Essay: Oxygen-free radicals

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Oxygen-free radicals are known to be reactive oxygen species (ROS) with the reactive nitrogen species (RNS) which play important role in deleterious and beneficial species. The redox active metals are like iron (Fe), copper (Cu), chromium (Cr), cobalt (Co) and other metals which have an ability to produce reactive radicals like superoxide anion radical and nitric oxide in biological systems. Toxic metals such as lead, cadmium, mercury and arsenic are which are mainly found in the environment. Human are exposed the metals so which contaminate the water, air, soil and food. These data of the V and Zn which induce tyrosine phosphate accumulation by inhibiting dephosphorylation and implicate kinase activation as the mechanism in HAEC exposed to As. The physiological consequences of the arsenic-induced stress and its usefulness in monitoring effects which results in the form that arsenic exposure in humans and other organisms are discussed mainly. The neurodegenerative diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD), are age-related disorders which are characterized by the deposition of abnormal forms of proteins in the brain. These metals have high affinity for thiol groups which containing enzymes and proteins, and are responsible for normal cellular defense mechanism. Long term exposure to these metals leads to apoptosis. Protein aggregation and oxidative stress which are both possess in the Parkinson’s disease, so the misfolded protein induces the oxidative stress and neuronal death remains unknown. The results cobalt and mercury shows that they are able to induce oxidative stress and cell cytotoxicity and increase the secretion of β-amyloid 1-40 and 1-42.Although carcinogenesis caused by metals which has been intensively investigated, so the mechanisms of action, and especially at the molecular level, are still unclear. Oxidative stress mechanistically and chronologically which are associated with other key features of AD, namely, metabolic, mitochondrial, metal, and cell-cycle abnormalities. The amyloid precursor protein (APP) of Alzheimer’s disease can reduce copper (II) to copper (I) in a cell-free system potentially leading to increased oxidative stress in neurons. Oxidative stress contributes to many pathological conditions and diseases, including cancer, neurological disorders, atherosclerosis, hypertension, ischemia/perfusion, diabetes, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma. Cancer induction by chemical and physical agents involves a multi-step process.

Metals play important roles in a wide variety of biological system of living systems. Homeostasis of metals which maintain by storage, uptake and secretion which are critical for life and are maintained within the strict limits (Bertini et al, 2008; Jomova, K et al 2011). Copper, manganese, iron, and other trace redox-active transition metals are involved in mediating the processes and can be involved in the neuropathology of disorders such as Parkinson disease (PD), Alzheimer disease (AD) and much other disease (Campbell. A et al 2001). K.U. Leuven team stems shows the interest in the mid-seventies in \”epidemic\” of interstitial lung disease among diamond polishers and the disease which had all the features of hard metal lung disease (Lahaye D et al 1984; Nemery B, et al 1992; Lison.D et al 1996).The stress response is a phenomenon of adaptation of organisms (Razo. L. M. Z et al 2001).Oxygen free radicals which are generated as “reactive oxygen species,” (ROS) and “reactive nitrogen species” (RNS) in experimental and clinical medicine.ROS mediators are which damage the cell structure including lipids and membranes, proteins and nucleic acids (Halliwell,B et al 1999; Poli, G et al 1996; Valko, M et al 2005). Reactive oxygen species (ROS) are highly reactive molecules, consist of a number of the chemical species like superoxide anion (O2−), hydroxyl radical (・OH), and hydrogen peroxide (H2O2) (Cui. H et al 2011; Sivasudha. T et al 2013).Overproduction of the free radicals are responsible for tissue injury oxidative damage can lead to a breakdown or even hardening of lipids, which are composition of cell walls. Breakdown or hardening is due to lipid peroxidation leads to death of cell (Sen. S et al 2010). Mechanism for stress are not clear but can be understood by redox active metal which induce oxidative stress (Stohs, S.J et al 1993; Hultberg .B et al 2001;Eracl .N et al 2001). Deleterious free radical-mediated oxidations occur in aerobic organisms which result in normal oxygen metabolism (Flora S.J.S 2009). Antioxidants cause protective effect which neutralizes the free radicals, which are toxic byproducts of the natural cell metabolism. Human body which produces the antioxidants is not effective 100 % in overwhelming production of free radicals and so effectiveness also declines with age (Sies H, 1991; Goldfarb AH, 1993; Sen. S et al 2010). From the decades primary target are studied in Alzheimer disease has been centered on Amyloid beta (Aβ),the amino acids appear as main constituent of amyloid plaques in the brains of Alzheimer’s disease (AD) patients (Selkoe DJ 2001; Varadarajan S, et al 2000; Jomova .K, et al 2010). In fact many articles are reporting that neurodegenerative disorders with direct evidence supporting that increase the oxidative stress of the brain in AD(Devi L, et al 2010 ; Block M.L, et al 2010; Jomova .K, et al 2010). These diseases occur rarely in inherited forms, but the predominant sporadically occurred in the forms to represent a multifactorial superposition of genetic, environmental (Dawson, R et al1995; Sayre, L.M et al 2001). The attempt at apoptosis is incomplete or Abortive (Raina AK, et al 2001; Nunomura , A. et al 2006), and this makes mechanistic sense given the evanescent time interval over which apoptosis occurs in general (Nunomura ,A. et al 2006). To test the hypothesis that APP can interact with copper and mediate oxidative stress in neurons (Multhaup et al., 1996, 1998; White. A .R et al 1999), we compared the effect of copper exposure on cultures of APP knock-out (APP2/2) and wild-type (WT) neurons (White. A. R et al 1999). Several essential transition metals like copper, zinc, iron and manganese participate in controlling various metabolic and signaling pathways. Metal induced toxicity is very well reported in the literature. On one mechanism heavy metals toxicity are reported as oxidative stress (Leonard SS, et al 2004; Flora S.J.S et al 2008). These metals possess the ability to generate reactive radicals, resulting in cellular damage like depletion of enzyme activities, damage to lipid bilayer and DNA (Stohs SJ, et al 1995; Flora S.J.S et al 2008).neurodegenerative diseases are becoming increasingly prevalent in the aging populations of the Western world. These diseases like Parkinson disease in which abnormally aggregated proteins in pathological inclusions containing amyloid fibrils (Chiti F et al 2006; Geddes JF, et al 1993; Deas .E et al 2016). Strong evidence exists to support a role of oxidative stress in the pathogenesis of many neurodegenerative diseases, including PD. There is clear evidence of oxidative damage to lipids, proteins, and DNA (Dexter DT, et al 1989; Deas .E et al 2016). Metals include such as the iron which are require in trace amount for the normal function of living organisms, longer exposure cause inflammation, cellular damage, and cancer, particularly of the lung and skin (Wang, al 2001; Desurmont.M,1993; STEPHEN S. et al 2004).one of the important ROS family superoxide anion radical (O2_), which can be dismutated to form hydrogen peroxide (H2O2) and the highly reactive hydroxyl radical (OH) in the presence of certain transition metal ions (Halliwell, B.; et al 1984; Chen, F. et al 2002; STEPHEN S. et al 2004). Similarly, the transition metals, cobalt and mercury, have been shown to induce oxidative stress and cell cytotoxicity within a neuroblastoma cell culture system (Olivieri et al., 2000, 2001b; OLIVIERI.G et al 2002). Estrogen is increasingly being shown, in biological systems, to play important and diverse roles. Which include the classical sex steroid (Evans, 1988; Beato, 1989; OLIVIERI.G et al 2002) such as: modulation of transmembrane receptor function (Wetzel et al., 1998; Gu et al., 1999; OLIVIERI.G et al 2002), affecting the intracellular signal transduction pathways (Marino et al., 1998; Watters and Dorsa, 1998; OLIVIERI.G et al 2002), affecting the morphology of the Golgi network (Scammell et al., 1986; Larson and Wise, 1994; OLIVIERI.G et al 2002).the oxidative nature is being supported by the hypothesis of metal-induce genotoxic damage which is provided by wide spectrum of nucleobase products typical for the oxygen attack on DNA in cultured cells and animals exposed to carcinogenic metals(Valko. M et al 2005). The toxic effects of metals involve hepatoxicity, neurotoxicity and nephrotoxicity (Valko. M et al 2005). Arsenic are well-known to ROS inducer, and generation of these species associated with As exposure has been shown to play an fundamental role in induction of adverse health effects. Arsenic exposure has been associated with different types of cancers like ; skin, bladder, liver, kidney and lung (Kumagai. Y et al 2007; Shi.H et al 2004; Kligerman A.D. et al 2007; Szymanska-Chabowska,.A et al 2007; Vizcaya-Ruiz. A. D et al 2009), diabetes, arteriosclerosis and cardiovascular diseases, hypertension and neurological diseases (Alzheimer and Parkinson) (Schmuck, E. M et al 2005; Vahidnia .A et al 2007; Vizcaya-Ruiz. A. D et al 2009). Chromium (Cr) is a naturally occurring heavy metal commonly found in the environment in two valence states: trivalent Cr (III) and hexavalent Cr (VI). Exposure of chromium (V) is more toxic and carcinogenic than chromium (III) (Connett, P.H. et a 1983; De Flora, S. et al 1990; Patlolla. A. K et al 2009). Once absorbed arsenic which are stored in liver, kidney, heart and lung while lower amount are present in muscle and neural tissues (Bhadauria. S et al 2006). Nanoparticals mediated ROS responses have been reported to orchestrate the series of pathological events like genotoxicity, inflammation, fibrosis, and carcinogenesis. The oxidative stress triggers cell signaling pathways which results in increase expression of proinflammatory and fibrotic cytokines (Li, J. J et al 2010; Manke. A et al 2013). Most of the nanoparticals which are metals-based have free radicals toxicity which play major role in the mitochondrial damage by ROS generation (Huang. Y et al 2010; Fubini .B et al 2003; He. X et al 2011; Manke. A et al 2013). Consequently, there is a major interest in efficient antioxidants which can protect against neuronal cell injury and death without showing toxic effects. The flavonoids are a group of polyphenolic compounds which are found in plants and one of the most important classes of compounds with biological activity (Peterson J, et al 1995; Areias. F.M et al 2001). In addition, the flavonoids are also potent antibacterial, antiviral, anticancer, immune-stimulant, hepatoprotector, antithrombotic, and anti-inflammatory agents (Middleton E, et al 1994; Middleton E. 1986; Areias. F.M et al 2001). The recent studies shows that the lowered antioxidant defense and alterations of enzymatic pathways in humans with poorly controlled diabetes mellitus can contribute to endothelial, vascular and neurovascular dysfunction. Consequences of oxidative stress are damage to DNA, lipids, proteins, disruption in cellular homeostasis and accumulation of damaged molecules (Jakus V 2000). Zinc is the only metal that is a cofactor to more than 300 enzymes (Rink et al 2000; Chasapis. C. T et al 2011), and its major role is in the stabilization of the structure of a huge number of proteins (Beyersmann 2002; Chasapis. C. T et al 2011). The mechanisms of cell death in neurodegenerative disorders, such as PD and AD, it is difficult to define targets for treatment and determine what should be considered as neuroprotective. Alzheimer’s disease (AD) affects approximately 4.5 million Americans, projected to increase to 11 and to 16 million by 2050; Parkinson’s disease (PD) afflicts approximately one million persons in the United States, 60,000 new cases are diagnosed every year, and its incidence is projected to quadruple by 2040(Wallace. D. C 2005; Melo. A et al 2011). Alzheimer’s disease (AD) is a devastating neurological condition with no disease-modifying therapy available so
far (Zatta. P, et al 2009). Cancer development shows the multistage such as initiation, promotion, and progression (Klaunig. J.E et al 2004; Galaris .D et al 2008). Zinc is the redox inert and has structural, catalytic, and regulatory roles in cellular biology (Bettger & O’Dell, 1981; Vallee, 1983;Williams, 1989;Math P. et al 1997). Among the other mechanisms proposed for Cd toxicity and carcinogenesis are interaction with the regulation of proto-oncogenes and inhibit DNA repair (Waisberg et al., 2003; Hartwig and Schwerdtle, 2002; Nzengue. Y et al 2008.) Flavonoids are potential therapeutic agents in human diseases like in cancer, cardiovascular disease, and also in AD (Hollman P.C.H et al 1999; Akaishi T, et al 2008; DeToma. A. S et al 2011. In addition to PD, several other neurodegenerative disorders including Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis are associated with oxidative stress as well, despite having distinct pathological and clinical features (Lin M.T, et al 2006; Dias. V et al 2013). However, several clinical studies demonstrated that not only malnutrition, but also the excess of certain nutrients (e.g. iron, alphatocopherol, beta-carotene, ascorbic acid) may set into motion oxidation phenomena and, therefore, cell injury (Brambilla.D et al 2008).
Redox active metals:
The redox active metals like iron (Fe), copper (Cu), chromium (Cr), cobalt (Co) and other metals undergo redox cycling reactions and possess the ability to produce reactive radicals such as superoxide anion radical and nitric oxide in biological systems(Jomova , K et al 2011 ) . Alterations in the levels of “anti-oxidant” metalloenzymes likely contribute to altered redox homeostasis in neurodegenerative diseases (Corson, L.B.; et al 1999; Sayre. L. M , et al 2001). These metals are the multitude of biological reactions and the accumulation of these metals tissues’ are excess capacity of cellular metalloprotein which is responsible for metal homeostasis (Sayre. L. M, et al 2001). A number of metals have been long known in literature for their toxicity and carcinogenicity (Flora, S. J. S et al 2009).

Oxidative stress, which is defined as the imbalance between biochemical processes leads to production of reactive oxygen species (ROS) and the cellular antioxidant cascade, which causes the damages in the molecules so that can lead to a critical failure of biological functions and ultimately cell death (Sayre. L. M , et al 2001).

Oxidative stress is a harmful condition which occurs when there is an excess of ROS and a decrease in antioxidant levels, that causes tissue damage by physical, chemical, psychological factors that lead to tissue injury in human and causes different diseases(Tian.Y, et al 2007; Sen. S, et al 2010). The term ‘‘oxidative stress” was originally introduced by Helmut Sies in 1985 in order to denote ‘‘a disturbance in the prooxidant–antioxidant balance in favor of the former(Sies, H, et al 1983;Galaris .D et al 2008 ). Oxygen derived free radical reactions has been implicated in the pathogenesis of many human diseases including (Pham-Huy LA, et al 2008; Valko M, et al 2007; Agarwal A, et al 2005; Sen S, et al 2009; Sen. S, et al 2010).

i) Neurodegenerative disorder such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, memory loss and depression.
ii) Cardiovascular disease like atherosclerosis, ischemic heart disease, cardiac hypertrophy, hypertension, shock and trauma.
iii) Pulmonary disorders such as inflammatory lung diseases like asthma and chronic obstructive pulmonary disease.
iv) Tumors and cancer include lung cancer, leukemia, breast, ovary, rectum cancers etc.

Free iron, more than any transition metal, which has been implicated in redox transitions and consequential generation of
oxygen free radicals (Campbell. A et al 2001). Oxidative state of iron is +II and +III. Ferrous ions are soluble and so generate hydroxyl radicals in the presence of oxygen damage Iron oxidizes form is insoluble in water at neutral pH and precipitates in the form of ferric hydroxide (Jones-Lee and Lee, 2005; Jomova, K et al 2011 ). Excess of iron leads to the biological disorder which catalyze the ROS (Formigari ,A et al 2007). Iron is the essential element used for growth and survival for organism (Valko, M et al 2005)

a) Oxidative stress :
The redox state of the cell is predominantly dependent on an iron redox couple and is maintained within strict physiological limits (Park et al., 2009; Jomova,K et al 2011). Iron-mediated formation of ROS leading to DNA and lipid damage which appears to from an exaggeration of the normal function of iron, which transport oxygen to tissues. Iron-induced free radical damage to DNA which are important for the development of cancer so cancer cells are known grow rapidly in response of iron. Genetic hemochromatosis increase the risk of hepatocellular carcinoma (Ullen, H. et al 2001;Valko,M. et al 2006) . Superoxide are present in the form of anions and remove by reaction (Liochev et al, 2000, Jomova ,K et al 2011):
2O2 − • +2H+−SO→DH2O2 + O2
This reaction precede very slowly .the kinetic constant of SOD-catalyzed the depletion of superoxide reaction has been estimated 2.5×109M−1 s−1 (Liochev et al 2003, Jomova ,K et al 2011).

B) Human diseases caused by Iron:
Initial steps of free radical attacks involves in the mutagenesis, carcinogenesis and ageing. It has been documented that various cancer tissues free radical-mediated in the DNA damage which has occurred (Durackova, 2010; Marnett, 2000; Jomova, K et al 2011). Iron metabolism can be found to act as significantly which are disturbed in
type 2 diabetes and which interferes with glucose metabolism (Lee et al.,2006; Jomova, K et al 2011). Increased amounts of iron in the
body poses enhanced risk of a variety of diseases including vascular
disease, cancer and certain neurological conditions(Berg D, et al 2001; Siah CW, et al 2000;Flora, S. J. S et al 2009). Animal studies of iron-induced carcinogenesis are well documented. Intramuscular injections of an iron–dextran complex, frequently used for the treatment of anemia in humans (Bhasin, G et al 2002; Valko,M. et al 2006). High contents of iron may cause disorders in the liver and heart disease neurodegenerative disorder and hormonal abnormalities and immune system abnormalities(Fraga , C.G. et al 2002;Berg, D. et al 2001; Rasmussen, M.L. et al 2001; Walker, E.M. et al 2000; Morris .H et al 2005).

• Copper:
The oxidation numbers which are found in living organism are Cu (II) and Cu (I).
A) Oxidative stress and copper:
Cu will be toxic in the case of excessive intracellular accumulation which play role in generation of ROS and apoptotic processes (Formigari ,A et al 2007).Cupric and cuprous ions can act in oxidation and reduction reactions. The cupric ion (Cu (II)), in the presence of superoxide anion radical or biological reductants such as ascorbic acid or GSH, can be reduced to cuprous ion (Cu (I)) which is capable of catalyzing the formation of reactive hydroxyl radicals through the decomposition of hydrogen peroxide via the Fenton reaction (Aruoma et al., 1991;Prousek, 1995; Barbusinski, 2009; Jomova, K et al 2011):
Cu(II) + O2 −• → Cu(I) + O2
Cu(I) + H2O2→ Cu(II) + •OH + OH− (Fenton reaction)

Immune system cells produce superoxide and nitric oxide during the inflammatory processes, so these two when combine produce significant amount of oxidatively active compound called peroxynitrite
anion(ONOO-) (Carr et al., 2000; Jomova, K et al 2011):

NO• + O2−• → ONOO−

b) Copper and human disease:
The most levels of copper have been recorded in cancer from which patients suffering from breast, cervical, ovarian, lung, prostate, stomach cancer and leukemia. .In non-physiological condition copper level increase which play role in development of various cancer (Gupte et al 2009;Roberts et al., 2010; Jomova, K et al 2011). Copper at high concentration is known to cause metastasis of cancer cells (Brewer GJ, et al 2000; Flora, S. J. S et al 2009).

ii) Neurological disorders:
copper is an integral part of many proteins necessary for neurological functioning so neurological disorder was studied in oxidative stress (Morris .H et al 2005).The majority of papers link the origin of Alzheimer‘s disease (AD), and to a lesser extent also to Parkinson‘s disease (PD), with direct evidence supporting that increased in oxidative stress of the brain . The “null hypothesis” in studies of Alzheimer’s disease has been centered on Amyloid-_β (Aβ) (Bush et al, 2008; Jomova et al.,2010; Cuajungco et al., 2000; Jomova, K et al 2011). Individuals with genetic alterations in one of the genes that code three transmembrane proteins, amyloid precursor protein (APP), presenilin-1 (PS1), and presenilin-2 (PS2), deposit large amounts of the amyloid fragment Aβ(1–42). (Hardy, J et al 2002; Jomova, K et al 2010; Valko .M et al 2011). Cobalt (II) complexes are known to produce oxygen radicals which cause heart toxicity (Leonard S, et al 1998; Bucher JR, et al 1999; Flora, S. J. S et al 2009).

iii) Chronic disease: diabetes, cardiovascular disease and
Ceruloplasmin has been noted to be increased in both type
1 and type 2 diabetic humans with respect to healthy subjects
(Uriu-Adams et al, 2005; Jomova, K et al 2011). Some dieses like Wilson\’s disease (hepatolenticular degeneration) is an inherited autosomal recessive disorder of Cu transport characterized by the failure to incorporate Cu into ceruloplasmin in the liver, and the failure
to excrete Cu from the liver into bile(Formigari ,A et al 2007). In addition, some studies reported increased concentration of copper in plasma of diabetic patients with complications, such as hypertension and retinopathy (Kang et al., 2000). Ceruloplasmin is independent risk of cardiovascular disease (Cunningham et al., 1995; Valko .M et al 2011). The heart and heart vessels are venerable to Cu deficiency. As Cu deficiency has been proposed which induce cardiac damage through the production of ROS, coupled with the relatively low oxidant defense enzyme activities in heart compared to other tissues (Chen et al., 1994; Janet al 2005).

• Chromium
Chromium, one of the most common elements in the earth’s exists in several oxidation states (Cieslak-Golonka, 1996’ Jomova, K et al 2011). Chromium (III), which occurs in nature, is an essential trace element that plays an important role in regulating blood levels of glucose. (Valko, M. et al 2006). Chromium deficiency has been associated with impaired glucose tolerance and hyperglycemia decreased lean body mass, cardiovascular disease, decreased sperm count, and impaired fertility (Cieslak-Golonka et al 1996 ; Morris .H et al 2005).

i) Oxidative stress and chromium:
Oxidative stress has therefore been proposed as a major pathway of Cr(III)- picolinate induced toxicity(Morris .H et al 2005).Cr (III) is an essential dietary mineral in low doses, found in most fresh foods, including breads, meats and vegetables and drinking water (Vincent, 2010). Carcinogenicity of Cr(VI) is site specific, targeted mainly to the lung and requires massive exposures (Singh et al., 1998). In the lungs (and also in the liver) Cr(VI) is efficiently reduced probably by the glutathione ( Izzotti et al., 1998; Jomova, K et al 2011). In a cell-free assay, chromate (VI) reacted with glutathione to yield chromium(V) and thiyl radicals (Wetterhahn et al. 198;9; Beyersmann.D et al2008)Generated hydroxyl radicals are able to react with DNA bases, e.g. guanine producing a variety of radical adducts, the best described is 8-hydroxyguanosine (8-OH-dG), a good marker of oxidative damage of an organism. Several types of DNA dam age occur in chromium(VI)-exposed cells, including single-strand breaks, DNA–DNA interstrand crosslinks, DNA–protein crosslinks, chromium–DNA adducts, oxidative nucleotide changes and chromosomal aberrations (De Flora et al, 1989; Singh et al.,1998; Jomova, K et al 2011).

Chromium and human disease:
Chromium traces are essential for human and animal nutrition and are taken up as complexes of Cr(III) with amino acids (Vincent 2000; Beyersmann.D et al2008). Breathing high levels of chromium (VI) can cause irritation to the nasal cavity, breathing difficulty (asthma and cough). Skin contact with certain chromium (VI) compounds can cause skin ulcers. Deficiency of chromium has been associated with disturbed glucose tolerance, fasting hyperglycemia, glucosuria, increased body fat, dyslipidemia and impaired fertility (De Flora et al., 1995; Jomova, K et al 2011).Chromium (VI) is toxic and contain high dose carcinogenic (Dayan, A.D, et al 2001; Cieslak-Golonka, M, 1998). Only chromium (VI) does not react with DNA in vitro, and in isolated nuclei. Inside the cell, the presence of cellular reductants, it causes a wide variety of DNA lesions including Cr–DNA adducts, DNA–protein crosslink’s, DNA–DNA crosslink’s and oxidative damage (Valko,M et al 2005; Valko,M. et al 2006). Hexavalent chromium causes lung cancers in humans. For example when workers are exposed to hexavalent chromium they inhale the air so chances of lungs cancer are increased and recently studies shows that chromium also increase the rate of breast cancer (Dayan, A.D, et al 2001;Kilic, E et al 2004; Valko,M. et al 2006)

Cobalt forms a number of organic and inorganic salts with the
most stable oxidation numbers being +3 [Co(III)], and +2 [Co(II)].

i) Cobalt and oxidative stress:
Cobalt particles in suspension [Co(0)] do not react with
hydrogen peroxide via the Fenton reaction. EPR spin trapping
experiments in the presence of oxygen indicated the generation of
the radical intermediate Co(I)-OO• species described by the reaction
(Leonard et al., 1998; Valko et al., 2005; Jomova, K et al 2011):
Co + O2→ Co(I) + O2−• → Co(I)-OO•
Cobalt ions are able to induce the reactive oxygen species (ROS) in vivo and in vitro (Beyersmann.D et al2008).The catalytic activity of cobalt ions depends on the chelators. Cobalt (II) complexed with GSH or cysteine has been found to generate under physiological conditions hydroxyl radicals and other oxygen- and carbon-centered radicals from model lipid peroxides (Shi et al., 1993a,b; Valko. M et al 2011).

Cobalt and human disease:
Toxicity of cobalt is vetted low as compared to others. Its higher concentration affects the lungs, leadings to asthma, pneumonia and wheezing. Inhalation of Co causes asthma (Gal et al., 2008; Barceloux, 1999a,b; Jomova, K et al 2011). When large quantity of cobalt is present which is toxic for heart and causes carcinogenic in animals ( Valko,M. et al 2006). Inorganic cobalt compounds which caused lung tumor the epidemiological Wndings of increased lung cancer incidence of cobalt-exposed workers are regarded as not conclusive because of co-exposure to other carcinogenic substances (IARC 1991, 2006a; DFG 2007c; Beyersmann.D et al2008).

Table 1
Redox active metals
Humans health Reference

DNA damage , vascular disease , cancer , diabetes type 2
Durackova, 2010; Berg D, et al 2001; Lee et al.,

Cancer ,Alzheimer disease , Parkinson disease Gupte et al 2009; Bush et al, 2008
Lung cancer and breast cancer , hyperglycemia, dyslipidemia
Dayan, A.D et al; De Flora et al., 1995

Cobalt asthma, pneumonia , wheezing , lung cancer, pulmonary edema, peripheral
vascular thrombosis, optic nerve atrophy, asthma. Gal et al., 2008; IARC 1991; Barceloux, 1999a,b

Redox Inactive metals:
The redox inactive metals, such as cadmium (Cd), arsenic (As) and lead (Pb) show their toxic effects via bonding to sulphydryl groups of proteins and depletion of glutathione. Interestingly, for arsenic an alternative mechanism of action based on the formation of hydrogen
peroxide under physiological conditions has been proposed. (Jomova, K et al 2011).

1) Cadmium:
Cadmium is highly toxic metal (Valko,M. et al 2006). Cadmium is heavy metal and common oxidation number of cadmium is +2 (Jomova, K et al 2011).Food is main source cadmium for non-smoking population (Cuypers et al, 2010; Jomova, K et al 2011).however cadmium unable to free radicals but they can generate the various radicals such as superoxide, hydroxyl radicals and nitric acids (Gala. A et al 2001; Valko,M. et al 2006). In some mechanism it was proposed that cadmium can replace iron and copper in the membrane and cytoplasmic proteins which increase the unbounded iron and copper ions which take part in oxidative stress via a Fenton reaction (Price, D.J et al 1983 ; Casalino , E et al 1997; Valko,M. et al 2006)

Cadmium, oxidative stress and human disease:

Intake of cadmium involves the lungs, intestine and skin cancer. Cadmium bodies are bounded to metallothioneins (Hamer, 1986 ;IARC 1993; DFG 2006a; Beyersmann.D et al2008).So this complex are distributed to various cells and tissues in the body and can reabsorbed by kidney tubuli in body (Ohta et al, 1991 ; Jomova, K et al 2011). Cadmium is a potent human carcinogen causing preferentially prostate, lung and gastro-intestinal (kidney and pancreas) cancers. Smoking synergistically increases the carcinogenic effect of cadmium (Flora et al., 2008; Flora ,et al 2010; Jomova, K et al 2011). Cadium can implicated in the pathogensis of human pancreatic cancer and renal carcinoma (Waisberg,M et al 2003 ; Valko,M. et al 2006). Cadmium (II) imitates insulin in that it causes the movement of glucose transporter to proteins from the cell surface, even though the effects of cadmium are independent of the insulin receptor itself (McNulty, T. J. et al 1999; Stephen S, et al 2004). Cadmium can cause osteoporosis, anemia, non-hypertrophic emphysema, irreversible renal tubular injury, eosinophilia, anosmia and chronic rhinitis (Flora .S.J.S et al 2008).

 DNA damage induced by cadmium:
Cd induces DNA damage in HaCaT cells. The FpG is known for its role in the 8-oxo desoxiguanosine (8-OHdG) elimination from DNA. If 8-OHdG is present, the action of this enzyme results in an increase of the DNA damage observed with the comet assay (Lazarova et al., 2006; Nzengue, Y et al 2008).

2) Arsenic:
The oxidation number which are common of arsenic are+3,+5 and -3 so that organic and inorganic both compounds are formed in the environment and in the human body ( Hei, et al 2004; Jomova, K et al 2011).
i) Arsenic and oxidative stress:
Arsenic generate the reactive oxygen which is a complex process which involves the generation of a variety of ROS including superoxide (O2•−), singlet oxygen (1O2), the peroxyl radical (ROO•), nitric oxide (NO•), hydrogen peroxide (H2O2), dimethylarsinic peroxyl radicals ([(CH3)2AsOO•]) and also the dimethylarsinic radical [(CH3)2As•] (Yamanaka, K et al 2001; Valko, M. et al 2006; Razo. L. M. Z et al 2001; Wang et al., 1996, Barchowsky et al., 1996, 1999; Chen et al., 1998; Gurr et al., 1998). Arsenic is one of the extensively studied metal which produce ROS (Shi H, et al 2004; Flora, S.J.S. et al 2008). Arsenite increases the generation of superoxide anions (O2 ¡) and hydrogen peroxide (H2O2) in diverse cellular systems, while the modulation of nitricoxid (NO) production appears to be restricted to higher concentrations (Beyersmann.D et al2008).

ii) Arsenic and human health:
Arsenic are known to be causes the cancer in many studies (Waalkes et al, 2004 Jomova, K et al 2011; Beyersmann.D et al2008). Cardiovascular disorders are caused by arsenic and when inorganic arsenic is inhaled they affect the cardiovascular systems. (Das et al 2010, Jomova, K et al 2011). Cancer is bingeing caused by arsenic (Roy, P et al 2002; Valko, M. et al 2006). Arsenic is associated with many other diseases like diabetes, hypertension (Lai, M.S et al 1994;Chen, J,C et al 1995;Nuran, E et al 2001) and tumor of skin, bladder, lung and liver(Chen, J.C et al 1990;Nuran, E et al 2001; Waalkes, M.P et al 2004; Morris .H et al 2005). Exposure of arsenic causes the neurotransmitter alteration (Tripathi N, et al 1997; Flora, S.J.S. et al 2008). When individuals are exposed to arsenic there antioxidant level is decreased in the plasma (Wu MM, et al 2006; Flora, S.J.S. et al 2008). Arsenic is known to cause skin cancer, but the role of p53 in these cancers is uncertain and for example, basal cell carcinomas induced by arsenic exposure were found to over express p53 less frequently than sporadic basal cell carcinomas(Boonchai, W. et al 2000; STEPHEN S. et al 2004).

• Oxidative DNA damage associated to arsenic exposure:
Several products of guanine oxidation in position 8 and excreted
in urine which is used as oxidative DNA damage markers in human studies, so in which are 8-hydroxy-guanine (8-oxo-G), 8 -hydroxyguanosine (8-oxy-Guo) and 8-hydroxy-2-deoxyguanosine (8-OHdG)( Halliwell,B et al 2004; Vizcaya-Ruiz, A. D, et al 2009).

3) Lead:
Lead is the metal and has the atomic number 82 .it is the metal and due to its physical-chemical properties it is used in the industrial applications (Brannvall et al., 1999; Jomova, K et al 2011).lead cannot undergo readily valence changes so its oxidative stress are not clear ( Gurer , H et al 2000; Nuran, E et al 2001).

I) Lead and oxidative stress :
Free radical-induced damage by lead are accomplished by two
Independents, which are related mechanisms. First mechanism involve the ROS formation so it include the single oxygen, hydrogen peroxide and hyper oxides and second mechanism involve the depletion of cellular antioxidant pool (Ercal et al., 2001; Jomova, K et al 2011). At different experimental levels, there are strong indications which are involve in ROS in the lead-induced genotoxicity (Beyersmann.D et al2008). Metals increase the oxidation of fatty acid but lead was found to be as ineffective ( Nuran, E et al 2001).

ii) Lead and human health:
Lead poisoning is one of the oldest and the
most commonly studied occupational and environmental hazards
(Flora et al. 2006; Sivasudha. T et al 2013). Lead which effects the cell membrane and red blood cell membrane ( Nuran, E et al 2001). These classifications were mainly based on animal experiments, where increased tumor incidences were observed in multiple organs, including kidney and brain( Beyersmann.D et al2008) Lead is known to induce a broad range of physiological, biochemical, and behavioral dysfunctions in laboratory animals and humans including central and peripheral nervous systems8, haemopoietic system, cardiovascular system , kidneys, liver, and male, and female reproductive systems(Lancranjan I, et al 1975;Damek-Poprawa M, et al 2004;Khalil-Manesh F,et al 1993;Lanphear B.P, et al 2000;Flora SJ..S,et al 2006; Ruff H.A, et al 1996;Ronis MJJ, et al 1998; Sharma R.P,et al 1980;Flora .S.J.S et al 2008). Lead induced decrease in brain GPx activity may arise as a consequence of impaired functional groups such as glutathione (GSH) and NADPH or selenium mediated detoxification of toxic metals (Nehru B, et al 1997; Flora, S. J. S et al 2009).

Table 2:
Inactive metals Human health Reference
Lead Depressed immune status, mental impairment, neuromuscular weakness, brain damage, and coma Anetor and Adeniyi (1998);
Flora et al. (2007)
Arsenic Skin and bladder cancer.
DNA damage Rossman, 1998.
Ahmad et al., 2000.
Cadmium Lungs and skin cancer.
DNA damage. Hamer, 1986
Lazarova et al., 2006

Redox inert Metal:
Redox inert metal is the zinc. The most common and most stable oxidation number of zinc is +2 [Zn (II)]. Zinc trace elements are to be found in plants and animals (Jomova, K et al 2011). The exact role of zinc is the regulation of apoptosis which remains ambiguous (Formigari A et al.2007). Zinc is an element which is present in more than 70 different enzymes function in the cellular metabolism like metabolism of protein, lipids and carbohydrate (Jomova, K et al 2011).

Zinc and oxidative stress:
Zinc deficiency is related to the poor intake of zinc so that chronic illness and excessive dietary phytate intake (Jomova, K et al 2011). Redox-inert zinc may serve as an antioxidant by preventing binding of pro-oxidant copper at tissue site (Cuajungco, M. P.; et al 2000; Campbell. A et al 2001). The glutathione peroxidase family is an important cellular antioxidant defense mechanism in the zinc (Jenner, 1993; Meister, 1983; Math al 1997).Zinc helps manage insulin action and blood glucose concentration and has an essential role in the development and maintenance of the body’s immune system (Jomova, K et al 2011). Zn greatly reduces the amount of amyloid plaques in the Alzheimer disease and also compounds which affects the Zn homeostasis so decreases Aβ deposition in the brain (Adlard, P.A. et al. 2008; Cherny, R.A. et al. (2001); Lee, J.Y. et al. 2004; Zatta. P, et al 2009).
ii) Zinc and human disease:
The zinc-supplemented group of patients with sickle cell disease has decreases incidence of infection as comparison to the placebo group. Chronic disease like atherosclerosis, cancers, neurological disorders, and autoimmune diseases are caused (Bao et al., 2008; Jomova, K et al 2011). Zinc which usually serves as a cofactor of many enzymes which can be replaced by lead, thereby making the enzyme inactive. The increased lipid peroxidation and inhibition of enzymes are responsible for prevention of oxidative damage which is demonstrated as lead induced oxidative injury (Monterio HP, et al 1991; Flora, S. J. S et al 2009).Lack of zinc causes the teratogenic and CNS abnormalities (Dreosti, 1989; McNall et al., 1995; Taubeneck et al., 1995; Math al 1997). Zinc deficiency leads to atrophy of the thymus and lymphoid tissue in experimental animals (Shankar AH, et al 1998; Fraker P.J et al, 1889–1895; Prasad. A. S et al 2009).

Zinc and cardiovascular diseases:
Cardiovascular disease (CVD) is the leading cause of death worldwide. Cardiovascular cells interact with zinc, so in the plasma level of zinc decreases with the age and so which has great combination with CVD (Little et al 2010; Christos T. et al 2011). Zinc deficiency also have adverse effects in patients like with heart failure (Witte et al. 2001, Christos T. et al 2011). So suggested that heart failure is a wasting syndrome with multiple nutritional deficiencies like calcium/vitamin D, magnesium, manganese, copper, selenium, and zinc(Christos T. et al 2011). Cardiovascular homeostasis involves the complex interplay of peptide hormones and enzymes so that are responsible for the metabolism (Christos T. et al 2011).

Some sever disease:
i) Alzheimer’s Disease:
Alzheimer’s disease (AD) is a progressive neurodegenerative
disorder characterized by amyloid plaques and neuronal cell loss or dysfunction. The major constituent of plaques is a 39–42 amino acid peptide amyloid-β protein (Aβ) (Glenner and Wong, 1984; Masters et al., 1985; White, A.R et l 1999). Alzheimer’s disease (AD) is the most common form of dementia and often diagnosed in people over 65 years of age (Cui. H et al 2011). The zinc-binding site may regulate homophilic binding interact with other ligands such as heparan sulfate, or regulate coagulation factor inhibition (Beher et al., 1996; Multhaup et al., 1994 ;Van Nostrand, 1995 White, A.R et l 1999) or protein folding. Metal-induced aggregation of Aβ may not be characteristic of redox chemistry and have the capacity to regulate reactive oxygen species production (Bondy et al., 1998; Huang et al., 1999a, b; Yang et al., 1999; Sayre et al., 2000; Perry et al., 2003; Moreira. P.I et al 2004). The ‘metal hypothesis of Alzheimer’s disease’, with the addition of the concept that the neuropathogenic effects of Ab in AD are promoted by (and possibly even dependent on) the conjugation of the peptide with selected metals, seems to be a very workable hypothesis ( Zatta. P, et al 2009).

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