Resveratrol is a class IA phosphoinositide 3-kinase inhibitor.

Resveratrol, a polyphenol found in fruits, possesses chemopreventive and chemotherapeutic properties and has been shown to increase lifespan in yeast and metazoans, including mice. Genetic evidence and in vitro enzymatic measurements indicate that the deacetylase Sir2/SIRT1, an enzyme promoting stress resistance and aging, is the target of resveratrol. Similarly, down-regulation of insulin-like pathways, of which PI3K (phosphoinositide 3-kinase) is a key mediator, promotes longevity and is an attractive strategy to fight cancer. We show here that resveratrol inhibits, in vitro and in cultured muscle cell lines, class IA PI3K and its downstream signalling at the same concentration range at which it activates sirtuins. Our observations define class IA PI3K as a target of resveratrol that may contribute to the longevity-promoting and anticancer properties and identify resveratrol as a natural class-specific PI3K inhibitor.

Extra cost of brain metastases (BM) in patients with non-squamous non-small cell lung cancer (NSCLC): a French national hospital database analysis.

PURPOSE: To assess the incremental cost associated with the management of patients with primary non-squamous non-small cell lung cancer (NSCLC) with brain metastases at the time of diagnosis. METHODS: Data were extracted from the French Hospital medical information database (Programme de Médicalisation des Systèmes d'Information (PMSI)). Patients with non-squamous NSCLC were identified through a diagnosis of lung cancer and a prescription of bevacizumab or pemetrexed. All such patients hospitalised with lung cancer for the first time in 2013 and with metastases identified at the first hospitalisation were eligible. Two cohorts were identified, one with brain metastases (group B: n=971) and one with metastases at other sites (group A: n=1529). For each patient, total in-hospital medical resource consumption associated with the initial hospitalisation in 2013 and with any follow-up stays in the following 24 months was documented. Costs were attributed from official French national tariffs and expressed in 2017 euros. RESULTS: The mean number of hospitalisations per patient in the 24-moth follow-up period was 17 in group A and 21 in group B. >99% of patients in both groups received chemotherapy. 58% of patients in group B and 13% in group A were managed by radiotherapy. 37% in group B and 24% in group A received palliative care. The associated cost was €2979 per patient-month for patients in group B and €2426 for patients in group A, representing a differential cost of €553 per month. Radiotherapy (+€164/month) and palliative care (+€130/month) were the principal drivers of the incremental cost. CONCLUSIONS: The presence of brain metastases at the time of diagnosis of non-squamous NSCLC carries a significant burden, and ways of lowering this burden are needed.

Short-term activation of peroxysome proliferator-activated receptor beta/delta increases fatty acid oxidation but does not restore insulin action in muscle cells from type 2 diabetic patients.

Defective fatty acid oxidation in skeletal muscle is one of the possible causes of insulin resistance. Peroxisome proliferator-activated receptor beta activators are strong inducers of fatty acid oxidation. The aim of this study was to verify whether activation of fatty acid oxidation by PPARbeta agonists in human skeletal muscle cells prepared from type 2 diabetic patients could improve the reduced responses to insulin that characterized this cell model. GW0742 (10 nM) significantly increased fatty acid oxidation and oxidative gene expression in myotubes prepared from both healthy subjects and type 2 diabetic patients. In cells from control subjects, incubation with the agonist for 48 h affected neither insulin-induced rate of glycogen synthesis nor the phosphorylation state of protein kinase B (PKB serine 473). Myotubes from type 2 diabetic patients displayed marked reduction in the effects of insulin on glycogen synthesis and on PKB phosphorylation. However, treatment with PPARbeta agonists did not restore these defects. Therefore, these results indicate that induction of fatty acid oxidation with PPARbeta activators during short-term exposition is not sufficient to correct for insulin resistance in muscle cells from type 2 diabetic patients. This suggests that additional studies are needed to better characterize the link between fatty acid oxidation and insulin sensitivity in humans.