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    • The PI K AKT pathway is

    2021-09-24

    The PI3K/AKT pathway is known to affect cell cycle, survival, and apoptosis (Yu et al., 2006; Park et al., 2008). After phosphorylation by AKT, the cytoplasmic apoptotic protein bad (bcl-xl/bcl-2) cannot be transferred to the mitochondria and dissociates from the inhibition protein bcl-2 and bcl-xl, thereby decreasing the level of free bcl-2 and down-regulating the bcl-2/bax ratio. The bcl-2/bax ratio is the key to determine cell survival and apoptosis index (Belkhiri et al., 2008); when the ratio decreases, the amount of cyto-c release decreases, thereby reducing the activation of caspase 9 and caspase 3 and inhibiting apoptosis (Mehlen and Puisieux, 2006). Apoptosis is the most important mechanisms of IR-induced cell death (Ueta et al., 2008). Our data showed that treatment with FAK siRNA or FAK inhibitor promoted HIEC cell apoptosis induced by radiation (Fig. 3), with concurrent upregulation of bax, cl-caspase-3, cyto-c and AIF, and down-regulation bcl-2. Mitochondrial apoptogenic effectors, for example cyto-c and AIF play critical roles in apoptosis (Kiziltepe et al., 2007). These results showed that radiation-induced apoptosis significantly increased when FAK MK-2461 synthesis was decreased. In vivo, our results showed that the ratio of bax/bcl-2 as well as the expression of cl-caspase-3 and cyto-c in rectum mucosa of mice treated with a FAK inhibitor was significantly higher than that of the control group. From these results, we can conclude that FAK increases radioresistance, possibly through targeting the AKT-related apoptotic pathway (Fig.5D).
    Conflicts of interest
    Acknowledgments This work was supported by grants from the National Natural Science Foundation of China (grant numbers 81602663,81401986); the Natural Science Foundation of Shanghai (grant number 18ZR1430800); Shanghai Municipal Commission of Health and Family Planning (grant number 20164Y0037); and the Shanghai Jiao Tong University Medical and Engineering Collaborative Research Fund Project (grant number YG2016MS24).
    Introduction Porcine hemagglutinating encephalomyelitis (PHE) is an acute and highly contagious disease caused by infection with porcine hemagglutinating encephalomyelitis virus (PHEV), which mainly affects piglets within 3 weeks of age, causing vomiting and wasting disease and/or obvious neurological symptoms (Li et al., 2017a; Li et al., 2016). PHEV is a member of the family Coronaviridae, which can cause susceptible neurological dysfunction in susceptible animals, including pigs, mice, and rats (Shi et al., 2018). In 1962, the virus was first isolated from the brains of infected piglets in Canada, and subsequent reports of isolation and acquisition of the pathogen occurred worldwide (Li et al., 2017b). At present, there are no effective vaccines and drugs to prevent and control the disease (Lv et al., 2017). Therefore, researches on the pathogenesis of PHEV and the development of antiviral drugs have become the focus of current research. Recent studies have shown that dynamic reorganization of the actin cytoskeleton is essential for viral entry, intracellular trafficking, and virion release (Spear and Wu, 2014). The virus has evolved a series of mechanisms to hijack cellular signaling pathways that regulate actin dynamics for efficient infection (Foo and Chee, 2015). Integrins are located on the cell surface in the form of heterodimers by the alpha and beta subunits (Zheng et al., 2017). It is an important receptor for fibronectin (FN) in the matrix, which mediates the interaction between cells and extracellular matrix proteins, and plays an important role in cell movement, migration, and neural cell remodeling (Wu et al., 2017). Integrins have been implicated to promote the entry of different types of viruses, such as human herpesvirus, Ross River virus (RRV), Human immunodeficiency virus (HIV) (Hussein et al., 2015; Lertjuthaporn et al., 2018; Yang et al., 2016). Upon integrin activation, the virus induces FAK phosphorylation, followed by activation of several related signaling molecules to facilitate entry into host cells, including Src, PI-3 K, Rho GTPases (RhoA, Rac and Cdc42) and other effector molecules such as AKT, PAK, MAPK (MEK, ERK1/2), LIMK, and cofilin (Abban and Meneses, 2010; Bottero et al., 2013; Krishnan et al., 2006). Our previous studies suggested that dynamic changes in the actin cytoskeleton are essential for PHEV entry and integrin α5β1-FAK signaling pathway plays a key role in this process (Lv et al., 2019). Therefore, drugs targeting integrin α5β1 are promising methods for treating PHE.