Chapter 5 │ Page 181 mediate RONS transfer between adjacent cells to cause cell death via oxidative stress [29-31] (Figure 5.1). RONS (e.g., H2O2, HO●, HO2 ●, O2 ●−, 1O2, ●NO) are products of normal cellular metabolism, generated within the mitochondria and cytoplasm. They are involved in cellular responses at physiological state [138], but elevated levels of RONS may lead to injurious oxidative stress; trigger damage to membrane lipids, proteins, and DNA; and ultimately can cause cell death [139]. When RONS permeate cell membranes, they can oxidize embedded proteins by direct reactions or indirect reactions with secondary products of oxidative stress, thus a ecting membrane structure and dynamics. In particular, cysteine and methionine protein residues are more susceptible to oxidation, due to high reaction susceptibility of the sulfur group in those amino acids [140]. Oxidative modifications of proteins can change their physical and chemical properties, including conformation, structure, solubility, susceptibility to proteolysis, and enzyme activities. These modifications may represent the first step involved in mutagenesis and carcinogenesis [139]. On the other hand, protein oxidation has also been used as a therapeutic strategy to kill cancer cells, via inhibition of proliferative signaling pathways inside tumor cells [141] and reducing immunosuppressive signals on the surface of cancer cells [142]. Figure 5. Schematic representation of the e ects of RONS-induced oxidative stress on GJs and connexons. (1) GJs are able to transport RONS between cells. (2) RONS induce
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