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 achieve stability by gaining the necessary electron; therefore, free radicals are very reactive.
• They react with other chemical compounds by capturing the required electron, thus triggering chain reactions with the formation of further radicals.
• These reactions are unregulated and unpredictable – they can generally affect all biological structures. && Molecules damage
• The following are particularly affected:
  Cell components (z.B. Damage to genetic material in the cell nucleus or DNA)
  • Fats (oxidation of lipoproteins) and carbohydrates
  • Proteins/Enzymes
  • Amino acids such as z.BL-Cysteine ​​(glutathione building block)

What do "oxidation" and "reduction" mean?

• An antioxidant donates an electron to the free radical, thereby neutralizing it; the free radical becomes a "healthy" molecule again.
• The release of electrons causes the antioxidant to be oxidized (radicalized) and then reduced again, etc.

What is "oxidative stress"?

• If there is an imbalance between oxidation and reduction, or more free radicals (oxidants) than antioxidants, this is referred to as oxidative stress in 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 mitochondriaIn the mitochondria, oxygen is reduced to water. However, this process is not complete: some of the reduced oxygen is converted into free radicals (compounds of oxygen with hydrogen or nitrogen). To prevent the reaction of oxygen and hydrogen from producing an explosive gas reaction in the body, the electrons are transferred in several stages – this occurs in the so-called "respiratory chain" (electron transport chain). This chain consists of several interconnected redox systems in which free radicals steal an electron from molecules, thereby radicalizing them in turn, and so on. For example, NADH is oxidized to NAD+ by free radicals, releasing H+ ions.
  • Cellular immune defense and inflammation (“Oxidative burst”): in the mitochondria of activated phagocytes (phagocytic cells such as granulocytes and macrophages that engulf viruses and bacteria), free radicals (e.g., H2O2 and hydroxyl radicals) are formed to support the killing of phagocytosed germs (viruses, bacteria) à When the immune system is overactive (e.g., due to autoimmune diseases) and there is a simultaneous deficiency of antioxidants, oxidative stress occurs!
  • detoxification (Detoxification phase I): In order for toxic substances to be eliminated, they must first be radicalized, d.h...be made "reactive". The products of phase I are therefore usually more aggressive than the actual toxin, making rapid detoxification or excretion in phase II important. In phase II, polar hydrophilic molecules such as glutathione or cysteine ​​are attached to the metabolites of phase I, making them available in a water-soluble form for excretion via the kidneys.
  • Homocysteine ​​metabolism: Formation of H2O2 radicals, for example.through interactions with transition metals or enzymes
  • Glucooxidation (in cases of high glucose levels or diabetes) with the formation of H2O2
  • Chronic diseases in general: lead to inflammation and increased free radical release
  • Physical stress (z.B(physical work, competitive sports)
• Exogenous:
  • Sun and UV light
  • Ozone O3
  • Radioactive environmental radiation (z.B(when flying)
  • Radioactive medical radiation (z.BTherapy, mammograms and other diagnostic procedures)
  • medication (z.B. Contraceptives, paracetamol, antibiotics, cytostatics)
  • Cigarettes and alcohol
  • Other environmental pollutants, z.BMetals, smog, nitrogen oxides, car exhaust, solvents, pesticides && other chemicals

What damage can be caused by free radicals?

• DNA damage
• Dysregulation in carbohydrate, amino acid and fat metabolism
• Acceleration of aging
• Reduction in performance
• Increased risk of so-called "free radical diseases" (affecting are v.a. Tissues with high oxygen turnover, such as heart muscle, skeletal muscle, 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 macular degeneration
  • diabetes
  • Cancer
• Acceleration of the progression and increase in the severity of many diseases
• Increased risk of relapse in many diseases

What positive functions do free radicals have in the body?

• Training function: Small amounts of radicals train the redox system.
  (promote performance, antioxidant production and resilience), comparable to a vaccination
• Immune function:
  • Macrophages and granulocytes form redox systems in mitochondria; in doing so, they kill free radicals. z.BBacteria and protozoa in conjunction with lytic enzymes
  • High doses of vitamin C with radical activity have a cytotoxic effect against cancer cells.
  • Radical-producing chemotherapeutic agents and radiation kill cancer cells; WARNING: Therefore, antioxidants should not be taken during chemotherapy and/or radiation therapy!
• Signaling function: Radicals can act as signaling substances, z.B. in inflammation (stimulation of the transport of immune cells to the site of inflammation), in the growth of nerve cells (z.B. after spinal cord injuries, in the context of adult neurogenesis) and during wound healing

What are antioxidants?

• Antioxidants are “free radical scavengers”, d.hThey donate an electron to the radical and thus reduce it (and are thereby destroyed). i.d.R(self-oxidized)
• 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 work synergistically and regenerate each other: they form a network. Enzymatic and non-enzymatic antioxidants: Vitamins 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 (low molecular weight)
• Formed in the body (“endogenous”) • Effects dependent on genetics (Enzymopathy) and synthesis rate • High reaction speed • They do not become radicalized themselves during detoxification (No chain reactions!) • Require cofactors for effect • Are not available indefinitely	• Are mostly ingested through food • Effects depend on supply • Slow reaction time • They become radicalized during detoxification itself (must be defused!) • Quick replacement possible • Are (theoretically) available indefinitely

Which are the most important antioxidant enzymes?

• Superoxide dismutases (SOD)
  • They 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
  • They catalyze the reduction of H2O2 to H2O (prevention of hydroxyl radicals)
  • With iron (Fe) as a cofactor
  • a. in liver, skin, kidney cells and erythrocytes
• Peroxidases
  • Catalyzing the reduction of H2O2 to H2O in an 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 --> act v.a. due to phenolic OH groups, they are antioxidant; 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: With an ORAC value of 1,711 units/g, it has the highest known ORAC value in a natural product (ORAC stands for "Oxygen Radical Absorbance Capacity", d.h. the ability to reduce oxygen radicals)
  • Brahmi: Scientific studies have v.a. the antioxidant effect of Brahmi in relation to neurodegenerative diseases was investigated (see 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 back to tocopherol E-OH by vitamin C or glutathione as a hydrogen donor.
  • "Vitamin E contributes to, "To protect DNA, proteins, and lipids from oxidative damage." (Official Health Claim)
  • Vitamin B2 (water-soluble): "Vitamin B2 (riboflavin) contributes to the protection of cells from oxidative stress. (Official health claim)
  • Vitamin A (fat-soluble)
  • Vitamin K (fat-soluble)
• Thiole (with SH group)
  • Glutathion
  • L-Cysteine
  • Alpha-lipoic acid
  • It can cross the blood-brain barrier and regenerate used antioxidants such as vitamins C and E, coenzyme Q10, or glutathione; therefore, it is a key component of synergistic antioxidant complexes.
  • German Pharmacists' Journal: "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." (cf. https://www.deutsche-apotheker-zeitung.de/daz-az/2009/daz-3-2009/liponsaeure-bei-alzheimer-demenz )
• Other sulfur-containing amino acids
  • Taurine
  • L-Methionine
• Medicinal mushrooms, especially Cordyceps: The antioxidant potency of Cordyceps extract was demonstrated in laboratory tests (see [reference]). 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	Groceries
Vitamin C Vitamin E selenium Glutathion β-Carotene Lycopene Sulforaphan Resveratrol Spermidine	Lemons, oranges, grapefruit, kiwi Olive oil, wheat germ oil, wheat germ Wheat germ, sesame seeds, whole grain products, saltwater 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 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 motivation.
  • I have more than 3 colds p.a.
  • My physical and mental performance is unsatisfactory.
• Lifestyle habits
  • I smoke.
  • I drink over 20g of alcohol on several days per week.
  • I often spend time in the sun and/or visit tanning salons.
  • I do intensive exercise several times a week.
• burdens
  • I am regularly stressed.
  • I am exposed to environmental pollutants (e.g., amalgam or radiation exposure).
  • I frequently go on diets.
  • I work a lot on the computer.
• Diseases and health risks
  • Overweight
  • Lipid metabolism disorders
  • Diabetes mellitus
  • Heart disease
  • Rheumatic diseases
  • Intestinal diseases
  • Respiratory diseases
  • Allergies
  • Cancer
• Medication intake
  • Painkillers
  • Hormone preparations
  • Contraceptives
  • Chemotherapeutic agents
• Nutrition
  • I eat less than 3 servings of fresh fruit and gently prepared vegetables daily.
  • I drink less than 2 glasses of fruit or vegetable juice daily.
  • My diet does not regularly include milk and dairy products.
  • I drink less than 1.5 liters of fluid daily.
  • I don't eat fish regularly.

Diagnostics of Oxidative Stress

• Antioxidants page
  • Determination of the most important antioxidant blood levels
    • Non-enzymatic substances such as glutathione, vitamins C and E, coenzyme Q10, and the cofactors selenium and zinc
    • Enzymatic enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx).
  • Screening to assess antioxidant protection: Total Antioxidant Capacity (TAS)/Antioxidant Potential (TEAC) (ability to react with free radicals)
    • In the laboratory: z.BPatient 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: z.B.FORD (Free Oxygen Radicals Defense) in capillary blood
• Radical side
  • Measurement of lipid peroxidation: Malondialdehyde (MDA-LDL as a long-term value over 7-10 days), since 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 consequence 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 lifespan of the radicals)

Examples of applications of antioxidants

• aging processes
• Sports (performance-oriented)
• Cardiovascular diseases (z.B. Arteriosclerosis)
• neurologist && Psyche (z.BAlzheimer's disease, Parkinson's disease, ALS, schizophrenia) (3)
• Immune system and inflammation in general (rheumatism, periodontitis, acute pancreatitis)
• Drug-induced disorders
• Other environmental pollution (z.B(Alcohol, smoking, pollutants)
• diabetes
• Respiratory diseases
• Eye diseases (z.B(Cataract)
• Reproductive medicine and infertility (2)
• Cancer prevention (Note: Antioxidants should be avoided during chemo-/radiation therapy, as they can prevent the (in this case) desired cell death!) (1)

(1) Antioxidants and cancer risk

A following up on SU.VI.MAXA study from France involving 12,741 adults (primary prevention, placebo-controlled, double-blind, monitoring of blood levels), conducted over five years, 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) resulted in a 31% reduction in the risk of cancer and a 37% reduction in mortality in individuals with an insufficient supply of antioxidants in the form of fruits and vegetables (see [reference]). https://pubmed.ncbi.nlm.nih.gov/20104528/ ).

(2) Antioxidants and infertility

Oxidative stress damages sperm. This damage can be counteracted by the body's own antioxidant defenses.
The risk of birth defects can be reduced. In female partners of infertile men who took antioxidants as part of a reproductive program, the birth rate increased. See: Review of 34 randomized controlled trials with 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-β aggregates. Amyloid
β in turn leads to mitochondrial dysfunction and an increase in ROS (cf. Leuner K et al.; mitochondrion derived ROS lead to enhanced 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.”