No abstract

Most cancers arise in old individuals, which also accumulate senescent cells. Cellular senescence can be experimentally induced by expression of oncogenes or telomere shortening during serial passage in culture. In vivo, precursor lesions of several cancer types accumulate senescent cells, which are thought to represent a barrier to malignant progression and a response to the aberrant activation of growth signaling pathways by oncogenes (oncogene toxicity). Here, we sought to define gene expression changes associated with cells that bypass senescence induced by oncogenic RAS. In the context of pancreatic ductal adenocarcinoma (PDAC), oncogenic KRAS induces benign pancreatic intraepithelial neoplasias (PanINs), which exhibit features of oncogene‐induced senescence. We found that the bypass of senescence in PanINs leads to malignant PDAC cells characterized by gene signatures of epithelial‐mesenchymal transition, stem cells, and mitochondria. Stem cell properties were similarly acquired in PanIN cells treated with LPS, and in primary fibroblasts and mammary epithelial cells that bypassed Ras‐induced senescence after reduction of ERK signaling. Intriguingly, maintenance of cells that circumvented senescence and acquired stem cell properties was blocked by metformin, an inhibitor of complex I of the electron transport chain or depletion of STAT3, a protein required for mitochondrial functions and stemness. Thus, our studies link bypass of senescence in premalignant lesions to loss of differentiation, acquisition of stemness features, and increased reliance on mitochondrial functions.

No abstract

The enzyme-assisted extraction of bioactive compounds from plants has been studied as an alternative green technology and the carbohydrases have been candidates to improve the extraction process of numerous such compounds from plants. Polyphenols are secondary plant metabolites, generally involved in the defense against different types of stress and yerba mate (Ilex paraguariensis A. St.-Hil., Aquifoliaceae) is a natural source of these antioxidant compounds. The aim of this work was to evaluate the enzyme-assisted extraction of polyphenols from green yerba mate employing response surface methodology (RSM), in order to determine the best extraction conditions. The independent variables were temperature (33.2 to 66.8 °C), enzyme concentration (0 to 336 FGBU/100g), reaction time (19 to 221 minutes) and pH (2.82 to 6.18). The use of carbohydrases increased the extraction of polyphenols from about 38.67% to 52.08%. The present results showed that all the independent variables were significant at the linear level and that temperature and pH were not significant at the quadratic level. The interactions of temperature and pH; enzyme and reaction time; and enzyme and pH were significant. The regression model presented a determination coefficient (R 2 ) close to 0.85 and a fitted value close to 0.45. Considering the results of this study and their industrial viability, the best conditions for the extraction of polyphenols from green yerba mate are a temperature of 50.0 °C, enzyme concentration of 168 FGB/100 g, reaction time of 120 minutes and pH value of 4.50. This study was the first RSM-based report of the optimization of the enzyme-assisted extraction of total phenolic compounds from green yerba mate.