and enormously increased our knowledge of the importance of the cell redox
status and the recognition of oxidative stress as a process with implications for
many pathophysiological states. From this multi- and inter-disciplinary interest
in oxidative stress emerges a concept that attests to the vast consequences of
the complex and dynamic interplay of oxidants and antioxidants in cellular and
tissue settings. Consequently, our view of oxidative stress is growing in scope
and new future directions. Likewise, the term reactive oxygen species— adopted at some stage in order to highlight non-radical oxidants such as H2O2 and 1O2— now fails to reflect the rich variety of other reactive species in free radical biology and medicine encompassing nitrogen- , sulfur- , oxygen- , and carboncentered
radicals. With the discovery of nitric oxide, nitrogen-centered radicals Oxidative Stress and Inflammatory Mechanisms gathered momentum and have matured into an area of enormous importance in biology and medicine. Nitric oxide or nitrogen monoxide (NO), a free radical generated in a variety of cell types by nitric oxide synthases (NOSs), is involved in a wide array of physiological and pathophysiological phenomena such as vasodilation, neuronal signaling, and inflammation. Of great importance is the radical–radical reaction of nitric oxide with superoxide anion. This is among the most rapid non-enzymatic reactions in biology (well over the diffusioncontrolled limits) and yields the potent non-radical oxidant, peroxynitrite. The involvement of this species in tissue injury through oxidation and nitration reactions is well documented. Virtually all diseases thus far examined involve free radicals. In most cases, free radicals are secondary to the disease process, but in some instances causality is established by free radicals. Thus, there is a delicate balance between oxidants and antioxidants in health and disease. Their proper balance is essential for ensuring healthy aging. Both reactive oxygen and nitrogen species are involved in the redox regulation of cell functions. Oxidative stress is increasingly viewed as a major upstream component in the signaling cascade involved in inflammatory responses, stimulation of cell adhesion molecules, and chemoattractant production and as an early component in age-related neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, and amyotrophic lateral sclerosis. Hydrogen peroxide is probably the most important redox signaling molecule that, among others, can activate NFκB, Nrf2, and other universal transcription factors. Increasing steady-state levels of hydrogen peroxide have been linked to a cell’s redox status with clear involvement in adaptation, proliferation, differentiation, apoptosis, and necrosis. The identification of oxidants in regulation of redox cell signaling and gene expression was a significant breakthrough in the field of oxidative stress: the classical definition of oxidative stress as an imbalance between the production of oxidants and the occurrence of cell antioxidant defenses proposed by Sies in 1985 now seems to provide a limited concept of oxidative stress, but it emphasizes the significance of cell redox status. Because individual signaling and control events occur through discrete redox pathways rather than through global balances, a new definition of oxidative stress was advanced by Dean P. Jones (Antioxidants & Redox Signaling [2006]) as a disruption of redox signaling and control that recognizes the occurrence of compartmentalized cellular redox circuits. Recognition of discrete thiol redox circuits led Jones to provide this new definition of oxidative stress. Measurements of GSH/GSSG, cysteine/ cystine, or thioredoxin reduced /thioredoxin
oxidized provide a quantitative definition of oxidative stress. Redox status is thus dependent on the degree to which tissue-specific cell components are in the oxidized state. In general, the reducing environments inside cells help to prevent oxidative
damage. In this reducing environment, disulfide bonds (S–S) do not spontaneously form because sulfhydryl groups are maintained in the reduced state (SH), thus preventing protein misfolding or aggregation. The reducing environment is Series Preface maintained by metabolism and by the enzymes involved in maintenance of thiol/disulfide balance and substances such as glutathione, thioredoxin, vitamins E and C, and enzymes such as superoxide dismutases, catalase, and the selenium dependent glutathione reductase and glutathione and thioredoxin-dependent hydroperoxidases (periredoxins) that serve to remove reactive oxygen species (hydroperoxides). Also of importance is the existence of many tissue- and cell
compartment-specific isoforms of antioxidant enzymes and proteins. Compelling support for the involvement of free radicals in disease development originates from epidemiological studies showing that enhanced antioxidant status is associated with reduced risk of several diseases. Of great significance is the role that micronutrients play in modulation of redox cell signaling; this establishes a strong linking of diet and health and disease centered on the abilities of micronutrients to regulate redox cell signaling and modify gene expression. These concepts are anticipated to serve as platforms for the development of tissue-specific therapeutics tailored to discrete, compartmentalized redox circuits. This, in essence, dictates principles of drug development-guided knowledge of mechanisms of oxidative stress. Hence, successful interventions will take advantage of new knowledge of compartmentalized redox control and free radical scavenging.
OXIDATIVE STRESS IN HEALTH AND DISEASE
Oxidative stress is an underlying factor in health and disease. In this series of
books, the importance of oxidative stress and diseases associated with organ systems of the body is highlighted by exploring the scientific evidence and clinical applications of this knowledge. This series is intended for researchers in the basic
biomedical sciences and clinicians. The potential of such knowledge for healthy aging and disease prevention warrants further knowledge about how oxidants and antioxidants modulate cell and tissue function.
Lester Packer
Enrique Cadenas
http://www.4shared.com/account/file/153883082/52d72dcc/Oxidative_Stress_and_inflammatory_mechanism_in_obesity_diabetes_and_metablic_syndrome.html
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