What are "free radicals"?

• A free radical is an atom or molecule with one or more unpaired electron(s)
• Free radicals are very unstable and try to gain 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 triggering chain reactions with the formation of further radicals.
• These reactions are unregulated and unpredictable - they can generally damage all biological structures and molecules
• Particularly affected are:
  cell components (e.g. damage to genetic material in the cell nucleus or DNA)
  • fats (oxidation of lipoproteins) and carbohydrates
  • proteins / enzymes
  • amino acids such as L- Cysteine ​​(glutathione building block)

What do "oxidation" and "reduction" mean?

• An antioxidant gives the free radical an electron and thereby defuses it à the free radical becomes a "healthy" molecule again
• Due to the release of electrons, the antioxidant is again oxidized (radicalized) and then has to be reduced again, etc.

What is "oxidative stress"?

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

How do free radicals form?

Free radicals are formed both exogenously (environmental factors) and endogenously (through endogenous processes):

• Endogenous:
  • Cellular energy generation in the mitochondria: in the mitochondria, oxygen is reduced to water. However, this does not happen completely: a part becomes free radicals (compounds of oxygen with hydrogen or nitrogen). So that the reaction of 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 This consists of several redox systems connected in series, in which an electron is withdrawn from molecules by free radicals, which in turn causes them to be radicalized etc. Example: NADH is oxidized by free radicals with the elimination of H+ to NAD+
  • Cellular immune defense and inflammation ("oxidative burst"): in the mitochondria of activated phagocytes (scavenger cells such as granulocytes and macrophages that absorb viruses and bacteria) free radicals (e.g. H2O2 and hydroxyl radicals) are formed to support the killing of phagocytosed germs (viruses, bacteria) à with an overly activated immune system (e.g. due to autoimmune diseases) and a simultaneous lack of antioxidants, oxidative stress occurs!
  • Detoxification (detoxification phase I): so that toxic substances can be excreted, they must first be radicalized, i.e. made "reactive". The products of phase I are therefore usually more aggressive than the actual toxin, so that rapid detoxification or elimination in phase II is important. In phase II, polar hydrophilic molecules such as glutathione or cysteine ​​are then attached to the phase I metabolites, making them available in a water-soluble form for excretion via the kidneys.
  • Homocysteine ​​metabolism: Formation of H2O2 radicals, e.g. through interactions with transition metals or enzymes
  • glucooxidation (at high glucose levels ordiabetes) with formation of H2O2
  • Chronic diseases in general: lead to inflammation and increased free radical release
  • Physical stress (e.g. physical work, competitive sports)
• Exogenous:
  • Sun and UV light
  • Ozone O3
  • Radioactive environmental radiation (e.g. when flying)
  • Radioactive medical radiation (e.g. therapy, mammography and other diagnostics)
  • Medications (e.g. contraceptives, paracetamol, antibiotics, cytostatics)
  • Cigarettes and alcohol
  • Other environmental pollutants e.g. metals, smog, nitrogen oxides, car exhaust, solvents, pesticides & other chemicals

What damage can free radicals cause?

• DNA damage
• Malfunctions in carbohydrate, amino acid and fat metabolism
• Acceleration of aging
• Reduction in efficiency
• Increased risk of so-called "free radical diseases" (tissues with high oxygen turnover such as heart and skeletal muscles, eye lenses, etc. are particularly affected):
  • Neurodegenerative diseases such as Alzheimer's disease
  • Atherosclerosis
  • Allergies
  • Aging processes
  • Amyotropic lateral sclerosis (ALS): Disruption of SOD degradation and destruction of motor nerve cells by free radicals
  • Cataract genesis macular degeneration
  • diabetes
  • cancer
• Speeding up the process and increasing the severity of many diseases
• Increased risk of recurrence 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. bacteria and protozoa in interaction with lytic enzymes
  • Vitamin C in high doses with radical activity has a cytotoxic effect on cancer cells
  • Radical-producing chemotherapy drugs and radiation kill cancer cells; WARNING: Antioxidants should therefore not be taken during chemotherapy and/or radiotherapy!
• Signaling function: Radicals can act as signaling substances, e.g. in inflammation (stimulation of the transport of immune cells to the site of inflammation), in the growth of nerve cells (e.g. after spinal cord injuries, as part of adult neurogenesis) and in wound healing

What are antioxidants?

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

Enzymatic (higher molecular weight)	Non-enzymatic (small molecule)
• Formed in the body ("endogenous") • Effects dependent on genetics (enzymopathy) and synthesis rate • High reaction speed • Do not become radicals themselves during detoxification ( no chain reactions!) • Need cofactors for effect • Are not unlimited available	• Are mostly supplied with food • Effects dependent on supply • Low reaction speed • Become radical themselves during detoxification (must be defused!) • Faster replacement possible • Are (theoretically) unlimitedly available

What are the most important antioxidant enzymes?

• Superoxide dismutases (SOD)
  • Catalyze the superoxide radical conversion (O2- ) to H2O2 + 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 the 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 compounds
  • zeaxanthin
  • Lutein
  • Lycopene
• Polyphenols --> have an antioxidant effect, mainly because of the phenolic OH group; the number of OH groups influences the antioxidant effect
  • Resveratrol --> 3 OH groups
  • Quercetin --> 5 OH groups and therefore a particularly strong antioxidant effect
  • Matcha: has the highest known ORAC value in a natural product with an ORAC value of 1,711 units/g (ORAC stands for "Oxygen Radical Absorbance Capacity", i.e. the ability to reduce oxygen radicals)
  • Brahmi: Scientific studies have primarily examined the antioxidant effect of brahmi 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 by 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)
• thiol (with SH group)
  • glutathione
  • L-cysteine
  • alpha lipoic acid
  • can pass the brain barrier and regenerate depleted 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 down the progression of the disease" (cf. https://www.deutsche-apotheker -zeitung.de/daz-az/2009/daz-3-2009/liponaeure-bei-alzheimer-demenz )
• Other sulfur-containing amino acids
  • taurine
  • L-methionine
• Vital fungi, 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	Lemon, orange, grapefruit, kiwi Olive oil, wheat germ oil, wheat germ Wheat germ, sesame, whole grains, sea fish, redfish Avocado, watermelon, asparagus, broccoli, spinach Carrot, tomato, apricot tomato juice broccoli red wine (moderate!), berries, peanuts wheat germ, soybeans

Indicators and risk factors for oxidative stress (the more questions are answered with "yes", the greater the risk for oxidative stress; does not replace the diagnostics below!)

• complaints
  • I'm often tired.
  • I suffer from lack of drive.
  • I have more than 3 colds per year
  • My physical and mental performance is not satisfactory.
• Habits of life
  • 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 vigorous exercise several times a week.
• loads
  • I am regularly stressed.
  • I am environmentally polluted (e.g. amalgam or exposure to radiation).
  • I often go on diets.
  • I work a lot on the computer.
• Diseases and health risks
  • Overweight
  • Fat metabolism disorders
  • Diabetes mellitus
  • Heart disease
  • Rheumatic diseases
  • Intestinal diseases
  • Respiratory diseases
  • Allergies
  • cancer
• taking medication
  • painkiller
  • Hormone preparations
  • Anticontraceptives
  • Chemotherapy drugs
• Nutrition
  • I eat fresh fruit and gently prepared vegetables less than 3 times a day.
  • I drink less than 2 glasses of fruit or vegetable juice a day.
  • My diet does not regularly contain milk and dairy products.
  • I drink less than 1.5 liters of liquid a 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
    • Enzymatic such as superoxide dismutase SOD, glutathione peroxidase GPx
  • Antioxidant Protection Screening: Total Antioxidant Capacity TAS / Antioxidant Potential TEAC (Ability to React with Free Radicals)
    • In the laboratory: e.g. 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. FORD (Free Oxygen Radicals Defense) in capillary blood
• Radical side
  • Recording 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-Ispoprostan 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 (DNS oxidation / 8-OHdG) (excretion of 8-hydroxy-deoxyguanosine as a result of oxidative damage to nucleic acids/DNA in the urine; biomarker for the assessment of individual mutagenic/carcinogenic effects from 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 the lack of availability and short-lived radicals)

Examples for the application of antioxidants

• Aging processes
• Sport (performance-oriented)
• Cardiovascular diseases (e.g. arteriosclerosis)
• Neurologist & psyche (e.g. 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. alcohol, smoking, pollutants)
• diabetes
• Respiratory diseases
• Eye diseases (e.g. cataracts)
• Reproductive medicine and infertility (2)
• Cancer prevention (note: 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

A five-year follow-up study carried out as a follow-up to the SU.VI.MAX study from France with 12,741 adults (primary preventive, placebo-controlled, double-blind, monitoring of blood levels) confirmed that long-term administration of an antioxidant complex in nutritive 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 reduced the risk of cancer by 31% and reduced mortality by 37% (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 antioxidant defenses
.Female partners of infertile males taking antioxidants as part of a reproductive program were associated with 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 defences. 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 jointly 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 the pathogenesis of sporadic AD.”

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