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1.
J Mol Cell Cardiol ; 194: 3-15, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38844061

RESUMO

Diabetic cardiomyopathy (DCM) is a heart failure syndrome, and is one of the major causes of morbidity and mortality in diabetes. DCM is mainly characterized by ventricular dilation, myocardial hypertrophy, myocardial fibrosis and cardiac dysfunction. Clinical studies have found that insulin resistance is an independent risk factor for DCM. However, its specific mechanism of DCM remains unclear. 8-hydroxyguanine DNA glycosylase 1(OGG1)is involved in DNA base repair and the regulation of inflammatory genes. In this study, we show that OGG1 was associated with the occurrence of DCM. for the first time. The expression of OGG1 was increased in the heart tissue of DCM mice, and OGG1 deficiency aggravated the cardiac dysfunction of DCM mice. Metabolomics show that OGG1 deficiency resulted in obstruction of glycolytic pathway. At the molecular level, OGG1 regulated glucose uptake and insulin resistance by interacting with PPAR-γ in vitro. In order to explore the protective effect of exogenous OGG1 on DCM, OGG1 adeno-associated virus was injected into DCM mice through tail vein in the middle stage of the disease. We found that the overexpression of OGG1 could improve cardiac dysfunction of DCM mice, indicating that OGG1 had a certain therapeutic effect on DCM. These results demonstrate that OGG1 is a new molecular target for the treatment of DCM and has certain clinical significance.

2.
Int Immunopharmacol ; 126: 111148, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37977070

RESUMO

One of abundant DNA lesions induced by reactive oxygen species is 8-oxoguanine (8-oxoG), which compromises genetic instability. 8-oxoG is recognized by the DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) that not only participates in base excision repair but also involves in transcriptional regulation.OGG1 has an important role inIdiopathic Pulmonary Fibrosis (IPF) processing and targeting fibroblasts is a major strategy for the treatment of pulmonary fibrosis, but whether OGG1 activate fibroblast is not clear. In this study, we show that OGG1 expression level is increased at the fibroblast activation stage in mouse lungs induced by bleomycin (BLM) treatment. OGG1 promoted the expression level of fibroblast activation markers (CTGF, fibronectin, and collagen 1) in a pro-fibrotic gene transcriptional regulation pathway via interacting with Snail1, which dependent on 8-oxoG recognition. Global inhibition of OGG1 at the middle stage of lung fibrosis also relieved BLM-induced lung fibrosis in mice. Our results suggest that OGG1 is a target for inhibiting fibroblast activation and a potential therapeutic target for IPF.


Assuntos
DNA Glicosilases , Fibrose Pulmonar , Animais , Camundongos , Dano ao DNA , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Reparo do DNA , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Fibrose Pulmonar/induzido quimicamente
3.
Clin Cardiol ; 46(9): 1082-1089, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37641542

RESUMO

BACKGROUND: Observational studies have revealed that a lack of physical exercise may be linked to a higher risk of heart failure (HF). Here, the causal relationship between sedentary behavior (SB) and HF was investigated using Mendelian randomization (MR). HYPOTHESIS: SB was considered as an important risk factor of HF. METHODS: Single nucleotide polymorphisms with a genome-wide statistical significance threshold of <5 × 10-8 among the SB-proxied phenotypes (TV screen time, computer use, and driving) from genome-wide association study (GWAS) datasets were identified as instrumental variables (IVs). The MR study was performed using the inverse-variance weighting (IVW) model as a primary standard to evaluate causal relationships. Simultaneously, MR-Egger regression, weighted median, and maximum likelihood models were used as supplements. Sensitivity analysis, consisting of a heterogeneity and horizontal pleiotropy test, was performed using Cochran's Q, MR-Egger intercept, and MR-PRESSO tests to ensure the reliability of conclusions. RESULTS: The IVW model results showed that increased TV screen time correlated with a higher genetic susceptibility for HF in both HF-associated GWAS datasets, which was also supported by weighted median and maximum likelihood model results. The odds ratios with 95% confidence intervals were 1.418 (1.182-1.700) and 1.486 (1.136-1.943), respectively. Although the results of Cochran's Q test indicated certain heterogeneity among the IVs. The MR-Egger intercept and MR-PRESSO tests suggested no horizontal pleiotropy and verified the reliability of the conclusion. CONCLUSIONS: This MR study identified that increased TV screen time may predispose individuals to the development of HF.


Assuntos
Insuficiência Cardíaca , Análise de Mediação , Humanos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Reprodutibilidade dos Testes , Comportamento Sedentário , Insuficiência Cardíaca/genética , Nonoxinol
4.
Biochem Biophys Res Commun ; 650: 123-131, 2023 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-36791545

RESUMO

Cardiomyocyte apoptosis caused by fat metabolism disorder plays an essential role in the pathogenesis of diabetic cardiomyopathy (DCM). Apurinic/apyrimidinic endonuclease 1 (APE1) has multiple functions, including regulating redox and DNA repair. However, the role of APE1 in the pathogenesis of DCM remains unclear. To investigate the mechanism of APE1 on high-fat induced apoptosis in H9C2 cells, we treated H9C2 cells with palmitic acid (PA) as an apoptosis model caused by hyperlipidemia. We found that PA reduced the viability and increased apoptosis of H9C2 cells by inducing up-regulation of APE1 protein and endoplasmic reticulum (ER) stress. APE1 knockdown enhanced PA-induced apoptosis, and ER stress and overexpression of APE1 demonstrated the opposite effect. Furthermore, APE1 regulated PA-induced apoptosis via ER stress. The APE1 mutant (C65A, lack of redox regulation) loses its protective effect against ER stress and apoptosis. These findings indicate that APE1 protects PA-induced H9C2 cardiomyocyte apoptosis through ER stress via its redox-regulated function. This study provided new insights into the therapy for DCM.


Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos) , Miócitos Cardíacos , Ácido Palmítico , Apoptose , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Endonucleases/metabolismo , Estresse do Retículo Endoplasmático , Miócitos Cardíacos/metabolismo , Ácido Palmítico/farmacologia , Ratos , Animais
5.
Environ Sci Pollut Res Int ; 29(4): 5852-5862, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34426868

RESUMO

Scarce epidemiologic research examined the associations between residential greenness and dyslipidemia or lipid levels in low/middle-income countries. Baseline statistics (2015-2017) of 39,259 rural-dwelling adults were obtained from a Chinese longitudinal study. The blood lipid level was measured utilizing an enzymatic assay method. According to the 2016 Chinese guidelines on dyslipidemia (revision), patients with dyslipidemia were defined. Participants' exposure to residential greenness was characterized by the satellite-based normalized difference vegetation index (NDVI). Mixed effects logistic regression and mixed effects linear regression were performed to assess the associations of residential greenness with dyslipidemia and lipid levels. The median (interquartile range, IQR) of 3-year average NDVI1000-m was 0.521 (0.089) units. Each IQR increase in NDVI1000-m was significantly linked with increased odds of hyperbetalipoproteinemia (OR = 1.33, 95%CI 1.21-1.46). The same increment in NDVI1000-m was associated with lower total cholesterol (TC) levels and increased low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels. For instance, the %changes in HDL-C levels was 0.71% (95%CI 0.17%-1.26%). The above relationships were partially mediated by reducing air pollution and lowering body mass index (BMI). Interaction effect analysis observed the greenness-lipid association was stronger in males than females (i.e., NDVI1000-m-TC association). Long-term exposure to residential greenness was associated with odds of dyslipidemia and lipid levels in Chinese rural-dwelling adults, particularly among males. Considering the cross-sectional study design, more longitudinal studies are needed to identify the causal associations.


Assuntos
Dislipidemias , Adulto , China/epidemiologia , Estudos de Coortes , Estudos Transversais , Dislipidemias/epidemiologia , Feminino , Humanos , Lipídeos , Estudos Longitudinais , Masculino
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