Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 47
Filtrar
1.
Circulation ; 149(22): 1752-1769, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38348663

RESUMO

BACKGROUND: Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated. METHODS: Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-iso-prostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2-/-) mice, smooth muscle cell-specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing ß-glycerophosphate and CaCl2 to investigate cell calcification and the underlying molecular mechanisms. RESULTS: Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell-specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE-induced upregulation of Runx2. CONCLUSIONS: Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification.


Assuntos
Aldeído-Desidrogenase Mitocondrial , Aldeídos , Subunidade alfa 1 de Fator de Ligação ao Core , Camundongos Knockout , Miócitos de Músculo Liso , Calcificação Vascular , Animais , Aldeídos/metabolismo , Calcificação Vascular/metabolismo , Calcificação Vascular/genética , Calcificação Vascular/patologia , Humanos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Camundongos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Feminino , Pessoa de Meia-Idade , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Células Cultivadas , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Idoso
2.
J Cell Mol Med ; 28(19): e70020, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39400961

RESUMO

Sepsis represents a critical condition characterized by multiple-organ dysfunction resulting from inflammatory response to infection. Disulfidptosis is a newly identified type of programmed cell death that is intimately associated with the actin cytoskeleton collapse caused by glucose starvation and disulfide stress, but its role in sepsis is largely unknown. The study was to adopt a diagnostic and prognostic signature for sepsis with disulfidptosis based on the differentially expressed genes (DEGs) between sepsis and healthy people from GEO database. The disulfidptosis hub genes associated with sepsis were identified, and then developed consensus clustering and immune infiltration characteristics. Next, we evaluated disulfidptosis-related risk genes by using LASSO and Random Forest algorithms, and constructed the diagnostic sepsis model by nomogram. Finally, immune infiltration, GSVA analysis and mRNA-miRNA networks based on disulfidptosis-related DEGs were screened. There are five upregulated disulfidptosis-related genes and seven downregulated genes were filtered out. The six intersection disulfidptosis-related genes including LRPPRC, SLC7A11, GLUT, MYH9, NUBPL and GYS1 exhibited higher predictive ability for sepsis with an accuracy of 99.7%. In addition, the expression patterns of the critical genes were validated. The study provided a comprehensive view of disulfidptosis-based signatures to predict the prognosis, biological features and potential treatment directions for sepsis.


Assuntos
Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Sepse , Sepse/genética , Humanos , Prognóstico , Apoptose/genética , MicroRNAs/genética , Regulação da Expressão Gênica , Biologia Computacional/métodos , Bases de Dados Genéticas , Biomarcadores/metabolismo , Transcriptoma/genética , Nomogramas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
3.
Mol Biol Rep ; 51(1): 475, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38553662

RESUMO

BACKGROUND: Patients with chronic liver disease were found nearly all to have liver fibrosis, which is characterized by excess accumulation of extracellular matrix (ECM) proteins. While ECM accumulation can prevent liver infection and injury, it can destroy normal liver function and architecture. miRNA's own regulation was involved in DNA methylation change. The purpose of this study is to detect DNA methylation landscape of miRNAs genes in mice liver fibrosis tissues. METHODS: Male mice (10-12 weeks) were injected CCl4 from abdominal cavity to induced liver fibrosis. 850 K BeadChips were used to examine DNA methylation change in whole genome. The methylation change of 16 CpG dinucleotides located in promoter regions of 4 miRNA genes were detected by bisulfite sequencing polymerase chain reaction (BSP) to verify chip data accuracy, and these 4 miRNA genes' expressions were detected by RT-qPCR methods. RESULTS: There are 769 differential methylation sites (DMS) in total between fibrotic liver tissue and normal mice liver tissue, which were related with 148 different miRNA genes. Chips array data were confirmed by bisulfite sequencing polymerase chain reaction (R = 0.953; P < 0.01). GO analysis of the target genes of 2 miRNA revealed that protein binding, cytoplasm and chromatin binding activity were commonly enriched; KEGG pathway enrichment analysis displayed that TGF-beta signaling pathway was commonly enriched. CONCLUSION: The DNA of 148 miRNA genes was found to have methylation change in liver fibrosis tissue. These discoveries in miRNA genes are beneficial to future miRNA function research in liver fibrosis.


Assuntos
Metilação de DNA , MicroRNAs , Sulfitos , Humanos , Masculino , Camundongos , Animais , Metilação de DNA/genética , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , DNA/metabolismo
4.
Arterioscler Thromb Vasc Biol ; 42(6): 700-716, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35354308

RESUMO

BACKGROUND: Clinical studies show that the most common single-point mutation in humans, ALDH2 (aldehyde dehydrogenase 2) rs671 mutation, is a risk factor for the development and poor prognosis of atherosclerotic cardiovascular diseases, but the underlying mechanism remains unclear. Apoptotic cells are phagocytosed and eliminated by macrophage efferocytosis during atherosclerosis, and enhancement of arterial macrophage efferocytosis reduces atherosclerosis development. METHODS: Plaque areas, necrotic core size, apoptosis, and efferocytosis in aortic lesions were investigated in APOE-/- mice with bone marrow transplanted from APOE-/-ALDH2-/- and APOE-/- mice. RNA-seq, proteomics, and immunoprecipitation experiments were used to screen and validate signaling pathways affected by ALDH2. Efferocytosis and protein levels were verified in human macrophages from wild-type and rs671 mutation populations. RESULTS: We found that transplanting bone marrow from APOE-/-ALDH2-/- to APOE-/- mice significantly increased atherosclerosis plaques compared with transplanting bone marrow from APOE-/- to APOE-/- mice. In addition to defective efferocytosis in plaques of APOE-/- mice bone marrow transplanted from APOE-/-ALDH2-/- mice in vivo, macrophages from ALDH2-/- mice also showed significantly impaired efferocytotic activity in vitro. Subsequent RNA-seq, proteomics, and immunoprecipitation experiments showed that wild-type ALDH2 directly interacted with Rac2 and attenuated its degradation due to decreasing the K48-linked polyubiquitination of lysine 123 in Rac2, whereas the rs671 mutant markedly destabilized Rac2. Furthermore, Rac2 played a more crucial role than other Rho GTPases in the internalization process in which Rac2 was up-regulated, activated, and clustered into dots. Overexpression of wild-type ALDH2 in ALDH2-/- macrophages, rather than the rs671 mutant, rescued Rac2 degradation and defective efferocytosis. More importantly, ALDH2 rs671 in human macrophages dampened the apoptotic cells induced upregulation of Rac2 and subsequent efferocytosis. CONCLUSIONS: Our study has uncovered a pivotal role of the ALDH2-Rac2 axis in mediating efferocytosis during atherosclerosis, highlighting a potential therapeutic strategy in cardiovascular diseases, especially for ALDH2 rs671 mutation carriers.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Placa Aterosclerótica , Proteínas rac de Ligação ao GTP/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Apolipoproteínas E/genética , Apoptose/fisiologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Doenças Cardiovasculares/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/patologia , Proteína RAC2 de Ligação ao GTP
5.
Int Heart J ; 63(5): 1004-1014, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36184541

RESUMO

Myocardial ischemia/reperfusion (I/R) injury can bring about more cardiomyocyte death and aggravate cardiac dysfunction, but its pathogenesis remains unclear. This study aimed to investigate the role of long intergenic noncoding RNA-p21 (LincRNA-p21) in myocardial I/R injury and its underlying mechanism. Mice were subjected to myocardial I/R injury by ligation and release of the left anterior descending artery, and HL-1 cardiomyocytes were treated with hydrogen peroxide. Infarct area, cardiac function, and cardiomyocyte apoptosis were determined. Consequently, LincRNA-p21 was found to significantly be elevated both in the reperfused hearts and H2O2-treated cardiomyocytes. Moreover, genetic inhibition of LincRNA-p21 brought about reduced infarct area and improved cardiac function in mice subjected to myocardial I/R injury. LincRNA-p21 knockdown was also demonstrated to inhibit cardiomyocyte apoptosis both in vivo and in vitro. Notably, LincRNA-p21 silencing increased the expression of microRNA-466i-5p (miR-466i-5p) and suppressed the expression of nuclear receptor subfamily 4 group A member 2 (Nr4a2). Mechanically, LincRNA-p21 downregulated and directly interacted with miR-466i-5p, while application of miR-466i-5p inhibitor promoted cardiomyocyte apoptosis that was improved by LincRNA-p21 inhibition. Furthermore, Nr4a2 upregulation caused by LincRNA-p21 overexpression was partially reversed by miR-466i-5p mimics. Thus, LincRNA-p21 positively regulated the expression of Nr4a2, through sponging miR-466i-5p, promoting cardiomyocyte apoptosis in myocardial I/R injury. The current study revealed a novel LincRNA-p21/miR-466i-5p/Nr4a2 pathway for myocardial I/R injury, indicating that LincRNA-p21 may serve as a potential target for future therapy.


Assuntos
MicroRNAs , Traumatismo por Reperfusão Miocárdica , RNA Longo não Codificante , Animais , Apoptose/genética , Peróxido de Hidrogênio/metabolismo , Infarto , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
6.
Eur Heart J ; 41(26): 2442-2453, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32428930

RESUMO

AIMS: Aortic aneurysm/dissection (AAD) is a life-threatening disorder lacking effective pharmacotherapeutic remedies. Aldehyde dehydrogenase 2 (ALDH2) polymorphism is tied with various risk factors for AAD including hypertension, atherosclerosis, and hypercholesterolaemia although direct correlation between the two remains elusive. METHODS AND RESULTS: Two independent case-control studies were conducted involving 307 AAD patients and 399 healthy controls in two geographically distinct areas in China. Our data revealed that subjects carrying mutant ALDH2 gene possessed a ∼50% reduced risk of AAD compared with wild-type (WT) alleles. Using 3-aminopropionitrile fumarate (BAPN)- and angiotensin II (Ang II)-induced AAD animal models, inhibition of ALDH2 was found to retard development of AAD. Mechanistically, ALDH2 inhibition ablated pathological vascular smooth muscle cell (VSMC) phenotypical switch through interaction with myocardin, a determinant of VSMC contractile phenotype. Using microarray and bioinformatics analyses, ALDH2 deficiency was found to down-regulate miR-31-5p, which further altered myocardin mRNA level. Gain-of-function and loss-of-function studies verified that miR-31-5p significantly repressed myocardin level and aggravated pathological VSMC phenotypical switch and AAD, an effect that was blunted by ALDH2 inhibition. We next noted that ALDH2 deficiency increased Max expression and decreased miR-31-5p level. Moreover, ALDH2 mutation or inhibition down-regulated levels of miR-31-5p while promoting myocardin downstream contractile genes in the face of Ang II in primary human VSMCs. CONCLUSIONS: ALDH2 deficiency is associated with a lower risk of AAD in patients and mice, possibly via suppressing VSMC phenotypical switch in a miR-31-5p-myocardin-dependent manner. These findings favour a role for ALDH2 and miR-31-5p as novel targets for AAD therapy.


Assuntos
Dissecção Aórtica , MicroRNAs , Aldeído-Desidrogenase Mitocondrial/genética , Dissecção Aórtica/genética , Dissecção Aórtica/prevenção & controle , Animais , Proliferação de Células , Células Cultivadas , China , Humanos , Camundongos , Músculo Liso Vascular , Miócitos de Músculo Liso , Fenótipo
7.
J Cardiovasc Pharmacol ; 73(4): 248-256, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30801261

RESUMO

Pathological stimulus-triggered differentiation of cardiac fibroblasts plays a major role in the development of myocardial fibrosis. Aldehyde dehydrogenase 2 (ALDH2) was reported to exert a protective role in cardiovascular disease, and whether ALDH2 is involved in cardiac fibroblast differentiation remains unclear. In this study, we used transforming growth factor-ß1 (TGF-ß1) to induce the differentiation of human cardiac fibroblasts (HCFs) and adopted ALDH2 activator Alda-1 to verify the influence of ALDH2 on HCF differentiation. Results showed that ALDH2 activity was obviously impaired when treating HCFs with TGF-ß1. Activation of ALDH2 with Alda-1 inhibited the transformation of HCFs into myofibroblasts, demonstrated by the decreased smooth muscle actin (α-actin) and periostin expression, reduced HCF-derived myofibroblast proliferation, collagen production, and contractility. Moreover, application of Smad2/3 inhibitor alleviated TGF-ß1-induced HCF differentiation and improved ALDH2 activity, which was reversed by the application of ALDH2 inhibitor daidzin. Finally, Alda-1-induced HCF alterations alleviated neonatal rat cardiomyocyte hypertrophy, supported by the immunostaining of α-actin. To summarize, activation of ALDH2 enzymatic activity inhibited the differentiation of cardiac fibroblasts via the TGF-ß1/Smad signaling pathway, which might be a promising strategy to relieve myocardial fibrosis of various causes.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Benzamidas/farmacologia , Benzodioxóis/farmacologia , Plasticidade Celular/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Animais , Animais Recém-Nascidos , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Cardiomegalia/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colágeno/metabolismo , Ativação Enzimática , Fibrose , Ventrículos do Coração/enzimologia , Ventrículos do Coração/patologia , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Miofibroblastos/enzimologia , Miofibroblastos/patologia , Comunicação Parácrina , Fenótipo , Fosforilação , Ratos , Transdução de Sinais
8.
Adv Exp Med Biol ; 1193: 175-194, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368104

RESUMO

Sepsis, defined as life-threatening tissue damage and organ dysfunction caused by a dysregulated host response to infection, is a critical disease which imposes global health burden. Sepsis-induced organ dysfunction, including circulatory and cardiac dysfunction, hepatic dysfunction, renal dysfunction, etc., contributes to high mortality and long-term disability of sepsis patients. Altered inflammatory response, ROS and reactive aldehyde stress, mitochondrial dysfunction, and programmed cell death pathways (necrosis, apoptosis, and autophagy) have been demonstrated to play crucial roles in septic organ dysfunction. Unfortunately, except for infection control and supportive therapies, no specific therapy exists for sepsis. New specific therapeutic targets are highly warranted. Emerging studies suggested a role of potential therapeutic target of ALDH2, a tetrameric enzyme located in mitochondria to detoxify aldehydes, in septic organ dysfunction. In this article, we will review the presentations and pathophysiology of septic organ dysfunction, as well as summarize and discuss the recent insights regarding ALDH2 in sepsis.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Sepse/genética , Apoptose , Autofagia , Humanos , Mitocôndrias/enzimologia
9.
Biochem Biophys Res Commun ; 504(4): 777-783, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30217444

RESUMO

Aldehyde dehydrogenase 2 (ALDH2) plays essential roles in drinking-associated diseases or effects. As we have previously reported, ALDH2 mediates acute ethanol-induced eNOS activation in vitro. However, whether chronic ethanol treatment has a dose-response endothelial protection, as well as the possible mediating role of ALDH2 involved, is unclear. Here, we show that appropriate dose of ethanol preserved the expression and activity of ALDH2 and eNOS, and alleviated senescence-associated phenotypes in human aortic endothelial cells. Furthermore, ALDH2 deficiency impairs the dose-response protection of ethanol against endothelial senescence by promoting the accumulation of 4-HNE, the formation of 4-HNE-SIRT1 protein adducts and the subsequent decrease in SIRT1-dependent p53 deacetylation. Collectively, our data indicate that ALDH2 mediates the protection of appropriate ethanol by modulating SIRT1/p53-dependent endothelial senescence.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Células Endoteliais/efeitos dos fármacos , Etanol/toxicidade , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Acetilação , Aldeído-Desidrogenase Mitocondrial/genética , Aorta/citologia , Células Cultivadas , Senescência Celular , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Transporte Proteico/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/genética , Testes de Toxicidade Crônica
10.
Biochim Biophys Acta Mol Basis Dis ; 1863(8): 1933-1941, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-27742538

RESUMO

Heart failure is one of the major causes of the ever-rising mortality globally. ALDH2 rs671 polymorphism is proven to be closely related to the prevalence of CAD, hypertension, diabetes mellitus and alcoholism, which are etiological factors of heart failure. In addition, growing evidence supports a possible role for ALDH2 in different forms of heart failure. In this mini-review, we will review the recent insights regarding the effects of ALDH2 polymorphism on etiological factors of heart failure and underlying mechanisms involved. In addition, we will also discuss the booming epigenetic information in this field which will greatly improve our understanding of the cardiovascular effect of ALDH2. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure edited by Dr. Jun Ren & Yingmei Zhang.


Assuntos
Aldeído-Desidrogenase Mitocondrial , Sistemas de Liberação de Medicamentos , Epigênese Genética , Insuficiência Cardíaca , Polimorfismo Genético , Aldeído-Desidrogenase Mitocondrial/antagonistas & inibidores , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Humanos
11.
Biochim Biophys Acta ; 1852(2): 290-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25229693

RESUMO

Phosphatase and tensin homolog (PTEN) deleted from chromosome 10 has been implicated in the maintenance of cardiac homeostasis although the underlying mechanism(s) remains elusive. We generated a murine model of cardiomyocyte-specific knockout of PTEN to evaluate cardiac geometry and contractile function, as well as the effect of metformin on PTEN deficiency-induced cardiac anomalies, if any. Cardiac histology, autophagy and related signaling molecules were evaluated. Cardiomyocyte-specific PTEN deletion elicited cardiac hypertrophy and contractile anomalies (echocardiographic and cardiomyocyte contractile dysfunction) associated with compromised intracellular Ca(2+) handling. PTEN deletion-induced cardiac hypertrophy and contractile anomalies were associated with dampened phosphorylation of PTEN-inducible kinase 1 (Pink1) and AMPK. Interestingly, administration of AMPK activator metformin (200mg/kg/d, in drinking H2O for 4weeks) rescued against PTEN deletion-induced geometric and functional defects as well as interrupted autophagy and autophagic flux in the heart. Moreover, metformin administration partially although significantly attenuated PTEN deletion-induced accumulation of superoxide. RNA interference against Pink1 in H9C2 myoblasts overtly increased intracellular ATP levels and suppressed AMPK phosphorylation, confirming the role of AMPK as a downstream target for PTEN-Pink1. Further scrutiny revealed that activation of AMPK and autophagy using metformin and rapamycin, respectively, rescued against PTEN deletion-induced mechanical anomalies with little additive effect. These data demonstrated that cardiomyocyte-specific deletion of PTEN leads to the loss of Pink1-AMPK signaling, development of cardiac hypertrophy and contractile defect. Activation of AMPK rescued against PTEN deletion-induced cardiac anomalies associated with restoration of autophagy and autophagic flux. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Deleção de Genes , Contração Miocárdica , Miócitos Cardíacos/enzimologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Quinases/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Autofagia/efeitos dos fármacos , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Ativação Enzimática/efeitos dos fármacos , Técnicas de Inativação de Genes , Espaço Intracelular/metabolismo , Metformina/farmacologia , Camundongos Knockout , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , PTEN Fosfo-Hidrolase/deficiência , Fosforilação/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Superóxidos/metabolismo
12.
Sheng Li Xue Bao ; 67(6): 535-44, 2015 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-26701629

RESUMO

Acute myocardial infarction is one of the major causes of mortality worldwide. Reperfusion in a timely fashion is the most effective way to limit infarct size. However, reperfusion can itself prompt further myocardial injury. This phenomenon is commonly known as myocardial ischemia-reperfusion (IR) injury. Mitochondrial aldehyde dehydrogenase (ALDH2) is an enzyme metabolizing acetaldehyde and toxic aldehydes. Increasing evidence has revealed a cardioprotective role of ALDH2 in myocardial IR injury. Evidence from animal studies has shown that ALDH2 diminishes acute myocardial infarct size, ameliorates cardiac dysfunction and prevents reperfusion arrhythmias. The activity of ALDH2 is severely compromised if it is encoded by the mutant ALDH2*2 gene, with an incidence of approximately 40% in Asian populations. Epidemiological surveys in the Asian population have depicted that ALDH2 polymorphism is closely associated with higher prevalence of acute myocardial infarction and coronary artery disease. Therefore, targeting ALDH2 may represent a promising avenue to protect against IR injury. This review recapitulates the underlying mechanisms involved in the protective effect of ALDH2 in cardiac IR injury. Translational potential of ALDH2 in the management of coronary heart disease is also discussed.


Assuntos
Aldeído Desidrogenase/metabolismo , Mitocôndrias Cardíacas/enzimologia , Traumatismo por Reperfusão Miocárdica , Animais , Coração/fisiopatologia , Humanos , Miocárdio/patologia
13.
IEEE Trans Biomed Eng ; PP2024 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-39446539

RESUMO

As the number of sensors in magnetocardiography (MCG) arrays increases to capture detailed cardiac activity, some channels contribute minimally to task performance, resulting in data redundancy and resource consumption. Although existing methods can reduce the number of channels required to meet task demands, they often struggle to balance computational time and the accuracy of the selected channels and overlook the scalability of the selected channels. This limitation means that when environmental conditions change, or when sensors malfunction, redesigning channel configurations becomes necessary, which increases experimental uncertainties. This study introduces a task-driven adversarial channel selection method tailored for binary classification of MCG signals. The optimal channel combination is determined through a group-wise search using a heuristic algorithm, whose objective function is designed to maximize the difference between the classification accuracy and cosine similarity of the selected channel. In evaluations using an MCG dataset from Qilu Hospital of Shandong University, the proposed method successfully reduced the number of channels from 36 to 5 without compromising classification performance. Furthermore, it outperforms existing hybrid sequential forward search method by achieving comparable accuracy with fewer channels, while also demonstrating superior scalability compared to both hybrid sequential forward search and pearson-rank methods. This approach strikes a balance between computational consumption and accuracy, while improving the scalability of the selected channel combinations, enhancing the efficiency and practicality of the MCG system.

14.
J Mater Chem B ; 12(41): 10635-10643, 2024 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-39310927

RESUMO

Mitochondrial viscosity serves as a critical indicator for assessing mitochondrial functionality and offers valuable insights into cellular homeostasis. Continuous, real-time monitoring of mitochondrial viscosity is indispensable for understanding and diagnosing diseases associated with these dynamic changes. In this study, we introduce a novel mitochondrial viscosity-responsive probe named "JL-JC" which is designed by using a molecular strategy, with a classic "D-π-A" molecular structure. Leveraging the distinctive twisted intramolecular charge transfer (TICT) properties of the probe, JL-JC exhibits exceptional sensitivity and a high signal-to-noise ratio, enabling precise detection of viscosity variations within its microenvironment while remaining unaffected by other factors. Upon rapid cellular uptake, JL-JC can efficiently evaluate the mitochondrial viscosity changes under diverse physiological and pathological conditions. Notably, this probe also enables viscosity imaging in zebrafish, offering insights into mitochondrial states in vivo. Our findings present JL-JC as a promising tool and potential diagnostic platform for mitochondria-related diseases.


Assuntos
Corantes Fluorescentes , Mitocôndrias , Imagem Óptica , Peixe-Zebra , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Viscosidade , Mitocôndrias/metabolismo , Mitocôndrias/química , Animais , Humanos , Razão Sinal-Ruído , Estrutura Molecular , Células HeLa
15.
Colloids Surf B Biointerfaces ; 244: 114173, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39191111

RESUMO

The quantification of cysteine (Cys) levels in the organisms holds paramount significance in biological research and disease diagnosis, which can give the correlation between abnormal Cys levels and diseases. In this study, two fluorescent probes, designated as DEA-OH and DEA-AC, featuring a coumarin-aurone backbone specifically engineered for Cys detection, were meticulously designed and synthesized. The diethylamino coumarin-aurone probe DEA-OH and the acrylate-substituted probe DEA-AC demonstrated remarkable sensitivity in detecting cysteine by means of copper displacement (DEA-OH) and acrylate hydrolysis mechanisms (DEA-AC) with fluorescence detection limits of 7.25 µM and 1.65 µM, respectively. Moreover, the fluorescence peak wavelength of the two probes displayed a linear relationship with solvent polarity in the ET (30) range of 30-65 kcal•mol-1, indicating the potential for monitoring changes in environmental polarity within this ET (30) range. The outstanding attributes exhibited by DEA-AC including superior photostability, remarkable selectivity, and swift response (kinetic rate constant: 0.00747 s-1), coupled with the exceptional anti-interference ability, have significantly broadened its scope of applications, for example detecting alterations in Cys within biological systems.


Assuntos
Cumarínicos , Cisteína , Corantes Fluorescentes , Cisteína/análise , Cisteína/química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Cumarínicos/química , Humanos , Espectrometria de Fluorescência , Células HeLa , Limite de Detecção , Estrutura Molecular
16.
Cell Mol Immunol ; 21(5): 510-526, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38472357

RESUMO

Acetaldehyde dehydrogenase 2 (ALDH2) mutations are commonly found in a subgroup of the Asian population. However, the role of ALDH2 in septic acute respiratory distress syndrome (ARDS) remains unknown. Here, we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS. Intriguingly, ALDH2rs671-ARDS patients showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than ALDH2WT-ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS, we utilized Aldh2 gene knockout mice and Aldh2rs671 gene knock-in mice. In clinically relevant mouse sepsis models, Aldh2-/- mice and Aldh2rs671 mice exhibited pulmonary and circulating NETosis, a specific process that releases neutrophil extracellular traps (NETs) from neutrophils. Furthermore, we discovered that NETosis strongly promoted endothelial destruction, accelerated vascular leakage, and exacerbated septic ARDS. At the molecular level, ALDH2 increased K48-linked polyubiquitination and degradation of peptidylarginine deiminase 4 (PAD4) to inhibit NETosis, which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP. Pharmacological administration of the ALDH2-specific activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis. Together, our data reveal a novel ALDH2-based protective mechanism against septic ARDS, and the activation of ALDH2 may be an effective treatment strategy for sepsis.


Assuntos
Aldeído-Desidrogenase Mitocondrial , Armadilhas Extracelulares , Camundongos Knockout , Neutrófilos , Síndrome do Desconforto Respiratório , Sepse , Animais , Sepse/complicações , Humanos , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/patologia , Camundongos , Armadilhas Extracelulares/metabolismo , Masculino , Modelos Animais de Doenças , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Camundongos Endogâmicos C57BL , Ubiquitinação , Feminino , Peroxidase/metabolismo , Mutação
17.
Nat Commun ; 15(1): 5729, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38977723

RESUMO

Risk prediction for subsequent cardiovascular events remains an unmet clinical issue in patients with coronary artery disease. We aimed to investigate prognostic metabolic biomarkers by considering both shared and distinct metabolic disturbance associated with the composite and individual cardiovascular events. Here, we conducted an untargeted metabolomics analysis for 333 incident cardiovascular events and 333 matched controls. The cardiovascular events were designated as cardiovascular death, myocardial infarction/stroke and heart failure. A total of 23 shared differential metabolites were associated with the composite of cardiovascular events. The majority were middle and long chain acylcarnitines. Distinct metabolic patterns for individual events were revealed, and glycerophospholipids alteration was specific to heart failure. Notably, the addition of metabolites to clinical markers significantly improved heart failure risk prediction. This study highlights the potential significance of plasma metabolites on tailed risk assessment of cardiovascular events, and strengthens the understanding of the heterogenic mechanisms across different events.


Assuntos
Biomarcadores , Doença da Artéria Coronariana , Metabolômica , Humanos , Doença da Artéria Coronariana/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Biomarcadores/sangue , Infarto do Miocárdio/sangue , Carnitina/sangue , Carnitina/análogos & derivados , Carnitina/metabolismo , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/metabolismo , Prognóstico , Medição de Risco , Estudos de Casos e Controles , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/metabolismo , Metaboloma , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Fatores de Risco
18.
Nat Commun ; 15(1): 8672, 2024 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-39375377

RESUMO

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRß fuels cell maturation in lung regeneration. Using a specific TRß agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRß in mice. Cellularly, TRß activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRß activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRß-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis.


Assuntos
Diferenciação Celular , Fatores de Transcrição Kruppel-Like , Pulmão , Fibrose Pulmonar , Animais , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Diferenciação Celular/efeitos dos fármacos , Camundongos , Pulmão/patologia , Pulmão/metabolismo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fibrose Pulmonar/genética , Camundongos Endogâmicos C57BL , Regeneração , Masculino , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Modelos Animais de Doenças , Proteínas Estimuladoras de Ligação a CCAAT
19.
Intern Emerg Med ; 19(4): 1071-1079, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38102447

RESUMO

Few studies have assessed sex differences in the management of suspected acute coronary syndrome (ACS). We aimed to compare the evaluation, treatment, and outcomes between males and females with suspected ACS in the emergency department. Data were obtained from a prospective registry of acute chest pain involving 21 emergency departments in Shandong Province, China. The primary endpoint was 30-day major adverse cardiac events (MACEs). Overlap propensity score weighting was used to address potential confounding. A total of 8046 patients were analysed (42.8% female). Overlap-weighted analysis showed no significant association of female sex with 30-day MACEs (odds ratio, 0.91; 95% CI 0.75 to 1.11; P = 0.363). Secondary analyses found that women were less likely to be identified as high risk at first presentation (odds ratio, 0.86; 95% CI 0.78 to 0.94; P < 0.001). In the emergency department, women were less likely to undergo antiplatelet therapy (odds ratio, 0.87; 95% CI 0.79 to 0.96; P = 0.004) or coronary angiography (odds ratio, 0.78; 95% CI, 0.69 to 0.88; P < 0.001). Women had a longer length of stay in the emergency department and were less likely to be admitted to a ward at disposition. These sex differences existed only in the non-ST-elevation subgroup and were independent of risk stratification. Women with non-ST-elevation chest pain in China received suboptimal treatment in the emergency department. However, their clinical outcomes were not significantly different from those of men. Further studies are needed to determine the causes and impacts of these sex differences.


Assuntos
Síndrome Coronariana Aguda , Serviço Hospitalar de Emergência , Humanos , Feminino , Masculino , Síndrome Coronariana Aguda/terapia , Síndrome Coronariana Aguda/diagnóstico , China/epidemiologia , Pessoa de Meia-Idade , Idoso , Fatores Sexuais , Estudos Prospectivos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Serviço Hospitalar de Emergência/organização & administração , Sistema de Registros/estatística & dados numéricos , Pontuação de Propensão
20.
Tohoku J Exp Med ; 229(1): 45-51, 2013 01.
Artigo em Inglês | MEDLINE | ID: mdl-23238616

RESUMO

Aldehyde dehydrogenase-2 (ALDH2) is the main enzyme responsible for acetaldehyde oxidation in ethanol metabolism and also provides protection against oxidative stress. Alpha-lipoic acid (α-LA), a natural dithiol compound with antioxidant properties, has been reported to increase ALDH2 activity in cultured cells. We analyzed the therapeutic efficacy of α-LA in 63 patients with confirmed acute coronary syndrome (ACS). These patients (52 men and 11 women, with age range 49-72 years) were randomized into two groups: untreated group (n = 30) and α-LA group (n = 33). Patients in the α-LA group were given an intravenous injection of 600 mg α-LA every day for 5 days while the patients in the untreated group were given saline. An isoprostane, 8-iso-prostaglandin F2α (8-iso-PGF2α), one product of arachidonic acid metabolism, was measured as a marker for oxidative stress. The serum levels of 8-iso-PGF2α and ALDH2 activity were determined at admission to the hospital (time 0), and at 24 hours and 1 week after treatment. At 24 hours and 1 week after treatment, ALDH2 activity was significantly higher in the α-LA group than in the untreated group (P < 0.05), whereas the levels of 8-iso-PGF2α were significantly lower in the α-LA group than in the untreated group (all P < 0.05). Importantly, the decrease of 8-iso-PGF2α levels correlated with the increased ALDH2 activity at both 24 hours (r = 0.6234, P < 0.001) and 1 week after treatment (r = -0.3941, P = 0.0014). α-LA may ameliorate oxidative stress through up-regulating ALDH2 activity in patients with ACS.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/enzimologia , Aldeído Desidrogenase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/farmacologia , Idoso , Aldeído-Desidrogenase Mitocondrial , Biomarcadores/sangue , Dinoprosta/análogos & derivados , Dinoprosta/sangue , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Ácido Tióctico/administração & dosagem , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa