In vitro models. Cocoa ethanolic and methanolic extracts have been shown to minimize the viability of tumor-derived cell lines from lung, breast, liver and cervical tissues and also to up-regulate genes related to the cellular defense against oxidative anxiety, such as epoxide hydrolase 2 (EPHX2) and cytochrome B-245 beta chain (CYBB) [23, 89]. Similar final results have already been obtained with water-chocolate extracts, cocoa liquor and cocoa phenolic extracts (CPEs) in Hep2, HepG2, RLE and SH-SY5Y cells [49, 925], as a consequence of the stimulation of Nrf2, the subsequentincrease in cytoprotective genes, like GPx and GR, and also the reduce in reactive oxygen species (ROS) formation. Interestingly, these outcomes have been observed even in high-glucose-induced oxidative stress situations [91] or within the presence of pro-oxidant agents, like tert-butyl-hydroperoxide [90] and hydrogen peroxide [92]. In addition, CPEs have shown prospective to induce the expression of genes involved in tension response and detoxifying pathways (e.g., cytochrome P450 family members 1 subfamily A member) [94], as well as to modulate the activation of mitogen-activated protein Caspase Activator Purity & Documentation kinases (MAPKs) [90, 92, 95], which can be essential taking into account that the MAPK signaling pathway is involved within the regulation of key cellular processes, which include proliferation, differentiation, apoptosis and anxiety responses [96]. Other research have evaluated the anti-inflammatory prospective of CPEs and purified molecules from cocoa. It was showed that CPEs down-regulate the activation in the vascular endothelial growth aspect (VEGF) expression by the modulation of the tumor necrosis factor (TNF-) in JB6 Pmouse epidermal cells [97], the reduction of prostaglandin E2 secretion in Caco-2 cells stimulated with GLUT1 Inhibitor custom synthesis interleukin-1 [98], along with the induction of anti-inflammatory cytokines in THP-1-derived macrophages [99]. This suggests that CPEs may have anti-inflammatory properties. Within the case of purified molecules from cocoa, procyanidins have been of wonderful interest on account of their beneficial properties to manage acute and chronic ailments. By way of example, in models of colonic inflammation, cocoa extracts and high-molecular-weight polymeric procyanidins have been by far the most efficient in lowering the secretion of interleukin-8 in response to inflammatory stimuli [100]. On top of that, procyanidins have shown intriguing biological activities, which include the induction of glutathione s-transferase pi 1 (GSTP1) expression and activity in colonic cells [101]; metalloproteinase 2 (MMP2) downregulation and induction of apoptosis through ROS-mediated mechanism in ovarian carcinoma cell lines [100]; along with the prevention of acrylamide induced apoptosis [102] and deoxycholic acid induced oxidant production [103] in colon cancer models by way of the modulation of protein kinase B (Akt), mitogen-activated protein kinases ERK1/2 and p38 activation. Within the context of pathological situations, e.g., cardiovascular illness and metabolic syndrome, in vitro models have been made use of in an effort to evaluate the protective impact of cocoa. CPEs modulates oxidative pressure in endothelial cells challenged with all the pro-oxidants tert-butyl-hydroperoxide and hydrogen peroxide, by limiting ROS production and inducing antioxidant enzymes activity [27, 95]. Alternatively, cocoa extracts and cocoa flavonols have been shown to minimize the expression of pro-inflammatory molecules and ROS production, and also to restore glutathione levels and mitochondrial-membrane potential and function in.