Antioxidants and human diseases.

CCA-13536; No of Pages 16 Clinica Chimica Acta xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim

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Article history: Received 4 April 2014 Received in revised form 4 June 2014 Accepted 5 June 2014 Available online xxxx

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Keywords: Antioxidant Oxidative stress Diabetes Cancer

NPO-International Laboratory of Biochemistry, 1-166, Uchide, Nakagawa-ku, Nagoya 454-0926, Japan Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Israel Oncology Department Soroka University Medical Center, Be'er-Sheva 84105, Israel d Department of Applied Zoology and Biotechnology, Vivekananda College (A Gurukula Institute of Life Training), Affiliated to Madurai Kamaraj University, Thiruvedakam West, Madurai 625234, India e Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel f Department of Clinical Biochemistry and Pharmacology, Soroka University Medical Center, Ben-Gurion University of the Negev, Be'er-Sheva 84105, Israel b c

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Oxidative stress plays a pivotal role in the development of human diseases. Reactive oxygen species (ROS) that includes hydrogen peroxide, hyphochlorus acid, superoxide anion, singlet oxygen, lipid peroxides, hypochlorite and hydroxyl radical are involved in growth, differentiation, progression and death of the cell. They can react with membrane lipids, nucleic acids, proteins, enzymes and other small molecules. Low concentrations of ROS has an indispensable role in intracellular signalling and defence against pathogens, while, higher amounts of ROS play a role in number of human diseases, including arthritis, cancer, diabetes, atherosclerosis, ischemia, failures in immunity and endocrine functions. Antioxidants presumably act as safeguard against the accumulation of ROS and their elimination from the system. The aim of this review is to highlight advances in understanding of the ROS and also to summarize the detailed impact and involvement of antioxidants in selected human diseases. © 2014 Published by Elsevier B.V.

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Introduction . . . . . . . . . . . . . . . . . Measuring oxidative stress . . . . . . . . . . 2.1. Pro-oxidants . . . . . . . . . . . . . 3. Potential antioxidant biomarkers . . . . . . . 3.1. Superoxide dismutase (SOD) . . . . . . 3.2. Catalase (CAT) . . . . . . . . . . . . 3.3. Glutathione peroxidase (GPx) . . . . . 3.4. Thiol index . . . . . . . . . . . . . . 3.5. Xanthine oxidase (XO) . . . . . . . . . 3.6. NADPH Oxidase . . . . . . . . . . . . 3.7. A biomarker of cardiovascular damage . 4. Mechanism of antioxidant action and nutrients . 5. Antioxidants vs human diseases . . . . . . . . 5.1. Antioxidant vs arthritis . . . . . . . . . 5.2. Anti oxidant vs cancer . . . . . . . . . 5.3. Antioxidant vs diabetes . . . . . . . . 5.4. Antioxidant vs arthrosclerosis . . . . . 5.5. Anti oxidant vs neurodegerative diseases 6. Conclusion . . . . . . . . . . . . . . . . . 7. Uncited references . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .

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Peramaiyan Rajendran a, Natarajan Nandakumar b, Thamaraiselvan Rengarajan a, Rajendran Palaniswami d, Edwinoliver Nesamony Gnanadhas e, Uppalapati Lakshminarasaiah f, Jacob Gopas b,c, Ikuo Nishigaki b,⁎

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Antioxidants and human diseases

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58 ⁎ Corresponding author. E-mail address: [email protected] (I. Nishigaki).

http://dx.doi.org/10.1016/j.cca.2014.06.004 0009-8981/© 2014 Published by Elsevier B.V.

Please cite this article as: Rajendran P, et al, Antioxidants and human diseases, Clin Chim Acta (2014), http://dx.doi.org/10.1016/j.cca.2014.06.004

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P. Rajendran et al. / Clinica Chimica Acta xxx (2014) xxx–xxx

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As oxidative stress is indicative of an inequity between oxidants and antioxidants, methods for quantifying oxidative stress mostly include straight or indirect measurement of oxidants and antioxidants [6,7]. In the following segment, some principles and commonly used methods for the measurement of oxidative stress and damage will be briefly outlined.

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2.1. Pro-oxidants

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The most abundant free radicals in biological systems are the oxygen-centered free radicals and their metabolites, usually referred to as ROS [7]. ROS are formed continuously as normal by-products of cellular metabolism; and, in low concentrations, they are essential for several physiological processes, including protein phosphorylation, transcription factor activation, cell differentiation, apoptosis, oocyte maturation, steroidogenesis, cell immunity, and cellular defense against microorganisms [7]. However, when produced in excess, ROS can damage cell functionality as they can harm cellular lipids, proteins, and DNA [7,8]. The plasma level of ROMs is considered an indicator of free-radical production [7]. ROMs is a collective term that includes not only oxygencentered free radicals such as the superoxide anion and hydroxyl radical, but also some non-radical derivatives of oxygen, such as hydrogen peroxide (H2O2) and hypochlorous acid [9]. A ROMs kit has been developed to assess oxidant levels in plasma and other biological fluids; and the ROMs test has been validated by electron spin resonance [10], which is considered the “gold standard” for measuring total oxidative status. However, electron spin resonance is not suitable for routine analysis, as the method is complex and requires specific technical assistance

81 82 83 84 85 86 87 88 89 90

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2. Measuring oxidative stress

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The beneficial effect of antioxidants on the maintenance of health in human has become an important subject that has engaged many scientists across the world over the last decade. In the last few years, antioxidants have become the indispensable nutrients of the nutritional world. Antioxidants are important in terms of their ability to protect against oxidative cell damage that can lead to conditions, such as Alzheimer's disease, cancer, heart disease and also linked with chronic inflammation [1]. It is defined as the substances which at low concentration significantly inhibits or delay the oxidative process, while often being oxidized themselves. Recent reports suggest that several endogenous and exogenous antioxidants are used to neutralize free radicals and protect the body from free radicals by maintaining redox balance [2,3]. Singh et al. (2010) [4] quoted that antioxidants have gone from “Miracle Molecules” to “Marvellous Molecules” and finally to “Physiological Molecules” that they play a vital role in metabolic pathways and protect cells. However recent conflicting evidence has forced the scientists to dig deeper in order to explore the role of antioxidants and pro-oxidants, since free radical reactions have been implicated in every human pathological condition which includes neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, memory loss, depression and cardiovascular diseases such as atherosclerosis, ischemic heart disease, cardiac hypertrophy, hypertension, shock and trauma. Further, it also implicated in pulmonary disorders which include inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease and additionally diseases associated with premature infants such as bronchopulmonary dysplasia, periventricular leukomalacia, intraventricular hemorrhage, retinopathy of prematurity and necrotizing enterocolitis and in some autoimmune diseases like rheumatoid arthritis and also in several renal disorders such as glomerulonephritis, tubulointerstitial nephritis, chronic renal failure, proteinuria, uremia and finally gastrointestinal diseases like peptic ulcer, inflammatory bowel disease and colitis, diabetes, tumors and cancers [5].

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not available in most laboratories. The utility of the ROMs assay in monitoring oxidative stress in goats [11], sheep [12], and dairy cows [13] has been reported. The concentrations of individual oxidant components can be measured separately in the laboratory; but such measurements are time-consuming, labor intensive, and costly. Free-radical analytical system 4 technology has been shown to offer a quick, simple, precise, and reliable method for assessing the oxidative status in dairy cows [14] and in horses [15]. Such technology is particularly useful in the field, where it is not always practical or possible to get samples to a laboratory immediately. The possibility of assessing oxidative stress directly in blood samples provides veterinarians with a simple and reliable method for measuring oxidative stress in clinical situations such as the monitoring of therapy and in the antioxidant supplementation of domestic animals. However, given the lack of reference values for ROMs in ruminants, it is difficult to establish if and when these animals are actually experiencing oxidative stress. Therefore, it is important to calculate the specific referral ranges; because a correct biochemical evaluation of oxidative status is an essential premise to prevent and eventually to treat the effects of oxidative stress in ruminant medicine. Advanced oxidation protein products (AOPPs) are terminal products of proteins exposed to free radicals and arise from the reaction between plasma proteins and chlorinated oxidants mediated by myeloperoxidase, a neutrophil enzyme [16,17]. In humans, AOPPs have been linked to several diseases, such as chronic renal failure [18], diabetes mellitus [19], diabetic nephropathy [20], coronary artery diseases [21], and obesity [22]. Chronic accumulation of AOPPs has been demonstrated to promote inflammatory processes in the diabetic kidney [20] and in chronic renal failure [18], indicating that these products might be a byproduct of neutrophil activation during infections. Studies in ruminants have shown higher levels of AOPPs than normal in lambs [23] and dairy cows [24] supplemented with Yerba Mate (Ilex paraguanensis). More information about the role of protein oxidation in ruminants' health and about oxidated proteins could be obtained by a comparison of AOPPs with other indicators of protein oxidation, such as advanced glycation end products (AGE). However, a correlation between AGE and inflammatory parameters is usually not found or is only weak, and the induction of proinflammatory activities caused by AOPPs seems to be more intense [25,26], suggesting that oxidative stress is more closely linked to inflammation and acute-phase reactions than to the advanced glycation process and its end products. AOPPs could thus better describe acute inflammation, whereas AGE might serve more as a marker of chronic long-lasting damage [25]. These observations are highly relevant, as increased levels of AOPPs could indicate the presence of inflammatory processes that can potentially compromise the correct embryonic development in dairy cows [14,27]. Lipids, in particular those that are polyunsaturated, are prone to oxidation. Lipids are one of the most susceptible substrates to damage by free radicals, and biomarkers of lipid peroxidation are considered the best indicators of oxidative stress [28]. Malondialdehyde (MDA) is one of several low-molecular-weight end products formed during radical-induced decomposition of polyunsaturated fatty acids [29]. MDA readily reacts with thiobarbituric acid, producing a red pigment that can be easily measured by spectrophotometry in the form of thiobarbituric acid-reactive substances (TBARS, [29]). It is worth noting that the MDA assay has been criticized for its low specificity and for artifact formation, since only a fraction of the MDA measured is actually generated in vivo. Furthermore, the TBARS assay, a common method used to measure MDA, is considered inaccurate, and returns results that differ according to the assay conditions used [30]. For example, studies on dairy cows have yielded contrasting results, with some reports failing to show any significant changes in plasma MDA concentrations during the peripartum period [31]; whereas in other studies MDA or TBARS concentrations were shown to increase around calving [8,16,32]. This apparent discrepancy could also have been mainly due to the great variation in individual MDA concentrations measured in the studies by Castillo et al. [31]. Similarly, studies on

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3.1. Superoxide dismutase (SOD)

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The term superoxide dismutase characterizes a family of enzymatic proteins differing in their structure and cofactors, among them being Mn-SOD and Cu–Zn-SOD. SOD activity enhances the spontaneous dismutation of superoxide radicals to H2O2 [52]. SOD can be measured by utilizing the technique of Misra and Fridovich [43], which is based on inhibition of the formation of nicotine amide adenine dinucleotide, phenazine methosulfate, and amino blue tetrazolium formazan.

218

3.2. Catalase (CAT)

219 220

The end product of the dismutation reaction, i.e., H2O2, can be removed by the activity of the enzyme catalase. CAT is an enzyme with a very high KM for its substrate and can remove H2O2 present in high concentrations [52]. The activity of CAT can be measured through the

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t1:1 t1:2

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Table 1 Biomarkers of oxidative stress. Biomarkers

t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22 t1:23 t1:24

Carbonyls Lipid peroxidation •Malondialdehyde •F2-isoprostane •4-Hydroxynonenal Ferric reducing ability of plasma Plasma vitamins •Vitamin C •Vitamin E Antioxidant enzymes •Superoxide dismutase •Catalase •Glutathione peroxidase •GSH/GSSG ratio in erythrocyte Prooxidant enzymes •Xanthine oxidase •NADPH oxidase Others •Endothelial microparticles •Endothelial progenitor cells •Ischemia modified albumin

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t1:3

Location

Reference

Extracellular

Mohanty et al. [36]

Extracellular Extracellular Extracellular Extracellular

Ohkawa et al. [37] Collins et al. [38] Halliwell and Gutteridge [39] Benzie and Strain [40]

Extracellular Extracellular

Roe and Kuether [41] Teissier [42]

Intracellular Intracellular Intracellular Intracellular

Misra and Fridovich [43] Aebi and Bergmeyer [44] Floh'e andGünzler [45] Hissin and Hilf [46]

Intracellular Intracellular

Haining and Legan [47] Nauseef [48]

Extracellular Extracellular Extracellular

Burger and Touyz [49] Touyz and Schiffrin [50] Sinha et al. [51]

226 227

3.4. Thiol index

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The biochemical function of glutathione peroxidase is to reduce lipid hydroperoxides to their corresponding alcohols and to reduce free H2O2 to water. In contrast to catalase, peroxidase possesses a high affinity for and can remove H2O2 even when it is present in a low concentration [52]. Its activity can be estimated by the method described by Flohe and Gunzler [45].

228 229 230 231

The GSH/GSSG index is a parameter of the intracellular redox status. GSH is the major endogenous antioxidant produced by cells; and it participates directly in the neutralization of free radicals and reactiveoxygen compounds, as well as in maintaining exogenous antioxidants such as vitamins C and E in their reduced forms [53]. GSH and GSSG levels can be measured in erythrocytes by the method described by Hissin and Hilf [46].

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3.5. Xanthine oxidase (XO)

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Epidemiologic literature that focuses on antioxidant status and chronic disease risk has in the past relied primarily upon biomarkers of exposure to antioxidant nutrients. However, this approach is in essence using exposure estimates to a select group of nutrients as a surrogate for estimating actual oxidative defense or oxidative stress status. Emphasis is now being placed on developing functional biomarkers of oxidative stress status, that is, biomarkers that integrate the effect of exposure to oxidants coupled with the full range of antioxidant protectivemechanisms in vivo. Many of such biomarkers are being studied including various measures of oxidation products of lipid, DNA, and protein (Table 1). Some of these biomarkers are now being applied in research of pathologies related to oxidative stress.

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3.3. Glutathione peroxidase (GPx)

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234 235 236 237 238 239

XO is a key enzyme involved in the formation of reactive oxygen species, and it plays a major role in cell oxidative stress. This enzyme catalyzes the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid [54]. Xanthine oxidase can be estimated by the method of Haining and Legan [47].

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3.6. NADPH Oxidase

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The NADPH-oxidase complex utilizes electrons to produce superoxide radicals from the oxygen molecule. NADPH oxidase may be measured by a chemiluminescence [55] or electrochemical method among others. Approaches to quantitate oxygen consumption, extracellular release of O∙2 or H2O2, and intracellular O∙2 production provide reliable assessment of NADPH oxidase activity in a given population of cells [56].

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3.7. A biomarker of cardiovascular damage

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Endothelial microparticles (EMPs) are nuclear fragments of cellular membrane shed from oxidatively stressed or damaged cells. Typically defined as having a diameter of 0.1 to 1.0 mm, these microparticles contain surface proteins and cytoplasmic material of the parental cells [57]. Many biomonitoring studies have investigated the role of antioxidants in reducing oxidatively generated DNA damage in urine and white blood cells. A collective interpretation is difficult because many studies lack sufficient control and have unreasonably high baseline levels of oxidatively damaged DNA. to investigating antioxidant effects has been the use of biomarkers of oxidatively damaged DNA. This is based on the mechanistic rationale that dietary antioxidants inhibit the oxidation of DNA. With the possibility of detecting 8-oxo-7,8dihydro-2′-deoxyguanosine (8-oxodG), the first of many antioxidant supplementation studies with focus on this lesion in WBC appeared in the beginning of the 1990s. At the same time, reliable detection of urinary 8-oxodG excretion was achieved, and this was soon followed by antioxidant supplementation studies using urinary 8-oxodG excretion as key biomarker. However, by far the most popular method in antioxidant intervention trials has been the comet assay that detects DNA strand breaks (SB). An enzyme-modified version of the comet assay has been developed to detect oxidatively altered nucleobases by including a DNA digestion step with DNA glycosylase or endonuclease enzymes [58]. The characteristics of the intervention studies are outlined in Table 2.

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non spontaneous decomposition of hydrogen peroxide, by the method 223 described by Aebi [44]. 224

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transported cattle have failed to report a consistent change in their MDA concentration. It seems that this discrepancy is partly due to the different methodologies employed to assess MDA levels. TBARS represent a wide range of lipid peroxidation products, and the thiobarbituric acid reaction is rather non-specific for MDA [33]. High-pressure liquid chromatography would be expected to be highly specific, and perhaps, more accurate than the spectrophotometric procedures [34]. More recently, an ELISAbased method for the detection of isoprostane, which is considered to be the most reliable marker of lipid oxidation [35], has become commercially available and might be able to shed more light on the role of lipid peroxidation during the peripartum period in ruminants.

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242 243 244 245

248 249 250 251 252

255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277

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Table 2 Administrations of dietary antioxidant with assessment of oxidatively DNA damage in white blood cells and urine.

t2:3

Supplement per day

Subjects

Age (years)

Effect

References

t2:4 t2:5 t2:6

β-carotene (20 mg) for 14 weeks β-carotene (30 mg) for 1 months Carotenoidsa for 3 weeks

122 M (S) 14 M (NS) 32 MF(NS)

39 (NR) 19–22 32 ± 11

[59] [60] [61]

t2:7

Vitamin C (500 mg as plain or slow release formulations) and vitamin E (182 mg) for 4 weeks Multi-vitamin tablet (100 mg vitamin C, 280 mg vitamin E, and 25 mg b-carotene) for 20 weeks Vegetable consumption (3.6 vs 12 servings) for 2 weeks Kiwi fruit (1–3 pieces) for 3 weeks Cranberry juice (750 ml) for 2 weeks Blackcurrant juice or anthocyanine drink (475–1000 ml) for 3 weeks Green tea or black tea (four cups) for 1–4 months

48 M (S)

39 ± 12

No effect on urinary excretion of 8-oxodG/24-h (HPLC) No effect on urinary excretion of 8-oxodG/24-h (HPLC) No effect versus baseline, but decreased urinary excretion of 8-oxodG ELISA) in active group post-supplementation Decreased ENDOIII and FPG sites (Comet) in the group that ingested tablets with the slowrelease vitamin C formulation 100 M (50S) 50–59 Decreased ENDOIII sites (Comet) after 20 weeks in WBC

Two interventions of green tea with 300 ml for 7 days or 32 oz for 7 days Green tea extract b for 3 weeks

68 MF (13S) 18–45 16 M (8S)

20–31

124 MF(NR) 38 F (NR)

NR

t2:17

Green tea (500 or 1000 mg) among high-risk subjects of liver cancer for 3 months Soya-hypocotyl tea (N1000 ml) for 1 months

t2:18 t2:19

Soy milk, rice milk, or cow milk (1 l) for 4 weeks Polyphenol-rich olive oils (25 ml) for 40 days

10 M (NS) 12 M (NS)

20–50 20–22

t2:20

Olive oil (25 ml) with three different content of phenolic 182 M (NS) compounds for 3 weeks Antioxidant rich diet or tabletsc for 5 weeks 55 MF (NR)

t2:15 t2:16

t2:21

14 MF (NS) 20 F (2S) 57 MF (6S)

26–54 18–40 19–52

Decreased ENDOIII and FPG (Comet) sites No effect on ENDOIII (Comet) in WBC No effect on ENDOIII and FPG sites (Comet) in WBC

[65] [66] [67]

120 MF(S)

18–79

Decreased excretion of 8-oxodG (ELISA) in spot urine samples after 4 mo in green tea group, but not before Decreased 12-h urinary excretion of 8-oxodG (HPLC)

NR

20–60 71 ± 6

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[64]

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t2:14

Lower 8-oxodG in WBC (HPLC) among those subjects eating 12 servings per day

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23–81

No effect related to supplementation on 24-h urinary excretion of 8-oxodG (HPLC) but a decreased excretion during the study in all groups Lower 8-oxodG/24-h (HPLC) after 3 months supplementation but not after 1 month Decreased excretion of 8-oxodG (ELISA) in active group (statistical test not reported) Decreased ENDOIII sites (Comet) for soy milk Decreased excretion of 8-oxodG (HPLC) in spot urinary samples following supplementation in a dose-dependent manner Decreased 8-oxodG/24-h urinary excretion, but no difference in urinary excretion of 8-oxoGua/24-h. No difference in the effect of the different olive oils No effect versus baseline, but decreased 24-h urinary excretion of 8-oxodG (ELISA) in active group post-supplementation

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t2:10 t2:11 t2:12

64 F (NR)

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t2:9

[63]

[68,69] [70] [71] [72] [73] [74] [75] [76] [77]

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t2:8

[62]

Number of subjects indicated as males (M) and females (F). Smokers (S) and non-smokers (NS) are indicated in brackets. Lacking information is indicated as NR (not reported) Age is shown as range or mean ± standard deviation. aSupplement constitute b-carotene (6 mg), a-carotene (1.4 mg), lycopene (4.5 mg), bixin (11.7 mg), lutein (4.4 mg), and paprika carotenoids (2.2 mg), b Consisted of 1000 mg extract/kg bodyweight in meat patties (total phenolics were 23.5 mg/10 MJ), cConsisted of tablets with vitamin antioxidants (400 mg vitamin C, 150 mg vitamin E, 4 mg b-carotene), capsules (90 mg vitamin C, 18 IU vitamin E, 2.4 mg b-carotene, and powder or extract of fruits and berries), or a carotenoid-rich diet.

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4. Mechanism of antioxidant action and nutrients

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288 289

It is reported that antioxidants can execute protective role against free radicals by a variety of different mechanism including the catalytic systems to neutralize or divert ROS, binding or inactivation of metal ions prevents generation of ROS by Haber–Weiss reaction, suicidal and chain breaking antioxidants scavenge and destroy ROS or absorb energy, electron and quenching of ROS. In 21st century, demand for intake of antioxidant food or dietary antioxidant increasing with the hope to keep body healthy and free from diseases [78,79] and the potential beneficial effects of antioxidants in protecting against disease have been well established. It is increasingly thought that nutrition may play a vital role in helping to defend against oxidative stress and damage

t3:1 t3:2

Table 3 Effects of the health associated to the intake of Antioxidants.

t3:3

Antioxidants Vitamin C

t3:4

Vitamin E t3:5

Polyphenol t3:6 t3:7 t3:8

C E

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286 287

C

284 285

N

282 283

induced by free radicals. Therefore, certain nutrients and dietary components with antioxidant properties are important for the protection against oxidative stress injury of the body. Food consumption is a major source of exogenous antioxidants and has been estimated that a typical diet provides more than 25,000 bioactive food constituents as nutrients and many of this may modify a multitude of processes that are related to different diseases. Generally, antioxidants are abundant in vegetables and fruits and are also found in grain cereals, peas, legumes, nuts and other food products. At this juncture, a systematic survey has also identified more than 3100 antioxidants in foods, like beverages, spices, herbs and supplements which are regularly consumed by different cultures [80]. It has been speculated that the decrease in the intake of nutritional and antioxidants rich food may

Cu, Zn, Mn, Se Other carotenoids (lycopene)

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t2:22 t2:23 t2:24 t2:25

Effect of health

References

Protects against cancers, Protects from heart disease, Improvement of the health of cartilage, joints and skin, Maintaining a healthy immune system, Improvement in the antibody production, Increase in the absorption of nutrients, Increases protection against H2O2-induced DNA strand breaks Prevents coronary heart disease, Prevents the formation of blood clots Decreases incidence of breast and prostate cancers, Brain protection, Reduces long-term risk of dementia Decreases risk of Parkinson's disease Inhibit oxidation of LDL, Inhibit platelet aggregation, Improve endothelial dysfunction Lower risk of myocardial infarction, Effect anticarcinogenic Prevent neurodegenerative diseases, Protect against neurotoxic drugs, treatment of diabetes, treatment to prevent osteoporosis, Inhibit non-heme iron absorption Cofactors of antioxidant enzymes SOD-Cu/Zn, Mn-SOD and GSH-Pox Protection against oxidation of lipids, LDL, proteins and DNA. Abduction and free radical scavenging

Barry [85], Liu et al. [86], Wang et al. [87], Wintergerst et al. [88], Woo et al. [89], Thankachan et al. [90] and Riso et al. [91].

Pryor [92], Traber et al. [93], Weinstein et al. [94], Muller et al. [95], Devore et al. [96] and Miyake et al. [97]. Manach et al. [98], Russo et al. [99], Schächinger et al. [100], Corder et al. [101], Yang et al. [102] Halliwell [103], Pan et al. [104], Zunino et al. [105], Atmaca et al. [106], Hurrell et al. [107]. Visioli F et al. [108] Visioli F et al. [108]


290 291 292 293 294 295 296 297 298 299 300 301 302


310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325

329

Chronic autoimmune inflammation, which is commonly observed in rheumatoid arthritis (RA), disrupts the delicate balance between bone resorption and calcification causing the destruction of the bone and joints. Multiple aetiologies are suspected to contribute to the formation of RA, including defective articular cartilage structure and biosynthesis, joint trauma, joint instability, congenital and developmental abnormalities, and inflammatory conditions [109,110]. Oxidative stress induced damage to essential cell components caused by oxygen free radicals is a mechanism in the patho-biology of degenerative rheumatoid arthritis [109]. Hydroxyl radicals cause degradation of isolated proteoglycans, and hypochlorous acid (HOCl) fragments of collagen. Hydrogen peroxide, which is highly diffusible, readily inhibits cartilage proteoglycan synthesis, by interfering with ATP synthesis, in part by inhibiting the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase in chondrocytes, aggravating the effects of proteolytic and free-radicalmediated cartilage degradation. Peroxynitrite and HOCl may facilitate cartilage damages by inactivating TIMPs. TIMP-1 inhibits stromelysins, collagenases and gelatinasesand this ability is lost after nitrus oxide (NO− 3 ) or HOCl treatment. HOCl can also activate latent forms of neutrophil collagenases and gelatinase with obvious consequences. − Hypochlorous acid, NO− 3 and O2 react with ascorbate, which is essential

330 331

U

N C O

R

R

E

C

T

E

D

326 327

5.1. Antioxidant vs arthritis

F

309

328

O

307 308

5. Antioxidants vs human diseases

R O

305 306

increase the chances of oxidative stress which may lead to cell damage, therefore intake of such natural antioxidants may give protective effect against free radical induced diseases [80,81]. In view of the importance of antioxidants, Suntres [82] reported that antioxidant liposomes will hold an important role in future research on antioxidants, and also reports that it facilitates the delivery of antioxidants to specific sites as well as achieving prophylactic and therapeutic action. In addition, Bouayed and Bohn [83] have suggested that the balance between oxidation and anti-oxidation is critical in maintaining a healthy biologic system and low doses of antioxidants may be favorable to this system, but high quantities may disrupt the balance. It is true that antioxidants are beneficial and display a useful role in the maintenance of the homeostasis in human ROS system, but so are pro-oxidants, therefore the scientific community should search deeper into the kinetics and in vivo mechanisms of antioxidants to uncover the optimal concentrations or desired functions in order to push forward against cancer, neurodegenerative and cardiovascular diseases [84] (Table 3). Various studies related to free radicals, oxidative stress and antioxidant activity of food reveals the prominent beneficial role of antioxidant and its specific role against different diseases individually. However the collective and concise data on the role of antioxidants in human diseases will be better and most appropriate one in order to know the exact role of antioxidants in all kinds of human diseases (Fig. 1). Hence, an attempt has been made in this review, to summarize the detailed role and impact of antioxidants in certain selected dreadful human diseases.

P

303 304

5

Q1

Fig. 1. Antioxidants/oxidative stress and health diseases.


332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350

6

U

Table 4 Clinical trials (variables observed: vitamins C, E, selenium, and β-carotene, ORAC).

N

t4:3

Study

t4:4

Hematologic malignancies Clemens et al. [157] Subjects: n = 19

CY, MEL, VP16, TBI

Clemens et al. [158]

Subjects: (TBI+) N = 16, mean age: 30.5 y, Controls: (TBI+) n = 10, mean age: 37.5 y Controls: n = 19, mean age: 33 y; Subjects: n = 10, mean age: 37 y Controls: n = 26, age range: 18–28 y; subjects: n = 16, intervention: n=6

CY, VP16, BU, TBI

Subjects: n = 56; controls: n = 44, mean age: 58.7 y

DXR, CY, CDDP, MELPH

Four arms: 1) VE 300 mg, Se 96 μg; 2) Se 96 μg; 3) VE 300 mg; 4) placebo (PO)

Controlled trial

Subjects: n = 18, age range: 51.8–69.6 y

CY, ADR, VP16, VCR, DXR, EPI CBPT, RT

MV β-Car 10,000–20,000 U, α-Toc 300–800 U, AA 2000– 5000 U, Se 856 μg (PO)

Nonrandomized controlled trial

Subjects: n = 32, age range: 32–81 y

Chemotx, RT, Surgery

VC 2850 mg, VE 2500 IU, β-Car 32,500 U, Se 387 μg (PO)

Nonrandomized, noncontrolled trial

Sample size and demographics

Cancer agents

C

O

t4:5

t4:6

Hunnisett et al.,[159]

t4:7

Lloyd et al. [160]

t4:8 t4:9 t4:10

Gynecologic cancer Sundstrom et al. [161]

t4:11 t4:12 t4:13

t4:14 t4:15 t4:16

t4:17 t4:18 t4:19 t4:20 t4:21 t4:22

Lung cancer Jaakola et al. [162]

Breast cancer Lockwood et al. [163]

Dosage and mode

Study design

Results

Strengths/weaknesses

α-Toc 9 mg (TPN)

Cohort study

Subjects (TBI+): serum α-Toc and β-Car 2 (baseline v day +12); TBI-α-Toc over time (P b .001), no significant changes in β-Car

Nonrandomized, nonblinded, controlled trial

↓ Hepatotoxicity; no significant differences in rates of relapse

20 sequential patients

Acute 2 in VC and VE (P b. .001; P b .001); no significant differences after day 0

Significant differences between two groups at baseline; nonrandomized, small cohort, no controls; intervention assessed the effects of RDA only Study groups received different TPN regimens; significant differences were not observed at each time point; P values NR; small cohort, different anticancer regimens; TBI+ also received 130 mg AA and 13.1 mg α-Toc by TPN Nonrandomized, small cohort; cancer diagnosis and agents NR

Cohort study

Prior to intervention: mean platelet and plasma ↓AA In CML controls (P b .001; P b .05), mean platelet AA↓ in CML v controls (P b .05); after intervention: ↑ in platelet and plasma AA in AL & CML (P b .025) ↑ plasma AA in CLL (P b .05)

Inquired about dietary intake/Cancer therapy NR; time of blood withdrawal, length of observation, and timing of intervention NR; methodology NR

↑ in serum Se in Se group 1 and group 2 v controls (P b .001; P b .001)

Placebo controlled trial/multiple gynecologic cancers, stages, and regimens

R

TBI+: α-Toc 825 mg, β-Car 45 mg, AA 450 mg, (PO); TBI+: AA 530 mg, α-Toc 9 mg (TPN)

R

E

High-dose chemotx, ±TBI

VC 25 mg; VE 1000 IU (TPN)

NR

AA 1 g X 4 days (mode NR)

C

T

E

D

P

Study group had increased survival rates compared to historical controls (P value NR); plasma Se, α-Toc NS, plasma AA, β-Car NR

R O

O

Whole blood β-Car, VE, and Se ↑ after 3 and 12 months (P b .01), P b .05), P b .01); no deaths, expected four; no subject had weight loss, ↓ use of pain killers, ↑ QOL

F

Variable doses administered depending on “individual” micronutrient analysis (methodology NR); multiple stages combined; one subject received no cancer therapy

Whole blood VC NR, no controls, chemotherapy agents NR; subjects also administered MV containing Co-Q10 and essential fatty acids; P values not consistently reported

Abbreviations: ORAC, Oxygen radical absorbance capacity; CY, cyclophosphamide; MELPH, melphalan; VP16, etoposide; 2, decrease; 1, increase; TBI, total body irradiation; α-Toc, alpha tocopherol; TPN, total parenteral nutrition; β-Car, beta carotene; RDA, recommended dietary allowances; y, years; BU, busulfan: PO, orally; AA, ascorbic acid; NR, not reported; VC, vitamin C; VE, vitamin E; DZ, diaziquone; TP, thiotepa; Ara-C, cytosine arabinoside; k-Cal, total caloric intake; CML, chronic myelocytic leukemia; AL, acute leukemia; CLL, chronic lymphocytic leukemia; VCR, vincristine; DXR, doxorubicin; EPI, epirubicin; CBPT, carboplatin; RT, radiation therapy; MV, multivitamin; NS, nonsignificant; CDDP, cisplatinum diammine dichloride; Se, selenium; chemotx, chemotherapy; QOL, quality of life; Co-Q10, coenzyme Q 10; y-TOC, gamma tocopherol (Modified from Elena J. Ladas et al., 2004).



t4:1 t4:2


372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389

394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414

C

370 371

E

F

O

368 369

R

366 367

R

364 365

N C O

362 363

U

360 361

R O

Reactive Oxygen Species is a hallmark of human cancer. ROS and their functions with respect to the cancer initiation and signalling in cancer cells is a prime concern of cancer research. Tobacco smoke also plays a very important role in increasing the risk for inflammation and cancer due to its high carcinogenic potential and the synergistic effects with other respirable particulate to generate ROS and catalyse redox reactions in the cells of humans, leading to oxidative stress and increased production of mediators of inflammation [117–119]. Inflammatory cells are particularly effective in generating most of the reactive oxygen species. The activation of the redox metabolism of the inflammatory cells generates a highly oxidative environment within an organ of aerobic organisms. Much of the oxygen biochemistry, through the activation of plasma membrane NADPH oxidase, of macrophages and neutrophils is directed towards the release of superoxide anion, hydrogen peroxide and hydroxyl radicals [120–122]. Inflammation acts through the formation of ROS and reactive nitro species (RNS) which cause oxidative damage to cellular components. Many pro-inflammatory mediators, especially cytokines, chemokines and prostagladins, turn on the angiogenesis switches mainly controlled by vascular endothelial growth factors [123]. Cancer-associated inflammation is also linked with immune-suppression that allows cancer cells to evade detection by the immune system. Inflammation is a critical component of tumor progression. Many cancers arise from sites of infection, chronic irritation

358 359

P

392 393

357

D

5.2. Anti oxidant vs cancer

355 356

and inflammation. It is now becoming clear that the tumor microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumor cells have co-opted some of the signalling molecules of the innate immune system such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development [124]. Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases. Chronic inflammation is associated with angiogenesis, a process that helps cancer cells to grow. Angiogenesis is necessary for expansion of tumor mass and macrophage, platelets, fibroblasts and tumor cells are a major source of angiogenic factors (vascular endothelial growth factors, chemokines, NO, etc.) [125,126]. The inflammation in the tumor microenvironment is characterized by leukocyte infiltration, ranging in size, distribution and composition, as: tumorassociated macrophages (TAM), mast cells, dendritic cells, natural killer (NK) cells, neutrophils, eosinophils and lymphocytes. These cells produce a variety of cytotoxic mediators such as ROS and RNS, serine and cysteine proteases, membrane perforating agents, matrix metalloproteinase (MMP), tumor necrosis factor α (TNFα), interleukins (IL-1, IL-6, IL-8), interferons (IFNs) and enzymes, likecyclooxygenase-2 (COX-2), lipooxygenase-5 (LOX-5) and phospholipase A2 (PLA2). Other researchers discovered that tumor-associated macrophages are key regulators of the link between inflammation and carcinogenesis [127] and experimental studies showed that, tobacco smoke produce ROS that have been associated with activation of mitogen-activated protein kinase (MAPK) family members and activation of transcription factors such as NF-κβ and AP-1. These signaling pathways have been implicated in processes of inflammation, apoptosis, proliferation, transformation and differentiation [128]. The activation protein-1 (AP-1) contributes to basal gene expression in biological systems. ROS can activate AP-1 through several mechanisms and the effect of AP-1 activation is an increased cell proliferation due to increased expression of growth stimulatory genes such as cyclin D1 and suppression of the protein p21waf. Studies showed that AP-1 and NF-kB, inducible by tumor promoters of oxidative stimuli, show differential protein levels or activation in response to tumor promoters in JB6 cells. Researchers suggest that as long as oxidative events regulate AP-1 and NF-kβ transactivation, these oxidative events can be important molecular targets for cancer prevention [129,130]. NF-kB is expressed and participates in a wide range of biological processes, such as cell survival, differentiation, inflammation and growth [131]. NF-kB activation has been linked to a wide spectrum of extracellular stimuli and oxidants and subsequent involvement in the carcinogenic process through promotion of angiogenesis and tumor cell invasion and metastasis [132,133]. Dietary factors like chlorogenic acid have also been found to protect against environmental carcinogen induced carcinogenesis by their upregulation of phase II conjugating enzymes and suppression of ROSmediated correct, AP-1, and MAPK activation [134]. Cellular defence system is comprised of several Phase II detoxification enzymes such as glutathione-S-transferases (GSTs), NADP (H) quinoneoxidoreductase (NQO1), Glutathione peroxidases (GPx), Catalase, superoxide dismutases (SODs), epoxide hydrolase, hemeoxygenase (HO-1), UDPglucuronosyltransferases (UGTs), gammaglutamylcysteinesynthetase and many others. Expression of these proteins protects cells from oxidative damage and can prevent mutagenesis and cancer [135–138]. To counterbalance the oxidative damage from ROS, aerobic organisms have created a variety of antioxidant mechanisms to maintain their genomic stability. These mechanisms include phase II detoxification and other anti-oxidation enzymes that act in cellular defence such as catalase and SOD, GPx, GST, other constitutive and inducible antioxidants, DNA repair enzymes, and other cellular mechanisms of genomic surveillance, such as cell cycle checkpoint control systems [134]. Moreover, several growth factors such as serum, insulin like growth factor I, or fibroblast growth factor 2 generates ROS in MIA PaCa-2 and PANC-1

E

391

353 354

T

390

for cartilage function, leading to low levels of ascorbate in synovial fluid. Low concentrations of hydrogen peroxide (H2O2), O.− 2 or both, accelerate bone resorption by osteoclasts, whereas nitric oxide (NO.) inhibits it and promotes chondrocyte apoptosis, thereby inhibits proteoglycan synthesis and activates latent metalloproteinases and cyclooxygenase. ROS, produced by activated phagocytes, could alter the antigenic behavior of immunoglobulin G, producing fluorescent protein aggregates that can further activate phagocytic cells. Radical-exposed IgG is able to bind rheumatoid factor and results in the generation of C3a. This reaction may be self-perpetuating within the rheumatoid joint, suggesting that free radicals play a role in the chronicity of the inflammatory reaction which is a key question regarding to which extent free radicals contribute to the consequences of inflammation, such as the cartilage and bone destruction. Reactive oxygen intermediates can also function as signaling messengers to activate transcription factors, like NF-κB Change all to NF-κBand activator protein 1(AP-1), and induce gene expression [111]. All this knowledge might serve to apply a rational selection of antioxidants for possible therapeutic purposes, of the inflammatory joint disease. Many raw foods contains natural antioxidants, including enzymes such as superoxide dismutase, glutathione peroxidase and catalase, which are usually inactivated during food processing, and nonenzymic antioxidants such as carotenoids (e.g. canthaxanthin and astaxanthin in some farmed fish), β-carotene, lutein, lycopene, tocopherols (in oils) and other compounds in plants. The latter include other carotenoids and ascorbate (vitamin C). The plasma concentrations of these are largely determined by dietary intake and it is possible that two or more antioxidants can act together synergistically [112,113]. In view of the high antioxidant content of the French diet which is rich in fruit, vegetables and red wine [114,115], it is intriguing to note the relatively low incidence of arthritis [116]. More work is required on tissue distributions and bioavailability of antioxidant molecules within joints since lipophilic antioxidant molecules, such as vitamin E or β-carotene, may not have the same access to tissues as hydrophilic antioxidants, such as vitamin C. Perhaps, the differences in their effects in disease processes may depend on the hydrophilicity of the antioxidant molecules concerned and the resulting pattern of tissue distribution in different tissue areas. One major problem is that there is no assay currently available to measure oxidant activity within joints and possibly the activity could occur from an alternative mechanism.

351 352

7


415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480

504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546

599

Glucose overload may damage the cells through oxidative stress. This is currently the basis of the “unifying hypothesis” that hyperglycemia-induced oxidative stress may account for the pathogenesis of all diabetic complications [165,166]. Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. Free radicals are formed disproportionately in diabetes by glucose oxidation, non-enzymaticglycation of proteins, and the subsequent oxidative degradation of glycatedproteins [167]. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased

600 601

O

F

5.3. Antioxidant vs diabetes

R O

502 503

P

500 501

547 548

D

498 499

cells. It has been suggested that, as a nutrition factor, POX may modulate apoptosis signals induced by p53 or other anti-cancer agents and enhance apoptosis in stress situations [148]. Components of the cell signaling network, especially those which converge on the ubiquitous eukaryotic redox-sensitive transcription factor nuclear factor-kappa B (NF-κB), have been implicated in pathogenesis of many inflammation-associated disorders. Under normal physiologic conditions, NF-κB is sequestered in the cytoplasm by binding to the inhibitory protein called IκBa. Phosphorylation and subsequent ubiquitination results in degradation of IκBa by proteasomes. Phosphorylation of IκBa is mainly mediated by the IκB kinase (IKK) complex. Phosphorylation of specific serine residues of p65 subunit of NF-κB has been considered to facilitate the translocation of NF-κB to nucleus and interaction with the coactivator CBP/p300. Induction of κphase-2 detoxifying or antioxidant genes represents an important cellular defense in response to oxidative and electrophilic insults. Nuclear transcription factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) plays a crucial role in regulating phase-2 detoxifying/antioxidant gene induction [149]. Like NF-κB, Nrf2 is present in the cytoplasm as an inactive complex with the inhibitory protein subunit, in this case Keap1. Dissociation of Nrf2 from Keap1 is prerequisite for nuclear translocation and subsequent transactivational activity. Once translocated into nucleus, Nrf2 interacts with a small Maf protein, forming a heterodimer that binds to antioxidant responsive elements (ARE) or electrophile responsive elements (EpRE) present in the promoter/enhancer regions of genes encoding many antioxidant and detoxifying enzymes. Keap1 contains several cysteine residues that function as sensors of redox changes. Oxidation or covalent modification of these critical cysteine thiols diminishes the affinity of Nrf2 for Keap1, releasing Nrf2 for nuclear translocation. Dissociation of the Nrf2-Keap1 complex is also assumed to be stimulated through the phosphorylation of Nrf2 by distinct upstream kinases such as MAPKs, PKC, PI3K, etc. As in the case of NF-κB, phosphorylation of Nrf2 is also considered to facilitate the interaction of this redox-sensitive transcription factor with CBP/p300.NRF2 is a known regulator of the antioxidant response [150,151]. NRF2regulated phase II enzymes protect against the development of cancer by catalyzing reactions that convert highly reactive, carcinogenic chemicals to less reactive products [152,153]. Singh et al. (2012) [154] recently demonstrated that vitamin C and BHA provide protection against E2-mediated oxidative DNA damage but the mechanism is not well understood. Many antioxidants derived from dietary and medicinal plants have been found to modulate Nrf2-Keap1 signaling, thereby potentiating cellular antioxidant capacity or facilitating detoxification of carcinogens and other toxicants [155,156]. Table 4 describes 7 observational studies reporting changes in serum, plasma, or whole blood levels of vitamins Cand E, selenium,β-carotene, and total radical antioxidant parameter (TRAP), which represents total body antioxidant status, in patients undergoing anticancer therapy. Information is grouped by malignancy and includes subject demographics, cancer data, cancer treatment, end points evaluated, results, and comments. No specific treatment was consistently associated with changes in the individual antioxidants (Table 4) [164].

T

496 497

C

494 495

E

492 493

R

490 491

R

488 489

O

487

C

485 486

N

483 484

cells, which are human pancreatic adenocarcinoma cells that promotes cell survival. Inhibiting ROS generation with the antioxidants or NADPH oxidase (Nox4) antisense, or MnSODover expression would stimulate apoptosis in PaCa-2 and PANC-1 cells. This mechanism might play an important role in pancreatic cancer resistance for treatment and thus represent a novel therapeutic target. In gastrointestinal and colon cancer, oxidative pentose pathway (OPP) and the glutathione (GSH) antioxidant defense system play an important role in the regulation of cell growth and apoptosis. The OPP modulate intracellular redox status and provides NADPH for the synthesis of GSH, which is responsible for the inactivation of intracellular ROS that induce apoptosis and cell injury. Depletion of GSH increases the sensitivity of cells to ROS. Therapeutic inhibition of the OPP and/or the GSH defense system might increase the sensitivity of gastric and colon cancer cells to anti-cancer therapy [139]. Recent studies have shown that the enzymatic product of thymidine phosphorylase (TP) generated ROS within cancer cells that help in maintaining the growth of colon cancer cells thus may provide improved therapeutic results as well as a preventative effect on carcinogenesis of the colorectum [125]. Emerging evidence also suggests that supranutritional doses of selenite could induce typical apoptosis in colorectal cancer cells in vitro and in xenografttumors by inducing ROS and it indicates that antioxidants can activate the apoptotic machinery through redox-dependent activation and could be useful in cancer therapy [140]. The MAPK signalling cascade is activated by a wide variety of receptors involved in growth and differentiation including receptor tyrosine kinases (RTKs), integrins and ion channels. This pathway has been reported to be activated in over 50% of acute myelogenous leukemia, acute lymphocytic leukemia and are frequently activated in breast, prostate cancers and other cancer types [141,142]. Under optimal growth conditions, transiently elevated ROS levels confer a growth advantage to tumor cells. However, exposure of these cells to anticancer agents induces a prolonged increase in ROS levels resulting in potentiating of apoptosis. Thus ROS modulates the ability of stress kinases to stimulate cell growth or cell death and it depends on signal intensity and signal duration [143]. This idea has been nurtured to explain the complex nature of ERK signaling in cell cycle regulation and in stress activated protein kinase signalling (SAPK). Transient, reduced activity of SAPK promotes cell proliferation, whereas persistent, increased activity results in cell killing [144]. Conversely, in drug-resistant tumors, phase II enzymes or other antioxidant defences are often up regulated, shielding cells from apoptosis. ASK1, an upstream regulator of SAPKs, is inhibited in normal cells through its association with thioredoxin, which is an antioxidant capable of metabolizing ROS. Increased levels of ROS lead to the dissociation of this complex and thereby facilitate the activation of ASK1 and subsequently SAPKs [145]. A similar redox control has been identified for JNK where increased level of ROS triggers the detachment of JNK associated glutathione-S-transferase-π (GSTp) and thereby facilitating JNK activation. Moreover, ROS-dependent activation of JNK may also lead to knock down of a JNK phosphatase via an unknown mechanism linking ROS and stress induced kinases an important player in cancer cell growth [146]. Growth inhibition of pancreatic cells is dependent on the efficiency of scavenging ROS as well as effective inhibition of ERK1/2 signaling pathway activation as demonstrated by using the free radical scavenger N-Acetyl Cysteine (NAC) or the MEK/ERK1/ 2 inhibitor (PD98059). Moreover, ERK1/2 induction is dependent on ROS production as demonstrated by a complete removal of ERK1/2 phosphorylation by NAC. Thus ROS act as pro-survival, anti-apoptotic factor in pancreatic cancer cells [52]. Moreover, treatment of SW620 (colon cancer cells) with berberine, which is a major constituents of Coptidisthizoma, resulted in activation of apoptosis by phosphorylation of JNK and p38 MAPK, as well as generation of the ROS [147]. Furthermore, proline oxidase (POX), that often considered as a ‘housekeeping enzyme’, induce apoptosis through both intrinsic and extrinsic pathways and is involved in nuclear factor of activated T cells (NFAT) signaling and regulation of the MEK/ERK pathway in colon cancer

U

481 482


E

8


549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598

602 603 604 605 606 607 608 609 610

9

T

E

D

P

R O

O

F


618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640

E

R

616 617

R

614 615

formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical anti-atherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species cause defective angiogenesis in response to ischemia, activate a number of pro-inflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized (“hyperglycemic memory”). Atherosclerosis and cardiomyopathy in diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of anti-atherosclerosis enzymes by ROS. Over expression of antioxidant enzymes in diabetic patients prevents diabetic retinopathy, nephropathy, and cardiomyopathy [168]. Antioxidants have proven to play a minimal if any role in the treatment of diabetic complications in humans [169]. Decreases in expression, and in some instances the activity of antioxidant enzymes, has been previously reported in diabetic microvascular disease [170]. Indeed, the over expression of Cu+Zn2+ superoxide dismutase (SOD) protects against end organ damage in models of type II diabetic nephropathy [171]. Other studies in mice with genetic deletions of various antioxidant enzymes have also provided insight into the specific relative contributions of Mn2+SOD [172] to the development of diabetes complications. Mn2+SOD mimetics such as MnTBAP have also shown efficacy in preventing ROS-induced injury in vitro, although the utility in vivo of such drugs may be limited [173,174]. Further strengthening a potential role for the antioxidant Mn2+SOD, specific polymorphisms of the Mn2+SOD gene are associated with the development of diabetic complications [175]. Interestingly, GPx-1-deficient mice have no increased

N C O

612 613

U

611

C

Fig. 2. Shows the involvement of cellular antioxidant enzymes in cardiovascular diseases.

risk for microvascular disease, in particular diabetic complications [176], most likely because of redundancy with respect to GPx isoforms. Over-expression of catalase in experimental models of type 2 diabetic appears to be protective the diabetic complications [177]. In contrast to Mn2+SOD, however, studies in humans have indicated no relationship between catalase gene polymorphisms that interfere with its cellular expression and the incidence of type 2 diabetic patients [178]. Kunisaki et al. [179] investigated the effects of treatments with classical antioxidants such as vitamin E,vitamin C and lipoic acid. Specifically, vitamin E normalizes retinal blood flow and protein kinase C (PKC) activity in the vascular tissue of diabetic rats. One short-term experimental study showed that high doses of vitamin C can improve some aspects of endothelial dysfunction in diabetes. Another experimental study has demonstrated that intra-peritoneal administration of αlipoic acid to streptozotocin (STZ) diabetic Wistar rats normalises TBARS levels in plasma, and the retina, liver, and pancreas [180]. Furthermore, it has been reported that α-lipoic acid leads to a decrease in the severity of diabetic neuropathy by maintaining GSH levels and/or by its direct antioxidant properties [181]. However, lipoic acid administration improved endothelial function in subjects with metabolic syndrome. In another study to determine the effects of vitamin E on oxidative stress and cell membrane fluidity in the brains of diabetesinduced experimental rats, Hong et al. [182] reported that vitamin E was found to be effective for strengthening the antioxidant defense system. They noted a reduction of the accumulation of ROS such as superoxide radicals, a decrease in the generation of oxidative damaging substances such as the carbonyl value, a significantly improved lipid composition, and maintenance of membrane fluidity in the brains of the rats. Coleman suggested that triple antioxidant therapy (vitamin E, lipoic acid and vitamin C) in diabetic volunteers attenuates the


641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670

696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720

726 727 728 729 730 731 732 733 734

C

694 695

E

692 693

R

690 691

R

688 689

O

686 687

C

684 685

N

682 683

U

680 681

F

The mechanisms of oxidative stress and antioxidants are in patients with atherosclerosis have been evaluated in extensive animal experiments and clinical research. There is a relationship between atherosclerotic risk factors (ARF) and increased vascular production of ROS; the most important ARFs are heredity, age, hypertension, dyslipidemia, diabetes and smoking [192]. It has been reported that in in-vitro studies an increased vascular production of ROS, particularly superoxide causes deleterious effects in cell death [193,194]. ROS and reactive nitrogen species (RNS) are closely linked to the disease process. Incomplete scavenging of ROS and RNS influences the mitochondrial lipid cardiolipin, stimulates the release of mitochondrial cytochrome c and finally

678 679

O

724 725

677

R O

5.4. Antioxidant vs arthrosclerosis

675 676

P

723

673 674

activates the intrinsic death pathway [195]. Local generation of RNS may contribute to vascular tissue injury. Therefore, ROS and RNS participate as signalling molecules that regulate diverse pathophysiological signalling pathways. High levels of ROS are potent inducers of the intrinsic apoptotic pathway and tissue injury in pathophysiological conditions as an integral part of atherosclerotic plaque stabilization. The most important sources of ROS production associated with CVD pathology are the mitochondrial respiratory chain, nicotinamide adenine dinucleotide phosphate oxidases (NADP oxidase). The pathogenesis of atherosclerosis is further related to inflammation, immune response and the proliferative process. Endothelial denuding injury leads to platelet aggregation and releases platelet-derived growth factor, which triggers the proliferation of smooth muscle cells forming the nidus of the atherosclerotic plaque in the arterial intima, implicating inflammatory changes in the development of the disease [196,197]. Supplementing treatment with antioxidants might be helpful to patients. Vitamin E reduces the consequences of lipid peroxide content in mouse peritoneal macrophages (MPMs) [198]. E-selectin has been proposed as an important factor in the development of the inflammatory process underlying atherothrombosis. The expression of E-selectin is decreased by vitamin E in the diabetic rats [199]. Vitamin C has also been investigated in studies on the prevention of atherosclerosis. The following proposals have been put forward regarding the mechanisms of vitamin C in preventing atherosclerosis: First, vitamin C has been shown to prevent apoptosis caused by cytokines in cultured endothelial cells [200]. It also decreases the release of micro-particles derived from endothelial cells and suppresses pro-apoptotic activity in congestive heart failure patients in vivo [201]. Second, vitamin C stimulates all types of collagen synthesis by specific hydroxylase enzymes [202]. Endothelial cell proliferation is, in part, associated with the synthesis of type IV collagen [203]. Thus, the lack of vitamin C prevents the generation of type IV collagen in cultured endothelial cells [204]. Third, vitamin C protects the vascular endothelium by enhancing endothelial NO synthase. Endothelial NO synthase activity is inhibited by ROS that oxidize and deplete the co-factor tetrahydrobiopterin [205]. Therefore, vitamin C prevents the loss of NO synthase activity by maintaining tetrahydrobiopterin [206]. Glutathione monoethyl ester, but not ascorbic acid, exerted protective effects against ischemia–reperfusion injury. Interestingly, the protective effects of glutathione monoethyl ester are enhanced by co-administration with vitamin C in rat hearts subjected to ischemia and reperfusion [207]. The oxidized LDL leads to increased platelet-endothelial cell adhesion, which can be prevented by superoxide dismutase (SOD) and catalase [208]. In fact, the vascular extracellular expression of SOD is stimulated by NO [209]. Narang et al. [210] reported that dietary palmolein oil, which is rich in monounsaturated fatty acid and antioxidant vitamins, “protected rat heart from oxidative stress associated with ischemiareperfusion injury”. Das et al. [211] found “a role for c-Src [a family of proto-oncogenic tyrosine kinases] in post ischemic cardiac injury and dysfunction and demonstrate direct cardio protective effects of [the tocotrienol-rich fraction of palm oil (TRF)]. The cardio protectiveproperties of TRF appear to be due to inhibition of c-Src activation and proteasome stabilization”. Carlson et al. [212] using a rat model, reported: “Antioxidant vitamin therapy [vitamin C, vitamin E, vitamin A and zinc] abrogated myocardial inflammatory cytokine signaling and attenuated sepsis-related contractile dysfunction, suggesting that antioxidant vitamin therapy may be a potential approach to treat injury and disease states characterized by myocardial dysfunction”. Hypertension is directly regulated by the kidneys and cardiovascular system and adversely affects these organs. Tian et al. [213] found that in salt sensitive rat model of hypertension, vitamin C and vitamin E treatments “decreased renal inflammatory cytokines and chemokines, renal immune cells, NF-κB, and arterial pressure and improved renal function and damage”. As noted above, chronic zidovudine administration promotes cardiovascular damage, and vitamin C has been found to combat this effect in rats [214]. Diabetes mellitus may initiate increased myocardial vulnerability to ischemia–

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experimental oxidative stress of met-hemoglobin formation in vitro and reduces haemoglobin glycation in vivo [183]. Panjwani et al. [184] suggested that vitamin C administered alone or in combination with vitamin E reduced the fall in ulnar nerve conduction velocity. Sivan and Reece [185] investigated whether dietary supplementation with vitamin E would reduce the incidence of diabetic embryopathy in an in vivo rat model. Fifty pregnant rats were designated as the control group and received a normal diet while the diabetic group received vitamin E supplements (400 mg/day). This experimental study found that supplementation with vitamin E reduces the incidence of neural tube defects by more than 75% [186]. These findings suggest that vitamin E reduces this oxidative load, confers a protective effect against diabetic embryopathy, and thus may potentially serve as a dietary prophylaxis in the future. These results are in line with the reports of Chang et al. [186] which showed that diabetic embryopathy of rat or mouse embryos is prevented by vitamin C, vitamin E, SOD, N-acetyl-cysteine, or glutathione ethyl ester. Another study by Otero et al. [187] showed the effects of supplementation with vitamin E to diabetic mice. The beneficial effect of vitamin E observed in this model was shown to retard coronary atherosclerosis accelerated by DM, and was demonstrated to be due to a reduction in oxidative stress, and not secondary to a decrease in plasma glucose or cholesterol since their respective plasma concentrations remained unchanged in the diabetic mice supplemented with vitamin E [188]. Furthermore, it has been recently reported that macrophages from diabetic mice are under excess oxidative stress, and that the antioxidant vitamin E can attenuate macrophage oxidative stress which exists in DM and leads to accelerated atherosclerosis development. In a placebocontrolled, randomized trial of diabetic patients, Reaven investigated the effect of 1600 IU of RRR-α-tocopherol supplementation daily for 10 weeks on hyperglycemia-induced LDL modifications. The result of the study pointed to a reduction of approximately 60% of plasma LDL oxidation in diabetic patients, which was statistically significant when compared to healthy controls [189]. These results are supported and confirmed by other similar clinical data. Salonen et al. [190] found that doses equal to or higher than 450 IU are sufficient to significantly ameliorate the susceptibility of LDL to oxidation, indicating that relatively high doses of RRR-α-tocopherol for supplementation are needed. Furthermore, Bellomo and others have shown that the effects of RRRα-tocopherolsupplementation on LDL oxidation are accompanied by a concomitant reduction in autoantibody levels againsthyperglycemiainduced LDL modifications. Moreover, clinical studies have shown an inhibitory effect of RRR-α-tocopherol supplementation on thehyperglycemia-induced LDL modifications inT1DM and T2DM diabetic patients. Based on nutrition recommendations and interventions for diabetes, there is no clear evidence of benefits that can be derived from vitamin or mineral supplementation in people with diabetes. Routine supplementation with antioxidants, such as vitamins E and C and carotene, is not advised because of lack of evidence of efficacy, and concern related to long term safety, and therefore cannot be recommended [191]. The majority of studies included in this review support a possible role of antioxidant supplementation in reducing the risk of diabetic complications

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6. Conclusion

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In summary the reactive oxygen species and oxidative stress play an important role in the aetiology and progression of major human degenerative diseases has triggered enormous and worldwide interest in endogenous and exogenous antioxidants. There is now abundant evidence that substances in fruit and vegetables are potent preventives of various diseases, especially arthritis, cancer, heart disease, diabetes and neurodegenerative diseases. With these recent developments in scientific knowledge which firmly establish the links between food factors and the prevention of disease. The present review reveals a vast number of relevant studies related to oxidative stress and selected human diseases. The research field actually presents a variety of approaches that have been produced suggestive evidence that antioxidants might have an impact against many diseases. However, more systematic research in this line is imperative in order to reveal the relationship and involvement of antioxidants with other diseases. The large diversity in the molecular mechanisms and the methodology of antioxidants discussed here are factors probably responsible for the consistent findings of their prevention of diseases. This shows that it will be very

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Neurodegenerative disorders are a heterogeneous group of diseases of the nervous system, including the brain, spinal cord, and peripheral nerves that have much different aetiology. ROS are particularly active in the brain and neuronal tissue as the excitatory amino acids and neurotransmitters, whose metabolism is factory of ROS, which are unique to the brain and serve as sources of oxidative stress. ROS attack glial cells and neurons, which are post-mitotic cells and therefore, they are particularly sensitive to free radicals, leading to neuronal damage [228]. It has been reported that deleterious effects of ROS on human cells may end in oxidative injury leading to programmed cell death i.e. apoptosis [229]. A multitude of genes involved in redox status, antiinflammation and detoxification are transcribed by Nrf2–ARE pathway activation. These genes are known to be involved in cytoprotection from various oxidative insult and cellular injuries in numerous different tissues and organs including brain. Intracellular peroxidases are cleared by a group of enzymes that are transcribed by Nrf2–ARE pathway. The peroxisomal CAT catalyses the conversion of H2O2 to water and molecular oxygen. However, the specific activity of CAT is much lower in brain than peripheral tissue [230]. Glutathione-s-peroxidase (Gpx) is another enzyme that metabolizes H2O2 and depends on reduced glutathione (GSH). The oxidized GSH (GS-SG) is recycled to GSH by glutathione reductase (GR). Glutathione (GSH), a tripeptide γ-glutamyl-cysteinylglycine, is the most abundant low molecular weight thiol expressed ubiquitously. It is widely recognized as an endogenous non-enzymatic antioxidant and an oxyradical scavenger, and is thereby critical to maintaining a reducing environment in the cell and protect against oxidative damage by ROS [231–235]. GSH has been implicated in a wide range of metabolic processes, including cell division, DNA repair, regulation of enzyme activity, and activation of transcription factors, modulation of anion and cation homeostasis, and protection against oxidative damage [236]. GSTs are key detoxification enzymes that catalyze the conjugation of various electrophiles, reactive alkenals, and numerous other xenobiotic to GSH. These GSH-S-conjugates are removed from cells by the multidrug resistant protein-1 (MRP-1), an ATP binding cassette (ABC) family protein [237,238]. MRP-1 is an integral plasma membrane protein that exports glutathione-S conjugates out of the cell in an ATP-dependent manner [239,240]. Studies have shown reduced GST activity in brain and ventricular fluids in AD [241]. Increased expression of GST leads to increased resistance towards oxidative stress in neuroblastoma cells and provides protection against HNE-mediated toxicity in neuronal cell culture [241]. Growing evidence demonstrates that the AD brain is under tremendous oxidative stress. A significantly increased HO-1 expression was reported in post-mortem AD temporal cortex and hippocampus compared to aged-matched control [242]. Additionally, an increased Nqo1 activity and expression was found in astrocytes and neurons of AD brain [231] and Nrf2 was predominantly localized in cytoplasm in AD hippocampal neurons [243]. Furthermore, there is increased protein oxidation [244,245] and lipid peroxidation [246–248] in AD brain when compared to aged matched controls. Recent studies in aged APP/PS1 AD mouse models showed reduced Nrf2, Nqo1, GCL catalytic subunit (GCLC) and GCL modifier subunit (GCLM) mRNA and Nrf2 protein levels [249]. Additionally, in a triple transgenic AD mouse, the GSH/GSSG ratio was reported to be reduced [250].

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5.5. Anti oxidant vs neurodegerative diseases

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The hallmark of PD is a severe reduction of dopamine in all components of the basal ganglia. Dopamine and its metabolites are depleted in the caudate nucleus, putamen, globuspallidus, nucleus accumbens, the ventral tegmental area, and the substantianigra pars compacta and reticulata. Moderate losses of dopamine are found in the lateral hypothalamus, medial olfactory region and amygdaloid nucleus [251]. In early parkinsonism, there appears to be a compensatory increase in dopamine receptors to accommodate the initial loss of dopamine neurons [252]. As the disease progresses, the number of dopamine receptors are decreases, apparently due to the concomitant degeneration of dopamine target sites on striatal neurons. In the remaining neurons in patients with PD, dopamine turnover seems greatly increased, judging from the concentrations of homovannilic acid [HVA] in the nerve terminals in the striatum and the cell bodies and dendrites in the substantia nigra [253] and the ROS production may very well increase in consequence. This hypothesis is strengthened by a study showing that the concentrations of GSH decrease when dopamine turnover increase after reserpine treatment in rats, indicating increased activity of the peroxide scavenging enzyme GSH-Px [254]. If the increase in ROS production due to increased dopamine turnover is not buffered by the scavenging enzymes (SOD, catalase, and GSH-Px), the compensatory hyperactivity of the dopaminergic neurons may become selfdestructive. Chronic administration of L-DOPA would then only exacerbate the production of destructive ROS [255]. The administration of L-DOPA itself has been postulated to enhance the accumulation of ROS [256]. Another index of oxidative stress in PD might be the evidence of a robust increase of NF-κB in the nuclei of dopaminergic neurons in the substantia nigra of PD patients [257]. This clinical finding is consistent with in vitro data showing that oxidative stress induced by C2ceramide treatment causes nuclear translocation of NF-κB in cultured mesencephalic neurons [258]. More recently, it has been shown that the neurotoxin 6-OHDA activates NF-κB in PC12 cells by enhancing intracellular ROS levels [259]. Interestingly, in this experimental model, NF-κB seems to sustain cell survival by stimulating the expression of the anti-apoptotic proteins Bcl-2 and Bfl-1144. Moreover, as already mentioned, the potent green tea polyphenol antioxidant EGCG exerts a neuroprotective effect in a MPTP mouse model of PD [260]. However, there are still few and controversial epidemiological data on this important point, which might be partly due to the intrinsic difficulties in performing epidemiological surveys regarding the dietary habits of large populations. Nevertheless, it is desirable that future studies aimed at investigating the relationship between dietary antioxidant intake and the relative risk for neurodegenerative disorders such as AD, PD, and ALS will throw more light on this very important aspect of public health.

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reperfusion injury and pro/antioxidant imbalance. Resistance to ischemia-induced ventricular arrhythmias and levels of endogenous antioxidants (α-tocopherol) has been found to be increased in diabetic rat myocardium [215]. The currently available evidence needs to be confirmed in clinical trials. Consumption of fruit and vegetable diets rich in antioxidant nutrients can be recommended for all individuals, and there is some indication that such a diet can be beneficial in the effects of cardiovascular events. Fig. 2 shows the involvement of cellular antioxidant enzymes in cardiovascular diseases.

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useful in controlling many oxidative stress mediated diseases as discussed above. In comparison with the effects of the antioxidants analysed in the previous study we can expect that many plant derived compounds which have excellent antioxidant property and were successfully investigated here and validates or corroborates the antioxidant hypothesis of many diseases [167,261–265]. Current review highlights the perspectives and possibilities of unrevealing the uncapped potentials of antioxidants in herbal plants for disease cure and warrants the need for systematic research in the field to clear the insights in this very complex matter. However, recent research work with antioxidant therapy suggests another promising area i.e., combining potential antioxidants and using them during the early onset of the disease as a prophylactic measure to prevent the disease that may eventually prove to be more effective in treating several devastating diseases.

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The Role of Oxidative Stress and Antioxidants in Liver Diseases.

Antioxidants: Impact on Redox Status in Brain Diseases.

Mitochondrion-Permeable Antioxidants to Treat ROS-Burst-Mediated Acute Diseases.

The antioxidants of human extracellular fluids.

Plasma lipid peroxides and antioxidants in human septic shock.

Food Antioxidants and Their Anti-Inflammatory Properties: A Potential Role in Cardiovascular Diseases and Cancer Prevention.

Helicases and human diseases.

Cytoprotective pyridinol antioxidants as potential therapeutic agents for neurodegenerative and mitochondrial diseases.

Orally Bioavailable Metal Chelators and Radical Scavengers: Multifunctional Antioxidants for the Coadjutant Treatment of Neurodegenerative Diseases.

Antioxidants and aging.

Scrapie and human neurodegenerative diseases.

Diabetic nephropathy and antioxidants.

Antioxidants and HIV infection.

Human transmissible neurodegenerative diseases (prion diseases).

Human papillomavirus-associated diseases.

[Inflammasomes in human diseases].

Human Genetic Diseases.

Phenolic antioxidants.

Antioxidants and Cardiovascular Risk Factors.

Antioxidants, inflammation and cardiovascular disease.

Oxidants and antioxidants in carcinogenesis.

Dietary antioxidants and cardiovascular disease.

Polyphenolic Antioxidants and Neuronal Regeneration.

Antioxidants in longevity and medicine.