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Afanas'ev I.,Vitamin Research Institute
Current Signal Transduction Therapy | Year: 2012

Cancer cells differ from the other cells by their ability to survive under conditions of enhanced oxidative stress. This property of cancer cells might also be an origin of resistance of tumors to drug treatment. Reactive oxygen species (ROS) overproduction (oxidative stress) might be responsible for both survival and death of cancer cells and the opposite effects of ROS signaling can depend on many reasons. In present work we consider several possible mechanisms of ROS effects on survival/death cancer cells: the different effects of two main reactive oxygen species paramagnetic free radical anion superoxide and diamagnetic molecule hydrogen peroxide, competition between protein kinases and phosphatases, and modification of ROS-depended enzyme/gene cascades. The oxidation of protein kinase B (Akt) by ROS might be of great importance for a shift of the survival to apoptotic signal in the enzymatic cascade. Dual effects of ROS overproduction on cancer cells appear to depend on the levels of oxidative stress: weak/moderate oxidative stress enhances survival while severe oxidative stress induces cell death. The regulation of ROS overproduction by antioxidants and prooxidants is possibly an important promising way for cancer treatment. © 2012 Bentham Science Publishers.


Afanas'ev I.,Vitamin Research Institute
Aging and Disease | Year: 2011

This work considers reactive oxygen species (ROS) signaling in solid tumors. Most (probably all) cancer cells are characterized by ROS overproduction that is they exist under conditions of incessant oxidative stress. For example ROS overproduction has been shown in prostate, pancreatic, melanoma, and glioma cells. ROS overproduction has been also demonstrated in breast, liver, bladder, colon, and ovarian cancers. Although these examples probably do not incorporate all the described data concerning ROS overproduction in cancer cells, they clearly support a proposal about enhanced oxidative stress in these cells. Therefore the mechanisms of ROS signaling in the survival and death of cancer cells and comparison with ROS signaling in senescent cells ought to be considered. It might be suggested that ROS overproduction in cancer cells is a major origin of their survival and resistance to anticancer treatment while the enhanced oxidative stress responsible for aging development. However it is of particular interest that additional ROS production by prooxidants can induce apoptosis in cancer cells. We suggest that moderate oxidative stress can stimulate proliferation and survival of cancer sells by conditioning mechanism while the enhancement of ROS overproduction by prooxidants under severe oxidative stress results in apoptosis and cell death. Aging development is always characterized by harmful ROS overproduction although the moderate increase in ROS formation in senescent cells might be not dangerous. Similar double-edged sword effects of ROS might be observed during the development of other pathologies for example diabetes mellitus.


Afanas'ev I.,Vitamin Research Institute
Oxidative medicine and cellular longevity | Year: 2010

Reactive oxygen species (ROS) superoxide and hydrogen peroxide perform important signaling functions in many physiological and pathophysiological processes. Cell senescence and organismal age are not exemptions.Aging-regulating genes p66shc, Sirtuin, FOXO3a and Klotho are new important factors which are stimulated by ROS signaling. It has been shown that ROS participate in initiation and prolongation of gene-dependent aging development.ROS also participate in the activation of protein kinases Akt/PKB and extracellular signal-regulated kinase ERK, which by themselves or through gene activation stimulates or retards cell senescence.Different retarding/stimulating effects of ROS might depend on the nature of signaling species-superoxide or hydrogen peroxide. Importance of radical anion superoxide as a signaling molecule with"super-nucleophilic" properties points to the possibility of the use of superoxide scavengers (SOD mimetics, ubiquinones and flavonoids) for retarding the development of aging.


Afanas'Ev I.,Vitamin Research Institute
Oxidative Medicine and Cellular Longevity | Year: 2011

There is not too much success in the antioxidant treatment of heart deceases in humans. However a new approach is now developed that suggests that depending on their structures and concentrations antioxidants can exhibit much more complicated functions in many pathological disorders. It is now well established that physiological free radicals superoxide and nitric oxide together with their derivatives hydrogen peroxide and peroxynitrite (all are named reactive oxygen species (ROS) and reactive nitrogen species (RNS)) play a more important role in heart diseases through their signaling functions. Correspondingly this work is dedicated to the consideration of damaging signaling by ROS and RNS in various heart and vascular disorders: heart failure (congestive heart failure or CHF), left ventricular hypertrophy (LVH), coronary heart disease, cardiac arrhythmias, and so forth. It will be demonstrated that ROS overproduction (oxidative stress) is a main origin of the transformation of normal physiological signaling processes into the damaging ones. Furthermore the favorable effects of low/moderate oxidative stress through preconditioning mechanisms in ischemia/reperfusion will be considered. And in the last part we will discuss the possibility of efficient application of antioxidants and enzyme/gene inhibitors for the regulation of damaging ROS signaling in heart disorders. © 2011 Igor Afanas'ev.


Afanas'ev I.,Vitamin Research Institute
Aging and Disease | Year: 2010

Harman's Free Radical Theory of Aging has been considered as a major theory of aging for more than 50 years. In 1956 Dr. Harman proposed that the accumulation of free radicals with the age causes the damage of biomolecules by these reactive species and the development of pathological disorders resulting in cell senescence and organismal aging. His hypothesis was supported by numerous experimental studies demonstrated an increase in free radical levels in cells and living organisms with aging. In subsequent years important discoveries of new physiological free radicals superoxide and nitric oxide have been made that led to understanding of other important functions of free radicals. It has been shown that superoxide and nitric oxide together with their diamagnetic reaction products hydrogen peroxide and peroxynitrite (all are now named reactive oxygen and nitrogen species, ROS and RNS) function as signaling species in many physiological enzymatic/gene processes. Furthermore, the disturbance of ROS and RNS physiological signaling can be an origin of various pathologies and aging. These discoveries demanded to widen original free radical theory of aging and to consider the damaging ROS signaling as an important, maybe major route to cell senescence and organismal aging. However, some experimental findings such as the extension of lifespan by calorie restriction of yeast, flies, worms, and mice, and favorable effects of physical exercises stimulated criticism of free radical theory because the expansion of lifespan accompanied in some cases by increasing oxidative stress. On these grounds such theories as Hormesis and Target of rapamycin (mTOR) theories refute the role of ROS and oxidative stress in aging. Accordingly, a major purpose of this review to show that ROS signaling is probably the most important enzyme/gene pathway responsible for the development of cell senescence and organismal aging and that ROS signaling might be considered as further development of free radical theory of aging. In spite of apparent contradictions the Hormesis or TOR theories are also describing processes of aging development regulated by ROS signaling.


Afanas'ev I.,Vitamin Research Institute
Current Drug Metabolism | Year: 2010

For many years the formation of reactive oxygen and nitrogen species (ROS) and (RNS) in living organisms has been considered to be dangerous phenomenon due to their damaging action on biomolecules. However, present studies demonstrated another important activity of ROS and RNS: their signaling functions in physiological and pathological processes. In this work we discuss the new data concerning a role of ROS and RNS in many enzymatic/gene cascades causing damaging changes during the development of skin diseases and pathological disorders (skin cancer, the toxic effects of irradiation on the skin, and skin wounding). It has been suggested that the enhancement of ROS formation in tumor cells through the inactivation of mitochondrial MnSOD or the activation of NADPH oxidase leads to apoptosis and might be applied for developing a new cancer therapy. On the other hand ROS overproduction might stimulate malignant transformation of melanoma. Role of ROS signaling is also considered in the damaging action of UVA, UVB, and IRA irradiation on the skin and the processes of wound healing. In the last part of review the possibility of the right choice of antioxidants and free radical scavengers for the treatment of skin disease is discussed. © 2010 Bentham Science Publishers Ltd.


Afanas'ev I.,Vitamin Research Institute
Aging and Disease | Year: 2015

Superoxide is a precursor of many free radicals and reactive oxygen species (ROS) in biological systems. It has been shown that superoxide regulates major epigenetic processes of DNA methylation, histone methylation, and histone acetylation. We suggested that superoxide, being a radical anion and a strong nucleophile, could participate in DNA methylation and histone methylation and acetylation through mechanism of nucleophilic substitution and free radical abstraction. In nucleophilic reactions superoxide is able to neutralize positive charges of methyl donors S-adenosyl-L-methionine (SAM) and acetyl-coenzyme A (AcCoA) enhancing their nucleophilic capacity or to deprotonate cytosine. In the reversed free radical reactions of demethylation and deacetylation superoxide is formed catalytically by the (Tet) family of dioxygenates and converted into the iron form of hydroxyl radical with subsequent oxidation and final eradication of methyl substituents. Double role of superoxide in these epigenetic processes might be of importance for understanding of ROS effects under physiological and pathological conditions including cancer and aging.


PubMed | Vitamin Research Institute
Type: Journal Article | Journal: Aging and disease | Year: 2015

Superoxide is a precursor of many free radicals and reactive oxygen species (ROS) in biological systems. It has been shown that superoxide regulates major epigenetic processes of DNA methylation, histone methylation, and histone acetylation. We suggested that superoxide, being a radical anion and a strong nucleophile, could participate in DNA methylation and histone methylation and acetylation through mechanism of nucleophilic substitution and free radical abstraction. In nucleophilic reactions superoxide is able to neutralize positive charges of methyl donors S-adenosyl-L-methionine (SAM) and acetyl-coenzyme A (AcCoA) enhancing their nucleophilic capacity or to deprotonate cytosine. In the reversed free radical reactions of demethylation and deacetylation superoxide is formed catalytically by the (Tet) family of dioxygenates and converted into the iron form of hydroxyl radical with subsequent oxidation and final eradication of methyl substituents. Double role of superoxide in these epigenetic processes might be of importance for understanding of ROS effects under physiological and pathological conditions including cancer and aging.


PubMed | Vitamin Research Institute
Type: Journal Article | Journal: Aging and disease | Year: 2012

Harmans Free Radical Theory of Aging has been considered as a major theory of aging for more than 50 years. In 1956 Dr. Harman proposed that the accumulation of free radicals with the age causes the damage of biomolecules by these reactive species and the development of pathological disorders resulting in cell senescence and organismal aging. His hypothesis was supported by numerous experimental studies demonstrated an increase in free radical levels in cells and living organisms with aging. In subsequent years important discoveries of new physiological free radicals superoxide and nitric oxide have been made that led to understanding of other important functions of free radicals. It has been shown that superoxide and nitric oxide together with their diamagnetic reaction products hydrogen peroxide and peroxynitrite (all are now named reactive oxygen and nitrogen species, ROS and RNS) function as signaling species in many physiological enzymatic/gene processes. Furthermore, the disturbance of ROS and RNS physiological signaling can be an origin of various pathologies and aging. These discoveries demanded to widen original free radical theory of aging and to consider the damaging ROS signaling as an important, maybe major route to cell senescence and organismal aging. However, some experimental findings such as the extension of lifespan by calorie restriction of yeast, flies, worms, and mice, and favorable effects of physical exercises stimulated criticism of free radical theory because the expansion of lifespan accompanied in some cases by increasing oxidative stress. On these grounds such theories as Hormesis and Target of rapamycin (mTOR) theories refute the role of ROS and oxidative stress in aging. Accordingly, a major purpose of this review to show that ROS signaling is probably the most important enzyme/gene pathway responsible for the development of cell senescence and organismal aging and that ROS signaling might be considered as further development of free radical theory of aging. In spite of apparent contradictions the Hormesis or TOR theories are also describing processes of aging development regulated by ROS signaling.


PubMed | Vitamin Research Institute
Type: Journal Article | Journal: Aging and disease | Year: 2014

It has been shown that ROS (reactive oxygen species, superoxide and hydrogen peroxide) regulate major epigenetic processes, DNA methylation and histone acetylation, although the mechanism of ROS action (ROS signaling) is still unknown. Both DNA methylation and histone acetylation are nucleophilic processes and therefore ROS signaling through typical free radical processes, for example hydrogen atom abstraction is impossible. However, being super-nucleophile superoxide can participate in these reactions. Now we propose new nucleophilic mechanisms of DNA methylation and histone modification. During DNA methylation superoxide can deprotonate the cytosine molecule at C-5 position and by this accelerate the reaction of DNA with the positive-charged intermediate S-adenosyl-L-methionine (SAM). Superoxide can also deprotonate histone N-terminal tail lysines and accelerate the formation of their complexes with acetyl-coenzyme A (AcCoA), the supplier of acetyl groups. In cancer cells ROS enhance DNA methylation causing the silencing of tumor suppressor and antioxidant genes and enhancing the proliferation of cancer cells under condition of oxidative stress. ROS signaling in senescent cells probably causes DNA hypomethylation although there are insufficient data for such proposal.

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