Accurate Education – Antioxidants & Oxidative Stress

Antioxidants and Oxidative Stress

 

See also:

Mitochondrial Dysfunction

NRF2 Activators

Nicotinamde Riboside (Niacel)

Vitamins

 

Individual antioxidants:

Alpha-Lipoic Acid

CoQ10

Curcumin (Meriva)

Green Tea

Milk Thistle (Silphos)

Palmitoylethanolamide (PEA)

PolyResveratrol

Quercetin

Vitamin C

 

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“A lot of people say they want to get out of pain, and I’m sure that’s true, but they aren’t willing to make healing a high priority.”
– Lindsay Wagner

Antioxidants & Oxidative Stress

Definitions

Reactive oxygen species (ROS)

Reactive oxygen species (ROS) is a generic term used for a variety of molecules derived from oxygen that react with most biomolecules by oxidizing them, a destructive process. ROS include free radicals such as hydroxyl radical (OH.), superoxide anion radical (O2.-) and nitric oxide (NO.) as well as non-radicalic molecules such as hydrogen peroxide (H2O2), hypochlorous acid (HOCl) and peroxynitrite (ONOO-).  ROS are widely believed to cause or aggravate many human pathologies such as neurodegenerative diseases, diabetes, high blood pressure, heart disease, cancer, stroke and many other ailments.

 

Free radicals

Free radicals are atoms or molecules with one or more unpaired electrons that are capable of independent existence (reason of term “free”). The unpaired electrons make free radicals extremely reactive towards other molecules including DNA, RNA, protein and other cellular components. Free radicals are not always “bad”: they are also involved in important physiological processes. For example, nitric oxide (NO) is protective in vasculature and is an important neurotransmitter in the nervous system and oxygen free radicals are vital to the immune system.

 

Oxidation

Oxidation is a chemical process that involves gain of oxygen or loss of electrons. Oxidation of biomolecules causes them to become damaged and then degraded by physiological processes or malfunction. An analogy is rust: oxygen, in the presents of water, oxidizes iron in steel causing it to rust, the product of oxidation.

 

Oxidative Stress

Since we are in constant contact with oxygen, ROS are continuously produced in our body, but they are always kept under control and their effect is counteracted by physiological antioxidant defense mechanisms that intercept the ROS, or repair the damage that has already occurred by them. Under normal conditions, the potentially harmful effect of the ROS is successfully restrained by the body’s defense mechanisms, including the manufacturing of antioxidants. However, the balance between ROS production and antioxidant protective mechanisms may be disturbed in favor of the ROS creating a situation called “oxidative stress.

 

Oxidative stress is now widely believed to be involved in the cause of major age-related diseases such as neurodegenerative diseases, cancer and a long list of other human diseases such as stroke, hypertension, diabetes, rheumatic diseases and multiple sclerosis.

 

Furthermore, oxidative stress is now determined to be highly associated with most major psychiatric disorders including anxiety and depression. The brain is especially susceptible to oxidative stress because it is metabolically active, possesses high levels of pro-oxidant iron, and is composed of unsaturated lipids (prone to lipid peroxidation). Furthermore, the blood–brain barrier prevents many exogenous anti-oxidants from quenching reactive oxygen species (ROS) in the brain.

  

Antioxidant

An antioxidant has been defined as “any substance that delays, prevents or removes oxidative damage to a target molecule.” Antioxidants are believed to counteract the harmful effects of ROS and therefore prevent or treat these oxidative stress-related diseases.

 

Antioxidants can be divided into “endogenous” molecules that are naturally synthesized in the human body or “exogenous” compounds that are mostly produced in plants (fruits and vegetables) and ingested as part of the diet. Large research studies have shown that higher intake of antioxidants in the diet is associated with lower risks of coronary heart disease, certain cancers and neurodegenerative diseases. Hence current recommendations for the Mediterranean Diet and the Paleo Diet. Nutrients in the diet that are important in balancing oxidative stress include not only dietary antioxidants such as Vitamin C & Vitamins E but also minerals important in the manufacture and function of endogenous antioxidants including zinc, copper, manganese, selenium and iron.

 

There has been much enthusiasm in the field of free radicals. Antioxidants have been advocated for therapy of a vast range of serious diseases in the 1980s and 1990s, however, in the light of recent research findings, many doubts have now been raised about the usefulness of taking antioxidant supplements. This has given rise to a pessimistic view of antioxidant therapy. However, the evidence from human research studies about the beneficial effects of dietary antioxidants is still compelling.

 

Managing Oxidative Stress

Elderly people are more susceptible to oxidative stress due to a reduction in the efficiency of their endogenous antioxidant systems. Organs such as heart and brain, with limited replication rate and high levels of oxygen consumption, are particularly vulnerable to this oxidative stress, explaining the high prevalence of neurological and cardiovascular diseases in the elderly.

 

A great deal of research has reported an inverse correlation between serum or plasma total antioxidant capacity and both the onset and progression of several diseases, primarily cardiovascular diseases,  diabetes,  respiratory and neurological disorders.

 

Consequently, theories of aging emerged including the Free Radical Theory of Aging (FRTA) and the more generalized Oxidative Stress Theory of Aging (OSTA) based on the assumption that lowering levels of ROS in the body might retard aging, increase life span and be effective in preventing and treating aging-associated diseases. Antioxidant supplementation, promoted as a promising therapy and met with general acceptance, is directed at counterbalancing oxidative stress.

 

However, the clinical response to antioxidants-based therapies has been mixed, in part due to the complexity of the interplay between endogenous and exogenous antioxidants within the overall cellular redox system.

 

Many natural antioxidant compounds have been studied for supplementation therapies, either singularly or in combination, with particular attention to Vitamin C, Vitamin E, resveratrol, curcumin, hydroxytyrosol and coenzyme Q10 (CoQ10).

 

Vitamin C

Vitamin C (ascorbic acid) plays different important roles in the cell; as a reducing agent and an antioxidant, Vitamin C reacts and inactivates ROS and regenerates α-tocopherol (Vitamin E). Supplementation with Vitamin C counteracts endothelial dysfunction,  one of the major contributors to the development and progression of cardiovascular diseases. It also inhibits LDL oxidation, offering a protective effect against elevated cholesterol levels. Higher plasma levels of Vitamin C are associated with lower cardiovascular risk factors.

See: Vitamin C

 

 

Vitamin E (α-tocopherol)

Vitamin E (α-tocopherol) has anti-inflammatory and antioxidative properties as well as other properties such as the modulation of the expression of genes involved in signaling and it is also involved in the metabolism of cholesterol.

 

However,  human and animal studies of the effectiveness of Vitamin E supplementation in aging-associated diseases, oxidative stress and inflammation have had mixed results, including beneficial and harmful effects.

See: Vitamin E

 

Coenzyme Q10 (CoQ10)

Coenzyme Q10 (CoQ10), referred to as ubiquinol in its most active (95%) and reduced form (Q10H2), is an essential lipophilic molecule present in the membranes of almost all human tissues, particularly the mitochondria (the energy producing “powerplants” of all cells).  It functions to transfer electrons in the respiratory chain, ultimately resulting in the reduction of oxygen to water and the generation of ATP, the energy source for metabolism. CoQ10 also recycles and regenerates other antioxidants such as Vitamin C and Vitamin E.

 

CoQ10 also modulates gene expression and protects DNA, proteins and lipoproteins such as very low density (VLDL), low density (LDL) and high density (HDL) lipoproteins from oxidation. CoQ has a number of independent anti-inflammatory effects including reducing the secretion of pro-inflammatory cytokines in inflammatory cells after an inflammatory stimulus.

 

CoQ10 levels may be pathologically reduced in conditions associated with oxidative stress, aging and in those treated with statins (Lipitor/lovastatin, etc) for high cholesterol since statins can lower CoQ10 synthesis as they inhibit HMG-CoA reductase, the rate-limiting enzyme in the pathway of cholesterol synthesis, includes the formation of the CoQ10. CoQ10 supplementation at 300 mg/day is reported to significantly enhance antioxidant enzymes activities and lower inflammation in patients who have coronary heart disease during therapy with statins. Moreover, dietary supplementation with CoQ10 has been reported to improve patients with diabetes  and to decrease hepatic inflammatory stress.

 

Research on the effect of CoQ10 in diseases depending on oxidative stress in elderly people are limited still and no generalized conclusions can be drawn on the benefits or harms of CoQ10 supplementation.

See: CoQ10Mitochondrial Dysfunction

 

Curcumin

Curcumin is a phenol derived from the rhizome of Curcuma longa, which is lipophilic and shows low solubility in water, potentially limiting its absorption from the digestive tract. It is commonly used in Indian foods such as curry as a flavoring and coloring agent. Orally ingested curcumin is metabolized into the active metabolite tetrahydrocurcumin by a reductase found in the intestinal epithelium. Extensive research during the last few decades has identified a strong therapeutic and pharmacological potential for curcumin as antioxidant, antimutagenic, antiprotozoal and antibacterial agent.

 

 Curcumin improves arterial endothelial function and research suggests that regular ingestion of curcumin could improve endothelial function and might be a potential alternative treatment for patients who are unable to exercise. Another study suggests that regular ingestion of curcumin significantly increased carotid arterial compliance possibly reducing the risk of stroke.

See: Curcumin (Meriva)

  

Olive Oil

Hydroxytyrosol is an ortho-diphenol (a catechol) abundant in olive, fruits and extra virgin olive oil. Hydroxytyrosol has significant antioxidant activity and inhibits LDL oxidation, platelet aggregation and it protects DNA from oxidation. It is thought to be a major contributor to the benefits associated with diets high in olive oil.

 

Research evaluating the effects of daily consumption of extra virgin olive oil found a significant improvement in lipid profiles, including a reduction of total cholesterol and LDL and a significant increase in HDL levels. Moreover, an increase in serum total antioxidant capacity was identified.

See: Diet & Pain

 

Resveratrol (3, 4′, 5-trihydroxystilbene)

Resveratrol belongs to the stilbene class of compounds, abundant in many plants, such as peanuts, blueberries, pine nuts and grapes where it mainly accumulates in a glycosylated form. Resveratrol appears to modulate numerous cell-signaling pathways through the regulation of different molecular targets including the AMP-regulated kinase AMPK and the NAD-dependent deacetylase Sirt-1. The molecular mechanisms triggered by resveratrol results in antioxidant and anti-inflammatory effects. Resveratrol is a good antioxidant and, like Vitamin C, blocks oxidation of LDL, lowering the risk of coronary heart disease and myocardial infarction and improves vascular function.

 

The anti-inflammatory properties of resveratrol include the suppression of NF-κB activity induced by beta- amyloid and the reduction of the production of IL-1 beta and TNF-alpha induced by LPS or beta-amyloid in the microglia, suggesting a neuroprotective effect against neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases.

See: Resveratrol

 

Influences on the Outcomes of Antioxidant Supplementation

As noted above, clinical trials involving the use of antioxidants supplementation often show conflicting results on the use of these antioxidants in the treatment of aging-associated diseases. What should be re-considered is the FRTA, the basic theory on which the antioxidants supplementation therapies are based. This theory suggests a linear dose-response relationship between increasing amounts of ROS and biological damages, which results in diseases and mortality. Therefore, oxidative stress is the main driving force of aging and a major determinant of lifespan.
 
 

Hormesis

Hormesis is any process in a cell or organism that exhibits a biphasic response to exposure to increasing amounts of a substance or condition. In other words, a low level stimulation may result in one effect but a high level stimulation results in the opposite effect. This concept may apply to the effects of oxidative stress.
 
 
Fasting and Caloric Restriction
A recent modification of this theory also takes into account “mitohormesis,” in which a large amount of ROS causes detrimental effects on the cells, whereas low or moderate levels of ROS may exert an opposite effect improving biological outcomes. Thus, the response to antioxidants may depend on other variables in the metabolic status of an individual. An example of this is the beneficial effects of fasting and caloric restriction  that can be considered both as oxidative stressors and inducers of the endogenous mitochondrial antioxidant system.  Fasting and caloric restriction promote an initial adaptive stimulation of mitochondrial activity resulting in the triggering of increased production of antioxidant enzymes as well as ROS within the mitochondria.
 
Fasting and caloric restriction induce this adaptive hormetic response through different molecular pathways, one of these involving sirtuins, a family of enzymes that play a crucial role in inducing formation of new mitochondria and mediating oxidative stress response through a number of proteins that promote the expression of antioxidant genes, such as peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 alpha 5 (PGC-1 α ).
 
 
Exercise
Physical inactivity is one of the major risk factors for diabetes, CVD, neurodegenerative disorders such as Alzheimers and many other diseases. The benefits of regular physical exercise in reducing risk of aging-related diseases including diabetes and cardiovascular disease (CVD) are well known. The increased ROS production following exercise acts as a stimulus to activate mitochondria and mediate potential health-benefits. Exercise induces an increase in the sirtuin SIRT1 which up-regulates the oxidative stress response. This up-regulation results in enhanced oxygen consumption in muscle fibers, which, in turn, promotes ROS generation. Moreover, beyond skeletal muscle, other tissues, such as blood, heart and lung, represent a source of ROS during exercise. In addition to enhanced ROS production, regular exercise leads to the up-regulation of several antioxidant enzymes, including SODs, catalase and glutathione peroxidase, reinforcing the concept that a certain amount of ROS may be necessary for exercise health-promoting effects.
 

Athletes

Due to the benefits for mitochondrial activity associated with exercise, in circumstances associated with extreme exercise such as athletic performance, supplementing with antioxidants such as Vitamin C and E may prove to prevent exercise benefits and possibly harm performance. In these more extreme circumstances, antioxidants appear to block some of the benefits of exercise. Therefore, supplementation of antioxidants should not be recommended to healthy athletes due to evidence that antioxidants have counter-productive effects on performance, health, and the onset of diseases.

 
 
It may not be surprising, then, that studies show mixed or inadequate benefits from supplementing with antioxidants, including prevention of certain diseases. A  transient increase of oxidative stress may contribute to health benefits and antioxidant supplementation may compromise these results. Other variables that may affect outcome from the use of antioxidants are genetic and epigenetic variants.
  

Genetics & Epigenetics

In addition to hormesis, another aspect to be considered regarding the conflicting results of antioxidant supplementation research is the variable genetic background of the patients enrolled in the studies. Research has established that a person’s susceptibility to diseases of aging depends not only on a person’s life style habits but also on their genetic background. Oxidative stress response is one of the most evolutionary conserved pathways involved in determination of lifespan from yeast to humans.
 
 
Genome wide association studies (GWAS) have identified genetic determinants associated with the levels of circulating antioxidants, which could be linked to human diseases. Genetic polymorphisms (variants) involving Vitamin E transport and metabolism are associated with response to vitamin E supplementation which in turn might determine the level of supplementation required to impact complex diseases such as CVD and diabetes. Previous studies may have failed to identify the benefit of vitamin E supplementation because of the inadequate selection of patient genotype. Recent studies have confirmed the impact of genotyping in determining potential benefits from antioxidant therapy and suggest the need for a pharmacogenomic strategy to personalize and fine-tune the treatment with vitamin E in patients with type 2 diabetes.
  
Epigenetics, the study of how genes are turned on or off, may also play a future role in determining the potential impact of antioxidant supplementation for specific antioxidants and disease processes. One problem is a lack of validated biomarkers to monitor the effects of antioxidants on human health. Clearly research is only just beginning to unravel clues to improve the management of oxidative stress with the hope of better reducing the risk of disease and the ravages of aging as well as human health optimization.
 
 
 

References

 

Antioxidants

  1. Antioxidant therapy- current status and future prospects – 2016
  2. CoQ10
  3. Glutathione
  4. Antioxidant Capacity of Selected Foods – 2007
  5. Antioxidant Supplementation in the Treatment of Aging-Associated Diseases – 2016

 

Oxidative Stress – Overviews

  1. oxidative-stress-implications-in-the-affective-disorders-main-biomarkers-animal-models-relevance-genetic-perspectives-and-antioxidant-approaches-2016
  2. oxidative-stress-in-health-and-disease-the-therapeutic-potential-of-nrf2-activation-2011
  3. adaptive-cellular-stress-pathways-as-therapeutic-targets-of-dietary-phytochemicals-focus-on-the-nervous-system-2014
  4. oxidative-stress-a-cause-and-therapeutic-target-of-diabetic-complications-2010
  5. a-randomized-trial-of-glutamine-and-antioxidants-in-critically-ill-patients-2013
  6. Inflammation, Oxidative Stress, and Antioxidants Contribute to Selected Sleep Quality and Cardiometabolic Health Relationships – 2015
  7. Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS) – 2014

 

Oxidative Stress – Anxiety and Depression

  1. Markers of Oxidative Stress and Neuroprogression in Depression Disorder – 2015
  2. Neuroinflammation and Depression – Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation – 2015
  3. Novel Therapeutic Targets in Depression and Anxiety – Antioxidants as a Candidate Treatment
  4. Oxidative:nitrosative stress and antidepressants: targets for novel antidepressants. – PubMed – NCBI

 

Oxidative Stress – Fibromyalgia

  1. Oxidative Stress Correlates with Headache Symptoms in Fibromyalgia – Coenzyme Q10 Effect on Clinical Improvement 2012
  2. Free radicals and antioxidants in primary fibromyalgia: an oxidative stress disorder? – PubMed – NCBI
  3. Current concepts in the pathophysiology of fibromyalgia: the potential role of oxidative stress and nitric oxide. – PubMed – NCBI
  4. Oxidative Stress in Fibromyalgia – Pathophysiology and Clinical Implications – 2011
  5. Oxidative Stress in Fibromyalgia and its Relationship to Symptoms – 2009
  6. Clinical Symptoms in Fibromyalgia Are Better Associated to Lipid Peroxidation Levels in Blood Mononuclear Cells Rather than in Plasma
  7. Evidence of central inflammation in fibromyalgia — Increased cerebrospinal fluid interleukin-8 levels 2012
  8. Oxidative Stress in Fibromyalgia – Pathophysiology and Clinical Implications – 2011
  9. Vitamins C and E treatment combined with exercise modulates oxidative stress markers in blood of patients with fibromyalgia: a controlled clinical … – PubMed – NCBI
  10. Total antioxidant capacity and the severity of the pain in patients with fibromyalgia. – PubMed – NCBI
  11. Stress, the stress response system, and fibromyalgia
  12. Serum prolidase enzyme activity and oxidative status in patients with fibromyalgia. – PubMed – NCBI
  13. Serum ischemia-modified albumin and malondialdehyde levels and superoxide dismutase activity in patients with fibromyalgia. – 2014 – PubMed – NCBI
  14. Pathophysiology and antioxidant status of patients with fibromyalgia. 2011 – PubMed – NCBI
  15. Metformin and caloric restriction induce an AMPK-dependent restoration of mitochondrial dysfunction in fibroblasts from Fibromyalgia patients. 2015 – PubMed – NCBI
  16. Fibromyalgia and chronic fatigue: the underlying biology and related theoretical issues. – PubMed – NCBI
  17. Antioxidant status, lipid peroxidation and nitric oxide in fibromyalgia: etiologic and therapeutic concerns. 2006 – PubMed – NCBI

 

Oxidative Stress – Fibromyalgia & Mitochondria

  1. Serum antioxidants and nitric oxide levels in fibromyalgia: a controlled study. 2009 – PubMed – NCBI
  2. Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients – implications in the pathogenesis of the disease
  3. Could mitochondrial dysfunction be a differentiating marker between chronic fatigue syndrome and fibromyalgia? – PubMed – NCBI
  4. Is Inflammation a Mitochondrial Dysfunction-Dependent Event in Fibromyalgia? – 2012
  5. The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia – 2013 – PubMed – NCBI
  6. Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS) – 2014

Oxidative Stress – Mitochondria

  1. Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS) – 2014
  2. The Mitochondrial Basis of Aging and Age-Related Disorders – 2017
  3. Mitochondrion-Permeable Antioxidants to Treat ROS-Burst-Mediated Acute Diseases – 2016 no highlights
  4. Current Experience in Testing Mitochondrial Nutrients in Disorders Featuring Oxidative Stress and Mitochondrial Dysfunction
  5. Mitochondrial biogenesis: pharmacological approaches. – PubMed – NCBI
  6. The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochondrial cytopathies. – PubMed – NCBI
  7. Oxidative Stress and Mitochondrial Dysfunction across Broad-Ranging Pathologies – Toward Mitochondria-Targeted Clinical Strategies
  8. Daily Nutritional Dose Supplementation with Antioxidant Nutrients and Phytochemicals Improves DNA and LDL Stability

  

Oxidative Stress – Pain

  1. Roles of Reactive Oxygen and Nitrogen Species in Pain – 2011

 

Oxidative Stress – Peripheral Neuropathy

  1. Oxidative stress – A cause and therapeutic target of diabetic complications – 2010

 

 

 Oxidative Stress – Treatment (Tx)

 

Oxidative Stress Tx – Overviews

  1. Inflammaging and Skeletal Muscle – Can Protein Intake Make a Difference? – 2016

 

Oxidative Stress Tx – Melatonin

  1. Melatonin leads to axonal regeneration, reduction in oxidative stress, and improved functional recovery following sciatic nerve injury. – PubMed – NCBI
  2. Evaluating the Oxidative Stress in Inflammation – Role of Melatonin -2015

 

 

Oxidative Stress Tx – NRF2 Activators

See: NRF2 Activators 

NRF2 Activators – Commercial Products

  1.    Curcumin (Meriva)
  2.    Green Tea Phytosome
  3.    Meriva (Curcumin)
  4.    Milk Thistle (Siliphos – Silybin Phytosome)
  5.    PolyResveratrol SR
  6.    Quercetin
  7.    Siliphos (Silybin Phytosome)

 

Nanoformulations

Nanoformulations –  Overview

  1. Blood–brain barrier – a real obstacle for therapeutics – 2012
  2. Natural product-based nanomedicine – recent advances and issues – 2015
  3. Particle size reduction to the nanometer range – a promising approach to improve buccal absorption of poorly water-soluble drugs – 2011

 

Nanoformulations – Phytosomes

  1. A Review on Phytosome Technology as a Novel Approach to Improve The Bioavailability of Nutraceuticals – 2012
  2. Bioavailability and activity of phytosome complexes from botanical polyphenols – the silymarin, curcumin, green tea, and grape seed extracts – 2009
  3. Phytosomes – A New Herbal Drug Delivery System – 2012
  4. Phytosome – A Novel Revolution in Herbal Drugs – 2012
  5. Phytosome – Phytolipid Drug Delivery System for Improving Bioavailability of Herbal Drugs – 2013

 

 

 

Emphasis on Education

 

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

 

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Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.

 

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