Myricetin alleviates diabetic cardiomyopathy by regulating gut microbiota and their metabolites.

BACKGROUND: The gut microbiota is involved in the pathogenesis of diabetic cardiomyopathy (DCM). Myricetin protects cardiac function in DCM. However, the low bioavailability of myricetin fails to explain its pharmacological mechanisms thoroughly. Research has shown that myricetin has a positive effect on the gut microbiota. We hypothesize that myricetin improves the development of DCM via regulating gut microbiota. METHODS: DCM mice were induced with streptozotocin and fed a high-fat diet, and then treated with myricetin by gavage and high-fat diet for 16 weeks. Indexes related to gut microbiota composition, cardiac structure, cardiac function, intestinal barrier function, and inflammation were detected. Moreover, the gut contents were transplanted to DCM mice, and the effect of fecal microbiota transplantation (FMT) on DCM mice was assessed. RESULTS: Myricetin could improve cardiac function in DCM mice by decreasing cardiomyocyte hypertrophy and interstitial fibrosis. The composition of gut microbiota, especially for short-chain fatty acid-producing bacteria involving Roseburia, Faecalibaculum, and Bifidobacterium, was more abundant by myricetin treatment in DCM mice. Myricetin increased occludin expression and the number of goblet cells in DCM mice. Compared with DCM mice unfed with gut content, the cardiac function, number of goblet cells, and expression of occludin in DCM mice fed by gut contents were elevated, while cardiomyocyte hypertrophy and TLR4/MyD88 pathway-related proteins were decreased. CONCLUSIONS: Myricetin can prevent DCM development by increasing the abundance of beneficial gut microbiota and restoring the gut barrier function.

Upregulation of NF-κB by USP24 aggravates ferroptosis in diabetic cardiomyopathy.

BACKGROUND: Recent investigations have proposed a potential causal association between the occurrence of ferroptosis, nuclear factor kappa B (NF-κB) and ubiquitin-specific protease 24 (USP24). Nevertheless, the mechanism of USP24 and NF-κB regulation of ferroptosis in the context of diabetic cardiomyopathy (DCM) remain unclear. METHODS: In this study, a high-fat diet and a streptozotocin-induced mouse DCM model were established, and high glucose and palmitic acid treatment of H9c2 cells and neonatal mouse primary cardiomyocytes (NMPCs) was used as an in vitro DCM models. Utilizing both the in vivo and in vitro DCM models, we assessed of USP24, NF-κB, and ferroptosis levels, and explored the relationship among them. RESULTS: In in vivo and in vitro DCM models, increased expression of USP24, NF-κB, phosphorylated NF-κB (p-NF-κB) and fatty acid-CoA ligase 4 (FACL4) were detected, along with accumulated iron, as well as reduced ferritin heavy chain 1 (FTH1), solute carrier family 7 member 11 (SLC7A11) and antioxidant capacity. Knockdown of USP24 resulted in a reduction of NF-κB levels, while knockdown of NF-κB did not lead to a decrease in USP24 expression. Moreover, in H9c2 cells, knockdown of USP24 and NF-κB separately resulted in reduced levels of FACL4, increased levels of SLC7A11 and FTH1, as well as improved antioxidant capacity and cell viability. In shUSP24 knockdown H9c2 cells, administration of phorbol 12-myristate 13-acetate (PMA) activated NF-κB, subsequently reversing the previously observed effect caused by USP24 knockdown. CONCLUSIONS: These findings show that USP24 upregulates NF-κB to promote ferroptosis in DCM.

Ubiquitin-conjugating enzyme E2 for regulating autophagy in diabetic cardiomyopathy: A mini-review.

The prevalence of diabetic cardiomyopathy (DCM) increases year by year with the increase in the prevalence of diabetes mellitus (DM), which is one of the most serious cardiovascular complications of DM and a major cause of death in diabetic patients. Although the pathological molecular features of DCM have not been fully elucidated, increasing evidence suggests that impaired autophagy in cardiomyocytes plays a nonnegligible role in the development of DCM. It has been shown that SUMOylation [SUMO = small ubiquitin-like modifier], a post-translational modification of proteins, and its associated ubiquitin-proteasome system mediates protein quality control in the heart and plays an important role in the proteotoxic environment of the heart. Specifically, the expression of ubiquitin-conjugating enzyme E2 (Ubc9), the only SUMO-E2 enzyme, exerts a positive regulatory effect on autophagy in cardiomyocytes with potential cardioprotective effects. This review focuses on the role that autophagy plays in DCM and the potential for Ubc9-regulated autophagy pathways to ameliorate DCM, highlighting the potential of Ubc9 as an interventional target in DCM and providing new insights into the pathogenesis of the disease.

Genetic and immunological insights into COVID-19 with acute myocardial infarction: integrated analysis of mendelian randomization, transcriptomics, and clinical samples.

Background: Globally, most deaths result from cardiovascular diseases, particularly ischemic heart disease. COVID-19 affects the heart, worsening existing heart conditions and causing myocardial injury. The mechanistic link between COVID-19 and acute myocardial infarction (AMI) is still being investigated to elucidate the underlying molecular perspectives. Methods: Genetic risk assessment was conducted using two-sample Mendelian randomization (TSMR) to determine the causality between COVID-19 and AMI. Weighted gene co-expression network analysis (WGCNA) and machine learning were used to discover and validate shared hub genes for the two diseases using bulk RNA sequencing (RNA-seq) datasets. Additionally, gene set enrichment analysis (GSEA) and single-cell RNA-seq (scRNA-seq) analyses were performed to characterize immune cell infiltration, communication, and immune correlation of the hub genes. To validate the findings, the expression patterns of hub genes were confirmed in clinical blood samples collected from COVID-19 patients with AMI. Results: TSMR did not find evidence supporting a causal association between COVID-19 or severe COVID-19 and AMI. In the bulk RNA-seq discovery cohorts for both COVID-19 and AMI, WGCNA's intersection analysis and machine learning identified TLR4 and ABCA1 as significant hub genes, demonstrating high diagnostic and predictive value in the RNA-seq validation cohort. Single-gene GSEA and single-sample GSEA (ssGSEA) revealed immune and inflammatory roles for TLR4 and ABCA1, linked to various immune cell infiltrations. Furthermore, scRNA-seq analysis unveiled significant immune dysregulation in COVID-19 patients, characterized by altered immune cell proportions, phenotypic shifts, enhanced cell-cell communication, and elevated TLR4 and ABCA1 in CD16 monocytes. Lastly, the increased expression of TLR4, but not ABCA1, was validated in clinical blood samples from COVID-19 patients with AMI. Conclusion: No genetic causal link between COVID-19 and AMI and dysregulated TLR4 and ABCA1 may be responsible for the development of immune and inflammatory responses in COVID-19 patients with AMI.

Effects of core resistance training on pugilism in boxers / Efeitos do treinamento de força do centro abdominal sobre o pugilismo em boxeadores / Efectos del entrenamiento de fuerza del centro abdominal sobre el pugilismo en boxeadores

ABSTRACT Introduction: Resistance training aims to improve the physical fitness of an athlete by improving their balance, movement, and agility skills. Boxers should have complementary attention to the strength of the core, a key area for boxing skills. Objective: Examine the effects of core strength training on pugilism in boxers. Methods: Ten volunteer professional boxers were selected. All undergo three months of core strength training under the described protocol. The athletes' sport quality index was studied using mathematical statistics. Results: After 3 months of core strength training, the physical test result was significantly higher (P<0.01). Although in 400-meter runs, sandbag training and interval running scores were higher than before training, the difference was insignificant (P>0.05). Conclusion: The core strength exercises improve the body mass of a boxing athlete and the level of their boxing. Supplementing athletes with core resistance training during regular exercise is indicated. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: O treinamento de força visa a melhorar a aptidão física de um atleta melhorando suas habilidades de equilíbrio, movimento e agilidade. Os boxeadores devem ter uma atenção complementar na força do centro abdominal, área fundamental para as habilidades pugilistas. Objetivo: Examinar os efeitos do treinamento de força do centro abdominal sobre o pugilismo em boxeadores. Métodos: Foram selecionados dez boxeadores profissionais voluntários. Todos passam por três meses de treinamento de força do centro abdominal sob protocolo descrito. O índice de qualidade esportiva dos atletas foi estudado com a utilização de estatísticas matemáticas. Resultados: Após 3 meses de treinamento de força do centro abdominal, o resultado de teste físico foi significativamente superior (P<0,01). Embora nos 400 metros de corrida, treinamento com saco de areia e pontuação de corrida em intervalos fossem mais altos do que aqueles antes do treinamento, a diferença não foi significativa (P>0,05). Conclusão: Exercícios de força do centro abdominal melhoram a massa corporal de um atleta do boxe e o nível de seu pugilismo. É indicado aos atletas um complemento com fortalecimento do centro abdominal durante o exercício regular. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: El entrenamiento de fuerza tiene como objetivo mejorar la condición física de un deportista mediante la mejora de sus habilidades de equilibrio, movimiento y agilidad. Los boxeadores deben prestar una atención complementaria a la fuerza del núcleo abdominal, una zona fundamental para las habilidades pugilísticas. Objetivo: Examinar los efectos del entrenamiento de la fuerza del núcleo abdominal en el pugilismo de los boxeadores. Métodos: Se seleccionaron diez boxeadores profesionales voluntarios. Todos se someten a tres meses de entrenamiento de fuerza en el centro abdominal según el protocolo descrito. El índice de calidad deportiva de los atletas se estudió mediante estadísticas matemáticas. Resultados: Después de 3 meses de entrenamiento de fuerza en el núcleo abdominal, el resultado de la prueba física fue significativamente mayor (P<0,01). Aunque en la carrera de 400 metros, el entrenamiento con saco de arena y la puntuación de la carrera a intervalos fueron superiores a los de antes del entrenamiento, la diferencia no fue significativa (P>0,05). Conclusión: Los ejercicios de fuerza del núcleo abdominal mejoran la masa corporal de un atleta de boxeo y el nivel de su boxeo. Para los deportistas está indicado un complemento con el entrenamiento de fuerza del núcleo abdominal durante el ejercicio regular. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.