Vitamin D induces SIRT1 activation through K610 deacetylation in colon cancer

Posttranslational modifications of epigenetic modifiers provide a flexible and timely mechanism for rapid adaptations to the dynamic environment of cancer cells. SIRT1 is an NAD+-dependent epigenetic modifier whose activity is classically associated with healthy aging and longevity, but its function in cancer is not well understood. Here, we reveal that 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol), the active metabolite of vitamin D (VD), promotes SIRT1 activation through auto-deacetylation in human colon carcinoma cells, and identify lysine 610 as an essential driver of SIRT1 activity. Remarkably, our data show that the post-translational control of SIRT1 activity mediates the antiproliferative action of 1,25(OH)2D3. This effect is reproduced by the SIRT1 activator SRT1720, suggesting that SIRT1 activators may offer new therapeutic possibilities for colon cancer patients who are VD deficient or unresponsive. Moreover, this might be extrapolated to inflammation and other VD deficiency-associated and highly prevalent diseases in which SIRT1 plays a prominent role.Funding for this work was provided by the Agencia Estatal de Investigación (PID2019-104867RB-I00/AEI/10.13039/501100011033, RTI2018-099343-B-100 and PID2021-127645OA-I00); Instituto de Salud Carlos III (CIBERONC, CB16/12/00273 and CB16/12/00326); Comunidad de Madrid (Ayudas Atracción de Talento 2017-T1/BMD-5334 and 2021–5 A/BMD-20951; A385-DROPLET Young Reserchers R&D Project 2019 CAM-URJC; PRECICOLON-CM, P2022/BMD7212); Universidad Rey Juan Carlos (ADIPOMELM, Proyecto Puente de Investigación 2020)S

Vitamin D induces SIRT1 activation through K610 deacetylation in colon cancer

Posttranslational modifications of epigenetic modifiers provide a flexible and timely mechanism for rapid adaptations to the dynamic environment of cancer cells. SIRT1 is an NAD+ -dependent epigenetic modifier whose activity is classically associated with healthy aging and longevity, but its function in cancer is not well understood. Here, we reveal that 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3 , calcitriol), the active metabolite of vitamin D (VD), promotes SIRT1 activation through auto-deacetylation in human colon carcinoma cells, and identify lysine 610 as an essential driver of SIRT1 activity. Remarkably, our data show that the post-translational control of SIRT1 activity mediates the antiproliferative action of 1,25(OH)2D3 . This effect is reproduced by the SIRT1 activator SRT1720, suggesting that SIRT1 activators may offer new therapeutic possibilities for colon cancer patients who are VD deficient or unresponsive. Moreover, this might be extrapolated to inflammation and other VD deficiency-associated and highly prevalent diseases in which SIRT1 plays a prominent role.Funding for this work was provided by the Agencia Estatal de Investigación (PID2019- 104867RB-I00 / AEI/10.13039/501100011033, RTI2018-099343-B-100 and PID2021-127645OAI00); Instituto de Salud Carlos III (CIBERONC, CB16/12/00273 and CB16/12/00326); Comunidad de Madrid (Ayudas Atracción de Talento 2017-T1/BMD-5334 and 2021-5A/BMD-20951; A385- DROPLET Young Reserchers R&D Project 2019 CAM-URJC; PRECICOLON-CM, P2022/BMD7212); Universidad Rey Juan Carlos (ADIPOMELM, Proyecto Puente de Investigación 2020).Peer reviewe

Granulocyte Colony-Stimulating Factor Improves Deficient In Vitro Neutrophil Transendothelial Migration in Patients with Advanced Liver Disease

Bacterial infections are frequent complications in patients with liver cirrhosis. Cirrhotic patients present abnormalities in both innate and adaptive immune responses, including a deficient neutrophil recruitment to infected sites. The purpose of this study was to assess neutrophil-endothelium interactions in cirrhotic patients and evaluate the effects of G-CSF on this process. We studied neutrophil adhesion and transendothelial migration in 14 cirrhotic patients and 14 healthy controls. We also analyzed neutrophil expression of the adhesion molecules CD62L and CD11b in whole blood by flow cytometry. Cirrhotic patients expressed higher levels of CD11b than healthy controls, whereas CD62L expression was significantly lower, suggesting exposure of neutrophils to activating agents within the bloodstream. Neutrophils from cirrhotic patients showed increased adhesion to both resting and tumor necrosis factor alpha-stimulated microvascular endothelial cells and decreased transendothelial migration. Granulocyte colony-stimulating factor (G-CSF) (100 ng/ml) significantly enhanced neutrophil adhesion to microvascular endothelial cells in healthy controls but not in cirrhotic patients. G-CSF also significantly improved neutrophil transmigration in cirrhotic patients and healthy controls. In conclusion, cirrhotic patients exhibit increased neutrophil adhesion to microvascular endothelium and deficient transendothelial migration. G-CSF enhances neutrophil transendothelial migration in cirrhotic patients despite having no effect on neutrophil adhesion. Therefore, G-CSF may be able to increase neutrophil recruitment into infected sites in these patients

Exercise benefits in cardiovascular diseases: from mechanisms to clinical implementation.

There is a pandemic of physical inactivity that appears to parallel the widespread prevalence of cardiovascular disease (CVD). Yet, regular physical activity (PA) and exercise can play an important role not only in primary cardiovascular prevention but also in secondary prevention. This review discusses some of the main cardiovascular effects of PA/exercise and the mechanisms involved, including a healthier metabolic milieu with attenuation of systemic chronic inflammation, as well as adaptations at the vascular (antiatherogenic effects) and heart tissue (myocardial regeneration and cardioprotection) levels. The current evidence for safe implementation of PA and exercise in patients with CVD is also summarized

Exercise and the Hallmarks of Cancer

A wealth of evidence supports an association between regular physical activity (PA) and decreased risk for cancer and cancer mortality. This is clearly an important issue given the growing worldwide incidence of both cancer and physical inactivity. Of further importance is unraveling the biological mechanisms that explain the potential preventive effects of PA against the development of cancer, as this might improve our understanding of cancer biology and assist researchers exploring novel treatment strategies. Here we review mechanistic studies that help explain the anticancer effects of exercise based on how exercise impacts hallmark features of cancer. We also discuss the emerging role of myokines, methodological caveats in the field, and potential questions that remain to be addressed in future research.Sin financiación7.038 JCR (2017) Q1, 26/223 Oncology3.281 SJR (2017) Q1, 16/221 Cancer Research, 19/363 OncologyNo data IDR 2017UE

Analytical solution to the circularity problem in the discounted cash flow valuation framework

En este artículo proponemos una solución analítica al problemade la circularidad entre el valor y el costo de capital. Nuestra soluciónse obtiene a partir de un principio central de las finanzas que estableceuna relación entre el valor actual y el valor, el flujo de caja y la tasa dedescuento en el siguiente período. Derivamos una formulación general delvalor del patrimonio, P, del costo del patrimonio con deuda, del valor totaly del costo promedio ponderado del capital, WACC, sin circularidad. Además,comparamos los resultados obtenidos usando estas fórmulas con losque resultan al usar el método de Valor Presente Ajustado, VPA (APV eninglés) sin circularidad, y la solución iterativa de circularidad basada enla función de iteración de una hoja de cálculo. Concluimos que todos losmétodos producen el mismo resultado. La ventaja de esta solución es queevita problemas como el uso de métodos manuales (es decir, el popular“Rolling WACC”) haciendo caso omiso de la cuestión de la circularidad, elestablecimiento de un apalancamiento objetivo (target leverage) por logeneral constante, con las inconsistencias que se derivan de ello, el usoinapropiado del valor en libros, o atribuir las diferencias entre los métodosde valoración a errores de redondeo

Aging effects on marathon performance insights from the New York City race

Most studies on aging and marathon have analysed elite marathoners, yet the latter only represent a very small fraction of all marathon participants. Also, analysis of variance or unpaired Student's t tests are frequently used to compare mean performance times across age groups. In this report we propose an alternative methodology to determine the impact of aging on marathon performance in both non-elite and elite marathoners participating in the New York City Marathon. 471,453 data points corresponding to 370,741 different runners over 13 race editions (1999-2011) were retrieved. Results showed that: i) the effect of aging on marathon performance was overall comparable in both sexes; ii) the effect of aging differed between the fastest and the slowest runners in both sexes; and iii) the magnitude of the sex differences was higher among the slowest runners compared with the fastest ones. Current data suggests that the biological differences between sexes allow men to have a better marathon performance across most of the human lifespan.3.042 JCR (2015) Q1, 10/82 Sport sciences; Q2, 26/83 PhysiologyUE