Antioxidants and stress reduction -
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. Antioxidants and cancer prevention External Link , National Cancer Institute, US National Institutes of Health. How much do we need each day?
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Medical News Today. Health Conditions Health Products Discover Tools Connect. How does oxidative stress affect the body? Medically reviewed by Stacy Sampson, D.
What is it? Free radicals Antioxidants Effects Conditions Risk factors Prevention Summary Oxidative stress is an imbalance of free radicals and antioxidants in the body, which can lead to cell and tissue damage.
What is oxidative stress? Share on Pinterest Many lifestyle factors can contribute to oxidative stress. Healthy aging resources To discover more evidence-based information and resources for healthy aging, visit our dedicated hub. Was this helpful?
What are free radicals? What are antioxidants? Share on Pinterest Fresh berries and other fruits contain antioxidants. Effects of oxidative stress. Conditions linked to oxidative stress. Risk factors for oxidative stress. How we reviewed this article: Sources.
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How does exercise support health later in life? Greater independence and higher self-worth are only some of the benefits of physical… READ MORE. When ROS function is impaired, there is more susceptibility to atopic disorders or diseases due to impairment of the attack-kill-present-respond behavior of the Th-1 immune response chain.
Over-consumption of antioxidants could thus lead to antioxidative stress, where antioxidants might weaken or block the adaptive stress responses and cause dangerous health conditions and cause harm. The concept of antioxidative stress may best be described by excessive or detrimental nutritional consumption of a diet rich in antioxidants, [3] unbalancing the immune systems' pathogenic response processes.
Serious health conditions can result if these processes are chronically unbalanced, ranging from acute to chronic. Immunological stress by over-supplementation of antioxidants facilitates adverse health effects specifically including allergies, asthma, and physiological alterations especially of the skin.
Many foods contain antioxidant content , while numerous dietary supplements are exceptionally rich in antioxidants. Many antioxidative compounds are also antinutrients , such as phenolic compounds, found in plant foods belonging to the families of phenolic acids, flavonoids, isoflavonoids, and tocopherols , among others.
Phenolic compounds found in foods generally contribute to their astringency and may also reduce the availability of certain minerals such as zinc. In more severe cases, zinc deficiency causes hair loss, diarrhea, delayed sexual maturation, impotence, hypogonadism in males, and eye and skin lesions.
High-dose supplements of antioxidants may be linked to health risks in some cases, including higher mortality rates. For example, high doses of beta-carotene and vitamin E was found to increase the risk of lung cancer and overall mortality in smokers.
Antioxidant supplements may also interact with some medicines. The primary factor in antioxidants causing or promoting the aforementioned health issues, is the attenuation or inactivation of reactive oxygen species ROS , which immune system responders utilize to kill or destroy pathogens, mainly bacteria and fungi.
ROS produce free-radicals as a by-product of the oxygen burst used to kill pathogens. Excess free-radicals that are not effectively scavenged and collected result in oxidative stress that can also be harmful.
Free-radicals are not the enemy that popular culture has made them out to be, as they aid in proper biochemical signaling that make them necessary in a healthy immune system. Several complex biological free-radical collection systems already exist for the purpose of scavenging, which normally, do not require augmentation by supplementation of antioxidants to function nominally.
Antioxidants attenuate the Th-1 immune response, responsible for eliminating bacterial and fungal threats, while the Th-2 immune response compensates for a weak Th-1 response by increasing its own responders, which may be not only ineffective, but overall destructive to healthy surrounding tissues, thus harmful.
The net result: over-supplementation of antioxidants are a direct, underlying cause of allergenic diseases and skin alterations, spurring signs objective indications and symptoms subjective states of localized and disseminated medical conditions. A diet rich in anti-oxidants could allow for skin alterations such as acute acne or chronic non-infectious lesions, especially when the Th-1 immune process is persistently compromised by an overload of dietary antioxidant sources, like daily ingesting of vitamin C supplements, for example.
Allergenic reactions by invading atopic pathogens, well beyond the scope of microbiota , can become initial factors triggering chronic atopic disease.
When relating to atopic skin conditions caused by chronic antioxidative stress, symptoms similar to Chronic granulomatous disease CGD may appear, a disease where phagocytes have an impaired ability to destroy pathogens due to a genetic inability to effectively kill pathogens by ROS, versus supplementation induced inability caused by antioxidative stress.
Nearly all living creatures consume antioxidants in some quantity. Inadequate consumption of dietary antioxidants can be detrimental. For example, a deficiency of vitamin C is a primary cause of scurvy.
Vitamin C can be ingested by eating certain fruits. A dietary balance of oxidants and antioxidants are critical in maintaining optimal health.
Strress Antioxidants and stress reduction peer-reviewed Antioxidants and stress reduction. Submitted: 14 October Reviewed: 15 February Published: 08 March com strss cbspd. Antioxidants are compounds that eliminate oxidative stress in biological systems. Oxidative stress is caused by various radicals formed in the system as a result of oxygen entering the biological system. Structures with unpaired electron are either free radicals or radical ions.Video
Oxygen, Stress, and Antioxidants (Ron Mittler, PhD) Antioxidative stress is Antioxidants and stress reduction overabundance Amtioxidants bioavailable Antioxidants and stress reduction compounds Anfioxidants interfere with the immune system 's Antioxidahts to neutralize pathogenic threats. The fundamental opposite is oxidative stress Antioxidanfs, which can lead to such Nutrition coaching for sports performance states as coronary heart disease or cancer. Antioxidant compounds reduce reactive oxygen species ROSwhich reduces emitted free-radicals. When ROS function is impaired, there is more susceptibility to atopic disorders or diseases due to impairment of the attack-kill-present-respond behavior of the Th-1 immune response chain. Over-consumption of antioxidants could thus lead to antioxidative stress, where antioxidants might weaken or block the adaptive stress responses and cause dangerous health conditions and cause harm.
Antioxidants and stress reduction -
When it comes to cancer prevention, the picture remains inconclusive for antioxidant supplements. Few trials have gone on long enough to provide an adequate test for cancer. High-dose antioxidant supplements can also interfere with medicines. Vitamin E supplements can have a blood-thinning effect and increase the risk of bleeding in people who are already taking blood-thinning medicines.
Some studies have suggested that taking antioxidant supplements during cancer treatment might interfere with the effectiveness of the treatment. Inform your doctor if starting supplements of any kind. One possible reason why many studies on antioxidant supplements do not show a health benefit is because antioxidants tend to work best in combination with other nutrients, plant chemicals, and even other antioxidants.
For example, a cup of fresh strawberries contains about 80 mg of vitamin C, a nutrient classified as having high antioxidant activity. Polyphenols also have many other chemical properties besides their ability to serve as antioxidants.
There is a question if a nutrient with antioxidant activity can cause the opposite effect with pro-oxidant activity if too much is taken. This is why using an antioxidant supplement with a single isolated substance may not be an effective strategy for everyone.
Differences in the amount and type of antioxidants in foods versus those in supplements might also influence their effects. For example, there are eight chemical forms of vitamin E present in foods. However, vitamin E supplements typically only include one form, alpha-tocopherol.
Epidemiological prospective studies show that higher intakes of antioxidant-rich fruits, vegetables, and legumes are associated with a lower risk of chronic oxidative stress-related diseases like cardiovascular diseases , cancer, and deaths from all causes.
The following are nutrients with antioxidant activity and the foods in which they are found:. Excessive free radicals contribute to chronic diseases including cancer, heart disease, cognitive decline, and vision loss.
Keep in mind that most of the trials conducted have had fundamental limitations due to their relatively short duration and inclusion of people with existing disease.
At the same time, abundant evidence suggests that eating whole in fruits , vegetables , and whole grains —all rich in networks of naturally occurring antioxidants and their helper molecules—provides protection against many scourges of aging.
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In , a rating tool called the Oxygen Radical Absorbance Capacity ORAC was created by scientists from the National Institute on Aging and the United States Department of Agriculture USDA.
It was used to measure the antioxidant capacity of foods. The USDA provided an ORAC database on its website highlighting foods with high ORAC scores, including cocoa, berries, spices, and legumes. Blueberries and other foods topping the list were heavily promoted in the popular press as disease-fighters even if the science was weak, from cancer to brain health to heart disease.
However, 20 years later the USDA retracted the information and removed the database after determining that antioxidants have many functions, not all of which are related to free radical activity. Although this was not a primary endpoint for the trial, it nevertheless represents an important outcome.
In the Heart Outcomes Prevention Evaluation HOPE trial, the rates of major cardiovascular events were essentially the same in the vitamin E A recent trial of vitamin E in Israel, for example, showed a marked reduction in coronary heart disease among people with type 2 diabetes who have a common genetic predisposition for greater oxidative stress.
In the Supplementation en Vitamines et Mineraux Antioxydants SU. MAX study, 13, French men and women took a single daily capsule that contained mg vitamin C, 30 mg vitamin E, 6 mg beta-carotene, mcg selenium, and 20 mg zinc, or a placebo, for seven and a half years.
The vitamins had no effect on overall rates of cardiovascular disease. Lung disease A study from the Journal of Respiratory Research found that different isoforms of vitamin E called tocopherols had opposing effects on lung function.
Cancer When it comes to cancer prevention, the picture remains inconclusive for antioxidant supplements. MAX randomized placebo-controlled trial showed a reduction in cancer risk and all-cause mortality among men taking an antioxidant cocktail low doses of vitamins C and E, beta-carotene, selenium, and zinc but no apparent effect in women, possibly because men tended to have low blood levels of beta-carotene and other vitamins at the beginning of the study.
Age-related eye disease A six-year trial, the Age-Related Eye Disease Study AREDS , found that a combination of vitamin C, vitamin E, beta-carotene, and zinc offered some protection against the development of advanced age-related macular degeneration, but not cataracts, in people who were at high risk of the disease.
However, relatively short trials of lutein supplementation for age-related macular degeneration have yielded conflicting findings. The study found that people taking the vitamins were less likely to progress to late-stage AMD and vision loss. However, the study authors noted that taking lutein and zeaxanthin alone or vitamin E alone did not have a beneficial effect on these eye conditions.
The Selenium and Vitamin E Cancer Prevention Trial SELECT Eye Endpoints Study, which followed 11, men for a mean of five years, did not find that vitamin E and selenium supplements, in combination or alone, protected from age-related cataracts. It did not find that antioxidant supplements of vitamin E or selenium, alone or in combination, protected against dementia compared with a placebo.
Early death A meta-analysis of 68 antioxidant supplement trials found that taking beta-carotene and vitamin A and E supplements increased the risk of dying.
It was also difficult to compare interventions because the types of supplements, the dosages taken, and the length of time they were taken varied widely.
The same authors conducted another systematic review of 78 randomized clinical trials on antioxidant supplements including beta-carotene, vitamin A, vitamin C, vitamin E, and selenium alone or in combination.
The study found that both people who were healthy and those with diseases taking beta-carotene and vitamin E supplements had a higher rate of death. The duration of the studies varied widely from one month to 12 years, with varying dosages. The first inkling came in a large trial of beta-carotene conducted among men in Finland who were heavy smokers, and therefore at high risk for developing lung cancer.
The trial was stopped early when researchers saw a significant increase in lung cancer among those taking the supplement compared to those taking the placebo. Again, an increase in lung cancer was seen in the supplement group.
MAX trial, rates of skin cancer were higher in women who were assigned to take vitamin C, vitamin E, beta-carotene, selenium, and zinc. These results came from the Selenium and Vitamin E Cancer Prevention Trial SELECT that followed 35, men for up to 12 years.
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This is due to its degradation through association with Kelch-like ECH-associated protein 1 KEAP1 , which facilitates its degradation by the 26S proteasome. Boosting NRF2 synthesis represents a therapeutic antioxidant approach. Using non-toxic electrophiles to alkylate KEAP1 represents another major therapeutic approach.
For KEAP1, SH is the thiol form and SX denotes the adduct formed with the electrophile X. The interaction of NRF2 and βTrCP is disrupted owing to oxidant-mediated inhibition of GSK3β and the phosphorylation of NRF2 at the Deh6 domain.
Inhibiting GSK3β is another potential therapeutic approach to modulate NRF2 signalling. p62 therefore provides another potential therapeutic target. Newly synthesized NRF2 that escapes degradation is translocated into the nucleus where it binds to EpRE sequences in the promoters of antioxidant genes and increases their expression.
NRF2 activity is also positively regulated through NRF2 phosphorylation by protein kinase C PKC and its interaction with other proteins such as p21 ref. Thus, compounds that inhibit BACH1 offer an alternative therapeutic approach for increasing expression of some NRF2-regulated genes.
Other negative regulators of NRF2, which represent potential therapeutic targets include HRD1, CRIF1, progerin and microRNA for NRF2 ref. For example, 11 clinical trials for turmeric extract and 55 clinical trials for broccoli or broccoli sprout supplement have been completed or are in an active phase for various conditions including COPD, osteoarthritis, joint stiffness and diabetic nephropathy www.
Yagishita et al. In general, some beneficial effects, including a boost of antioxidant capacity, were observed in the clinical trials, but more effort is required to develop and validate biomarkers of pharmacodynamic action in humans.
As pointed out above, an increase in antioxidant defence may be limited in disease treatment or prevention if oxidative stress has only a secondary role in the pathology.
The underlying mechanism of the antioxidant properties of these dietary supplements, often the coumarins and polyphenols present in vegetables and fruits, relies upon their oxidation to electrophilic quinones that form adducts with KEAP1 cysteines 6.
The effectiveness of many of these NRF2 activators in inducing antioxidant enzymes and in alleviating oxidative damage has been confirmed in non-human animal studies, and there have been significant advances in drug development based on the mechanism of NRF2 activation and antioxidant induction.
Several dietary NRF2 activators, including curcumin, sulforaphane and resveratrol, have been developed as daily supplements, while some NRF2 activators are in clinical trials for disease treatment 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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The process of oxidation in the human Website performance optimization tips damages cell membranes and other structures, including Antioxidants and stress reduction reduxtion, lipids and DNA. The body ans cope reductiin some free radicals and sterss them to function effectively. However, the damage caused by an Antioxidants and stress reduction of free radicals over time may become irreversible and lead to certain diseases including heart and liver disease and some cancers such as oral, oesophageal, stomach and bowel cancers. Oxidation can be accelerated by stresscigarette smokingalcoholsunlight, pollution and other factors. Antioxidants are found in certain foods and may prevent some of the damage caused by free radicals by neutralising them. These include the nutrient antioxidants, vitamins A, C and E, and the minerals copper, zinc and selenium. Other dietary food compounds, such as the phytochemicals in plants, are believed to have greater antioxidant effects than vitamins or minerals.
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