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    • Intracellular signaling pathways leading to

    2022-01-17

    Intracellular signaling pathways leading to IR injury are initiated by an increase in reactive oxygen species (ROS). This occurs principally at the time of initiation of reperfusion, which is accompanied by the re-admission of oxygen to the ischemic tissue. The resulting cascade of downstream events leads ultimately to hepatocyte injury, necrosis and apoptosis, and inflammation (Datta et al., 2013; Elias-Miro et al., 2013; Prieto and Monsalve, 2017; Quesnelle et al., 2015; Reiniers et al., 2014). To reduce ROS-mediated liver damage following IR, surgical ischemic pre-conditioning and pharmacological strategies have been developed and, in some cases, trialed and used clinically (Akhtar et al., 2013; Cheng and Rong, 2017; Liu and Qian, 2015). One such pharmacological strategy is to increase the capacity of hepatocytes to remove ROS by activating, or increasing the expression of, heme oxygenase-1 (HO-1) and other antioxidant enzymes (Amersi et al., 1999; Cheng and Rong, 2017; Kato et al., 2001; Lai et al., 2008; Li et al., 2018; Liu and Qian, 2015; Nakamura et al., 2018; Tullius et al., 2002; Wang et al., 2005; Yun et al., 2010). Moreover, in the absence of any pharmacological pre-treatment, increases in the activity of HO-1 initiated by IR itself may contribute to the beneficial effects of ischemic preconditioning (Liu et al., 2014; Su et al., 2006). While ROS are detrimental to normal hepatocytes, ROS promote the proliferation of hepatocellular carcinoma cells, and there is some evidence to indicate that reduction of ROS in hepatocellular carcinoma Afuresertib may inhibit the growth of these cells (Cabré and Joven, 2016; Font-Burgada and Karin, 2016; Karin and D, 2016; Qi et al., 2014). We have previously shown that rapamycin (sirolimus) can induce the expression of HO-1 and another antioxidant enzyme, peroxiredoxin-1 (Prx-1), in hepatocytes (Kist et al., 2012). Other recent studies have shown that pre-treatment with rapamycin or analogues of rapamycin attenuates IR injury (Lee et al., 2016; Liu et al., 2010; Zhu et al., 2015a; Zhu et al., 2015b). Taken together, these results suggest that pre-treatment with rapamycin may offer a strategy to reduce ROS and hence IR injury following liver resection or transplant (Kist et al., 2012). Rapamycin is presently employed as an immunosuppressant following liver transplant, and in HCC patients, to inhibit cancer cell regrowth (Cholongitas et al., 2014; Ghazal et al., 2018; Liu et al., 2017; Sanchez Antolin et al., 2011; Soll and Clavien, 2011; Toso et al., 2010; Zhang et al., 2018). Thus, the potential use of rapamycin pre-treatment in patients undergoing liver resection or liver transplant has the advantage that rapamycin is already approved for clinical use as an immunosuppressant (Cholongitas et al., 2014; Sanchez Antolin et al., 2011; Soll and Clavien, 2011; Toso et al., 2011). Rapamycin inhibits mTORC1 kinase, leading to, among other consequences, inhibition of cell proliferation (Dibble and Cantley, 2015). The aim of this study was to further investigate the actions of rapamycin in inducing HO-1 and Prx-1 in hepatocytes. Since, in HCC patients who might be treated with rapamycin prior to liver surgery, tumorigenic liver tissue as well as normal liver tissue would be exposed to rapamycin, the effects of the drug on HO-1 and Prx-1 expression in tumorigenic liver cells have also been investigated.
    Materials and methods
    Results
    Discussion The aim of this study was to investigate the actions of rapamycin on the expression of HO-1 and Prx-1 in hepatocytes and in tumorigenic liver cells. The main findings can be summarized as follows. In liver in vivo and in normal hepatocytes cultured in vitro, pre-treatment with rapamycin caused a large induction of HO-1 and Prx-1, with maximum induction at 0.1 μM rapamycin. The dose-response curve was biphasic, whereby at rapamycin concentrations higher than 0.1 μM, the induction was reversed, although some increase in mRNA expression, relative to that in untreated cells, was still observed at 1.0 μM rapamycin. In tumorigenic liver cells, the basal level of expression of HO-1 and Prx-1 mRNA was substantially lower than that in normal hepatocytes. Moreover, in contrast to its action on normal hepatocytes, pre-treatment of tumorigenic liver cells with rapamycin decreased expression of the antioxidant enzyme mRNA. Oltipraz, an activator of the transcription factor Nrf2 (Ramos-Gomez et al., 2001), induced the expression of HO-1 and Prx-1 mRNA in tumorigenic liver cells. In tumorigenic liver cells incubated in the presence of oltipraz, maximal inhibition by rapamycin of the expression of HO-1 and Prx-1 mRNA was observed at 0.01 μM rapamycin.