosurveys. It also highlights that endemicity, cross-reactivities, and kit availabilities affect assay choice in serosurveys.

Mucopolysaccharidosis type II (MPS II or Hunter Syndrome) is a lysosomal disease caused by deficient degradation of glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate due to the deficiency of the enzyme iduronate-2-sulfatase. The main treatment for MPS II is the administration of the recombinant form of the enzyme, in a process known as enzyme replacement therapy (ERT). Oxidative damage can contribute to the pathophysiology of MPS II and treatment with ERT can reduce the effects of oxidative stress. For a better understanding of pathophysiology of MPS II, we evaluated biomarkers of mitochondrial dysfunction, DNA (Deoxyribonucleic acid) damage, antioxidant defenses, reactive species production and lysosomal size in IDS -deficient HEK 293 cells and investigate the in vitro effect of genistein and coenzyme Q10 (CoQ) on these biomarkers. An increase in the production of reactive species was demonstrated, as well as an increase in the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Also, an increase in lysosomal volume and oxidative damage to DNA were verified. There was no evidence of a change in mitochondrial function in this cell model. In the HEK 293 (human embryonic kidney 293) knockout (KO) HP10 cell model we found that genistein at concentrations of 25 and 50 μm decreased in vitro the production of reactive species and the activity of the SOD enzyme, showing an antioxidant protective effect. Still, in these cells we verified that the coenzyme Q10 in the concentrations of 5 and 10 μm decreased in vitro the activity of the SOD enzyme and in the concentration of 10 μm decreased in vitro the DNA damage, also demonstrating antioxidant protection. In conclusion, MPS II knockout cells demonstrated oxidative stress and DNA damage and genistein, as well as coenzyme Q10, have been shown to have an important protective effect in vitro against these oxidative damages.

Phenylketonuria is a genetic disorder characterized by high phenylalanine levels, the main toxic metabolite of the disease. Hyperphenylalaninemia can cause neurological impairment. In order to avoid this symptomatology, patients typically follow a phenylalanine-free diet supplemented with a synthetic formula that provides essential amino acids, including L-carnitine. This work aims to evaluate the potential neuroprotective effects of L-carnitine treatment in the cerebral cortex of rats submitted to a chronic chemically-induced model of Hyperphenylalaninemia, evaluating brain oxidative damage and neuroinflammation. We confirm the effectiveness of the animal model, through the increase of phenylalanine and L-carnitine in blood and cerebral cortex. L-carnitine treatment was effective in significantly decreasing the generation of reactive species and attenuating the superoxide dismutase (SOD) activity. Significant negative correlations between L-carnitine and superoxide dismutase as well as L-carnitine and reactive species generation were also found, reinforcing the involvement of oxidative stress and the effect of L-carnitine. Besides, L-carnitine attenuated the decrease in IL-4 levels, demonstrating both anti-inflammatory properties and a neuroprotective effect, through the decrease in the overexpression of the glial fibrillary acidic protein (GFAP) present in the cerebral cortex of rats with Hyperphenylalaninemia. Our results highlight the neuroprotective role of L-carnitine in the treatment of Phenylketonuria, mainly against neuroinflammation and the oxidative process, contributing to better clarify the pathophysiology of the disease.

Resumo Introdução: Garantir a saúde como direito e dever do Estado, assegurada por políticas sociais e econômicas, persiste como desafio para o poder público, principalmente em relação ao seu financiamento. Objetivo: Identificar a evolução da despesa pública com saúde, do acesso e da resolutividade da Atenção Primária à Saúde em municípios mineiros entre 2006 e 2015. Método: Trata-se de um estudo ecológico descritivo, utilizando indicadores e variáveis provenientes de dados secundários do Departamento de Informação e Informática do Sistema Único de Saúde (DataSUS) e Departamento de Atenção Básica (DAB), abrangendo os 853 municípios do estado de Minas Gerais, agregados por macrorregiões de saúde. Resultados: A média do percentual de recursos próprios aplicados em saúde elevou de 20,6 para 23,27%. A despesa pública municipal com saúde por habitante aumentou de R$ 251,85 para R$ 671,09. Houve ampliação da cobertura populacional pelas Equipes de Saúde da Família (ESF) de 58,99 para 79,24%. A proporção de Internações por Condições Sensíveis à Atenção Primária (ICSAP) reduziu de 36,18% para 31,36%. Conclusão: As despesas públicas com saúde cresceram, o acesso foi ampliado pela expansão da cobertura populacional pelas ESF, e a melhoria da resolutividade da Atenção Primária à Saúde foi demonstrada pela redução do indicador \"proporção de ICSAP\".