RESUMEN

AIMS: Physical activity has a protective effect against mortality and cardiovascular events in chronic kidney disease (CKD) patients. Nonetheless, how different levels of physical activity affect the health benefits in CKD remains unclear. This study aimed to investigate the dose-response effects of physical activity on mortality and major cardiorenal events in CKD. METHODS AND RESULTS: We evaluated a longitudinal cohort of 4508 Taiwanese CKD patients between 2004 and 2017. Physical activity was assessed by the NHANES questionnaire and quantified in metabolic equivalent-hours per week (MET-hour/week). Patients were categorized into highly active (≥7.5 MET-h/week), low-active (0.1 to <7.5 MET-h/week), or inactive (0 MET-h/week) groups. Cox regression and restricted cubic spline models were utilized to explore the association between physical activity and the risks of study outcomes, including all-cause mortality, end-stage renal disease (ESRD), and major adverse cardiovascular events (MACE, a composite of cardiovascular death, myocardial infarction, ischaemic stroke, and hospitalized heart failure). During a median follow-up of 686 days, 739 death, 1059 ESRD, and 521 MACE events occurred. Highly active group had the lowest chance of all study outcomes, followed by low-active and inactive groups (P < 0.001). Multivariable Cox regression showed that only highly active group was independently associated with lower risks for all-cause mortality [hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.53-0.74], ESRD (HR 0.83, 95% CI 0.72-0.96), and MACE (HR 0.63, 95% CI 0.51-0.76) compared to the inactive group. The risks of MACE did not further decrease once physical activity surpassed 15 MET-h/week, indicating a U-shaped association. The results were consistent in the subgroup and sensitivity analyses. CONCLUSION: Physical activity of 7.5 to <15 MET-h/week is associated with lower risks of adverse cardiorenal outcomes and should be integrated into the care of CKD.

Asunto(s)

Isquemia Encefálica , Enfermedades Cardiovasculares , Fallo Renal Crónico , Insuficiencia Renal Crónica , Accidente Cerebrovascular , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/prevención & control , Ejercicio Físico , Humanos , Fallo Renal Crónico/complicaciones , Encuestas Nutricionales , Insuficiencia Renal Crónica/complicaciones

Asunto(s)

Lesión Renal Aguda/etiología , Fiebre/etiología , Tifus por Ácaros/diagnóstico , Piel/patología , Lesión Renal Aguda/tratamiento farmacológico , Anciano , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/aislamiento & purificación , Fiebre/tratamiento farmacológico , Humanos , Masculino , Orientia tsutsugamushi/genética , Orientia tsutsugamushi/aislamiento & purificación , Tifus por Ácaros/complicaciones , Tifus por Ácaros/tratamiento farmacológico , Tifus por Ácaros/microbiología , Piel/microbiología , Tigeciclina/uso terapéutico

RESUMEN

The expression of thrombomodulin (TM), a calcium-dependent adhesion molecule, is frequently downregulated in various cancer types. However, the mechanism responsible for the low expression level of TM in tumorigenesis is unknown. Here, an inverse expression of TM and Snail was detected in different cancer cell lines. We further confirmed this inverse relation using the epithelial-mesenchymal transition cell model in HaCaT and A431 cells. We demonstrated that Snail suppressed TM expression by binding to E-box (CACCTG) in TM promoter. Moreover, TM knockdown by short hairpin RNA disrupted E-cadherin-mediated cell junctions and contributed to tumorigenesis. In the calcium switch assay, E-cadherin lost the ability to associate with ß-catenin and accumulated in cytoplasm in TM knockdown cells. Meanwhile, wound healing and invasive assays showed that TM knockdown promoted cell motility. A subcutaneous injection of TM knockdown transfectants into immunocompromised mice induced squamous cell carcinoma-like tumors. Besides, forced expression of murine TM in TM knockdown cells made the cells reassume epithelium-like morphology and increased calcium-dependent association of E-cadherin and ß-catenin. In conclusion, TM, a novel downstream target of Snail in epithelial-mesenchymal transition, is required for maintaining epithelial morphology and functions as a tumor suppressor.

Asunto(s)

Carcinoma de Células Escamosas/etiología , Trombomodulina/genética , Trombomodulina/metabolismo , Factores de Transcripción/metabolismo , Animales , Secuencia de Bases , Cadherinas/genética , Cadherinas/metabolismo , Calcio/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Regulación hacia Abajo , Epitelio/metabolismo , Epitelio/patología , Técnicas de Silenciamiento del Gen , Humanos , Mesodermo/metabolismo , Mesodermo/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Regiones Promotoras Genéticas , ARN Interferente Pequeño/genética , Transducción de Señal , Factores de Transcripción de la Familia Snail , Trombomodulina/antagonistas & inhibidores , Factores de Transcripción/genética , Transfección , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , beta Catenina/metabolismo