Oxidative stress apoptotic pathways

In conclusion, it should be stressed that the competition between pro- and antiapoptotic effects of nitric oxide must probably depends on its relevant levels [137] the low physiological levels of NO principally suppress the apoptotic pathway by several mechanisms, whereas the higher rates of NO production may overcome cellar protective mechanisms and stimulate apoptosis. Furthermore, the simultaneous formation of nitric oxide and superoxide increases the possibility of apoptosis activation due to the formation of peroxynitrite. 

Glucose deprivation has been shown to cause activation of Lyn kinase, c-Jun W-terminal kinase 1 and to increase the expression of basic fibroblast growth factor and c-Myc in adri-amycin-resistant human breast cancer cells. Thus, glucose oxidation may be linked to cellular oxidative stress as evidenced from increase in the steady state of oxidized glutathione and intracellular peroxides [85]. A unique glucose-dependent apoptotic pathway is induced by the cellular oncogen c-Myc in transformed fibroblasts [86]. 

The mitochondria have emerged as a central component of the intrinsic apoptotic signaling pathways and are now known to control apoptosis via the release of apopto-genic proteins (Fig.15.8). The apoptotic signals that are channeled through the mitochondrial pathway of apoptosis include various stresses like DNA damage, oxidative stress, UV radiation, protein kinase inhibition, and growth factor deprivation. 

Won MH, Kang TC, Jeon GS, Lee JC, Kim DY, Choi EM, Lee KH, Choi CD, Chung MH, Cho SS (1999) Immunohistochemical detection of oxidative DNA damage induced by ischemia-reperfusion insults in gerbU hippocampus in vivo. Brain Res 836 70-78 Wong CH, Crack PJ (2008) Modulation of neuro-inflammation and vascular response by oxidative stress following cerebral ischemia-reperfusion injury. Curr Med Chem 15 1-14 Woo El, Kim YG, Kim MS, Han WD, Shin S, Robinson H, Park SY, Oh BH (2004) Structural mechanism for inactivation and activation of CAD/DFF40 in the apoptotic pathway. Mol Cell 14 531-539... 

Central among the toxic responses to oxidative stress is the induction of apop-totic death (Curtin et al, 2002 Fleury et al, 2002 Polster and Fkskum, 2004 Ryter et al, 2007). While it is clear that it can be an initiator as well as a signaling event within the apoptotic process, the specific mechanisms underlying these remain uncertain. Likely, these responses could be related to the damage of cellular components e.g. DNA, lipids, and polysaccharides. One potential pathway by which ethanol-mediated oxidative stress may elicit apoptosis of neurons is associated with the oxidation of polyunsaturated fatty acids within mitochondria (Ramachandran et al, 2001, 2003). Among the variety of oxidation products of these fatty acids are toxic/pro-apoptotic aldehydes, the most potent being 4-hydrox-ynonenal (Esterbauer et al, 1990 Uchida et al., 1993). This compound readily induces apoptotic death of neurons (Lovell and Markesbery, 2006 Dwivedi et al., 2007) and is produced in neurons secondary to ethanol-related oxidative stress (Ramachandran et al, 2001, 2003)... 

In summary, there is abundant evidence both in vivo and in cultured neurons that ethanol can induce apoptotic death, primarily by intrinsic pathways of the sort that are activated by oxidative stress. While it is tempting to flag this as the key player in this death process, it must be recognized that there may be layers of mechanisms at play. In the in vivo setting, neurons exist in an immensely complex milieu, their survival dependent on the presence and paracrine functions of multiple cell types, notably astrocytes. Ethanol impacts on these other cells as well as on receptor-mediated events on the neuron. Dissection and identification of these pathways is in progress. 

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