Apoptosis refers to programmed cell death occurring at certain stages of development. It is an important homeostasis mechanism of multicellular organisms. The regulation disorder of apoptosis caused by various factors is an important cause of tumor formation and development. Inducing apoptosis is an effective strategy for anti-tumor. At present, the signal transduction pathway of apoptosis mainly includes the endogenous pathway and endoplasmic reticulum pathway. Apoptosis is regulated by a variety of apoptosis suppressor genes and apoptosis promoting genes, such as caspase family, Bcl-2, p53 and C-myc.
The pharmacological activity of dihydromyricetin is very extensive, in addition to antitumor, anti-oxidation, anti-inflammatory and so on, it also shows some biological activity, such as anti-fatigue, antithrombotic and blood lipid regulation.
Dihydromyricetin could prolong the time of swimming and the time of survival of the mice. It was found that dihydromyricetin could increase the liver glycogen, reduce the amount of serum lactic acid and urea nitrogen, and significantly reduce the MDA of liver tissue. Under the simulated high latitude environment, Dihydromyricetin of different concentrations were given to rats. The results showed that dihydromyricetin could prolong the anti-fatigue time of rats in a dose-dependent manner and observe the mitochondrial morphology under a transmission electron microscope. Dihydromyricetin could reduce the mitochondrial damage induced by hypoxia and reduce the hypoxia. The activity of low blood urea, serum lactate dehydrogenase and creatine kinase, up-regulation of the expression of peroxisome activation receptor (PPAR), nuclear respiratory factor 1 (NRF1) and adenylate activated protein kinase (AMPK), by promoting the biosynthesis of mitochondria in skeletal muscle and the dynamic changes of mitosis and fusion of mitochondria.
During the process of apoptosis, various death signals induce the opening of mitochondrial membrane permeability change hole (PTpore), which leads to the decrease of mitochondrial transmembrane potential. Cytochrome C is released into the cytoplasm from mitochondria and forms apoptotic body with Apaf1 and ATP/dATP. The apoptotic body activates caspase-9 precursor, which makes it activated by my shear and activates the caspase cascade reaction. The downstream caspase-3 and caspase-7 were activated to complete the cutting of their corresponding substrates and promote apoptosis. It is reported that dihydromyricetin has an apoptosis-promoting effect on human breast cancer cell MDA-MB-231. With the increase of the concentration of dihydromyricetin, the intracellular calcium concentration increases gradually, the mitochondrial transmembrane potential decreases gradually, and the concentration of dihydromyricetin depends on the activation of Caspase-3 and caspase-9 in MDA-MB-231 cells, causing apoptosis and apoptosis. The effect is likely to be related to the influence of the mitochondrial pathway. The TUNEL results showed that dihydromyricetin could induce apoptosis of AGZY-83-a cells in lung adenocarcinoma cells, and increase the intracellular calcium concentration and enhance the activity of Caspase-3 to play an antitumor effect.
As a key cancer suppressor gene, p53 can increase cell sensitivity to apoptosis. It was found that two HP can inhibit the growth of HepG2 cells, enhance the expression of p53, effectively reduce the expression of Bcl-2 and induce apoptosis of tumor cells, which is time and dose-dependent. It was also reported that dihydromyricetin had an inhibitory effect on hepatoma cells, showing time and dose dependence, but had no significant effect on the activity of HL7702 and L02 cells in normal liver cells. After the action of 12 h, it was found that the expression of p53 increased, which may be related to the activation of p53 mediated apoptosis signaling pathway.
Mitochondria produce a large number of active oxygen (ROS), which causes the opening of permeability transition pores, causing the decrease of mitochondrial transmembrane potential, resulting in the release of cytochrome C and other apoptotic factors into the cytoplasm, activating caspase and inducing apoptosis. Dihydromyricetin can induce MCF-7 and MDA-MB-231 to produce ROS in breast cancer cells, up the expression of p-PERK and p-elF2 an in breast cancer cell GRP78, thus activating endoplasmic reticulum stress, while ROS scavenger can reduce the production of ROS, and dihydromyricetin can inhibit the proliferation of MCF-7 and MDA-MB-231 in human breast cancer cells. It induces apoptosis but does not produce a cytotoxic effect on human normal breast cells. This effect is closely related to the production of ROS and the endoplasmic reticulum stress pathway.
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