Also, metabolomics demonstrated metabolic biphasic responses related to CUR dose and duration of cotreatment with DTX, a chemotherapy agent. Biphasic behavior or hormesis likely accounts for apparently paradoxical effects reported for CUR used at different doses, in various therapeutic combinations and cell types, including oxidative and inflammatory status. Such behavior, here demonstrated at the metabolome level and probably underlaid by generalized cellular stress responses, challenges the widely accepted beneficial effects of the phytochemical. Differentiation requires orchestration of numerous parallel cellular responses and altered physiological states associated with the novel cell fate. Such changes are often induced by environmental cues, that are transduced to the nucleus and translated into spatio-temporal reprofiling of gene expression. On their way to becoming terminally differentiated chondrocytes, chondrogenic progenitor cells undergo a well-described sequential series of events at the cell biology level: initially resting growth plate stem cells undergo a transient replicative burst. In vivo, this rapid progenitor expansion in the so-called proliferative zone is a distinctive feature of developing cartilage. During endochondral ossification, as cells move away 
from the growth plate, they simultaneously differentiate, become hypertrophic and are ultimately replaced by mineralized bone tissue. Chondrogenesis is controlled by numerous well-described environmental and endocrine factors. Per example, signaling through the insulin receptor has been intensively studied because of its mobilizing effect on resting stem cells and stimulatory effects on cells in the proliferative zone. Progression through chondrogenesis is in part driven by Silmitasertib 1009820-21-6 interaction with a constantly changing microenvironment, which is defined by soluble growth and differentiation factors, hormones, oxygen tension, cell-cell and cell-ECM contacts. Cells respond to these changes in the microenvironment by altering their transcriptome. Post-translational modification of histone tails serves to recruit transcriptional activators or repressors and/or nucleosome remodeling machineries, and as such constitutes an epigenetic register of WZ8040 purchase expression potential. Although pathways and mechanisms involved in chondrogenesis are continuously being defined, important issues surrounding the most primary steps in chondrogenic commitment and differentiation remain to be elucidated. This includes what connects environmental cues to chromatin and which signaling factors are involved in early epigenomic remodeling and, hence, in differentiation. Polycomb Repressive Complexes are important factors in cell fate determination: PRCs provide cells with an epigenetic memory function. An increasing number of studies links Polycomb function to important developmental processes and provide evidence for regulation of PRCs by multiple signaling pathways. Relevant to the study herein: many single and compound PRC1 loss-of function mouse models display antero-posterior segmentation abnormalities due to defective Hox gene expression boundary maintenance within the Hox-clusters. The abnormal skeletogenesis in PRC1 LOF mice suggests a potential direct link to endochondral ossification. Immediate early gene induction denotes the first line of cellular responses to environmental and intrinsic stimuli, including growth factors, cytokines, differentiation signals and DNAdamaging agents.