Atomoxetine: toxicological aspects of a new treatment for Attention Deficit Hyperactivity Disorder in Brazil.

Atomoxetine is a drug widely used for the treatment of the attention deficit hyperactivity disorder (ADHD) with reduced risk of adverse motor reactions and chemical dependence. However, the pharmacokinetics characteristics as well as the toxicological risk of atomoxetine deserves further investigation to comprehensively analyze the therapeutic and safety aspects of this drug. This study aimed to predict the physicochemical profile and medicinal chemistry characteristics of atomoxetine, alongside its pharmacokinetic properties-namely absorption, distribution, metabolism, and excretion-as well as its toxicology (ADMET) potential through the utilization of web-based in silico tools. This research emphasizes predicted physicochemical, medicinal chemistry, and absorption parameters of atomoxetine that could influence the efficacy and safety of this drug for ADHD treatment. Additionally, atomoxetine also presents noteworthy predicted risks of hepatotoxicity, cardiotoxicity, neurotoxicity, nephrotoxicity, respiratory system toxicity, skin toxicity, and carcinogenicity. These findings underscore the necessity for further assessments of atomoxetine's safety profile, particularly considering different patient populations and durations of drug treatment. The data reported here from in silico predictions suggest that closer monitoring is warranted when atomoxetine is administered to patients with ADHD. Moreover, controlled studies detailing reliable protocols for personalized dosing, considering the multifactorial variability in metabolism efficiency and toxicological potential, would enable a more comprehensive assessment of atomoxetine's safety profile.

Advancing molecular modeling and reverse vaccinology in broad-spectrum yellow fever virus vaccine development.

Yellow fever outbreaks are prevalent, particularly in endemic regions. Given the lack of an established treatment for this disease, significant attention has been directed toward managing this arbovirus. In response, we developed a multiepitope vaccine designed to elicit an immune response, utilizing advanced immunoinformatic and molecular modeling techniques. To achieve this, we predicted B- and T-cell epitopes using the sequences from all structural (E, prM, and C) and nonstructural proteins of 196 YFV strains. Through comprehensive analysis, we identified 10 cytotoxic T-lymphocyte (CTL) and 5T-helper (Th) epitopes that exhibited overlap with B-lymphocyte epitopes. These epitopes were further evaluated for their affinity to a wide range of human leukocyte antigen system alleles and were rigorously tested for antigenicity, immunogenicity, allergenicity, toxicity, and conservation. These epitopes were linked to an adjuvant ( ß -defensin) and to each other using ligands, resulting in a vaccine sequence with appropriate physicochemical properties. The 3D structure of this sequence was created, improved, and quality checked; then it was anchored to the Toll-like receptor. Molecular Dynamics and Quantum Mechanics/Molecular Mechanics simulations were employed to enhance the accuracy of docking calculations, with the QM portion of the simulations carried out utilizing the density functional theory formalism. Moreover, the inoculation model was able to provide an optimal codon sequence that was inserted into the pET-28a( +) vector for in silico cloning and could even stimulate highly relevant humoral and cellular immunological responses. Overall, these results suggest that the designed multi-epitope vaccine can serve as prophylaxis against the yellow fever virus.

Computational antigenic insights into the novel NADC-34-like Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) isolate YC-2020.

In this computational study, we advanced the understanding of the antigenic properties of the NADC-34-like isolate of the Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), named YC-2020, relevant in veterinary pathology. We utilized sequence comparison analyses of the M and N proteins, comparing them with those of NADC34, identifying substantial amino acid homology that allowed us to highlight conserved epitopes and crucial variants. Through the application of Clustal Omega for multiple sequence alignment and platforms like Vaxijen and AllerTOP for predicting antigenic and allergenic potential, our analyses revealed important insights into the conservation and variation of epitopes essential for the development of effective diagnostic tools and vaccines. Our findings, aligned with initial experimental studies, underscore the importance of these epitopes in the development of targeted immunodiagnostic platforms and significantly contribute to the management and control of PRRSV. However, further studies are required to validate the computational predictions of antigenicity for this new viral isolate. This approach underscores the potential of computational models to enable ongoing monitoring and control of PRRSV evolution in swine. While this study provides valuable insights into the antigenic properties of the novel PRRSV isolate YC-2020 through computational analysis, it is important to acknowledge the limitations inherent to in silico predictions, specifically, the absence of laboratory validation.

Understanding SARS-CoV-2 spike glycoprotein clusters and their impact on immunity of the population from Rio Grande do Norte, Brazil.

SARS-CoV-2 genome underwent mutations since it started circulating within the human population. The aim of this study was to understand the fluctuation of the spike clusters concomitant to the population immunity either due to natural infection and/or vaccination in a state of Brazil that had both high rate of natural infection and vaccination coverage. A total of 1725 SARS-CoV-2 sequences from the state of Rio Grande do Norte, Brazil, were retrieved from GISAID and subjected to cluster analysis. Immunoinformatics were used to predict T- and B-cell epitopes, followed by simulation to estimate either pro- or anti-inflammatory responses and to correlate with circulating variants. From March 2020 to June 2022, the state of Rio Grande do Norte reported 579,931 COVID-19 cases with a 1.4% fatality rate across the three major waves: May-Sept 2020, Feb-Aug 2021, and Jan-Mar 2022. Cluster 0 variants (wild type strain, Zeta) were prevalent in the first wave and Delta (AY.*), which circulated in Brazil in the latter half of 2021, featuring fewer unique epitopes. Cluster 1 (Gamma (P.1 + P.1.*)) dominated the first half of 2021. Late 2021 had two new clusters, Cluster 2 (Omicron, (B.1.1.529 + BA.*)), and Cluster 3 (BA.*) with the most unique epitopes, in addition to Cluster 4 (Delta sub lineages) which emerged in the second half of 2021 with fewer unique epitopes. Cluster 1 epitopes showed a high pro-inflammatory propensity, while others exhibited a balanced cytokine induction. The clustering method effectively identified Spike groups that may contribute to immune evasion and clinical presentation, and explain in part the clinical outcome.

Cigarros eletrônicos e suas consequências histopatológicas relacionadas à doenças pulmonares / E-cigarettes and histopathological consequences related to lung diseases

O cigarro eletrônico surgiu como uma tentativa para minimizar a dependência ao uso de tabaco, entretanto, engloba controvérsias e dúvidas acerca das reais implicações para o organismo humano. Diante disso, o presente estudo tem como objetivo realizar uma revisão da literatura a fim de relacionar o uso de cigarro eletrônico com suas consequências para os humanos. Os estudos analisados relatam experimentos in vitro e in vivo em camundongos, demonstrando menor concentração de poluentes e nocividades no cigarro eletrônico comparado ao convencional, porém, seu potencial efeito maléfico está relacionado à composição do e-líquido, à maneira do uso e à variedade de aromas presentes nos produtos. Além disso, foram verificadas lesões celulares, hiperreatividade das vias aéreas, liberação de citocinas ­ IL-8, IL-10 e TNF, redução da ação antimicrobiana de queratinócitos e potencial apoptose nas células alveolares. Foi observado também um aumento em até cinco vezes da concentração de carboxihemoglobina em comparação ao cigarro comum e um aumento na auto renovação de células de adenocarcinoma pulmonar de células não pequenas, devido à expressão de SOX2. Observa-se também que em casos de DPOC, o cigarro eletrônico não apresenta agravamentos na fisiologia respiratória, contrapondo outras ocorrências como asma, pneumonia, câncer de pulmão e doenças infecciosas que podem ser ocasionadas ou exacerbadas pelo seu uso. Contudo, pelo curto prazo de observação de seus efeitos, não é possível determinar com precisão a segurança dos cigarros eletrônicos, dessa forma, faz-se necessário que mais pesquisas longitudinais sejam desenvolvidas, auxiliando, assim, na construção de evidências sobre a segurança dos cigarros eletrônicos e na regulamentação futura do produto.

Electronic cigarettes emerged as an attempt to minimize tobacco dependence. However, its use is surrounded by controversies and doubts about the real implications for the human organism. Therefore, this study aims at performing a review of the most recent literature to corelate the use of e-cigarettes with their consequences for the human body. The analyzed studies relate in vitro and in vivo experiments on mice, demonstrating lower concentration of pollutants and harmfulness in the electronic cigarette than in conventional cigarettes. However, its potential harmful effect is related to the composition of the e-liquid, in its use and in the variety of aromas in the products. In addition, cellular lesions, airway hyperreactivity, release of IL-8, IL-10 and TNF cytokines could be observed, as well as reduced keratinocyte antimicrobial action and potential apoptosis in alveolar cells. An increase of up to five-fold the concentration of carboxyhemoglobin in comparison to ordinary cigarettes and an increase in self-renewal of non-small pulmonary adenocarcinoma cells due to the expression of SOX2 have also been related. It could also be observed that in COPD cases, e-cigarettes do not present worsening in respiratory physiology, which contrasts with other occurrences such as asthma, pneumonia, lung cancer, and infectious diseases that can be caused or exacerbated by its use. However, due to the short term of observation of the effects, the safety of e-cigarettes could not be accurately determined, thus, the need for further longitudinal research is necessary, which could be used to help build evidence about the safety of e-cigarettes and also to create future regulation of the product.

Favorable outcome of COVID-19 in a young woman with severe Crohn's disease on regular use of adalimumab and prednisone: a case report.

COVID-19 is a viral disease caused by SARS-CoV-2 that compromises the host immune response in severe cases, promoting a hyperinflammation that results in acute lung injury and multiple organs failure. In this context, patients presenting with immune-related diseases, such as Crohn's disease, affected by COVID-19, may have an uncertain prognosis. We report on a case of a young female patient with a severe Crohn's disease that presented with COVID-19 pneumonia and a favorable outcome even maintaining the use of adalimumab, TNF - alpha inhibitor and prednisone. This case raises the hypothesis that aside from prednisone, TNF-α inhibitors such as adalimumab could be used to stop the progression to COVID-19 complications by blocking the TNF-alpha-driven inflammatory process that occurs in severe COVID-19.

Dual immune modulatory effect of vitamin A in human visceral leishmaniasis.

Vitamin A supplementation has shown to prevent mortality by diarrheal and respiratory diseases in several countries. Nevertheless, there are few studies investigating the effect of vitamin A in visceral leishmaniasis (VL), although there are reports of its deficiency in children with symptomatic VL in Brazil and Bangladesh. This study analyzed the effect of vitamin A on a subset of Treg cells and monocytes isolated from symptomatic VL and from healthy children residing in an endemic area for VL in Northeast Brazil. Serum retinol concentrations correlated inversely with IL-10 and TGF-ß productions in CD4(+)CD25(high)Foxp3(+) T cells isolated from children with VL stimulated with leishmanial antigens. All-trans retinoic acid in vitro induced IL-10 in CD4(+)CD25(high)Foxp3(+) T cells; IL-10 and TGF-ß production in CD4(+)CD25-Foxp3- T cells, and IL-10 in monocytes isolated from healthy children. However, the use of all-trans retinoic acid together with leishmanial antigens in vitro prevented increases in IL-10 production in Treg cells and monocytes isolated from VL children. Strikingly, those results show a potential dual role of vitamin A in the immune system: improvement of a regulatory profile in cells from healthy children after leishmanial stimulation and down modulation of IL-10 in Treg cells and monocytes during symptomatic VL. Therefore, the use of vitamin A concomitant to VL therapy might be useful in improving recovery from disease status caused by Leishmania infantum infection and warrants additional study.