RESUMEN
Myocardial infarction (MI) is the main cause of heart failure (HF). N6-methyladenosine (m6A) methylation is associated with the progression of HF. The study aimed to explore whether METTL3 regulates ferroptosis of cardiomyocytes in HF. We evaluated ferroptosis by detecting lactic dehydrogenase (LDH) release, lipid reactive oxygen species (ROS), Fe2+, glutathione (GSH), and malonaldehyde (MDA) levels. M6A methylation was assessed using methylated RNA immunoprecipitation assay. The binding relationship was assessed using RNA immunoprecipitation assays. The mRNA stability was assessed using actinomycin D treatment. The results showed that METTL3 was upregulated in oxygen glucose deprivation/recovery (OGD/R) cells, which knockdown suppressed OGD/R-induced ferroptosis. Moreover, METTL3 could bind to SLC7A11, promoting m6A methylation of SLC7A11. Silencing of SLC7A11 abrogated the suppression of ferroptosis induced by METTL3 knockdown. Additionally, YTHDF2 was the reader that recognized the methylation of SLC7A11, reducing the stability of SLC7A11. The silencing of METTL3 inhibited OGD/R-induced ferroptosis by suppressing the m6A methylation of SLC7A11, which is recognized by YTHDF2. The findings suggested that METTL3-mediated ferroptosis might be a new strategy for MI-induced HF therapy.
Asunto(s)
Ferroptosis , Insuficiencia Cardíaca , Infarto del Miocardio , Humanos , Miocitos Cardíacos , ARN , Adenina , Glucosa , Glutatión , Metiltransferasas/genética , Sistema de Transporte de Aminoácidos y+/genética , Proteínas de Unión al ARNRESUMEN
The widespread presence of soil microplastics (MPs) has become a global environmental problem. MPs of different properties (i.e., types, sizes, and concentrations) are present in the environment, while studies about the impact of MPs having different properties are limited. Thus, this study investigated the effects of three common polymers (polystyrene, polyethylene, and polypropylene) with two concentrations (0.01% and 0.1% w/w) on growth and stress response of lettuce (Lactuca sativa L.), soil enzymes, and rhizosphere microbial community. Lettuce growth was inhibited under MPs treatments. Moreover, the antioxidant system, metabolism composition, and phyllosphere microbiome of lettuce leaves was also perturbed. MPs reduced phytase activity and significantly increased dehydrogenase activity. The diversity and structure of rhizosphere microbial community were disturbed by MPs and more sensitive to polystyrene microplastics (PSMPs) and polypropylene microplastics (PPMPs). In general, the results by partial least squares pathway models (PLS-PMs) showed that the presence of MPs influenced the soil-rhizosphere-plant system, which may have essential implications for assessing the environmental risk of MPs.
Asunto(s)
Microbiota , Microplásticos , Poliestirenos , Plásticos , Polietileno/toxicidad , Polipropilenos , Suelo , RizosferaRESUMEN
Worldwide, myocardial infarction (MI) is the leading cause of death and disability-adjusted life years lost. Recent researches explored new methods of detecting biomarkers that can predict the risk of developing myocardial infarction, which includes identifying genetic markers associated with increased risk. We induced myocardial infarction in mice by occluding the left anterior descending coronary artery and performed TTC staining to assess cell death. Next, we performed ChIP assays to measure the enrichment of histone modifications at the promoter regions of key genes involved in mitochondrial fission. We used qPCR and western blot to measure expression levels of relative apoptotic indicators. We report that miR-181a inhibits myocardial ischemia-induced apoptosis and preserves left ventricular function after MI. We show that programmed cell death protein 4 (PDCD4) is the target gene involved in miR-181a-mediated anti-ischemic injury, which enhanced BID recruitment to the mitochondria. In addition, we discovered that p53 inhibits the expression of miR-181a via transcriptional regulation. Here, we discovered for the first time a mitochondrial fission and apoptosis pathway which is controlled by miR-181a and involves PDCD4 and BID. This pathway may be controlled by p53 transcriptionally, and we presume that miR-181a may lead to the discovery of new therapeutic and preventive targets for ischemic heart diseases.
Asunto(s)
MicroARNs , Infarto del Miocardio , Isquemia Miocárdica , Ratones , Animales , Dinámicas Mitocondriales/genética , Proteína p53 Supresora de Tumor/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Infarto del Miocardio/genética , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Apoptosis/genética , Miocitos Cardíacos/metabolismoRESUMEN
HMG (high mobility group) proteins are a diverse family of nonhistone chromosomal proteins that interact with DNA and a wide range of transcriptional regulators to regulate the structural architecture of DNA. HMGXB4 (also known as HMG2L1) is an HMG protein family member that contains a single HMG box domain. Our previous studies have demonstrated that HMGXB4 suppresses smooth muscle differentiation and exacerbates endotoxemia by promoting a systemic inflammatory response in mice. However, the expression of Hmgxb4 in vivo has not fully examined. Herein, we generated a mouse model that harbors a gene trap in the form of a lacZ gene insertion into the Hmgxb4 gene. This mouse enables the visualization of endogenous HMGXB4 expression in different tissues via staining for the ß-galactosidase activity of LacZ which is under the control of the endogenous Hmgxb4 gene promoter. We found that HMGXB4 is widely expressed in mouse tissues and is a nuclear protein. Furthermore, the Hmgxb4 gene trap mice exhibit normal cardiac function and blood pressure. Measurement of ß-galactosidase activity in the Hmgxb4 gene trap mice demonstrated that the arterial injury significantly induces Hmgxb4 expression. In summary, the Hmgxb4 gene trap reporter mouse described here provides a valuable tool to examine the expression level of endogenous Hmgxb4 in both physiological and pathological settings in vivo.
Asunto(s)
Proteínas del Grupo de Alta Movilidad , Ratones Endogámicos C57BL , Animales , Masculino , Ratones , beta-Galactosidasa/metabolismo , beta-Galactosidasa/genética , Proteínas del Grupo de Alta Movilidad/genética , Proteínas del Grupo de Alta Movilidad/metabolismo , Operón Lac/genética , Ratones Transgénicos , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Background: The public health burden of cardiomyopathies and competency in their management by health agencies in China are not well understood. Methods: This study adopted a multi-stage sampling method for hospital selection. In the first stage, nationwide tertiary hospital recruitment was performed. As a result, 88 hospitals with the consent of the director of cardiology and access to an established electronic medical records system, were recruited. In the second stage, we sampled 66 hospitals within each geographic-economic stratification through a random sampling process. Data on (1) the outpatient and inpatient visits for cardiomyopathies between 2017 and 2021 and (2) the competency in the management of patients with cardiomyopathies, were collected. The competency of a hospital to provide cardiomyopathy care was evaluated using a specifically devised scale. Findings: The outpatient and inpatient visits for cardiomyopathies increased between 2017 and 2021 by 38.6% and 33.0%, respectively. Most hospitals had basic facilities for cardiomyopathy assessment. However, access to more complex procedures was limited, and the integrated management pathway needs improvement. Only 4 (6.1%) of the 66 participating hospitals met the criteria for being designated as a comprehensive cardiomyopathy center, and only 29 (43.9%) could be classified as a primary cardiomyopathy center. There were significant variations in competency between hospitals with different administrative and economic levels. Interpretation: The health burden of cardiomyopathies has increased significantly between 2017 and 2021 in China. Although most tertiary hospitals in China can offer basic cardiomyopathy care, more advanced facilities are not yet universally available. Moreover, inconsistencies in the management of cardiomyopathies across hospitals due to differing administrative and economic levels warrants a review of the nation allocation of medical resources. Funding: This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2023-I2M-1-001) and the National High Level Hospital Clinical Research Funding (2022-GSP-GG-17).