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  • Our previous study provided some evidence that the p http

    2021-10-21

    Our previous study provided some evidence that the pre-treatment of livers with rapamycin induces the expression of HO-1 and Prx-1 (Kist et al., 2012). The present results define the dose-response curve for the induction of HO-1 and Prx-1 expression by rapamycin in normal hepatocytes. While, in the majority of the experiments, expression of mRNA encoding HO-1 and Prx-1 was measured, western blot confirmed for HO-1 the key observation that the expression of this protein is increased in liver following pre-treatment with rapamycin. Moreover, previous studies on the expression of HO-1 and Prx-1 have shown a good correlation between results obtained with qPCR and western blot (Atef et al., 2017; Ge et al., 2017). The intracellular signaling mechanisms involved in the induction by rapamycin of HO-1 and Prx-1 in normal hepatocytes most likely involve the transcription factor Nrf2. This is the major transcription factor which regulates the expression of HO-1, Prx-1, and several other antioxidant Fluorescein TSA (Ishii et al., 2000; Kim et al., 2007; Nguyen et al., 2009b; Paine et al., 2010; Xu et al., 2017). Moreover, there is evidence that rapamycin can indirectly activate Nrf2. Thus, it has been shown that the inhibition of mTORC1 kinase by rapamycin leads to the inhibition of S6 kinase, which in turn, results in indirect activation of the phosphoinositide 3-kinase (PI3K)/ serine/threonine kinase protein kinase B (AKT) pathway and the activation of Nrf2 (Klempner et al., 2013; Yao et al., 2016; Zhang et al., 2016a; Zhang et al., 2016b). The observation that oltipraz, an established activator of Nrf2 (Weerachayaphorn et al., 2009), increases the expression of HO-1 and Prx-1 mRNA provides some evidence for the involvement of Nrf2 in induction of the expression of HO-1 and Prx-1 in hepatocytes and tumorigenic liver cells. The observation that rapamycin inhibits the ability of oltipraz to increase the expression of HO-1 and Prx-1 mRNA suggests that rapamycin activates another pathway which decrease or inhibits the activation of Nrf2 and/or alters the concentration of another transcription factor which inhibits the expression of HO-1 and Prx-1 independent of Nrf2. Such a putative mechanism might also explain why rapamycin induction of HO-1 and Prx-1 mRNA is attenuated by subsequent IR. Further experiments are warranted to define the mechanisms involved, and the reasons underlying the difference in the dose response curves for the inhibition by rapamycin of HO-1 and Prx-1 mRNA expression in normal hepatocytes compared with tumorigenic liver cells. It has previously been shown that pre-treatment of Fluorescein TSA livers with rapamycin provides protection against IR injury (Lee et al., 2016; Liu et al., 2010; Zhu et al., 2015a; Zhu et al., 2015b). The mechanisms involved are thought to include reduction of endoplasmic reticulum stress, enhanced autophagy and activation of the mammalian target of rapamycin complex 2 (mTOR2) pathway (Liu et al., 2010; Zhu et al., 2015a; Zhu et al., 2015b). The present results suggest that an additional, or complimentary, mechanism may involve induction of the synthesis of the antioxidant enzymes HO-1 and Prx-1. Moreover, the observation that the rapamycin-induced increase in HO-1 and Prx-1 expression in isolated hepatocytes in culture is comparable to that in liver in vivo indicates that a substantial proportion of the enzyme induction observed in liver in vivo is due to induction of these enzymes in hepatocytes rather than other cell types present in liver. Elevated expression of HO-1 and Prx-1 would increase the capacity of hepatocytes to remove ROS formed at the beginning of liver reperfusion and reduce endoplasmic reticulum stress during reperfusion (Bozaykut et al., 2016; Pagliassotti et al., 2016). In this connection, it is interesting to note that one recent study has provided evidence that rapamycin can decrease the production of ROS in liver (Martinez-Cisuelo et al., 2016).