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Finally, it was observed that the administration of NaHS attenuated apoptosis and apoptosis-related proteins in the ischaemic�Creperfused liver. Jha et al. (2008) investigated the hepatoprotective effects of H2S in a murine model of HI/R by subjecting mice to 60 min of ischaemia followed by 5 h reperfusion. In this model, Na2S was administered 5 min before reperfusion. Levels of ALT and AST were used to measure liver injury. The Na2S treatment reduced AST levels by 71% and ALT levels by 69%, suggesting that H2S attenuates HI/R injury. Furthermore, the authors showed a decrease in lipid peroxidation levels, an increase in antioxidant signalling Alectinib supplier and an increase in anti-apoptotic signalling with the administration of H2S. Hydrogen sulfide exerts a wide range of physiological roles in mammalian tissue that contribute to cellular homeostasis and protect the cell against oxidative stress, apoptosis and necrosis. The above studies demonstrate the cytoprotective role of endogenous and exogenous H2S in the heart and liver. However, to understand the protective role of H2S more fully, the cellular mechanisms of action must be defined. There are several known molecular targets of H2S protection (Fig. 1). These may include the following: (1) cell signalling, which may play a role in anti-inflammation and anti-apoptotic actions; (2) modulation of ion channels (i.e. KATP channel activation); (3) protein modification (i.e. sulfyhydration); and (4) metabolism (i.e. mitochondrial ATP production). In the following sections, the role GPX4 of H2S will be discussed with regard to the molecular sites of cytoprotection. The first reported Osimertinib in vivo molecular target for H2S was the ATP-sensitive potassium channel (KATP channel; Zhao et al. 2001). KATP channels are located on the sarcolemma, the inner mitochondrial membrane and the nuclear membrane (Seino & Miki, 2003). The channels play an important role in glucose metabolism in the cell by membrane hyperpolarization (Seino et al. 2000). It has been proposed that H2S-induced dilatation of blood vessels is a result of the opening of KATP channels and hyperpolarization of smooth muscle cells (Hosoki et al. 1997; Zhao et al. 2001; Cheng et al. 2004). Several studies have shown that H2S contributes to cardioprotection through the opening of KATP channels (Zhao et al. 2001; Bian et al. 2006; Sivarajah et al. 2009). The precise mechanism of how H2S activates KATP channels is not clear; however, some proposed mechanisms have emerged. For example, Wang et al. (2001) and Murata et al. (2001) both showed that mitochondrial KATP channel opening attenuated mitochondrial Ca2+ during ischaemia. A decrease in mitochondrial Ca2+ loading could result in protection of isolated mitochondria and could explain the anti-apoptotic effects of mitochondrial KATP channel opening.