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BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. METHODS: This was a collaborative trial-level meta-analysis from the SGLT2i Meta-analysis Cardio-Renal Trialists Consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across 3 patient populations (patients with diabetes at high risk for atherosclerotic cardiovascular disease, heart failure [HF], or chronic kidney disease). The outcomes of interest were MACE (composite of cardiovascular death, myocardial infarction , or stroke), individual components of MACE (inclusive of fatal and nonfatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i versus placebo were meta-analyzed across trials and examined across key subgroups (established atherosclerotic cardiovascular disease, previous myocardial infarction, diabetes, previous HF, albuminuria, chronic kidney disease stages, and risk groups). RESULTS: A total of 78 607 patients across 11 trials were included: 42 568 (54.2%), 20 725 (26.4%), and 15 314 (19.5%) were included from trials of patients with diabetes at high risk for atherosclerotic cardiovascular disease, HF, or chronic kidney disease, respectively. SGLT2i reduced the rate of MACE by 9% (hazard ration [HR], 0.91 [95% CI, 0.87-0.96], P<0.0001) with a consistent effect across all 3 patient populations (I2=0%) and across all key subgroups. This effect was primarily driven by a reduction in cardiovascular death (HR, 0.86 [95% CI, 0.81-0.92], P<0.0001), with no significant effect for myocardial infarction in the overall population (HR, 0.95 [95% CI, 0.87-1.04], P=0.29), and no effect on stroke (HR, 0.99 [95% CI, 0.91-1.07], P=0.77). The benefit for cardiovascular death was driven primarily by reductions in HF death and sudden cardiac death (HR, 0.68 [95% CI, 0.46-1.02] and HR, 0.86 [95% CI, 0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (Pinteraction=0.02). CONCLUSIONS: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of atherosclerotic cardiovascular disease, diabetes, kidney function, or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of cardiovascular death, particularly HF death and sudden cardiac death, without a significant effect on myocardial infarction in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.
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Enfermedades Cardiovasculares , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Humanos , Enfermedades Cardiovasculares/mortalidad , Insuficiencia Renal Crónica/mortalidad , Insuficiencia Renal Crónica/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Masculino , Resultado del Tratamiento , AncianoRESUMEN
Ralstonia solanacearum causes bacterial wilt disease in solanaceous crops. Identification of avirulence type III-secreted effectors recognized by specific disease resistance proteins in host plant species is an important step toward developing durable resistance in crops. In the present study, we show that R. solanacearum effector RipJ functions as an avirulence determinant in Solanum pimpinellifolium LA2093. In all, 10 candidate avirulence effectors were shortlisted based on the effector repertoire comparison between avirulent Pe_9 and virulent Pe_1 strains. Infection assays with transgenic strain Pe_1 individually carrying a candidate avirulence effector from Pe_9 revealed that only RipJ elicits strong bacterial wilt resistance in S. pimpinellifolium LA2093. Furthermore, we identified that several RipJ natural variants do not induce bacterial wilt resistance in S. pimpinellifolium LA2093. RipJ belongs to the YopJ family of acetyltransferases. Our sequence analysis indicated the presence of partially conserved putative catalytic residues. Interestingly, the conserved amino acid residues in the acetyltransferase catalytic triad are not required for effector-triggered immunity. In addition, we show that RipJ does not autoacetylate its lysine residues. Our study reports the identification of the first R. solanacearum avirulence protein that triggers bacterial wilt resistance in tomato. We expect that our discovery of RipJ as an avirulence protein will accelerate the development of bacterial wilt-resistant tomato varieties in the future.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.
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Ralstonia solanacearum , Solanum , Proteínas Bacterianas/genética , Resistencia a la Enfermedad , Enfermedades de las PlantasRESUMEN
BACKGROUND: It is difficult to assess the impact of multiple comorbidities on clinical outcomes in chronic obstructive pulmonary disease (COPD). In this study, we aimed to investigate exacerbation-associated comorbidities, determine whether the number of comorbidities is an independent risk factor for exacerbation, and identify other exacerbation-associated factors in a Korean COPD population using a nationwide population-based cohort. This study focused on severe exacerbations that required hospitalisation or emergency room visits. METHODS: The National Health Insurance Service-National Sample Cohort, version 2.0, data sampled between 2002 and 2015 were analysed. Data from two years after the diagnosis of COPD were analysed for each participant (N = 12,554, entire cohort). Moreover, 42% of the participants underwent additional health examinations (N = 5306, health-screening cohort). Fifteen comorbidities that were previously reported as risk factors for exacerbations were examined. A logistic regression model was used to analyse association with exacerbations. RESULTS: Asthma (1.57 [1.39-1.76] and 1.24 [1.06-1.44]), lung cancer (1.84 [1.30-2.59] and 2.28 [1.54-3.37]), and heart failure (1.39 [1.16-1.67] and 1.52 [1.18-1.97]) were associated with exacerbation in both cohorts (odds ratio [95% confidence interval] in the entire cohort and health-screening cohort, respectively). The number of comorbidities was an independent risk factor, and old age, male sex, low body mass index, and current smoking were also independent risk factors. High cholesterol levels and body mass index exerted protective effects against exacerbation. CONCLUSIONS: The number of comorbidities, certain comorbidities such as asthma, lung cancer and heart failure, and low BMI were associated with an increased risk of severe exacerbation in COPD patients.
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Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Anciano , Anciano de 80 o más Años , Asma/epidemiología , Índice de Masa Corporal , Estudios de Cohortes , Comorbilidad , Progresión de la Enfermedad , Femenino , Insuficiencia Cardíaca/epidemiología , Humanos , Modelos Logísticos , Neoplasias Pulmonares/epidemiología , Masculino , Persona de Mediana Edad , República de Corea/epidemiología , Factores de RiesgoRESUMEN
OBJECTIVES: The hemoglobin glycation index (HGI) quantifies interindividual variations in glycated hemoglobin (HbA1c) and is associated with diabetic complications and metabolic diseases. However, information on the association between HGI and non-alcoholic fatty liver disease (NAFLD) in healthy subjects is limited, particularly in Asian populations. This study aimed to investigate the association between HGI and NAFLD in a healthy Korean cohort. DESIGN: Subjects were stratified in quartiles according to their HGI level. NAFLD was diagnosed by hepatic ultrasonography, hepatic steatosis index and fatty liver index. Multiple logistic regression analysis was performed to evaluate the association between HGI quartiles and the risk of NAFLD. PATIENTS: Data from subjects without diabetes who underwent liver ultrasonography during routine health examinations were retrospectively reviewed. RESULTS: Data from 14 465 subjects were included in the analysis. The prevalence of NAFLD increased significantly with each HGI quartile (24.8%, 29.7%, 32.6% and 40.6% in quartiles 1-4, respectively; P < 0.001). In comparison with the lowest HGI quartile group, the highest quartile exhibited worse metabolic parameters, including body weight, waist circumference, body mass index and lipid profiles. Multiple logistic regression analysis adjusted for multiple factors showed that the odds ratio of having NAFLD was 1.564 (95% CI: 1.350-1.813, P < 0.001) in the highest HGI quartile. CONCLUSIONS: Elevated HGI levels are independently associated with NAFLD in a healthy Asian population.
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Hemoglobina Glucada/análisis , Voluntarios Sanos/estadística & datos numéricos , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Adulto , Asia/epidemiología , Pueblo Asiatico/estadística & datos numéricos , Índice de Masa Corporal , Femenino , Encuestas Epidemiológicas/métodos , Encuestas Epidemiológicas/estadística & datos numéricos , Humanos , Lípidos/sangre , Hígado/diagnóstico por imagen , Modelos Logísticos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Prevalencia , Estudios Retrospectivos , Ultrasonografía/métodos , Circunferencia de la CinturaRESUMEN
OBJECTIVE: SFRP5 (secreted frizzled-related protein 5) is an endogenous inhibitor of WNT5A (wingless-type family member 5a), which has been implicated in atherosclerosis. However, contradictory results have been reported about the role of SFRP5 in atherosclerosis. We aimed to investigate whether SFRP5 could restore WNT5A-induced endothelial dysfunction in vitro and ex vivo. In addition, we sought to determine whether the serum concentration of SFRP5 is associated with atherosclerosis in humans. APPROACH AND RESULTS: We measured endothelium-dependent vasorelaxation in the isolated thoracic aorta of Sprague-Dawley rats. In addition, we measured intracellular nitric oxide (NO) in human endothelial cells. The protein abundance of total and phosphorylated JNK (c-Jun N-terminal kinase), AKT (protein kinase B), and endothelial NO synthase was analyzed in human endothelial cells. Circulating SFRP5 and WNT5A levels and brachial-ankle pulse wave velocity were measured in 282 human subjects with type 2 diabetes mellitus. SFRP5 dose dependently restored Wnt5-induced impaired vasorelaxation in rat thoracic aorta by an endothelial NO synthase-dependent mechanism. SFRP5 treatment restored the WNT5A-induced reduction of NO production via endothelial NO synthase in human endothelial cells. WNT5A-induced changes in the phosphorylation of JNK, AKT, and endothelial NO synthase were ameliorated with SFRP5 administration. In humans with type 2 diabetes mellitus, the serum SFRP5 concentration positively correlated with brachial-ankle pulse wave velocity (r=0.146; P=0.024). Multivariate linear regression analysis demonstrated that the serum SFRP5 concentration was independently associated with brachial-ankle pulse wave velocity after adjustment for potential confounders [B (SE)=7.40 (3.35); P=0.028]. CONCLUSIONS: Our data suggest the possible compensatory action of SFRP5 against atherosclerosis under conditions of metabolic dysfunction.
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Aorta Torácica/metabolismo , Diabetes Mellitus Tipo 2/sangre , Proteínas del Ojo/sangre , Proteínas de la Membrana/sangre , Rigidez Vascular , Vasodilatación , Proteína Wnt-5a/sangre , Proteínas Adaptadoras Transductoras de Señales , Adiponectina/sangre , Anciano , Animales , Índice Tobillo Braquial , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiopatología , Biomarcadores/sangre , Células Cultivadas , Estudios Transversales , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatología , Proteínas del Ojo/farmacología , Femenino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Proteínas de la Membrana/farmacología , Persona de Mediana Edad , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Vasodilatación/efectos de los fármacos , Proteína Wnt-5a/farmacologíaRESUMEN
Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)-containing plasmalogens, expression of glyceronephosphate O-acyltransferase (Gnpat; the rate-limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of FC in the liver. Cyclodextrin-induced depletion of FC transactivated Δ-6 desaturase by increasing sterol regulatory element-binding protein 2 expression in cultured hepatocytes. DHA, the major product of Δ-6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat small interfering RNA treatment significantly decreased peroxisome proliferator-activated receptor α (Pparα) expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA-containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor, alkyl glycerol (AG), prevented hepatic steatosis and NASH through a PPARα-dependent increase in fatty acid oxidation. Gnpat+/- mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH. CONCLUSION: Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis through GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH. (Hepatology 2017;66:416-431).
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Hígado Graso/metabolismo , Glucosamina 6-Fosfato N-Acetiltransferasa/metabolismo , Subunidad 1 del Complejo Mediador/metabolismo , Plasmalógenos/metabolismo , Análisis de Varianza , Animales , Biomarcadores/metabolismo , Biopsia con Aguja , Modelos Animales de Enfermedad , Ácidos Grasos Monoinsaturados/farmacología , Hígado Graso/patología , Fluvastatina , Glucosamina 6-Fosfato N-Acetiltransferasa/efectos de los fármacos , Inmunohistoquímica , Indoles/farmacología , Masculino , Subunidad 1 del Complejo Mediador/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Distribución Aleatoria , Sensibilidad y Especificidad , Transducción de SeñalRESUMEN
OBJECTIVE: Metabolically healthy obese (MHO) phenotype refers to obese individuals with a favourable metabolic profile. Its prognostic value remains controversial and may partly depend on differences in how the phenotype is defined. We aimed to investigate whether the MHO phenotype is associated with future development of incident hypertension in a Korean population according to various definitions of metabolic health. SUBJECTS AND METHODS: The study population comprised 31 033 Koreans without hypertension. Participants were stratified into metabolically healthy nonobese (MHNO), metabolically unhealthy nonobese (MUNO), metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) by body mass index (cut-off value, 25·0 kg/m(2) ) and metabolic health state, using four different definitions: Adult Treatment Panel (ATP)-III, Wildman, Karelis and the homoeostasis model assessment (HOMA) criteria. RESULTS: Over the median follow-up period of 35·0 months (range, 4·5-81·4 months), 4589 of the 31 033 individuals (14·8%) developed incident hypertension. Compared with the MHNO group, the MHO group showed increased association with incident hypertension with multivariate-adjusted odds ratios of 1·56 (95% confidence interval [CI], 1·41-1·72), 1·58 (95% CI 1·42-1·75), 1·52 (95% CI 1·35-1·71) and 1·46 (95% CI 1·33-1·61), when defined by ATP-III, Wildman, Karelis and HOMA criteria, respectively. CONCLUSION: MUO individuals showed the highest association with the incident hypertension (adjusted odds ratios up to 2·00). MHO subjects showed an approximately 1·5-fold higher association with incident hypertension than their nonobese counterpart regardless of the definition of metabolic health used. Thus, considering both metabolic health and obesity is important for the assessment of potential cardiovascular outcomes.
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Hipertensión/etiología , Obesidad/complicaciones , Adulto , Enfermedades Cardiovasculares/etiología , Femenino , Humanos , Hipertensión/complicaciones , Corea (Geográfico)/epidemiología , Masculino , Metabolismo/fisiología , Persona de Mediana Edad , Fenotipo , Factores de RiesgoRESUMEN
BACKGROUND: We aimed to investigate the mortality rate (MR), causes of death and standardized mortality ratio (SMR) in Korean type 2 diabetic patients from 2002 to 2013 using data from the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC). METHODS: From this NHIS-NSC, we identified 29,807 type 2 diabetic subjects from 2002 to 2004. Type 2 diabetes was defined as a current medication history of anti-diabetic drugs and the presence of International Classification of Diseases (ICD)-10 codes (E11-E14) as diagnosis. Specific causes of death were recorded according to ICD-10 codes as the following: diabetes, malignant neoplasm, disease of the circulatory system, and other causes. RESULTS: A total of 7103 (23.8 %) deaths were recorded. The MR tended to increase with age. In particular, the ratio of MR for men versus women was the highest in their 40s-50s. The overall SMR was 2.32 and the SMRs attenuated with increasing age. The causes of death ascribed to diabetes, malignant neoplasm, ischemic heart disease, cerebrovascular disease, and other causes were 22.0, 24.8, 6.2, 11.2 and 31.3 %, respectively. The SMRs according to each cause of death were 9.73, 1.76, 2.60, 2.04 and 1.89, respectively. CONCLUSIONS: The MRs among type 2 diabetic subjects increased with age, and diabetic men exhibited a higher mortality risk than diabetic women in Korea. Subjects with type 2 diabetes exhibited an excess mortality when compared with the general population. Approximately 78.0 % of the diabetes-related deaths was not ascribed to diabetes, and malignant neoplasm was the most common cause of death among those not recorded as diabetes.
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Trastornos Cerebrovasculares/mortalidad , Diabetes Mellitus Tipo 2/mortalidad , Isquemia Miocárdica/mortalidad , Neoplasias/mortalidad , Adulto , Distribución por Edad , Factores de Edad , Anciano , Anciano de 80 o más Años , Causas de Muerte , Trastornos Cerebrovasculares/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Encuestas Epidemiológicas , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/diagnóstico , Neoplasias/diagnóstico , Pronóstico , Modelos de Riesgos Proporcionales , Sistema de Registros , República de Corea/epidemiología , Medición de Riesgo , Factores de Riesgo , Distribución por Sexo , Factores Sexuales , Factores de TiempoRESUMEN
Obesity has become an important risk factor for chronic kidney disease (CKD). The metabolically healthy obese (MHO) phenotype refers to obese individuals with a favorable metabolic profile. However, its prognostic value remains controversial and may depend on the health outcome being investigated. To assess this, we examined the risk of MHO phenotype with incident CKD in a Korean population of 41,194 people without CKD. Individuals were stratified by body mass index (cutoff value, 25.0 kg/m(2)) and metabolic health state (assessed using Adult Treatment Panel-III criteria). Incident CKD was defined as a glomerular filtration rate of <60 ml/min per 1.73 m(2) calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Over the median follow-up period of 38.7 months, 356 of the individuals developed incident CKD. Compared with the metabolically healthy nonobese (MHNO) group, the MHO group showed increased risk of incident CKD with a multivariate-adjusted hazard ratio of 1.38 (95% CI, 1.01-1.87). Nonobese but metabolically unhealthy individuals were at an increased risk of incident CKD (multivariate-adjusted hazard ratio, 1.37 (95% CI, 1.02-1.93)) than the MHNO group. Metabolically unhealthy obese individuals were at the highest risk of incident CKD. Thus, a healthy metabolic profile does not protect obese adults from incident CKD. Hence, it is important to consider metabolic health along with obesity when evaluating CKD risk.
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Obesidad Metabólica Benigna/epidemiología , Insuficiencia Renal Crónica/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Distribución de Chi-Cuadrado , Femenino , Tasa de Filtración Glomerular , Humanos , Incidencia , Estimación de Kaplan-Meier , Riñón/fisiopatología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Modelos Biológicos , Análisis Multivariante , Obesidad Metabólica Benigna/diagnóstico , Obesidad Metabólica Benigna/fisiopatología , Fenotipo , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/fisiopatología , República de Corea/epidemiología , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Although recent animal studies have suggested that angiopoietin-like protein 2 (ANGPTL2), a novel inflammatory adipokine, is likely to be involved in the pathogenesis of atherosclerosis, in rodents, little is known regarding whether serum ANGPTL2 level is also associated with atherosclerosis in humans, especially in patients with type 2 diabetes. The aim of this study was to investigate whether serum ANGPTL2 concentration is associated with atherosclerosis by measuring carotid intima-media thickness (IMT) in subjects with type 2 diabetes without previous history of cardiovascular diseases. In addition, we examined the clinical and biochemical variables associated with serum ANGPLT2 concentration. METHODS: We measured the circulating ANGPTL2 level in 166 subjects (92 men and 74 women; mean age of 60.0 years) with type 2 diabetes. Measurements of carotid IMT were performed in all subjects. RESULTS: Serum ANGPTL2 concentration was positively correlated with carotid IMT (r = 0.220, p = 0.004). In multiple linear regression, serum ANGPTL2 concentration was independently associated with increased carotid IMT along with older age, male gender, and higher systolic blood pressure. Higher levels of hemoglobin A1c and high-sensitivity C-reactive protein were significantly associated with elevated serum ANGPTL2 concentration in subjects with type 2 diabetes. CONCLUSIONS: Serum ANGPTL2 concentration was significantly and positively associated with carotid atherosclerosis in patients with type 2 diabetes, suggesting that ANGPTL2 may be important in the atherosclerosis in humans.
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Angiopoyetinas/sangre , Aterosclerosis/sangre , Aterosclerosis/diagnóstico , Grosor Intima-Media Carotídeo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Adulto , Anciano , Proteína 2 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND: Vaspin is an adipocytokine that was recently identified in the visceral adipose tissue of diabetic rats and has anti-diabetic and anti-atherogenic effects. We hypothesized that vaspin prevents inflammatory cytokine-induced nuclear factor-kappa B (NF-κB) activation by activating AMP-activated protein kinase (AMPK) in vascular endothelial cells. METHODS: We examined the effects of vaspin on NF-κB activation and the expression of the NF-κB-mediated genes intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and monocyte chemoattractant protein-1 (MCP-1). Human aortic endothelial cells (HAECS) were used. Tumor necrosis factor alpha (TNFα) was used as a representative proinflammatory cytokine. RESULTS: Treatment with vaspin significantly increased the phosphorylation of AMPK and acetyl-CoA carboxylase, the down-stream target of AMPK. Furthermore, treatment with vaspin significantly decreased TNFα-induced activation of NF-κB, as well as the expression of the adhesion molecules ICAM-1, VCAM-1, E-selectin, and MCP-1. These effects were abolished following transfection of AMPKα1-specific small interfering RNA. In an adhesion assay using THP-1 cells, vaspin reduced TNFα-induced adhesion of monocytes to HAECS in an AMPK-dependent manner. CONCLUSIONS: Vaspin might attenuate the cytokine-induced expression of adhesion molecule genes by inhibiting NF-κB following AMPK activation.
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Proteínas Quinasas Activadas por AMP/metabolismo , Moléculas de Adhesión Celular/biosíntesis , Citocinas/farmacología , Células Endoteliales/metabolismo , FN-kappa B/metabolismo , Serpinas/farmacología , Moléculas de Adhesión Celular/antagonistas & inhibidores , Células Cultivadas , Citocinas/antagonistas & inhibidores , Células Endoteliales/efectos de los fármacos , Humanos , FN-kappa B/antagonistas & inhibidoresRESUMEN
Plant-specific transcription factors (TFs) are responsible for regulating the genes involved in the development of plant-specific organs and response systems for adaptation to terrestrial environments. This includes the development of efficient water transport systems, efficient reproductive organs, and the ability to withstand the effects of terrestrial factors, such as UV radiation, temperature fluctuations, and soil-related stress factors, and evolutionary advantages over land predators. In rice and Arabidopsis, INDETERMINATE DOMAIN (IDD) TFs are plant-specific TFs with crucial functions, such as development, reproduction, and stress response. However, in tomatoes, IDD TFs remain uncharacterized. Here, we examined the presence, distribution, structure, characteristics, and expression patterns of SlIDDs. Database searches, multiple alignments, and motif alignments suggested that 24 TFs were related to Arabidopsis IDDs. 18 IDDs had two characteristic C2H2 domains and two C2HC domains in their coding regions. Expression analyses suggest that some IDDs exhibit multi-stress responsive properties and can respond to specific stress conditions, while others can respond to multiple stress conditions in shoots and roots, either in a tissue-specific or universal manner. Moreover, co-expression database analyses suggested potential interaction partners within IDD family and other proteins. This study functionally characterized SlIDDs, which can be studied using molecular and bioinformatics methods for crop improvement.
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Arabidopsis , Solanum lycopersicum , Solanum lycopersicum/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Plantas/metabolismo , Regulación de la Expresión Génica de las Plantas , FilogeniaRESUMEN
We have investigated radiation-sensitive expressed genes (EGs), their signal pathways, and the effects of ionizing radiation in the thymus of ICR and AKR/J mice. Whole-body and relative thymus weights were taken and microarray analyses were done on the thymuses of high-dose-rate (HDR, (137) Cs, 0.8 Gy/min, a single dose of 4.5 Gy) and low-dose-rate (LDR, (137) Cs, 0.7 mGy/h, a cumulative dose of 1.7 Gy) irradiated ICR and AKR/J mice. Gene expression patterns were validated by quantitative polymerase chain reaction (qPCR). The effect of ionizing radiation on thymus cell apoptosis was measured terminal deoxynucleotidyl-transferase-mediated dUTP-end labeling (TUNEL). LDR-irradiation increased the mean whole-body weight, but decreased the relative thymus weight of AKR/J mice. Radiation-sensitive EGs were found by comparing HDR- and LDR-irradiated ICR and AKR/J mice. qPCR analysis showed that 12 EGs had dose and dose-rate dependent expression patterns. Gene-network analysis indicated that Ighg, Igh-VJ558, Defb6, Reg3g, and Saa2 may be involved in the immune response, leukocyte migration, and apoptosis. Our data suggest that expression of the HDR (Glut1, Glut4, and PKLR) and LDR radiation-response genes (Ighg and Igh-VJ558) can be dose or dose-rate dependent. There was an increased number of apoptotic cells in HDR-irradiated ICR mice and LDR-irradiated AKR/J mice. Thus, changes of the mean whole-body weight and relative thymus weight, EGs, signal pathways, and the effects of ionizing radiation on the thymus of ICR and AKR/J mice are described.
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Radiación Ionizante , Timo/efectos de la radiación , Animales , Apoptosis/efectos de la radiación , Peso Corporal/efectos de la radiación , Femenino , Regulación de la Expresión Génica/efectos de la radiación , Redes Reguladoras de Genes , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos ICRRESUMEN
AKR/J mice carrying leukemia viral inserts develop thymic lymphoma. Recently, we demonstrated that the incidence of thymic lymphoma was decreased when these mice were raised in a low-dose-rate γ-irradiation facility. In contrast, mice irradiated at a high-dose rate developed severe thymic lymphoma and died much earlier. To understand the genetic changes occurred by low- versus high-dose-rate γ-irradiation whole genome microarray was performed. Both groups of mice demonstrated up-regulation of Ifng, Igbp1, and IL7 in their thymuses, however, mice exposed to high-dose-rate γ-irradiation exhibited marked down-regulation of Sp3, Il15, Traf6, IL2ra, Pik3r1, and Hells. In contrast, low-dose-rate irradiated mice demonstrated up-regulation of Il15 and Jag2. These gene expression profiles imply the impaired immune signaling pathways by high-dose-rate γ-irradiation while the facilitation of anti-tumor immune responses by low-dose-rate γ-irradiation. Therefore, our data delineate common and distinct immune-associated pathways downstream of low- versus high-dose-rate irradiation in the process of cancer progression in AKR/J mice.
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Rayos gamma , Genes Relacionados con las Neoplasias/efectos de la radiación , Linfoma/genética , Neoplasias Inducidas por Radiación/genética , Timo/efectos de la radiación , Neoplasias del Timo/genética , Animales , Apoptosis/efectos de la radiación , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Relación Dosis-Respuesta en la Radiación , Femenino , Rayos gamma/efectos adversos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Estimación de Kaplan-Meier , Linfoma/inmunología , Ratones , Ratones Endogámicos AKR , Ratones Transgénicos , Neoplasias Inducidas por Radiación/inmunología , Análisis de Secuencia por Matrices de Oligonucleótidos , Timo/inmunología , Neoplasias del Timo/inmunología , Irradiación Corporal TotalRESUMEN
While a high-dose of ionizing radiation is generally harmful and causes damage to living organisms, a low-dose of radiation has been shown to be beneficial in a variety of animal models. To understand the basis for the effect of low-dose radiation in vivo, we examined the cellular and immunological changes evoked in mice exposed to low-dose radiation at very low (0.7mGy/h) and low (3.95mGy/h) dose rate for the total dose of 0.2 and 2Gy, respectively. Mice exposed to low-dose radiation, either at very low- or low-dose rate, demonstrated normal range of body weight and complete blood counts. Likewise, the number and percentage of peripheral lymphocyte populations, CD4(+) T, CD8(+) T, B, or NK cells, stayed unchanged following irradiation. Nonetheless, the sera from these mice exhibited elevated levels of IL-3, IL-4, leptin, MCP-1, MCP-5, MIP-1alpha, thrombopoietin, and VEGF along with slight reduction of IL-12p70, IL-13, IL-17, and IFN-gamma. This pattern of cytokine release suggests the stimulation of innate immunity facilitating myeloid differentiation and activation while suppressing pro-inflammatory responses and promoting differentiation of naïve T cells into T-helper 2, not T-helper 1, types. Collectively, our data highlight the subtle changes of cytokine milieu by chronic low-dose gamma-radiation, which may be associated with the functional benefits observed in various experimental models.
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Citocinas/metabolismo , Rayos gamma , Inmunidad/efectos de la radiación , Animales , Células Sanguíneas/inmunología , Células Sanguíneas/efectos de la radiación , Peso Corporal/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Femenino , Linfocitos/inmunología , Linfocitos/efectos de la radiación , Ratones , Ratones Endogámicos C57BLRESUMEN
This study evaluated the effects of low dose radiation on spermatogenic cells using the morphological characteristics of sperm in the caudal epididymis of ICR mice. In this study, six abnormal sperm shapes (amorphous heads, blunt hooks, excessive hooks, two heads and tails, folded tails and short tails) were observed at eight days after gamma-irradiation ((137)Cs, 0, 0.2, 0.5, 1, 2 or 4 Gy) with both a high-dose-rate (0.8 Gy/min) and a low-dose-rate (0.7 mGy/hr). Fewer abnormal forms of sperm were observed in low-dose-rate irradiated mice than in mice that received a high-dose-rate irradiation (P = 0.002). The ratio of the dose rate effect among low-dose-rate irradiated mice to high-dose-rate irradiated mice was approximately 0.6. In addition, sperm with blunt hooks and two heads and tails significantly increased in number after irradiation, potentially providing an endpoint marker for estimating the effects of radiation. This study suggests that low-dose-rate (0.7 mGy/hr) radiation does not damage stem spermatogonia and probably stimulates repair in damaged spermatogonial stem cells in male mice.
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Epidídimo/anomalías , Rayos gamma , Espermatozoides/anomalías , Animales , Relación Dosis-Respuesta en la Radiación , Epidídimo/efectos de la radiación , Masculino , Ratones , Espermatozoides/efectos de la radiaciónRESUMEN
We aimed to investigate the clinical factors affecting the therapeutic effectiveness of the sodium-glucose cotransporter-2 inhibitor empagliflozin in patients with type 2 diabetes mellitus (T2DM). We reviewed the medical records of 374 T2DM patients aged between 20 and 75 years who were prescribed empagliflozin 10 mg or 25 mg as add-on therapy for more than 90 consecutive days. Changes in hemoglobin A1c (HbA1c) from baseline levels and the reduction in body weights of the study participants were assessed. We found that younger patients (≤ 50 years), patients with the highest levels of HbA1c (>9%) at baseline, patients with an estimated glomerular filtration rate (eGFR) of >90 mL/min/1.73 m2, and patients with a shorter duration of T2DM (< 10 years) were more likely to exhibit a better glycemic response. Multivariate linear regression analysis revealed that a shorter duration of T2DM, higher baseline levels of HbA1c, and higher eGFR were positively associated with HbA1c reduction. Higher BMI and lower HbA1c levels were predictors of a more significant reduction in body weight among patients taking empagliflozin. The glucose-lowering effect of empagliflozin was more evident in T2DM patients with higher baseline HbA1c levels, better renal function, and shorter duration of T2DM.
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Compuestos de Bencidrilo/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Adulto , Factores de Edad , Anciano , Índice de Masa Corporal , Peso Corporal , Diabetes Mellitus Tipo 2/patología , Femenino , Tasa de Filtración Glomerular , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
The aim of this study was to investigate the association of nonalcoholic fatty liver disease (NAFLD) with diabetes and the impact of waist circumference (WC) changes in subjects with prediabetes. We enrolled 6240 subjects with prediabetes who underwent health check-ups in 2007 and revisited our hospital at least once for a follow-up examination between 2008 and 2013. Subjects were stratified by WC changes into three groups. The relative risks (RRs) for diabetes according to the NAFLD status and WC change were evaluated. The prevalence of NAFLD was 45.4% (2830/6240). During follow-up, the incidence of diabetes was 8.1% (505/6240). Subjects with NAFLD had a higher incidence of diabetes and the adjusted RRs were 1.81 (95% confidence interval [CI], 1.47 to 2.21), after adjustment for potential confounding factors. The adjusted RRs were related to WC changes. The adjusted RRs for diabetes according to tertiles of WC change (first, second, and third tertile) were 1.64 (95% CI, 1.08 to 2.49), 1.73 (95% CI, 1.28 to 2.34), and 2.04 (95% CI, 1.42 to 2.93), respectively. NAFLD has significantly increased risk of incident diabetes in subjects with prediabetes. The risk for diabetes is gradually increased with tertiles of WC change.
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Diabetes Mellitus/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Estado Prediabético/metabolismo , Adulto , Índice de Masa Corporal , Diabetes Mellitus/metabolismo , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Estado Prediabético/epidemiología , Prevalencia , Factores de Riesgo , Circunferencia de la Cintura/fisiologíaRESUMEN
BACKGROUND: Based on reported results of three large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), we aimed to investigate the overall effect of GLP-1 RAs on major adverse cardiovascular events (MACEs) and to identify subpopulations exhibiting the greatest cardiovascular (CV) benefit. METHODS: Three CVOTs reporting effects of long-acting GLP-1 RAs were included: LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide once weekly). In all studies, the primary endpoint was three-point MACE, comprising CV death, non-fatal myocardial infarction, and non-fatal stroke. Overall effect estimates were calculated as hazard ratios and 95% confidence intervals (CIs) using the random-effects model; subgroup analyses reported in the original studies were similarly analyzed. RESULTS: Overall, statistically significant risk reductions in MACE and CV death were observed. Subgroup analysis indicated a significant racial difference with respect to CV benefit (P for interaction <0.001), and more substantial risk reductions were observed in subjects of African origin (relative risk [RR], 0.78; 95% CI, 0.60 to 0.99) and in Asians (RR, 0.35; 95% CI, 0.09 to 1.32). However, post hoc analysis (Bonferroni method) revealed that only Asians exhibited a significantly greater CV benefit from treatment, compared with white subjects (P<0.0001). CONCLUSION: Long-acting GLP-1 RAs reduced risks of MACE and CV deaths in high-risk patients with type 2 diabetes mellitus. Our findings of a particularly effective reduction in CV events with GLP-1 RA in Asian populations merits further exploration and dedicated trials in specific populations.
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Pueblo Asiatico , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/etnología , Exenatida/farmacología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Péptidos Similares al Glucagón/farmacología , Hipoglucemiantes/farmacología , Liraglutida/farmacología , Anciano , Población Negra , Enfermedades Cardiovasculares/mortalidad , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Exenatida/efectos adversos , Exenatida/uso terapéutico , Femenino , Péptidos Similares al Glucagón/efectos adversos , Péptidos Similares al Glucagón/uso terapéutico , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Liraglutida/efectos adversos , Liraglutida/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Resultado del Tratamiento , Población BlancaRESUMEN
AIMS: We hypothesized that transitions in metabolic health status and obesity affect the cardiovascular (CV) risk and mortality in population with metabolically healthy obesity (MHO). METHODS: This study enrolled 514,866 participants from the Korean National Health Insurance Service-National Sample Cohort. Changes in metabolic health status and obesity from the baseline examination in 2009-2010 to the next biannual health examination in 2011-2012 were determined. Study participants were categorized into four groups: (1) metabolically healthy, non-obese (MHNO), defined as BMIâ¯<â¯25â¯kg/m2 and no or one metabolic risk factor; (2) metabolically unhealthy, non-obese (MUNO), defined as BMIâ¯<â¯25â¯kg/m2 and ≥2 metabolic risk factors; (3) MHO, defined as BMIâ¯≥â¯25â¯kg/m2 and no or one metabolic risk factor; and (4) metabolically unhealthy, obese (MUO), defined as BMIâ¯≥â¯25â¯kg/m2 and ≥2 metabolic risk factors. The study subjects were followed-up from 2011 to 2015 for cardiovascular events, CV mortality and all-cause mortality. RESULTS: Among the subjects classified as MHO in 2009-2010, 45.6% were classified as MHO in 2011-2012, whereas 11.6%, 6.0%, and 36.8% were classified as MHNO, MUNO, and MUO, respectively. The risk of CV events was higher in baseline MHO group than MHNO group (HR, 1.14; 95% CI, 1.05-1.24). However, in baseline MHO group, CV mortality was not increased (HR, 0.85; 95% CI, 0.69-1.06) and all-cause mortality was even lower than that of MHNO group (HR, 0.86; 95% CI, 0.79-0.93). Compared to the stable MHO subjects, the risk of CV events was significantly higher in the subjects who transitioned from MHO to MUO with multivariate-adjusted HRs of 1.24 (95% CI: 1.00-1.54). When weight loss and progression to metabolic unhealthy phenotype occur simultaneously in the MHO population, the all-cause mortality was increased compared to the stable MHO group (HR, 1.96; 95% CI, 1.45-2.65). CONCLUSIONS: Subjects with MHO constitute a heterogeneous group. Our finding supports that evolving to a metabolically unhealthy status and losing weight simultaneously is associated with the adverse outcome in the MHO population.