Potential targets for the hepatitis C virus-mediated autoimmune thyroiditis

Introduction: The mechanisms by which hepatitis C virus (HCV) infection induces autoimmune thyroiditis (AIT) have been studied, and it was suggested that inflammatory cytokines during HCV infection would change the thyroperoxidase (TPO) signaling cascade and thyroglobulin (Tg) determining autoimmune thyroid disease. Objective: To show the signaling pathway, of TPO and Tg, and their potential targets mediated HCV in individuals with hepatitis C. Methods: The mapping of the signaling pathway was based on a review study approach and performed using the automatic annotation server of the Kyoto and Genome Encyclopedia (KEGG). PathVisio is free software for analysis and design of open source routes, and was used for the graphic representation of the signaling pathway. Results: The contigs were extracted from the KEGG database and their mapped transcription represents the signaling pathway of the main biomolecules that triggers the AIT. The action of HCV or its treatment can trigger AIT that is characterized by the presence of autoantibodies against TPO and Tg. In AIT, autoreactive CD4 + T lymphocytes recruit B cells and CD8 + T cells in the thyroid. The progression of the disease leads to the death of thyroid cells and hypothyroidism. Conclusion: HCV or its treatment activates several signaling pathways with thyroid cells damage resulting in AIT and secondary hypothyroidism to cellular apoptosis

“Incidentalormones” - Macro-hormones

Introduction: Complexes of monomeric hormone molecules immunoglobulin-associated lead to the formation of macro-complexes biologically inactive that are called macro-hormones. Patients’ presenting unexpectedly elevated hormones values indicates the need that the existence of macro-hormones must be researched. Objective: To describe the macro-hormones discovered incidentally in laboratory tests, which we refer to as "incidentalormones". Methods: An integrative review was conducted, and data was gathered from the published articles in medical database. The different forms of macro-hormones are reviewed; the biochemical significance and laboratory assays of macro-hormones are also revised within the ambit of current laboratory medicine. We discussed diagnostic difficulty encountered in patients with "incidentalormones”, as well as methods of macro-hormone detection, immunoglobulin involved, clinical significance and associations with other diseases. Conclusion: The presence of macro-hormones, often guides us to intervention in laboratory trials, and could result in false-positive diagnosis with inadequate therapy. Laboratories should follow a diagnostic algorithm to carefully recognize and examine possible immunoassay interferences

Structural similarity between thyroid peroxidase [Homo sapiens] and SARS-CoV-2 spike glycoprotein: An autoimmune thyroiditis triggering mechanism in COVID-19 carriers?

Introduction: there are reports of autoimmune disease related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) such neurological syndromes and hematological syndromes, and more recently autoimmune thyroid dysfunctions have been described. These reports suggest that SARS-CoV-2 acts as a probable trigger for triggering the autoimmunity process. Aim: to evaluate structural similarity between thyroid peroxidase [Homo sapiens] (TPO) and SARS-CoV-2 spike glycoprotein (COVID-19), and to propose this similarity as a likely trigger for autoimmune thyroiditis. Methodology: using bioinformatics tools, we compare the amino acids (AA) sequences between protein structure of TPO and chain A COVID-19, chain B COVID-19, and chain C COVID-19, accessible in the National Center for Biotechnology Information database, by Basic Local Alignment Search Tool in order to locate the homologous regions between the sequences of AA. Results: the homology sequence between the TPO and COVID-19 ranged from 27.0 % (10 identical residues out of 37 AA in the sequence) to 56.0% (5 identical residues out of 9 AA in the sequence). The similar alignments demonstrated relatively high E values in function of short alignment. Conclusion: data suggest a possible pathological link between TPO and COVID-19. The structural similarity of AA sequences between TPO and COVID-19 may present a molecular mimicry suggesting the possibility of antigen crossover between TPO and COVID-19 that might represent an immunological basis for autoimmune thyroiditis associated with COVID-19

Myocardial Insulin Resistance

Background: The low available of Glut-4 transporters in sarcolemma of the cardiac cells is what characterizes the myocardial insulin resistance (MIR), which is triggered separately of generalized insulin resistance. Insulin receptors are quite evident in the heart muscle and vessels, and mitochondrial activity performs a significant function in MIR preserving cellular homeostasis by cell reproduction, cells livelihoods, and energy generation. Objective: To evaluate the MIR mechanism and through the signaling pathway design. Methods: PubMed database was employed to search for reviews publications with MIR. The referenced data of the signaling pathway was chosen aggregating references of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. A signaling pathway was designed based on MIR research manuscripts, where we show several mechanisms included in the MIR. The KEGG server was employed to exploit the interrelationship protein-protein, and elaborate signaling pathway diagram. The signaling pathway mapping was carried out with PathVisio software. Results: We selected 42 articles from a total of 450 articles in the PubMed database that presented a significant association between the terms "insulin resistance myocardial" AND "signaling pathway". Founded on database-validated research papers, we choose well-founded pathways and we succeeded representative description of these pathways. The reproduction contigs taken from the KEGG database designed the signaling pathway of the bio-molecules that lead to MIR. Thus, the acting among multiple mechanisms releases factors that participate of the development of MIR. Conclusion: The interaction among various mechanisms and molecular interactions are important factors in development of MIR

The Connection Between Bile Acids and Type 2 Diabetes Mellitus

Bile acids (BAs) are steroid molecules that have a hydrophilic and a hydrophobic end, and are synthesized exclusively in the liver, being end product of cholesterol catabolism. Type 2 diabetes mellitus (DM2) is a chronic degenerative disease, with a pathophysiology characterized by insulin resistance (IR), insulin deficiency due to insufficient production of pancreatic ß-cells, and elevated serum glucose levels leading to multiple complications. BAs are related to several metabolic alterations, including metabolic syndrome and DM2. It is currently known that BAs act as a ligand for the nuclear farnesoid X receptor, a receptor with an important role in glucose metabolism, lipids and cellular energy production, as well as in the regulation of production, elimination and mobilization of BAs. BAs have also been reported to act as a signaling pathway through of Takeda G protein-coupled receptor 5. In this manuscript, we describe the interface between BAs and metabolic disorders, in particular DM2, including discussing possibilities in the development of therapeutic procedures targeting BAs as an optional pathway in the treatment of DM2

THE CONNECTION BETWEEN BILE ACIDS AND TYPE 2 DIABETES MELLITUS - A REVIEW

ABSTRACT Background: Bile acids (BAs) are steroid molecules synthesized exclusively in the liver, being end products of cholesterol catabolism. BAs are known to be involved in several metabolic alterations, including metabolic syndrome and type 2 diabetes mellitus (DM2). DM2 is a chronic degenerative disease characterized by insulin resistance, insulin deficiency due to insufficient production of pancreatic ß-cells, and elevated serum glucose levels leading to multiple complications. Objective: The objective of this study is to investigate the role of BAs in the pathophysiology of DM2, highlighting the possibilities in the development of therapeutic procedures targeting BAs as an optional pathway in the treatment of DM2. Methods: The research was carried out through narrative review and publications on the relationship between BAs and DM2. The databases used for the search include PubMed, Scopus, and Web of Science. The keywords used for the search include bile acids, type 2 diabetes mellitus, metabolic syndrome, and metabolic disorders. Results: The studies have reported the involvement of BAs in the pathophysiology of DM2. BAs act as a ligand for the nuclear farnesoid X receptor, regulating glucose metabolism, lipid metabolism, and cellular energy production. Additionally, BAs modulate the production, elimination, and mobilization of BAs through the farnesoid X receptor. BAs also act as a signaling pathway through Takeda G protein-coupled receptor 5, further contributing to metabolic regulation. These findings suggest that targeting BAs may offer a novel therapeutic approach in the treatment of DM2. Conclusion: This study highlights the important role of BAs in DM2, specifically through their interactions with key metabolic pathways. Targeting BAs may represent an innovative and effective approach to the treatment of DM2

SARS-CoV-2 / COVID e Diabetes Mellitus Tipo 1: Uma abordagem com imunoinformática

Contact with viruses which have an aminoacid (AA) sequence simile to that of the auto-antigens can lead to autoimmune diseases in genetically susceptible individuals. SARS-CoV-2 has been implied as a possible causer of new-onset type 1 diabetes mellitus (DM1), however, no consistent evidence yet that SARS-CoV-2 take to DM1 on your own initiative. Objective: Evaluate the possible similarity between the AA sequences of human insulin and human glutamic acid decarboxylase-65 (GAD65) with SARS-CoV-2/COVID proteins, to explain the possible trigger of DM1. Methods: AA sequences of the human insulin (4F0N), GAD65 (2OKK), and SARS-CoV-2 (SARS-Cov2 S protein at open state (7DDN), SARS-Cov2 S protein at close state (7DDD), SARS CoV-2 Spike protein (6ZB5), Crystal structure of SARS-CoV-2 nucleocapsid protein N-terminal RNA binding domain (6M3M), Crystal structure of SARS-CoV-2 nucleocapsid protein C-terminal RNA binding domain (7DE1), Crystal Structure of NSP1 from SARS-CoV-2 (7K3N), and SARS-CoV-2 S trimer (7DK3)) available in the Protein Data Bank were compared using the Pairwise Structure Alignment. Results: Sequence identity percentage (SI%) and sequence similarity percentage (SS%) were found among the 4F0N, 2OKK and SARS-CoV-2. The SI% between the 4F0N and SARS-CoV-2 ranged from 4.76% to 14.29% and SS% ranged from 5.00% to 45.45%, distributed like this: 4F0N and 7DDN = SI% 4.76 and SS% 28.57; 4F0N and 7DDD = SI% 14.39 and SS% 23.81; 4F0N and 6ZB5 = SI% 4.76 and SS% 28.57; 4F0N and 6M3M = SI% 5.00 and SS% 5;00; 4F0N and 7DE1 = SI% 4.76 and SS% 9.21; 4F0N and 7K3N = SI% 9.09 and SS% 45.45; 4F0N and 7DK3 = SI% 4.76 and SS% 28.57. The SI% between the between the 2OKK and SARS-CoV-2 ranged from 3.19% to 6,70% and SS% ranged from 10.45 % to 22.22%, distributed like this: 2OKK and 7DDN = SI% 6.70 and SS% 15.64; 2OKK and 7DDD = SI% 7.53 and SS% 18.84; 2OKK and 6ZB5 = SI% 6.68 and SS% 17.38; 2OKK and 6M3M = SI% 4.48 and SS% 10.45; 2OKK and 7DE1 = SI% 6.67 and SS% 22.22; 2OKK and 7K3N = SI% 3.19 and SS% 15.97; 2OKK and 7DK3 = SI% 3.95 and 17.98. Conclusion: Immunoinformatics data suggest a potential pathogenic link between DM1 and SARS-CoV-2/COVID. Thus, by means of molecular mimicking we check that sequences similarity among SARS-CoV-2/COVID and human insulin and human glutamic acid decarboxylase-65 may lead to production of an immune cross-response to self-antigens, with breakage of self-tolerance that can trigger DM1.O contato com vírus que têm uma sequência de aminoácidos (AA) semelhante à dos autoantígenos podem desencadear doenças autoimunes em indivíduos geneticamente suscetíveis. SARS-CoV-2 foi sugerido como um possível causador de diabetes mellitus tipo 1 de início recente (DM1), no entanto, não há evidências consistentes de que o SARS-CoV-2 possa desencadear DM1. Objetivo: Avaliar a possível semelhança entre as sequências AA da insulina humana e da descarboxilase-65 do ácido glutâmico humano (GAD65) com as proteínas SARS-CoV-2 / COVID, para explicar o possível desencadeamento do DM1. Métodos: Sequências de AA da insulina humana (4F0N), GAD65 (2OKK) e SARS-CoV-2 SARS-Cov2 S protein at open state (7DDN), SARS-Cov2 S protein at close state (7DDD), SARS CoV-2 Spike protein (6ZB5), Crystal structure of SARS-CoV-2 nucleocapsid protein N-terminal RNA binding domain (6M3M), Crystal structure of SARS-CoV-2 nucleocapsid protein C-terminal RNA binding domain (7DE1), Crystal Structure of NSP1 from SARS-CoV-2 (7K3N), and SARS-CoV-2 S trimer (7DK3))  disponíveis no Protein Data Bank foram comparadas utilizando o Pairwise Structure Alignment. Resultados: O percentual de identidade de sequências (SI%) e o percentual de similaridade de sequências (SS%) foram encontrados entre o 4F0N, 2OKK e o SARS-CoV-2. O SI% entre o 4F0N e o SARS-CoV-2 variou de 4,76% a 14,29% e o SS% variou de 5,00% a 45,45%, assim distribuídos: 4F0N e 7DDN = SI% 4,76 e SS% 28,57; 4F0N e 7DDD = SI% 14,39 e SS% 23,81; 4F0N e 6ZB5 = SI% 4,76 e SS% 28,57; 4F0N e 6M3M = SI% 5,00 e SS% 5; 00; 4F0N e 7DE1 = SI% 4,76 e SS% 9,21; 4F0N e 7K3N = SI% 9,09 e SS% 45,45; 4F0N e 7DK3 = SI% 4,76 e SS% 28,57. O SI% entre o 2OKK e o SARS-CoV-2 variou de 3,19% a 6,70% e o SS% variou de 10,45% a 22,22%, assim distribuídos: 2OKK e 7DDN = SI% 6,70 e SS% 15,64; 2OKK e 7DDD = SI% 7,53 e SS% 18,84; 2OKK e 6ZB5 = SI% 6,68 e SS% 17,38; 2OKK e 6M3M = SI% 4,48 e SS% 10,45; 2OKK e 7DE1 = SI% 6,67 e SS% 22,22; 2OKK e 7K3N = SI% 3,19 e SS% 15,97; 2OKK e 7DK3 = SI% 3,95 e 17,98. Conclusão: Os dados de imunoinformática sugerem uma potencial ligação patogênica entre SARS-CoV-2 / COVID e o DM1. Assim, por meio de mimetização molecular, verificamos que a similaridade das sequências de AA entre SARS-CoV-2 / COVID e insulina humana e a descarboxilase-65 do ácido glutâmico humano pode levar à produção de uma resposta cruzada imunológica para autoantígenos, com quebra de auto-tolerância, podendo desencadear o DM1

Quantificação da ecogenicidade da doença pancreática gordurosa não alcoólica – esteatometria pancreática

Introdução: a ultrassonografia tem sido utilizada na identificação da doença pancreática gordurosa não alcoólica (DPGNA), entretanto ométodo apresenta como desvantagem a subjetividade do examinador. Objetivo: quantificar a ecogenicidade pancreática para classificarem graus a DPGNA. Metodologia: utilizou-se a análise de histograma de escala de cinzas para quantificar a ecogenicidade, com afinalidade de análise mais acurada das características do tecido pancreático. Inicialmente, foi calculado o intervalo representativo daecogenicidade pancreática e renal (média ± 2 desvios-padrão, que corresponde aos 97,5% mais representativos do tecido). Posteriormente,foi determinado o percentual de sobreposição da ecogenicidade do pâncreas com o rim analisado. Resultados: consideraram-se comonormal quando o percentual de sobreposição de ecogenicidade estava em até 25%; esteatose grau I para percentual entre 25 e 50%;esteatose grau II para percentual entre 50 e 75%; esteatose grau III para percentual acima de 75%.Conclusão: os autores concluem que,com quantificação de ecogenicidade, a classificação de DPGNA torna-se não examinador-dependente

Surfactant in SARS-CoV-2 - a therapeutic option based on underlying lung cell damage?

Introduction: the severe acute respiratory syndrome – coronavirus 2 (SARS Cov-2), leads to a diffuse alveolar deterioration due infection of type II pneumocytes. The type II pneumocytes are involved in synthesis and secretion of pulmonary surfactant in pulmonary alveoli. Objective: the purpose of this study is to discuss the indication of surfactant replacement as a potential adjunctive treatment modality for SARS CoV-2, similarly treatment to neonatal respiratory distress syndrome. Methodology: we argue that SARS can be triggered by surfactant deficiency secondary to production deficiency determined by type 2 pneumocyte injuries. In this sense, we carried out a bibliographic review. Conclusion: thus, the replacement of human surfactant could be a potential treatment modality for SARS CoV-2, in the same way that it is indicated for the treatment of neonatal respiratory distress syndrom

Examination of the scientific evidences for off-label use of medications in non-alcoholic fatty liver disease

Introduction: non-alcoholic fatty liver disease (NAFLD) is considered to be a representation in the liver of insulin resistance or metabolicsyndrome, and is a common cause of chronic hepatitis, which can lead to cirrhosis and hepatocellular carcinoma. Currently, there are nopharmacologic therapies approved by the U.S. Food and Drug Administration (FDA) and National Health Surveillance Agency of Brazil(ANVISA) for the NAFLD treatment. Objective: the aim of this study is to assess the evidences for off-label use of medication in NAFLD.Methodology: a systematic search was made in MEDLINE-PubMed for papers published between January 1990 and December 2017,addressing the off-label use or unlicensed drugs for NAFLD treatment. An integrative review was conducted and the data analyzedthematically. Results: of the 3540 studies retrieved, 50 met the inclusion criteria by to contain information about the off-label prescriptionsin NAFLD. In this integrative review of the published literature, off-label treatment of NAFLD was generally associated with good shorttermand long term outcomes. Conclusions: after analyzing the data, may conclude that literature includes studies that provides scientificevidence for the off-label drugs use in NAFLD. The evidence of the evaluated studies, suggest that metformin treatment has best effecton reducing hepatocyte fat deposition with regard to other drugs evaluated. However, randomized, placebo controlled studies shouldbe performed to confirm this evidence