SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation

Sirtuin 3(SIRT3)is a deacetylase that modulates proteins that control metabolism and protects against oxidative stress.Modulation of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating metabolic diseases and associated cardiac disturbances.In this study,we investigated the role of SIRT3 in inflammation and fibrosis in the heart using male mice with constitutive and systemic deletion of SIRT3 and human cardiac AC16 cells.SIRT3 knockout mice showed cardiac fibrosis and inflammation that was characterized by augmented transcriptional activity of AP-1.Consistent with this,SIRT3 overexpression in human and neonatal rat cardiomyocytes partially prevented the inflammatory and profibrotic response induced by TNF-α.Notably,these effects were associated with a decrease in the mRNA and protein levels of FOS and the DNA-binding activity of AP-1.Finally,we demonstrated that SIRT3 inhibits FOS transcription through specific histone H3 lysine K27 deacetylation at its promoter.These findings highlight an important function of SIRT3 in mediating the often intricate profibrotic and proinflammatory responses of cardiac cells through the modulation of the FOS/AP-1 pathway.Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy,heart failure,and diabetic cardiomyopathy,our results point to SIRT3 as a potential target for treating these diseases.

The animal cachexia score(ACASCO)

Background:None of the published studies involving cancer cachexia experimental models have included a measure of the severity of the syndrome like the scoring system previously developed for human subjects.The aim of the present investigation was to define and validate a cachexia score usable in both rat and mouse tumor models.Methods:In order to achieve this goal,we included in the study one rat model(Yoshida AH‐130ascites hepatoma)and two mouse models(Lewis lung carcinoma and Colon26 carcinoma).The Animal cachexia score(ACASCO)includes five components:(a)body and muscle weight loss,(b)inflammation and metabolic disturbances,(c)physical performance,(d)anorexia,and(e)quality of life measured using discomfort symptoms and behavioral tests.Results:Using the ACASCO values,three cut‐off values were estimated by applying hierarchical cluster analysis.Four groups were originally described,one exactly below the observed mean,a second exactly over the mean,and two other groups adjusted to every cue(inferior and superior).The three cut‐off values were estimated through maximization of the classification function.This was accomplished by using a similarity matrix based on the metric properties of the variables and assuming multinormal distribution.The results show that the four groups were:no cachexia,mild cachexia,moderate cachexia and advanced cachexia.Conclusions:The results obtained allow us to conclude that the score could be very useful as an endpoint in pre‐clinical studies involving therapeutic strategies for cancer cachexia.The potential usefulness of ACASCO relates to the primary endpoint in pre‐clinical cancer cachexia drug evaluations.

Clinical applications of high-throughput genetic diagnosis in inherited retinal dystrophies: Present challenges and future directions

The advent of next generation sequencing(NGS) tech-niques has greatly simplified the molecular diagnosis and gene identification in very rare and highly heterogeneous Mendelian disorders. Over the last two years, these approaches, especially whole exome sequencing(WES), alone or combined with homozygosity mapping and linkage analysis, have proved to be successful in the identification of more than 25 new causative retinal dystrophy genes. NGS-approaches have also identified a wealth of new mutations in previously reported genes and have provided more comprehensive information concerning the landscape of genotype-phenotype correlations and the genetic complexity/diversity of human control populations. Although whole genome sequencing is far more informative than WES, the functional meaning of the genetic variants identified by the latter can be more easily interpreted, and final diagnosis of inherited retinal dystrophies is extremely successful, reaching 80%, particularly for recessive cases. Even considering the present limitations of WES, the reductions in costs and time, the continual technical improvements, the implementation of refined bioinformatic tools and the unbiased comprehensive genetic information it provides, make WES a very promising diagnostic tool for routine clinical and genetic diagnosis in the future.