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1.
J Transl Med ; 22(1): 855, 2024 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-39313824

RESUMEN

BACKGROUND: Several abdominal obesity indices including waist circumference (WC), waist-hip ratio (WHR), visceral adiposity index (VAI), lipid accumulation product (LAP), and Chinese visceral adiposity index (CVAI) were considered effective and useful predictive markers for cardiovascular disease (CVD) in general populations or diabetic populations. However, studies investigating the associations between these indices among postmenopausal women are limited. Our study aimed to investigate the associations of the five indices with incident CVD and compare the predictive performance of CVAI with other abdominal obesity indices among postmenopausal women. METHODS: A total of 1252 postmenopausal women without CVD at baseline were analyzed in our investigation based on a 10-year follow-up prospective cohort study. Link of each abdominal obesity index with CVD were assessed by the Cox regression analysis and the Kaplan-Meier curve. The receiver operating characteristic (ROC) curves were drawn to compare the predictive ability for CVD. RESULTS: During the median follow-up of 120.53 months, 121 participants newly developed CVD. Compared to quartile 1 of LAP and CVAI, quartile 4 had increased risk to develop CVD after fully adjusted among postmenopausal women. When WC, VAI and CVAI considered as continuous variables, significant increased hazard ratios (HRs) for developing CVD were observed. The areas under the curve (AUC) of CVAI (0.632) was greatly higher than other indices (WC: 0.580, WHR: 0.538, LAP: 0.573, VAI: 0.540 respectively). CONCLUSIONS: This study suggested that the abdominal obesity indices were associated with the risk of CVD excluded WHR and highlighted that CVAI might be the most valuable abdominal obesity indicator for identifying the high risk of CVD in Chinese postmenopausal women.


Asunto(s)
Adiposidad , Enfermedades Cardiovasculares , Grasa Intraabdominal , Obesidad Abdominal , Posmenopausia , Curva ROC , Humanos , Femenino , Posmenopausia/fisiología , Obesidad Abdominal/complicaciones , Enfermedades Cardiovasculares/epidemiología , Persona de Mediana Edad , Pueblo Asiatico , Modelos de Riesgos Proporcionales , Relación Cintura-Cadera , Circunferencia de la Cintura , China/epidemiología , Factores de Riesgo , Estimación de Kaplan-Meier , Anciano , Estudios Prospectivos , Pueblos del Este de Asia
2.
Cardiovasc Diabetol ; 23(1): 39, 2024 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-38245734

RESUMEN

BACKGROUND: The triglyceride-glucose (TyG) index has been linked to the onset, progression, and prognosis of cardiovascular disease (CVD) in middle-aged and elderly individuals. Nevertheless, the relationship between the TyG index and impaired cardiovascular fitness (CVF) remains unexplored in non-diabetic young population. METHODS: We used data from the National Health and Nutrition Examination Survey (NHANES) study (1999-2004) to conduct a cross-sectional study of 3364 participants who completed an examination of CVF. Impaired CVF was defined as low and moderate CVF levels determined by estimated maximal oxygen consumption (Vo2max), based on sex- and age-specific criteria. The TyG index was calculated by [Formula: see text]. RESULTS: The age (median with interquartile range) of the study population was 28 (19-37) years, and the TyG index (median ± standard deviation) was 8.36 ± 0.52. A significant association between the TyG index and impaired CVF was found in multivariable logistical regression analysis (per 1-unit increase in the TyG index: OR, 1.46; 95% Cl 1.13-1.90). A dose‒response relationship between the TyG index and impaired CVF was presented by restricted cubic splines (RCS). A significant interaction (p = 0.027) between sex and the TyG index for impaired CVF was found in the population aged < 20 years. CONCLUSIONS: In non-diabetic young population, individuals with higher TyG index values are at an increased likelihood of encountering impaired CVF. Furthermore, sex may exert an impact on CVF, as males tend to be more susceptible to impaired CVF under comparable TyG index conditions.


Asunto(s)
Enfermedades Cardiovasculares , Sistema Cardiovascular , Anciano , Masculino , Persona de Mediana Edad , Humanos , Encuestas Nutricionales , Estudios Transversales , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Glucosa , Triglicéridos , Glucemia , Biomarcadores , Factores de Riesgo
3.
Cardiovasc Diabetol ; 23(1): 182, 2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38811950

RESUMEN

BACKGROUND: Left ventricular global longitudinal strain (GLS) holds greater diagnostic and prognostic value than left ventricular ejection fraction (LVEF) in the heart failure (HF) patients. The triglyceride-glucose (TyG) index serves as a reliable surrogate for insulin resistance (IR) and is strongly associated with several adverse cardiovascular events. However, there remains a research gap concerning the correlation between the TyG index and GLS among patients with chronic heart failure (CHF). METHOD: 427 CHF patients were included in the final analysis. Patient demographic information, along with laboratory tests such as blood glucose, lipids profiles, and echocardiographic data were collected. The TyG index was calculated as Ln [fasting triglyceride (TG) (mg/dL) × fasting plasma glucose (FPG) (mg/dL)/2]. RESULTS: Among CHF patients, GLS was notably lower in the higher TyG index group compared to the lower TyG index group. Following adjustment for confounding factors, GLS demonstrated gradual decrease with increasing TyG index, regardless of the LVEF level and CHF classification. CONCLUSION: Elevated TyG index may be independently associated with more severe clinical left ventricular dysfunction in patients with CHF.


Asunto(s)
Biomarcadores , Glucemia , Insuficiencia Cardíaca , Triglicéridos , Disfunción Ventricular Izquierda , Función Ventricular Izquierda , Humanos , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/diagnóstico , Masculino , Femenino , Estudios Transversales , Triglicéridos/sangre , Persona de Mediana Edad , Anciano , Glucemia/metabolismo , Enfermedad Crónica , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/diagnóstico , Biomarcadores/sangre , Volumen Sistólico , Valor Predictivo de las Pruebas , Resistencia a la Insulina , Pronóstico , Tensión Longitudinal Global
4.
BMC Cancer ; 24(1): 1214, 2024 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-39350055

RESUMEN

BACKGROUND: Pre-clinical data suggests a potential synergistic effect of eribulin and platinum. However, clinical data on the combination for metastatic breast cancer (mBC) is lacking. We evaluated the efficacy and safety of eribulin plus carboplatin (ErCb) in patients with mBC. PATIENTS AND METHODS: This multicenter, real-world cohort study included patients with pre-treated metastatic triple negative breast cancer (TNBC) or endocrine-refractory hormone receptor (HR) positive, HER2-negative mBC who received ErCb. Eribulin (1.4 mg/m2) and carboplatin (target AUC = 2) were administered intravenously on day 1 and 8 of 21-day cycle. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. RESULTS: From March 2022 to December 2023, a cohort of 37 patients were recruited to the study. Among them, 22 patients have TNBC and 15 have HR + HER2 - mBC. Of the 22 patients with TNBC, 8 had an initial diagnosis of the HR + HER2 - subtype. The median treatment was 6 cycles (range, 2 - 8 cycles). In the full cohort, TNBC, and HR + HER2 - subgroup, the ORR were 51.4%, 54.5% and 46.7%, the DCR were 81.1%, 81.8% and 80%, and the median PFS were 5 months, 5 months, and 5.2 months, respectively. The median OS was 12.7 months in the entire cohort and 12.8 months in TNBC subgroup. The most common grade 3/4 hematological AEs were neutropenia (37.8%), leukopenia (35.1%), febrile neutropenia (10.8%), thrombocytopenia (5.4%), and anemia (2.7%). No grade 3/4 non-hematological AEs were observed. CONCLUSION: ErCb demonstrated favorable efficacy and tolerability in patients with heavily pre-treated mBC, especially TNBC. The findings of the current study warrant further investigation of the application of this combination in earlier lines of mBC treatment.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatino , Furanos , Cetonas , Receptor ErbB-2 , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Persona de Mediana Edad , Cetonas/uso terapéutico , Cetonas/administración & dosificación , Cetonas/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Furanos/uso terapéutico , Furanos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Adulto , Receptor ErbB-2/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/mortalidad , Estudios de Cohortes , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Metástasis de la Neoplasia , Policétidos Poliéteres
5.
Diabetes Obes Metab ; 26(7): 2673-2683, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38558498

RESUMEN

AIM: To investigate the association between cardiovascular health metrics defined by Life's Essential 8 (LE8) scores and vascular complications among individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: This prospective study included 11 033 participants with T2D, all devoid of macrovascular diseases (including cardiovascular and peripheral artery disease) and microvascular complications (e.g. diabetic retinopathy, neuropathy and nephropathy) at baseline from the UK Biobank. The LE8 score comprised eight metrics: smoking, body mass index, physical activity, non-high-density lipoprotein cholesterol, blood pressure, glycated haemoglobin, diet and sleep duration. Cox proportional hazards models were established to assess the associations of LE8 scores with incident macrovascular and microvascular complications. RESULTS: During a median follow-up of 12.1 years, we identified 1975 cases of incident macrovascular diseases and 1797 cases of incident microvascular complications. After adjusting for potential confounders, each 10-point increase in the LE8 score was associated with an 18% lower risk of macrovascular diseases and a 15% lower risk of microvascular complications. Comparing individuals in the highest and lowest quartiles of LE8 scores revealed hazard ratios of 0.55 (95% confidence interval 0.47-0.62) for incident macrovascular diseases, and 0.61 (95% confidence interval 0.53-0.70) for incident microvascular complications. This association remained robust across a series of sensitivity analyses and nearly all subgroups. CONCLUSION: Higher LE8 scores were associated with a lower risk of incident macrovascular and microvascular complications among individuals with T2D. These findings underscore the significance of adopting fundamental strategies to maintain optimal cardiovascular health and curtail the risk of developing diabetic vascular complications.


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Angiopatías Diabéticas , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Masculino , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/etiología , Reino Unido/epidemiología , Anciano , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Adulto , Factores de Riesgo , Índice de Masa Corporal , Fumar/efectos adversos , Fumar/epidemiología , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Ejercicio Físico , Estudios de Seguimiento , Presión Sanguínea , Incidencia
6.
Clin Exp Nephrol ; 28(4): 325-336, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38151608

RESUMEN

BACKGROUND: The AHA has recently introduced a novel metric, Life's Essential 8, to assess cardiovascular health (CVH). Nevertheless, the association between varying levels of LE8 and the propensity for CKD is still unclear from a large prospective cohort. Our objective is to meticulously examine the relationship between LE8 and its associated susceptibilities to CKD. METHODS: A total of 251,825 participants free of CKD from the UK Biobank were included. Cardiovascular health was scored using LE8 and categorized as low, moderate, and high. Cox proportional hazard models were employed to evaluate the associations of LE8 scores with new-onset CKD. The genetic risk score for CKD was calculated by a weighted method. RESULTS: Over a median follow-up of 12.8 years, we meticulously documented 10,124 incident cases of CKD. Remarkably, an increased LE8 score correlated with a significant reduction of risk in new-onset CKD (high LE8 score vs. low LE8 score: HR = 0.300, 95% CI 0.270-0.330, p < 0.001; median LE8 score vs. low LE8 score: HR = 0.531, 95% CI 0.487-0.580, p < 0.001). This strong LE8-CKD association remained robust in extensive subgroup assessments and sensitivity analysis. Additionally, these noteworthy associations between LE8 scores and CKD remained unaffected by genetic predispositions to CKD. CONCLUSIONS: An elevated degree of CVH, as delineated by the discerning metric LE8, exhibited a pronounced and statistically significant correlation with a marked reduction in the likelihood of CKD occurrence.


Asunto(s)
Enfermedades Cardiovasculares , Insuficiencia Renal Crónica , Humanos , Estados Unidos , Biobanco del Reino Unido , Bancos de Muestras Biológicas , Estudios Prospectivos , Predisposición Genética a la Enfermedad , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/genética , Factores de Riesgo
7.
Cardiovasc Diabetol ; 22(1): 230, 2023 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-37649025

RESUMEN

BACKGROUND: The triglyceride-glucose (TyG) index has been evaluated as a reliable surrogate for insulin resistance (IR) and has been proven to be a predictor of poor outcomes in patients with cardiovascular diseases. However, data are lacking on the relationship of the TyG index with prognosis in nondiabetic patients who underwent coronary artery bypass grafting (CABG). Thus, the purpose of our current study was to investigate the potential value of the TyG index as a prognostic indicator in patients without diabetes mellitus (DM) after CABG. METHODS: This multicenter, retrospective cohort study involving 830 nondiabetic patients after CABG from 3 tertiary public hospitals from 2014 to 2018. Kaplan-Meier survival curve analysis was conducted followed by the log-rank test. Cox proportional hazards regression models were used to explore the association between the TyG index and major adverse cardiovascular events (MACEs). The incremental predictive power of the TyG index was evaluated with C-statistics, continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: An incrementally higher TyG index was associated with an increasingly higher cumulative incidence of MACEs (log-rank test, p < 0.001). The hazard ratio (95% CI) of MACEs was 2.22 (1.46-3.38) in tertile 3 of the TyG index and 1.38 (1.18-1.62) per SD increase in the TyG index. The addition of the TyG index yielded a significant improvement in the global performance of the baseline model [C-statistic increased from 0.656 to 0.680, p < 0.001; continuous NRI (95% CI) 0.269 (0.100-0.438), p = 0.002; IDI (95% CI) 0.014 (0.003-0.025), p = 0.014]. CONCLUSIONS: The TyG index may be an independent factor for predicting adverse cardiovascular events in nondiabetic patients after CABG.


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus , Humanos , Estudios Retrospectivos , Puente de Arteria Coronaria/efectos adversos , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/etiología , Glucosa , Triglicéridos
8.
Cardiovasc Diabetol ; 22(1): 103, 2023 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-37131230

RESUMEN

BACKGROUND: Elevated serum uric acid (SUA) is regarded as a risk factor for the development of cardiovascular diseases. Triglyceride-glucose (TyG) index, a novel surrogate for insulin resistance (IR), has been proven to be an independent predictor for adverse cardiac events. However, no study has specifically focused on the interaction between the two metabolic risk factors. Whether combining the TyG index and SUA could achieve more accurate prognostic prediction in patients undergoing coronary artery bypass grafting (CABG) remains unknown. METHODS: This was a multicenter, retrospective cohort study. A total of 1225 patients who underwent CABG were included in the final analysis. The patients were grouped based on the cut-off value of the TyG index and the sex-specific criteria of hyperuricemia (HUA). Cox regression analysis was conducted. The interaction between the TyG index and SUA was estimated using relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). The improvement of model performance yielded by the inclusion of the TyG index and SUA was examined by C-statistics, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). The goodness-of-fit of models was evaluated using the Akaike information criterion (AIC), Bayesian information criterion (BIC) and χ2 likelihood ratio test. RESULTS: During follow-up, 263 patients developed major adverse cardiovascular events (MACE). The independent and joint associations of the TyG index and SUA with adverse events were significant. Patients with higher TyG index and HUA were at higher risk of MACE (Kaplan-Meier analysis: log-rank P < 0.001; Cox regression: HR = 4.10; 95% CI 2.80-6.00, P < 0.001). A significant synergistic interaction was found between the TyG index and SUA [RERI (95% CI): 1.83 (0.32-3.34), P = 0.017; AP (95% CI): 0.41 (0.17-0.66), P = 0.001; SI (95% CI): 2.13 (1.13-4.00), P = 0.019]. The addition of the TyG index and SUA yielded a significant improvement in prognostic prediction and model fit [change in C-statistic: 0.038, P < 0.001; continuous NRI (95% CI): 0.336 (0.201-0.471), P < 0.001; IDI (95% CI): 0.031 (0.019-0.044), P < 0.001; AIC: 3534.29; BIC: 3616.45; likelihood ratio test: P < 0.001). CONCLUSIONS: The TyG index interacts synergistically with SUA to increase the risk of MACE in patients undergoing CABG, which emphasizes the need to use both measures concurrently when assessing cardiovascular risk.


Asunto(s)
Enfermedades Cardiovasculares , Glucosa , Masculino , Femenino , Humanos , Ácido Úrico , Triglicéridos , Estudios Retrospectivos , Teorema de Bayes , Glucemia/metabolismo , Biomarcadores , Factores de Riesgo , Puente de Arteria Coronaria/efectos adversos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/etiología
9.
Diabetes Metab Res Rev ; 39(8): e3710, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37537868

RESUMEN

AIMS: We aimed to investigate the independent and combined association of the triglyceride-glucose (TyG) index and EuroSCORE II with major adverse cardiovascular event (MACE) after coronary artery bypass grafting (CABG), and examine whether the addition of the TyG index improves the predictive performance of the EuroSCORE II. MATERIALS AND METHODS: This study included 1013 patients who underwent CABG. The primary endpoint was MACE, which was defined as the composite of all-cause death, repeat coronary artery revascularisation, non-fatal myocardial infarction and non-fatal stroke. The patients were grouped by the TyG index and EuroSCORE II tertiles and the combination of these risk indicators. RESULTS: During the follow-up, 211 individuals developed MACE. Elevated levels of the TyG index and EuroSCORE II were associated with an increased risk of MACE. The hazard ratio [95% confidence interval (CI)] was 3.66 (2.34-5.73) in patients with the highest tertile of the TyG index and EuroSCORE II. Compared with the EuroSCORE II alone, combining the TyG index with EuroSCORE II achieved a better predictive performance [C-statistic increased 0.032, p < 0.001; continuous net reclassification improvement (NRI) (95% CI): 0.364 (0.215-0.514), p < 0.001; integrated discrimination improvement (IDI) (95% CI): 0.015 (0.007-0.023), p < 0.001, Akaike's information criteria (AIC) and Bayesian information criterion (BIC) decreased, and the likelihood ratio test, p < 0.001]. CONCLUSIONS: The TyG index and EuroSCORE II are independently associated with poor prognosis. Furthermore, the TyG index is an important adjunct to the EuroSCORE II for improving risk stratification and guiding early intervention among post-CABG patients.


Asunto(s)
Puente de Arteria Coronaria , Glucosa , Humanos , Triglicéridos , Teorema de Bayes , Medición de Riesgo , Puente de Arteria Coronaria/efectos adversos , Factores de Riesgo , Glucemia , Biomarcadores , Estudios Retrospectivos
10.
BMC Public Health ; 23(1): 2123, 2023 10 30.
Artículo en Inglés | MEDLINE | ID: mdl-37899473

RESUMEN

BACKGROUND: Commencing work at an early age has been linked to various risk factors for coronary heart disease (CHD), such as shift work and intensive job strain. However, the relationship between starting work too early and CHD risk remains largely unclear. We examined the association between age at job initiation and the risk of CHD. METHODS: UK Biobank participants aged 38 to 70 years without cardiovascular disease who provided data on their age at job initiation were included. The primary outcome was CHD, which was ascertained using hospital and death records. The hazard ratios (HRs) and 95% confidence interval (CIs) for the association between age at job initiation and CHD were calculated using multivariable Cox regression. RESULTS: Of the 501,971 participants, 114,418 eligible participants were included in the final analysis. The median age at job initiation was 19.0 years. During the mean follow-up of 12.6 years, 6,130 (5.4%) first CHD events occurred. We observed that age at job initiation was inversely associated with CHD (HR 0.98, 95% CI 0.97-0.99), and the association was potentially J-shaped. The HRs for the < 17-year, 17-18-year, and 19-21-year age groups were 1.29 (95%CI 1.18-1.41), 1.12 (95% CI 1.03-1.22) and 1.05 (95% CI 0.97-1.14), respectively, compared with those of the ≥ 22-year group. CONCLUSIONS: Age at job initiation was associated with incident CHD, which was independent of socioeconomic status. Participants who commenced employment before the age of 19 years exhibited a higher risk of developing CHD later in adulthood.


Asunto(s)
Bancos de Muestras Biológicas , Enfermedad Coronaria , Humanos , Adulto Joven , Adulto , Estudios de Cohortes , Enfermedad Coronaria/epidemiología , Factores de Riesgo , Reino Unido/epidemiología
12.
Angew Chem Int Ed Engl ; 56(4): 1002-1006, 2017 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-27990729

RESUMEN

A protein can be in different conformations when fulfilling its function. Yet depiction of protein structural ensembles remains difficult. Here we show that the accurate measurement of solvent paramagnetic relaxation enhancement (sPRE) in the presence of an inert paramagnetic cosolute allows the assessment of protein dynamics. Demonstrated with two multi-domain proteins, we present a method to characterize protein microsecond-millisecond dynamics based on the analysis of the sPRE. Provided with the known structures of a protein, our method uncovers an ensemble of structures that fully accounts for the observed sPRE. In conjunction with molecular dynamics simulations, our method can identify protein alternative conformation that has only been theorized before. Together, our method expands the application of sPRE beyond structural characterization of rigid proteins and complements the established PRE NMR technique.


Asunto(s)
Simulación de Dinámica Molecular , Proteínas/química , Conformación Proteica , Solventes/química
13.
J Biol Chem ; 289(8): 4723-34, 2014 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-24403073

RESUMEN

mTORC1 plays critical roles in the regulation of protein synthesis, growth, and proliferation in response to nutrients, growth factors, and energy conditions. One of the substrates of mTORC1 is 4E-BP1, whose phosphorylation by mTORC1 reverses its inhibitory action on eIF4E, resulting in the promotion of protein synthesis. Raptor in mTOR complex 1 is believed to recruit 4E-BP1, facilitating phosphorylation of 4E-BP1 by the kinase mTOR. We applied chemical cross-linking coupled with mass spectrometry analysis to gain insight into interactions between mTORC1 and 4E-BP1. Using the cross-linking reagent bis[sulfosuccinimidyl] suberate, we showed that Raptor can be cross-linked with 4E-BP1. Mass spectrometric analysis of cross-linked Raptor-4E-BP1 led to the identification of several cross-linked peptide pairs. Compilation of these peptides revealed that the most N-terminal Raptor N-terminal conserved domain (in particular residues from 89 to 180) of Raptor is the major site of interaction with 4E-BP1. On 4E-BP1, we found that cross-links with Raptor were clustered in the central region (amino acid residues 56-72) we call RCR (Raptor cross-linking region). Intramolecular cross-links of Raptor suggest the presence of two structured regions of Raptor: one in the N-terminal region and the other in the C-terminal region. In support of the idea that the Raptor N-terminal conserved domain and the 4E-BP1 central region are closely located, we found that peptides that encompass the RCR of 4E-BP1 inhibit cross-linking and interaction of 4E-BP1 with Raptor. Furthermore, mutations of residues in the RCR decrease the ability of 4E-BP1 to serve as a substrate for mTORC1 in vitro and in vivo.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Portadoras/metabolismo , Reactivos de Enlaces Cruzados/farmacología , Espectrometría de Masas/métodos , Fosfoproteínas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/química , Secuencia de Aminoácidos , Animales , Proteínas Portadoras/química , Proteínas Portadoras/genética , Secuencia Conservada , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular , Lisina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina , Datos de Secuencia Molecular , Complejos Multiproteicos/metabolismo , Mutación/genética , Péptidos/metabolismo , Fosfoproteínas/química , Fosfoproteínas/genética , Unión Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Ratas , Proteína Reguladora Asociada a mTOR , Especificidad por Sustrato/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo
14.
Biochemistry ; 53(9): 1403-9, 2014 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-24555491

RESUMEN

Bacterial periplasmic binding proteins (PBPs) are involved in the translocation of small molecules in the periplasm. To unload, the two domains of a PBP open up, allowing the ligand to exit. However, it is not clear whether there are dynamics near the binding site which can facilitate the rapid dissociation of a ligand. To visualize such dynamics, we utilized paramagnetic relaxation enhancement (PRE) NMR and introduced a rigid paramagnetic probe to a PBP, glutamine-binding protein (QBP) with its cognate ligand bound. A paramagnetic Cu(II) ion is sandwiched between an engineered di-histidine motif at a helix and an NTA capping molecule. The afforded paramagnetic probe is so rigid that PRE values calculated from a single structure of holo QBP largely agree with the observed values. The remaining PRE discrepancies, however, manifest dynamics of a loop in the opposite domain from the paramagnetic probe. This loop packs against the glutamine ligand in the holo QBP and undergoes fluctuations upon ligand dissociation, as assessed by steered molecular dynamics simulations. As such, the loop dynamics, occurring for a small population in nanosecond to microsecond time scale, may be related to the ligand dissociation process. The rigid paramagnetic probe described herein can be grafted to other protein systems for structure and dynamics studies.


Asunto(s)
Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Glutamina/química , Glutamina/metabolismo , Ligandos , Simulación de Dinámica Molecular , Resonancia Magnética Nuclear Biomolecular , Unión Proteica , Estructura Secundaria de Proteína
15.
J Biomol NMR ; 58(3): 149-54, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24510274

RESUMEN

Solvent paramagnetic relaxation enhancement (sPRE) arises from random collisions between paramagnetic cosolvent and protein of interest. The sPRE can be readily measured, affording protein structure information. However, lack of an inert cosolvent probe may yield sPRE values that are not consistent with protein structure. Here we synthesized a new sPRE probe, triethylenetetraamine hexaacetate trimethylamide gadolinium, or Gd(III)-TTHA-TMA. With a total of 10 coordination sites, this paramagnetic cosovlent eliminates an inner-sphere water molecule that can otherwise transfer relaxation to protein through exchange. With the metal ion centered, the new probe is largely spherical with a radius of 4.0 Å, permitting accurate back calculation of sPRE. The effectiveness Gd(III)-TTHA-TMA as a sPRE probe was demonstrated on three well-studied protein systems.


Asunto(s)
Ácido Edético/análogos & derivados , Gadolinio/química , Proteínas/química , Ácido Edético/química , Espectroscopía de Resonancia por Spin del Electrón/métodos , Espectroscopía de Resonancia Magnética , Resonancia Magnética Nuclear Biomolecular/métodos , Proteínas/ultraestructura , Agua/química
16.
Angew Chem Int Ed Engl ; 53(43): 11501-5, 2014 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-25131700

RESUMEN

Proteins interact with each other to fulfill their functions. The importance of weak protein-protein interactions has been increasingly recognized. However, owing to technical difficulties, ultra-weak interactions remain to be characterized. Phosphorylation can take place via a K(D)≈25 mM interaction between two bacterial enzymes. Using paramagnetic NMR spectroscopy and with the introduction of a novel Gd(III)-based probe, we determined the structure of the resulting complex to atomic resolution. The structure accounts for the mechanism of phosphoryl transfer between the two enzymes and demonstrates the physical basis for their ultra-weak interaction. Further, molecular dynamics (MD) simulations suggest that the complex has a lifetime in the micro- to millisecond regimen. Hence such interaction is termed a fleeting interaction. From mathematical modeling, we propose that an ultra-weak fleeting interaction enables rapid flux of phosphoryl signal, providing a high effective protein concentration.


Asunto(s)
Proteínas/química , Simulación de Dinámica Molecular , Resonancia Magnética Nuclear Biomolecular , Fosforilación , Transducción de Señal
17.
Respir Med ; 222: 107523, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38171404

RESUMEN

BACKGROUND AND OBJECTIVE: Patients with preserved ratio impaired spirometry (PRIsm) have higher incidence rate of cardiovascular disease (CVD). However, few studies focused on PRIsm in China. We determined the prevalence and characteristics of patients with PRIsm in Chinese population. We also aimed to investigate the significant predictive factors of CVD in PRIsm patients. METHODS: In total, 6994 subjects aged from 35 to 70 years old and free of CVD at baseline were categorized into normal (n = 3895), PRIsm (the ratio of forced expired volume in the first second (FEV1) to forced vital capacity (FVC) ≥0.7 and FEV1 <80 % predicted; n = 1997) and obstructive spirometry (FEV1:FVC<0.7; n = 1102). Cox proportional hazards multivariable regression was performed to investigate how baseline characteristics impact CVD incidence. RESULTS: In participants with PRIsm, men had a 0.68-fold higher risk of CVD incidence than women (HR, 1.68; 95%CI, 1.09-2.59; p = 0.020). Our study showed that the rate of CVD incidence increased by 6.0 % with every year's increase in age (HR, 1.06; 95%CI, 1.04-1.09; p < 0.001). A 0.1 increase in FEV1/FVC was significantly associated with a 23.0 % decrease in CVD incidence (HR, 0.77; 95%CI, 0.61-0.97; p = 0.028). Family history of CVD greatly increased the risk of cardiovascular disease incidence (HR, 1.83; 95%CI, 1.18-2.83; p = 0.007). Higher BMI was also a significant risk factor of CVD incidence (HR, 1.06; 95%CI, 1.01-1.10; p = 0.013). CONCLUSION: The prevalence of PRIsm in China was high. PRIsm subjects should be monitored carefully, especially for the older, male, those with higher BMI, lower FEV1/FVC and family history of CVD.


Asunto(s)
Enfermedades Cardiovasculares , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Enfermedades Cardiovasculares/epidemiología , Estudios Prospectivos , Prevalencia , Volumen Espiratorio Forzado , Pulmón , Espirometría , Capacidad Vital
18.
Aging (Albany NY) ; 16(7): 6364-6383, 2024 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-38568104

RESUMEN

BACKGROUND: The Metabolic Score for Insulin Resistance (METS-IR) index serves as a simple surrogate marker for insulin resistance (IR) and is associated with the presence and severity of coronary artery disease (CAD). However, the prognostic significance of METS-IR in patients with premature CAD remains unclear. This study aims to investigate the prognostic value of METS-IR in premature CAD. METHODS: This retrospective study included 582 patients diagnosed with premature CAD between December 2012 and July 2019. The median follow-up duration was 63 months (interquartile range, 44-81 months). The primary endpoint was Major Adverse Cardiovascular Events (MACE), defined as a composite of all-cause death, non-fatal myocardial infarction (MI), repeat coronary artery revascularization, and non-fatal stroke. RESULTS: Patients with MACE had significantly higher METS-IR levels than those without MACE (44.88±8.11 vs. 41.68±6.87, p<0.001). Kaplan-Meier survival curves based on METS-IR tertiles demonstrated a statistically significant difference (log-rank test, p<0.001). In the fully adjusted model, the Hazard Ratio (95% CI) for MACE was 1.41 (1.16-1.72) per SD increase in METS-IR, and the P for trend based on METS-IR tertiles was 0.001 for MACE. Time-dependent Receiver Operator Characteristic (ROC) analysis of METS-IR yielded an Area Under the Curve (AUC) of 0.74 at 2 years, 0.69 at 4 years, and 0.63 at 6 years. CONCLUSIONS: METS-IR serves as a reliable prognostic predictor of MACE in patients with premature CAD. Therefore, METS-IR may be considered a novel, cost-effective, and dependable indicator for risk stratification and early intervention in premature CAD.


Asunto(s)
Enfermedad de la Arteria Coronaria , Resistencia a la Insulina , Humanos , Masculino , Femenino , Enfermedad de la Arteria Coronaria/metabolismo , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Pronóstico , Infarto del Miocardio/metabolismo , Factores de Riesgo , Medición de Riesgo
19.
Heart Rhythm ; 21(6): 743-751, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38336194

RESUMEN

BACKGROUND: Emerging evidence has linked daytime napping with the risk of cardiovascular events. Cardiac arrhythmias are considered an early clinical stage for cardiovascular diseases. However, whether napping frequency is associated with incident arrhythmias remains unknown. OBJECTIVE: This study aimed to prospectively investigate the association between napping frequency and cardiac arrhythmias. METHODS: Daytime napping frequency was self-reported in response to touchscreen questionnaires. The primary outcomes were incident arrhythmias including atrial fibrillation/flutter (AF/Af), ventricular arrhythmia, and bradyarrhythmia. Cox regression analysis was conducted on the basis of 491,117 participants free of cardiac arrhythmias from the UK Biobank. The 2-sample mendelian randomization (MR) and 1-sample MR were used to ensure a causal effect of genetically predicted daytime napping on the risk of arrhythmias. RESULTS: During a median follow-up of 11.91 years, 28,801 incident AF/Af cases, 4132 incident ventricular arrhythmias, and 11,616 incident bradyarrhythmias were documented. Compared with never/rarely napping, usually napping was significantly associated with higher risks of AF/Af (hazard ratio, 1.141; 95% CI, 1.083-1.203) and bradyarrhythmia (hazard ratio, 1.138; 95% CI, 1.049-1.235) but not ventricular arrhythmia after adjustment for various covariates. The 2-sample MR and 1-sample MR analysis showed that increased daytime napping frequency was likely to be a potential causal risk factor for AF/Af in FinnGen (odds ratio, 1.626; 95% CI, 1.061-2.943) and bradyarrhythmia in the UK Biobank (odds ratio, 1.005; 95% CI, 1.002-1.008). CONCLUSION: The results of this study add to the burgeoning evidence of an association between daytime napping frequency and an increased risk of cardiac arrhythmias including AF/Af, ventricular arrhythmia, and bradyarrhythmia.


Asunto(s)
Arritmias Cardíacas , Análisis de la Aleatorización Mendeliana , Sueño , Humanos , Análisis de la Aleatorización Mendeliana/métodos , Femenino , Masculino , Estudios Prospectivos , Arritmias Cardíacas/epidemiología , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatología , Incidencia , Persona de Mediana Edad , Sueño/fisiología , Reino Unido/epidemiología , Factores de Riesgo , Estudios de Seguimiento , Anciano
20.
Heart Rhythm ; 21(8): 1258-1266, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-38815780

RESUMEN

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia with high morbidity and mortality implications. Several studies have described a paradoxical inverse relationship between serum cholesterol and the risk of AF, but it remains unknown whether remnant cholesterol (RC) is associated with AF incidence. OBJECTIVE: This study aims to prospectively investigate the association between RC and AF. METHODS: A total of 392,783 participants free of AF at baseline from the UK Biobank were included for the analysis. Cox proportional hazards model, subgroup analysis, and sensitivity analyses were used to evaluate the independent association between RC levels and the risk of new-onset AF. Furthermore, we performed a discordance analysis by using the median cutoff points of low-density lipoprotein cholesterol (LDL-C) and RC. RESULTS: After a median follow-up of 12.8 years (interquartile range 12.0-13.6 years), a total of 23,558 participants experienced incident AF. Compared with the highest RC level, the lower RC level was associated with an increased risk of AF incidence (quartile 1 vs quartile 4: hazard ratio 1.396; 95% confidence interval [CI] 1.343-1.452). The results remained robust across a series of sensitivity analyses. In the discordance analyses, a significantly higher risk of AF was observed in participants with discordant low RC/high LDL-C levels than in those with concordant high RC/LDL-C levels. In the low LDL-C group, RC reduction even contributed to an additional 15.8% increased rate of incident AF (low RC/low LDL-C: hazard ratio 1.303; 95% CI 1.260-1.348 vs high RC/low LDL-C: hazard ratio 1.125; 95% CI 1.079-1.172). CONCLUSION: Low RC levels were associated with an increased risk of incident AF independent of traditional cardiovascular risk factors.


Asunto(s)
Fibrilación Atrial , Colesterol , Humanos , Fibrilación Atrial/epidemiología , Fibrilación Atrial/sangre , Masculino , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Incidencia , Colesterol/sangre , Factores de Riesgo , Reino Unido/epidemiología , Estudios de Seguimiento , LDL-Colesterol/sangre , Anciano , Medición de Riesgo/métodos , Biomarcadores/sangre
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