FIGURE 4.

Cell death by apoptosis is induced by physalins through different pathways related to mitogen-activated protein kinase (MAPK). Physalins increase the phosphorylation levels of ERK1/2, JNK, and p38 MAPK. ERK1/2 activation induces mitochondrial ROS (mTOR) production, leading to the release of cytochrome c and activation of caspases 3, 6, and 9, triggering apoptosis. JNK activation promotes the phosphorylation of c-Jun, which leads to the formation of activator protein 1 (AP-1), a protein that regulates the transcription of pro-apoptotic factors and leads to apoptosis. P38 activation results in increase of ROS levels, which leads to p53 activation, which in turn increases the transcription of pro-apoptotic proteins, such as Noxa, BAX, and BAK, and decreases the transcription of the anti-apoptotic BCL-2 protein, leading to apoptosis through the mitochondrial pathway.