Video
What Is Oxidative Stress? And The Best Way To Combat It: Oxidative stress plays an essential role in the pathogenesis of chronic rellief such as cardiovascular diseases, diabetes, neurodegenerative diseases, and cancer. Long term exposure to increased levels Ozidative pro-oxidant factors Oxidative stress relief cause structural Oxidative stress relief at a mitochondrial Oxidative stress relief level, as well Oxidayive functional alteration of several enzymes and Boosting energy before workouts structures leading strees aberrations stresw 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. Finally, both the beneficial and detrimental effects of antioxidant molecules that are used to reduce oxidative stress in several human conditions are discussed.Oxidative stress relief -
Oxidative stress is also responsible for the toxicity of the widely used chemical herbicide, paraquat. When ingested, paraquat is actively taken up by alveolar type II cells and leads to pneumonitis and progressive lung fibrosis with poor prognosis.
Paraquat also causes injury to other organs including liver and kidney. Long-term exposure to paraquat is associated with Parkinson disease In atherosclerosis, plaque builds up in the intimal layer of arteries and over time the arteries narrow, leading to infarction and stroke.
Substantial evidence indicates that oxidative stress has a crucial role in the pathogenesis of atherosclerosis. Since the first identification of lipid hydroperoxides in human atherosclerotic aorta 18 , many studies have shown an increase in oxidized lipids and other oxidative stress markers in the atherosclerotic lesions.
Furthermore, isoprostanes, peroxidation products of arachidonic acid, have been reported to be increased at least fivefold in human atherosclerotic lesions compared with human umbilical veins, and oxidized linoleic acid was detected only in human lesions In many diseases, oxidative stress occurs secondary to the initiation of pathology by other factors.
Oxidative stress can disturb various signalling pathways and affect multiple biological processes through modifying proteins, promoting inflammation, inducing apoptosis, deregulating autophagy , impairing mitochondrial function and many other mechanisms.
These effects frequently accelerate pathological progression and exacerbate the symptoms of diseases, as discussed in representative examples below. Cigarette smoking, the main cause of COPD, is an abundant source of oxidants.
Oxidative stress can lead to oxidation and inhibition of α1-antitrypsin, thus reducing its ability to inhibit neutrophil elastase, a major factor in the pathogenesis of COPD In addition, chronic exposure to oxidants in cigarette smoke causes and promotes the inflammatory response and other pathological cascades such as cell death and fibrosis in COPD pathogenesis The sources of oxidants in COPD are both exogenous for example, cigarette smoking and air pollution and endogenous for example, NOX, mitochondria, inducible nitric oxide synthase iNOS and myeloperoxidase Increased levels of oxidants and lipid peroxidation products, including 8-isoprostane, have been consistently detected in exhaled breath condensate of patients with COPD compared with healthy controls The level of oxidative stress was inversely correlated with lung function of the patients Together, these results suggest that oxidative stress occurs both in the lung and systemically in patients with COPD and contributes to disease pathogenesis.
The pathology of idiopathic pulmonary fibrosis IPF is characterized by diffuse and progressive mesenchymal fibrosis and mild inflammation in the lung with unknown aetiology. Many studies have shown the presence of oxidative stress in IPF. Oxidative stress markers such as H 2 O 2 , 8-isoprostane, 8-isoprostaglandin-F2α 8-iso-PGF2α and ethane are significantly increased in the exhaled breath condensate of patients with IPF compared with healthy individuals In addition, 8-isoprostane is elevated fivefold 28 and oxidized proteins twofold 29 in bronchoalveolar lavage fluid BALF of patients with IPF.
HNE in lung 30 and 8-isoprostane in blood 31 are also significantly elevated in IPF. The glutathione GSH level in epithelial lining fluid and sputum of patients with IPF is fourfold lower than in healthy controls 32 , indicating a deficiency of this important component of antioxidant defence in IPF.
H 2 O 2 production is apparently mainly from NOX4 ref. Mounting evidence suggests that oxidative stress plays a significant part in IPF, by promoting fibrogenesis through causing apoptosis of alveolar epithelial cells, activating myofibroblasts and inducing an inflammatory response Besides oxidative stress, IPF pathogenesis involves a number of processes including apoptosis, senescence, epithelial—mesenchymal transition, endothelial—mesenchymal transition, epithelial cell migration, increased production of chemokines, cytokines and growth factors, as well as mitochondrial dysfunction, endoplasmic reticulum stress, hypoxia and inflammation These mechanisms are interrelated, with oxidative stress representing an important component of the IPF pathogenesis.
Multiple risk factors such as diet, smoking, lifestyle, genetics and comorbidities contribute to hypertension. At the molecular level, however, oxidative stress is a common feature of this condition. Experimental studies suggest that oxidants are mainly from NOXs in hypertension Oxidative markers, including H 2 O 2 ref.
H 2 O 2 has a role in the development and progression of hypertension, through influencing angiotensin II signalling, NO signalling and other cellular processes However, a causative role of oxidative stress in hypertension has not yet been established.
Patients with type 2 diabetes mellitus display substantial evidence of oxidative stress that results in microvascular and macrovascular complications Markers of oxidative stress, including OxLDL to LDL ratio 44 , 8-OHdG 45 , 8-iso-PGF2α 46 , protein carbonyls 47 and GSH conjugation to haemoglobin 48 , have been reported to be significantly elevated in the plasma of patients with type 2 diabetes mellitus, as have urine 8-OHdG and 8-iso-PGF2α levels The increased oxidants in type 2 diabetes mellitus arise from dysfunctional mitochondria 50 and NOX1 ref.
Alzheimer disease is characterized by the progressive accumulation of extracellular amyloid-β plaques and neurofibrillary tangles inside neurons. Several risk factors age, genetics, sex, trauma and air pollution for Alzheimer disease have been identified, but the exact cause remains unclear. However, accumulating evidence suggests that oxidative stress may have a crucial role through multiple pathways Increased levels of nuclear and mitochondrial DNA oxidation were also found in frontal, parietal and temporal lobes of the brain of patients with Alzheimer disease compared with age-matched control subjects In addition, protein oxidation in the hippocampus 60 and protein carbonyls in the cerebral cortex 58 were significantly elevated in the brains of patients with Alzheimer disease.
Claims have been made that Aβ 1—42 61 , activated microglia 62 , iron accumulation 63 and dysfunctional mitochondria contribute to increased oxidant production Through aberrantly altering signalling transduction pathways that damage DNA and exacerbate inflammation, oxidants are involved in various phases of tumorigenesis, including transformation of normal cells to tumour cells, tumour cell growth, proliferation, invasion, angiogenesis and metastasis Conversely, oxidative stress can also trigger apoptosis and ferroptosis, and reduce the opportunity for transformation and thereby prevent tumorigenesis In addition, oxidative stress is the main mechanism of action of radiation see Radiation-induced lung injury subsection above and many chemotherapeutic drugs Therefore, oxidative stress is implicated in almost all phases of cancer.
Cancer cells produce more oxidants than normal cells, and therefore cancer cells are exposed to increased oxidative stress in the loci. The increased oxidants in cancer cells are mainly from mitochondria 67 , NOX4 ref.
Oxidants in the loci may also come from normal cells in or surrounding the tumour mass, such as endothelial cells and inflammatory immune cells.
The increase in oxidative markers has been observed in various types of cancer. For example, patients with non-small-cell lung cancer have been shown to exhale more H 2 O 2 than control individuals In addition, increased levels of 8-OHdG 71 were detected in breast cancer tissues compared with matched normal tissues, and 8-OHdG was significantly elevated in prostate cancers 72 and lung cancers Systemic inflammatory response syndrome SIRS is a disorder caused by an exaggerated inflammatory response in the whole body to infectious pathogens or non-infectious insults SIRS involves the release of oxidants and inflammatory cytokines leading to reversible or irreversible end organ dysfunction and even death.
Sepsis is a SIRS caused by infection, which shares common features of inflammation and oxidative stress with SIRS caused by non-infectious insults, and is more frequently studied.
Plasma F2-isoprostanes 75 , HNE 76 and 8-OHdG 77 have been reported to be significantly increased in patients with severe sepsis. In patients with acute respiratory distress syndrome from SIRS, the level of 8-iso-PGF2α is increased in exhaled breath condensate 78 as is nitrotyrosine in BALF In addition, the levels of antioxidants such as vitamin C 84 , vitamin E 85 and GSH 86 are decreased in sepsis.
Although timely reperfusion is essential to avoid irreversible injury from ischaemia interrupted blood flow , extensive damage to both the local and distant organs can occur through initiation of a systemic inflammatory response. Ischaemia—reperfusion injury IRI has a major role in the pathophysiological changes of several critical clinical conditions including heart attack, stroke and organ transplantation.
The molecular mechanisms underlying IRI are multifactorial and involve the inflammatory response and oxidative stress. Markers of oxidative stress including urinary 8-iso-PGF2α are elevated in patients with acute myocardial infarction given thrombolytic therapy, when compared with both age-matched, healthy control subjects and patients with stable coronary heart disease 90 , and in patients with coronary angioplasty following carotid reperfusion A study involving 66 individuals with stroke and control subjects showed that plasma and urinary F2-isoprostanes were elevated immediately and up to day 7 after onset of ischaemic stroke Urinary 8-OHdG was also increased after reperfusion in acute myocardial infarction It should be noted that most oxidative markers measured in IRI studies were systemic and few studies determined the presence of these markers in the lesion site.
To defend against oxidative injury, organisms have evolved defences primarily dependent upon antioxidant enzymes, supply of their substrates and repair of injury. Agents that enhance these defences are the principal strategies underlying antioxidant therapy.
Extensive studies on the induction of antioxidant enzymes have focused on the regulatory mechanisms, the implications in diseases and potential inducers with therapeutic purpose. Although several transcription factors are redox sensitive and are involved in the induction of antioxidant genes for example, the induction of haem oxygenase 1 HO1, encoded by HMOX1 through activator protein 1 AP-1 94 and peroxisome proliferator-activated receptor-γ PPARγ 95 , and the induction of glutamate—cysteine ligase GCL 96 and SOD1 ref.
However, these oxidants react too rapidly with membrane lipids, proteins and nucleic acids to be effectively scavenged by exogenous small molecules. SODs and enzymes that remove H 2 O 2 and lipid hydroperoxides form the front line of defence against oxidative stress.
However, there are major differences between the extracellular fluids and within cells, which have therapeutic implications. Extracellular SOD EC-SOD, SOD3 is generally associated with the outer membrane of cells and is not present in all extracellular fluids.
Although the outer surface of some cells binds to EC-SOD, the additional catalase activity of most SOD mimics also catalyses removal of H 2 O 2 , which EC-SOD cannot achieve.
Some of the GPXs and PRDXs also reduce lipid hydroperoxides, with two of them PRDX6 and GPX4 being able to reduce phospholipid hydroperoxides. Nonetheless, SOD mimics are useful in extracellular environments that lack significant EC-SOD.
Compounds with combined SOD and catalase activities have an advantage over SOD alone. The second line of antioxidant defence includes the synthesis of thioredoxin TRX , GCL and glutathione synthetase responsible for the synthesis of GSH, glutathione reductase and thioredoxin reductase, which use NADPH to reduce GSSG and TrxS 2.
It should be noted that both first-line and second-line enzymes also have a role in physiological redox signalling and the maintenance of redox homeostasis, and that total elimination of H 2 O 2 would adversely alter cellular function Scavenging of H 2 O 2 and other hydroperoxides by small molecules is negligible compared with removal by the 15 enzymes that reduce H 2 O 2 and lipid hydroperoxides and the two enzymes that reduce phospholipid hydroperoxides.
Nonetheless, a few mimics of GPX, including ebselen see below , have rate constants that approach those of the enzymes. Although GSH is normally in the millimolar range in cells, it can be depleted during oxidative stress. Thus, compounds that increase GSH by either supplying cysteine, which is limiting for GSH synthesis, or are precursors for GSH, increase the effectiveness of endogenous GPXs or GPX mimics.
Increasing synthesis of GSH by induction of GCL, the enzyme that kinetically limits GSH synthesis, also offers a therapeutic advantage. Indeed, finding agents that induce GCL through activation of the NRF2 transcription factor has been a major goal for more than two decades.
A third line of antioxidant defence is repair or removal of oxidized macromolecules. This broad area of research is not directly relevant to the present Review; however, the enzymatic systems for removal of oxidized proteins , oxidized fatty acid removal and replacement , and oxidized DNA removal and repair are induced by oxidants.
It was first identified as a transcription factor regulating the expression of β-globin by Moi et al. in ref. Many detailed studies established that NRF2—ARE signalling has a central role in the regulation of antioxidant gene expression NRF2—EpRE signalling regulates the basal and inducible expression of more than genes that encode proteins involved in antioxidant defence, detoxification, apoptosis, DNA repair, removal of oxidized protein by the proteasome, inflammation and other processes , , Mounting evidence suggests that deficiency of NRF2 signalling suppresses the induction of target antioxidant enzymes in response to oxidative stress, increases susceptibility to oxidative damage and accelerates the inflammatory response , whereas enhancing NRF2 activity increases the expression of antioxidant enzymes and the defence against oxidative stress.
The molecular mechanism and regulation of NRF2 activation in response to oxidative stress has been discussed in many recent articles. Most relevant to therapeutics is the recent review by Cuadrado et al.
Thus, we only briefly describe the regulation of NRF2 Fig. KEAP1 is an adaptor for Cullin 3-containing ubiquitin ligase E3 complex , and βTrCP is a substrate receptor for Cul1-based ubiquitin ligase In response to oxidative stimuli, KEAP1 is oxidatively modified and loses the capacity to present NRF2 for degradation.
Simultaneously, oxidative inhibition of glycogen synthase kinase 3β GSK3β -mediated NRF2 phosphorylation at the Neh6 domain stops the interaction of NRF2 and βTrCP. NRF2 can also be activated through pmediated autophagic degradation of KEAP1 ref. With the activation of these pathways, NRF2, both dissociated from KEAP1 and newly synthesized, escapes from degradation and is then translocated into the nucleus where it forms heterodimers with small Maf or Jun family proteins, binds to EpRE in the promoter and increases transcription of target genes.
In the nucleus, NRF2 is competitively suppressed by BACH1 ref. ChIP-seq assays identified a considerable overlap of BACH1 in HEK cells and NRF2 in mouse MEF cells target genes Evidence suggests that the suppressive effect of BACH1 on NRF2 signalling may be gene selective. BACH1 inactivation is required for the induction of HO1 but not for that of thioredoxin reductase 1, even though both genes are regulated by NRF2 ref.
It should be noted that NRF2 regulation is far more complicated than the simplified pathways, as nuclear factor-κB NF-κB , PKC, p21, BRCA1, HRD1, CRIF1 and microRNAs are involved in regulating NRF2 signalling by acting on NRF2 expression, protein stability, activation and translocation With more regulators and interaction pathways being identified, NRF2 activity is clearly regulated by a network of signalling pathways allowing it to hold important roles in multiple biological processes and response to multiple circumstances.
Some puzzles remain for NRF2 regulation, including how NRF2 is transported in and out of the nucleus, and the dysregulation and ceiling effect of NRF2 induction under some pathophysiological conditions.
Multiple antioxidant therapeutic strategies are being explored, some of which are currently undergoing clinical trials. See Box 1 for reactions. Several antioxidant enzyme mimics have been and are currently in clinical trials Table 1. The therapeutic potential of SOD has therefore generated interest since its discovery in ref.
These mimetics include the metalloporphyrins, Mn cyclic polyamines, nitroxides, Mn—salen complexes and fullerenes, and their chemical properties have previously been well summarized , The protective effects of many of these compounds have been demonstrated in non-human animal studies or even clinical trials.
Mimics of SOD and catalase have rate constants several orders of magnitude lower than the enzymes. Thus, when they enter cells, their contribution to cytosolic antioxidant defence is relatively minor. However, SOD and catalase mimics appear to be effective in extracellular spaces where the concentrations of antioxidant enzymes and substrates are very low or absent Fig.
Some of the mimics may also be effective in the mitochondrial matrix, but they can act as pro-oxidants instead of as protectors of mitochondrial function Most SOD mimics appear to have catalase activity. Although NOX4, which is primarily in intracellular organelle membranes, has also been found in the plasma membrane, this has only been reported for one cell type and so its extracellular location remains debatable indicated by the question mark.
NOS, nitric oxide synthase. In addition, some SOD mimics, such as Mn porphyrins, Mn ii cyclic polyamines and M, can act as pro-oxidants and react with thiols , ascorbate and tetrahydrobiopterin , thereby affecting redox-sensitive signalling pathways and cellular transcription , Therefore, some protective effects of SOD mimics might be attributable to activities other than mimicking SOD.
SOD itself was first developed as a drug called orgotein in the late s, but it has not been approved for human use However, several clinical trials based on the anti-inflammatory property of orgotein have been conducted.
A double-blind, placebo-controlled study has demonstrated that orgotein can be used safely and effectively to ameliorate or prevent the side effects of radiation therapy in patients with bladder cancer, such as the incidence of radio-induced acute cystitis and rectitis , However, in another clinical trial, orgotein showed no beneficial effect on radiation response or the acute radiation reactions, and caused side effects such as marked subcutaneous infiltration and redness at local injection site in some patients Currently orgotein is used as an anti-inflammatory agent in non-human animals.
The best-studied class of SOD mimics is probably the Mn porphyrins. These preclinical results suggest the potential of Mn porphyrins in the clinical therapy of diseases in which oxidative stress plays a significant part. Another promising SOD mimetic is GC, a novel, highly stable Mn ii -containing penta-azamacrocyclic.
GC selectively removes superoxide anions without reacting with other oxidants In addition, GC has exhibited therapeutic effects in several non-human animal models of inflammation , joint disease and myocardial IRI A recent phase I clinical trial in severe oral mucositis of oropharyngeal cancer with radiation and chemotherapy indicates that the safety of GC in patients is acceptable Salens, aromatic, substituted ethylenediamine metal complexes, represent an emerging class of SOD mimics.
The typical representative salens are EUK-8, EUK and EUK, which have been shown to be protective in many non-human animal models of human diseases, including sepsis , heart ischaemia—reperfusion , cardiomyopathy , haemorrhage and amyotrophic lateral sclerosis EUK-8 ; IRI and stroke EUK ; radiation lung fibrosis , cognitive impairment , diaphragm muscle weakness in monocrotalin-induced pulmonary hypertension and hyperthermia EUK However, no human clinical trial for salens has yet been reported.
A variety of mimics of GPXs have been developed Among these mimetics, the selenoorganic compound ebselen 2-phenyl-1,2-benzisoselenazol-3 2H -one is best known, with its broad specificity for substrates from H 2 O 2 and smaller organic hydroperoxides to membrane-bound phospholipid and cholesterol hydroperoxides Ebselen may also induce phase II detoxification enzymes In non-human animal studies, ebselen has been shown to reduce oxidative damage , prevent the acute loss of outer hair cells and reduce hearing loss , and decrease inflammation Accordingly, several clinical trials have been conducted in diseases including Meniere disease phase III, NCT , bipolar disorder , complete occlusion of the middle cerebral artery , delayed neurological deficits after aneurysmal subarachnoid haemorrhage and acute ischaemic stroke In these studies, oral administration of ebselen was well tolerated, exerted therapeutic effects and displayed favourable bioavailability.
ALT BXT is a newer analogue of ebselen, displaying increased GPX activity and potency. In vitro, ALT inhibited the inflammatory response in endothelial cells , reduced oxidative damage and prevented neuronal death , and in a mouse model of heart ischaemia—reperfusion it reduced infarct size A phase II clinical trial of ALT NCT in diabetes and coronary artery disease has been completed but data are not yet available.
Another clinical trial on psoriasis NCT was terminated but the reasons for this remain unknown. Although most cells have a concentration of GSH in the millimolar range, GSH is often significantly decreased by oxidative stress. Thus, approaches to maintaining or replenishing GSH using GSH esters or agents that provide its precursor, cysteine, the limiting amino acid in GSH synthesis, have shown effectiveness in various diseases.
N -acetylcysteine NAC is one of the most studied antioxidant agents for therapeutic treatment Table 1. It is water soluble and quickly absorbed primarily via the anion exchange protein on the cell membrane NAC in cells is deacetylated to produce cysteine. Evidence indicates that the antioxidant function of NAC is primarily mediated via replenishing GSH NAC can also reduce cysteine conjugates in plasma NAC has been used therapeutically for the treatment of many pathologies, including liver paracetamol also known as acetaminophen toxicity , cystic fibrosis, where it is delivered through the airways and nephropathy In non-human animal studies and clinical trials, NAC is being investigated for prevention or treatment of many other diseases and conditions.
The results from these studies are conflicting and a consensus has yet to be reached. Failure of NAC to exert a therapeutic effect may be due to oxidative stress being a secondary contributor to the disease being studied.
GSH itself is not effectively transported into most cells, and exogenously administered GSH is rapidly degraded in plasma Thus, using derivatives of GSH is a strategy for more successful delivery. Ester derivatives of GSH, including monomethyl GSH-OMe , monoethyl GSH-MEE , diethyl GSH-DEE and isopropyl esters have been synthesized and evaluated for the efficiency of GSH supplementation.
In GSH-MEE, the carboxyl group of the glycine residue is esterified Glu-Cys-Gly-OEt ; whereas in GSH-DEE both glutamate and glycine residues are esterified tEO-Glu-Cys-Gly-OEt. GSH esters are lipophilic, more efficiently transported across the cellular membrane and resistant to degradation by γ-glutamyl transpeptidase in plasma Once inside cells, GSH esters are rapidly hydrolysed by nonspecific esterases and form GSH.
The transport of GSH-DEE into cells seems more efficient than that of the monoester , and human cells can rapidly convert the diethyl ester into the monoester, which is hydrolysed into GSH. Subcutaneous or intraperitoneal injection of GSH esters into animals was able to increase GSH levels in various tissues including liver , kidney , spleen, pancreas and heart , but not brain Brain GSH levels can be increased via intracerebroventricular delivery of GSH-MEE Although oral administration could also increase tissue GSH levels, this is less effective The relative efficacy of various GSH esters to increase tissue GSH remains unclear owing to limited evidence.
Some cell culture-based studies suggest that GSH-DEE is more effective than GSH-MEE in increasing GSH levels GSH-DEE is metabolized differently in the plasma of non-human animals and humans. In mouse and rat, plasma GSH-DEE is rapidly converted into GSH-MEE by plasma α-esterase, whereas human and many other species including hamster, guinea pig, rabbit and sheep plasma has no α-esterase activity, meaning that GSH-DEE can be transported into tissues more efficiently than GSH-MEE However, no direct comparison study has been conducted on the relative efficacy of the different GSH esters in clinical settings.
Although the reports above suggest that humans have apparently been treated with GSH without adverse effects, and the efficacy of GSH esters to increase GSH levels and alleviate oxidative damage in cells and non-human animals has been demonstrated, no clinical trials have been reported with any GSH ester.
Figure 2 summarizes the strategies for maintaining GSH in cells. Glutathione GSH is synthesized through reactions catalysed by glutamate—cysteine ligase GCL and GSH synthetase GS , with GCL as the rate-limiting enzyme and cysteine as the rate-limiting substrate.
Both reduced GSH and glutathione disulfide GSSG are exported from cells through multidrug resistance protein MRP , and extracellular GSH is sequentially metabolized by membrane-bound γ-glutamyl transpeptidase GGT into cysteinylglycine and γ-glutamyl products, and dipeptidase hydrolyses cysteinylglycine to cysteine and glycine.
The amino acids are transported back into cells and participate in GSH synthesis. N -acetylcysteine NAC is deacetylated by esterase action into cysteine, while GSH esters GSH-E are directly converted by esterase into GSH. γ-Glutamylcysteine γ-glu-cys can bypass GCL, the rate-limiting step for GSH synthesis.
Electrophiles cause the activation of NRF2, which regulates the transcription of the two subunits of GCL, and also GS. Dysregulation of NRF2 signalling Box 3 ; Fig.
Therefore, NRF2 activators are regarded as potential agents to induce antioxidant capacity and alleviate pathology. The induction of antioxidant enzymes, particularly through NRF2, is a major way in which antioxidant therapy is being developed.
Indeed, when the small molecules such as polyphenols are effective, they act primarily through antioxidant enzyme induction mediated by NRF2 signalling 6. NRF2 activators comprise five categories, according to their mechanisms of action Fig.
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.
Sies, H. Oxidative Stress ed. This article introduces the concept of oxidative stress. Flohé, L. Looking back at the early stages of redox biology. Antioxidants 9 , This article provides a history of oxidative stress from a current perspective. Article PubMed Central Google Scholar.
Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: oxidative eustress. Redox Biol. This article explains the central role of hydrogen peroxide in redox signalling.
Article CAS PubMed PubMed Central Google Scholar. Oxidative stress. Article CAS PubMed Google Scholar. Valko, M. et al. Free radicals and antioxidants in normal physiological functions and human disease. Cell Biol.
This article provides a review of redox signalling in disease. Forman, H. How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo.
Free Radic. This article provides a review of the mechanisms of nutritional antioxidants. Strategies of antioxidant defense. Signaling functions of reactive oxygen species.
Biochemistry 49 , — This article explains why hydrogen peroxide is the principal redox second messenger. Evans, J. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes.
This article examines the links between oxidative stress and type 2 diabetes mellitus. Liochev, S. The role of O2. Castro, L. Aconitases: non-redox iron-sulfur proteins sensitive to reactive species. Zhang, H. Giuranno, L. Radiation-induced lung injury RILI.
Article PubMed PubMed Central Google Scholar. Barnes, P. Oxidative stress-based therapeutics in COPD. This article examines the current state of redox-based therapy in COPD. Fleckenstein, K. Temporal onset of hypoxia and oxidative stress after pulmonary irradiation.
Rappold, P. Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter Natl Acad. USA , — Bus, J. Paraquat: model for oxidant-initiated toxicity. Health Perspect. Article CAS Google Scholar. Glavind, J. Studies on the role of lipoperoxides in human pathology.
The presence of peroxidized lipids in the atherosclerotic aorta. Acta Pathol. Suarna, C. Human atherosclerotic plaque contains both oxidized lipids and relatively large amounts of alpha-tocopherol and ascorbate. Salomon, R. HNE-derived 2-pentylpyrroles are generated during oxidation of LDL, are more prevalent in blood plasma from patients with renal disease or atherosclerosis, and are present in atherosclerotic plaques.
Gniwotta, C. Prostaglandin F2-like compounds, F2-isoprostanes, are present in increased amounts in human atherosclerotic lesions. Yang, X. Oxidative stress-mediated atherosclerosis: mechanisms and therapies. This article examines the current state of redox-based therapy in atherosclerosis.
Pryor, W. Human alphaproteinase inhibitor is inactivated by exposure to sidestream cigarette smoke. Montuschi, P. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers.
Care Med. Rahman, I. Article PubMed Google Scholar. Igishi, T. Elevated urinary 8-hydroxydeoxyguanosine, a biomarker of oxidative stress, and lack of association with antioxidant vitamins in chronic obstructive pulmonary disease. Respirology 8 , — Psathakis, K.
Exhaled markers of oxidative stress in idiopathic pulmonary fibrosis. Lenz, A. Oxidized BAL fluid proteins in patients with interstitial lung diseases. Tsubouchi, K. Involvement of GPx4-regulated lipid peroxidation in idiopathic pulmonary fibrosis pathogenesis.
Malli, F. Food Chem. Cantin, A. Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Ble-Castillo, J. Effect of alpha-tocopherol on the metabolic control and oxidative stress in female type 2 diabetics.
Schuliga, M. Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts. Cell Mol. Liu, R. Transforming growth factor beta suppresses glutamate-cysteine ligase gene expression and induces oxidative stress in a lung fibrosis model.
Kliment, C. Oxidative stress, extracellular matrix targets, and idiopathic pulmonary fibrosis. Phan, T. Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis.
Life Sci. Montezano, A. Reactive oxygen species, vascular Noxs, and hypertension: focus on translational and clinical research.
Redox Signal. This article examines the role of NOXs in disease. Lacy, F. Plasma hydrogen peroxide production in human essential hypertension: role of heredity, gender, and ethnicity. Hypertension 36 , — Redon, J. Antioxidant activities and oxidative stress byproducts in human hypertension. Hypertension 41 , — Rodrigo, R.
Cell Biochem. Touyz, R. Oxidative stress: a unifying paradigm in hypertension. Oguntibeju, O. Type 2 diabetes mellitus, oxidative stress and inflammation: examining the links.
CAS PubMed PubMed Central Google Scholar. Girona, J. Oxidized to non-oxidized lipoprotein ratios are associated with arteriosclerosis and the metabolic syndrome in diabetic patients. Al-Aubaidy, H. Oxidative DNA damage and obesity in type 2 diabetes mellitus.
Gopaul, N. Plasma 8-epi-PGF2 alpha levels are elevated in individuals with non-insulin dependent diabetes mellitus. FEBS Lett.
Pandey, K. Protein oxidation biomarkers in plasma of type 2 diabetic patients. Niwa, T. Davi, G. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation 99 , — Nishikawa, T.
Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications. Gray, S. NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis. Circulation , — Butterfield, D. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease.
This article examines the role of oxidative stress in Alzheimer disease. Montine, T. Increased CSF F2-isoprostane concentration in probable AD. Neurology 52 , — Pratico, D. FASEB J. Lovell, M. Aging 22 , — Aging 18 , — Perluigi, M.
Ansari, M. Oxidative stress in the progression of Alzheimer disease in the frontal cortex. Wang, J. Simpson, D. ROS generation in microglia: understanding oxidative stress and inflammation in neurodegenerative disease. Article CAS PubMed Central Google Scholar. Smith, M.
Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. USA 94 , — Swerdlow, R. Neurology 49 , — Hayes, J. Oxidative stress in cancer.
Cancer Cell 38 , — Conklin, K. Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Cancer Ther. Raimondi, V. Oncogenic pathways and the electron transport chain: a dangeROS liaison. Cancer , — Graham, K. NADPH oxidase 4 is an oncoprotein localized to mitochondria.
Cancer Biol. Jiang, W. Aberrant expression of 5-lipoxygenase-activating protein 5-LOXAP has prognostic and survival significance in patients with breast cancer.
Prostaglandins Leukot. Acids 74 , — Chan, H. Elevated levels of oxidative stress markers in exhaled breath condensate. Matsui, A. Cancer Lett. Ohtake, S. Oxidative stress marker 8-hydroxyguanosine is more highly expressed in prostate cancer than in benign prostatic hyperplasia.
An, A. Association between expression of 8-OHdG and cigarette smoking in non-small cell lung cancer. Chakraborty, R.
Systemic Inflammatory Response Syndrome StatPearls Ware, L. Shock 36 , 12—17 Alonso de Vega, J. Oxidative stress in critically ill patients with systemic inflammatory response syndrome.
Bahar, I. Increased DNA damage and increased apoptosis and necrosis in patients with severe sepsis and septic shock. Care 43 , — Carpenter, C.
Exhaled breath condensate isoprostanes are elevated in patients with acute lung injury or ARDS. Chest , — Sittipunt, C. Nitric oxide and nitrotyrosine in the lungs of patients with acute respiratory distress syndrome. They are crucial for certain bodily functions, such as fighting off pathogens.
Research also suggests that free radicals may be beneficial in the process of wound healing. However, because free radicals have an uneven number of electrons, they are more reactive.
Exposure to an excessive amount of free radicals causes oxidative stress in your body. This can happen because of:. Oxidative stress may lead to adverse health effects such as:.
Your body naturally produces some free radicals in response to exercise or certain food or drink. For example, drinking alcohol can cause an increase in free radicals. Cumulative exposure to free radicals from these sources can lead to oxidative stress and cause cell and tissue damage.
Lifestyle factors that can increase oxidative stress, such as sun exposure and smoking, may also cause skin damage. Since antioxidants fight free radicals, some experts consider an antioxidant-rich diet helpful in defending against oxidative stress.
Studies are mixed on whether supplementing with antioxidants is an effective way to fight oxidative stress. C60 is an example of a supplement that may provide antioxidant benefits. That said, more research on the potential benefits and risks of taking supplements is needed.
Talk with your doctor to find out if supplements are right for you. Though your body needs some free radicals to function, exposure to high levels through your environment and lifestyle choices can lead to oxidative stress, potentially causing damage and disease.
Ways to help defend your body against oxidative stress include exercising, sleeping enough, reducing stress, limiting alcohol consumption, quitting smoking, and eating a healthy diet high in antioxidant-rich foods. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available.
Brain fog is a symptom of another medical condition. Chronic inflammation refers to a response by your immune system that sticks around long after infection or injury. Learn the common symptoms and….
Inflammation is one way your body fights infection, injury, and disease. Sometimes inflammation can become a painful problem. Your doctor can perform…. What is oxidative stress, and why does it matter? We explain how this imbalance affects your body and ways to prevent it. A Quiz for Teens Are You a Workaholic?
How Well Do You Sleep? Health Conditions Discover Plan Connect. Oxidative Stress: Your FAQs Answered. Medically reviewed by Adam Bernstein, MD, ScD — By Lizzy Sherman — Updated on July 24,
An srress between antioxidant defenses Oxidatuve free radicals in your body Oxidative stress relief oxidative Oxidative stress relief. Oxidatlve can lead to disease or inflammation, but an antioxidant-rich Natural isotonic drinks can Oxidative stress relief prevent oxidative stress. It can be hard to keep up with the latest updates in our ever-evolving, health-conscious world. Having a better understanding of oxidative stress and how it impacts your body can help you make informed lifestyle choices. Free radicals are oxygen-containing molecules with unpaired electrons. They are crucial for certain bodily functions, such as fighting off pathogens.
die sehr gute Mitteilung
Auffallend! Erstaunlich!
Die gute Sache!