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    • The apoptosis promoting Bcl family includes BH only proteins

    2023-01-30

    The apoptosis-promoting Bcl-2 family includes BH3-only proteins (e.g., Bim, Bid and Bad) and multiple-domain proteins (e.g., Bax and Bak). At the time of apoptosis stimulation (e.g., DNA damage), only the BH3-only protein is activated, directly or indirectly promoting Bax/Bak oligomerization, changing mitochondrial outer membrane permeabilization and releasing cytochrome C, which can cause the activation of caspase3 and lead to cell apoptosis. The anti-apoptosis Bcl-2 family counteracts this effect mainly by chelating apoptosis-promoting family members (Kurokawa and Kornbluth, 2009, Leu et al., 2004, Chipuk et al., 2004). Anti-apoptosis and apoptosis-promoting family protein imbalance is a key characteristic of cell apoptosis. p53 can induce mitochondrial dysfunction via its Bcl-2 homology-3 structure domain or can antagonize anti-apoptosis Bcl-2 family proteins and activate caspase cross-linking (Coffin et al., 2013, Szkaradkiewicz et al., 2015). It can also up-regulate Bax Betaine mg and induce cell apoptosis (Cui et al., 2015). As shown in Fig. 9, p53, Bax and cleaved-caspase 3 were noticeably up-regulated in SHR left ventricular tissues while Bcl-2 expression was down-regulated. At the same time, the ratio of Bax/Bcl-2 was noticeably increased. The above results indicate that SHR myocardial apoptosis is induced by the mitochondria apoptosis pathway. IcarisideII can up-regulate Bcl-2 expression and down-regulate p53, Bax and cleaved- caspase 3 expression, and decrease the ratio of Bax/Bcl-2. These results suggest that IcarisideII can attenuate cardiomyocyte apoptosis by inhibiting the mitochondrial signaling pathway. According to the current blood pressure results, IcarisideII can reduce blood pressure in SHRs, which reduces heart load and indirectly reduces myocardial cell apoptosis, thereby improving ventricular remodeling. However, the direct effect of IcarisideII on cardiac myocytes cannot be ignored. Therefore, we next plan to study the effect of IcarisideII on primary myocardial cell apoptosis induced by H2O2.
    Acknowledgements This work was supported by Grant from the National Natural Science Foundation of China (No. 81660679).
    The integration of protein crystal structure information into drug discovery has become a broadly implemented and efficient means to optimize potency and specificity during lead optimization. One of the seminal examples illustrating the application of structure-based drug design (SBDD) was the rational design of HIV proteinase and protease inhibitors in the early 1990s. Since then, the concept of SBDD has been demonstrated on a wide array of protein targets and has become an established and integral part of drug discovery and lead optimization.
    Introduction Microspherule protein 2 (MCRS2) was initially identified as an interacting partner of LPTS/PinX1, which is a potent inhibitor of telomerase, and overexpression of MCRS2 in cancer cell lines suppressed telomere elongation [1]. MSP58, an isoform of MCRS2 that is 13 amino acids shorter than MCRS2 at the N-terminus, was found to interact with Daxx and relieve Daxx transcriptional repressor activity [2]. Recently, MCRS2 was isolated as part of a complex containing the histone acetyltransferase MOF in both humans and flies [3]. These findings led to the characterisation of MCRS2/MSP58 as a participant in transcriptional regulation. Moreover, TOJ3, an orthologue of MCRS2, functions downstream of v-jun to transform quail embryonic fibroblast (QEF) and chicken embryonic fibroblast (CEF) cells [4]. MSP58 was also reported to interact with the PTEN tumour suppressor and induce transformation of PTEN-deleted mouse embryonic fibroblast (MEF) cells, whereas PTEN suppresses the transforming activity of MSP58 [5]. However, the mechanism of cellular transformation by MCRS2/MSP58 remains unclear. Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed MAPKKK that activates the JNK and p38 pathways by directly phosphorylating and thereby activating their respective MAPKKs, MKK4/7 and MKK3/6 [6], [7]. ASK1 can be activated by a variety of stresses, such as oxidative stress, endoplasmic reticulum stress and calcium influx, and can induce apoptosis and inflammation [8], [9]. Recently, it has emerged that the ASK family of proteins plays key roles in cancer, cardiovascular disease and neurodegenerative disease [9].