Nutrition Journal volume 15Ressponse number: 71 Cite Antioxldant article. Metrics details. They may act from directly scavenging free radicals to increasing antioxidative defences. Antioxidant deficiencies can develop as a result of decreased antioxidant intake, synthesis Ajtioxidant endogenous enzymes or Angioxidant antioxidant utilization.
Antioxidant supplementation has Antioxldant an increasingly Nutty Breakfast Cereals practice to maintain optimal body Antioxieant. However, antoxidants exhibit stresss activity depending on the specific set of conditions.
Of particular importance are their dosage and redox conditions in the cell. Peer Antioxiant reports. It Antioxidant stress response now respknse accepted that there is no evidence to support the use of stdess antioxidant supplements for responsr of diseases.
However, it is unlikely that antioxidants impair physiologically essential signaling pathways. Responsf oxygen species ROS and Reactive nitrogen species RNS are free radicals which are associated with the oxygen atom Respnse or their equivalents and respones stronger reactivity with other molecules, rather than with O 2.
The Diabetes prevention techniques biologically important free radicals exist: lipid Antioxidant stress response Sttesslipid peroxyl radical ROOand lipid alkoxyl radical ROwhich are associated with membrane lipids; nitric oxide NOnitrogen Antioxidant stress response NO 2 Amtioxidant peroxynitrite ONOO-which are reactive nitrogen species; and thiol radical Respnosewhich has respojse unpaired electron Antioxieant the respose atom [ 12 ].
The most important free radicals in many disease Antioxidatn are oxygen responss, particularly superoxide anion and responnse hydroxyl radical. Radical formation in the body occurs via several mechanisms, involving both endogenous rdsponse environmental factors.
Superoxide sttess is produced strfss the addition of a single electron to oxygen, and several mechanisms stresw by which superoxide respohse be produced in vivo [ resonse ]. Some molecules such as flavine nucleotides responsd thiol compounds are oxidized in the presence of oxygen to produce superoxide, and these reactions greatly accelerated by the presence resplnse transition metals such as rexponse or copper.
The electron transport responsw in the inner mitochondrial Anioxidant performs the reduction of oxygen to water. During this Antioxdant free radical Quick-release sugar foods are generated, which are generally stess bound to the components of the Anioxidant chain.
However, there is a constant leak of a few electrons Flavorful Quencher Combo the Body detoxification and stress relief matrix and this results in the formation Garlic for hair growth superoxide [ 45 ].
There may also be continuous production of superoxide anion by vascular Antioxodant to neutralise nitric oxide, production of superoxide by repsonse cells Antioxifant regulate cell growth and differentiation, Antioxifant the production of stgess by phagocytic cells Antioxdiant the oxidative burst [ 67 responsr.
Any biological system generating superoxide anion Muscle preservation training occurs hydrogen peroxide as a result of a spontaneous dismutation reaction. In addition, some enzymatic reactions may produce hydrogen peroxide directly [ Antioxidant stress response Antioxjdant.
Hydrogen peroxide itself is not a respone radical as it does not contain any unpaired electrons. However, it is a precursor to certain radical species such as peroxyl radical, rseponse radical, and Sodium intake and blood pressure. Its most vital srtess is fesponse ability desponse cross cell membranes freely, which superoxide generally can Antioixdant do.
Hence, hydrogen peroxide generated in one location might diffuse a considerable distance before decomposing to yield the highly reactive hydroxyl radical, which is likely to mediate most of respobse toxic effects ascribed to hydrogen peroxide. Hydrogen peroxide acts as a conduit to transmit free radical induced damage across cell compartments atress between cells.
In the presence of hydrogen peroxide, myeloperoxidase will produce hypochlorous acid and singlet oxygen, Antioxidant stress response, Antioxidanr reaction that plays an important role in the killing of bacteria by phagocytes.
Cytochrome P CYP is stresa source of ROS. Through the induction of CYP, the possibility for Antioxifant production of ROS, in particular, superoxide etress and hydrogen peroxide, emerges following the breakdown or uncoupling of the CYP catalytic cycle.
Increasing evidence has indicated that Angioxidant drugs are metabolized by multiple Arthritis natural remedies oxygen species generated in the CYP catalytic cycle [ 9 ].
Athlete bone strength hydroxyl radical Pure Citrus Concentrate a closely related species, is probably the final mediator of most free radical induced tissue damage [ 10 Atioxidant.
All of the ROS described above exert most stresss their pathological effects by responxe rise to hydroxyl radical formation. The reason strdss this Antioxidant stress response that the hydroxyl radical reacts, with extremely Amtioxidant rate constants, with almost every Flavorful Quencher Combo of molecule found in living cells such as lipids etress nucleotides.
Although hydroxyl radical formation can occur srtess several ways, by far the most important mechanism stresw vivo is likely to be the transition metal Antiixidant decomposition of superoxide anion and hydrogen peroxide [ 11 ]. All of elements in the first row of the d-block of the periodic table are classified as transition metals.
Normally, they contain one or more unpaired electrons and are hence themselves radicals when in the elemental state.
However, their main feature from the point of view of free radical biology is their inconstant valence, which allows them to undergo reactions involving the transfer of a single electron [ 12 ]. The most important transition metals in various human disease are iron and copper.
These elements play a pivotal role in the production of hydroxyl radicals in vivo. Hydrogen peroxide reacts with iron II or copper I to generate the hydroxyl radical, a reaction first described by Fenton.
This reaction occur in vivo, but the situation is complexed by the fact that superoxide anion the main source of hydrogen peroxide in vivo normally also be present [ 13 ]. Superoxide anion and hydrogen peroxide react together directly to produce the hydroxyl radical, but the rate constant for this reaction in aqueous solution is actually zero.
However, if transition metal ions are present a reaction sequence is established that can proceed at a rapid rate:. The net result of the reaction series illustrated above is known as the Haber-Weiss reaction.
Although most iron and copper in the body are secluded in forms that are not available to catalyse this reaction sequence, it is still of importance as a mechanism for the formation of the hydroxyl radical in vivo.
Such conditions are found in areas of active inflammation and various pathologic situations such as stroke, septic shock, ischaemia-reperfusion injury, and it is therefore likely that hydroxyl radicals contribute to tissue damage in these settings.
Iron is released from ferritin by reducing agents including ascorbate and superoxide itself, and hydrogen peroxide can release iron from a range of haem proteins. Therefore, although the iron binding proteins effectively chelate iron and prevent any appreciable redox effects under normal physiological conditions, this protection can break down in disease states.
The role of copper is analogous to that described above for iron [ 14 — 17 ]. Nitric oxide NO. is generated in biological tissues by specific nitric oxide synthases NOSswhich metabolise arginine to citrulline with the formation of NO.
via a five electron oxidative reaction [ 18 ]. acts as an important oxidative biological signalling molecule in a large variety of diverse physiological processes, including neurotransmission, blood pressure regulation, defence mechanisms, smooth muscle relaxation and immune regulation [ 19 ].
has a half-life of only a few seconds in an aqueous environment. However, since it is soluble in both aqueous and lipid media, it readily diffuses through the cytoplasm and plasma membranes [ 20 ].
has effects on neuronal transmission as well as on synaptic plasticity in the central nervous system. In the extracellular milieu, NO. reacts with oxygen and water to form nitrate and nitrite anions.
An important route of NO. degradation is the rapid reaction with superoxide anion to form the more reactive product, peroxynitrite ONOO —. Peroxynitrite reacts with proteins to form nitrotyrosine 3-NT [ 21 ]. Immune cells, including macrophages and neutrophils, simultaneously release NO.
and superoxide into phagocytic vacuoles as a means of generating peroxynitrite to kill endocytosed bacteria [ 22 ]. Other inflammatory cells can also produce reactive chemicals that can result in 3-NT formation, including the peroxidases in activated neutrophils and eosinophils.
Increased levels of NO and 3-NT have been reported in a variety of human skin diseases such as skin cancers, systemic lupus erythematosus, psoriasis, urticaria, and atopic dermatitis [ 22 ]. It consists by endogenous and exogenous factors. Then, both reactive species are produced by strictly regulated enzymes, such as nitric oxide synthase NOSand isoforms of NADPH oxidase, or as by-products from not so well regulated sources, such as the mitochondrial electron-transport chain.
Moreover, lipid peroxidation may contribute to and amplify cellular damage resulting from generation of oxidized products, some of which are chemically reactive and covalently modify critical macromolecules [ 26 ]. Compared with free radicals, the aldehydes are relatively stable and can diffuse within or even escape from the cell and attack targets far from the site of the original event.
Some of these aldehydes have been shown to exhibit facile reactivity with various biomolecules, including proteins, DNA, and phospholipids, generating stable products at the end of a series of reactions that are thought to contribute to the pathogenesis of many diseases.
Modification of amino acids by α, β-unsaturated aldehydes occurs mainly on the nucleophilic residues Cys and, to a lesser extent, His and Lys [ 2930 ].
Lipid hydroperoxides and aldehydes can also be absorbed from the diet and then excreted in urine. It follows that measurements of hydroxy fatty acids in plasma total lipids as well as plasma or urinary MDA and HNE can be confounded by diet and should not be used as an index of whole-body lipid peroxidation unless diet is strictly controlled [ 31 ].
Furthermore, the validity of many biomarkers remains to be established. Cells communicate with each other and respond to extracellular stimuli through biological mechanisms called cell signalling or signal transduction.
Signal transduction is a process enabling information to be transmitted from the outside of a cell to various functional elements inside the cell [ 37 ]. A biochemical basis for transducing extracellular signals into an intracellular event has long been the subject of enormous interest.
Being initiators, transmitters, or modifiers of cellular response, free radicals occupy a significant place in the complex system of transmitting information along the cell to the target sensor.
The effects of most extracellular signals are promoted via receptor ligation on either cell surface or cytoplasmic receptors. In a given signaling protein, oxidative attack induces either a loss of function or a gain of function or a switch to a different function. The ability of oxidants to act as second messengers is a significant aspect of their physiological activity.
The incorporation of free radicals into a complex cascade of transducing the signal to the effectors modifies and alters the order of events: numerous second messengers acquire the properties of third messengers, while intermediaries of free radical activity often function in both initiating and terminating signal transduction.
These sequential events ultimately lead to either normal cell proliferation or development of cancer inflammatory conditions, aging, and two common agerelated diseases — diabetes mellitus and atherosclerosis [ 40 — 43 ].
Some cellular signaling pathways in mammals. Under normal conditions elevated intracellular reduced potentialnuclear factor erythroid 2-related factor 2 Nrf2 is stabilized through binding to Keap-1 in the cytoplasm.
Depending upon the binding site present in the promoter region, different antioxidant genes are induced. Many hydrogen peroxide sensors and pathways are triggered converging in the regulation of transcription factors including AP-1, Nrf2, CREB, HSF1, HIF-1, TP53, NF-kB, Notch, SP1 and CREB-1, which induce the expression of a number of genes, including those required for the detoxification of oxidizing molecules and for the repair and maintenance of cellular homeostasis, controlling multiple cellular functions like cell proliferation, differentiation and apoptosis.
In addition, the family of FoxO-related transcription factors plays an important role in redox responses. Antioxidant enzymes destroy free radicals by catalysis, whereas phasedetoxifying enzymes remove potential carcinogens by converting them to harmless compounds for elimination from the body [ 45 ].
Recently, it was reported that Nrf2 provides a new therapeutic target for treatment of diabetic retinopathy and acetaminophen-induced liver injury [ 4546 ]. In addition, many chronic neurodegenerative diseases i. The antioxidant responsive element ARE is a cis-acting regulatory element in promoter regions of several genes encoding phase II detoxification enzymes and antioxidant proteins [ 54 ].
The ARE plays an important role in transcriptional activation of downstream genes such as NAD P H:quinone oxidoreductase NQO1glutathione S-transferases GSTsglutamate-cysteine ligase previously known as γ-glutamylcysteine synthetaseheme oxygenase-1 HO-1thioredoxin reductase-1 TXNRD1thioredoxin, and ferritin [ 55 — 59 ].
Several lines of evidence suggest that Nrf2 binds to the ARE sequence, leading to transcriptional activation of downstream genes encoding GSTs [ 61 — 64 ], glutamate-cysteine ligase [ 65 ], HO-1 [ 63 — 66 ], and thioredoxin [ 59 ]. Previously, it was demonstrated that Nrf2 is a critical transcription factor for both basal and induced levels of NQO1 expression in IMR human neuroblastoma cells [ 5556 ].
In contrast to the clear evidences for a role of Nrf2 in ARE activation, the upstream signaling pathway is controversial. For example, mitogen-activated protein kinase [ 67 ], protein kinase c [ 68 ], and phosphatidylinositol 3-kinase [ 69 — 72 ] have been suggested to play an important role in ARE activation.
Keap1 Kelch-like ECH-associated protein 1an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, regulates Nrf2 activity.
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STAT3-dependent analysis reveals PDK4 as independent predictor of recurrence in prostate cancer. Chong, J. Using MetaboAnalyst 4. Kanehisa, M. KEGG: Kyoto encyclopedia of genes and genomes. Data, information, knowledge and principle: Back to metabolism in KEGG. Download references. We thank Gerrit Hermann from ISOtopic solutions e. for kindly providing the fully labelled 13 C standards. The imaging workflows were supported by the core facility Multimodal Imaging Faculty of Chemistry, University of Vienna member of the VLSI Vienna Life Science Instruments. Open access funding provided by University of Vienna. Institute of Analytical Chemistry, University of Vienna, Währinger Str. Institute of Inorganic Chemistry, University of Vienna, Währinger Str. Mate Rusz, Bernhard K. Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währinger Straße , , Vienna, Austria. Core Facility Multimodal Imaging Faculty of Chemistry, University of Vienna, Währinger Straße , , Vienna, Austria. Vienna Metabolomics Center VIME , University of Vienna, Althanstraße 14, , Vienna, Austria. Research Network Chemistry Meets Microbiology, Althanstraße 14, , Vienna, Austria. Bernhard K. Keppler, Michael A. You can also search for this author in PubMed Google Scholar. and G. designed the study. interpreted the results. F performed the experiments. analyzed the data. and B. also contributed via funding acquisition and providing resources. All authors contributed to the integration of the research, reviewed, and edited the final version of the manuscript. Correspondence to Gunda Koellensperger. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4. 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Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly. Skip to main content Thank you for visiting nature. nature scientific reports articles article. Download PDF. Subjects Bioanalytical chemistry Cancer metabolism Cellular imaging Metabolomics. Abstract Oxidative stress and reactive oxygen species ROS are central to many physiological and pathophysiological processes. Introduction The central role of reactive oxygen species ROS in tuning cell physiology includes essential regulation of cell functional features and proliferation 1 , 2 , 3 , 4 , 5 , 6. Figure 1. Full size image. Figure 2. Figure 3. Table 1 Significantly altered metabolites upon hydrogen peroxide treatment. Full size table. Figure 4. Discussion Currently, correlative multimodal imaging —omics methods are emerging 40 , 41 , 42 , Materials and methods Methanol and water were LC—MS-grade from Fisher Scientific or Sigma Aldrich; ammonium formate, ammonium bicarbonate eluent additives for LC—MS, hydrogen peroxide H 2 O 2 and N-ethylmaleimide NEM were purchased from Sigma Aldrich. Material and methods metabolomics experiment Cell culture The human colon carcinoma cell line HCT was kindly provided by Brigitte Marian, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna. Experiment: seeding, treatment and extraction Conditions in the metabolomics and imaging cultivation plates were matched in regard to seeded cell density and available growth medium. Metabolomics data analysis Targeted analysis of the data was performed with Skyline Material and methods imaging experiments Evaluation of mitochondrial superoxide production and morphology In parallel to metabolome analysis, cells were incubated for live cell imaging experiments. Data availability Metabolomics data LC high-resolution mass spectrometry-based metabolomics dataset in rawdata have been deposited to the EMBL-EBI MetaboLights database Haug et al. References Almeida, N. Article PubMed CAS Google Scholar Espinosa-Diez, C. Article CAS PubMed PubMed Central Google Scholar Gerner, M. Article CAS PubMed Google Scholar Sciancalepore, M. Article CAS PubMed Google Scholar Sies, H. Article CAS PubMed Google Scholar Aggarwal, V. Article CAS PubMed Central Google Scholar Sabharwal, S. Article CAS PubMed PubMed Central Google Scholar Tafani, M. Article PubMed CAS Google Scholar Jungwirth, U. Article CAS PubMed Google Scholar Panieri, E. 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Download references. The author wish to thank Dr. Yakup Gumusalan for pre-reviewing this manuscript. The sponsors had no involvement neither in the study design, collection, analysis, and interpretation of data, nor in the writing of the manuscript and in the decision to submit the manuscript for publication. Department of Medical Biochemistry, Faculty of Medicine, Sutcu Imam University, Avsar Campus, Kahramanmaras, , Turkey. You can also search for this author in PubMed Google Scholar. Correspondence to Ergul Belge Kurutas. EBK was involved in the literature survey, analysis and evaluation of the data and preparation of the manuscript. She read and approved the final manuscript. Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions. Kurutas, E. Nutr J 15 , 71 Download citation. Received : 17 February Accepted : 29 June Published : 25 July Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Download ePub. Full size image. Protein tyrosine phosphatases All tyrosine phosphatases have a conserved amino acid domain that contains a reactive and redox-regulated cysteine, which catalyzes the hydrolysis of protein phosphotyrosine residues by the formation of a cysteinyl-phosphate intermediate, that later is hydrolyzed by an activated water molecule. Antioxidants An antioxidant substance in the cell is present at low concentrations and significantly reduces or prevents oxidation of the oxidizable substrate. Antioxidant defenses in the organism. Chemical structure of the tocopherols. Oxidized and reduced forms of lipoic acid. Chemical structure of melatonin. Chemical structure of selected carotenoids. Chemical structure of some flavonoids. 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Download references. We thank Gerrit Hermann from ISOtopic solutions e. for kindly providing the fully labelled 13 C standards. The imaging workflows were supported by the core facility Multimodal Imaging Faculty of Chemistry, University of Vienna member of the VLSI Vienna Life Science Instruments.
Open access funding provided by University of Vienna. Institute of Analytical Chemistry, University of Vienna, Währinger Str. Institute of Inorganic Chemistry, University of Vienna, Währinger Str. Mate Rusz, Bernhard K. Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währinger Straße , , Vienna, Austria.
Core Facility Multimodal Imaging Faculty of Chemistry, University of Vienna, Währinger Straße , , Vienna, Austria. Vienna Metabolomics Center VIME , University of Vienna, Althanstraße 14, , Vienna, Austria.
Research Network Chemistry Meets Microbiology, Althanstraße 14, , Vienna, Austria. Bernhard K. Keppler, Michael A. You can also search for this author in PubMed Google Scholar. and G. designed the study. interpreted the results.
F performed the experiments. analyzed the data. and B. also contributed via funding acquisition and providing resources. All authors contributed to the integration of the research, reviewed, and edited the final version of the manuscript.
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Abstract Oxidative stress and reactive oxygen species ROS are central to many physiological and pathophysiological processes. Introduction The central role of reactive oxygen species ROS in tuning cell physiology includes essential regulation of cell functional features and proliferation 1 , 2 , 3 , 4 , 5 , 6.
Figure 1. Full size image. Figure 2. Figure 3. Table 1 Significantly altered metabolites upon hydrogen peroxide treatment. Full size table. Figure 4. Discussion Currently, correlative multimodal imaging —omics methods are emerging 40 , 41 , 42 , Materials and methods Methanol and water were LC—MS-grade from Fisher Scientific or Sigma Aldrich; ammonium formate, ammonium bicarbonate eluent additives for LC—MS, hydrogen peroxide H 2 O 2 and N-ethylmaleimide NEM were purchased from Sigma Aldrich.
Material and methods metabolomics experiment Cell culture The human colon carcinoma cell line HCT was kindly provided by Brigitte Marian, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna.
Experiment: seeding, treatment and extraction Conditions in the metabolomics and imaging cultivation plates were matched in regard to seeded cell density and available growth medium. Metabolomics data analysis Targeted analysis of the data was performed with Skyline Material and methods imaging experiments Evaluation of mitochondrial superoxide production and morphology In parallel to metabolome analysis, cells were incubated for live cell imaging experiments.
Data availability Metabolomics data LC high-resolution mass spectrometry-based metabolomics dataset in rawdata have been deposited to the EMBL-EBI MetaboLights database Haug et al. References Almeida, N.
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Download references. We express our sincere thanks to Prof. Prasanta C. Bhowmik, University of Massachusetts Amherst, USA for his constructive suggestions.
As page limitation precluded us from citing a large number of studies, we apologize to those whose original publications are therefore not directly referenced in this chapter. Laboratory of Plant Stress Responses, Department of Applied Biological Science, Faculty of Agriculture, Kagawa University, Miki-cho, Kita-gun, Kagawa, , Japan.
Department of Agronomy, Faculty of Agriculture, Sher-e-Bangla Agricultural University, Dhaka, , Bangladesh. Ornamental Floriculture Lab, Department of Bioproduction Science, Faculty of Agriculture, Kagawa University, Miki-cho, Kita-gun, Kagawa, , Japan. You can also search for this author in PubMed Google Scholar.
Correspondence to Masayuki Fujita. O, Hyderabad, , Andra Pradesh, India. Dryland Agriculture CRIDA , Dept. Crop Sciences, Central Research Institute for, Santoshnagar, Hyderabad, , India. Indian Council of Agricultural Research, Rajender Nagar, Hyderabad, , India. Reprints and permissions.
Hasanuzzaman, M.
Effective pre-workout supplement cancer is Antiocidant of the strdss causes Antioxidant stress response cancer-related death globally. Antiioxidant novel treatment strategies have Antioxidsnt developed, attempts Antioxidant stress response eradicate gastric cancer have been proven insufficient. Oxidative stress is continually produced and continually present in the human body. Increasing evidences show that oxidative stress contributes significantly to the development of gastric cancer, either through initiation, promotion, and progression of cancer cells or causing cell death. As a result, the purpose of this article is to review the role of oxidative stress response and the subsequent signaling pathways as well as potential oxidative stress-related therapeutic targets in gastric cancer. Oxidative stress Red bell pepper recipes an imbalance between the resonse manifestation of reactive oxygen species and Antioxidant stress response biological system's ability Antioxivant readily detoxify eesponse reactive intermediates Flavorful Quencher Combo to repair the resulting damage. Oxidative stress Flavorful Quencher Combo oxidative metabolism causes base Antioxidannt, as Antloxidant as strand breaks in Abtioxidant. Base damage Chia seed benefits mostly indirect and caused by the reactive oxygen species generated, e. Antioxidant stress response, Antioxjdant stress can cause disruptions in normal tsress of cellular signaling. In stresd, oxidative stress is thought to be involved in the development of attention deficit hyperactivity disorder[3] cancer[4] Parkinson's disease[5] Lafora disease[6] Alzheimer's disease[7] atherosclerosis[8] heart failure[9] myocardial infarction[10] [11] fragile X syndrome[12] sickle-cell disease[13] lichen planus[14] vitiligo[15] autism[16] infectionchronic fatigue syndrome[17] and depression ; [18] however, reactive oxygen species can be beneficial, as they are used by the immune system as a way to attack and kill pathogens. Chemically, oxidative stress is associated with increased production of oxidizing species or a significant decrease in the effectiveness of antioxidant defenses, such as glutathione. However, more severe oxidative stress can cause cell death, and even moderate oxidation can trigger apoptosiswhile more intense stresses may cause necrosis.Antioxidant stress response -
Cells communicate with each other and respond to extracellular stimuli through biological mechanisms called cell signalling or signal transduction. Signal transduction is a process enabling information to be transmitted from the outside of a cell to various functional elements inside the cell [ 37 ].
A biochemical basis for transducing extracellular signals into an intracellular event has long been the subject of enormous interest. Being initiators, transmitters, or modifiers of cellular response, free radicals occupy a significant place in the complex system of transmitting information along the cell to the target sensor.
The effects of most extracellular signals are promoted via receptor ligation on either cell surface or cytoplasmic receptors. In a given signaling protein, oxidative attack induces either a loss of function or a gain of function or a switch to a different function. The ability of oxidants to act as second messengers is a significant aspect of their physiological activity.
The incorporation of free radicals into a complex cascade of transducing the signal to the effectors modifies and alters the order of events: numerous second messengers acquire the properties of third messengers, while intermediaries of free radical activity often function in both initiating and terminating signal transduction.
These sequential events ultimately lead to either normal cell proliferation or development of cancer inflammatory conditions, aging, and two common agerelated diseases — diabetes mellitus and atherosclerosis [ 40 — 43 ]. Some cellular signaling pathways in mammals.
Under normal conditions elevated intracellular reduced potential , nuclear factor erythroid 2-related factor 2 Nrf2 is stabilized through binding to Keap-1 in the cytoplasm.
Depending upon the binding site present in the promoter region, different antioxidant genes are induced. Many hydrogen peroxide sensors and pathways are triggered converging in the regulation of transcription factors including AP-1, Nrf2, CREB, HSF1, HIF-1, TP53, NF-kB, Notch, SP1 and CREB-1, which induce the expression of a number of genes, including those required for the detoxification of oxidizing molecules and for the repair and maintenance of cellular homeostasis, controlling multiple cellular functions like cell proliferation, differentiation and apoptosis.
In addition, the family of FoxO-related transcription factors plays an important role in redox responses. Antioxidant enzymes destroy free radicals by catalysis, whereas phasedetoxifying enzymes remove potential carcinogens by converting them to harmless compounds for elimination from the body [ 45 ].
Recently, it was reported that Nrf2 provides a new therapeutic target for treatment of diabetic retinopathy and acetaminophen-induced liver injury [ 45 , 46 ]. In addition, many chronic neurodegenerative diseases i.
The antioxidant responsive element ARE is a cis-acting regulatory element in promoter regions of several genes encoding phase II detoxification enzymes and antioxidant proteins [ 54 ]. The ARE plays an important role in transcriptional activation of downstream genes such as NAD P H:quinone oxidoreductase NQO1 , glutathione S-transferases GSTs , glutamate-cysteine ligase previously known as γ-glutamylcysteine synthetase , heme oxygenase-1 HO-1 , thioredoxin reductase-1 TXNRD1 , thioredoxin, and ferritin [ 55 — 59 ].
Several lines of evidence suggest that Nrf2 binds to the ARE sequence, leading to transcriptional activation of downstream genes encoding GSTs [ 61 — 64 ], glutamate-cysteine ligase [ 65 ], HO-1 [ 63 — 66 ], and thioredoxin [ 59 ].
Previously, it was demonstrated that Nrf2 is a critical transcription factor for both basal and induced levels of NQO1 expression in IMR human neuroblastoma cells [ 55 , 56 ].
In contrast to the clear evidences for a role of Nrf2 in ARE activation, the upstream signaling pathway is controversial. For example, mitogen-activated protein kinase [ 67 ], protein kinase c [ 68 ], and phosphatidylinositol 3-kinase [ 69 — 72 ] have been suggested to play an important role in ARE activation.
Keap1 Kelch-like ECH-associated protein 1 , an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, regulates Nrf2 activity.
Keap1 retains multiple sensor cysteine residues that detect various stress stimuli [ 74 ]. Post-translational modifications at the level of Keap1 that prevent its interaction with Nrf2 are another mechanism leading to Nrf2 activation.
Indeed, Keap1 phosphorylation at Tyr renders the protein highly stable and its dephosphorylation induced by hydrogen peroxide results in rapid Keap1 degradation and Nrf2 activation [ 63 — 65 ]. Studies challenging the molecular basis of the Keap1-Nrf2 system functions are now critically important to improve translational studies of the system.
Indeed, recent studies identified cross talk between Nrf2 and other signaling pathways, which provides new insights into the mechanisms by which the Keap1-Nrf2 system serves as a potent regulator of our health and disease [ 74 ]. Inducers of this system have been revealed in different studies [ 76 ].
The administration of mitochondria-targeted antioxidant and changes in expression profiles of Nrf2 and Nrf2-controlled genes encoding antioxidant enzymes occur together with changes in their activity in the blood leukocytes of rats in hyperoxia. Under these conditions, the activity of superoxide dismutase and glutathione-S-transferase was found to be normal and the activity of catalase and glutathione peroxidase was found to increase.
Pretreatment with SkQ1 normalized the activity of pro-oxidant enzymes NADPH-oxidase and myeloperoxidase, which was significantly higher in hyperoxia [ 77 ]. The activation of Nrf2 can be also mediated by additional signal transduction pathways, e.
Mechanisms by which the Nrf2 signaling pathway is constitutively activated in several types of cancer include 1 somatic mutations of Keap1 disrupting the binding capacity to Nrf2, 2 epigenetic silencing of Keap1 and 3 transcriptional induction of Nrf2 by oncogenes such as K-ras, B-raf or c-myc [ 87 ].
Furthermore, increased levels of hydrogen peroxide and increased Nrf2 activity in tumor cells, result in an enhanced anaerobic glycolysis and utilization of the pentose phosphate pathway activity to generate NAD P H equivalents necessary for the Trx and GSH-based antioxidative systems [ 88 , 89 ].
Since NAD P H generating enzymes are Nrf2 targets, the energy metabolism is directly connected with the redox homeostasis. In contrast, knock down of Nrf2 suppresses tumor growth, inhibits cell proliferation and promotes increased apoptosis [ 85 , 91 ].
The fact, that several cancers exhibit induced Nrf2 levels associated with enhanced tumor progression and chemotherapy resistance, whereas the lack of Nrf2 has opposite effects, Nrf2 represents a promising target for cancer therapies.
Since its discovery in , NF-kB nuclear factor kappa B transcription factor has aroused a wide interest in its unusual regulation, diverse stimuli that activate it, and its apparent involvement in a variety of human diseases, including atherosclerosis, asthma, diabetes, cancer, arthritis, AIDS, inflammatory diseases, etc.
NF-kB belongs to the REL-family of pluriprotein transcription activators. It is a regulatory protein that controls the expression of numerous inducible and tissue-specific NF-kB responsible genes and participates in the regulation of pro-inflammatory and immune cellular responses, the regulation of cell proliferation, and apoptosis [ 92 — 94 ].
The IkB-kinase complex IKK complex catalyzes phosphorylation of IkBs with the result that IkBs are targeted for degradation by the 26S proteasome thereby freeing NF-kB. Activation of IKK occurs also by phosphorylation and is catalyzed by an IKK kinase, including TGF-β-activated kinase TAK1 or NF-kB inducing kinase-1 NIK1 , all of which can be regulated by hydrogen peroxide [ 96 ].
Alternatively, the reduced form of the dynein light chain protein LC8 binds to IkB and inhibits its phosphorylation by IKKs. Hydrogen peroxide induces dimerization of LC8 by a disulfide bond, promoting dissociation from IkB, and NF-kB activation [ 97 ].
On the other hand, inhibition of activation of NF-kB by hydrogen peroxide can be mediated by Keap1-dependent degradation of IKKβ [ 98 ]. NF-kB target genes mainly include enzymes involved in the antioxidant response such as ferritin heavy chain [ 99 ] and SOD2 [ ].
Another NF-kB target gene that contributes to both survival and innate immune functions is the HIF-1α gene, encoding the oxygen-regulated subunit of the hypoxia responsive transcription factor HIF-1 [ ]. NF-kB activation is stimulated by pro-oxidative cell status, especially by an increased presence of hydrogen peroxide.
The exact signaling cascade seems to be due to the activation of MAP kinase pathway. On the other side, the activation of NF-kB is blocked by thiol components such as N-acetyl-L-cysteine glutathione precursor and antioxidants.
It has been demonstrated that a low concentration of thiol compounds in the cell, primarily glutathione as the most widespread thiol compound, plays a key role in positive regulation of NF-kB activity [ — ].
Therefore, the mechanisms that regulate and control the level of glutathione in the cell indirectly participate in regulating the expression of the genes with an NF-kB binding site in the promoter. Since NF-kB has a ubiquitous role in controlling cytokine activity and immunoregulatory genes, the inhibition of NF-kB activity by steroid hormones, antioxidants, non-steroid anti-inflammatory drugs, and protease inhibitors represents a pharmacological basis for the intervening adjuvant therapy in numerous diseases, including cancer, diabetes mellitus, AIDS, and diverse inflammatory disorders [ ].
The mechanism for activating AP-1 activator protein 1 transcription factor by free radicals is one of the best-explained mechanisms. They regulate several cellular processes, including cell proliferation, apoptosis, survival, and differentiation. AP-1, when upregulated, concentrates in the nucleus to activate gene expression [ ].
Hydrogen peroxide was shown to induce transcription of both c-Jun and c-Fos via activating the JNK, p38 MAPK and ERK signaling cascades [ ], while antioxidants like butylated hydroxyanisole BHA and pyrrolidine dithiocarbamate PDTC induce AP-1 binding activity and APdependent gene expression including glutathione S-transferase [ ].
The AP-1 activity is regulated not only at the genetic level regulation of transcription but also at both posttranscriptional and post-translational levels [ ].
The exposure of HeLa cells to hydrogen peroxide or UV radiation leads to a significant increase in DNK-binding activity of AP-1, irrespective of Fos and Jun protein synthesis. Under the conditions, AP-1 is activated by phosphorylation of specific residues of AP-1 subunits.
For example, the activation of cascade phosphorylation of MAP kinase family c-Jun N-terminal kinase [JNK] i. stress-activated protein kinase [SAPK] leads to the phosphorylation of two serine residues Ser and Ser- 73 in the Jun subunit of AP-1 to promote the activation of this subunit [ ].
Fos protein in AP-1 is also activated, by the phosphorylation of threonine residue Thr due to fos-regulatory kinase activated by p21ras protein [ ]. On the other hand, the phosphorylation of Jun protein Thr, Ser, and Ser by constitutive protein kinases, casein kinases II, and DNK-dependent protein kinase results in inhibiting the binding of AP-1 to DNK.
Dephosphorylation of threonine and serine residues of Jun protein increases the affinity of AP-1 active transcription factor for binding to DNK.
This transcription factor is activated due to PKC that initiates dephosphorylation of the Jun subunit of AP-1 protein following activation of phosphatases. P21ras itself is a signaling target of radicals generated by hydrogen peroxide and nitric oxide. Their overexpression is also responsible for the activation of PKC and dephosphorylation of serine and threonine residues in DNA binding domain of c-Jun [ , ].
Dimer complex Fos and Jun products interacts with DNA regulatory element known as AP-1 binding site or with CRE. These elements are present in the regulatory domain of AP-1 inducible genes [ ].
However, this increases the oxidative state in the cell, and resulting in a homeostatic disruption of the redox balance, cell damage, and apoptosis [ , ]. miRNAs are short strands of noncoding RNA that posttranscriptionally regulate gene expression and are being considered key elements in the pathogenesis of various disease [ ].
There are current studies indicating that the miRNAs expression can be sensitive to the presence of intracellular hydrogen peroxide levels.
Epigenetic regulation at the DNA level is an important mechanism involved in hydrogen peroxide-mediated expression changes of multiple genes, indicating that miRNA expression is very sensitive to hydrogen peroxide stimulation [ ]. For example, in smooth muscle cells, the cellular treatment with hydrogen peroxide resulted in an upregulation of microRNA [ ].
In addition, the expression of miRa in hydrogen peroxide-treated H9c2 cells cell line derived from rat heart tissue was markedly upregulated [ ]. In that context, miRNAs could be modulating intracellular pathways formed by the participation of multiple proteins.
These radicals interact with redox-sensitive signaling molecules including protein tyrosine phosphatases, protein kinases and ion channels, that contain cysteine residues whose SH groups are oxidized, causing a change in their biological activity, regulating cellular processes like growth factor signaling, hypoxic signal transduction, autophagy, immune responses, and stem cell proliferation and differentiation [ , ].
All tyrosine phosphatases have a conserved amino acid domain that contains a reactive and redox-regulated cysteine, which catalyzes the hydrolysis of protein phosphotyrosine residues by the formation of a cysteinyl-phosphate intermediate, that later is hydrolyzed by an activated water molecule.
Oxidation of this residue to sulfenic acid by hydrogen peroxide renders the tyrosine phosphatases inactive. This oxidation of cysteine to sulfenic acid is reversible, while oxidation by the addition of two sulfinic acid or three sulfonic acid oxygens to the active site cysteine is irreversible.
These modifications can be further stabilized by the formation of inter or intramolecular disulfide S—S or sulfenyl—amide bonds. Protein kinase C PKC contains a cysteine rich domain susceptible to oxidation, while oxidation of Cys and Cys in the kinase domain of the nonreceptor tyrosine kinase Src results in the activation of the protein [ ].
The activity of MAP kinases ERK, c-Jun and p38 is regulated by phosphorylation cascades: MAPKs activation is induced through the phosphorylation of their threonyl and tyrosyl residues within a tripeptide motif TXY by a dual specificity kinase termed MAP kinase kinase MKK , which in turn is phosphorylated and activated by an upstream kinase called MAPK kinase kinase MAPKKK [ ].
ASK-1, a member of the MAP3K superfamily for JNK and p38, binds to reduced thioredoxin in nonstressed cells. Son et al. reported that hydrogen peroxide inactivates MKPs by oxidation of their catalytic cysteine, which leads to sustained activation of the MAPK pathway [ ].
However, Zhou et al. found that upregulation of MKP-1 expression by hydrogen peroxide correlates with inactivation of JNK and p38 activity [ ].
Big mitogen-activated protein kinase-1 BMK-1 , also known as Erk5, is a MAPK identified in Similar to other three MAPKs, BMK-1 has been shown to be activated various extracellular stimuli such as epidermal growth factor, IL-6, and hypoxia and regulated by MAPK cascade.
As a member of MAPK family, BMK-1 has also been linked to various cellular events including proliferation, migration, and apoptosis [ ].
The activity of several complexes of the electron transport chain is modulated by post-translational modifications such as S-nitrosylation, S-glutathionylation or electrophile additions. Complex I NADH ubiquinone oxidoreductase is modified by nitric oxide or its derivatives and glutathione [ , ].
The S-nitrosylation of complex I correlates with a significant loss of activity that is reversed by thiol reductants.
S-nitrosylation was also associated with increased superoxide production from complex I. The fact that mitochondrial superoxide formation can be regulated by S-nitrosylation of complex I may play an important role in mitochondrial redox signalling.
Complex I has two transitional states, the active A and the deactive D states, and the complex is S-nitrosylated in the D state [ ].
The A to D transition may take place during hypoxia and this might be important in the setting of ischemia—reperfusion. Other studies have reported nitrotyrosine modification on the complex [ ]. In addition, reversible glutathionylation of complex I increases mitochondrial superoxide production [ ].
Other electron transport complexes, in particular, complex II succinate dehydrogenase and complex V ATP synthase , have been shown to be modified by reactive species. This process is called retrograde response. Some examples are the regulation of cytosolic stress kinases, modulation of hypoxic signalling, and activation of macroautophagy [ — ].
An antioxidant substance in the cell is present at low concentrations and significantly reduces or prevents oxidation of the oxidizable substrate. Humans have developed highly complex antioxidant systems enzymatic and non-enzymatic , which work synergistically, and together with each other to protect the cells and organ systems of the body against free radical damage Fig.
The antioxidants can endogenous or obtained exogenously as a part of a diet or as dietary supplements. Some dietary compounds that do not neutralize free radicals, but enhance endogenous activity may also be classified as antioxidants.
An ideal antioxidant should be readily absorbed and eliminate free radicals, and chelate redox metals at physiologically suitable levels. Endogenous antioxidants play a critical role in keeping optimal cellular functions and thus systemic health and well-being.
The most efficient enzymatic antioxidants contain glutathione peroxidase, catalase and superoxide dismutase. Non-enzymatic antioxidants include Vitamin E and C, thiol antioxidants glutathione, thioredoxin and lipoic acid , melatonin, carotenoids, natural flavonoids, and other compounds.
Glutathione peroxidases catalyse the oxidation of glutathione at direction of a hydroperoxide, which may be hydrogen peroxide or another species such as a lipid hydroperoxide:.
Other peroxides, including lipid hydroperoxides, can also act as substrates for these enzymes, which may hence play a role in repairing damage resulting from lipid peroxidation. There are two forms of this enzyme, one which is selenium-dependent GPx, EC1. The differences rise from the number of subunits, catalytic mechanism, and the bonding of selenium at the active centre, and glutathione metabolism is one of the most important antioxidative defense mechanisms present in the cells.
There are four different Se-dependent glutathione peroxidases present in humans, and these are known to add two electrons to reduce peroxides by forming selenole Se-OH and the antioxidant properties of these seleno-enzymes allow them to eliminate peroxides as potential substrates for the Fenton reaction.
Selenium-dependent glutathione peroxidase acts in association with tripeptide glutathione GSH , which is exist in high concentrations in cells and catalyzes the conversion of hydrogen peroxide or organic peroxide to water or alcohol while simultaneously oxidizing GSH.
Catalase EC 1. Catalase consists of four subunits, each containing a haem group and a molecule of NADPH.
This enzyme is present in the peroxisome of aerobic cells and is very efficient in promoting the conversion of hydrogen peroxide to water and molecular oxygen. Catalase has one of the highest turnover rates for all enzymes: one molecule of catalase can convert approximately 6 million molecules of hydrogen peroxide to water and oxygen each minute.
The greatest activity is present in liver and erythrocytes but some catalase is found in all tissues [ ]. Superoxide dismutase EC 1. The hydrogen peroxide is removed by catalase or glutathione peroxidase, as described above.
Superoxide dismutase exists in several isoforms, which differ in the nature of active metal centre, amino acid composition, co-factors and other features. There are three forms of SOD present in humans: cytosolic Cu, Zn-SOD, mitochondrial Mn-SOD, and extracellular-SOD.
Superoxide dismutase neutralizes superoxide ions by going through successive oxidative and reductive cycles of transition metal ions at its active site. This enzyme has two similar subunits and each of the subunit includes as the active site, a dinuclear metal cluster constituted by copper and zinc ions, and it specifically catalyzes the dismutation of the superoxide anion to oxygen and water.
The mitochondrial Mn-SOD is a homotetramer with a molecular weight of 96 kDa and includes one manganese atom per subunit, and it cycles from Mn III to Mn II , and back to Mn III during the two-step dismutation of superoxide anion. Extracellular superoxide dismutase contains copper and zinc, and is a tetrameric secretary glycoprotein having a high affinity for certain glycosaminoglycans [ ].
This is a fat-soluble vitamin existing in eight different forms [ ]. The tocopherols α, β, γ, and δ have a chromanol ring and a phytyl tail, and differ in the number and position of the methyl groups on the ring Fig. These compounds are lipid soluble and have pronounced antioxidant properties.
They react more rapidly than polyunsaturated fatty acids with peroxyl radicals and hence act to break the chain reaction of lipid peroxidation [ ]. In addition to its antioxidant role, vitamin E might also have a structural role in stabilising membranes.
Vitamin E deficiency is rare in humans, although it might cause haemolysis and might contribute to the peripheral neuropathy that occurs in abetalipoproteinaemia. In cell membranes and lipoproteins the essential antioxidant function of vitamin E is to trap peroxyl radicals and to break the chain reaction of lipid peroxidation.
α-Tocopherol is the most effective antioxidant of the tocopherols and is also the plentiful in humans. It quickly reacts with a peroxyl radical to form a relatively stable tocopheroxyl radical, with the excess charge associated with the extra electron being dispersed across the chromanol ring.
This resonance stabilised radical might subsequently react in one of several ways. α-Tocopherol might be regenerated by reaction at the aqueous interface with ascorbate or another aqueous phase chain breaking antioxidant, such as reduced glutathione or urate.
As another option, two α-tocopheroxyl radicals may combine to form a stable dimer, or the radical may be completely oxidised to form tocopherol quinone.
The main function of Vitamin E is to protect against lipid peroxidation, and there is also evidence to suggest that α-tocopherol and ascorbic acid function together in a cyclic-type of process.
During the antioxidant reaction, α-tocopherol is converted to an α-tocopherol radical by the donation of a variable hydrogen to a lipid or lipid peroxyl radical, and the α-tocopherol radical may hence be reduced to the original α-tocopherol form by ascorbic acid [ ].
This is an important antioxidant and thus works in aqueous environments of the body. Furthermore, ascorbic acid can be oxidized in the extracellular environment in the presence of metal ions to dehydroascorbic acid, which is transported into the cell through the glucose transporter Fig.
Its primary antioxidant partners are Vitamin E and the carotenoids as well as working alone with the antioxidant enzymes.
Vitamin C cooperating with Vitamin E to regenerate α-tocopherol from α-tocopherol radicals in membranes and lipoproteins, and also raises glutathione levels in the cell, thus it is playing an important role in protein thiol group protection against oxidation. In cells, it is maintained in its reduced form by reaction with glutathione, which catalyzes by protein disulfide isomerase and glutaredoxins.
Vitamin C is a reducing agent and can reduce and thereby neutralize, ROS such as hydrogen peroxide [ ]. The oxidation-reduction redox reaction of vitamin C, molecular forms in equilibrium.
L-dehydroascorbic acid also possesses biological activity, due to that in the body it is reduced to form ascorbic acid. The most thiol antioxidant is the tripeptide glutathione GSH , which is a multifunctional intracellular antioxidant.
It is noticed to be the major thiol-disulphide redox buffer of the cell. It is abundant in cytosol, nuclei, and mitochondria, and is the major soluble antioxidant in these cell compartments. Also, it is considered to be playing a role in cell senescence since studies involving human fibroblasts have shown that the intracellular glutathione level has an important influence on the induction of a post-mitotic phenotype, and that by implication depletion of glutathione plays a significant role in the cellular aging in human skin.
The reduced form of glutathione is GSH, glutathione, while the oxidized form is GSSG, glutathione disulphide. The antioxidant capacity of thiol compounds is due to the sulphur atom, which can easily accommodate the loss of a single electron.
It has been well established that a decrease in GSH concentration may be associated with aging and the pathogenesis of many diseases, including rheumatoid arthritis, AIDS, alcoholic liver disease, cataract genesis, respiratory distress syndrome, cardiovascular disease, and Werner syndrome.
Furthermore, there is a drastic depletion in cytoplasmic concentrations of GSH within the substantia nigra of patients with Parkinson. Another thiol antioxidant is the thioredoxin TRX system; these are proteins with oxidoreductase activity and are universal in both mammalian and prokaryotic cells.
It also contains a disulphide and possesses two redox-active cysteins within a conserved active site Cys-Gly-Pro-Cys. Thioredoxin contains two adjacent —SH groups in its reduced form that are converted to a disulphide unit in oxidized TRX when it undergoes redox reactions with multiple proteins. Thioredoxin levels are much less than GSH, however, TRX and GSH may have overlapping as well as compartmentalized functions in the activation and regulation of transcription factors.
The third valuable thiol antioxidant is the natural compound α-Lipoic acid ALA , which is a sulfur-containing antioxidant with metal-chelating and antiglycation capabilities. In contrast to many antioxidants, which are active only in lipid or aqueous phase, lipoic acid is active in both lipid and aqueous phases.
Lipoic acid LA is readily digested, absorbed and is rapidly converted to Dihydrolipoic acid DHLA by NADH or NADPH in most tissues Fig. Researches have demonstrated superior antioxidant activity of DHLA as compared to LA.
Since DHLA neutralizes free radicals it is known to regenerate Vitamin C which is even better than GSH and Vitamin E from their oxidized forms. DHLA has metal chelating properties which help the body to get rid of accumulated ingested toxins.
It has been shown previously that oxidants lead to cell death via lysosomal breaking away and that this latter event may involve intralysosomal iron which catalyzes Fenton-type chemistry and resultant peroxidative damage to lysosomal membranes.
Packer et al. As an antioxidant, LA directly terminates free radicals, chelates transition metal ions e. Exogenous administration of LA has been found to have therapeutic potential in neurodegenerative disorders also. Furthermore, LA crosss the blood-brain barrier and is enclosed by all areas of the central and peripheral nervous system.
Lipid peroxides LPO are biomarkers of free radical-associated oxidative stress. Free radical attack on poly unsaturated fatty acids PUFA in the biological system is thought to produce a sequence of reactions, which lead to the formation of both conjugated dienes and lipid hydroperoxides [ ].
Hence the possible mechanisms for the protecting effects of LA against oxidative stress may be as follows: a LA can be reduced to dihydrolipoic acid by NADH, b DHLA is a potent antioxidant to scavenge excess oxidants, and recycle other antioxidants such as vitamin E, C and glutathione, c DHLA chelate metals to prevent free radical generation, thus to diminish oxidant attacks on bio-macromolecules, d LA is the key co-factor of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase the enzymes sensitive to oxidative stress, e supplementation of sufficient LA can stimulate activities of enzymes, thereby promoting and ameliorating oxidative phosphorylation and mitochondrial respiration and f LA promotes the antioxidant defense by inducing phase two enzymes, such as glutathione synthetase to increase antioxidant GSH.
It reduces liver damage caused by paracetamol over dosage in human, and attenuates liver damage and prevents liver and plasma GSH depletion in mice [ ]. Furthermore, NAC is generally used for the treatment of acetaminophen-induced hepatotoxicity, although it has a drawback as it must be given within 8 h after acetaminophen intoxication, and it can also cause other side-effects including vomiting, nausea, and even shock.
Therefore, the need for alternative, more effective, and widely applicable antidotes for acetaminophen-induced liver injury is warranted [ , ]. NAC, is quickly deacetylated to cysteine and thus may increase GSH levels by providing the substrate for the rate limiting step in GSH synthesis.
Structure of NAC along with possible chelating sites is presented in Fig. NAC is known to have metal-chelating properties and has been used in several clinical conditions. Thiol groups present in NAC act to decrease free radical and provide chelating site for metals.
Thus, NAC has a potent ability to renovate the impaired prooxidant antioxidant balance in metal poisoning and various diseases [ ]. Structure of N-acetyl cysteine NAC depicting 1 two chelating sites thiol and hydroxyl and 2 deacetylation responsible for its antioxidant potential due to the generation of glutathione.
Melatonin N-acetylmethoxytryptamine is a chief secretory product of the pineal gland in the brain which is well known for its functional versatility. In hundreds of investigations, melatonin has been documented as a direct free radical scavenger and an indirect antioxidant, as well as an important immunomodulatory agent Fig.
Furthermore, melatonin stimulates a number of antioxidative enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase.
Additionally, melatonin experimentally enhances intracellular glutathione another important antioxidant levels by stimulating the rate-limiting enzyme in its synthesis, gamma-glutamylcysteine synthase. Melatonin also inhibits the pro-oxidant enzymes such as nitric oxide synthase, xanthine oxidase and lipoxygenase.
Finally, there is evidence that melatonin stabilizes cellular membranes, thereby probably helping them resist oxidative damage. Most recently, melatonin has been shown to increase the efficiency of the electron transport chain and, as a consequence, to reduce electron leakage and the generation of free radicals.
These multiple actions make melatonin a potentially useful agent in the treatment of neurological disorders that have oxidative damage as part of their etiological basis [ ]. The carotenoids are a group of lipid soluble antioxidants which based around an isoprenoid carbon skeleton.
The most important of these is α-carotene, although these present in membranes and lipoproteins. They are particularly efficient scavengers of singlet oxygen, but can also trap peroxyl radicals at low oxygen pressure with an efficiency at least as major as that of α-tocopherol.
Because these conditions prevail in many biological tissues, the carotenoids play a role in preventing in vivo lipid peroxidation. Carotenoids with bring are characterized with pro-vitamin A activity; the highest activity is represented by β-carotene because it contains two brings on both ends of the carbon chain Fig.
Vitamin A also has antioxidant properties, which do not, but, show any dependency on oxygen concentration [ ]. These are a broad class of low molecular ubiquitous groups of plant metabolites and are an integral part of the human diet.
Flavonoids are benzo-γ-pyrone derivatives consisting of phenolic and pyrane rings and during metabolism hydroxyl groups are added, methylated, sulfated or glucuronidated Fig. There is intense interest in flavonoids due to their antioxidant and chelating properties and their possible role in the prevention of chronic diseases.
Flavonoids are present in food mainly as glycosides and polymers and these comprise a substantial fraction of dietary flavonoids. The biological properties of flavonoids are determined by the extent, nature, and position of the substituents and the number of hydroxyl groups.
These factors also determine whether a flavonoid acts as an antioxidant or as a modulator of enzyme activity, or whether it has antimutagenic or cytotoxic properties. Thus flavonoids can scavenge peroxyl radicals, and are effective inhibitors of lipid peroxidation, and can chelate redox-active metals, and therefore prevent catalytic breakdown of hydrogen peroxide Fenton chemistry.
On the other hand, under certain conditions, flavonoids can also display pro-oxidant activity and this is thought to be directly proportional to the total number of hydroxyl groups, and they have also been reported to modulate cell signaling [ ].
The last 60 years have been characterized by the understanding of the impact of nutrition and dietary patterns on health. An important part of the population is exposed to the risk of trace element and vitamin deficiency for multiple reasons e.
Children, young women and elders are the most exposed. Antioxidants balances the cell-damaging effects of free radicals.
Furthermore, people eat fruits and vegetables, which happen to be good sources of antioxidants, have a lower risk for various diseases such as heart, neurological diseases and there is evidence that some types of vegetables and fruits in general, protect against a number of cancers [ — ].
However, this hypothesis has now been tested in many clinical trials and does not seem to be true, since antioxidant supplements have no clear effect on the risk of chronic diseases such as cancer, diabetes mellitus and heart disease.
Under such conditions supplementation with exogenous antioxidants is required to provide the redox homeostasis in cells.
Therefore, antioxidant supplementation has become an increasingly popular practice to maintain optimal body function [ — ]. Much debate has arisen about whether antioxidant supplementation alters the efficacy of cancer chemotherapy.
Others suggest antioxidants may mitigate toxicity and thus allow for uninterrupted treatment schedules and a reduced need for lowering chemotherapy doses. Drugs with free radical mechanisms include but are not limited to alkylating agents e.
topotecan, irinotecan [ ]. None of the trials reported evidence of significant decreases in efficacy from antioxidant supplementation during chemotherapy. Many of the studies indicated that antioxidant supplementation resulted in either increased survival times, increased tumor responses, or both, as well as fewer toxicities than controls [ ].
Studies are now attempting to develop new antioxidants either of natural or synthetic origin. The use of biomarkers provides a logical scientific basis for major intervention trials of antioxidants; such trials could, in turn, eventually validate or disprove the biomarker concept. Any intervention trial that does take place should be accompanied by measurements of one or more relevant biomarkers at intervals during the study.
If the endpoint of the trial is disease incidence or mortality, such studies could help to validate or disprove the biomarker concept. On the contrary, free radical-mediated lipid peroxidation proceeds randomly without specificity.
Lipid peroxidation can neither be programmed nor regulated. Furthermore, some negative effects of antioxidants when used in dietary supplements ascorbic acid, flavanoids, carotenoids, α-lipoic acid and synthetic compounds have came out in the last few decades [ ].
For example, Ascorbic acid has both antioxidant and pro-oxidant effects, depending upon the dose [ ]. Low electron potential and resonance stability of ascorbate and the ascorbyl radical have enabled ascorbic acid to enjoy the privilege as an antioxidant [ , ].
In ascorbic acid alone treated rats, ascorbic acid has been found to act as a CYP inhibitor. Similar activity has also been observed for other antioxidants-quercetin and chitosan oligosaccahrides [ ], which may act as potential CYP inhibitors.
Specifically, Phase I genes of xenobiotic biotransformation, namely, CYP1A1, CYP2E1, and CYP2C29, have been previously reported to be downregulated in female rats in the presence of a well known antioxidant, resveratrol [ ].
At higher oxygen tension, carotenoids tend to lose their effectiveness as antioxidants. In a turn around to this, the pro-oxidant effect of low levels of tocopherol is evident at low oxygen tension [ ]. Moreover, α-lipoic acid exerts a protective effect on the kidney of diabetic rats but a prooxidant effect in nondiabetic animals [ ].
The pro-oxidant effects have been attributed to dehydroxylipoic acid DHLA , the reduced metabolite of α-lipoic acid owing to its ability to reduce iron, initiate reactive sulfur-containing radicals, and thus damage proteins such as alpha 1-antiproteinase and creatine kinase playing a role in renal homeostasis [ ].
An increase in α-lipoic acid and DHLA-induced mitochondrial and submitochondrial production in rat liver and NADPH-induced and expression of p47phox in the nondiabetic kidney has also been observed [ ]. Depending on the type and level of ROS and RNS, duration of exposure, antioxidant status of tissues, exposure to free radicals and their metabolites leads to different responses—increased proliferation, interrupted cell cycle, apoptosis, or necrosis [ ].
There has been ever increasing knowledge in the role of oxygen derived pro-oxidants and antioxidants that play crucial role in both normal metabolism and several clinical disease states. Antioxidants exhibit pro-oxidant activity depending on the specific set of conditions. Furthermore, while antioxidants may have reduced free-radical damage to normal tissues leading to diminished toxicity, the non-oxidative cytotoxic mechanisms of the drugs may remain unaffected by antioxidant supplementation.
Further, the significant reductions in toxicity may alleviate dose-limiting toxicities to such an extent that more patients successfully complete prescribed regimens. Advances in the field of biochemistry including enzymology have led to the use of various enzymes as well as endogenous and exogenous antioxidants having low molecular weight that can inhibit the harmful effect of oxidants.
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Int J Cancer. Karki R, Igwe OJ. PLoS One. Gasparini C, Celeghini C, Monasta L, Zauli G. NF-kB pathways in hematological malignancies. Cell Mol Life Sci. Yamamoto Y, Gaynor RB. Oxidative stress is thought to be linked to certain cardiovascular disease , since oxidation of LDL in the vascular endothelium is a precursor to plaque formation.
Oxidative stress also plays a role in the ischemic cascade due to oxygen reperfusion injury following hypoxia. This cascade includes both strokes and heart attacks.
In hematological cancers, such as leukemia, the impact of oxidative stress can be bilateral. Reactive oxygen species can disrupt the function of immune cells, promoting immune evasion of leukemic cells.
On the other hand, high levels of oxidative stress can also be selectively toxic to cancer cells. Oxidative stress is likely to be involved in age-related development of cancer. The reactive species produced in oxidative stress can cause direct damage to the DNA and are therefore mutagenic , and it may also suppress apoptosis and promote proliferation, invasiveness and metastasis.
Oxidative stress can cause DNA damage in neurons. The use of antioxidants to prevent some diseases is controversial. The American Heart Association therefore recommends the consumption of food rich in antioxidant vitamins and other nutrients, but does not recommend the use of vitamin E supplements to prevent cardiovascular disease.
AstraZeneca 's radical scavenging nitrone drug NXY shows some efficacy in the treatment of stroke. Oxidative stress as formulated in Denham Harman 's free-radical theory of aging is also thought to contribute to the aging process.
While there is good evidence to support this idea in model organisms such as Drosophila melanogaster and Caenorhabditis elegans , [67] [68] recent evidence from Michael Ristow 's laboratory suggests that oxidative stress may also promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of reactive oxygen species.
The USDA removed the table showing the Oxygen Radical Absorbance Capacity ORAC of Selected Foods Release 2 table due to the lack of evidence that the antioxidant level present in a food translated into a related antioxidant effect in the body. Metals such as iron , copper , chromium , vanadium , and cobalt are capable of redox cycling in which a single electron may be accepted or donated by the metal.
This action catalyzes production of reactive radicals and reactive oxygen species. These metals are thought to induce Fenton reactions and the Haber-Weiss reaction, in which hydroxyl radical is generated from hydrogen peroxide. For example, meta- tyrosine and ortho- tyrosine form by hydroxylation of phenylalanine.
Other reactions include lipid peroxidation and oxidation of nucleobases. Metal-catalyzed oxidations also lead to irreversible modification of arginine, lysine, proline, and threonine.
Excessive oxidative-damage leads to protein degradation or aggregation. The reaction of transition metals with proteins oxidated by reactive oxygen or nitrogen species can yield reactive products that accumulate and contribute to aging and disease.
For example, in Alzheimer's patients, peroxidized lipids and proteins accumulate in lysosomes of the brain cells. Certain organic compounds in addition to metal redox catalysts can also produce reactive oxygen species. One of the most important classes of these is the quinones.
Quinones can redox cycle with their conjugate semiquinones and hydroquinones , in some cases catalyzing the production of superoxide from dioxygen or hydrogen peroxide from superoxide. The immune system uses the lethal effects of oxidants by making the production of oxidizing species a central part of its mechanism of killing pathogens; with activated phagocytes producing both reactive oxygen and nitrogen species.
Sperm DNA fragmentation appears to be an important factor in the aetiology of male infertility , since men with high DNA fragmentation levels have significantly lower odds of conceiving.
In a rat model of premature aging, oxidative stress induced DNA damage in the neocortex and hippocampus was substantially higher than in normally aging control rats. However, it was recently shown that the fluoroquinolone antibiotic Enoxacin can diminish aging signals and promote lifespan extension in nematodes C.
elegans by inducing oxidative stress. The great oxygenation event began with the biologically induced appearance of oxygen in the Earth's atmosphere about 2. The rise of oxygen levels due to cyanobacterial photosynthesis in ancient microenvironments was probably highly toxic to the surrounding biota.
Under these conditions, the selective pressure of oxidative stress is thought to have driven the evolutionary transformation of an archaeal lineage into the first eukaryotes. Selective pressure for efficient repair of oxidative DNA damages may have promoted the evolution of eukaryotic sex involving such features as cell- cell fusions , cytoskeleton -mediated chromosome movements and emergence of the nuclear membrane.
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Download as PDF Printable version. Free radical toxicity. Further information: Antioxidant. Further information: Ageing. Antioxidative stress Acatalasia Bruce Ames Malondialdehyde , an oxidative stress marker Mitochondrial free radical theory of aging Mitohormesis Nitric oxide Pro-oxidant Reductive stress.
Handbook of Disease Burdens and Quality of Life Measures. New York, NY: Springer New York. doi : ISBN Definition: Imbalance between oxidants and antioxidants in favor of the oxidants.
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In a Antioxidant stress response changing environment, plants Dehydration and sunburn constantly challenged by various abiotic Antioxidant stress response such as redponse, drought, Antioxjdant extremes, heavy metal toxicity, strses intensity, Aging gracefully inspiration Flavorful Quencher Combo, UV-B radiation, ozone, etc. Antioxidant stress response cause substantial losses in the yield and quality of a crop. Antioxidany are extremely reactive in nature because they can interact with rfsponse number of cellular molecules and metabolites, thereby leading to irreparable metabolic dysfunction and death. Plants have well-developed enzymatic and non-enzymatic scavenging pathways or detoxification systems to counter the deleterious effects of ROS that include the enzymes superoxide dismutase SODcatalase CATascorbate peroxidase APXmonodehydroascorbate reductase MDHARdehydroascorbate reductase DHARglutathione reductase GRglutathione S-transferase GSTglutathione peroxidase GPX and peroxidases POX as well as non-enzymatic compounds such as ascorbate AsAglutathione GSHcarotenoids and tocopherols. In plant cells, specific ROS-producing and scavenging systems are found in different organelles and the ROS-scavenging pathways from different cellular compartments are coordinated.
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