“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

Inflammation

Antioxidants and Oxidative Stress

“Oxidative stress” is an imbalance in the body of excessive “oxidants” (oxidizing or chemically active, agents, including free radicals obtained from the diet or produced by the body) and insufficient “anti-oxidants” (chemically active agents that are also obtained from the diet or produced by the body) and neutralize oxidants. Oxidative stress contributes to chronic inflammation and many chronic diseases.

 

See:

 

Individual antioxidants:

 

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Definitions and Terms Related to Pain

 

 

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 molecules with one or more unpaired electrons that are capable of independent existence (reason for term “free”). The unpaired electrons make free radicals extremely reactive towards biomolecules including DNA, RNA, protein and other cellular and tissue components. Free radicals are not always “bad”: they are produced in the body (endogenous free radicals) and have beneficial roles in important physiological processes. For example, nitric oxide (NO) is protective in vasculature and is an important neurotransmitter in the nervous system while oxygen free radicals are vital in the immune system to fend off infections. The human body produces free radicals and other reactive species as byproducts of numerous physiological, metabolic and biochemical processes. In addition to reactive oxygen species (ROS), there are also reactive nitrogen species (RNS). The most common cellular free radicals are hydroxyl (OH·), superoxide (O –·) and nitric monoxide (NO·). Other molecules like hydrogen peroxide (H2O2) and peroxynitrite (ONOO–) generate free radicals through various biochemical reactions.

Excessive levels of free radicals however can lead to tissue damage.  People are constantly exposed to free radicals in their environment (exogenous free radicals) like those created by electromagnetic radiation and those associated with foods, pollutants, cigarette smoke and natural sources such as radon and cosmic radiation.

 

Oxidation

Oxidation is a chemical process that involves a gain of oxygen or loss of electrons. “Oxidants” are oxidizing or chemically active agents such as free radicals that trigger oxidation. 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 become impaired in a situation called “oxidative stress.”

 

“Oxidative stress“ is an imbalance in the body of excessive “oxidants” (oxidizing or chemically active, agents, including free radicals obtained from the diet or produced by the body) and insufficient “antioxidants” (chemically active agents that are also obtained from the diet or produced by the body) and neutralize oxidants. This overabundance of oxidants causes damage to biomolecules, (lipids, proteins, DNA), cells and tissue, eventually contributing to aging and many chronic diseases including chronic inflammation, arthritis and pain, atherosclerosis, cancer, diabetes, heart diseases and stroke.

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 RNS 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. Endogenous antioxidants are produced in the mitochondria within cells throughout the body and serve to detoxify free radicals and protect tissues from such damage.

 

Fruits and vegetables are especially rich in exogenous antioxidants including vitamin E, vitamin C, vitamin A, curcumin, resveratrol, glutathione, arginine, citrulline, taurine, creatine, selenium, zinc, and polyphenols found in tea. .Diets rich in fruits and vegetables result in high blood antioxidant capacity and reduced oxidative stress. Antioxidant activity is further supported by antioxidant enzymes, e.g. superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase that exert synergistic actions in removing free radicals. Minerals are also important in the manufacture and function of endogenous antioxidants, including zinc, copper, manganese, selenium and iron.

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 that emphasize intake of fruits and vegetables.

 

Assessing for 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.

 

Testing for Oxidative Stress

Direct testing using blood-based biomarkers to assess the level of a person’s individual oxidative stress remain lacking, aside from possible research tools not generally available to the medical practitioner. Perhaps the best available alternatives are to measure hemoglobin A1c (HbA1c) levels which reflect prolonged elevated blood sugars and C-reactive protein (CRP) levels which is a marker of inflammation.

HbA1c

While not a direct measurement of oxidative stress, the HbA1c level is an indirect measure since increased oxidative stress is associated with prolonged elevated blood sugars which generate increased reactive oxygen species (ROS) leading to oxidative damage. While HbA1c is a good indicator of average blood glucose control, it doesn’t directly measure oxidative stress and may not fully capture short-term fluctuations in blood sugar which can also contribute to oxidative damage.

 

C-Reactive Protein (CRP)

Research indicates a strong positive association between oxidative stress levels and C-reactive protein (CRP) levels, meaning that increased oxidative stress is often linked to higher CRP levels. Oxidative stress damages cells and tissues, triggering the release of inflammatory signals that stimulate CRP production, leading to elevated CRP production.

High CRP levels are associated with an increased risk of cardiovascular diseases, and studies have shown that individuals with elevated oxidative stress tend to have higher CRP levels as well.

 

Advanced glycation end products (AGEs)

Advanced glycation end products (AGEs) are formed when sugar molecules attach to hemoglobin and they can be a marker of oxidative damage. AGEs are formed on proteins under influence of high blood sugars and oxidative stress. Testing for levels of AGEs at this time is limited to research and has not yet been proven to have clinical applications.

 

Tumor Necrosis Factor-alpha (TNF-α))

Tumor Necrosis Factor-alpha (TNF-α) is a chemical messenger (cytokine), originally named for its antitumor properties, that plays a key role in the body’s inflammatory response. It is produced by activated immune cells and is a major regulator of inflammation and is involved in many processes, including immunity and cell survival. 

TNF is considered a biomarker for oxidative stress because elevated levels of this inflammatory cytokine are strongly linked to increased production of reactive oxygen species (ROS). TNF-α triggers various cellular pathways that lead to increased ROS generation, including activating enzymes like NADPH oxidase, which produces superoxide radicals and directly contributes to oxidative stress. So essentially, high TNF-α levels can indicate an imbalance towards oxidative stress due to its pro-inflammatory effects.

TNF-α plays a role in the pathogenesis of inflammatory and autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. TNF inhibitors, drugs that block the action of TNF-α, have been effective therapies for rheumatoid arthritis and inflammatory bowel disease. 

Blood test to check TNF-α levels are available and higher-than-normal levels can indicate inflammation, infection, or a chronic inflammatory disease, but the results are non-specific.  Measuring TNF-alpha levels can sometimes be useful in assessing the presence of oxidative stress in conditions like cardiovascular disease, inflammatory diseases, and cancer, where high TNF-alpha levels are often observed. At this time however, measuring TNF-α levels are not routinely obtained. 

 

Managing Oxidative Stress

Managing oxidative stress requires a multi-modal lifestyle approach that includes exercise and reduction of stress including mindful exercises such as yoga and meditation or simply practicing stress-reducing activities like fishing and playing with pets. These lifestyle elements can be further investigated here: Meditation & Mindful Exercise

 

Diet to Reduce Oxidative Stress.

It is important to engage a healthy diet to reduce oxidative stress. Currently the most healthful diet is described as an anti-inflammatory diet (AID), one with many bioactive compounds that reduce systemic inflammation which in turn reduces oxidative stress. Bioactive food compounds are mainly found naturally in plant products. These include unsaturated fatty acids, probiotics, dietary fiber, vitamins, polyphenols, and certain trace elements. These anti-inflammatory compounds suppress the activity of the pro-inflammatory compounds (cytokines) produced by the fat cells (adipocytes) and immune cells (M2 macrophages) found in fat tissue, especially visceral fat.The AID can be investigated further here: The Anti-inflammatory Diet.

 

Dietary Antioxidant Supplementation

Finally, the use of  supplements is commonly advocated to suppress systemic oxidation, improve health and reduce the risk of developing cardiovascular disease, type 2 diabetes and certain forms of cancer. The role of supplementing with antioxidants has been the focus of many studies to assess their benefits. 

Theories of aging include the Free Radical Theory of Aging (FRTA) and the more generalized Oxidative Stress Theory of Aging (OSTA) which is 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. Based on these theories, antioxidant supplementation directed at counterbalancing oxidative stress is promoted as a promising therapy and has met with general acceptance in the medical community.

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. Consequently, doubts have been raised about the usefulness of taking antioxidant supplements. Despite this, however, the evidence from human research studies about the beneficial effects of dietary antioxidants is still compelling, leading to the question of which antioxidant supplements may be the most useful.

Selecting a Dietary supplement

Due to the complex interplay between inflammation and oxidative stress, many recommended dietary supplements act as an antioxidant and/or an anti-inflammatory. Because of this, it is preferable to identify a compound as one that acts as an antioxidant or anti-inflammatory or that has antioxidant or anti-inflammatory properties rather than label them as an “antioxidant” or an anti-inflammatory.”

The most important elements of selecting an antioxidant supplement include safety and potential for toxicity, evidence for benefit, bioavailability and accessibility which is largely dependent on costs.

Safety and Potential for Toxicity of Supplements

Supplements listed here are generally considered safe as long as taken as directed. Please confer with your physician prior to starting dietary supplements.

Evidence for Benefit

Supplements listed here will have adequate evidence of benefit to consider their use. However, research is largely lacking at this time for most compounds due to limited research available. As such, definitive recommendations and proof of benefit is generally in need of further research.  Such research may take years and may never be forthcoming for any number of reasons.  Again, please confer with your physician prior to starting dietary supplements.

Bioavailability of Supplements

In some cases, orally ingested supplemental compounds are not able to adequately access the tissues for which they are targeted, in which their “bioavailability” is considered impaired or limited. There are many reasons for bioavailability to be compromised:

  • They may be destroyed by stomach acidity
  • They may not be absorbed through the gut wall
  • They may be rapidly broken down by the liver before gaining access to the blood
  • They may not access target tissue due to barriers, like the blood brain barrier which limits if compounds in the blood to enter the central nervous system and brain
  • They may not penetrate cell membrane tissue access the intracellular space

In these cases, products may need to be formulated to enhance absorption and delivery of the compounds to targeted tissues, especially the blood or the central nervous system. Many supplements are marketed with enhanced absorption and bioavailability features due to incorporation of delivery systems designed to enhance their bioavailability. Such delivery systems include phytosomes, liposomes and nano-formulations. The benefits of such delivery systems may be important in selecting a particular nutraceutical to purchase.

Phytosomes, Liposomes and Nano-formulations

Phytosomes and Liposomes

Phytosomes and liposomes are both designed to enhance the bioavailability of individual compounds.  They are structurally related, but they have some key differences:

    • Structure
      Liposomes are concentric vesicles with a lipid bilayer that surrounds an aqueous volume. Phytosomes are a complex of phospholipids and natural active phytochemicals that are chemically bound together.
    • Active compounds
      In liposomes, the active compounds are dissolved in the internal aqueous core or bilayer lipid membrane. In phytosomes, the active compounds are conjugated to the hydrophilic choline head of the phospholipid.
    • Stability
      Phytosomes are more stable than liposomes due to the chemical bonds between the phospholipid and active compounds.
    • Bioavailability
      Phytosomes are better absorbed than liposomes due to their higher bioactive/lipid ratio.
    • Uses
      Liposomes are primarily used in cosmetics to deliver water-soluble substances to the skin. Phytosomes are used in both dietary supplements and skin care products

Nano-formulations

The “nanosome” encapsulation system is very similar to liposomes but nanosomes possess only a single lipid monolayer and are much smaller. Drug formulations in the nanometer range have better pharmacokinetics than those in the micrometer range because smaller carriers have a greater effective surface area. This greater surface area increases the dissolution rate and bioavailability of the active agents.The liposome diameter varies from 400 nm to 2.5 μm. Nanoparticles (NPs) are smaller particles ranging in size from 1 to 100 nm.

Because of their extremely small size, NPs have unique physical and chemical properties that can be exploited for drug delivery by conjugation with drugs. They can pass through the cracks found in the basement membrane and then reach and internalize into different organs as needed.  Nanoparticles can improve the bioavailability of micronutrients, for example, vitamin B12, vitamin A, folic acid, and iron.

 

Recommended Supplements

The following is a list of supplements recommended to reduce oxidative stress, including vitamins, amino acids, fatty acids, polyphenols and other compounds. Dr. Ehlenberger’s level of confidence (LOC) in recommending a compound based on its safety profile, evidence for benefit and cost accessibility is noted as low, medium or high. Please note that the following list is not comprehensive and the information provided for each compound is presented as a brief summary. Please click on the associated active link to explore the compound in greater depth.

 

Alpha Lipoic acid (ALA)

Alpha-Lipoic Acid (ALA) is an antioxidant manufactured in the body and present in certain foods including spinach and collard greens, broccoli, brewer’s yeast, beef and organ meats. It is a supplement with good evidence for benefit of use in neuropathic pain including peripheral neuropathy, low back pain and sciatica as well as the “brain fog” cognitive impairment associated with fibromyalgia.

LOC: High

Bioavailability:

Relatively poor, but R-ALA is more bioavailable than standard formulations of ALA (racemic equal mixture of R-ALA and L-ALA). When commercially available, nano-formulations likely to be preferred choice.

Dose: 600 mg/day

    • ALA should be ingested on an empty stomach, at least 30 minutes before eating or at least 2 hours after eating
    • In order to maximize blood levels, take three 600-mg R-ALA doses (as NaR-ALA) at 15-minute intervals

Benefits:

    • The benefits of ALA appear not to be limited solely to the symptoms of diabetic neuropathy. Indeed, ALA can be considered as the only treatment that acts on the pathogenesis of the diseases, I.e. to prevent diabetic neuropathy
    • ALA is helpful in many diseases and conditions. ALA may reduce diabetic polyneuropathy (DPN), diabetic peripheral neuropathy pain, promote weight reduction in obese patients and alleviate MS symptoms,
    • ALA may also significantly decrease levels of triglycerides, total cholesterol, and low-density lipoproteins (LDLs – the “bad” cholesterol) but it will not affect levels of high-density lipoproteins (HDLs – the “good” cholesterol).
    • ALA has been shown to offer improvement in learning and memory along with anti-dementia properties
    • ALA has powerful antioxidant effects acting as a free radical scavenger but it also helps replenish other antioxidants including Vitamin C and Vitamin E, glutathione and CoQ10.

Forms:

ALA has two forms, R- and S- Lipoic Acid (R-ALA and S-ALA). Both are present equally in ALA supplements unless specified as R-Lipoic Acid, but only the natural R- form is present in foods while the S-form is synthetic and is present only in supplements.

Special Considerations:

    • Probably, for most people,the best anti-oxidant supplement to take if only adding one
    • S-ALA, the synthetic form, may interfere with important functions of R-ALA
    • Recommend R-ALA supplement (NaR-ALA) – Life Extension) over standard LA (depending on cost). When they become available, choose enhanced absorption formula (nano-based)
    • ALA liquid formulations have greater blood levels and bioavailability compared to solid ALA.
    • In rare cases in genetically predisposed individuals, ALA may trigger low blood sugar and should be discontinued

 

 TO BE UPDATED

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. Recent studies suggest that vitamin C, especially in combination with vitamin E, may be helpful in reducing risk of cognitive impairment associated with Alzheimer’s .

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. Recent studies suggest that vitamin C, especially in combination with vitamin E, may be helpful in reducing risk of cognitive impairment associated with Alzheimer’s .

See: Vitamin E

 

CoQ-10 (ubiquinol or ubiquinone)

See: CoQ10 & Mitochondrial Dysfunction

LOC: High

Coenzyme Q10 (CoQ10) is highly safe and an essential compound and an important antioxidant present in the membranes of virtually every cell in the human body, particularly the mitochondria (the energy producing “powerplants” of all cells).  It functions to generate ATP, the energy source for metabolism and is essential for energy production in cells. CoQ10 also recycles and regenerates other antioxidants such as Vitamin C and Vitamin E.

Dietary supplementation to raise CoQ10 levels has been shown to have multiple beneficial effects in many different conditions. Many cardiovascular diseases, fibromyalgia, diabetes, cancer, and muscular and  neurodegenerative disorders have been associated with low CoQ10 levels.

Bioavailability: Ubiquinol (preferred) & Ubiquinone Ubiquinol is better absorbed than ubiquinone

Forms: Ubiquinol (preferred) & Ubiquinone

Benefits:

  • Most useful in diseases associated with CoQ10 deficiency, including diabetes mellitus, mitochondrial diseases (fibromyalgia, diabetic peripheral neuropathy), and cardiovascular disease (including moderate to severe heart failure.
  • CoQ10 supplementation significantly improves some of the parameters of lipid profile including total cholesterol and HDL-cholesterol levels in those with coronary artery disease, but may not affect the other lipid profiles
  • As an antioxidant, CoQ10 protects DNA, proteins and lipoproteins such as very low density (VLDL), low density (LDL) and high density (HDL) lipoproteins from oxidation.
  • CoQ has independent anti-inflammatory benefits includingthe release of pro-inflammatory cytokines in inflammatory cells.

Dose: 100-200 mg/day up to 1,200 mg/day

  Migraines: 100-400 mg/day improves migraine frequency, duration and severity

  Fibromyalgia: 300 mg/day – may improve energy production & reduce pain by >50%

  Coronary heart disease during therapy with statins: 300 mg 

Dosing based on blood levels:

The blood level necessary for uptake of CoQ10 into specific tissues appears to be different for different tissues. For example, higher than “normal” CoQ-10 blood levels appear necessary to facilitate tissue uptake and transfer across the blood brain barrier and into the brain and spinal cord.

  •   “Normal” CoQ10 levels range from 0.34–1.65 μg/ml (0.40 to 1.91 μmol/l )
  •    Higher blood levels may be advised related to increased tissue needs
  •    Steady-state blood levels with doses of 1,200 mg/day generally range from 5 to 10 μg/ml

Special Considerations:

CoQ10 levels may be pathologically reduced in conditions associated with oxidative stress, aging and in those taking statins (Lipitor/lovastatin, etc) for high cholesterol since statins lower CoQ10 synthesis because they inhibit HMG-CoA reductase, the rate-limiting enzyme in the pathway of cholesterol synthesis, includes the formation of the CoQ10.

Increased tissue needs for CoQ-10 are associated with:

  • Illness or disease processes
  • Advancing age
  • Use of cholesterol medications (statins: atorvastatin (Lipitor), lovastatin (Mevacor), and pravastatin (Prevachol)
  • Use of tricyclic antidepressants (Elavil/amitriptyline & doxepin)
  • Use of beta blockers (propranolol (Inderal) and metoprolol (Toprol)

Curcumin

See: Curcumin

Curcumin is a phenol derived from tturmeric (Curcuma longa).  It is commonly used in Indian foods such as curry as a flavoring and coloring agent. The beneficial health effects of turmeric are associated with curcuminoids, a group of chemically related low-molecular-weight polyphenols containing around 77% curcumin. Turmeric contains more than 100 bioactive compounds.

Curcumin is well tolerated (even at dosages of up to 12 g/day with no side effects).  It is estimated that the average intake of turmeric n India is 2 gms/day, which corresponds to 200 mg of curcumin. The nutritional value of 100 gms of turmeric contains about 354 calories, 8 gms of protein, 19 gms of fats (with no cholesterol), 65 gms of carbohydrates (including 21 gms of fiber and 3 gms of sugar), and minerals such as sodium (38 mg) and potassium (about 2.5 g).

LOC: High

Benefits: Strong therapeutic and pharmacological benefits as an antioxidant with anti-inflammatory and anti-obesity properties. 

Bioavailability:

Poor oral bioavailability, even at high dosage (12 gms/day) and especially at low doses. Curcumin is only weakly absorbed in the intestines and requires enhancement for proper absorption:

    • Ingest with other compounds, such as black pepper (piperine) or lecithin to enhance its solubility, extend the half-life, and improve the pharmacokinetic profile and the cellular uptake
    • Natural oils found in turmeric root and turmeric powder can enhance the bioavailability of curcumin seven- to eight-fold. When eaten with fat, curcumin can be absorbed directly into the bloodstream through the lymphatic system, thereby in part bypassing breakdown by the liver.

    • Ingestion of 2 g of curcumin with 20 mg of piperine was shown to result in a 20-fold increase in bioavailability compared with 2 gm of pure curcumin alone. Even just a little pinch of pepper—1/20th of a teaspoon—can significantly boost curcumin levels.

    • Phytosomal or nano-formulations may increase bioavailability up to 15–20 fold

    • Nanoparticle encapsulation improves oral bioavailability of curcumin by at least 9-fold when compared to curcumin administered with piperine as an absorption enhancer

.

Dose: Based on formulation

Forms: piperine (found in black pepper),

Meriva (a combination of curcumin-phospholipids) 5-fold higher than for unbound curcumin

Special Considerations:

  • Curcumin blocks the formation of reactive-oxygen species (ROS), neutralizes free radicals, and prevents oxidative stress and DNA damage.
  •  Curcumin also possesses anti-inflammatory properties as a result of inhibition of cyclooxygenases (COX) and other enzymes involved in inflammation with comparable benefit to the NSAID diclofenac (Voltaren) in knee osteoarthritis but with less side effects

  • Should be ingested with lecithin-rich ingredients like eggs or vegetable oils, in order to increase absorption

  • Curcumin, due to its lipophilicity is able to cross the blood–brain barrier and able to reach the brain in biologically effective concentrations promoting neuroprotection.

  • Drug interactions may be comparable to other anti-inflammatory medications including Antiplatelets, anticoagulants, thrombolytic agents, NSAIDs/salicylates
  • Kidney Stones – Turmeric is high in soluble oxalates, which can bind to calcium and form insoluble calcium oxalate, which is responsible for approximately three-quarters of all kidney stones. Those with a tendency to form kidney stones should limit turmeric intake to one teaspoon per day. Curcumin supplements, however, are not likely to share this increased risk
  • May lessen transition from prediabetic state to diabetes

  • Piperine (found in black pepper) is a potent inhibitor of drug metabolism and significantly increases the oral absorption of curcumin, reduces its systemic clearance, and consequently increases its bioavailability by more than fourfold. About 5 percent of black pepper by weight is comprised of piperine, the compound that gives the spice its pungent flavor. Ways piperine increases curcumin bioavailability:

      • Piperine inhibits liver enzymes that metabolize curcumin, such as cytochrome P450 and UDP-glucoronyltransferase. 

      • Piperine may increase intestinal permeability 

 

N-Acetylcysteine (NAC)

N-Acetylcysteine (NAC) is an antioxidant that reduces ROS both directly and indirectly. It does so directly by chemically reacting with ROS molecules neutralizing the free radical. The indirect effects of NAC are derived by it providing cysteine for the formation of glutathione from the essential amino acid, L-cysteine. Glutathione, a potent physiological antioxidant, has poor oral bioavailability and therefore is  limited in its benefit directly as a supplement while supplemental NAC can being effectively utilized in many treatment protocols and clinical studies with relatively few side effects.

 

NAC and Obesity

The benefits of NAC in obesity has been demonstrated in countless studies. Since obesity is characterized by elevated levels of both oxidative stress and inflammation, NAC has been a target for research to minimize the progression of obesity and associated co-morbidities. Studies have shown a beneficial role of NAC in reducing biomarkers associated with fat production. The reduction in these biomarkers with NAC supplementation was shown to correlate with elevation of glutathione levels and reduction of ROS. This suggests that supplementation with NAC can reduce production of fat by increasing glutathione levels. Furthermore, animal studies have shown that supplementation with NAC in a high fat diet reduces triglyceride and cholesterol content in the liver suggesting a role for NAC in preventing obesity-related fatty liver.

A major factor associated with obesity is the oxidative stress-related inflammation present in various metabolic tissues linked to insulin resistance, atherosclerosis, and ischemic strokes. The effectiveness of NAC in counteracting obesity-associated inflammation and the progression of metabolic disorders is attributed to NAC’s ability to reduce inflammatory chemicals (cytokines) while increasing antioxidant components.

 

NAC and Type 2 Diabetes (T2DM)

The ability of NAC to reduce inflammatory pathways and ROS generation may allow for improvement in insulin sensitivity in obese individuals that begin to develop T2DM. Recent studies have shown treatment with NAC improves plasma insulin levels and increases insulin sensitivity across multiple tissues including muscles.

NAC and the Heart

Current evidence strongly suggests that NAC may be cardioprotective by reducing hyperglycemia induced oxidative damage to the heart. This improvement in oxidative stress of the heart reduces the progressive loss in cardiac efficiency and cardiac fibrosis (scarring) that occurs with oxidative stress. Multiple studies have demonstrated that NAC increases levels of glutathione in cardiac muscle cells, while reducing levels of ROS and various biomarkers for oxidative stress.

 

 

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

 

Dietary Compounds: Dietary vs. Supplemental

In some cases the evidence for benefit of some compounds is high when associated with dietary intake from food, but definitive evidence for benefit when taken as a separate and additional dietary supplement remains unclear and at this time not specifically recommended except as noted.

 

Dietary Fats

Dietary fatty acids are divided into saturated and unsaturated (mono- and polyunsaturated) depending on the presence and number of unsaturated bonds. Omega-3 fatty acids have the strongest anti-inflammatory benefits. The following are common food rich in omega-3:

    • Fish and other seafood (especially cold-water fatty fish, such as salmon, mackerel, tuna, herring, and sardines)
    • Nuts and seeds (such as flaxseed, chia seeds, and walnuts)
    • Plant oils (such as flaxseed oil and canola oil)

 

Probiotics

Much attention is paid to the gut microbiota (GM). The GM is defined as a complex and dynamic ecosystem of microorganisms inhabiting the gastrointestinal tract, composed of bacteria, fungi, archaea, viruses, and their genomes.

The human GM consists of five main bacterial genera, including Firmicutes and Bacteroidetes, which account for about 90% of the total number of bacteria, and Proteobacteria, Actinobacteria, and Verrucomicrobia. Among Firmicutes, the human microbiota is mainly composed of butyrate-producing Eubacterium, Faecalibacterium, and Roseburia, as well as Lactobacillus, Ruminococcus, and Clostridium. Among the Bacteroidetes, there are Bacteroides, Prevotella, and Xylanibacter.

In healthy adults, the most prevalent are Eubacterium, Clostridium, Ruminococcus, Lactobacillus, and Bacteroides. However, the GM’s composition, diversity, and abundance varies from person to person depending on many factors, including prenatal factors, age, ethnicity, the environment, medications and supplements taken, and overall lifestyle.

Apart from the inter-individual variation, three main GM enterotypes are distinguished depending on the dominant type of microorganisms in the environment: Bacteroides, Prevotella, and Ruminoccocus. The GM is involved in various biological processes, and is a key regulator of  energy homeostasis, the growth of pathogens, gut epithelial integrity, and immune function.

Studies have shown that GM dysfunction (dysbiosis) is characterized by an increased Firmicutes-to-Bacteroideses ratio, reduced diversity, and changes in the activity of the GM. Dysbiosis is closely linked to a variety of health problems, such as obesity and metabolic syndrome, cardiovascular diseases, and gastrointestinal disorders, as well as a chronic inflammatory disease. Therefore, maintaining or restoring the balance of the GM through probiotics is a promising and safe tool in obesity and obesity-related inflammation management.

Studies have shown that probiotic supplementation leads to beneficial changes in body weight and body composition, especially reductions in body fat, BMI, and waist circumference as well as improving the cardio-metabolic profile. Probiotics have been proposed as a new promising strategy in obesity treatment, not only because they are substances affecting body weight reduction or the restoration of glucose and lipid homeostasis but also because they positively affect markers of inflammation.

Overall, probiotics seems to offer promise for for treating obesity and improving obesity-induced chronic low-grade inflammation. However, specific recommendations are lacking as are specific supplements.

For now, supplementation with dietary sources can be recommended only for yogurt-based products as tolerated.

Lactobacillus

Of all the studies concerning probiotic intake, most have focused on Lactobacillus, the bacterial strains found in fermented foods such as yogurt form lactic acid in the gut which have numerous beneficial health benefits including reducing cytokines. The lactic acid produced by these bacteria also has an antioxidant effect which reduces ROS and enhances the production of the antioxidants superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH).

 

Other

Animal studies provide evidence that different strains of Bifidobacterium attenuate obesity-induced inflammation and oxidative stress. Akkermansia muciniphila is also promising in treating obesity and metabolic disorder treatment due to its anti-inflammatory properties but no specific recommendations can be made for these strains at this time.

 

Dietary Fiber

Dietary fiber is the element of plant products not digested by human digestive enzymes, including cellulose, hemicelluloses, pectins, gums and lignins. Dietary fiber has an antioxidant effect mainly due to the high contents of phenolic compounds.  Dietary fiber also reduces the production of endothelial pro-inflammatory cytokines.

 

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

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

New:

The Role of Antioxidants Supplementation in Clinical Practice- Focus on Cardiovascular Risk Factors – 2021

  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.    Green Tea Phytosome
  2.    Meriva (Curcumin)
  3.    Milk Thistle (Siliphos – Silybin Phytosome)
  4.    PolyResveratrol SR
  5.    Quercetin
  6.    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
  6. Bioavailability and activity of phytosome complexes from botanical polyphenols – the silymarin, curcumin, green tea, and grape seed extracts. – 2009
  7. Phospholipid Complex Technique for Superior Bioavailability of Phytoconstituents – 2017

 

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.

 

For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.

 

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.

 

For more information, please contact Accurate Clinic.

 

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