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  • Dihydroartemisinin and SIRT is a representative member of Si

    2019-08-29

    SIRT1 is a representative member of Sirtuins, which is a family of highly conserved NAD+-dependent class III histone deacetylases. SIRT1 deacetylates plentiful nonhistone protein substrates [Atgs, Foxo1, Foxo3, PGC-1α, NF-kB, E2F1 and p53] (Conrad et al., 2016; Gu et al., 2016; Tu et al., 2018) to play a key role in resistance of cell stress. Many studies back it up that SIRT1 is a vital negative regulator of p53. SIRT1 (Luo et al., 2001; Wang et al., 2018) may deacetylate p53 and intensively inhibit p53-dependent transcription, thereby inverting p53-mediated cell growth arrest and apoptosis in response to DNA damage or oxidative stress. However, SIRT1-p53 relationship is somewhat complicated. Therefore, aim of this study was to investigate the impact of SIRT1 and p53 in fluoride-induced apoptosis and Dihydroartemisinin and arrest in MC3T3-E1 cells.
    Materials and methods
    Results
    Discussion Fluoride is an important industrial chemical and mostly used in power-generating stations, welding operations, in the manufacture of fluoridated dental preparations and the fluoridation of drinking water (Choubisa and Choubisa, 2016). Fluorosis not only injury teeth and the skeletal system but also damage the structure and functions of the non-skeletal systems such as liver, kidney and ovary (Dharmaratne, 2015; Yin et al., 2015; Zhou et al., 2015). The present study was undertaken to investigate the effect of different concentrations of sodium fluoride on oxidative stress, mitochondria-dependent apoptosis pathway, cell cycle as well as acetylation status of p53 and explore the acetylation regulation by SIRT1. The intracellular redox situation of MC3T3-E1 cells after exposure with fluoride has been investigated and results revealed that the generation of ROS increased at a concentration-dependent manner, which indicated that NaF induced oxidative stress damage in MC3T3-E1 cells. Fluoride-mediated inducement of oxidative stress brings out significant depletion of the activities of the antioxidant enzymes and augment of lipid peroxidation (Wang et al., 2014). Chronic fluorosis leads to the generation of free radicals and alterations in antioxidants or reactive oxygen species scavenging enzymes via oxidative stress abduction (Barbier et al., 2010; Suzuki et al., 2015). An increase of ROS production was also considered as a typical event in the process of mitochondrial-mediated early apoptosis (Huang et al., 2015). Previous studies have emphasized that fluoride induces apoptosis through elevating oxidative stress-induced lipid peroxidation, thereby causing mitochondrial dysfunction and the induction of downstream signaling pathways (Ameeramja et al., 2016; Cao et al., 2015; Inkielewicz-Stepniak et al., 2014; Ke et al., 2016). Therefore, the apoptosis parameters of MC3T3-E1 cells in response to fluoride treatment were evaluated in this study. Flow cytometer and Western blotting data indicated that NaF induces a significant increase in the apoptotic rate, and the significant upregulation of ratio of Bax and Bcl-2 expression, as well as the increase of protein expression of Cyt c and Caspase-3 suggested that fluoride induces mitochondria-dependent cell apoptosis. Furthermore, fluoride significantly increased protein expression of p53 and up-acetylated p53 at L379 site in MC3T3-E1 cells. p53 as a transcription factor regulates the expression of genes and miRNAs which are associated with a number of important cellular processes including proliferation, DNA repair, apoptosis, autophagy, metabolism, and cell migration (Liu et al., 2017; Tiwari et al., 2018). Acetylation of p53 increases the protein stability of p53, binding to low-affinity promoters, interaction with other proteins, antiviral potentials as well as checkpoint responses to DNA damage and activated oncogenes (Brooks and Gu, 2011; Munoz-Fontela et al., 2011; Reed and Quelle, 2014). It is widely reported that the inhibition of histone deacetylases (HDACs) may remove acetyl groups from p53 (i.e., HDAC1 and SIRT1) and promotes p53 acetylation and p53-dependent apoptosis and senescence (Schafer et al., 2017). In the present study, fluoride-induced acetylation of p53 might exert vital role in apoptosis promotion.