What are “free radicals”?

• A free radical is an atom or molecule with one or more unpaired electrons
• Free radicals are very unstable and try to achieve stability by gaining the needed electron; therefore free radicals are very reactive
• They react with other chemical compounds by capturing the required electron and thus trigger chain reactions with the formation of further radicals.
• These reactions are unregulated and unpredictable - they can generally damage all biological structures and molecules
• The following are particularly affected:
  Cell components (e.g.b Damage to genetic material in the cell nucleus or DNA)
  • Fats (oxidation of lipoproteins) and carbohydrates
  • Proteins / enzymes
  • Amino acids such as.b L-cysteine ​​(glutathione building block)

What do “oxidation” and “reduction” mean?

• An antioxidant donates an electron to the free radical and thereby defuses it - the free radical becomes a “healthy” molecule again
• By releasing electrons, the antioxidant is in turn oxidized (radicalized) and then has to be reduced again, etc.

 

What is “oxidative stress”?

• Is there a disproportion between oxidation and reduction or If there are more free radicals (oxidants) than antioxidants, this is called oxidative stress for the body.

 

How are free radicals formed?

Free radicals are formed both exogenously (environmental factors) and endogenously (through the body's own processes):

• Endogenous:
  • Cellular energy production in the mitochondria: in the mitochondria, oxygen is reduced to water. However, this does not happen completely: some of it becomes free radicals (compounds of oxygen with hydrogen or nitrogen). To ensure that the reaction between oxygen and hydrogen does not lead to an oxyhydrogen effect in the body, the electrons are transferred in several stages - this happens in the so-called “Respiratory chain” (= electron transport chain). This consists of several redox systems connected in series, in which an electron is removed from molecules by free radicals, which in turn radicalizes them, etc. E.g.: NADH is oxidized to NAD+ by free radicals with the elimination of H+
  • Cellular immune defense and inflammation (“Oxidative burst”): free radicals (e.g. H2O2 and hydroxyl radicals) are formed to support the killing of phagocytosed germs (viruses, bacteria) when the immune system is excessively activated (e.g. due to autoimmune diseases) and simultaneous antioxidant deficiency, oxidative stress occurs!
  • Detoxification (detoxification phase I): in order for toxic substances to be excreted, they must first be radicalized, i.e.H “responsive”. The products of phase I are therefore usually more aggressive than the actual toxin, so that rapid detoxification or Excretion in phase II is important. In phase II, polar hydrophilic molecules such as Glutathione or cysteine ​​are attached to the phase I metabolites, making them available in water-soluble form for excretion via the kidneys.
  • Homocysteine ​​metabolism: Formation of H2O2 radicals, for example. through interactions with transition metals or enzymes
  • Glucooxidation (at high glucose levels or Diabetes) with the formation of H2O2
  • Chronic diseases in general: lead to inflammation and increased radical release
  • Physical stress (e.g.b physical work, competitive sports)
• Exogenous:
  • Sun and UV light
  • Ozone O3
  • Radioactive environmental radiation (e.g.b while flying)
  • Radioactive medical radiation (e.g.b Therapy, mammograms and other diagnostics)
  • Medicines (e.g.b Contraceptives, paracetamol, antibiotics, cytostatics)
  • Cigarettes and alcohol
  • Other environmental pollutants, e.g.b Metals, smog, nitrogen oxides, car exhaust, solvents, pesticides & other chemicals

What damage can be caused by free radicals?

• DNA damage
• Improper control of carbohydrate, amino acid and fat metabolism
• Acceleration of aging
• Reduction in performance
• Increase in the risk of so-called “Free Radical Diseases” (affected primarilya Tissues with high oxygen turnover such as Heart, skeletal muscles, eye lens etc):
  • Neurodegenerative diseases such as Alzheimer's disease
  • Arteriosclerosis
  • Allergies
  • Aging processes
  • Amyotropic lateral sclerosis (ALS): Disruption of SOD breakdown and destruction of motor nerve cells by free radicals
  • Cataractogenesis Maculde degeneration
  • Diabetes
  • Cancer diseases
• Accelerating the process and increasing the severity of many diseases
• Increasing the risk of recurrences in many diseases

 

What positive tasks do free radicals have in the body?

• Training function: Small amounts of radicals train the redox system
  (promote performance, antioxidant formation and resilience), comparable to a vaccination
• Immune function:
  • Macrophages and granulocytes form redox systems in mitochondria; free radicals kill e.g.b Bacteria and protozoa in interaction with lytic enzymes
  • Vitamin C in high doses with radical activity has a cytotoxic effect against cancer cells
  • Radical-producing chemotherapy drugs and radiation kill cancer cells; ATTENTION: Therefore, antioxidants should not be taken during chemotherapy and/or radiation therapy!
• Signal function: Radicals can act as signaling substances, e.g.b in inflammation (stimulation of the transport of immune cells to the site of inflammation), in the growth of nerve cells (e.g.b after spinal cord injuries, as part of adult neurogenesis) and during wound healing

 

What are antioxidants?

• Antioxidants are “radical scavengers”, i.e.H They donate an electron to the radical and thus reduce it (and thereby become i.dR itself oxidized)
• They have a reduced OH, SH or NH group and react more quickly with radicals than other biological structures (e.g.: 1 molecule of the antioxidant vitamin E protects up to 1000 fatty acid chains!)
• Antioxidants work synergistically and regenerate each other: they form a network enzymatic and non-enzymatic antioxidants: Vitamin C, E, coenzyme Q10 (ubiquinone as oxidized, ubiquinol as reduced form ), glutathione and alpha-lipoic acid regenerate (reduce) each other after oxidation

 

Enzymatic (higher molecular weight)	Non-enzymatic (small molecules)
• Formed in the body (“endogenous”) • Effects depend on genetics (enzymopathy) and synthesis rate • High reaction speed • Do not become radicals themselves during detoxification ( no chain reactions!) • Require cofactors for effect • Are not available in unlimited quantities	• Mostly supplied with food • Effects depend on supply • Low reaction speed • Become radical when detoxified (must be defused!) • Quick replacement possible • Are (theoretically) available indefinitely

 

What are the most important antioxidant enzymes?

• Superoxide dismutases (SOD)
  • Catalyze the superoxide radical conversion (O2- ) into H202 + O2
  • with copper (Cu)/zinc (Zn) as a cofactor in the cytoplasm and extracellular space
  • with manganese (Mn) as a cofactor in mitochondria
• Catalases
  • Catalyze the reduction of H202 to H20 (prevention of hydroxyl radicals)
  • With iron (Fe) as a cofactor
  • a. in liver, skin, kidney cells and erythrocytes
• Peroxidases
  • Catalyze reduction of H202 to H20
  in the aqueous cell environment
  • Selenium-independent peroxidases (iron (Fe)-dependent)
  • Selenium-dependent phospholipid hydroperoxide glutathione peroxidase
  • a. in erythrocytes, liver, lungs and kidneys

 

What are the most important non-enzymatic antioxidants?

• Carotenoids
  • Beta-carotene: antioxidant effect through inactivation (so-called "Quenching") of reactive substance compounds
  • Zeaxanthin
  • Lutein
  • Lycopene
• Polyphenols --> work primarily.a antioxidant due to phenolic OH group; the number of OH groups influences the antioxidant effect
  • Resveratrol --> 3 OH groups
  • Quercetin --> 5 OH groups and therefore particularly strong antioxidant effect
  • Matcha: has an ORAC value of 1.711 units/g is the highest known ORAC value in a natural product (ORAC stands for “Oxygen Radical Absorbance Capacity”, i.e.H the ability to reduce oxygen radicals) 
  • Brahmi: Scientific studies have v.a the antioxidant effect of Brahmi has been investigated in relation to neurodegenerative diseases (cf. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564646/ )
• Vitamins
  • Vitamin C (water soluble)
  • Vitamin E (fat-soluble)
  • Tocopherol E-OH is oxidized to tocopheroxyl radical and then reduced again to tocopherol E-OH
  using vitamin C or glutathione as a hydrogen donor
  • "Vitamin E helps protect DNA, proteins and lipids from oxidative damage." (official health claim)
  • Vitamin B2 (water soluble): "Vitamin B2 (riboflavin) helps protect cells from oxidative stress." (official health claim)
  • Vitamin A (fat-soluble)
  • Vitamin K (fat-soluble)
• Thiols (with SH group)
  • Glutathione
  • L-cysteine
  • Alpha lipoic acid
  • can pass through the brain barrier and regenerate used antioxidants such as vitamin C, E, coenzyme Q10 or glutathione; therefore a central component of synergistic antioxidant complexes
  • Deutsche Apotherkerzeitung: "A clinical study in patients with mild to moderate Alzheimer's dementia showed that the additional administration of alpha-lipoic acid to acetylcholinesterase inhibitors extremely slows the progression of the disease." (see.https://www.deutsche-apotheker-zeitung.de/daz-az/2009/daz-3-2009/liponsaeure-bei-alzheimer-demenz )
• Other sulfur-containing amino acids
  • Taurine
  • L-Methionine
• Vital mushrooms, esp. Cordyceps: The antioxidant potency of Cordyceps extract was demonstrated in laboratory tests (cf.https://pubmed.ncbi.nlm.nih.gov/11114006/ )
• Coenzyme Q10
• L-Carnitine
• NADP (active vitamin B3)
• Cofactors of enzymatic antioxidants
  • Selenium (Se)
  • Zinc (Zn)
  • Iron (Fe)
  • Manganese (Mn)
  • Copper (Cu)

 

Which foods are particularly rich in antioxidants?

Antioxidant	Food
Vitamin C Vitamin E Selenium Glutathione β-carotene Lycopene Sulforaphane Resveratrol Spermidine	Lemons, oranges, grapefruit, kiwi Olive oil, wheat germ oil, wheat germ Wheat germ, sesame, whole grain products, sea fish, redfish Avocado, watermelon, asparagus, broccoli, spinach Carrots, tomatoes, apricots Tomato juice Broccoli Red wine (moderate!), berries, peanuts Wheat germ, soy

 

Indicators and risk factors for oxidative stress (The more questions that are answered with “yes”, the greater the risk of oxidative stress; does not replace u.G Diagnostics!)

• Complaints
  • I am often tired.
  • I suffer from a lack of drive.
  • I have more than 3 colds p.a
  • My physical and mental performance is not satisfactory.
• Life habits
  • I smoke.
  • I drink over 20g of alcohol several days a week.
  • I often spend time in the sun and/or visit solariums.
  • I do intensive exercise several times a week.
• Loads
  • I am regularly stressed.
  • I am polluted by the environment (e.g. amalgam or radiation exposure).
  • I often go on diets.
  • I work a lot on the computer.
• Illnesses and health risks
  • Overweight
  • Fat metabolism disorders
  • Diabetes mellitus
  • Heart diseases
  • Rheumatic diseases
  • Intestinal diseases
  • Respiratory diseases
  • Allergies
  • Cancer diseases
• Medication intake
  • Pain relievers
  • Hormonal preparations
  • Anticontraceptives
  • Chemotherapeutic agents
• Nutrition
  • I eat fresh fruit and carefully prepared vegetables less than three times a day.
  • I drink less than 2 glasses of fruit or vegetable juice every day.
  • My diet does not regularly contain milk and dairy products.
  • I drink less than 1.5 liters of liquid every day.
  • I don't eat fish regularly.

 

Diagnostics of oxidative stress

• Antioxidants page
  • Determination of the most important antioxidant blood levels
    • Non-enzymatic ones such as glutathione, vitamin C + E, coenzyme Q10 and the cofactors selenium and zinc
    • Enzymatics such as superoxide dismutase SOD, glutathione peroxidase GPx
  • Screening to determine antioxidant protection: Total antioxidant capacity TAS / antioxidant potential TEAC (ability to react with free radicals)
    • In the laboratory: e.g.b Patient serum (with antioxidants) + defined amount of free radicals; Measurement of the residual amount of radicals after detoxification (dye reaction):
      Initial amount – residual amount = antioxidant potential (normal value: 1.3-1.77 mmol/l blood)
    • In practice: e.g.b FORD (Free Oxygen Radicals Defense) in capillary blood
• Radical page
  • Detection of lipid peroxidation: Malondialdehyde (MDA-LDL as a long-term value over 7-10 days), as aldehyde is a measurable breakdown product of free radicals
    • 4-Hydroxnonenal HNE (alkenal/aldehyde): oxidative damage to polyunsaturated fatty acids
    • 8-Ispoprostane F2 α(8-iso-prostaglandin F2 α): oxidative damage to prostaglandin synthesis (from arachidonic acid)
    • 2-Propenal (acrolein/aldehyde): oxidative damage to polyunsaturated fatty acids
  • Detection of oxidative damage to genetic material: Deoxyguanosine test (DNA oxidation / 8-OHdG) (excretion of 8-hydroxy-deoxyguanosine as a result of oxidative damage to nucleic acids/DNA in urine; biomarker for the assessment of individual mutagenic/carcinogenic effects of oxidative stress)
  • Detection of protein oxidation: nitrotyrosine (oxidation of tyrosine with peroxynitrite)
  • Electron spin resonance ESR: Direct detection of radicals (principle: absorption of microwave radiation by unpaired electrons; but not established due to lack of availability and short-lived radicals)

Examples of areas of application of antioxidants

• Aging processes
• Sport (performance-oriented)
• Cardiovascular diseases (e.g.b arteriosclerosis)
• Neurologist & Psyche (e.g.b Alzheimer's disease, Parkinson's disease, ALS, schizophrenia) (3)
• Immune system and inflammation in general (rheumatism, periodontal disease, acute pancreatitis)
• Drug-induced disorders
• Other environmental pollution (e.g.b Alcohol, smoking, harmful substances)
• Diabetes
• Respiratory diseases
• Eye diseases (e.g.b Cataract)
• Reproductive medicine and infertility (2)
• Cancer prevention (Attention: antioxidants should be avoided during chemotherapy/radiation therapy, as they can prevent the (in this case yes) desired cell death! (1)

 

(1) Antioxidants and cancer risk

One following the SU.VI.MAX study from France with 12,741 adults (primary prevention, placebo-controlled, double-blind, blood level control), five-year follow-up study confirmed that long-term administration of an antioxidant complex in nutritional doses (vitamin C 120 mg/day, vitamin E 30 mg/day, beta-carotene 6 mg/day, selenium 100 mcg/day, zinc 20 mg/day) in people with an insufficient supply of antioxidants in the form of fruits and vegetables by 31% reduced risk of cancer and a 37% reduction in mortality (cf. https://pubmed.ncbi.nlm.nih.gov/20104528/ ).

(2) Antioxidants and infertility

Oxidative stress damages sperm. The damage can be reduced by the body's own antioxidant defense
. Female partners of infertile men who took antioxidants as part of a reproductive program experienced an increase in birth rates. See.:  Review of 34 randomized controlled trials involving 2876 couples; Showell et al, Antioxidants for male subfertility; Cochrane 2012; DOI: 10.1002/14651858.CD007411.pub2 (“Oxidative stress may cause sperm cell damage. This damage can be reduced by the body's own natural antioxidant defenses. Antioxidants can be part of our diet and taken as a supplement. It is believed that in many cases of unexplained subfertility, and also in instances where there may be a sperm-related problem, taking an oral antioxidant supplement may increase a couple's chance of conceiving when undergoing fertility treatment.”)

(3) Antioxidants and dementia
Mitochondrial radicals are partly responsible for the formation of amyloid-ß aggregates. Amyloid
ß in turn leads to mitochondrial dysfunction and an increase in ROS (cf. Leuner K et al.; mitochondrion-derived ROS lead to increased amyloid-beta formation; Antioxid Redox Signal 2012; 16; 1421-1433; “Conclusion: Several lines of evidence show that mitochondrion-derived ROS result in enhanced amyloidogenic amyloid precursor protein processing, and that Aβ itself leads to mitochondrial dysfunction and increased ROS levels. We propose that starting from mitochondrial dysfunction a vicious cycle is triggered that contributes to the pathogenesis of sporadic AD.”