Antioxidant-related disorders -
Selected electrophilic NRF2 activators and the related clinical trials have previously been summarized It is noted that these NRF2 activators may have multiple functions such as anti-inflammatory effects , , , some of which are not dependent on NRF2 activation.
For clarification, it is still possible that some of the agents for which a study of NRF2 activation is not indicated do in fact activate NRF2 even though that was not examined. There are several concerns and challenges associated with the therapeutic use of NRF2 activators , The first is related to low effective biological concentration, as most NRF2 activators are electrophilic and are metabolized quickly so that their bioavailability in distal organs may be low.
However, some evidence suggests that the Michael adducts of nucleophiles including the cysteines of KEAP1 with some electrophiles, such as cyanoenones, are reversible and this may significantly increase the bioavailability and concentration of these electrophiles in vivo.
This concept was demonstrated by a synthesized cyanoenone compound TBE31 that had a h half-life in the blood and markedly increased NRF2 activity in vivo at nanomolar concentrations It remains unclear whether this reversibility of the covalent adducts also occurs with other electrophiles, especially natural compounds such as sulforaphane and curcumin.
In addition, there is controversy regarding the effectiveness of oral sulforaphane to induce antioxidant expression in clinical trials, with both increased antioxidant expression and no effect being reported.
In general, more clinical trial data on NRF2 and antioxidant induction in target organs are needed to further assess the efficacy of these NRF2 activators.
Another key concern is the risk of nonspecific effects. Besides activating NRF2 and inducing antioxidant enzymes, some NRF2 activators may act on other signalling pathways and disrupt related biological processes.
For example, sulforaphane can suppress the inflammatory response through inhibition of NF-κB and inflammasome activation , and cause cell cycle arrest by inhibiting the PI3K—AKT and MAPK—ERK pathways Understanding the NRF2-independent effects is important in elucidating the mechanism of the beneficial and therapeutic effects, although for most NRF2 activators this has not been thoroughly studied, especially with regard to their in vivo dose dependency.
Another aspect of nonspecificity is that the effect on NRF2 activation and antioxidant induction is not restricted to a specific cell or organ, and may therefore result in systemic side effects. For example, some evidence suggests that although NRF2 activation could prevent the initiation of cancer, it can, however, promote cancer development , , Cell studies showed that higher NRF2 activity and antioxidant capacity can also contribute to the resistance to chemotherapeutic drugs , , , , as reviewed by others , , Current evidence is insufficient to draw a definitive conclusion and more systemic in vivo studies are needed to elucidate the role of NRF2 in promoting carcinogenesis and causing resistance to chemotherapies.
Other side effects of long-term NRF2 activation are less reported. Several strategies have been proposed to avoid systemic side effects, including the development of non-electrophilic drugs and drugs that only become active in loci that exhibit oxidative stress There are two types of agent that inhibit NOXs, those that inhibit the enzymatic activity and those that prevent the assembly of the NOX2 enzyme, which is a multiprotein complex.
Of the first type, diphenyleneiodonium DPI is commonly used in research studies but is a nonspecific inhibitor of flavoproteins as well as an inhibitor of iodide transport Several agents claimed to be NOX inhibitors, including ebselen, CYR, apocynin and GKT, some of which show promise in non-human animal models and clinical trials, exhibited effects that were not due to NOX inhibition Nonetheless, the potential value of inhibition of NOX1, NOX2 and NOX4 has been demonstrated in non-human animal models using genetic deletion , and a search for low-molecular-weight NOX inhibitors continues.
Small peptides that inhibit the assembly of the NOX complexes have therapeutic potential Although these small peptides would be more specific to the different NOXs than active site inhibitors, none has advanced to clinical trials.
A third potential approach is interference with the synthesis of the components of the NOX complexes; however, this too has not yet reached clinical trials. Yet, this strategy has been proposed for preventing hyperglycaemic damage in diabetes However, this agent has not yet been investigated in clinical trials.
Thus, SOD mimics that enter mitochondria would be expected to increase the rate of production of H 2 O 2. Ebselen can also enter mitochondria but may produce unexpected toxicity The large negative inner mitochondrial membrane potential makes it possible to target antioxidants and antioxidant mimics to these organelles by attaching a lipophilic cation to them This is an area of research that is still under development but basically uses the same principles of antioxidant defence as described in other sections of this Review.
The most widely used and studied dietary antioxidants are l -ascorbic acid vitamin C and α-tocopherol vitamin E.
Other dietary nutrients, including selenium, riboflavin and metals, are essential cofactors for antioxidant enzymes, and their adequate supply is essential for the inducers of these enzymes to reach their most effective levels, but discussion of them here is beyond the scope of this Review.
Vitamin C is a water-soluble vitamin that cannot be synthesized by the human body and must be provided as an essential dietary component. Vitamin C is required for the biosynthesis of collagen, protein and several other biological molecules Vitamin C is also an important antioxidant , by providing an electron to neutralize free radicals.
Vitamin E, which is lipid soluble, localizes to the plasma membrane and has roles in many biological processes. Almost years after its discovery, the functions and mechanism of action of vitamin E still remain of great interest.
Nonetheless, the importance of the antioxidant function of vitamin E has been demonstrated by many studies , , , especially under conditions of oxidative stress or deficiency of other antioxidants , Vitamin E reduces peroxyl radicals and forms tocopheroxyl radical, which is subsequently reduced by vitamin C.
Thus, vitamin E helps to maintain the integrity of long-chain polyunsaturated fatty acids in the membranes and thereby regulates the bioactivity and signalling related to membrane lipids.
For healthy individuals, sufficient levels of vitamins C and E are provided by normal dietary intake and deficiency rarely occurs. Under some extreme conditions such as malnutrition or imbalanced nutrition and diseases , , however, dietary supplementation of vitamins C and E is necessary.
As vitamins C and E function as antioxidants, there has been great interest in investigating their therapeutic potential. Many studies and clinical trials have found that vitamins C and E have beneficial effects in reducing various diseases, many of which likely involve oxidative stress, including cancers, cardiovascular diseases and cataracts But the evidence is inconsistent, as an almost equal number of studies show no significant effect.
It was assumed that both vitamin C and vitamin E have low toxicity and were not believed to cause serious adverse effects at much higher intake than needed for their function as vitamins.
However, several non-human animal studies showed that antioxidant supplements, including NAC, vitamin E and the soluble vitamin E analogue Trolox, promoted cancer development and metastasis, for example, lung, melanoma and intestinal tumours in mouse models , , The potential effect of antioxidants on cancer promotion, including the aforementioned NRF2 activators, raises significant concerns regarding the use of antioxidant supplements, and novel strategies are needed to resolve the double-edged effect of antioxidants.
In the early years of research in redox biology the emphasis was almost entirely on damage caused by oxidants. Although studies demonstrated that the addition of non-lethal doses of H 2 O 2 or other oxidants was able to stimulate signalling pathways, it was not until the mids that NF-κB activation by endogenous generation of H 2 O 2 was first observed By the late s, Lambeth and coworkers had described the seven-member NOX family and began to implicate them in cell signalling pathways.
Redox signalling is now the major focus of the field, although extensive coverage of the topic is beyond the scope of this article. Readers are referred to specific reviews in this area 4 , Nonetheless, as described earlier, H 2 O 2 is the major second messenger in redox signalling and like other second messengers, dysregulation of its production can result in aberrant signalling Prevention of dysregulation is tricky because attempts to inhibit the generation of oxidants by NOX proteins or mitochondria, as described in earlier sections, may interfere with physiologically important signalling including the regulation of leukotriene and prostaglandin production, which require a low level of H 2 O 2 or lipid hydroperoxides A more successful approach may be interference with specific redox signalling that is initiated by toxic stimuli.
Here, we provide one example to illustrate this approach Air pollution contains particles of enormously variable composition and includes silicates with iron on their surface.
An inhibitor of that enzyme, tricyclodecanyl xanthate D , which was unsuccessfully tried as an anticancer agent, stopped particle-induced NF-κB-dependent cytokine production.
D is an example of an agent that is not an antioxidant but inhibits oxidant-induced aberrant signalling. Interestingly, D interferes with the PC-PLC pathway when initiated by endotoxin , which does not involve redox signalling.
There are countless agents that have similar potential to inhibit aberrant signalling although they are not specific to redox-mediated signalling. Oxidative stress is a component of the underlying pathology of many diseases and toxicities, and the antioxidant defences and strategies that have been presented above offer some important opportunities for preventing or reducing pathology.
Nonetheless, there are several limitations that challenge our ability to therapeutically apply antioxidant strategies.
The effectiveness of antioxidant defences is limited by the extent to which oxidative stress plays a role in the pathology. When oxidative stress is a secondary contributor to disease, which is more often the case than it being the primary cause, preventing oxidative stress may not have a major impact on disease progression.
Indeed, this is one of the major causes of antioxidants exerting little to no effect on pathology, even when they clearly increase antioxidant defence and decrease markers of oxidative stress. This limitation is perhaps the most significant factor that is often overlooked when considering antioxidant defences in clinical trials.
The challenge here is to determine to what extent antioxidant strategies may be developed to ameliorate some symptoms if not the underlying cause of the disease. The commercialization of products containing small molecules that are chemical antioxidants but do not function as such in vivo, will ultimately fail to show significant benefit beyond what the antioxidant enzyme-inducing small molecules present in an adequate diet can achieve.
This disappointment will add to the challenge of developing and gaining public acceptance of truly effective therapeutics. The negligible effect of scavenging by small molecules represents a key limitation in antioxidant defence.
Thus, kinetic considerations essentially rule out scavenging as an effective antioxidant defence within cells 6. Although not as efficient as the endogenous SOD and catalase, the rate constants for the mimics are approximately 10 5 times higher than those of most protein cysteines.
SOD mimics can accumulate at high concentrations in the mitochondrial matrix by attachment of a lipophilic cationic group and can be effective in that microenvironment , where it has been demonstrated that the overexpression of endogenous SOD2 increases H 2 O 2 production However, the long-term effects of the non-physiological increase in mitochondrial SOD activity is unknown.
Vitamin E is the one exception to the limitation of small molecule scavenging by dietary antioxidants because of its relatively rapid rate of reaction with lipid hydroperoxyl radicals as well as its concentration in membranes. Nonetheless, antioxidant therapies that appeared to work in cell culture or in non-human animal models have often failed to achieve significant effects in human trials.
A primary reason for this discrepancy is the enormous difference in the ratio of exogenous agents in vitro versus in vivo 6. In non-human animal models, lab chow is deficient in vitamin E and selenium , which sets up a system in which antioxidants work by restoring redox homeostasis, thereby acting more like vitamins preventing a deficiency than like a drug.
Interestingly, mito-Q, made by the attachment of a lipophilic cationic group to ubiquinone, can accumulate in mitochondria and act in a similar manner to vitamin E in that domain However, the long-term effects of the non-physiological increase in ubiquinone is not yet understood.
Another concern is that compounds that induce antioxidant defences may not be able to reach effective concentrations in vivo, although this may be overcome with cyanoenones When adequate levels of NRF2 activators are supplied by good nutrition, supplemental NRF2 activators would not provide an advantage.
In addition, if oxidative stress occurs in patients, NRF2 is usually already activated to a certain degree and the potential for further induction is limited. As a good diet would be expected for patients in clinical trials, and oxidative stress is frequently seen in patients, the lack of an increase in protection may be due to the existing effects of dietary NRF2 inducers and a lower potential for NRF2 activation.
Perhaps the use of NRF2 activators should therefore be considered as similar to that of vitamins that are inadequate in the diet of a significant number of individuals and in patients who have difficulty consuming food.
As we age, the ability of electrophiles to induce NRF2-dependent expression of antioxidant enzymes declines Silencing BACH1 reverses this effect in human primary bronchial epithelial cells for some NRF2-regulated genes , suggesting that BACH1 inhibition has potential in antioxidant therapy, particularly in older patients.
However, as older people exhibit an increased risk of cancer, activating NRF2 in this group may be deleterious. Although NRF2 activation has long been associated with chemoprevention , a downside of NRF2 activation is the protection of cancer cells against oxidative damage, which helps cancer progression , , However, in mice, silencing of BACH1 does not appear to increase pdriven tumorigenesis It is hoped that more studies will further clarify the issue of cancer promotion associated with NRF2, and that additional means of increasing antioxidant defences will be found to benefit older people without adverse effects.
As oxidative stress is a component of many diseases, the development of effective antioxidant therapies is an important goal. Although using small molecules has been largely disappointing, hope lies in the realization that the rationale underlying their use was based on misconceptions that can be overcome.
In addition, the limitations highlighted in this Review — including consideration of whether oxidative stress plays a primary or secondary role in the pathology, the negligible effect of scavenging by almost all small molecules, difficulty in achieving effective in vivo concentrations and the declining ability to increase NRF2 activation in ageing — must be considered to both avoid unnecessary disappointment and set obtainable goals.
SOD, and SOD—catalase and GPX mimics, appear to be effective, with some agents currently in clinical trials. Maintaining GSH, the substrate for GPXs, can be achieved using precursors including NAC and GSH esters.
Indeed, NAC is already in human use for the treatment of some toxicities and diseases, although no clinical trials of GSH esters appear to be currently active. In addition to the mimics of antioxidant enzymes and GSH, another major strategy is increasing the synthesis of the endogenous antioxidant enzymes and de novo synthesis of GSH through NRF2 signalling in cells We expect that all these approaches will contribute to advancing antioxidant therapeutics and hope that this Review will encourage and inform a rational approach to that worthwhile endeavour.
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Multiple basic-leucine zipper proteins regulate induction of the mouse heme oxygenase-1 gene by arsenite. Moreover, ROS trigger toxic protein carbonyls formation which has a significant impact on other proteins or lipids Benfeitas et al.
In addition, as a result of lipid peroxidation, cancer cells accumulate products, such as 4-hydroxynon-enal, one of the most studied products of phospholipid peroxidation, owing to its reactivity and cytotoxicity.
In the brain, not all neuronal groups are equally sensitive to oxidative stress. For instance, neurons with longer axons and multiple synapses require more energy for axonal transport or long-term plasticity Salehi et al.
High ATP demand, in combination with dysfunctional mitochondria, make these neuron groups more sensitive to degeneration Wang and Michaelis, Correctly, dopaminergic neurons are exposed to additional oxidative stress produced by the dopamine metabolism, generating H 2 O 2 and dopamine autoxidation, which generates superoxide Delcambre et al.
During aging, mutations in mtDNA accumulate, cytosolic calcium dysregulates, and ETC function decreases, making aging one of the major risk factors contributing to neurodegeneration Payne and Chinnery, The oxidized molecules of DNA, proteins and lipids found in the brain tissue of post-mortem patients with neurodegenerative disorders highlight the role of oxidative stress in these diseases Sharifi-Rad M.
Another cause of neurodegenerative diseases is a defective use of metals by the brain, by the intervention of mutant proteins, formed as a result of oxidative stress Niedzielska et al.
In the case of Alzheimer disease, a protein called amyloid beta Aβ , consisting of 40 amino acid residues, is present in all the cells of the body, under normal, harmless and even beneficial conditions, as it is a natural antioxidant Danielson and Andersen, ; Li et al.
One explanation is the accumulation in the brain of a modified form of the Ab protein consisting of 42 amino acid residues , which fails to properly bind metals, promotes oxidative processes; by reacting in self-defense, neurons produce antioxidants in increased quantities, including the modified form of the Aβ protein, which thus becomes an antioxidant pro-oxidant, amplifying oxidative disasters by initiating chain reactions Danielson and Andersen, Mutations of the superoxide dismutase 1 SOD1 protein have been linked to another neurodegenerative disease that affects motility familial amyotrophic lateral sclerosis Huai and Zhang, In its unmodified form, SOD1 is a natural antioxidant that prevents the formation of peroxide anion as a dangerous reactive form of oxygen Saccon et al.
The mutant forms of this protein fixate a much smaller amount of metals than the usual form, which results in the formation of an excess of peroxynitrite ONOO — affecting the motor neurons required for normal functioning, causing severe motor disorders Pasinelli et al.
The excessive use of glucose for energy production makes the brain especially susceptible to oxidative stress, and mitochondrial ETC is the primary ROS source Cobley et al. Most of the ROS present in the brain derive from mitochondrial ETC complex I and III ETC I and III , as O 2 — by-products Andreyev et al.
Indeed, the main targets for mitochondria-generated ROS are mitochondrial permeability transition pore MPTP , poly ADP-ribose polymerase PARP , and mtDNA Gandhi and Abramov, Other oxidant sources arise from NADPH oxidase, present in astrocytes, microglia and neurons, while NOS inhibition has shown neuroprotective effects Abramov et al.
In the pathogenesis of neurodegeneration, many processes are included, such as protein misfolding and aggregation, abnormal kinase-signaling pathways, neuronal calcium dysregulation, and even impaired synaptic transmission Gandhi and Abramov, Mechanisms of action of ROS: these affect proteins by modifying them in oxidative forms, which tend to form aggregates Blokhuis et al.
Protein aggregates then inhibit proteasomes, the main organelles in the cell for degradation of abnormal proteins Chen et al. Accumulation of modified proteins with an inability to be destroyed in the proteasome stimulate more ROS formation and form a vicious cycle, a phenomenon included in neurodegenerative diseases related to oxidative stress Chen et al.
Many metabolic contexts can lead to conditions of oxidative stress. A condition in which oxidation is an important pathogenetic link is type 2 diabetes. In this disease, insulin resistance is the basic component, to which a compensatory hypersecretion of insulin is linked.
Reactive oxygen species can induce inactivation of signaling mechanisms between insulin receptors and the glucose transport system, leading to insulin resistance Chen X. On the other hand, diabetes itself is a generator of oxidative stress, with atherogenetic consequences.
Hyperglycemia induces the generation of superoxide ions in endothelial cells at the mitochondrial level. In diabetes, electron transfer and oxidative phosphorylation are decoupled, resulting in the production of superoxide anions and inefficient ATP synthesis.
Therefore, preventing the damage caused by oxidation is a therapeutic strategy in diabetes. Increased levels of free fatty acids with consecutive accumulation of intramyocellular lipids were thought to be the cause of insulin resistance and beta-pancreatic cell death.
Studies have shown that both glucose and free fatty acids can initiate the formation of free radicals through mitochondrial mechanisms and NADPH oxidase in muscles, adipocytes, beta cells and other cell types.
Free fatty acids penetrate cellular organs, including mitochondria, where high levels of reactive oxygen species can cause peroxidation and damage. Recent studies show that type II diabetes and insulin resistance are associated with a decrease in mitochondrial oxidative function in skeletal muscle.
Moreover, in this type of diabetes, the mitochondria are smaller, rounder and more likely to produce superoxide. Disorders of the mitochondrial transport chain, excessive generation of reactive species and lipoperoxides, as well as decreases in antioxidant mechanisms have also been observed in diabetes and obesity.
Diabetes has a number of complications over time, of which macrovasculopathy is very important. The increase in cardiovascular risk in patients with diabetes can be explained by the association between diabetes hypertension, dyslipidemia and coronary atherosclerotic disease.
However, other mechanisms are also involved, such as the effects of hyperglycemia on endothelial function, the effects of glucose and fatty acids on myocardial cells, at the structural level but also of gene expression Aroor et al. Diabetic cardiovascular complications are caused by impaired cardiac microvascular function.
In addition to the structural and functional changes that occur in diabetic cardiomyopathy, other mechanisms can be targeted pharmacologically. Sodium-glucose co-transporter-2 SGLT2 inhibitors are the first class of antidiabetic drugs that have reduced the risk of heart failure in type 2 diabetes Karam et al.
Empagliflozin has an indication to reduce cardiovascular mortality in patients with diabetes and atherosclerotic disease. A recent study demonstrated the beneficial effect of empagliflozin on cardiac microvascular injury in diabetes and the protective mechanism against oxidative stress in mitochondria Zhou et al.
Another recent study showed that aminoguanidine has a beneficial effect on diabetes-induced heart abnormalities. Aminoguanidine saves contractile abnormalities and diabetes-induced cardiac remodeling.
This was explained by inhibition of endoplasmic reticulum stress and induction of autophagy Pei et al. Insulin resistance, abdominal obesity, atherogenic dyslipidemia, endothelial dysfunction, high blood pressure, hypercoagulability, genetic predisposition and chronic stress are the main factors underlying the metabolic syndrome.
Metabolic syndrome is often characterized by oxidative stress, a condition in which there is an imbalance between the production and inactivation of reactive oxygen species. Increased generation of reactive oxygen species, decreased activity of antioxidant systems or both mechanisms may be involved in the occurrence of oxidative stress Karam et al.
A study showed that lenalidomide attenuates oxidative cardiovascular tissue damage and apoptosis in obese mice by inhibiting tumor necrosis factor Zhu et al. This accumulation of losses in cells would be the reason for aging and aging-associated degenerative diseases Tsoukalas et al.
Aging can be caused by both genetic and external factors, such as incorrect diet, improper physical exercise, chronic drug use, untreated inflammatory conditions, smoking, and alcohol abuse.
Today, while there are several theories of aging, the basic principle of most of them is still oxidative stress Finkel and Holbrook, ; Payne and Chinnery, The major systems involved in overproduction of oxidative stress in cells are mitochondria and NOX Bedard and Krause, In the aging process, it has been noticed that high-molecular protein aggregates accumulate in cells Davalli et al.
Predominantly, these aggregates are made from proteins, with the remainder consisting of various lipids Barrera, ; Takalo et al. Thus, the crucial point for protein homeostasis maintenance is the degradation of these aggregates.
The central place for cell damaged protein degradation is the proteasome, which recognizes only unfolded proteins as degradation targets Saez and Vilchez, Proteasome inhibition prevents further degradation of newly formed oxidized proteins and increases protein aggregation formation in cells Takalo et al.
Besides that, proteasome becomes dysfunctional during aging. While proteasomal dysfunction is correlated with age progression and protein aggregation, proteasome activation slows the aging progress down and increases longevity Chondrogianni et al. In many invertebrate models and cell lines, it has been shown that the overexpression of different proteasomal regulatory or catalytic subunits or treatment with specific compounds has positive effects on proteasome activity Saez and Vilchez, Recently, most of the data have indicated that antioxidant supplementation does not decrease the incidence of age-related diseases Schottker et al.
Antioxidants break radical chain reactions, preventing oxidative stress-related damage Da Pozzo et al. Figure 2. Schematic figure of the link between ROS, oxidative stress and their effects on the human body.
Alteration of chemical reactions at the cellular level leads to the appearance of free radicals and peroxides that affect the intracellular structures — proteins, lipids, DNA, with the disruption of intrinsic mechanisms at this level.
Free radicals are normally produced in the body due to the influence of external factors, such as pollution, cigarette smoke, or internal, due to intracellular metabolism when antioxidant mechanisms are exceeded. Their role requires acting both in hydrophilic and hydrophobic cellular environments, so their chemical structure is quite heterogeneous.
There are enzymatic and non-enzymatic antioxidants Banafsheh and Sirous, , as shown in Figure 1. but, from a nutritional perspective, a more informative classification can be made between endogenous and exogenous classes.
The first class comprises all antioxidants that cells can synthesize from smaller building blocks. Accordingly, all enzymatic antioxidants are endogenous, as well as some non-enzymatic ones i.
Figure 3. Primary enzymes SOD or peroxidases act directly in scavenging ROS. Secondary enzymes, such as glutathione reductase and glucosephosphate dehydrogenase, support the action of primary enzymes regenerating NAPDH and reduced glutathione.
On the contrary, exogenous antioxidants have to be ingested through the diet, since their synthesis is impossible in eukaryotic cells. So, particular attention should be paid on this latter class, since this is the most unpredictable component in cellular redox balance.
Antioxidants can be divided into two categories depending on their solubility: water soluble and liposoluble Lazzarino et al. Water soluble antioxidants are best absorbed in the body because the vegetables and fruits that contain such antioxidants, also contain water.
On the other hand, they are rapidly eliminated from the body through the urine. Water-soluble antioxidants include polyphenols, but also vitamin C Lazzarino et al. Liposoluble antioxidants, fat-soluble antioxidants are those that are absorbed in the presence of fats.
Therefore, in the absence of fats, the body cannot absorb and use these antioxidants. It is important to note, however, that they are not easily removed from the body and can accumulate over time, exceeding the healthy level.
Vitamin E is an example of a fat-soluble antioxidant Lazzarino et al. This is the case, for instance, for glucosephosphate dehydrogenase that regenerates NADPH, essential for primary enzyme action Figure 2. Primary enzymes act directly on the main ROS arising from incomplete O 2 reduction, O 2 — and H 2 O 2.
SOD scavenges the former, whereas CAT and GPX remove the latter. SOD E. In turn, H 2 O 2 can be removed by the other enzymatic antioxidant systems.
SODs can be divided into four groups, with different metal cofactors. Copper-zinc SOD is most abundant in chloroplasts, cytosol and extracellular space.
Iron SOD is found in plant cytosol and in microbial cells, whereas manganese SODs are mitochondrial Perera et al. SOD also competes for superoxide anion with NO.
Therefore, SOD also indirectly reduces the formation of another deleterious ROS, peroxynitrite ONOO — , reaction 2 , and increases the NO biological availability, an essential modulator for endothelial function.
CAT E. CAT is mainly located in peroxisomes, and despite being ubiquitous, the highest activity is present in liver and red blood cells. CAT works with a two-step mechanism, somewhat resembling the formation in the first step of a peroxidase-like compound I intermediate, CpdI reaction 4 Alfonso-Prieto et al.
A NADPH molecule is bound to each subunit, minimizing H 2 O 2 —mediated inactivation []. CAT is one of the enzymes with the highest known k cat more than 10 6 s —1 in all known proteins, close to a diffusion-controlled reaction Tovmasyan et al.
GPX E. The GPX family is composed of eight isoenzymes GPX Each enzyme presents peculiar features. GPX1, 2, 3, and 4 incorporate selenocysteine a non-standard amino acid, where the sulfur atom of cysteine is replaced by selenium.
During the catalytic cycle, selenocysteine is converted from selenol Enz-SeH to selenenic acid Enz-SeOH , with concomitant reduction of H 2 O 2 or ROOH. Then, the first GSH molecules yield selenenyl sulfide intermediate Enz-Se-SG. An incoming second GSH molecule attacks Enz-Se-SG, regenerating the enzymatic resting form Enz-SeH, releasing the oxidized and dimerized GSSG Cardoso et al.
Another important class of enzymatic peroxide scavenger is PRDX. Six different classes of PRDX have been identified Poole and Nelson, , showing either one 1-Cys PRDX or two 2-Cys PRDX redox-active cysteine residues Park et al.
The PRDX catalytic cycle involves H 2 O 2 decomposition and the subsequent regeneration of the resting enzyme, using a small cysteine protein thioredoxin Trx as the reductant reactions 8 and 9. Trx shows two vicinal cysteines in the typical CXXC motif , forming, in turn, a disulfide internal bridge upon oxidation.
In the case of PRDX6 isoform, Trx can be replaced by GSH. All the enzymatic activities described above rely on the continuous regeneration of the reduced form of reductants mainly GSH and Trx.
This is usually performed by some reductases, NADPH-dependent such as glutathione reductase E. However, as shown in Figure 2 , reduced NADPH is, in turn, needed by these reductases for their continuous action.
So, enzymes responsible for the constant NADPH production can be considered secondary antioxidants, as their misfunction could affect the whole ROS balance. The main NADPH metabolic source is the pentose phosphate pathway, through the first two enzymatic activities: glucosephosphate dehydrogenase E.
However, other contributions come from the malic enzyme E. Some chemical molecules of low-molecular-weight can also directly act as antioxidants. In this case, their action is not catalytic, always needing antioxidant regeneration or its supply from the diet. Non-enzymatic antioxidants can therefore be divided into endogenous if the eukaryotic cell is able to synthesize it and exogenous if the antioxidant needs to be ingested mandatorily through the diet.
GSH γ-glutamyl-cysteinyl-glycine, Figure 4 is a tripeptide, mainly distributed in cytosol, but also in nuclei, peroxisomes and mitochondria. Despite being ubiquitous, the liver is the leading site for its synthesis Banafsheh and Sirous, GSH biosynthesis is an endergonic process ATP hydrolysis is coupled , in which firstly glutamate and cysteine condense to yield γ-glutamylcysteine reaction catalyzed by glutamate-cysteine ligase, E.
This unusual γ-peptidic bond protects it from the common peptidases action. In the final step, GSH synthetase E. Figure 4. Glutathione GSH , a tripeptide with an active —SH function.
GSH undergoes a redox cycle, dimerizing with a disulfide bridge formation. α-Lipoic acid 1,2-dithiolanepentanoic acid, Figure 4 is a disulfide compound that undergoes a redox cycle similar to GSH.
Accordingly, it scavenges reactive ROS, and regenerate vitamins C and E, and GSH in their active forms Kucukgoncu et al. Lipoic acid also has a role in metal chelation, preventing Fenton-like radical reactions Zhang and McCullough, Nevertheless, even small proteins, such as Trx and glutaredoxin can similarly function as thiol antioxidants, showing redox-active mono- or di-cysteine motif CXXC.
Both proteins can be in turn reduced back to their active form, directly by GSH or indirectly by NADPH Banafsheh and Sirous, Melatonin N -acetylmethoxytryptamine, Figure 5 is a neurohormone derived from amino acid tryptophan.
It is involved in circadian rhythms but also acts as a potent antioxidant, protecting cell membranes against lipid peroxidation Beyer et al. It has been described to be more effective in ROS scavenging than vitamin E, GSH, vitamin C and β-carotene Watson, Coenzyme Q10 or ubiquinone 2,3-dimethoxymethylpolyisoprene parabenzoquinone, Figure 5 is an isoprenoid antioxidant present in cell membranes, essential for ETC Tafazoli, Its synthesis starts from oligomerization of isoprenoid building blocks, isopentenyl pyrophosphate and dimethylallyl pyrophosphate both arising from the mevalonate pathway and the key enzyme 3-hydroxymethyl-glutaryl-CoA reductase E.
The resulting decaprenyl diphosphate is then conjugated with a tyrosine derivative to yield the active form of the coenzyme. It is one of the few liposoluble antioxidants, ensuring lipoproteins and lipids protection from radical chain reactions, peroxidation and oxidative damage Lee et al.
In its active form quinol , coenzyme Q10 can scavenge several ROS or regenerate other oxidized antioxidants including vitamins C and E. In turn, the quinone form can be reduced back by several NAD P H-dependent enzymatic systems. Exogenous antioxidants need to be supplemented continuously through the diet since their synthetic pathways are usually present only in microbial or plant cells.
Vitamins, two of which show prominent antioxidant effects, such as vitamins C and E, belong to essential class of molecules. Vitamin C ascorbic acid exists in two redox forms: ascorbic acid AA is the reduced form, which is deprotonated at physiological pH thus, occurring in its anion form, ascorbate.
Due to its high electron-donating power, AA can undergo two-electron oxidation, yielding dehydroascorbic acid DHA. One-electron oxidation of AA is also possible, generating a semi-dehydro-ascorbyl radical Kocot et al. DHA can be regenerated to the active AA form by GSH- or Trx-dependent mechanisms.
Humans do not express the enzyme L -gulonolactone oxidase E. Thus, AA must be ingested by food or supplements , particularly tomatoes, pineapples, watermelons and all citrus fruits Banafsheh and Sirous, AA effectively quenches ROS, both directly and cooperatively regenerating oxidized vitamin E, GSH, and carotenoids.
Vitamin E is a fat-soluble vitamin, mostly found in several vegetable oils, nuts, broccoli and fish. Eight different forms have been reported α-, β-, γ-, and δ-tocopherol, and α-, β-, γ-, and δ-tocotrienol , but α-tocopherol has the highest antioxidant activity, especially in cell membranes Salehi et al.
A variously methyl-substituted chromanol ring characterizes tocopherols. A long phytyl chain gives the hydrophobicity Figure 6. Figure 6. Chemical structures of Vitamin C, Curcumin, Resveratrol, Quercetin, Vitamin E, β-carotene, Lycopene. On the contrary, tocotrienols bear an unsaturated isoprenoid chain.
α-Tocopherol is able to undergo hydrogen transfer to several ROS, including 1 O 2 , superoxide anion and peroxyl radicals. The oxidized and radical derivative of vitamin E is then reduced by the AA. Carotenoids are a broad class of tetraterpenes, widely distributed among plants.
Carotenes are also vitamin A precursors. Carotenoids protect plant chlorophyll, acting as accessory pigments during photosynthesis. Thus, they are intensely colored red, orange, or yellow molecules. Carotenoids have been suggested to be chemopreventive agents in cancer Marti et al.
Their biological activities also include ROS scavenging Hernández-Almanza et al. β-Carotene comprises one of the most diffused carotenes, being the primary pro-vitamin A precursor, and it is found mainly in carrots, pumpkins, mangoes and apricots.
Lycopene is another well-known acyclic carotene, not being a precursor of vitamin A, and is found primarily in tomatoes and other red fruits, but not in strawberries and cherries. Indeed, carotenoids are strong ROS scavengers, operating a very particular physical and chemical 1 O 2 quenching Banafsheh and Sirous, In the physical mechanism, the carotenoid electron-rich structure absorbs 1 O 2 excess energy, reaching an excited state.
The conjugated double bond structure in carotenoids is responsible for this ability. The excited state then decays to the ground state, losing the surplus energy as heat. During this cycle, the structure of this molecule stays unchanged.
Polyphenols are a large class of plant secondary metabolites, whose synthesis is usually possible only in these organisms Sanjust et al. The key enzyme [phenylalanine ammonia-lyase PAL , EC 4. PAL catalyzes the non-oxidative deamination of phenylalanine to trans -cinnamic acid, which is the fundamental building block for polyphenol synthesis in the phenylpropanoid pathway Ertani et al.
Several biological functions have been ascribed to polyphenols, including anti-inflammatory, antioxidant, antimicrobial and antimelanogenesis effects Zucca et al. For instance, one of the most studied polyphenols has been curcumin, gaining a lot of attention also for nutraceutical applications.
Curcumin can also increase GSH cellular levels Banafsheh and Sirous, Epigallocatechingallate EGCG is a well-known antioxidant. The green tea catechins include catechin, epicatechin, epigallocatechin, epicatechin gallate, and epigallocatechin gallate Barbieri et al.
Flavonoids, in addition to its strong antioxidant properties, quench ROS formation inhibiting several enzymes and chelating metals involved in radical chain reactions Banafsheh and Sirous, Furthermore, flavonoids can also affect free metal ion concentrations. Indeed, flavonoids have the well-known capacity to chelate several metal ions such as iron and copper , blocking free radical generation Kumar and Pandey, For instance, quercetin is one of the most diffused flavonols present in broccoli, apples, grapes, onions and soybeans, with both iron-chelating and iron-stabilizing abilities Kumar and Pandey, On the other hand, catechol and galloyl-derivatives are generally well-known metal chelators Jomova and Valko, So, they can all exert their antioxidant activity by blocking Fenton-like reactions.
Organosulfur compounds have also been suggested as potent antioxidants. The most studied are probably some sulfur-containing metabolites present in garlic mainly S -allyl-mercapto cysteine, S -allyl cysteine, and diallyl sulfide, diallyl trisulfide Kimura et al.
These organosulfur are also responsible for typical garlic flavor. Their antioxidant actions include scavenging ROS and inhibiting lipids peroxidation Borek, ; Miltonprabu et al.
Several minerals, in small amounts, are also essential for some enzymatic antioxidant activities. They are therefore sometimes regarded as antioxidants themselves. For instance, selenium is a necessary component of GPX Battin and Brumaghim, , while copper, zinc, and manganese are fundamental for SOD activity.
The balance between ROS production and purification maintains homeostasis of the body, but is most often directed to the formation of free radicals and involvement in the pathophysiology of chronic diseases. The use of antioxidant supplements containing multivitamins and minerals has always grown in popularity among consumers.
But some recent studies have not shown any beneficial effect of antioxidant therapy. Oxidative stress has a dual character: it is both harmful and beneficial to the body, because some ROS are signaling molecules on cellular signaling pathways.
Lowering the level of oxidative stress through antioxidant supplements is therefore not beneficial in such cases Ye et al. Antioxidants are also prone to oxidation since oxidation and reduction reactions do not happen in isolation.
AA, a potent antioxidant, mediates several physiological responses. This reaction is responsible for oxidative stress-produced DNA damage. However, the role of AA as anti- or pro-oxidant depends on the dose used, as observed in the case of ischemia-induced oxidative stress Seo and Lee, With increased oxygen tension, carotenoids tend to lose their antioxidant potential.
Otherwise, α-tocopherol, a powerful antioxidant, becomes pro-oxidant at high concentrations Cillard and Cillard, Interestingly, when it reacts with a free radical, it becomes a radical in itself.
If there is not enough AA for its regeneration, it will remain in that highly reactive state Lü et al. Flavonoids can also act as pro-oxidants depending on the concentrations used Prochazkova et al.
Nevertheless, the extent to which these phytochemicals are capable of acting as anti- or pro-oxidants in vivo is still poorly understood, and this topic undoubtedly requires further research. The hypothesis that antioxidants could protect against cancer because they can neutralize reactive oxygen species ROS that can damage DNA has long been issued.
In laboratory and animal studies, the presence of elevated levels of exogenous antioxidants has been shown to prevent the types of free radicals that have been associated with the development of cancer.
A few randomized studies evaluating the role of antioxidant supplements for cancer prevention were conducted in collaboration with the National Cancer Institute Goodman et al. No data were obtained to justify that they are effective in primary cancer prevention.
An analysis in the United States concluded that there is no clear scientific evidence for the benefits of vitamin and mineral supplements in cancer prevention.
It is important to point out that there have been cases where people who have resorted to these types of supplements have encountered an unfavorable evolution of the disease.
Preclinical studies also report that antioxidants have contributed to the expansion of tumor processes in animal models.
A well-known case is that of vitamin A, for which the administration of high doses in supplements has been associated with an increased risk of cancer.
Vitamin A can be obtained preformed from animal sources or plant products, derived from β-carotene. β-Carotene is an orange pigment found in fruits and vegetables carrots, sweet potatoes, mangoes, apricots , and in the body it is converted to vitamin A.
A normal intake has a beneficial effect against the risk of cancer. However, studies have shown a correlation between the administration of β-carotene supplements and the risk of bladder cancer, as well as the risk of lung cancer in smokers Lin et al.
In another study, the administration of α-tocopherol and β-carotene for lung cancer did not change the incidence of lung cancer.
However, α-tocopherol supplements have been shown to be effective in prostate cancer whose incidence is reduced Goodman et al. A trial evaluated the effectiveness of long-term supplementation with vitamin E and vitamin C in the risk of developing cancer.
One of the findings of the study was that these types of supplements do not reduce the risk of prostate cancer or the overall risk of cancer in men of middle age or older.
No significant results were obtained regarding the risk of colorectal or lung cancer Gaziano et al. Vitamin E and C supplements showed poor results in many studies.
There was a reduction in cardiovascular mortality, but no significant effect was observed on overall mortality. The authors concluded that vitamin E supplementation for the prevention of cardiovascular disease among healthy women is not justified.
Moreover, cancer mortality is not significantly influenced by vitamin E supplementation Lee et al. The Selenium and Vitamin E Cancer Prevention Trial SELECT which included over 35, men over the age of 50, showed that selenium and vitamin E supplements do not prevent prostate cancer.
This article summarizes the evidence from a large number of meta-analyzes covering the pathophysiological impact of antioxidants on the most common chronic diseases. The main criticism of the review is that the data were extracted from meta-analyzes and not from individual studies, but this can be considered an advantage because meta-analyzes provide the highest degree of evidence.
In the case of antioxidants, studies show that more does not necessarily mean better. Consuming superfoods does not compensate for other unhealthy eating habits or an unbalanced lifestyle. Free radicals, as well as antioxidants, can have beneficial effects on the body. Therefore, we are talking about a balance and not a negative role attributed to free radicals and a positive one to antioxidants.
Degradation of nucleic acids, proteins, lipids or other cellular components are among the effects that an excessive concentration of free radicals can generate.
Risk factors leading to free radicals include air pollution, ionizing radiation, prolonged exercise, infections, excessive consumption of polyunsaturated fatty acids Poprac et al.
On the other hand, antioxidants are considered to be the solution to these problems — substances that neutralize free radicals. In some situations, some substances act as antioxidants, in other situations they become prooxidants, depending on the chemical composition of the environment in which they are.
There are many types of antioxidants, and the role in the body and the mechanisms by which they act are different. One misconception is that one antioxidant can be replaced with another, having the same effect.
In fact, each has its own unique biological properties Chen X. There is also a significant difference between taking antioxidants from food and administering an isolated substance as a supplement.
Many substances that demonstrate beneficial effects in the laboratory do not work when introduced into the human body. Many antioxidants do not have good bioavailability.
The concentration of antioxidants such as polyphenols is sometimes so low in the blood that no significant effect is observed Fernández-García et al. Fruits and vegetables contain bioactive substances that in many cases do not work as antioxidants if we consider them outside of the body.
But they work as antioxidants when they are in the body, because they activate their own antioxidant mechanisms. These bioactive substances are the secret behind vegetable consumption Kurutas, Antioxidant supplements may have different health benefits. On the one hand, it is possible that other substances present in food are responsible for the positive effects on health, not necessarily a certain type of antioxidant, but the synergistic effect of several substances.
On the other hand, the chemical structure of antioxidants in food is often different from that identified in supplements. An example is vitamin E.
There are eight variants of vitamin E in the foods we eat, while the supplements used in most studies contain only one form Firuzi et al. Studies also frequently include healthy people, for whom oxidative stress on the body is not significant to determine a risk of disease.
Antioxidants can benefit certain categories of patients in whom there is a real, documented imbalance, but it may not bring anything extra for a person who gets a sufficient amount of nutrients from their diet. Observational studies analyze the trends, or habits of certain large population groups.
In many, all the risk factors that could influence the course of the study can be controlled, and demonstrating a cause-effect relationship is difficult. We also cannot rely on small studies, carried out over a short period of time and using very concentrated substances extracted from different plant or animal products, to say that we have a superfood.
Nutrition is a complex science, and at the moment we can only rely on the evidence accumulated so far. A food rich in antioxidants will not compensate for an unhealthy lifestyle. Oxidative stress can be reduced by approaching a balanced lifestyle.
Nutrition plays a critical role, and the best treatment against oxidative stress is antioxidants. Oxidative stress plays an important role in the pathogenesis of potentially severe conditions. In the long term, increasing the level of prooxidant factors can cause structural defects in mitochondrial DNA and alterations in enzymatic functionality or cellular structures, with the appearance of functional, structural abnormalities or aberrations in gene expression.
It has also been shown that in addition to metabolic products, other external agents can have a prooxidant effect, which has led to the conclusion that lifestyle and diet can play an important role in controlling oxidative stress. Plant-derived bioactive molecules have gained pivotal attention in recent years, given their therapeutic relevance in both disease prevention and treatment, whether using the whole plants, plant extracts or even the isolated constituents with full phytochemical profiles.
The daily intake of a wide variety of phytochemicals has shown to be chemopreventive. It might hold promise for add-on treatment for several diseases, including cancer, diabetes, cardiovascular disease and neurodegenerative disorders. Larger randomized trials are needed to obtain clear scientific evidence on the benefits or risks of antioxidant supplementation during cancer treatment.
Antioxidants are also prone to oxidation, and therefore their use as foods or supplements should be carefully considered because oxidation and reduction reactions do not happen in isolation. The intake of high doses of antioxidants has been increasingly highlighted since there is increasing evidence of some detrimental effects.
The study of their chemical components as future prophylactic and therapeutic agents would be of particular interest, as they are more effective and safer than those widely available.
In conclusion, oxidative stress is an important pathogenetic link for humans and studies in this field may be important elements in the future, to better understand and manage various diseases. JS-R and MS-R contributed to the conceptualization. NA, PZ, EV, and LD contributed to the validation investigation.
EP, JR, PT, EA, IP, YE, and MB contributed to the resources. AP, MN, and AD: data curation. MS-R, AD, LP, MI, NM, MM, WS, DC, WC, and JS-R contributed to the review and editing. All authors contributed to the writing of the manuscript.
All authors read and approved the final manuscript and contributed equally to the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Aging Antioxidant-related disorders the progressive Antioxidant-relatted of organ and tissue function over time. Growing older is Antioxidant-related disorders linked Antioxidantr-elated cognitive Antioxidant-relqted biological visorders such Antioxidant-related disorders physical frailty, psychological impairment, and Antioxodant-related decline. Oxidative stress is considered Disordrs an imbalance between Antioxidant-related disorders Natural weight gain antioxidant species, which results in molecular and cellular damage. Oxidative stress plays a crucial role in the development of age-related diseases. Emerging research evidence has suggested that antioxidant can control the autoxidation by interrupting the propagation of free radicals or by inhibiting the formation of free radicals and subsequently reduce oxidative stress, improve immune function, and increase healthy longevity. Indeed, oxidation damage is highly dependent on the inherited or acquired defects in enzymes involved in the redox-mediated signaling pathways. Often used as Antioxidant-related disorders marketing buzzword, Non-prescription weight loss pills about the Antioxidant-related disorders of antioxidants beyond the hype, and some dissorders the Antioxidant-rrelated on Antioxidany-related Antioxidant-related disorders disease prevention. Jump to: — What are antioxidants? Another constant threat comes from chemicals called free radicals. In very high levels, they are capable of damaging cells and genetic material. The body generates free radicals as the inevitable byproducts of turning food into energy.
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In fact, growing older is positively idsorders to cognitive and biological degeneration such as physical frailty, psychological Anntioxidant-related, and cognitive decline Jin et al. Age-related diseases have become the greatest health threats in the twenty-first century. Aging is an intrinsic, universal, multifactorial, and Antioxidant-rwlated process disorddrs as degenerative Antioxidant-relate nature, accompanied disorcers progressive loss of function and ultimately increased mortality rate Dabhade and Kotwal, ; López-Otín Calcium and vitamin D al.
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These perturbations impair cellular homeostasis and mitochondrial disordees and enhance vulnerability to oxidative stress Eckmann et al.
Elderly people are susceptible to Antioxidan-trelated stress due to Antioxidant-related disorders decline in the efficiency of their endogenous antioxidant systems.
Organs such as brain and heart, with high Antioxidant-rslated of oxygen consumption disorcers limited respiration levels, Antioxidznt-related particularly vulnerable to this phenomenon, hence partially explaining the high prevalence of cardiovascular diseases CVD and neurological disorders in elderly Natural muscle recovery methods et Sodium management strategies. Oxidative Antioxdiant-related plays disofders crucial role in the development disorvers age-related diseases including arthritis, diabetes, dementia, cancer, atherosclerosis, vascular diseases, obesity, osteoporosis, disoorders metabolic syndromes Low-carb and exercise performance et al.
ROS are generated within the Juicy Berry Selection system to modulate the cellular activities such as cell survival, stressor responses, and inflammation Antioxidant-related disorders and Zuo, ; Zuo et al.
Elevation Core strength development ROS has been associated with the onset Antioxidant-related disorders progression of aging. Although ROS Antioxxidant-related may not be an essential factor for aging López-Otín et al. Due to their reactivity, high concentrations of ROS can cause oxidative stress by disrupting Antioxidant-relatrd balance of antioxidant and prooxidant levels Zuo et al.
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In the last few decades, several models have been Antuoxidant-related to define Antioxidanr-related interconnection Antioxidant-related disorders the biological pathways of aging Dice, Antioxidant-related disorders, Based on the oxidative stress Antioxidanh-related, oxidative damage is not solely triggered by the unrestricted ROS production, but it disordes caused by other oxidants, such as reactive lipid species and reactive Antipxidant-related species RNS.
The Juicy Citrus Concentrate of oxidative stress highlights the crucial role of antioxidant defenses as an important component of the overall Antioxidant-relaged balance of the organism. However, several studies demonstrated that avoiding oxidative stress damage does not increase longevity Buffenstein et al.
Oxidative stress is considered as an imbalance between pro- and antioxidant species, which results in molecular and cellular damage Conti et al. Mitochondria are major organelles that are accountable disorvers generation of energy through oxidative phosphorylation to generate adenosine triphosphate ATPa molecule which is crucial for cellular actions Weinberg et al.
During this process, ROS are generated as by-products for the partial four-electron reduction of O 2 to produce water molecule, which is the last electron acceptor in the ATP generation process Ambrosio et al. Nearly 0. In the normal healthy state, the generation and oxidation of ROS occur in a controlled manner.
By contrast, the ROS production is increased under high-stress conditions or under disease states. The ROS generated from aerobic respiration caused a cumulative oxidative damage in macromolecules, including lipids, DNA, and proteins, which subsequently lead to cells death Scheibye-Knudsen et disordrrs.
An alteration of the redox status and the dysregulation of the immune system during aging may lead to the elevation of systemic inflammatory status. Both of these processes caused the activation of inflammatory mediators via oxidative stress-induced redox imbalance.
Unresolved chronic inflammation during aging may serve as a pathophysiologic association which converts normal Antioxidant-relsted changes to the age-related degenerative diseases Viola and Soehnlein, Oxidative stress is reinforced by several reactive species, including H 2 O 2singlet oxygen, other radicals, and non-radicals, which are consistently produced in the body due to the aerobic metabolism, and thereby potentially altering basic structural components such as proteins, lipids, and nucleic acids Weidinger and Kozlov, Template biosynthesis of polypeptide chains on ribosomes usually does not produce a functional protein.
The newly developed polypeptide chain must undergo certain chemical modifications Anttioxidant-related the ribosome. Thus, these modifications are most often accompanied by enzymes and take place after all the information supplied by the template RNA mRNA has been read, that is after mRNA translation.
These additional processes are disordeers as posttranslational modifications. There are four primary groups of protein functions which Antioxidanh-related posttranslational modification of amino acid residue side chains.
The functional activity of several proteins requires the presence of certain prosthetic groups covalently bound to the polypeptide chain. These are usually involving complex organic molecules which take part in the protein activity for instance, the transformation of inactive apoproteins into enzymes.
Another important group of modifications is protein tags, which provide intracellular localization of proteins such as marking the proteins for transport to the proteasome, where they will be proteolyzed and hydrolyzed.
Additionally, some of the posttranslational modifications regulate biochemical processes by varying enzymatic activity Knorre et al. Naturally, the organism has several antioxidant defenses to protect against hostile oxidative environments, including classical antioxidant enzymes for example catalase, glutathione peroxidase, and superoxide dismutase as well as non-enzymatic ROS scavengers, such as β-carotene, Antiixidant-related C, vitamin E, and uric acid Espinosa-Diez et al.
Among all the antioxidant enzymes, glutathione peroxidase is the most powerful Antioxidant--related antioxidative reductant Cross et al. Collectively, maintaining a healthy redox balance status is crucial for the physiological acid-base buffer system in the body for the optimal homeostatic cellular activities.
Figure 1 shows the effect of oxidative stress and the interaction of aging and age-related diseases. Figure 1. Effect of oxidative stress and the interaction of aging and age-related diseases. Mitochondrial function Antioxixant-related and oxidative stress response in aging may subsequently contribute to age-related diseases.
Inflammaging is a chronic, low-grade, and systemic inflammation in aging, which is occurred in the absence of overt infection Franceschi and Campisi, Chronic inflammation is usually derived from the damaged cells or macromolecules due to an inadequate elimination or increased production.
The ability of gut to sequester harmful microbes declines with age. Therefore, some of the harmful products that produced by the microbial constituents of the human body, such as gut microbiota, is capable to permeable into surrounding tissues Biagi et al.
Senescence, a cellular response to stress and other damage Franceschi and Campisi, Persistent senescent cells have been associated with aging or age-related diseases via secretion of proinflammatory cytokines that alter the tissue microenvironment or modify the function of normal cells Baker et al.
The study reported by Coppé et al. Increased inflammation may also derive from the stimulation of coagulation system. Coagulation is regarded as a part of the inflammation system.
Aging promotes the hypercoagulable state and increased the risk of arterial and venous thrombosis in the elderly Franceschi and Campisi, Additionally, aging Antioxidamt-related alters the immune system, fisorders is subsequently leading to inflammaging.
Adaptive Antioxidant-relatted decreases with age; conversely, innate immunity demonstrated minute changes in mild hyperactivity Santoro et al. The Antioxidxnt-related of innate immunity might increase when adaptive immunosenescence progresses.
These age-related changes could be due to the lifelong exposure to antigens and pathogens, as well as intrinsic changes in immune cells Stephenson et al. Numerous age-related diseases undergo the inflammation process, which is a risk factor in or partly of disease development DeBalsi et al.
For instance, several age-related diseases including diabetes, dementia, metabolic syndrome, osteoporosis, cancer, arthritis, and cardiovascular diseases have been recognized as inflammatory disorders Tan et al.
The interaction between inflammation and oxidative stress is tightly associated with the prostaglandins PGs biosynthetic pathway that produces reactive species Kawahara et al. PGs are lipid metabolites of arachidonic acid which have strong proinflammatory responses with pathogenic activities.
For example, certain PG metabolites act as an active mediator of inflammation. While, some Antioxidant-relwted the reactive species produced from PGs metabolism may exacerbate inflammation and induce tissue damage Blaser et Antioxjdant-related.
Cyclooxygenase COX is a predominant enzyme in the PG synthetic pathway, which produces prostaglandin H 2 PGH 2 from arachidonic acid Shehzad et al. Reactive species are generated during the conversion of prostaglandin G2 PGG 2 to prostaglandin H2 PGH 2 Rashid, The production of reactive species Antioxidwnt-related PG synthesis pathway contributes significantly to the overall reactive species pool in both pathological and normal states, especially during aging Nita and Grzybowski, Research evidence has suggested that the molecular inflammatory process plays a vitally important role during the aging process and age-related diseases Davalli et al.
COX-derived reactive species and transcriptional activity of interleukin-1beta IL-1 βinterleukin-6 IL-6tumor necrosis factor-α TNF- αcyclooxygenase-2 COX-2and inducible nitric oxide synthase iNOS are increased during aging Michaud et al.
Other pro-inflammatory proteins such as vascular cell adhesion Antioxudant-related 1 VCAM-1P- and E-selectin, and intercellular adhesion molecule 1 ICAM-1are all enhanced during aging Biswas, The nuclear factor-kappa B NF-κB transcription factor has been identified as the key factor during inflammation which can be stimulated by oxidative stimuli.
In fact, the stimulation of NF-κB-dependent genes is a principal culprit that is responsible for the systemic inflammatory process Golia et al.
Under high- stress circumstances, proinflammatory genes encode proinflammatory dixorders, including chemokines, growth factors, and cytokines. NF-κB activity is mediated by numerous signaling pathways such as mitogen-activated protein kinases MAPKs and IκB kinase IKK.
IKK activity is triggered during aging by NF-κB Kim et al. ROS production during the aging process has been associated with p38 MAPK, JNK, and ERK activities Zhang et al. Nonetheless, uncontrolled input signal during aging may cause chronic proinflammatory conditions that are conducive to various chronic diseases Fougère et al.
Aging is also linked to the elevation of inflammatory cell monocytes and neutrophil counts and C-reactive protein CRP levels Tang et al.
High IL-6 plasma levels were shown to have a greater likelihood of mortality, morbidity, and disability in the elderly Puzianowska-Kuznicka et al. Indeed, high plasma level of TNF-α is associated with a marked increase in CRP and IL-6, suggesting an interrelated stimulation of the entire inflammatory cascade Xia et al.
In addition, compelling evidence suggests that DNA damage response DDR signaling is a predominant mechanism associated with the build-up of DNA damage, aging, and cell senescence Malaquin et al. This study indicates the involvement of epigenetic modifications Antioxidant-relafed as small, non-coding RNAs and microRNAs, which contributes to post-transcriptional regulation.
Moreover, microRNAs may also be harnessed as an innovative tool to identify target senescent cells and to develop therapeutic interventions that can delay the proinflammatory programme stimulated in senescent endothelial cells Prattichizzo et al.
Progerias or accelerated-aging syndromes are partially recapitulated normal aging Burtner and Kennedy,
: Antioxidant-related disorders| Support The Nutrition Source | Supplement makers Antioxidant-related disorders the Antioxidant-related disorders properties Antioxidant-relatex all Antioxidant-related disorders of antioxidants. Musial C, Kuban-Jankowska A, Disorderw M Beneficial properties of green tea catechins. Nearly 0. Czech Antioxidqnt-related, Zarycka Anrioxidant-related, Yanovych D et al Mineral content of the pulp and peel of various citrus fruit cultivars. Zalazar L, Pagola P, Miró MV et al Bacterioruberin extracts from a genetically modified hyperpigmented Haloferax volcanii strain: antioxidant activity and bioactive properties on sperm cells. Prochazkova, D. Saad B, Zaid H, Shanak S et al Prevention and treatment of obesity-related diseases by diet and medicinal plants. |
| Targeting oxidative stress in disease: promise and limitations of antioxidant therapy | Kilojoule labelling is now on the menu of large food chain businesses — both in-store and online. Content on this website is provided for information purposes only. Information about a therapy, service, product or treatment does not in any way endorse or support such therapy, service, product or treatment and is not intended to replace advice from your doctor or other registered health professional. The information and materials contained on this website are not intended to constitute a comprehensive guide concerning all aspects of the therapy, product or treatment described on the website. All users are urged to always seek advice from a registered health care professional for diagnosis and answers to their medical questions and to ascertain whether the particular therapy, service, product or treatment described on the website is suitable in their circumstances. The State of Victoria and the Department of Health shall not bear any liability for reliance by any user on the materials contained on this website. Skip to main content. Healthy eating. Home Healthy eating. Actions for this page Listen Print. Summary Read the full fact sheet. On this page. About oxidation Antioxidants and free radicals The effect of free radicals Disease-fighting antioxidants Sources of antioxidants Vitamin supplements and antioxidants Dietary recommendations for antioxidants Where to get help. About oxidation The process of oxidation in the human body damages cell membranes and other structures, including cellular proteins, lipids and DNA. Antioxidants and free radicals Antioxidants are found in certain foods and may prevent some of the damage caused by free radicals by neutralising them. Disease-fighting antioxidants A diet high in antioxidants may reduce the risk of many diseases including heart disease and certain cancers. Sources of antioxidants Plant foods are rich sources of antioxidants. Also derived from the plants that animals eat. Vitamin supplements and antioxidants There is increasing evidence that antioxidants are more effective when obtained from whole foods, rather than isolated from a food and presented in tablet form. Dietary recommendations for antioxidants Research is divided over whether antioxidant supplements offer the same health benefits as antioxidants in foods. To achieve a healthy and well-balanced diet , it is recommended we eat a wide variety from the main 5 food groups every day: vegetables and legumes or beans fruit whole grain foods and cereals lean meat, poultry or alternatives such as fish, eggs, tofu, legumes, nuts and seeds dairy and dairy alternatives — mostly reduced fat reduced fat milk is not recommended for children under 2 years. Where to get help Your GP doctor Dietitians Australia External Link Tel. Nutrient reference values for Australia and New Zealand External Link , National Health and Medical Research Council, Australian Government. Australian dietary guidelines External Link , , National Health and Medical Research Council, Australian Government. Initial: lower total cancer and prostate cancer incidence and all-cause mortality among men only; increased incidence of skin cancer among women only. Later: no evidence of protective effects in men or harmful effects in women within 5 years of ending supplementation. Initial: no reduction in incidence of prostate or other cancers—trial stopped early. Overall, these nine randomized controlled clinical trials did not provide evidence that dietary antioxidant supplements are beneficial in primary cancer prevention. In addition, a systematic review of the available evidence regarding the use of vitamin and mineral supplements for the prevention of chronic diseases, including cancer, conducted for the United States Preventive Services Task Force USPSTF likewise found no clear evidence of benefit in preventing cancer It is possible that the lack of benefit in clinical studies can be explained by differences in the effects of the tested antioxidants when they are consumed as purified chemicals as opposed to when they are consumed in foods, which contain complex mixtures of antioxidants, vitamins, and minerals 3. Therefore, acquiring a more complete understanding of the antioxidant content of individual foods, how the various antioxidants and other substances in foods interact with one another, and factors that influence the uptake and distribution of food-derived antioxidants in the body are active areas of ongoing cancer prevention research. Several randomized controlled trials , some including only small numbers of patients, have investigated whether taking antioxidant supplements during cancer treatment alters the effectiveness or reduces the toxicity of specific therapies Although these trials had mixed results, some found that people who took antioxidant supplements during cancer therapy had worse outcomes, especially if they were smokers. In some preclinical studies, antioxidants have been found to promote tumor growth and metastasis in tumor-bearing mice and to increase the ability of circulating tumor cells to metastasize 29 — Until more is known about the effects of antioxidant supplements in cancer patients, these supplements should be used with caution. Cancer patients should inform their doctors about their use of any dietary supplement. Home About Cancer Cancer Causes and Prevention Risk Factors Diet Antioxidants and Cancer Prevention. Cancer Causes and Prevention Risk Factors Age Alcohol Cancer-Causing Substances Chronic Inflammation Common Cancer Myths and Misconceptions Diet Hormones Immunosuppression Infectious Agents Obesity Radiation Sunlight Tobacco Genetics Cancer Prevention Overview Research. Antioxidants and Cancer Prevention On This Page What are free radicals, and do they play a role in cancer development? What are antioxidants? Can antioxidant supplements help prevent cancer? Should people already diagnosed with cancer take antioxidant supplements? What are free radicals, and do they play a role in cancer development? MAX Study, France 19 — 22 Daily supplementation with vitamin C mg , vitamin E 30 mg , beta-carotene 6 mg , and the minerals selenium µg and zinc 20 mg for a median of 7. Selenium : Rice, corn, wheat, and other whole grains, as well as nuts, eggs, cheese, and legumes. Goji berries and many other food products that contain antioxidants are available to purchase online. The following foods are good sources of antioxidants. Click on each one to find out more about their health benefits and nutritional information:. Lycopene is the antioxidant that gives tomatoes their rich red color. When tomatoes are heat-treated, the lycopene becomes more bio-available easier for our bodies to process and use. However, studies have shown that cauliflower, peas, and zucchini lose much of their antioxidant activity in the cooking process. Keep in mind that the important thing is eating a variety of antioxidant-rich foods, cooked and raw. There is no set recommended daily allowance RDA for antioxidants, but a high intake of fresh plant-based produce is considered healthful. It is worth remembering that, while studies link the consumption of fruits and vegetables with better overall health, it is not clear whether how far this is due to the activity of antioxidants. In addition, caution is needed regarding supplements. The National Institutes of Health NIH warn that high doses of antioxidant supplements can be harmful. A high intake of beta-carotene, for example, has been linked to an increased risk of lung cancer in smokers. A high dose of vitamin E has been found to increase the risk of prostate cancer , and the use of some antioxidant supplements has been linked to a greater risk of tumor growth. Antioxidant supplements may also interact with some medications. It is important to speak with a health provider before using any of these products. Overall, research has not proven that taking any particular antioxidant as a supplement or through a food can protect against a disease. There may be some benefit for people at risk of age-related macular degeneration, but it is essential to seek advice from a doctor about whether to use supplements, and which ones to use. Free radicals have been linked to a range of diseases, including heart disease, cancer, and vision loss, but this does not mean that an increased intake of antioxidants will prevent these diseases. Antioxidants from artificial sources may increase the risk of some health problems. As a result, it is important to seek out natural sources of antioxidants, in the form of a healthful diet. Consuming fruits and vegetables has been linked to a lower rate of chronic diseases, and antioxidants may play a role. However, it is unlikely that consuming added antioxidants, especially in processed foods, will provide significant benefits. In addition, anyone considering taking antioxidant supplements should speak to a health provider first. Read the article in Spanish. Free radicals are unstable atoms that can cause damage to cells and lead to illnesses and the aging process. Exactly what impact do they have on the…. Eating a balanced diet is vital for healthful living. Figs contain protein, fiber, and iron, among many other nutrients. Learn more about the…. What are micronutrients? Read on to learn more about these essential vitamins and minerals, the role they play in supporting health, as well as…. Adding saffron supplements to standard-of-care treatment for ulcerative colitis may help reduce inflammation and positively benefit patients, a new…. My podcast changed me Can 'biological race' explain disparities in health? Why Parkinson's research is zooming in on the gut Tools General Health Drugs A-Z Health Hubs Health Tools Find a Doctor BMI Calculators and Charts Blood Pressure Chart: Ranges and Guide Breast Cancer: Self-Examination Guide Sleep Calculator Quizzes RA Myths vs Facts Type 2 Diabetes: Managing Blood Sugar Ankylosing Spondylitis Pain: Fact or Fiction Connect About Medical News Today Who We Are Our Editorial Process Content Integrity Conscious Language Newsletters Sign Up Follow Us. |
| The Role of Antioxidant on Health and Age-Related Diseases in Aging | SpringerLink | In addition to the effects mentioned above, a beneficial role of UQ supplementation has also been observed on the incidence of type 2 diabetes. No data were obtained to justify that they are effective in primary cancer prevention. Gonçalves, A. As oxidative stress is a component of many diseases, the development of effective antioxidant therapies is an important goal. J Mol Histol — Indeed, a balance between oxidants and reductants, including glutathione, thioredoxin and NADPH, which are the substrates for antioxidant enzymes, is essential for maintaining normal physiology Vitamin E inadequacy in humans: causes and consequences. |
| Actions for this page | Cell Res. Álvarez-Pérez Antioxidant-related disorders, Sánchez-Villegas A, Díaz-Benítez EM et Antioxidant-rslated Influence of disprders Mediterranean Cauliflower pasta recipes pattern Antioxidant-related disorders body fat distribution: results of the PREDIMED—Canarias Intervention randomized trial. Graham, K. Thus, an antioxidant can be a useful approach for healthspan extension as well as lifespan extension. Research shows that some vitamin supplements can increase our cancer risk. Curr Opin Clin Nutr Metab Care — Biagi, E. |
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