Idebenone Antagonizes P53-Mediated Neuronal Oxidative Stress Injury by Regulating CD38-SIRT3 Protein Level.

Idebenone, an antioxidant used in treating oxidative damage-related diseases, has unclear neuroprotective mechanisms. Oxidative stress affects cell and mitochondrial membranes, altering Adp-ribosyl cyclase (CD38) and Silent message regulator 3 (SIRT3) protein expression and possibly impacting SIRT3's ability to deacetylate Tumor protein p53 (P53). This study explores the relationship between CD38, SIRT3, and P53 in H2O2-injured HT22 cells treated with Idebenone. Apoptosis was detected using flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining after determining appropriate H2O2 and Idebenone concentrations.In this study, Idebenone was found to reduce apoptosis and decrease P53 and Caspase3 expression in H2O2-injured HT22 cells by detecting apoptosis-related protein expression. Through bioinformatics methods, CD38 was identified as the target of Idebenone, and it further demonstrated that Idebenone decreased the expression of CD38 and increased the level of SIRT3. An increased NAD+/NADH ratio was detected, suggesting Idebenone induces SIRT3 expression and protects HT22 cells by decreasing apoptosis-related proteins. Knocking down SIRT3 downregulated acetylated P53 (P53Ac), indicating SIRT3's importance in P53 deacetylation.These results supported that CD38 was used as a target of Idebenone to up-regulate SIRT3 to deacetylate activated P53, thereby protecting HT22 cells from oxidative stress injury. Thus, Idebenone is a drug that may show great potential in protecting against reactive oxygen species (ROS) induced diseases such as Parkinson's disease, and Alzheimer's disease. And it might be able to compensate for some of the defects associated with CD38-related diseases.

Fração de Ejeção do Ventrículo Esquerdo Aumentada, Diminuída ou Estável ao Longo do Tempo em uma Série de 626 Pacientes com Insuficiência Cardíaca que Receberam Tratamento Médico / Increased, Decreased, or Stable Left Ventricle Ejection Fraction over Time in a Series of 626 Heart Failure Patients Receiving Medical Treatment

Resumo Fundamento: A fração de ejeção (FE) tem sido utilizada em análises fenotípicas e na tomada de decisões sobre o tratamento de insuficiência cardíaca (IC). Assim, a FE tornou-se parte fundamental da prática clínica diária. Objetivo: Este estudo tem como objetivo investigar características, preditores e desfechos associados a alterações da FE em pacientes com diferentes tipos de IC grave. Métodos: Foram incluídos neste estudo 626 pacientes com IC grave e classe III-IV da New York Heart Association (NYHA). Os pacientes foram classificados em três grupos de acordo com as alterações da FE, ou seja, FE aumentada (FE-A), definida como aumento da FE ≥10%, FE diminuída (FE-D), definida como diminuição da FE ≥10%, e FE estável (FE-E), definida como alteração da FE <10%. Valores p inferiores a 0,05 foram considerados significativos. Resultados: Dos 377 pacientes com IC grave, 23,3% apresentaram FE-A, 59,5% apresentaram FE-E e 17,2% apresentaram FE-D. Os resultados mostraram ainda 68,2% de insuficiência cardíaca com fração de ejeção reduzida (ICFEr) no grupo FE-A e 64,6% de insuficiência cardíaca com fração de ejeção preservada (ICFEp) no grupo FE-D. Os preditores de FE-A identificados foram faixa etária mais jovem, ausência de diabetes e fração de ejeção do ventrículo esquerdo (FEVE) menor. Já os preditores de FE-D encontrados foram ausência de fibrilação atrial, baixos níveis de ácido úrico e maior FEVE. Em um seguimento mediano de 40 meses, 44,8% dos pacientes foram vítimas de morte por todas as causas. Conclusão: Na IC grave, a ICFEr apresentou maior percentual no grupo FE-A e a ICFEp foi mais comum no grupo FE-D.

Abstract Background: Ejection fraction (EF) has been used in phenotype analyses and to make treatment decisions regarding heart failure (HF). Thus, EF has become a fundamental part of daily clinical practice. Objective: This study aims to investigate the characteristics, predictors, and outcomes associated with EF changes in patients with different types of severe HF. Methods: A total of 626 severe HF patients with New York Heart Association (NYHA) class III-IV were enrolled in this study. The patients were classified into three groups according to EF changes, namely, increased EF (EF-I), defined as an EF increase ≥10%, decreased EF (EF-D), defined as an EF decrease ≥10%, and stable EF (EF-S), defined as an EF change <10%. A p-value lower than 0.05 was considered significant. Results: Out of 377 severe HF patients, 23.3% presented EF-I, 59.5% presented EF-S, and 17.2% presented EF-D. The results further showed 68.2% of heart failure with reduced ejection fraction (HFrEF) in the EF-I group and 64.6% of heart failure with preserved ejection fraction (HFpEF) in the EF-D group. The predictors of EF-I included younger age, absence of diabetes, and lower left ventricular ejection fraction (LVEF). The predictors of EF-D were absence of atrial fibrillation, lower uric acid level, and higher LVEF. Within a median follow-up of 40 months, 44.8% of patients suffered from all-cause death. Conclusion: In severe HF, HFrEF presented the highest percentage in the EF-I group, and HFpEF was most common in the EF-D group.