Antioxidant therapy in chronic diseases -
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.
NM would like to thank the Portuguese Foundation for Science and Technology FCT—Portugal for the Strategic project ref.
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Dietary antioxidants are nutrients that help protect cells from a normal -- but damaging -- physiological process known as "oxidative stress. They also have been added to some foods and are available in the form of dietary supplements.
For years, researchers have sought to understand the role of these antioxidants in reducing the risk of chronic diseases such as cancer, cardiovascular disease, eye diseases, and neurodegenerative diseases, which include Alzheimer's and Parkinson's.
But many unanswered questions remain. Krinsky, chair of the study's Panel on Dietary Antioxidants and Related Compounds, and a professor of biochemistry, Tufts University School of Medicine, Boston. But much more research is needed to determine whether dietary antioxidants can actually stave off chronic disease.
DRIs contain four categories of reference intakes -- including RDAs, which are a set of values intended to help people maintain their health; and another set of values to help them avoid taking too much of a nutrient.
Scientists from the United States and Canada collaborated on the studies. Additional reports will be issued on DRIs for trace elements and other vitamins; electrolytes and water; protein, carbohydrates, fiber, and fats; and other food components.
Setting New Dietary Recommendations The report examines available scientific data on both beneficial and harmful health effects of four nutrients typically found in food: vitamins C and E; selenium; and carotenoids, some of which are sources of vitamin A for human beings.
Whether carotenoids, including beta-carotene, function as antioxidants when consumed is still unknown. Although numerous epidemiological studies have suggested that foods rich in dietary antioxidants have a positive effect on chronic diseases, insufficient evidence exists to conclude that such nutrients, even in very high doses, will reduce the risk of diseases such as cancer; cardiovascular disease; cataracts; age-related macular degeneration, a common form of blindness in elderly people; diabetes mellitus; and neurodegenerative diseases.
In addition to setting daily intakes for vitamins C and E and selenium, the report establishes "tolerable upper intake levels" for each of these three nutrients.
The report underscores the finding that upper levels, or ceilings, should not be considered the recommended amount.
Instead, they represent the maximum intake of a nutrient that is likely to pose no risk of adverse health effects in almost all individuals in the general population. Following are highlights of the report's recommendations: Vitamin C -- Recommended intake levels of this nutrient were increased to achieve maximum saturation in the body.
Women should consume 75 milligrams per day, and men should consume 90 milligrams daily. Because smokers are more likely to suffer from biological processes that damage cells and deplete vitamin C, they need an additional 35 milligrams per day. Food sources of the nutrient include citrus fruit, potatoes, strawberries, broccoli, and leafy green vegetables.
The report sets the upper intake level for vitamin C, from both food and supplements, at 2, milligrams per day for adults.
Intakes above this amount may cause diarrhea. Vitamin E -- Recommended daily intake levels also were increased for this nutrient; both women and men should consume 15 milligrams from food.
This is equivalent to 22 International Units IU of natural-source vitamin E or 33 IUs of the synthetic form. Alpha-tocopherol is the only type of vitamin E that human blood can maintain and transfer to cells when needed.
Food sources include vegetable oils, nuts, seeds, liver, and leafy green vegetables. The upper level, based only on intake from vitamin supplements, is 1, milligrams of alpha-tocopherol per day for adults. This amount is equivalent to roughly 1, IU of "d-alpha-tocopherol," sometimes labeled as "natural source" vitamin E, or 1, IU of "dl-alpha-tocopherol," a synthetic version of vitamin E.
People who consume more than this amount place themselves at greater risk of hemorrhagic damage because the nutrient can act as an anticoagulant. Selenium -- The recommended intake level for this nutrient was set at the amount associated with the highest activity of enzymes that guard against oxidants in the body.
Women and men should take 55 micrograms per day, the report says. However, limited evidence supports the effectiveness of vitamins and minerals in cancer prevention Fortmann et al.
Additionally, there is a lack of randomized control trials investigating diets and cancer due to difficulty in whole diet interventions as well as ethical issues in the proposed research Norat et al. Hence, current recommendations are based on the effectiveness of a healthy diet rich in fruits, vegetables, and grains, and low on red meat and alcohol and lifestyle on reducing cancer risk Norat et al.
It is well established that intestinal inflammation-associated OS plays an essential role in the pathophysiology of various gastrointestinal GI diseases, such as inflammatory bowel diseases IBD Balmus et al.
Although the exact etiology of IBD remains unclear, the underlying pathologies can be partially attributed to excess ROS formation Zhu and Li, ; Bhattacharyya et al. Due to the presence of food particles, pathogens, or microbiota imbalance, the GI tract may become irritated, generating excess ROS and compromising endogenous antioxidant defenses Moura et al.
OS disrupts the intestinal epithelial barrier and increases intestinal permeability, further exacerbating inflammation Figure 2 Balmus et al.
IBD, which is comprised of CD and ulcerative colitis UC , is characterized by chronic and prominent inflammation associated with OS in the GI tract Balmus et al.
Elevated levels of pro-inflammatory mediators such as platelet activating factor PAF and leukotriene B 4 LTB 4 observed in the mucosal samples from active IBD patients have been shown to trigger the release of cytotoxic reactive oxygen metabolites by overstimulating phagocytes Ingraham et al.
Moreover, myeloperoxidases are released during the massive infiltration of polymorphonuclear neutrophils and macrophages into the inflamed mucosa, producing hypochlorous acid, a potent oxidizing agent, via the metabolism of H 2 O 2. Other sources of ROS include enzymes such as cyclooxygenase, xanthine oxidase, and 5-lipoxygenase that reside in the intestinal mucosa Alzoghaibi, FIGURE 2.
Schematic illustrating the roles of OS and nutrient antioxidants in IBD. IBD, inflammatory bowel diseases; OS, oxidative stress; Se, selenium; Zn, zinc. Despite ROS overproduction, a deficiency in dietary and enzymatic antioxidants also contributes to the development of OS Alzoghaibi, For example, low levels of enzymatic antioxidants and vitamins have been observed in patients with CD, which is partly due to malnutrition Buffinton and Doe, ; Alzoghaibi, In malnourished IBD patients, the reduced dietary intakes of fruits and vegetables greatly influence the concentration of carotenoid vitamin A Balmus et al.
Vitamin C, which helps to repair and protect mucosal lining against detrimental insults, is depleted in peptic ulcers and gastritis Aditi and Graham, Notably, the increased incidence of vitamin D deficiency in CD patients is highly associated with skeletal morbidity and a worsened quality of life Figure 2 van Hogezand and Hamdy, ; Alastair et al.
Persistent OS can damage the intestinal barrier and increase the permeability of GI epithelium via lipid peroxidation and tight junction disruption. This alters the composition of commensal microbiota in the GI tract and interrupts their ability to establish colonization resistance, thus promoting the invasion of pathogenic bacteria Buffie and Pamer, ; Moura et al.
Such infections further aggravate ROS production and inflammation and potentially increase the risk of inflammatory bowel syndrome Zhu and Li, Considering a strong indication of ROS elevation in IBD and other GI diseases, the adjuvant or treatment potential of antioxidants are largely investigated.
Antioxidant applications have been shown to restore redox balance, thereby attenuating intestinal damages and maintaining GI health Bhattacharyya et al. For example, studies have shown that CuZn-SOD and 5-aminosalicylic acid effectively alleviate mucosal injuries in CD by scavenging or inducing rapid decomposition of ROS Emerit et al.
In a randomized placebo-controlled study, 3 months of oral antioxidant supplementation markedly improved the serum antioxidant status in CD patients in remission. The combination of antioxidants with n -3 fatty acids further attenuated pro-inflammatory activities, thus serving as a potential treatment for CD Geerling et al.
Compared to supplements, dietary intakes of antioxidants from natural fruits and vegetables may be a safer approach to avoid overconsumption. Inappropriate antioxidant application can be harmful by scavenging of physiological ROS Bjelakovic et al.
Foods rich in micronutrients such as α-tocopherol vitamin E and minerals have been reported to be beneficial in alleviating ROS damage. For example, selenium and zinc interact with GPx and SOD, respectively, to combat OS.
The combination of selenium and vitamin E has demonstrated protective effects against oxidative damage in the colon of UC rats Figure 2 and Table 1 Bitiren et al. Several functional foods may be beneficial for IBD without undesirable effects.
Free radical theory, which was first proposed by Harman in , suggests that aging is process related with progressive and irreversible accumulation of oxidative damage in the cells Harman, ; Mariani et al. This alteration of redox profile may blunt cellular capability of buffering ROS produced both under physiological conditions and in response to external stress Kregel and Zhang, Excessive ROS accumulation can directly damage DNA, protein, and lipids, which disturbs normal cellular function Zuo et al.
Mitochondrial DNA mtDNA is particularly susceptible to OS and the mutation of mtDNA has been closely linked with the aging process Trifunovic et al.
It was reported that mice with somatic mtDNA mutation exhibited an earlier onset of aging-related features such as hair loss, osteoporosis, and decreased subcutaneous fat as well as a shorter lifespan Trifunovic et al.
Exposure to high levels of ROS can also accelerate telomere shortening, which ultimately triggers cellular senescence Kregel and Zhang, For example, fibroblast cells cultured under high OS showed increased rate of telomere shortening and a reduced lifespan Vonzglinicki et al.
Additionally, aging-associated OS could be responsible for the chronic systematic inflammation as commonly seen in the elderly via the activation of NF-κB Chung et al.
NF-κB is a key regulator for inflammatory factors such as tumor necrosis factor-alpha TNF-α , interleukin IL -1β, and IL-6 Chung et al.
OS-induced NF-κB signaling is short-lived under normal conditions in contrast to chronic activation during aging Chung et al. The persistent low-level inflammation could be responsible for the development of age-related diseases such as atherosclerosis, cancer, and dementia Chung et al.
Aging population are at a higher risk of suffering from malnutrition due to a general decline in body function including decreased metabolic rate, digestive and absorptive capability Brownie, Therefore, the elderly are more likely to be affected by diseases associated with nutritional inadequacy.
For example, aging-related vitamin D deficiency has been shown to result in bone loss, susceptibility to fracture, and hyperparathyroidism Lips, Therefore, appropriate supplementation with vitamin D can reduce the risk of hip and other fractures in housebound elderly Table 1 Lips, In recent years, focus on the diet has increased due to the diet being an essential source of exogenously obtained antioxidants.
It appears that dietary antioxidants have the anti-aging activity by their ability to suppress the generation of free radicals Kandola et al. Cognitive decline represents a major health concern in aging population Kang et al. A key study by Kang et al. It was found that women who consumed more green leafy or cruciferous vegetables demonstrated the lowest cognitive decline; while fruit consumption did not affect their cognitive function Kang et al.
Interestingly, higher intake of green and yellow vegetables was also correlated with a slower rate of skin aging in Japanese women after adjustment for age, BMI, smoking status, and sun exposure Nagata et al.
Energy restriction ER has recently been put up as a potential way to extend life expectancy. This was partially due to the favorable effects of ER on redox management. Various natural antioxidants, nutraceuticals, and functional foods have been identified as free radical or progressive oxygen hunters.
Therefore, functional foods and nutraceuticals which control the antioxidant activity may represent an important role in slowing the aging process Peng et al. A diet rich in antioxidant has been shown to increase lifespan in animal models Miquel, ; Peng et al.
For instance, a diet supplemented blueberry extract was found to markedly improve the lifespan in fruit flies and Caenorhabditis elegans Wilson et al. This was accompanied by an increased expression of SOD and catalase. The prolongevity induced by blueberry extract was not observed in SOD or catalase-mutated fruit flies.
These results suggest that the beneficial effects of blueberry to extend lifespan are potentially linked with boosted endogenous antioxidant system Peng et al.
Other nutritional antioxidants including apple polyphenols, black rice anthocyanin extract, and black tea theaflavins all demonstrated prominent prolongevity effects by upregulating the endogenous antioxidant levels in animal models Table 1 Peng et al.
Further research is needed to evaluate the potential effects of natural antioxidants on life expectancy in human beings.
The implication of OS in the etiology of several chronic and inflammatory diseases indicates that antioxidant-based therapy could be promising for these disorders. However, many problems remain elusive regarding antioxidant supplements in disease prevention. It remains to be elucidated about the precise roles of ROS in the pathogenesis of various diseases.
Current recommendations are based on the intake of a healthy diet rich in fruits, vegetables, and grains and low on red meat and alcohol and healthy lifestyle, which has demonstrated the ability to reduce the risk for diseases.
Further research is warranted before using antioxidant supplements as an adjuvant therapy. In the meantime, avoiding oxidant sources such as cigarette smoke and alcohol must be considered when taking dietary antioxidants.
LZ conceptualized and designed the review. ZL, ZR, and JZ summarized the literature and wrote the manuscript. LZ, EK, C-CC, and TZ critically revised the manuscript. TZ prepared the figures and abstract. All authors agreed to be accountable for the content of this work.
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. We thank Paige Henry, Alicia Simpson, and Denethi Wijegunawardana for their assistance during the manuscript preparation.
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Oxidative Antiocidant plays an essential Body image comparison in the pathogenesis of chronic diseases such as cardiovascular diseases, Antioxisant, Metabolic support for weight management diseases, and cancer. Long term exposure to Foot cramps at night levels of chrobic factors can cause structural defects at a mitochondrial DNA level, as Body image comparison as functional alteration of several disesaes and cellular Anntioxidant leading to aberrations in gene expression. The modern lifestyle associated with processed food, exposure to a wide range of chemicals and lack of exercise plays an important role in oxidative stress induction. However, the use of medicinal plants with antioxidant properties has been exploited for their ability to treat or prevent several human pathologies in which oxidative stress seems to be one of the causes. In this review we discuss the diseases in which oxidative stress is one of the triggers and the plant-derived antioxidant compounds with their mechanisms of antioxidant defenses that can help in the prevention of these diseases. Consumers, increasingly aware of Body image comparison impact of their diet on their health, are seeking to introduce thsrapy foods therayp their dietary routine. While this Diswases becoming almost automatic, Antioxidwnt can ask ourselves: ttherapy are antioxidants, where are they Body image comparison and precisely what role do they play in the prevention of chronic diseases? To date, the term antioxidant is not clearly defined, but it can be associated with a compound that inhibits oxidation. To understand what an antioxidant is, we must first understand what oxidation is and how it is generated. In our body, oxidation is a chemical reaction that corresponds to the attack of a cell or a compound by free radicals of an oxygenated species. Free radicals attack the components of the cell, such as proteins and DNA. They are unstable and highly reactive molecules.
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