RESUMO
Ferroptosis is a regulatory cell death process pivotal in myocardial ischemia-reperfusion (I/R) injury. However, the precise mechanism underlying myocardial ferroptosis remains less known. In this study, we investigated the pathophysiological mechanisms of methylmalonic acid (MMA) associated with ferroptosis activation in cardiomyocytes after I/R. We found an increase level of MMA in patients with acute myocardial injury after reperfusion and AC16 cells under hypoxia/reoxygenation (H/R) condition. MMA treatment was found to be associated with excessive oxidative stress in cardiomyocytes, leading to ferroptosis-related myocardial injury. In mice with I/R injury, MMA treatment aggravated myocardial oxidative stress and ferroptosis, which amplified the myocardial infarct size and cardiac dysfunction. Mechanistically, MMA promoted NOX2/4 expression to increase reactive oxygen species (ROS) production in cardiomyocytes, aggravating myocardial injury. Notably, the increased ROS further activated ferroptosis by inhibiting solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. In addition, MMA decreased the ectopic nuclear distribution of nuclear factor E2-related factor 2 (NRF2) by increasing the interaction between NRF2 and kelch-like ECH-associated protein 1 (KEAP1). This impeded the activation of GPX4/SLC7A11, downstream of NRF2, activating ferroptosis and aggravating myocardial cell injury. Collectively, our study indicates that MMA activates oxidative stress and ROS generation, which induces ferroptosis to exacerbate cardiomyocyte injury in an I/R model. These findings may provide a new perspective for the clinical treatment of I/R injury and warrant further investigation.
Assuntos
Ferroptose , Traumatismo por Reperfusão Miocárdica , Humanos , Animais , Camundongos , Espécies Reativas de Oxigênio , Proteína 1 Associada a ECH Semelhante a Kelch , Ácido Metilmalônico , Fator 2 Relacionado a NF-E2 , MitocôndriasRESUMO
BACKGROUND: Cost-related medication nonadherence (CRN) is associated with poor prognosis among patients with chronic obstructive pulmonary disease (COPD), a population that requires long-term treatment for secondary prevention. In this study, we aimed to estimate the prevalence and sociodemographic characteristics of CRN in individuals with COPD in the US. METHODS: In a nationally representative survey of US adults in the National Health Interview Survey (2013-2020), we identified individuals aged ≥18 years with a self-reported history of COPD. Cross-sectional study. RESULTS: Of the 15,928 surveyed individuals, a weighted 18.56% (2.39 million) reported experiencing CRN, including 12.50% (1.61 million) missing doses, 13.30% (1.72 million) taking lower than prescribed doses, and 15.74% (2.03 million) delaying filling prescriptions to save costs. Factors including age < 65 years, female sex, low family income, lack of health insurance, and multimorbidity were associated with CRN. CONCLUSIONS: In the US, one in six adults with COPD reported CRN. The influencing factors of CRN are multifaceted and necessitating more rigorous research. Targeted interventions based on the identified influencing factors in this study are recommended to enhance medication adherence among COPD patients.
Assuntos
Doença Pulmonar Obstrutiva Crônica , Adulto , Humanos , Feminino , Estados Unidos/epidemiologia , Adolescente , Idoso , Estudos Transversais , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Inquéritos e Questionários , Seguro Saúde , Adesão à MedicaçãoRESUMO
BACKGROUND: Asthma is a chronic disease that needs long-term control for secondary prevention. Health-related expenditures resulting from asthma are rising in the United States, and medication nonadherence is associated with adverse health outcomes in patients with asthma. OBJECTIVE: To estimate the prevalence and risk factors of cost-related medication nonadherence (CRN) in individuals with asthma in the United States. METHODS: We identified patients aged above or equal to 18 years with a history of asthma in nationally representative cross-sectional data, the National Health Interview Survey 2013 to 2020. Participants were considered to have experienced CRN if at any time in the 12 months they reported skipping doses, taking less medication, or delaying filling a prescription to save money. The weighted prevalence of CRN was estimated overall and by subgroups. Logistic regression was used to identify CRN-related characteristics. RESULTS: Of the 26,539 National Health Interview Survey participants with a history of asthma, 4360 (15.77%; representing 3.92 million of the US population) reported CRN, with 10.12% (weighted 2.51 million) of patients skipping doses to save money, 10.82% (weighted 2.69 million) taking less medication to save money, and 13.35% (weighted 3.31 million) delaying filling a prescription to save money. The subgroups young, women, low income, no health insurance, currently smoking, and with comorbidities had a higher prevalence of CRN. The results of this sensitivity analysis did not differ from the overall results. CONCLUSION: In the United States, 1 in 6 adults with a history of asthma is nonadherence with medications due to costs. Removing financial barriers to accessing medication can improve medication adherence in patients with asthma.
Assuntos
Asma , Gastos em Saúde , Humanos , Adulto , Feminino , Estados Unidos/epidemiologia , Idoso , Estudos Transversais , Inquéritos e Questionários , Adesão à Medicação , Asma/tratamento farmacológico , Asma/epidemiologiaRESUMO
BACKGROUND: The inconsistent relationship between Vitamin B12 (B12), methylmalonic acid (MMA, marker of B12 deficiency) and mortality was poorly understood, especially in patients with coronary heart disease (CHD). This study aims to investigate the association of serum MMA, and B12-related biomarkers (serum level, dietary intake, supplement use, and sensibility to B12) with all-cause and cardiovascular mortality in adults with CHD. METHODS: The data of this study were from a subcohort within the US National Health and Nutrition Examination Survey (NHANES). We included adults with preexisting CHD with serum MMA and B12, and dietary B12 intake measurements at recruitment. All participants were followed up until 31 December 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CI of mortality risk. RESULTS: Overall, 1755 individuals (weighted mean [SE] age, 65.2 [0.5] years; 1047 men [weighted 58.5%]) with CHD were included, with geometric mean levels of serum MMA 182.4 nmol/L, serum B12 494.5 pg/ml, and dietary B12 intake 4.42 mg/day, and percentage of B12 supplements use 39.1%. During a median follow-up of 7.92 years, 980 patients died. Serum B12 concentration, dietary B12 intake and supplements use were not significantly associated with mortality risk (each p ≥ 0.388). In contrast, individuals in the top tertile of MMA had multivariable-adjusted HRs (95% CIs) of 1.70 (1.31-2.20) for all-cause mortality, and 2.00 (1.39-2.89) for cardiovascular mortality (both p trend < 0.001) compared to those in the bottom tertile of MMA. MMA-related mortality risk was particularly higher among participants with sufficient serum B12 (p < 0.001). CHD patients with increased levels of both MMA and B12 had a doubled mortality risk compared to those with lower MMA and B12 (p < 0.001). CONCLUSION: MMA accumulation but not serum or dietary vitamin B12 was associated with increased cardiovascular mortality risk among patients with CHD. This paradox may be related to decreased response to vitamin B12.
Assuntos
Doenças Cardiovasculares , Deficiência de Vitamina B 12 , Adulto , Masculino , Humanos , Idoso , Vitamina B 12 , Ácido Metilmalônico , Inquéritos Nutricionais , Deficiência de Vitamina B 12/complicações , Deficiência de Vitamina B 12/diagnóstico , Estudos ProspectivosRESUMO
BACKGROUND Diabetes is related to higher risk of multiple cancers. This study aimed to explore the effect and mechanism of diabetes on liver metastasis of CRC. MATERIAL AND METHODS Overall and liver metastasis-free survival in diabetic and non-diabetic CRC patients were compared by Kaplan-Meier analysis. Expression of alphavß6 was detected by immunohistochemistry in clinical specimens. Effects of hyperglycemia on alphavß6 expression in colon cancer cells were assessed by western blot, real-time PCR, and flowcytometry. Effects of hyperglycemia on migration and invasion were demonstrated by Transwell assay. Expression and activity of MMP-9 and MMP-2 were determined by real-time PCR and gelatin zymography. Liver metastatic nodules were counted and b6 expression was detected by western blot in a liver metastasis mouse model. RESULTS CRC patients with diabetes had poorer overall and liver metastasis-free survival, and diabetes was associated with higher alphavß6 expression in CRC specimens. Hyperglycemia promoted the invasion and migration of colon cancer cells, and upregulated the expression and activity of MMP-9, which were attenuated by inhibition of alphavß6. Hyperglycemia upregulated the expression of ß6 and cell surface expression of avb6, which was reduced by ERK inhibitor. The in vitro results were confirmed in vivo in the mouse model. CONCLUSIONS Our study demonstrated the enhancing effect of hyperglycemia on liver metastasis of CRC, and showed that alphavß6 was involved in this process, suggesting that control of glucose levels and inhibition of alphavß6 can reduce the risk of liver metastasis in diabetic CRC patients.
Assuntos
Antígenos de Neoplasias/metabolismo , Neoplasias Colorretais/sangue , Hiperglicemia/metabolismo , Integrinas/metabolismo , Adulto , Animais , Antígenos de Neoplasias/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal , Feminino , Expressão Gênica , Humanos , Hiperglicemia/patologia , Integrinas/genética , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Metástase Neoplásica , RNA Longo não Codificante , Regulação para CimaRESUMO
BACKGROUND: Plaque rupture (PR) and plaque erosion (PE) are main causes of acute myocardial infarction with different demographic and histology characteristics and need different treatment strategy. PR and PE can be identified with optical coherence tomography (OCT) accurately, but convenient and effective noninvasive markers for them are rarely found. History of diabetes mellitus (DM) was reported to be a potential predictor of PR in ST-segment elevated myocardial infarction (STEMI) patients, but the predictive value of other glucose-related variables for it is still uncertain. Present study aimed to clear the relationship between some glucose-related variables and plaque morphology in patients with STEMI. METHODS: We consecutively enrolled 872 STEMI patients and divided them into PR group (n = 616) and PE group (n = 256) based on OCT diagnostic criteria. The relationship of glucose-related variables, including random plasma glucose on admission (ARPG), glycosylated hemoglobin (HbA1c), post-PCI fasting plasma glucose (PFPG), DM history, glucose variable tendency (GVT) and the acute-to-chronic glycemic ratio (A/C), to the PR risk of STEMI patients was analyzed. The correlation between the glucose-related variables and plaque morphology was analyzed meanwhile. RESULTS: Among the glucose-related variables, ARPG and GVT were confirmed to be independent predictors for PR after adjusting for other traditional risk factors in nondiabetic patients. The higher the ARPG level, the more PR risk the STEMI patients had. And high HbA1c and APPG were demonstrated to have a weak and positive correlation with lipid constituents and stenosis degree of culprit vessel. CONCLUSIONS: Compared to HbA1c, DM history, and some other glucose-related variables, ARPG and GVT were risk factors for PR in STEMI patients, especially those without DM. And high HbA1c and ARPG were positively correlated with the development of vulnerable plaque in culprit vessels. Trial registration Present study is a retrospective one and the population came from the EROSION study of our center previously. It was approved by the Ethics Committee of the Second Affiliated Hospital of Harbin Medical University (Approval reference number, KY2017-249), and all patients provided written informed consent prior to the inclusion in the study and the investigation conformed to the principles outlined in the Declaration of Helsinki.
Assuntos
Glicemia/metabolismo , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Diabetes Mellitus/sangue , Placa Aterosclerótica , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Tomografia de Coerência Óptica , Biomarcadores/sangue , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/terapia , Vasos Coronários/patologia , Diabetes Mellitus/diagnóstico , Hemoglobinas Glicadas/metabolismo , Humanos , Intervenção Coronária Percutânea , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Ruptura Espontânea , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Fatores de TempoRESUMO
BACKGROUND: Plaque erosion (PE) has been considered a secondary pathogenesis of ST-segment elevated myocardial infarction (STEMI) following plaque rupture (PR). Previous studies demonstrated that they had different demographic and histology characteristics and need different treatment strategy. But there are few non-invasive plasma biomarkers for distinguishing them. The present study aimed to identify non-invasive predictive biomarkers for PE and PR in patients with STEMI.MethodsâandâResults:A total 108 patients were recruited and grouped into a PE group (n=36), a PR group (n=36), and an unstable angina pectoris (UAP) (n=36) group for analysis. A 9-plex tandem mass tag (TMT)-based proteomics was used to compare plasma protein profiles of PE, PR, and UAP. In total, 36 significant differential proteins (DPs) were identified among groups, 10 of which were screened out using bio-information analysis and validated with enzyme-linked immunosorbent assay (ELISA). The relationship of angiography and optical coherence tomography (OCT) imaging data and the 10 target DPs was analyzed statistically. Logistic regression showed elevated collagen type VI α-2 chain (COL6A2) and insulin-like growth factor 1 (IGF1), and decreased fermitin family homolog 3 (FERMT3), were positively associated with PE. Multivariate analysis indicated IGF1, FERMT3, and COL6A2 had independent predictive ability for PE. IGF1 was inversely correlated with lumen stenosis and the lipid arc of the plaque. CONCLUSIONS: IGF1, COL6A2, and FERMT3 are potential predictive biomarkers of PE in STEMI patients. And IGF1 was negatively correlated with the developing of culprit plaque.
Assuntos
Colágeno Tipo VI/sangue , Doença da Artéria Coronariana/diagnóstico , Fator de Crescimento Insulin-Like I/análise , Proteínas de Membrana/sangue , Proteínas de Neoplasias/sangue , Placa Aterosclerótica , Proteômica , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Ensaios de Triagem em Larga Escala , Humanos , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Ruptura Espontânea , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Espectrometria de Massas em TandemRESUMO
Apoptosis is associated with various myocardial diseases. Angiotensin II (Ang II) plays a central role in the pathogenesis of RAAS-triggered cardiac apoptosis. Our previous studies showed that mammalian Ste20-like kinase 1 (Mst1) aggravates cardiac dysfunction in cardiomyocyte under pathological conditions, but its role in Ang II-mediated cardiomyocyte apoptosis is not known. We addressed this in the present study by investigating whether cardiac-specific Mst1 knockout can alleviate Ang II-induced cardiomyocyte apoptosis along with the underlying mechanisms. In vitro and in vivo experiments showed that Ang II increased intracellular reactive oxygen species (ROS) production and cardiomyocyte apoptosis; these were reversed by administration of the ROS scavenger N-acetylcysteine and by Mst1 deficiency, which suppressed c-Jun N-terminal kinase (JNK) phosphorylation and downstream signaling. Interestingly, Mst1 knockout failed to alleviate Ang II-induced phosphorylation of extracellular signal-regulated kinase 1/2, and inactivated apoptosis signal-regulating kinase1 (ASK1) by promoting its association with thioredoxin (Trx), which reversed the Ang II-induced activation of the ASK1-JNK pathway and suppressed Ang II-induced cardiomyocyte apoptosis. Thus, cardiac-specific Mst1 knockout inhibits ROS-mediated JNK signalling to block Ang II-induced cardiomyocyte apoptosis, suggesting Mst1 as a potential therapeutic target for treatment of RAAS-activated heart failure.
Assuntos
Angiotensina II/metabolismo , Apoptose/fisiologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Acetilcisteína/metabolismo , Animais , Cardiomiopatias/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/patologia , Fosforilação/fisiologia , Tiorredoxinas/metabolismoRESUMO
AIMS: Angiotension II (Ang II) plays a central role in the pathogenesis of renin-angiotensin-aldosterone system (RAAS)-induced heart failure. Mst1 exerts its function in cardiomyocytes subjected to pathological stimuli via inhibiting autophagy and aggravating apoptosis, but its role in RAAS-mediated cardiac injury is still unknown. Here, we aimed to determine whether cardiomyocyte-specific Mst1 knockout can alleviate Ang II-induced cardiac injury by improving cardiomyocyte autophagy and whether these functions depend on Ang II receptors. RESULTS: Mst1 knockout alleviated Ang II-induced heart failure, without affecting blood pressure and compensatory concentric hypertrophy. Mst1 specific knockout improved the effects of Ang II on cardiomyocyte autophagy, as evidenced by further increased LC3-II expression and decreased P62 expression. More typical autophagosomes accompanied by less damaged mitochondria were also observed by electron microscopy in Ang II-treated Mst1Δ/Δ mice. In vitro, Mst1 knockdown promoted cardiomyocyte autophagic flux, as demonstrated by more GFP-mRFP-LC3 puncta per cell. Increased LC3-II and decreased P62 expression both in the presence and absence of chloroquine were observed in Mst1 knockdown cardiomyocytes administered with Ang II. Treatment with 3-MA, an inhibitor of autophagy, abolished the beneficial effects of Mst1 knockout against Ang II-induced cardiac dysfunction. The compensatory effects of Ang II on upregulated autophagy were associated with Mst1 inhibition. Interestingly, the knockdown or antagonization of AT1R inhibited cardiomyocyte autophagy, which may represent a threat to cardiac function. Importantly, Mst1 knockout consistently enhanced cardiomyocyte autophagy following the knockdown or blocking of AT1R and AT2R. CONCLUSION: Cardiomyocyte-specific Mst1 knockout alleviates Ang II-induced cardiac injury by enhancing cardiomyocyte autophagy. Mst1 inhibition may counteract the undesirable effects of Ang II receptors blockage on cardiomyocyte autophagy and represent a promising complementary treatment strategy against Ang II-induced cardiac injury.
Assuntos
Angiotensina II/toxicidade , Cardiomiopatias/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores de Angiotensina/metabolismo , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Autofagia/fisiologia , Western Blotting , Cardiomiopatias/induzido quimicamente , Células Cultivadas , Fator de Crescimento de Hepatócito/genética , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Proteínas Proto-Oncogênicas/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Angiotensina/genéticaRESUMO
Mitophagy eliminates dysfunctional mitochondria and thus plays a cardinal role in diabetic cardiomyopathy (DCM). We observed the favourable effects of melatonin on cardiomyocyte mitophagy in mice with DCM and elucidated their underlying mechanisms. Electron microscopy and flow cytometric analysis revealed that melatonin reduced the number of impaired mitochondria in the diabetic heart. Other than decreasing mitochondrial biogenesis, melatonin increased the clearance of dysfunctional mitochondria in mice with DCM. Melatonin increased LC3 II expression as well as the colocalization of mitochondria and lysosomes in HG-treated cardiomyocytes and the number of typical autophagosomes engulfing mitochondria in the DCM heart. These results indicated that melatonin promoted mitophagy. When probing the mechanism, increased Parkin translocation to the mitochondria may be responsible for the up-regulated mitophagy exerted by melatonin. Parkin knockout counteracted the beneficial effects of melatonin on the cardiac mitochondrial morphology and bioenergetic disorders, thus abolishing the substantial effects of melatonin on cardiac remodelling with DCM. Furthermore, melatonin inhibited Mammalian sterile 20-like kinase 1 (Mst1) phosphorylation, thus enhancing Parkin-mediated mitophagy, which contributed to mitochondrial quality control. In summary, this study confirms that melatonin rescues the impaired mitophagy activity of DCM. The underlying mechanism may be attributed to activation of Parkin translocation via inhibition of Mst1.
Assuntos
Cardiomiopatias Diabéticas/tratamento farmacológico , Fator de Crescimento de Hepatócito/genética , Melatonina/administração & dosagem , Proteínas Proto-Oncogênicas/genética , Ubiquitina-Proteína Ligases/genética , Animais , Apoptose/efeitos dos fármacos , Autofagossomos/efeitos dos fármacos , Autofagossomos/patologia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , Modelos Animais de Doenças , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/genética , Camundongos , Mitocôndrias/genética , Mitocôndrias/patologia , Mitofagia/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidoresRESUMO
BACKGROUND: Cardiomyocyte autophagy and apoptosis are crucial events underlying the development of cardiac abnormalities and dysfunction after myocardial infarction (MI). A better understanding of the cell signaling pathways involved in cardiac remodeling may support the development of new therapeutic strategies for the treatment of heart failure (HF) after MI. METHODS: A cardiac MI injury model was constructed by ligating the left anterior descending (LAD) coronary artery. Neonatal cardiomyocytes were isolated and cultured to investigate the mechanisms underlying the protective effects of nicorandil on MI-induced injury. RESULTS: Nicorandil reduced cardiac enzyme release, mitigated left ventricular enlargement and cardiac dysfunction after MI, as evaluated by echocardiography and hemodynamic measurements. According to the results of the western blot analysis and immunofluorescence staining, nicorandil enhanced autophagic flux and reduced apoptosis in cardiomyocytes subjected to hypoxic injury. Interestingly, nicorandil increased Mst1 and p-Mst1 levels in cardiomyocytes subjected to MI injury. Mst1 knockout abolished the protective effects of nicorandil on cardiac remodeling and dysfunction after MI. Mst1 knockout also abolished the beneficial effects of nicorandil on cardiac enzyme release and cardiomyocyte autophagy and apoptosis. CONCLUSIONS: Nicorandil alleviates post-MI cardiac dysfunction and remodeling. The mechanisms were associated with enhancing autophagy and inhibiting apoptosis through Mst1 inhibition.
Assuntos
Fator de Crescimento de Hepatócito/antagonistas & inibidores , Fator de Crescimento de Hepatócito/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Nicorandil/administração & dosagem , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Cardiotônicos/administração & dosagem , Relação Dose-Resposta a Droga , Fator de Crescimento de Hepatócito/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/complicações , Proteínas Proto-Oncogênicas/genética , Resultado do Tratamento , Disfunção Ventricular Esquerda/etiologia , Remodelação Ventricular/efeitos dos fármacosRESUMO
BACKGROUND: Diabetic cardiomyopathy is identified as cardiac ventricular dysfunction induced by an insulin shortage in diabetic patients. Our previous studies have shown that Polydatin (PD) alleviates cardiac dysfunction after myocardial infarction (MI) injury. Nevertheless, the mechanism by which PD regulates diabetic cardiomyopathy has not been reported. METHODS: In this study, we demonstrated the effects and described the mechanisms of PD in diabetic cardiomyopathy in both adult mouse hearts and neonatal mouse cardiomyocytes. We injected streptozotocin (STZ) to induce the DM model in wild-type (WT) and Sirt3 knockout (Sirt3-/-) mice. Mitochondrial bioenergetics in diabetic mice were detected by measuring citrate synthase activity and ATP content. The extent of autophagy regulation by PD was investigated by detecting the levels of Beclin 1, Atg5, LC3 and p62. RESULTS: Compared to the WT mouse hearts, hearts from the diabetic mice exhibited better cardiac function and a higher level of autophagy. Moreover, mitochondrial function in the diabetic mouse hearts was improved after PD treatment. However, PD treatment had no effect on the Sirt3 knockout diabetic mouse hearts. Additionally, PD increased autophagy flux in the cardiomyocytes that were cultured in high-glucose medium for 48 h. In addition, PD had no effects on the cardiomyocytes under high-glucose conditions when we down-regulated Sirt3. CONCLUSIONS: Altogether, PD attenuated cardiac dysfunction, increased autophagy flux and improved mitochondrial bioenergetics by up-regulating Sirt3 in the diabetic mice.
Assuntos
Cardiomiopatias Diabéticas/tratamento farmacológico , Glucosídeos/farmacologia , Sirtuína 3/metabolismo , Estilbenos/farmacologia , Animais , Autofagossomos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cardiotônicos/farmacologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/ultraestrutura , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Sirtuína 3/genética , Regulação para Cima/efeitos dos fármacosRESUMO
This study investigated the effects of melatonin on diabetic cardiomyopathy (DCM) and determined the underlying mechanisms. Echocardiography indicated that melatonin notably mitigated the adverse left ventricle remodeling and alleviated cardiac dysfunction in DCM. The mechanisms were attributed to increased autophagy, reduced apoptosis, and alleviated mitochondrial dysfunction. Furthermore, melatonin inhibited Mst1 phosphorylation and promoted Sirt3 expression in DCM. These results indicated that melatonin may exert its effects through Mst1/Sirt3 signaling. To verify this hypothesis, a DCM model using Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1-/- ) mice was constructed. As expected, melatonin increased autophagy, reduced apoptosis and improved mitochondrial biogenesis in Mst1 Tg mice subjected to DCM injury, while it had no effects on Mst1-/- mice. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe the mechanisms involved. Melatonin administration promoted autophagic flux as demonstrated by elevated LC3-II and lowered p62 expression in the presence of bafilomycin A1. The results suggest that melatonin alleviates cardiac remodeling and dysfunction in DCM by upregulating autophagy, limiting apoptosis, and modulating mitochondrial integrity and biogenesis. The mechanisms are associated with Mst1/Sirt3 signaling.
Assuntos
Cardiomiopatias Diabéticas , Fator de Crescimento de Hepatócito , Miócitos Cardíacos , Proteínas Proto-Oncogênicas , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3 , Animais , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Macrolídeos/farmacologia , Melatonina , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/biossíntese , Proteínas Associadas aos Microtúbulos/genética , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/genética , Sirtuína 3/genética , Sirtuína 3/metabolismoRESUMO
A high serum anion gap (AG) at the time of patient admission can lead to the deterioration or even death; data are lacking for patients who suffer acute heart failure (AHF). The present study aimed at exploring the impact of serum AG (SAG) levels on the in-hospital mortality in AHF patients. The study conducted retrospective analysis on the data from the medical information mart for intensive care (MIMIC-IV) database in severe AHF cases. Serum AG, age, sex, concomitant diseases and laboratory tests were collected from patients at admission. Multivariate Cox proportional hazard regression model together with Kaplan Meier (K-M) survival curve served for analyzing the relationship of serum AG with the hospital all-cause mortality (ACM). In addition, subgroup analysis assisted in assessing the concordance. Data from 2774 AHF patients were collected in the study. The hospital ACM rate was 9.2% (254/2774). After correcting potential confounders, multivariate analysis compared the high serum AG level (≥ 16 mmol/L) and the low serum AG level (< 16 mmol/L) (hazard ratio (HR): 1.89 [95% CI 1.42-2.51]). In a similar way, K-M survival curve indicated that hospital survival was lower in patients with high serum, suggesting that high serum AG level could lead to poor AHF prognosis. In patients with AHF, high serum AG level could increase the hospital ACM.
Assuntos
Equilíbrio Ácido-Base , Insuficiência Cardíaca , Humanos , Estudos Retrospectivos , Mortalidade Hospitalar , PrognósticoRESUMO
BACKGROUND: Elevated serum methylmalonic acid (MMA), a marker of cobalamin (vitamin B12) deficiency, has been linked to cancer progression. However, the impact of MMA or cobalamin on mortality risk in cancer survivors remains unknown. OBJECTIVES: To explore the relationship between MMA, serum, dietary, and supplement of cobalamin, MMA metabolism-related genes, and poor prognosis in adult cancer survivors. METHODS: We analyzed data from 1988 cancer survivors aged ≥20 y. Patients were selected from the National Health and Nutrition Examination Survey and followed up until December 31, 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for mortality risk assessment. Genomic analysis identified MMA metabolism-related genes linked to early death in a 33-cancer-type cohort from The Cancer Genome Atlas. RESULTS: Among 1988 participants, 872 deaths occurred over a 10-year follow-up. Higher serum MMA levels were significantly linked to increased long-term mortality risk (tertile 3 compared with tertile 1: adjusted HR: 1.37; 95% CI: 1.11, 1.70; P-trend < 0.001). No associations were found between serum, dietary, and supplement of cobalamin and cancer survivor mortality (each P-trend > 0.143). However, MMA-associated mortality was notable in patients without deficiency. When combining cobalamin and MMA categories, multivariate-adjusted HR (95% CI) for all-cause mortality was 2.06 (95% CI: 1.60, 2.65) in participants with >250 nmol/L and cobalamin >295.1 pmol/L compared with those with MMA ≤250 nmol/L and cobalamin >295.1 pmol/L. Moreover, reduced transcriptional levels of MMA metabolism-related genes, indicating decreased mitochondrial MMA metabolism capability, are linked to an unfavorable prognosis in certain cancer types. CONCLUSIONS: Serum MMA was associated with long-term mortality risk in adult cancer survivors, which was more significant among individuals with higher levels of serum cobalamin. These findings suggest that mortality related to MMA was attributed to the insufficient flux of MMA metabolism, not cobalamin deficiency.
Assuntos
Biomarcadores , Sobreviventes de Câncer , Ácido Metilmalônico , Vitamina B 12 , Humanos , Ácido Metilmalônico/sangue , Vitamina B 12/sangue , Feminino , Masculino , Estudos Prospectivos , Pessoa de Meia-Idade , Biomarcadores/sangue , Adulto , Neoplasias/mortalidade , Neoplasias/sangue , Estudos de Coortes , Idoso , Fatores de RiscoRESUMO
BACKGROUND: The evidence on the association between cobalamin (Cbl) and aging or relevant outcomes is limited and controversial. We aimed to investigate the relationships between cobalamin intake- and function-related biomarkers and biological aging. METHODS: The study encompassed 22,812 participants aged 20 years and older from the National Health and Nutrition Examination Survey. A panel of biomarkers or algorithms was used to assess biological aging, including Klemera-Doubal Age Acceleration (KDMAccel), Phenotypic age acceleration (PhenoAgeAccel), telomere length, α-Klotho, and PhenoAge advancement. Weighted generalized linear regression analysis was used to assess the associations between cobalamin-intake biomarkers (serum cobalamin, cobalamin intake from food, cobalamin supplement use, serum methylmalonic acid [MMA], and homocysteine [Hcy]) and function-related biomarkers (functional cobalamin deficiency and cobalamin insensitivity index). RESULTS: Among the 22,812 individuals, the weighted mean (SE) age was 48.3 (0.2) years and 48.0% were males. Unexpectedly, serum and dietary cobalamin as well as serum MMA and Hcy levels were positively associated with most indicators of biological aging. Cobalamin sensitivity was assessed by the combination of binary Cbllow/high and MMAlow/high or Hcylow/high (cutoff values: 400 pg/mL for cobalamin, 250 nmol/L for MMA, and 12.1 µmol/l for Hcy) and a newly constructed cobalamin insensitivity index (based on the multiplicative term of serum cobalamin and serum MMA or Hcy). The multivariable-adjusted ß (95%CIs) of KDMAccel in the MMAlowCbllow, MMAlowCblhigh, MMAhighCbllow, and MMAhighCblhigh groups were reference, 0.27 (0.03 to 0.51), 0.85 (0.41 to 1.29), and 7.97 years (5.77 to 10.17) respectively, which were consistent for the combination of serum Hcy and cobalamin. Both cobalamin insensitivity indices were robustly associated with biological aging acceleration in a dose-response pattern (each p < 0.001). CONCLUSIONS: Decreased cobalamin sensitivity but not cobalamin insufficiency might be associated with biological aging acceleration. Further studies would improve understanding of the underlying mechanisms between decreased cobalamin sensitivity and biological aging acceleration.
Assuntos
Envelhecimento , Biomarcadores , Homocisteína , Ácido Metilmalônico , Deficiência de Vitamina B 12 , Vitamina B 12 , Humanos , Vitamina B 12/sangue , Masculino , Feminino , Envelhecimento/fisiologia , Envelhecimento/sangue , Pessoa de Meia-Idade , Ácido Metilmalônico/sangue , Biomarcadores/sangue , Deficiência de Vitamina B 12/sangue , Deficiência de Vitamina B 12/epidemiologia , Homocisteína/sangue , Adulto , Inquéritos Nutricionais , Suplementos Nutricionais , Idoso , Dieta/estatística & dados numéricosRESUMO
BACKGROUND: The specific effects of adverse childhood experiences (ACEs) in adulthood and senectitude were less known. We aim to examine the relationship between early ACEs and overall health condition as well as specific dimensions in the middle-aged and elderly population. METHODS: In the 2019-2021 Behavioral Risk Factor Surveillance System Study, robust Poisson regression models were used to estimate the relationship between ACE exposure and current health status among adults aged 45 ≥ years. RESULTS: Of the 195,472 participants, 53.8 % were female and the mean age was 65.0 years. Compared to populations without ACE, ACE exposures were more significantly associated with depression (PR: 2.03, 95 %CI: 1.94-2.21), frequent mental health (PR: 1.85, 95 %CI: 1.74-1.97) and subject cognitive decline (PR: 1.99, 95 %CI:1.85-2.14) than with physical health (PR: 1.37, 95 %CI: 1.32-1.44), with dose-response patterns. The association with mental disorder was especially significant among the elderly population. CONCLUSION: Early ACEs are associated with adverse health outcomes that persist into later life, particularly mental disorders and cognitive decline. Poor mental health may indirectly influence associations with ACEs and cognitive decline as well as physical health. Our findings emphasize the importance of lifelong psychological screening and support for the ACE-exposed middle-aged and elderly population.
Assuntos
Experiências Adversas da Infância , Disfunção Cognitiva , Nível de Saúde , Humanos , Feminino , Masculino , Experiências Adversas da Infância/estatística & dados numéricos , Idoso , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Estudos Retrospectivos , Disfunção Cognitiva/epidemiologia , Depressão/epidemiologia , Depressão/psicologia , Sistema de Vigilância de Fator de Risco Comportamental , Saúde Mental , Transtornos Mentais/epidemiologia , Transtornos Mentais/psicologia , Idoso de 80 Anos ou maisRESUMO
Background: Homocysteine (Hcy) is a recognized cardiovascular disease (CVD) risk factor linked with atherosclerosis. However, the association between Hcy and myocardial injury is little known. Objectives: This study aimed to examine the associations between Hcy metabolism, subclinical myocardial injury, and cardiovascular mortality. Methods: We included 10,871 participants without diagnosed CVD. Generalized linear regression was used to investigate the relationship between Hcy-related indicators (plasma total Hcy [tHcy], vitamin B12, and folate) and myocardial injury biomarkers (high-sensitivity troponin T [hs-cTnT], high-sensitivity troponin I [hs-cTnI] measured using 3 assays [Abbott, Siemens, and Ortho], and N-terminal pro-B-type natriuretic peptide [NT-proBNP]). Results: Among 10,871 participants, the weighted mean levels for tHcy, folate, and vitamin B12 were 8.58 µmol/L, 32.43 nmol/L, and 447.08 pmol/L, respectively. Plasma tHcy levels were positively associated with elevated hs-cTnT, hs-cTnI, and NT-proBNP, whereas folate and vitamin B12 were not inversely related to myocardial injury biomarkers. Multivariable-adjusted odds ratios for elevated hs-cTnT (19 ng/L) and NT-proBNP (125 pg/mL) per doubling of tHcy were 2.80 (95% CI: 1.17-6.73; P < 0.001) and 1.58 (95% CI: 1.20-2.08; P < 0.001), respectively. The associations of tHcy levels with elevated hs-cTnI (Abbott: 28 ng/L; Siemens: 46.5 ng/L; Ortho: 11 ng/L) were consistent. Indirect effects of tHcy on cardiovascular mortality risk via hs-cTnT and NT-proBNP explained up to 26.6% and 12.3% of the total effect, respectively. Conclusions: Plasma tHcy, not folate or vitamin B12, is significantly associated with elevated hs-cTnT, hs-cTnI, and NT-proBNP in adults without CVD. Subclinical myocardial injury may substantially mediate Hcy-related cardiovascular mortality risk.
RESUMO
Diabetic cardiomyopathy (DCM) is a cardiovascular complication with no known cure. In this study, we evaluated the combination of ultrasound-targeted microbubble destruction (UTMD) and cationic microbubbles (CMBs) for cardiac S-adenosyl homocysteine hydrolase (SAHH) gene transfection as potential DCM therapy. Models of high glucose/fat (HG/HF)-induced H9C2 cells and streptozotocin-induced DCM rats were established. Ultrasound-mediated SAHH delivery using CMBs was a safe and noninvasive approach for spatially localized drug administration both in vitro and in vivo. Notably, SAHH overexpression increased cell viability and antioxidative stress and inhibited apoptosis of HG/HF-induced H9C2 cells. Likewise, UTMD-mediated SAHH delivery attenuated apoptosis, oxidative stress, cardiac fibrosis, and myocardial dysfunction in DCM rats. Activation of the AMPK/FOXO3/SIRT3 signaling pathway may be a key mechanism mediating the role of SAHH in regulating myocardial injury. Thus, UTMD-mediated SAHH transfection may be an important advancement in cardiac gene therapy for restoring ventricular function after DCM.