SIRT6 stabilization and cytoplasmic localization in macrophages regulates acute and chronic inflammation in mice.

Acute and chronic inflammations are key homeostatic events in health and disease. Sirtuins (SIRTs), a family of NAD-dependent protein deacylases, play a pivotal role in the regulation of these inflammatory responses. Indeed, SIRTs have anti-inflammatory effects through a myriad of signaling cascades, including histone deacetylation and gene silencing, p65/RelA deacetylation and inactivation, and nucleotide­binding oligomerization domain, leucine rich repeat, and pyrin domain­containing protein 3 inflammasome inhibition. Nevertheless, recent findings show that SIRTs, specifically SIRT6, are also necessary for mounting an active inflammatory response in macrophages. SIRT6 has been shown to positively regulate tumor necrosis factor alpha (TNFα) secretion by demyristoylating pro-TNFα in the cytoplasm. However, how SIRT6, a nuclear chromatin-binding protein, fulfills this function in the cytoplasm is currently unknown. Herein, we show by Western blot and immunofluorescence that in macrophages and fibroblasts there is a subpopulation of SIRT6 that is highly unstable and quickly degraded via the proteasome. Upon lipopolysaccharide stimulation in Raw 264.7, bone marrow, and peritoneal macrophages, this population of SIRT6 is rapidly stabilized and localizes in the cytoplasm, specifically in the vicinity of the endoplasmic reticulum, promoting TNFα secretion. Furthermore, we also found that acute SIRT6 inhibition dampens TNFα secretion both in vitro and in vivo, decreasing lipopolysaccharide-induced septic shock. Finally, we tested SIRT6 relevance in systemic inflammation using an obesity-induced chronic inflammatory in vivo model, where TNFα plays a key role, and we show that short-term genetic deletion of SIRT6 in macrophages of obese mice ameliorated systemic inflammation and hyperglycemia, suggesting that SIRT6 plays an active role in inflammation-mediated glucose intolerance during obesity.

A nitroalkene derivative of salicylate alleviates diet-induced obesity by activating creatine metabolism and non-shivering thermogenesis.

Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

Falla del ventrículo derecho en el posoperatorio de cirugía cardíaca valvular: prevalencia, características clínicas y ecocardiográficas y pronóstico

Introducción: la falla aguda del ventrículo derecho (VD) en el posoperatorio de cirugía cardíaca (POCC) constituye un desafío clínico por su importante morbimortalidad. El reconocimiento de la importancia de la función del VD en el POCC es un hecho reciente, lo que puede evidenciarse por la ausencia de parámetros de función ventricular derecha en los scores de estratificación del riesgo quirúrgico. Su definición varía según diferentes autores; es difícil conocer su prevalencia y los factores asociados a su desarrollo. Objetivo: analizar la prevalencia, las características clínicas, ecocardiográficas y el pronóstico de los pacientes con falla del VD en el POCC valvular intervenidos en el Instituto Nacional de Cirugía Cardíaca (INCC) en el año 2021 y establecer una comparación con los pacientes intervenidos en el mismo período que no desarrollaron dicha complicación. Método: estudio observacional retrospectivo, analítico. Se incluyeron los pacientes sometidos a cirugía cardíaca valvular en el INCC durante el 2021 que no presentaban ciertos criterios de exclusión preestablecidos. Se consideró la falla aguda del VD en el POCC como la evidencia ecocardiográfica de disfunción ventricular derecha definida cualitativamente en el ecocardiograma posoperatorio. El análisis estadístico se realizó con el software SPSS versión 26.0. Resultados: se incluyeron en el estudio 45 pacientes, de los cuales 7 (15,6%) desarrollaron falla del VD en el POCC. No hubo diferencias entre las características basales. El grupo que desarrolló falla del VD en el POCC presentó una fracción de eyección del ventrículo izquierdo (FEVI) significativamente menor en el ecocardiograma preoperatorio (p = 0,010). No se objetivaron diferencias en las variables intraoperatorias. Respecto al pronóstico, falleció un paciente de cada grupo en el POCC inmediato. Conclusiones: la FEVI preoperatoria podría cumplir un rol predictor de falla aguda del VD en el POCC valvular, hallazgo para comprobar en estudios prospectivos. El impacto de la falla del VD en la mortalidad no pudo definirse, dado el limitado número de pacientes.

Introduction. acute right ventricle (RV) failure in the postoperative period of cardiac surgery (POCC) constitutes a clinical challenge due to its significant morbidity and mortality. Recognition of the RV function importance in POCC is a recent fact, which can be evidenced by the absence of right ventricular function parameters in surgical risk stratification scores. Its definition varies according to different authors, it is difficult to know its prevalence and the factors associated with its development. Objective: to analyze the prevalence, clinical and echocardiographic characteristics, and prognosis of patients with RV failure in valvular POCC operated at the National Institute of Cardiac Surgery (INCC) in 2021 and to establish a comparison with patients operated on in the same period who did not develop this complication. Method: retrospective analytical observational study. Patients undergoing heart valve surgery in the INCC during 2021 were included. Acute RV failure in the POCC was considered as echocardiographic evidence of qualitatively defined right ventricular dysfunction in the postoperative echocardiogram. Statistical analysis was performed using SPSS version 26.0 software. Results: forty-five patients were included in the study, of which 7 (15.6%) developed RV failure in the POCC. There were no differences between baseline characteristics. The group that developed RV failure in POCC had a significantly lower left ventricular ejection fraction (LVEF) on preoperative echocardiography (p = 0.010). No differences were observed in the intraoperative variables. Regarding the prognosis, one patient from each group died in the immediate POCC. Conclusions: preoperative LVEF could play a role in predicting acute RV failure in valvular POCC, a finding to be verified in prospective studies. The impact of RV failure on mortality could not be defined given the limited number of patients.

Introdução: a insuficiência aguda do ventrículo direito (VD) no pós-operatório de cirurgia cardíaca (CCPO) constitui um desafio clínico devido à sua significativa morbidade e mortalidade. O reconhecimento da importância da função do VD no CCPO é fato recente, o que pode ser evidenciado pela ausência de parâmetros de função ventricular direita nos escores de estratificação de risco cirúrgico. Sua definição varia de acordo com diferentes autores, é difícil conhecer sua prevalência e os fatores associados ao seu desenvolvimento. Meta: analisar a prevalência, as características clínicas e ecocardiográficas e o prognóstico dos pacientes com insuficiência de VD em POCC valvular operados no Instituto Nacional de Cirurgia Cardíaca (INCC) em 2021 e estabelecer uma comparação com pacientes operados no mesmo período que não desenvolveram essa complicação. Método: estudo observacional analítico retrospectivo. Foram incluídos pacientes submetidos à cirurgia valvar no INCC durante o ano de 2021. Insuficiência aguda do VD no POCC foi considerada como evidência ecocardiográfica de disfunção ventricular direita qualitativamente definida no ecocardiograma pós-operatório. A análise estatística foi realizada com o software SPSS versão 26.0. Resultados: quarenta e cinco pacientes foram incluídos no estudo, dos quais 7 (15,6%) desenvolveram falência do VD no POCC. Não houve diferenças entre as características basais. O grupo que evoluiu com falência do VD no POCC apresentou fração de ejeção do ventrículo esquerdo (FEVE) significativamente menor no ecocardiograma pré-operatório (p = 0,010). Não foram observadas diferenças nas variáveis intraoperatórias. Quanto ao prognóstico, um paciente de cada grupo faleceu no POCC imediato. Conclusões: a FEVE pré-operatória poderia desempenhar um papel na predição de insuficiência aguda do VD no CCPO valvular, achado para ser verificado em estudos prospectivos. O impacto da falência do VD na mortalidade não pôde ser definido devido ao número limitado de pacientes.