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    • br Redox regulation in the brain Reactive oxygen species are

    2022-01-21


    Redox regulation in the brain Reactive oxygen species are generated in 4064 by the mitochondrial respiratory chain, which occurs on the inner mitochondrial membrane (Murphy, 2009, Jensen, 1966, Dickinson and Chang, 2011). Interestingly, although most cancer cells are thought to primarily rely on glycolysis for energy production (Gatenby and Gillies, 2004), they produce an even higher level of ROS than normal cells (Szatrowski and Nathan, 1991). Different theories exist as to how cancer cells produce ROS, including enhanced metabolism (Hlavata et al., 2003), mitochondrial mutations and malfunction (Carew et al., 2003), and chronic inflammation (Hussain et al., 2003). Regardless, the production of ROS in both non-malignant and malignant cells necessitates the production of intracellular antioxidants to neutralize these free radicals to prevent cell death.
    Redox imbalance in neurological disease Many diseases have been found to either cause or result from oxidative stress and altered glutathione levels. Some of these include atherosclerotic vascular, heart, liver, kidney, and neurological disease, among a host of others (Dringen, 2000, Uttara et al., 2009). Multiple sclerosis, a chronic inflammatory disease of the CNS, has characteristic white matter lesions, which have been found to contain oxidized lipids and DNA, suggesting profound oxidative damage in oligodendrocytes (Haider et al., 2011). Reduced glutathione levels and increasing GSSG/GSH ratios are seen in Wilson disease, a disorder in which copper aberrantly accumulates in different tissues, causing hepatotoxicity and neurological pathologies (Sauer et al., 2011). Neurodegenerative disorders have been increasingly associated with redox imbalance and oxidative stress. Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and Huntington’s are the most well studied disorders regarding pathology associated with loss of redox homeostasis (Dringen, 2000, Uttara et al., 2009). Familial ALS was traced to a mutation in the Superoxide Dismutase (SOD-1) gene responsible for encoding the enzyme copper-zinc superoxide dismutase (SOD) (Orrell et al., 1995, Rosen et al., 1993. SOD is an important enzyme that catalyzes the neutralization of the superoxide anion to prevent cellular damage. Additionally, one theory revolves around the interaction of ROS and Ca2+ signaling. A combination of oxidative stress and perturbed energy metabolism may compromise Ca2+-regulating mechanisms, leading to brain cell death (Zundorf and Reiser, 2011, Gleichmann and Mattson, 2011). In Parkinson’s disease, sustained intracellular calcium in dopaminergic neurons has been detected, which increases mitochondrial oxidant stress (Surmeier et al., 2011). Increased ROS generation is detected in Alzheimer’s disease and Parkinson’s disease, along with many other neural disorders, ultimately leading to brain cell dysfunction and death. For a more in depth review on the role of oxidative stress in neurodegenerative diseases see Uttara et al. (2009).
    The role of glutamate transporters and glutathione in the biology and treatment of glioma Clinically, we take advantage of exogenous ROS production for the treatment of cancer. Ionizing radiation is used to kill cancer cells by two mechanisms. The direct mechanism of cell death is achieved when ionizing radiation directly interacts with DNA, creating DNA damage and ultimately leading to cellular apoptosis. The most common mechanism of irradiation-induced cell death is through the indirect method, whereby radiation interacts with water molecules, which are abundant in cells, creating hydroxyl free radicals (OH), that then interact with and damage DNA, causing cell death (Cadet et al., 2004). Glutathione is an important player in cancer biology and treatment resistance. In fact, GSH is increased in many human cancers including breast, colon, pancreas, and brain, among many others (Yeh et al., 2006, Suess et al., 1991, Schnelldorfer et al., 2000, Grubben et al., 2006, Lo et al., 2008, Louw et al., 1997). Studies have found a link between increased GSH levels and chemotherapy and radiation resistance in many cancer types (Britten et al., 1992, Bracht et al., 2006) and it seems that cancer cells may respond to radiation therapy by increasing their production and utilization of GSH (Kuppusamy et al., 2002, Brouazin-Jousseaume et al., 2002). Additionally, loss of GSH is thought to either allow or trigger the activation of the apoptotic cascade in cells, and there seems to be a correlation between GSH depletion and apoptosis in some cell types (Kern and Kehrer, 2005, Franco and Cidlowski, 2006, Hammond et al., 2007, Armstrong and Jones, 2002). Cells with higher levels of GSH tend to have more resistance to apoptosis (Cazanave et al., 2007, Friesen et al., 2004).