Pharmacogenet Genomics
June 2024
Objectives: This study explored the association of deleterious variants in pharmacodynamics (PD) genes with statin response and adverse effects in patients with familial hypercholesterolemia (FH) and analyzed their potential effects on protein structure and stability.
Methods: Clinical and laboratory data were obtained from 144 adult FH patients treated with statins. A panel of 32 PD genes was analyzed by exon-targeted gene sequencing.
Cardiovascular diseases (CVDs) pose a significant global health threat, with familial hypercholesterolemia (FH) being a key genetic contributor. The apolipoprotein E (APOE) gene plays a vital role in lipid metabolism, and its variants are associated with CVD risk. This study explores prevalent APOE variants (p.
View Article and Find Full Text PDFAAPS PharmSciTech
November 2023
AAPS PharmSciTech
October 2023
Fridericia platyphylla (Cham.) L.G.
View Article and Find Full Text PDFTuberculosis (TB) is a major global cause of mortality, primarily stemming from latent tuberculosis infection (LTBI). Failure to fully treat LTBI can result in drug-resistant forms of TB. Therefore, it is essential to develop novel drugs with unique mechanisms of action to combat TB effectively.
View Article and Find Full Text PDFIntroduction: Exposure to pesticides may be related to overweight and associated comorbidities. The aim of this work was to evaluate occupational exposure to pesticides, overweight and associated comorbidities among farmers in Southern Brazil.
Methods: This cross-sectional study included a random sample of 257 farmers, living in the municipality of Mafra and Planalto, southern Brazil.
Familial Hypercholesterolemia (FH) is a genetic disorder associated with premature atherosclerosis and increased risk of cardiovascular diseases. LDLR deleterious mutations are associated with FH, however the role of some missense variants in FH pathogenicity remains to be elucidated. This study explored the predictive impact of LDLR missense variants on protein structure and investigated their functional effects on LDLR expression in HepG2 cells transfected with CRISPR/Cas9 constructs.
View Article and Find Full Text PDFNeglected diseases, primarily found in tropical regions of the world, present a significant challenge for impoverished populations. Currently, there are 20 diseases considered neglected, which greatly impact the health of affected populations and result in difficult-to-control social and economic consequences. Unfortunately, for the majority of these diseases, there are few or no drugs available for patient treatment, and the few drugs that do exist often lack adequate safety and efficacy.
View Article and Find Full Text PDFThe macrophage mannose receptor (RMM) is a crucial component of the immune system involved in immune responses, inflammation resolution, and tissue remodeling. When RMM is activated by a specific ligand, it undergoes internalization, forming an endosome that matures into a lysosome. Within the lysosome, structural changes in RMM facilitate the dissociation of ligands for further processing.
View Article and Find Full Text PDFFamilial hypercholesterolemia (FH) is a monogenic disease characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and increased risk of premature atherosclerotic cardiovascular disease. Mutations in FH-related genes account for 40% of FH cases worldwide. In this study, we aimed to assess the pathogenic variants in FH-related genes in the Brazilian FH cohort FHBGEP using exon-targeted gene sequencing (ETGS) strategy.
View Article and Find Full Text PDFThe Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptors (LDLR). Gain-of-function (GOF) variants of PCSK9 significantly affects lipid metabolism leading to coronary artery disease (CAD), owing to the raising the plasma low-density lipoprotein (LDL). Considering the public health matter, large-scale genomic studies have been conducted worldwide to provide the genetic architecture of populations for the implementation of precision medicine actions.
View Article and Find Full Text PDFFamilial hypercholesterolemia (FH) is caused by deleterious mutations in the LDLR that increase markedly low-density lipoprotein (LDL) cholesterol and cause premature atherosclerotic cardiovascular disease. Functional effects of pathogenic LDLR variants identified in Brazilian FH patients were assessed using in vitro and in silico studies. Variants in LDLR and other FH-related genes were detected by exon-target gene sequencing.
View Article and Find Full Text PDFFarnesoid X receptor (FXR) is a nuclear receptor with an essential role in regulating bile acid synthesis and cholesterol homeostasis. FXR activation by agonists is explained by an αAF-2-trapping mechanism; however, antagonism mechanisms are diverse. We discuss microsecond molecular dynamics (MD) simulations investigating our recently reported FXR antagonists 2a and 2 h.
View Article and Find Full Text PDFPCSK9 gain-of-function (GOF) variants increase degradation of low-density lipoprotein receptor (LDLR) and are potentially associated with Familial Hypercholesterolemia (FH). This study aimed to explore the effects of PCSK9 missense variants on protein structure and interactions with LDLR using molecular modeling analyses and in vitro functional studies. Variants in FH-related genes were identified in a Brazilian FH cohort using an exon-target gene sequencing strategy.
View Article and Find Full Text PDFBackground: Zika fever affects poor and vulnerable populations, presenting cycles observed in, at least 86 countries, with no vaccine prevention or treatment available. It is known that the genus Flavivirus causes Zika Virus (ZIKV), as Dengue and Yellow Fever, whose genetic material decodes, among other proteins, a series of non-structural (NS) proteins essential for viral replication, such as NS2B-NS3 protease. Additionally, chemical and biological systems are commonly studied using molecular modeling approaches allowing, among several other processes, to elucidate mechanisms of action, molecule reactivity and/or chemical properties and the design of new drugs.
View Article and Find Full Text PDFSARS-CoV-2's papain-like protease (PL) interaction with ligands has recently been explored with a myriad of crystal structures. We used molecular dynamics (MD) simulations to study different PL-ligand complexes, their ligand-induced conformational changes, and interactions. We focused on inhibitors reported with known IC against PL, namely GRL-0617, XR8-89, PLP_Snyder530, and Sander's recently published compound 7 (CPD7), and compared these trajectories against the apostructure (Apo), with a total of around 60 µs worth simulation data.
View Article and Find Full Text PDFPharmaceutics
April 2022
Statins are the first-line treatment for familial hypercholesterolemia (FH), but response is highly variable due to genetic and nongenetic factors. Here, we explored the association between response and genetic variability in 114 Brazilian adult FH patients. Specifically, a panel of 84 genes was analyzed by exon-targeted gene sequencing (ETGS), and the functional impact of variants in pharmacokinetic (PK) genes was assessed using an array of functionality prediction methods.
View Article and Find Full Text PDFToxics
May 2022
Anticholinesterase pesticides are a main cause of the intentional or accidental poisoning of animals. Anticholinesterases include several substances that cause the overstimulation of both central and peripheral acetylcholine-dependent neurotransmission. Forensic analyses of poisoning cases require high levels of expertise, are costly, and often do not provide reliable quantitative information for unambiguous conclusions.
View Article and Find Full Text PDFHuman ornithine aminotransferase (hOAT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that contains a similar active site to that of γ-aminobutyric acid aminotransferase (GABA-AT). Recently, pharmacological inhibition of hOAT was recognized as a potential therapeutic approach for hepatocellular carcinoma. In this work, we first studied the inactivation mechanisms of hOAT by two well-known GABA-AT inactivators ( and ).
View Article and Find Full Text PDFThe Carnitine Palmitoyltranferase I (CPT1) catalyzes the rate-limiting step of long-chain fatty acid (LCFA) mitochondrial β-oxidation. The enzyme promotes the conjugation of LCFA with l-carnitine, which allows LCFA to enter the mitochondria matrix. The structural features involved in CPT1 and LCFA-CoA interactions have not been fully elucidated, mainly due to the absence of CPT1 crystallographic data.
View Article and Find Full Text PDFSARS-CoV-2's main protease (M) interaction with ligands has been explored with a myriad of crystal structures, most of the monomers. Nonetheless, M is known to be active as a dimer but the relevance of the dimerization in the ligand-induced conformational changes has not been fully elucidated. We systematically simulated different M-ligand complexes aiming to study their conformational changes and interactions, through molecular dynamics (MD).
View Article and Find Full Text PDFCentralities determined from Residue Interaction Networks (RIN) in proteins have been used to predict aspects of their structure and dynamics. Here, we correlate the Eigenvector Centrality (E) with the rate constant for thermal denaturation (k) of the HisF protein from Thermotoga maritima based on 12 single alanine substitution mutants. The molecular basis for this correlation was further explored by studying a mutant containing a replacement of a high E residue, Y182A, which displayed increased k at 80 °C.
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