The fact that the identity of the cells that initiate metastasis in most human cancers is unknown hampers the development of antimetastatic therapies. Here we describe a subpopulation of CD44 cells in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosts the metastatic potential of CD36 metastasis-initiating cells in a CD36-dependent manner. The use of neutralizing antibodies to block CD36 causes almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects. Clinically, the presence of CD36 metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas, and inhibition of CD36 also impairs metastasis, at least in human melanoma- and breast cancer-derived tumours. Together, our results indicate that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis.

Hepatic steatosis is a major risk factor in ischemiareperfusion. The present study evaluates whether preconditioning, demonstrated to be effective in normal livers, could also confer protection in the presence of steatosis and investigates the potential underlying protective mechanisms. Fatty rats had increased hepatic injury and decreased survival after 60 minutes of ischemia compared with lean rats. Fatty livers showed a degree of neutrophil accumulation and microcirculatory alterations similar to that of normal livers. However, in presence of steatosis, an increased lipid peroxidation that could be reduced with glutathione-ester pretreatment was observed after hepatic reperfusion. Ischemic preconditioning reduced hepatic injury and increased animal survival. Both in normal and fatty livers, this endogenous protective mechanism was found to control lipid peroxidation, hepatic microcirculation failure, and neutrophil accumulation, reducing the subsequent hepatic injury. These beneficial effects could be mediated by nitric oxide, because the inhibition of nitric oxide synthesis and nitric oxide donor pretreatment abolished and simulated, respectively, the benefits of preconditioning. Thus, ischemic preconditioning could be an effective surgical strategy to reduce the hepatic ischemia-reperfusion injury in normal and fatty livers under normothermic conditions, including hepatic resections, and liver transplantation. The ischemia-reperfusion (I/R) injury is an important cause of liver damage occurring during surgical procedures that include hepatic resections and liver transplantation.

Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions. Here we report the identification of Cardiac Glycosides (CGs) as a family of compounds with senolytic activity. CGs, by targeting the Na+/K+ATPase pump, cause a disbalanced electrochemical gradient within the cell causing depolarization and acidification. Senescent cells present a slightly depolarized plasma membrane and higher concentrations of H+, making them more susceptible to the action of CGs. These vulnerabilities can be exploited for therapeutic purposes as evidenced by the in vivo eradication of tumors xenografted in mice after treatment with the combination of a senogenic and a senolytic drug. The senolytic effect of CGs is also effective in the elimination of senescence-induced lung fibrosis. This experimental approach allows the identification of compounds with senolytic activity that could potentially be used to develop effective treatments against age-related diseases.

This study aims to determine if the protective role of adenosine in liver ischemic preconditioning is mediated by the activation of adenosine receptors and to ascertain which of these receptors is implicated in the process. Administration of adenosine A 1 and A 2 receptor antagonists to preconditioned animals indicates that hepatic preconditioning is mediated by the activation of adenosine A 2 receptors. Propentofylline (an inhibitor of adenosine transport into cells) in the preconditioned group, subjected to previous administration of an adenosine A 2 receptor antagonist, prevented the negative effect of the latter on the protection offered by preconditioning. An increase of NO production was detected just immediately after hepatic preconditioning, and the administration of an adenosine A 2 receptor antagonist to the preconditioning group prevented this increase, thus abolishing the protective effect of preconditioning. However, the administration of a NO donor to the preconditioned group subjected to previous administration of the adenosine A 2 receptor antagonist was able to maintain the preconditioning effects. In conclusion, these results indicate that, in preconditioning, the protective effect of adenosine could be a result of an increase in extracellular adenosine. This in turn would induce the activation of adenosine A 2 receptors, which, by eliciting an increase in NO generation, would protect against the injury associated with hepatic ischemia-reperfusion. (HEPATOLOGY 1999;29: 126-132.)Ischemic preconditioning, first shown in the myocardium has become a phenomenon described in the intestine, 1 brain, 2 and liver. 3 We have previously shown that ischemic preconditioning, induced by brief ischemia and reperfusion periods, renders the liver more tolerant to subsequent sustained ischemia-reperfusion. 4 We have also shown that the administration of adenosine mimics the effect of preconditioning in ischemic livers, and that the metabolization of endogenous adenosine by adenosine deaminase abolished the protective effect of preconditioning. We have further shown the beneficial effect of adenosine in inducing NO synthesis in ischemic tissue, 4 although the exact mechanism by which adenosine offered protection was not determined in that study. Recent work in heart preconditioning has shown that preconditioning-induced protection may require the activation of adenosine receptors. Thus, an adenosine receptor agonist can simulate the preconditioning whereas an adenosine receptor antagonist blocks its beneficial effect. 5 Also, recent studies in cerebral ischemia, have obtained evidence that the response to adenosine persists or is enhanced by nucleoside transport inhibitors such as propentofylline. Inhibition of adenosine uptake would increase its concentration in the extracellular space and hence potentiate its effects, particularly if adenosine binds to a specific receptor site on the external surface of the membrane. 6 Adenosine receptors have been divided into three major subclasses: A 1 , A 2 , and A 3 , 5,7 ...

Highlights d The identity of old dermal fibroblasts becomes undefined and noisy d Old dermal fibroblasts acquire adipogenic traits d CR and HFD prevent and potentiate fibroblast aging, respectively d Loss of cell identity is a possible mechanism underlying aging