Some reasons of exogennic free radicals formation
X-rays-glow, radiation, UV-radiation, car exhaust, smoking, air pollution, ozone, food processing, increased consumation of meet (purins), chemicals, psychical and oxidative stress, increase of transitional metals (Fe,Cu,Pb,Al,Ni and others)
Some reasons of endogennous free radicals formation
One-electron reduction of oxygen, degradation of purines and formation of uric acid, metabolism of catecholamines, origin of prostaglandins, pain, reperfusion after previous ischemia, diabetes, renal insufficience and others.
Cardiovascular diseases.
Hypertension
Free radicals oxidate LDL-cholesterol to oxLDL. Modified LDL are absorbed by scavenger receptors of macrophaghes. In the cells they damage the Ca-ATP pump. This leads to increased level of Ca++ , proteases activation and to formation of foam cells – start of atherosclerosis and later hypertension. Antioxidants for blocking of these reactions are needed. Another possible therapy: histidine, koenzym Q10, n-3 and n-6 PUFA are cardioprotective.
Another pathway of OxLDL formation is the reaction with myeloperoxidase. This enzyme forms hypochlorous acid (HClO) from hydrogen peroxide and supports LDL oxidation. This reaction is not influenced by vitamin C or E.
Endothelial dysfunction
Is a systemic pathological state of the endothelium. Endothelium is responsible for maintaining vascular tone and regulates oxidative stress by releasing mediators as vasodilatating nitric oxide, prostacyclin and vasoconstrictive endothelin. Endothelial dysfunction is involved in development of atherosclerosis. Endothelial nitric oxide synthese is increased by folate, which decreases the level of homocysteine. Fluvastatin increases nitric oxide and decreases superoxide and so has antioxidative capacity.
Myocardial infarction
- 1. Ischemia followed by reperfusion (I/R) leads to the formation of free radicals, which cause often lethal arrhythmias. Successful recanalization increases intracellular activity of free radicals and it works to transitional decrease of antioxidative capacity. Another possible therapy : histidine, koenzym Q10). (Literature:Holeček V., Kulich Vl..: Influences on the synthesis of nicotinamidemononucleotide in human erythrocytes in vitro. Clin. Chim. Acta 7, 1962, 652-656, Holland, Elsevier PC).
Free radicals are removed gradualy and the last reaction is catalyzed by glutathion reductase and NADPH:
Biosynthesis of pyridine coenzymes is in myocardial infarction increased after application of nicotinic acid (Literature: Holeček V., Kulich Vl..:Influences on the synthesis of nicotinamidemononucleotide in human erythrocytes in vitro. Clin. Chim. Acta 7, 1962, 652-656, Holland, Elsevier
PC). Another possible therapy: Reduction of free radicals : Nicotinic acid, glutathione (GSH).
Tumors
Oxidative stress is initiated by an abundant formation of free radicals and/or due to a decrease in the total antioxidant defenses of an organism. Free radicals can oxidate f.ex. purins. Oxidated adenine binds cytosine instead of thymin, oxidated guanine binds adenine instead of cytosine. These mutations of DNA may contribute to the origin of tumors. Free radicals cause lipoperoxidation, the created aldehydes (malondialdehyde, 4-hydroxynonenal) are carcinogenic. The growth of tumors is dependent on angiogenesis, which can be slowed by some antioxidants. Without angiogenesis the tumor can only reach a size of about 1 mm3. Smoking of 1 cigarette creates about 1017 of free radicals. Free radicals are often found in advanced carcinomas, however, in these cases the administration of antioxidants could interfere with the therapy (x-rays, adriamycine). It is also known that cancer cells absorb antioxidants more rapidly than healthy cells. This in turn protects them from radical therapy. Administration of unsaturated fatty acids increase their content in cancer cell membranes, which are than apt to be killed by lipoperoxidation. Cancer cells can arise as a reaction on hypoxia. Therapy of tumors must target not only on proliferating cells, but also on tumor stemm cells (in G0 phase). Conventional therapy decreases the size of tumor, but do not cure the patient. It must be destroyed tumor stemm cells. (Literature: Holecek V.: Oxidative stress in tumor diseases. Klin. Biochem. Metab. 18(39), 2010, No 4,p.225-230).
Tremendous amount of informations on this topics are available.
Inflammations
Emerging free radicals kill the attacking invasing microorganisms but also damage tissues. Leucocytes kills microorganisms due to its high content of free radicals. Leucocytes are releasing superoxide, hydrogen peroxide is increasing. Cytokines are released, prostaglandins and leucotriens are formed and others. Free radicals block the substances which defend splitting of proteins and elastase, collagenase and others which are released.
Renal diseases
In renal insufficiency free radicals are high. (Literature: Racek, J., Vesela, E., Holecek, V., Treska, V.: The importance of free radicals in patients with failure of kidneys and of kidney transplantation. Klin. Biochem. Metab., 3 (24), 1995, Supplementum, pp. 4 – 6).
Septical states
Different pathological processes are involved in sepsis. One of them are increased levels of free radicals and the lack of antioxidants. Free radicals are formed in sepsis from different reasons like reperfusion after ischemia, hyperglycemia, increased pathway of one-electrone reduction of oxygen, increased formation in fagocytes and catecholamines, decrease of pH, inflammation, activation of myeloperoxidase and liberation of some metal from their components. Nitric oxide has a special role in sepsis. In low concentrations ameliorates the perfusion of the tissues, in high concentrations has cytotoxical properties and increases the formation of peroxynitrite which evokes vascular dysfunction. Therapeutically helps in sepsis substitution of antioxidants, especially ascorbic acid, selenium, glutathione and vitamin E. (Literature: Holecek V., Racek J., Liska J.: Free radicals in septical states. Klin. Biochem. Metab. 2004, 12(33), No 2, pp.101-105.
Dermatology
Free radicals and antioxidants are engaged in skin wounds, UV –radiation, carcinogenesis, ulcus cruris, aging of the skin, lipoperoxidaton of hair follicles (alopecia seborrhoica), psoriasis. lichen planus, celulitis, vitiligo, SLE, erythema, oedema, graying of the hair, old stains (lipofuscin) of the skin, fighting gases, sclerodermia and others.
(Literature: Resl Vl., Goetzova R., Holecek V.: Electrophoreogram of proteins of fibre liquid from femoral ulcer. Cs. Dermatologie 50, 320-324, 1975.
Holecek V., Resl Vl., Goetzova R., Andel Zd.: The biochemistry of the ulcus cruris and its therapy by ion exchangers. Abstracts 2nd Europian Congress on Clinical Chemistry, Prague, October 3-8, pp.126, 1976.
Resl, V., Holecek, V., Racek, J.: The importance of free radicals in dermatovenerology. Cs. Dermatologie, 70, 1995, č. 3, s. 157 – 159.
Fikrle T., Resl V., Racek J., Holecek V.: Antioxidants and skin protection before exposure of UV irradiation. Cas. lek. ces. 139 (12), 2000, 358-360.)
Resl V., Racek J., Holecek V., Fikrle T., Cetkovska P.: Free oxygen radicals in Dermatology. Ces-slov. Derm. 76 (2), 2001, 83-89.
Degenerative nervous diseases
Very important in the therapy is the penetration of drugs through the blood-brain barrier. To such diseases with are influenced by free radicals and antioxidants belong: Alzheimer and Parkinson disease, sclerosis multiplex, amyotrophic lateral sclerosis, Huntington disease, schizophrenia, tarditive diskinesis and chronic fatigue syndrome.
(Literature: Holecek V., Rokyta R.: Chronic fatigue syndrome Ceskoslovenska fyziologie, 65, 2016, 69-74.
Holecek V. Rokyta R.: : Possible etiology and treatment of amyotrophic lateral sclerosis. Neuroendocrinology letters 02/2018,38(8):528-531.
Rokyta, R., Racek, J., Holecek, V.: Free radicals in central nervous system. Cs. fysiol., 4, 1996, č. 1, s. 4 – 12
Rokyta R., Stopka P., Holecek V., Krikava K., Pekarkova I.: Direct measurement of free radicals in the brain cortex and the blood serum after nociceptive stimulation in rats. Neuroendocrinol. Letters No 4, 25, 2004, pp.252-256.
Esmaeil Mousavi S, Heydarpour P, Reis J, Amiri M, Sahraian MA: Multiple sclerosis and air pollution exposure: Mechanisms toward brain autoimmunity. Med Hypotheses. 2017 Mar;100:23-30. doi: 10.1016/j.mehy.2017.01.003. Epub 2017 Jan 11.
(Wu JQ, Kosten TR, Zhang XY.: Free radicals, antioxidant defense systems, and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Oct 1;46:200-6. doi: 10.1016/j.pnpbp.2013.02.015. Epub 2013 Mar 5.)
Reasons of increased free radical damage:
- lack of free radical scavengers
- inflammations
- hemodynamic disturbances
- degenerative diseases
Psychiatric bimodal disease – serotonin is protected by IMAO (inhibitor of monoaminooxidase, and/or by antixoxidants.
Migrain – (Literature: Rathnasiri Bandara SM: Migraine and psychiatric disorders co-morbidity explained by sinus hypoxic nitric oxide theory – a new hypothesis on the Sino rhinogenic theory.Med Hypotheses. 2014 Mar;82(3):257-65. doi: 10.1016/j.mehy.2013.11.045. Epub 2013 Dec 12.)
Méniere´s syndrome (Literature: Raponi G, Alpini D, Volontè S, Capobianco S, Cesarani A.: The role of free radicals and plasmatic antioxidant in Ménière’s syndrome. Int Tinnitus J. 2003;9(2):104-8)
Congestive heart disease
Increased malondialdehyde (lipoperoxidation), TNFα, purine degradation (increased superoxide).
Obstructive sleep apnea
Is the most type of sleep apnea and is caused by complete or partial obstructions of the upper airway. Reoxydation leads to increased production of free radicals.
Transplantations
Transplantations of organs and tissues is accompanied by ischemia and reperfusion and so free radicals formation. Cell necroses are the source of purin bases, which are metabolised to uric acid and superoxide production is on the level of xanthin oxidase. Activation of neutrophiles and decrease of pH aswell as stress are another sources of free radicals. High level of antioxidants protects the graft before damage. Also reperfusion fluid containing antioxidants during transportation of the graft is used. There are many publications of these problems in different organs or tissues during transplantation.
Intoxication by chemical compounds
Many different chemicals can damage the workers. Increased free radicals are one of the reasons of intoxication: f. ex. styren
(Literature: Kohout, J., Holecek, V., Machartova, V., Racek, J., Jerabek, Z.., Senft, V.: Monitoring of the effect of free radicals by workers in risk of styrene. Vnitrní Lek., 42, 1996, č. 8, pp. 537 – 539),
Pneumoconiosis (Literature: Kohout, J., Holecek, V., Soukupova, K., Machartova, V., Racek, J., Senft, V.: Monitoring of the effect of free radicals by patients with pneumoconiosis. Vnitr. Lek., 42, 1996, No. 1, pp. 20 – 22),
LEAD (Literature: Machartova, V., Racek, J., Kohout, J., Holecek,V.,Krejcova, I., Senft, V.: Pointers of action of free radicals by workers in risk of lead. Vnitr. Lék., 44, 1998, č. 2, pp. 83 – 85).
Diabetes mellitus (DM)
There is an increased level of TBARS (malondialdehyde) in serum, AGE –substances (advanced glycation end-products) are formed in the reaction of glucose and free radicals. Decreased activity of glutathione peroxidase leads to the increase of hydrogen peroxide, which damages β-cells of pancreas. Lower pH increases the effect of free radicals. In prediabetical state usually is a high level of uric acid which is decreasing during the generation of diabetes mellitus. IL-1 from macrophages increases selectively nitric oxide in β-cells → lesion of enzymes containing Fe and S → decreased energy production. Antioxidants decrease glycated hemoglobin, but not current glykemia. AGE substances accumulates in proteins with long half-life: retina, vascular endothelium, myelin, glomerular membranes. Diabetical complications follow. Creation of AGE proteins are prevented by phosphopyridoxal, guanidine, acetylsalicylic acid, D-lysin (glycation of it will arise a carcinogenic substance) and others. Formation of AGE-substaces is faster than their degradation, which is performed after its binding to AGE-receptor (RAGE). AGE cause cell proliferation, they support coagulopathy. In diabetes mellitus paradoxically is a lack of energy due to its insufficient use a due to hypoxia, which leads to the decrease of aerobic glycolysis. At the same time reduction potencial is decreased (especially NADPH), which is intracellularly consumed by free radicals and by metabolic pathways (f. ex. glutathione reductase, NO synthase, formation of PGH2 , aldosoreductase).
Pulmonary diseases
Cystic fibrosis, hyperoxidative damage of lung of prematures, ARDS, fibrotic alveolitis, palliative lungs, fibromuscular lung dysplasia, asthma bronchiale, carcinoma of the lungs.
(Literature: Pesek, M., Racek, J., Holecek, V.: Free radicals in respiratory diseases. Stud. Pneumol. Pthiseol. 59, No.5, pp. 211-215, 1999.
Pesek, M., Racek, J., Holecek, V.: Free radicals un Pathogenesis and Therapy of the Lung Cancer. Stud. Pneumol. Pthiseol., 60, 2000, No.3, pp.. 99-103)
Gynecology and obstetrics
SOD levels decrease during the pregnancy, GPx levels rise, AOC levels significantly decrease during the pregnancy, but they rise before the labor, during the labor the AOC levels decrease significantly and free radicals increase (ischemic reperfusion?, pain). It leads to the rupture of amniotic sack and event. premature birth. Children have significantly higher TBARS than mothers and the controls. Extremely high TBARS levels can damage some tissues, especially the fetal brain. There still remains the question whether to use the antioxidants during the pregnancy prophylacticly.
Gynecological inflammations, tumors, fertility (men and women), preeclampsia, amniotic fluid and others. (Literature: Rokyta, Z., Racek, J., Holecek, V., Marik, J. J.: I. Free radicals and antioxidants in gynecology. Ces. Gynekol., 63, 1998, No. 4, pp. 334 – 339
Rokyta, Z., Racek, J., Holecek, V., Marik, J. J.: II. Free radicals and antioxidants in obstetrics. Ces. Gynekol., 63, 1998, No.4, pp. 340 – 345)
Otorhinolaryngology (ENT)
Sinusitis, inflammations, diseases of nose, allergic rhinitis, polyps, tumors, cochlear homeostasis, hearing loss and others.
See monography: J.Miller, Coleen G. Le Prell, L.Rybak et al. : Free radicals in ENT Pathology, 2015 ISSN 2197-7224, ISSN 2197-7232 (electronic), ISBN 978-3-319-13472-7, DOI 10.1007/978-3-319-13473-4. (e book).
Human Press is a brand of Springer. Springer International Publishing AG Schwitzerland (www.springer.com). My contribution: V.Holecek, R.Rokyta, J.Slipka chapter 24, pp. 479-492 ).
Obesity
There are 3 types of obesity: gynoid, android obesity and obesity of children. Android obesity (apple, visceral fat) has higher risk of cardiovascular diseases, gynoid obesity (pear) suffers more often of gall bladder diseases, venous diseases, spondylosis and constipation.
Obese people during excercise have lower anaerobic threshold and higher level of uric acid: = higher free radical damage. Free radicals damage membranes of erythrocytes and so decrease tissue oxidation. On other side in obesity may be surplus of vasodilatating nitric oxide, but also of vasocontricting endothelin, the result may be vasoconstriction. In obesity there is a higher production of free radicals, higher lipoperoxidation and other free radical damage. Antioxidant may help. ROS activates HMG-CoA reductase, enzyme producing cholesterol. Obese people have low levels of zinc.
Stomatology
Origin of free radicals in stomatogy: inflammations, tumors,leucocytes, reperfusion after ischemia, cell necrosis, hyperglycemia, hyperlipidemia, bleeding in presence of some metals (Fe, Hg,Cu-seals), osteoclasts, UV light directed on erythrocytes in the mucous membrane, administration of some foodstuff, inhalation of pollutants (exhaust gases), pain, peroxides in bleaching of teath, toothpaste.
How free radicals act in oral cavity?
During lipoperoxidation are created harmful substances f.ex. carcinogenic aldehydes. Lipoperoxidation works degenerative changes to necroses in periodontal tissue, destruction of bone mass in the place of inflammation infiltration (decreased SOD, GPx, GSH-R and increased malondialdehyde).
Products of free radical reactions f.ex. malondialdehyde (MDA) are bound on free –NH2 groups of proteins with damage of them. Malondialdehyde in saliva is dependent on age and smoking,
MDA and PBI don´t correlate together. Acid environment increases the effect of free radicals, sweet drinks and dehydratation decrease the protective effect of saliva. Children with frequent dental carries drink less water and milk. Free radicals decrease the total antioxidant capacity of saliva and tissues, AGE´s and free radicals increase the digestion of dentin by collagenase: ROS are increasing in periodontits, antioxidant enzymes (SOD, GPx, glutathion reductase) increase the lipoperoxidation. Massive oxidation effect has hydrogen peroxide, increases enamel permeability and penetrates to roots of teeth. Free radicals release calcium from dentin. Vitamin C decreases the incidence of teeth carries and oral cariogenic flora(streptococcus mutans).
Salicylic acid decrease supeoxide production, myeloperoxidase forms hypochlorous acid, which damage dentin, but HClO may be used for desinfection of channels.
(Literature: Holecek V., Masek V., Hecova H., Zicha A., Netolicky J.: Free radicals and antioxidants in stomatology. Ces. Stomatol. 2008, 108(1), 20-23.)
Pain
In animal’s experiments, we have found out that after the mechanical nociceptive stimulation the final products of free oxygen radicals thiobarbituric acid reactive substances (TEARS) and malondialdehyde (MDA) are increased as well as the participating enzymes-superoxiddismutase (SOD) and glutathionperoxidase (GPx). These changes were measured in sensorimotor brain cortex. Antioxidants decreased the perception of pain. (Literature: Rokyta R., Stopka P., Kafunkova E., Krizova J., Fricova J., Holecek V.: The evaluation of nociceptive intensity by using free radicals direct measurement by EPR method in the tail of anaesthetized rats. Neuroendocrinology Letters 29, 2008(6): 1007-1014.
Immunology, alergy, posibility of pre- and postnatal consequences.
IgE, AGE
(Literature: Liska J., Siala K., Culakova B., Holecek V., Sobotova St., Sykora J., Sefrna Fr.: Signifikance of Immunoglobin E in Umbilical Blood in Relation to an Allergic Family History, Seasonality, Immunity and Impact of Applied Non-pathogenic E.Coli on Children´s Microbiome. J.of Life Science 11 (2017): 105-124.
Liska J., Holecek V., Siala K., Sobotova S., Trefil L., Racek J., Sykora J. and Sefrna F. : Umbilical IgE and Advanced Glycation Products in Association with Allergies in Childhood.Immun., Endoc. & Metab. Agents in Med. Chem., 2016, 16, 1-5.)
Opthalmology
There are many publications about free radicals in opthalomology, possible use of antioxidants are in: retinopathy, aging of skimmer, age related macular degeneration, cataracta, conjunctivitis, UV irradiation of the eyes.
Main antioxidant of the eyes is ascorbic acid. Metabolism of glutathione is very active in eye lens, corneal epithelium and in retina. Oxidative stress leads to cataracta and to the rise of peroxides. Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for age-related macular degeneration.
(Literature: Racek J., Holecek V., Ricarova R.: Free radicals and antioxidants in opthalmology. Klin. Biochem. Metab. 9(30).2001, No1, str. 20 – 24.
Rohrer B, Bandyopadhyay M, Beeson C: Reduced Metabolic Capacity in Aged Primary Retinal Pigment Epithelium (RPE) is Correlated with Increased Susceptibility to Oxidative Stress. Adv Exp Med Biol. 2016;854:793-8. doi: 10.1007/978-3-319-17121-0_106.
Marazita MC, Dugour A, Marquioni-Ramella MD, Figueroa JM, Suburo AM.: Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration. Redox Biol.10.1016/j. redox.2015.11.011. Epub 2015 Nov 29.
Giacintov P., Giacitov A.: Dry form of age-related macular degeneration and dietary supplemenmts, use of microperimetry. In Print.
Lymphoedema
(Literature: Holecek V.: Lymphoedema and free radicals. Lympho 2010, 15.-16.X., Praque, Abstracts , pp. 36.).
Membrane lipids
Free radicals or phospholipase release free arachidonic acid from the membranes. Arachidonic acid is metabolised by cyclooxygenase to malondialdehyde, prostaglandins, prostacyclines, thromboxans and by 5-lipoxygenase to leucotriens.
Nutrition
Antioxidant capacity of beverages and food.
(Literature:Holecek V., Rokyta R., Vlasak R.: Antioxidants and their gastrointestinal absorption and interferention of their effect. Ceskoslovenská fyziologie, 57, 2008, No.1, 24-32.)
Sport
Sport performance increases the production of free radicals due to repeated muscle hypoxia and reperfusion. Increased creation of heat proteins helps to suffer hypoxia. Sufficient antioxidant protection prevents the losses of important substances from muscles (creatin kinase, myoglobin etc.). Muscle fatigue shortens. Lack of antioxidants decreases physical performance by 40% and decreases also immunity. Red muscle fibers (endurance) have 4 times more of vitamin E than white fibers (fast), which decrease by lack of antioxidants and by aging.
(Literature: Jeschke, J., Holecek, V., Racek, J., Krejcova, I.: Importance of administration of multrivitamin mixture with trace elements on biochemical parameters of top handball players before intensive training and after. Med. Sport. Boh. Slov., 4, 1995, No 4, pp. 107 – 112
Holecek, V., Racek, J., Jeschke, J.: Free radicals and sport performance. Med. Sport. Boh. Slov., 4, 1995, No 3, pp.. 78 – 80.)
Aging
Aging is a progressive unfavorable loss of adaptation ability, increased vulnerability, decreased vitality and impairment of life expectancy. Mitochondria (“biological hours of aging”) are the source of energy, but also the source of free radicals. Every human cell is daily attacted 10 000 times by free radicals. How to slow down the speed od aging?:
Increase enzymatic and other antioxidants, increase antioxidant capacity, decrease the load of free radicals. Women live longer than men, their mitochondria produce less ROS.
Long haired people have increased SOD activity, higher levels of vitamins C and E and have less PUFA (polyunsaturated fatty acids).
Transfusion
Leucocytes in stored blood have high levels of free radicals, which influence the integrity of stored erythrocytes (hemolysis, decrease of glutathione, increased malondialdehyde, lactate dehydrogenase and potassium in plasma). Antioxidants improve this findings.
(Literature: Racek, J., Herynková, R., Holecek, V., Jerabek, Z., Slama, V.: The influence of antioxidants on the quality of stored blood of blood donors. Proceedings of the Laboratory Medicine ’95 11th IFCC European Congress of Clinical Chemistry, Tampere, Finland, 2 – 7 July 1995 (No 361).
Osteoarthritis a osteoarthrosis, osteoporosis,
revmatitic artrititis
Kucera, M., Racek, J., Holecek, V., Krejcova, I.: The question of possible importance of free radicals in ethiopathogenesis of osteoarthrosis. Ces. Revmatol., 7, 1998, No 4, pp. 175 – 177
Author: MUDr Václav Holeček PhD. , Mulac Hospital, Pilsen, 32002 Dvořákova 17.
Mobil: 307870854, e-mail: vholecek@volny.cz. Privat: Plzeň 32600, V Kamení 61. Czech Republik.