Glutathione in multiple sclerosis
Department of Clinical Analysis and Public Health, Coimbra Health School, Polytechnic Institute of Coimbra, Portugal.British journal of biomedical science (Impact Factor: 1.3). 07/2013; 70(2):75-9.
Multiple sclerosis is a chronic inflammatory disease of the central nervous system, characterised mainly as an autoimmune neurodegenerative disorder. Its cause is unknown but multifactorial; however, some studies suggest that oxidative stress may be one of the sources, or a consequence of the disease, from loss of oxidant/antioxidant balance. This review studies glutathione, one of the most important agents of the endogenous antioxidant defence system, protecting cells from damage caused by oxidative stress. It evaluates glutathione and the enzymes glutathione peroxidase and glutathione reductase in various forms and stages of the disease. Analysis of a literature search suggests that the scientific community is not unanimous in its views, so more studies are required of patients with different forms of the disease and its manifestations, taking into account that the body functions as a whole and reacts in a compensatory manner. It would seem imperative to achieve a consensus on the pathogenesis responsible for severe disability, and explore sensitive biomarkers of its progression and indicators of oxidative stress. It is also important to promote the development of new therapies, with more studies on other substances such as acrolein, lipoic acid and dimethyl fumarate. Clarification of the mechanisms involved in oxidative stress, in different forms of multiple sclerosis, could result in improvements in the monitoring and prognosis of the disease, with subsequent increases in a patient's quality of life.
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ABSTRACT: Reactive oxygen species (ROS) are mainly produced by microglia and macrophages during inflammation-driven oxidative burst. However, they can in turn affect the reactivity and function of immune cells. For the first time, the relationship between these two key players involved in Multiple Sclerosis (MS) was evaluated at peripheral level. We performed an in-depth immune-phenotypic and functional analysis of MBP (Myelin Basic Protein)-stimulated Peripheral Blood Mononuclear Cells (PBMCs) by flow-cytometry. In addition, blood Coenzyme-Q10 (CoQ10), total, oxidized and reduced forms of glutathione (GSTot, GSSG, GSH), malondialdehyde (MDA), ROS, anti-oxidized-low-density-lipoproteins antibodies (anti-oxLDL), and anti-oxidant-power (PAO) were studied in 31 untreated MS patients (MSnoTP), 23 MS patients (MSTP) treated with Disease Modifying Drugs (DMDs) and 39 matched controls (HC). The focus of our study was the correlation between oxidative stress biomarkers and distribution of immune-phenotypes across the 3 studied groups. In MSnoTP an inverse correlation between MDA and apoptotic cells (CD4+ AnnexinV+ TIM3+) was detected (rs=-0.50, p=0.01). Ml functional phenotype (CD14+IL6+) and TH17 cells (CD4+ IL22+) inversely (rs=-0.48) and directly (rs=0.46) correlated (p = 0.01) with Anti-oxLDL antibodies and GSSG, respectively. The latter direct correlation was shown also in MSTP. Notably, in this group, we also detected a direct correlation between CD4+ IL4+ and CD4+ IL25+ (TH2 phenotype) with CoQ10 (rs=0.54) and GSH (rs=0.46) (p<0.03), two crucial anti-oxidants. Again, a direct correlation was found between CD8+ BDNF+ cells (suppressor phenotype) and anti-oxLDL (rs=0.48, p=0.03). Surprisingly, we measured an inverse correlation between CD14+ IL10+ cells (M2 immune-regulatory cells) with GSH (rs=-0.59, p<0.001). Our findings endorse the idea of a relationship between pro-inflammatory cells and pro-oxidative environment, even at peripheral level. Interestingly, the correlation between CD4+ IL10+ cells and a defective anti-oxidant equipment might be regarded as evidence of the involvement of these cells during an inflammatory/oxidative phase that they try to control. The finding of this link only in MSTP patients might suggest that DMDs can provide an alternative way to counteract inflammation, regardless of an absolute increase of these immune-regulatory cells.
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ABSTRACT: Chromatin is subject to proofreading and repair mechanisms during the process of DNA replication, as well as repair to maintain genetic and epigenetic information and genome stability. The dynamic structure of chromatin modulates various nuclear processes, including transcription and replication, by altering the accessibility of the DNA to regulatory factors. Structural changes in chromatin are affected by the chemical modification of histone proteins and DNA, remodeling of nucleosomes, incorporation of variant histones, noncoding RNAs, and nonhistone DNA-binding proteins. Phenotypic diversity and fidelity can be balanced by controlling stochastic switching of chromatin structure and dynamics in response to the environmental disruptors and endogenous stresses. The dynamic chromatin remodeling can, therefore, serve as a sensor, through which environmental and/or metabolic agents can alter gene expression, leading to global cellular changes involving multiple interactive networks. Furthermore its recent evidence also suggests that the epigenetic changes are heritable during the development. This review will discuss the environmental sensing system for chromatin regulation and genetic and epigenetic controls from developmental perspectives.
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ABSTRACT: Glutathione (GSH) is a major endogenous antioxidant. Several studies have implicated GSH redox imbalance in brain disorders. Here, we summarize current evidence on how GSH depletion and GSH-related enzyme deficit are involved in the pathology of brain disorders such as autism, schizophrenia, bipolar disorder, Alzheimer's disease, and Parkinson's disease. Many studies with animal models of various brain disorders and/or with clinical samples from humans with neurodegenerative and neuropsychiatric disorders have demonstrated altered levels of GSH and oxidized GSH (GSSG), decreased ratio of GSH/GSSG, and/or impaired expressions or activities of GSH-related enzymes in the blood or brain of these individuals. GSH depletion can lead to abnormalities in methylation metabolism and mitochondrial function. A few studies showed that a GSH deficit occurs prior to neuropathological abnormalities in these diseases. The potential therapeutic agents for brain disorders include N-acetylcysteine, liposomes encapsulated with GSH, and whey protein supplement, which can increase the GSH levels in the brain and alleviate oxidative stress-associated damage and may improve the behavior of individuals with brain diseases. GSH plays an important role during the onset and progression of neuropsychiatric and neurodegenerative diseases. GSH redox imbalance may be a primary cause of these brain disorders and may be used as a biomarker for diagnosis of these diseases. N-acetylcysteine and other agents that can increase the concentration of GSH in the brain are promising approaches for the treatment of these brain disorders.
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