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Monkeypox is a zoonotic disease. Since the first human monkeypox case was detected in 1970, it has been prevalent in some countries in central and western Africa. Since May 2022, monkeypox cases have been reported in more than 96 non-endemic countries and regions worldwide. As of September 14, 2022, there have been more than 58,200 human monkeypox cases, and there is community transmission. The cessation of smallpox vaccination in 1980, which had some cross-protection with monkeypox, resulted in a general lack of immunity to monkeypox, which caused global concern and vigilance. As of September 14, 2022, there are four monkeypox cases in China, including three in Taiwan province and one in Hong Kong city. Previous foreign studies have shown that children are vulnerable to monkeypox and are also at high risk for severe disease or complications. In order to improve pediatricians' understanding of monkeypox and achieve early detection, early diagnosis, early treatment, and early disposal, we have organized national authoritative experts in pediatric infection, respiratory, dermatology, critical care medicine, infectious diseases, and public health and others to formulate this expert consensus, on the basis of the latest "Clinical management and infection prevention and control for monkeypox" released by The World Health Organization, the "guidelines for diagnosis and treatment of monkeypox (version 2022)" issued by National Health Commission of the People's Republic of China and other relevant documents. During the development of this consensus, multidisciplinary experts have repeatedly demonstrated the etiology, epidemiology, transmission, clinical manifestations, laboratory examinations, diagnosis, differential diagnosis, treatment, discharge criteria, prevention, disposal process, and key points of prevention and control of suspected and confirmed cases.
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Mpox , Humanos , Niño , Mpox/diagnóstico , Mpox/epidemiología , Mpox/prevención & control , Salud Pública , Diagnóstico Diferencial , Vacunación , China/epidemiologíaRESUMEN
Simulated photoelectron spectroscopy was conducted to investigate the structural evolution and electronic properties of TiASil (A = Sc, Ti; l ≤ 12) clusters and their anions via the Perdew-Burke-Enzerhof scheme and extensive cluster search using the ABCluster software. The results revealed that the ground-state structures of the TiASil (A = Sc, Ti) clusters generally exhibited similar configurations except for the Ti2Si3, ScTiSi3, and TiScSi10 clusters. Furthermore, the TiASil clusters exhibited an adsorptive evolution pattern, and the TiASi4 unit was considered the basic constituent framework of the structure, excluding several distortions and minor changes. With the increase in the cluster size, the lowest-energy structures varied from the exohedral to the cage structures of the single-metal atom at the center. Regarding the second energy difference data, the neutral TiASi4 clusters exhibited better stability among the neutral and anionic TiASil (A = Sc, Ti; l ≤ 12) clusters. Furthermore, the chemical bonding in the TiASi4 clusters was analyzed by molecular orbitals (MOs), highest occupied MO-lowest unoccupied MO gaps, and adaptive natural density partitioning analyses for the best Ti2Si4 cluster especially, and the results were combined with the natural population analysis data. The hybridization of the spd orbital of the metal atoms, eight localized bonds, and four delocalized bonds may primarily account for the relative stabilities of the neutral, square bipyramidal structure of Ti2Si4. Thus, the TiASi4 clusters may be assembled as the basic units of silicon-based semiconductor clusters of large-size neutral and anionic TiASil.
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The growth patterns, simulated photoelectron spectra, and electronic properties of LaASil (A = Sc, Y, and La; l ≤ 10) compounds and their anions were studied via quantum chemistry calculations using the Perdew-Burke-Ernzerhof (PBE) method and unprejudiced structural searching software ABCluster. The results revealed that the growth patterns of the most stable structures of neutral and anionic LaASil showed an adsorptive mode. The lowest-energy structures (LESs) of the LaASil (l ≤ 7) clusters were similar, except for those of anionic LaYSi4- and LaYSi5- and neutral LaScSi7. Additionally, we investigated and calculated the photoelectron spectra, vertical detachment energies, adiabatic electron affinities, relative stability, charge transfer, magnetic moment, and chemical bond analysis of the LaASil ground-state structures. The La2Sil clusters exhibited higher stability than the LaYSil and LaScSil systems owing to their higher dissociation energies (DEs). The DEs of the LESs in the LaASi3 molecule are higher than those of other clusters. Thus, the LaASi3 cluster shows potential as a building framework for Si-based cluster materials with good stability. The natural population analysis data and chemical bond analysis results showed that the spd hybridization of the orbitals of the metal atoms in the LaASil system occurred. Except for the LaScSi9 and LaScSi10 clusters, the neutral LaASil compounds transform into the corresponding anions when an extra electron is accepted by the Si clusters.
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Objective: To investigate the effects of NOD-like receptor protein 3 (NLRP3) signaling pathway on insulin resistance and the intervention of lactic acid receptor G protein-coupled receptor 81 (GPR81) agonist in nonalcoholic fatty liver disease (NAFLD) rats. Methods: Thirty SD male rats were randomly divided into three groups: control group, NAFLD group and GPR81 agonist group, with 10 rats in each group. Nonalcoholic fatty liver rat model was established by high fat diet. The rats in GPR81 agonist group were injected intraperitoneally with GPR81 specific agonist lactate (50 nmol/L) on the basis of nonalcoholic fatty liver model once a week, and the other two groups were injected with the same amount of normal saline for 12 weeks. The levels of liver biochemical indexes, fasting blood glucose, insulin and inflammatory factors in liver homogenate were measured, and the histopathological morphology of liver in each group was observed. The protein expressions of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), cysteinyl aspartate specific proteinase-1 (caspase-1), insulin receptor substrate 1 (IRS-1), Tyr465-IRS-1, Ser636-IRS-1, glucose transporter 4 (GLUT4) in liver tissue were detected by Western blot. The mRNA expression levels of NLRP3, ASC, caspase-1, IRS-1 and GLUT4 in liver tissue were detected by qRT-PCR. Results: Compared with the control group, the serum levels of triglyceride (TG), alanine aminotransfease (ALT), aspartate aminotransfease (AST), fasting plasma glucose (FPG), fasting insulin (FINS) and homeostasis model assessment of insulin resistance (HOMA-IR) of NAFLD group were increased significantly (Pï¼ 0.05). The results of liver histopathology showed that in NAFLD group, there were obvious fatty changes in liver tissue, fat droplets in hepatocytes and inflammatory cell infiltration. And the mRNA and protein expressions of NLRP3, ASC, caspase-1 and the protein expression of Ser636-IRS-1 in NAFLD group were increased significantly, and the contents of interleukin 1ß (IL-1ß) and interleukin 18 (IL-18) in liver and serum were increased, while the mRNA and protein expressions of IRS-1 and GLUT4 and Tyr465-IRS-1 were decreased significantly (Pï¼0.05). Compared with NAFLD group, the above indexes of GPR81 agonist group were all significantly improved. Conclusion: The activation of NLRP3 signaling pathway mediates the production of inflammatory factors and promotes the development of NAFLD. GPR81 agonist may be a potential treatment for NAFLD.
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Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Animales , Insulina , Hígado , Masculino , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas GRESUMEN
OBJECTIVES: The aim of this study was to explore the difference in target vessel failure (TVF) 3 years after intravascular ultrasound (IVUS) guidance versus angiographic guidance among all comers undergoing second-generation drug-eluting stent (DES) implantation. BACKGROUND: The multicenter randomized ULTIMATE (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in "All-Comers" Coronary Lesions) trial showed a lower incidence of 1-year TVF after IVUS-guided DES implantation among all comers compared with angiographic guidance. However, the 3-year clinical outcomes of the ULTIMATE trial remain unknown. METHODS: A total of 1,448 all comers undergoing DES implantation who were randomly assigned to either IVUS guidance or angiographic guidance in the ULTIMATE trial were followed for 3 years. The primary endpoint was the risk for TVF at 3 years. The safety endpoint was definite or probable stent thrombosis (ST). RESULTS: At 3 years, TVF occurred in 47 patients (6.6%) in the IVUS-guided group and in 76 patients (10.7%) in the angiography-guided group (p = 0.01), driven mainly by the decrease in clinically driven target vessel revascularization (4.5% vs. 6.9%; p = 0.05). The rate of definite or probable ST was 0.1% in the IVUS-guided group and 1.1% in the angiography-guided group (p = 0.02). Notably, the IVUS-defined optimal procedure was associated with a significant reduction in 3-year TVF relative to that with the suboptimal procedure. CONCLUSIONS: IVUS-guided DES implantation was associated with significantly lower rates of TVF and ST during 3-year follow-up among all comers, particularly those who underwent the IVUS-defined optimal procedure compared with those with angiographic guidance. (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in "All-Comers" Coronary Lesions; NCT02215915).
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Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Angiografía Coronaria , Humanos , Intervención Coronaria Percutánea , Resultado del Tratamiento , Ultrasonografía IntervencionalRESUMEN
Protein deglycase DJ-1 (DJ-1) is a multifunctional protein involved in various biological processes. However, it is unclear whether DJ-1 influences atherosclerosis development and plaque stability. Accordingly, we evaluated the influence of DJ-1 deletion on the progression of atherosclerosis and elucidate the underlying mechanisms. We examine the expression of DJ-1 in atherosclerotic plaques of human and mouse models which showed that DJ-1 expression was significantly decreased in human plaques compared with that in healthy vessels. Consistent with this, the DJ-1 levels were persistently reduced in atherosclerotic lesions of ApoE-/- mice with the increasing time fed by western diet. Furthermore, exposure of vascular smooth muscle cells (VSMCs) to oxidized low-density lipoprotein down-regulated DJ-1 in vitro. The canonical markers of plaque stability and VSMC phenotypes were evaluated in vivo and in vitro. DJ-1 deficiency in Apoe-/- mice promoted the progression of atherosclerosis and exaggerated plaque instability. Moreover, isolated VSMCs from Apoe-/- DJ-1-/- mice showed lower expression of contractile markers (α-smooth muscle actin and calponin) and higher expression of synthetic indicators (osteopontin, vimentin and tropoelastin) and Kruppel-like factor 4 (KLF4) by comparison with Apoe-/- DJ-1+/+ mice. Furthermore, genetic inhibition of KLF4 counteracted the adverse effects of DJ-1 deletion. Therefore, our results showed that DJ-1 deletion caused phenotype switching of VSMCs and exacerbated atherosclerotic plaque instability in a KLF4-dependent manner.
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Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Placa Aterosclerótica/etiología , Placa Aterosclerótica/metabolismo , Proteína Desglicasa DJ-1/deficiencia , Animales , Apolipoproteínas E/deficiencia , Biomarcadores , Biopsia , Arterias Carótidas/metabolismo , Arterias Carótidas/patología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Técnica del Anticuerpo Fluorescente , Inmunohistoquímica , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/metabolismo , Lipoproteínas LDL/metabolismo , Ratones , Ratones Noqueados , Modelos Biológicos , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Fenotipo , Placa Aterosclerótica/patología , Transducción de SeñalRESUMEN
The aim of the present study was to investigate the effects of atorvastatin against heart ischemia/reperfusion (I/R) injury and its potential underlying mechanism. Rats were allocated into the following groups: Sham, I/R, atorvastatin (10 mg/kg daily), fasudil (10 mg/kg daily) and atorvastatin + fasudil in combination. Drugs were administered for 2 weeks prior to I/R injury. I/R was established by ligating the left anterior descending branch (LAD) for 30 min and releasing the ligature for 180 min. The I/R group was found to have increased myocardial infarct size, cardiomyocyte apoptosis, levels of plasma interleukin (IL)-6 and tumor necrosis factor (TNF)-α, superoxide dismutase (SOD) activity, malondialdehyde (MDA) levels and Rho-kinase activity compared with the other treatment groups (P<0.05). Moreover, pretreatment with atorvastatin significantly attenuated Rho-kinase activity, myocardial infarct size, cardiomyocyte apoptosis, levels of plasma IL-6 and TNF-α, SOD activity and MDA levels, and upregulated nitric oxide production. It was also indicated that the specific Rho-kinase inhibitor, fasudil, had the same effects as atorvastatin in I/R. Therefore, the present results suggested atorvastatin may lead to cardiovascular protection, which may be mediated by Rho-kinase inhibition in heart I/R injury.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Accelerated atherosclerotic calcification is responsible for plaque burden, especially in diabetes. The regulatory mechanism for atherosclerotic calcification in diabetes is poorly characterized. Here we show that deletion of PARP-1, a main enzyme in diverse metabolic complications, attenuates diabetic atherosclerotic calcification and decreases vessel stiffening in mice through Runx2 suppression. Specifically, PARP-1 deficiency reduces diabetic arteriosclerotic calcification by regulating Stat1-mediated synthetic phenotype switching of vascular smooth muscle cells and macrophage polarization. Meanwhile, both vascular smooth muscle cells and macrophages manifested osteogenic differentiation in osteogenic media, which was attenuated by PARP-1/Stat1 inhibition. Notably, Stat1 acts as a positive transcription factor by directly binding to the promoter of Runx2 and promoting atherosclerotic calcification in diabetes. Our results identify a new function of PARP-1, in which metabolism disturbance-related stimuli activate the Runx2 expression mediated by Stat1 transcription to facilitate diabetic arteriosclerotic calcification. PARP-1 inhibition may therefore represent a useful therapy for this challenging complication.
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Aterosclerosis/enzimología , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Complicaciones de la Diabetes/enzimología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Factor de Transcripción STAT1/metabolismo , Calcificación Vascular/enzimología , Animales , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerosis/genética , Aterosclerosis/metabolismo , Complicaciones de la Diabetes/genética , Macrófagos/metabolismo , Ratones , Ratones Noqueados , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , Osteogénesis/genética , Fenantrenos/farmacología , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Regiones Promotoras Genéticas , Unión Proteica , Factor de Transcripción STAT1/genética , Calcificación Vascular/genéticaRESUMEN
BACKGROUND/AIM: No-reflow is a serious and frequent event during primary percutaneous coronary intervention (PPCI) for acute ST segment elevation myocardial infarction (STEMI). The aim of this study was to identify possible predictors for no-reflow. PATIENTS AND METHODS: We investigated 218 patients with acute anterior STEMI who underwent PPCI from December 2016 to December 2018. No-reflow was defined as a coronary TIMI flow grade of ≤ 2. TIMI flow grade 3 was defined as normal reflow. RESULTS: In our study, the no-reflow phenomenon was observed in 39 patients (18%) during angiography. The patients of no-reflow group were found to be more older, diabetics, longer pain-to-balloon time, lower blood pressure, higher platelet counts and higher levels of D-Dimer and Cystatin C (Cys-C). In multivariate logistic regression analysis, only diabetes (OR = 0.371, 95% CI: 0.157-0.872, P = 0.023), longer pain-to-balloon time (OR = 1.147, 95% CI: 1.015-1.297, P = 0.028) and higher Cys-C level (OR = 10.07, 95% CI: 2.340-43.377, P = 0.002) were predictors for no-reflow. CONCLUSION: Cys-C might be a useful predictor for the no-reflow phenomenon after PPCI in STEMI patients. It might help to screen STEMI patients with high risk of no-reflow on admission.
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Cistatina C/sangre , Fenómeno de no Reflujo/sangre , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST/cirugía , Anciano , Angiografía Coronaria , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Fenómeno de no Reflujo/diagnóstico , Fenómeno de no Reflujo/diagnóstico por imagen , Fenómeno de no Reflujo/fisiopatología , Intervención Coronaria Percutánea/efectos adversos , Infarto del Miocardio con Elevación del ST/sangre , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/fisiopatologíaRESUMEN
OBJECTIVE: To determine if high fasting blood glucose (FBG) level is an independent predictor of serious coronary lesions in patients with coronary artery disease (CAD). METHODS: We enrolled 64 patients who had symptoms of chest discomfort and who underwent coronary angiography. FBG was determined from blood samples and the extent of coronary artery lesions was analyzed according to Gensini score. We examined the relationships among diabetes, FBG, and coronary artery severity. RESULTS: Diabetes and FBG were significantly and positively related to Gensini score. Diabetes, but not FBG, was independently correlated with the occurrence of a Gensini score >41. However, FBG was significantly associated with Gensini score >41 in non-diabetic patients. CONCLUSION: Hyperglycemia is an independent predictor of severe CAD in non-diabetic patients. Clinicians should be aware of this and should carry out appropriate early interventions.
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Glucemia/metabolismo , Enfermedad de la Arteria Coronaria/diagnóstico , Hiperglucemia/diagnóstico , Factores de Edad , Anciano , Biomarcadores/sangre , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/fisiopatología , Estudios Transversales , Diabetes Mellitus/sangre , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/fisiopatología , Ayuno/sangre , Femenino , Humanos , Hiperglucemia/sangre , Hiperglucemia/complicaciones , Hiperglucemia/fisiopatología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
BACKGROUND/AIM:\: Rho kinase is a downstream effector of Rho GTPase that is known to regulate various pathological processes. The aim of this study was to evaluate the regulation of Rho kinase activity in leukocytes in patients with ischemia/reperfusion (I/R) injury. PATIENTS AND METHODS: We investigated 38 patients with acute ST-segment elevation myocardial infarction (STEMI), 26 patients with atherosclerosis (AS) and 22 normal subjects. All patients underwent coronary angiography (CAG) and all STEMI patients received primary percutaneous coronary intervention (PPCI) of the left anterior descending artery (LAD) within 12 h after chest pain on-set. Blood samples for leukocyte Rho kinase activity were obtained before CAG and 3 and 24 hours after CAG/PCI. RESULTS: Rho kinase activity increased in the I/R and AS groups. Compared with the AS group, Rho kinase activity was significantly higher in peripheral blood leukocytes in STEMI/PPCI. Furthermore, there was no correlation between changes in Rho kinase activity and changes in high-sensitivity troponin I (hs-TnI) and C-reactive protein (CRP). There was a negative correlation between Rho kinase activity and IL-6. CONCLUSION: Rho kinase is involved in the pathogenesis of heart I/R injury in patients. Inhibition of Rho kinase may be an additional therapeutic intervention for the treatment of I/R.
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Biomarcadores/metabolismo , Infarto del Miocardio con Elevación del ST/enzimología , Quinasas Asociadas a rho/metabolismo , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST/terapia , Troponina I/metabolismoRESUMEN
INTRODUCTION: Provisional stenting (PS) for simple coronary bifurcation lesions is the mainstay of treatment. A systematic two-stent approach is widely used for complex bifurcation lesions (CBLs). However, a randomised comparison of PS and two-stent techniques for CBLs has never been studied. Accordingly, the present study is designed to elucidate the benefits of two-stent treatment over PS in patients with CBLs. METHODS AND ANALYSIS: This DEFINITION II study is a prospective, multinational, randomised, endpoint-driven trial to compare the benefits of the two-stent technique with PS for CBLs. A total of 660 patients with CBLs will be randomised in a 1:1 fashion to receive either PS or the two-stent technique. The primary endpoint is the rate of 12-month target lesion failure defined as the composite of cardiac death, target vessel myocardial infarction (MI) and clinically driven target lesion revascularisation. The major secondary endpoints include all causes of death, MI, target vessel revascularisation, in-stent restenosis, stroke and each individual component of the primary endpoints. The safety endpoint is the occurrence of definite or probable stent thrombosis. ETHICS AND DISSEMINATION: The study protocol and informed consent have been approved by the Institutional Review Board of Nanjing First Hospital, and accepted by each participating centre. Written informed consent was obtained from all enrolled patients. Findings of the study will be published in a peer-reviewed journal and disseminated at conferences. TRIAL REGISTRATION NUMBER: NCT02284750; Pre-results.
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Angioplastia Coronaria con Balón/métodos , Enfermedad de la Arteria Coronaria/cirugía , Estenosis Coronaria/terapia , Vasos Coronarios/cirugía , Stents , Anciano , Enfermedad de la Arteria Coronaria/patología , Vasos Coronarios/patología , Stents Liberadores de Fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etiología , Infarto del Miocardio/prevención & control , Intervención Coronaria Percutánea/métodos , Estudios Prospectivos , Diseño de Prótesis , Proyectos de Investigación , Resultado del TratamientoRESUMEN
Emerging evidence indicates that irisin provides beneficial effects in diabetes. However, whether irisin influences the development of diabetic cardiomyopathy (DCM) remains unclear. Therefore, we investigated the potential role and mechanism of action of irisin in diabetes-induced myocardial dysfunction in mice. Type 1 diabetes was induced in mice by injecting streptozotocin, and the diabetic mice were administered recombinant r-irisin (low or high dose: 0.5 or 1.5 µg/g body weight/day, I.P.) or PBS for 16 weeks. Irisin treatment did not alter blood glucose levels in the diabetic mice. However, the results of echocardiographical and histopathological assays indicated that low-dose irisin treatment alleviated cardiac fibrosis and left ventricular function in the diabetic mice, whereas high-dose irisin failed to mitigate the ventricular function impairment and increased collagen deposition. The potential mechanism underlying the effect of low-dose irisin involved irisin-mediated inhibition of high glucose-induced endothelial-to-mesenchymal transition (EndMT); conversely, high-dose irisin treatment enhanced high glucose-induced MMP expression by stimulating MAPK (p38 and ERK) signalling and cardiac fibroblast proliferation and migration. Low-dose irisin alleviated DCM development by inhibiting high glucose-induced EndMT. By contrast, high-dose irisin disrupted normal MMP expression and induced cardiac fibroblast proliferation and migration, which results in excess collagen deposition. Thus, irisin can inhibit high glucose-induced EndMT and exert a dose-dependent bidirectional effect on DCM.
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Cardiomiopatías Diabéticas/patología , Fibronectinas/farmacología , Glucosa/toxicidad , Células Endoteliales de la Vena Umbilical Humana/patología , Mesodermo/patología , Animales , Glucemia/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Colágeno/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Cardiomiopatías Diabéticas/sangre , Cardiomiopatías Diabéticas/fisiopatología , Activación Enzimática/efectos de los fármacos , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Mesodermo/efectos de los fármacos , Ratones Endogámicos C57BL , Miocardio/metabolismo , Miocardio/patología , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteínas Smad/metabolismo , Estreptozocina , Factor de Crecimiento Transformador beta/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Ulinastatin exhibits anti-inflammatory activity and protects the heart from ischemia/reperfusion injury. However, whether ulinastatin has a protective effect in diabetic cardiomyopathy is yet to be elucidated. The aim of the present study was to investigate the protective effects of ulinastatin against diabetic cardiomyopathy and its underlying mechanisms. A C57/BL6J mice model of diabetic cardiomyopathy was used and mice were randomly assigned to three groups: Control group, diabetes mellitus (DM) group and DM + ulinastatin treatment group. Cardiac function was assessed using echocardiography and the level of inflammatory cytokine high mobility group box 1 (HMGB1) expression was measured using histopathological examination and reverse transcription-quantitative polymerase chain reaction. The levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were measured using western blotting and ELISA. The apoptosis rate in the myocardium was assessed by TUNEL assay. Caspase-3 activation, expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated × (Bax) were measured using western blotting, as was the activity of the mitogen activated protein kinase (MAPK) signaling pathway. The results indicated that ulinastatin significantly improved cardiac function in mice with DM. Ulinastatin treatment significantly downregulated HMGB1, TNF-α and IL-6 expression (P<0.05) and significantly reduced the percentage of apoptotic cardiomyocytes (P<0.05) via reduction of caspase-3 activation and the ratio of Bax/Bcl-2 in diabetic hearts (P<0.05). In addition, ulinastatin attenuated the activation of the MAPK signaling pathway. In conclusion, ulinastatin had a protective effect against DM-induced cardiac dysfunction in a mouse model. This protective effect may be associated with the anti-inflammatory and anti-apoptotic abilities of ulinastatin via the MAPK signaling pathway.
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The aim of the present study was to identify the genetic defect responsible for familial coronary artery disease/myocardial infarction (CAD/MI), which exhibited an autosomal dominant pattern of inheritance, in an extended Chinese Han pedigree containing 34 members. Using exome and Sanger sequencing, a novel 6base pair (bp) 'CAGCCG' deletion in exon 11 of the myocyte enhancer factor 2A (MEF2A) gene was identified, which cosegregated with CAD/MI cases in this family. This 6bp deletion was not detected in 311 sporadic cases of premature CAD/MI or in 323 unrelated healthy controls. Determination of a genetic risk profile has a key role in understanding the pathogenesis of CAD and MI. Among the reported riskconferring genes and their variants, mutations in MEF2A have been reported to segregate with CAD/MI in Caucasian families. Causative missense mutations have also been detected in sporadic CAD/MI cases. However, this suggested genetic linkage is controversial, since it could not be confirmed by ensuing studies. The discovery of a novel MEF2A mutation in a Chinese family with premature CAD/MI suggests that MEF2A may have a significant role in the pathogenesis of premature CAD/MI. To better understand this association, further in vitro and in vivo studies are required.
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Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/genética , Factores de Transcripción MEF2/genética , Eliminación de Secuencia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Pueblo Asiatico , Biomarcadores , Niño , China , Mapeo Cromosómico , Angiografía Coronaria , Exoma , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Linaje , Adulto JovenRESUMEN
Cardiac fibrosis is an important pathological process of diabetic cardiomyopathy, the underlying mechanism remains elusive. This study sought to identify whether inhibition of Myocyte enhancer factor 2A (MEF2A) alleviates cardiac fibrosis by partially regulating Endothelial-to-mesenchymal transition (EndMT). We induced type 1 diabetes mellitus using the toxin streptozotocin (STZ) in mice and injected with lentivirus-mediated short-hairpin RNA (shRNA) in myocardium to inhibit MEF2A expression. Protein expression, histological and functional parameters were examined twenty-one weeks post-STZ injection. We found that Diabetes mellitus increased cardiac MEF2A expression, aggravated cardiac dysfunction and myocardial fibrosis through the accumulation of fibroblasts via EndMT. All of these features were abolished by MEF2A inhibition. MEF2A gene silencing by shRNA in cultured human umbilical vein endothelial cells (HUVECs) ameliorated high glucose-induced phenotypic transition and acquisition of mesenchymal markers through interaction with p38MAPK and Smad2. We conclude that inhibition of endothelial cell-derived MEF2A might be beneficial in the prevention of diabetes mellitus-induced cardiac fibrosis by partially inhibiting EndMT through interaction with p38MAPK and Smad2.
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Diabetes Mellitus Experimental/terapia , Fibrosis/terapia , Factores de Transcripción MEF2/antagonistas & inhibidores , Miocardio/patología , Animales , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Transición Epitelial-Mesenquimal , Fibrosis/genética , Fibrosis/metabolismo , Fibrosis/patología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Factores de Transcripción MEF2/biosíntesis , Factores de Transcripción MEF2/genética , Factores de Transcripción MEF2/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismo , Transducción de Señal , TransfecciónRESUMEN
PURPOSE: Increased lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and Rho kinase activity may be associated with atherosclerosis. The principal aim of this study was to examine whether darapladib (a selective Lp-PLA2 inhibitor) could reduce the elevated Lp-PLA2 and Rho kinase activity in atherosclerosis. MATERIALS AND METHODS: Studies were performed in male Sprague-Dawley rats. The atherosclerosis rats were prepared by feeding them with a high-cholesterol diet for 10 weeks. Low-dose darapladib (25 mg·kg⻹·d⻹) and high-dose darapladib (50 mg·kg⻹·d⻹) interventions were then administered over the course of 2 weeks. RESULTS: The serum levels of triglycerides, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), high-sensitivity C-reactive protein (hs-CRP), and Lp-PLA2, significantly increased in atherosclerosis model groups, as did Rho kinase activity and cardiomyocyte apoptosis (p<0.05 vs. sham group), whereas nitric oxide (NO) production was reduced. Levels of TC, LDL-C, CRP, Lp-PLA2, and Rho kinase activity were respectively reduced in darapladib groups, whereas NO production was enhanced. When compared to the low-dose darapladib group, the reduction of the levels of TC, LDL-C, CRP, and Lp-PLA2 was more prominent in the high-dose darapladib group (p<0.05), and the increase of NO production was more prominent (p<0.05). Cardiomyocyte apoptosis of the high-dose darapladib group was also significantly reduced compared to the low-dose darapladib group (p<0.05). However, there was no significant difference in Rho kinase activity between the low-dose darapladib group and the high-dose darapladib group (p>0.05). CONCLUSION: Darapladib, a Lp-PLA2 inhibitor, leads to cardiovascular protection that might be mediated by its inhibition of both Rho kinase and Lp-PLA2 in atherosclerosis.
Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/enzimología , Benzaldehídos , Oximas , Inhibidores de Fosfolipasa A2/administración & dosificación , Quinasas Asociadas a rho/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterasa/sangre , 1-Alquil-2-acetilglicerofosfocolina Esterasa/efectos de los fármacos , Animales , Aterosclerosis/sangre , Proteína C-Reactiva/metabolismo , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Relación Dosis-Respuesta a Droga , Masculino , Inhibidores de Fosfolipasa A2/efectos adversos , Ratas , Ratas Sprague-Dawley , Triglicéridos/sangreRESUMEN
Prohibitin (PHB) is a highly conserved protein implicated in various cellular functions including proliferation, apoptosis, tumor suppression, transcription, and mitochondrial protein folding. However, its function in diabetic cardiomyopathy (DCM) is still unclear. In vivo, type 2 diabetic rat model was induced by using a high-fat diet and low-dose streptozotocin. Overexpression of the PHB protein in the model rats was achieved by injecting lentivirus carrying PHB cDNA via the jugular vein. Characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. Rats with DCM showed severe insulin resistance, left ventricular dysfunction, fibrosis and apoptosis. PHB overexpression ameliorated the disease. Cardiofibroblasts (CFs) and H9c2 cardiomyoblasts were used in vitro to investigate the mechanism of PHB in altered function. In CFs treated with HG, PHB overexpression decreased expression of collagen, matrix metalloproteinase activity, and proliferation. In H9c2 cardiomyoblasts, PHB overexpression inhibited apoptosis induced by HG. Furthermore, the increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was significantly decreased and the inhibited phosphorylation of Akt was restored in DCM. Therefore, PHB may be a new therapeutic target for human DCM.
Asunto(s)
Cardiomiopatías/fisiopatología , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Miocardio/metabolismo , Proteínas Represoras/metabolismo , Animales , Animales Recién Nacidos , Apoptosis/genética , Western Blotting , Cardiomiopatías/etiología , Cardiomiopatías/genética , Línea Celular , Células Cultivadas , Diabetes Mellitus Experimental/etiología , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/genética , Dieta Alta en Grasa/efectos adversos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibrosis/genética , Expresión Génica , Pruebas de Función Cardíaca , Humanos , Resistencia a la Insulina/genética , Masculino , Microscopía Fluorescente , Miocardio/patología , Fosforilación , Prohibitinas , Ratas Sprague-Dawley , Proteínas Represoras/genética , Disfunción Ventricular Izquierda/genéticaRESUMEN
Age-related endothelial dysfunction is closely associated with the local production of reactive oxygen species (ROS) within and in the vicinity of the vascular endothelium. Oxidant-induced DNA damage can activate the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1), leading to endothelial dysfunction in various pathophysiological conditions. The present study aimed to investigate the role of PARP-1 in age-dependent changes in endothelial cell function and its underlying mechanism. Wild-type (WT) and PARP-1(-/-) mice were divided into young (2 months) and old (12 months) groups. Isolated aortic rings were suspended to record isometric tension to assess endothelial function. Nitric oxide (NO) production and content in plasma were detected by spectrophotometry. Superoxide (O2(-) production was detected by dihydroethidium. Expression of PARP-1, endothelial nitric oxide synthase (eNOS), induced nitric oxide synthase (iNOS), and arginase-2 (Arg2) was assessed by western blot analysis. Endothelium-dependent relaxation in response to acetylcholine was lost in old WT, but not PARP-1(-/-), mice. Endothelium-independent vasodilation was not impaired in aging mice. Production of O2(-) was greater in aging WT mice than young or aging PARP-1(-/-) mice. eNOS expression was not affected by aging in WT or PARP-1(-/-) mice, but p-eNOS expression decreased and iNOS and Arg2 levels were upregulated only in aging WT mice. In conclusion, PARP-1 inhibition may protect against age-dependent endothelial dysfunction, potentially by regulating NO bioavailability via iNOS. Inhibition of PARP-1 may help in vascular aging prevention.