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  • CK 666 sale The concentration of rapamycin that gave

    2021-11-22

    The concentration of rapamycin that gave half-maximal induction of the expression of HO-1 and Prx-1 mRNA in normal hepatocytes was 0.05 μM, with maximal induction at about 0.1 μM rapamycin. While, at rapamycin concentrations higher than 0.1 μM, the degree of enzyme induction decreased, elevated expression of mRNA encoding the anti-oxidant CK 666 sale (relative to untreated cells) was observed at concentrations of rapamycin up to 1.0 μM. In liver transplant patients treated with rapamycin, the blood concentration of the drug is about 0.005- 0.01 μM (5-10 nM). Thus, the pre-treatment of patients with rapamycin at doses currently employed for immunosuppression would be predicted to lead to elevated expression of HO-1 and Prx-1 in hepatocytes. The results of a recent study also suggest that maintenance of adequate levels of HO-1 in the liver following a liver transplant reduces post-transplant deterioration of liver function (Nakamura et al., 2017). Rapamycin pre-treatment of the livers of patients undergoing liver resection or liver transplant, or the pre-treatment of donor livers, in order to reduce IR injury might be considered for use in combination with one or more drugs targeting other sites in the pathways which mediate or enhance IR injury. Increased expression of HO-1 and Prx-1 in livers subject to IR in the absence of any pre-treatment likely represents the activation of endogenous mechanisms to protect the liver from IR injury. Increases in expression and activity of HO-1, Prx-1 and other antioxidant enzymes are thought to mediate protection against IR injury in ischemic pre-conditioning (Liu et al., 2014; Liu et al., 2016). While subsequent IR in livers pre-treated with rapamycin attenuated the rapamycin-induced increase in HO-1 and Prx-1 mRNA, in livers pre-treated with rapamycin expression of these antioxidant enzymes was still increased about 4-5 fold compared to untreated liver at the end of the reperfusion period. Moreover, in the context of the potential ability of elevated levels of HO-1 and Prx-1 to protect against IR injury, the level of these enzymes at the beginning of the reperfusion is likely to be critical. Thus, in livers subject to IR, the generation of high levels of ROS, an increase in hepatocyte intracellular Ca2+ concentrations, and onset of apoptotic and necrotic pathways leading to injury occurs principally at the time of unclamping of the portal triad and re-admission of blood and oxygen (Elias-Miro et al., 2013; Han et al., 2018; Quesnelle et al., 2015). Pre-treatment with rapamycin leads to an increase in expression of antioxidant enzymes before or at this time point, whereas IR alone leads to an increase in expression of antioxidant enzymes at a later time point. While an increase in ROS is detrimental to normal hepatocytes, several studies indicate that ROS promote the survival and proliferation of tumorigenic liver cells (Cabré and Joven, 2016; Font-Burgada and Karin, 2016; Karin and D, 2016). Moreover, interventions that decrease ROS reduce the proliferation of tumorigenic liver cells (Qi et al., 2014). We found that the expression of HO-1 and Prx-1 in tumorigenic H4IIE rat liver cells is substantially lower than that in normal rat hepatocytes. Moreover, pre-treatment with rapamycin led to a further decrease in HO-1 and Prx-1 expression in H4IIE cells. While the differentiation of H4IE cells increased the basal expression of HO-1 and Prx-1, it did not alter the effects of rapamycin, which inhibited expression of HO-1 and Prx-1 in differentiated as well as in undifferentiated H4IIE cells. These results suggest that the capacity of tumorigenic rat liver cells to remove ROS may be lower than that of normal rat hepatocytes. Moreover, treatment with rapamycin would further reduce the capacity of tumorigenic liver cells to remove ROS. If this situation applies in human HCC, these actions of rapamycin would not be relevant to the pharmacological treatment of livers before liver surgery for HCC since the tumorigenic liver tissue is surgically removed. However, they would be relevant to any HCC patient receiving rapamycin in the absence of surgical removal of the tumorigenic tissue. The level of expression of HO-1 and Prx-1 in tumorigenic liver may depend on several factors, including the mutations involved in the onset and progression of HCC and the stage of HCC. Thus, several studies have reported an increase, or no change in, the expression of Prx-1 in human HCC liver tissue compared with that in normal liver, and no change in expression of HO-1 (Aguilar-Melero et al., 2013; Cheng et al., 2015; Song et al., 2009; Sun et al., 2014).