ArticlePDF Available

Free Radicals and Their Role in Different Clinical Conditions: An Overview

Authors:

Abstract and Figures

Free Radicals are molecules with an unpaired electron and are important intermediates in natural processes involving cytotoxicity, control of vascular tone, and neurotransmission. Free radicals are very unstable and react quickly with other compounds, and try to capture the needed electron to gain stability. A chain reaction thus gets started. Once the process is started, it can cascade, and inally results in the disruption of a living cell. Generally, harmful effects of reactive oxygen species on the cell are most often like damage of DNA, oxidations of polydesaturated fatty acids in lipids, oxidations of amino acids in proteins, oxidatively inactivate specific enzymes by oxidation of co-factors. Free radicals cause many human diseases like cancer Alzheimer’s disease, cardiac reperfusion abnormalities, kidney disease, fibrosis, etc. The free radicals formed in our body are combated by antioxidants that safely interact with free radicals and terminate the chain reaction before vital molecules are damaged. Excessive exercise has been found to increase the free radical level in the body and causes intense damage to the Regular physical exercise enhances the antioxidant defense system and protects against exercise induced free radical damage. Apart from the destructive effects of free radical they are also responsible for some vital actions like destroy the bacteria and other cells of foreign matter, kill cancer cells, turning on and off of genes and fight infection, to keep our brain alert and in focus.
Content may be subject to copyright.
Abheri Das Sarma et. al. / International Journal of Pharma Sciences and Research (IJPSR)
Vol.1(3), 2010, 185-192
Free Radicals and Their Role in Different Clinical Conditions: An
Overview
2Abheri Das Sarma, 1Anisur Rahaman Mallick and 1A. K. Ghosh*
1Department of Pharmacology, Gupta College of Technological Sciences
Asansol, Burdwan, West Bengal, Pin - 713301, India
2Department of Pharmaceutics, Gupta College of Technological Sciences
Asansol, Burdwan, West Bengal, Pin - 713301, India
Abstract
Free Radicals are molecules with an unpaired electron and are important intermediates in natural processes
involving cytotoxicity, control of vascular tone, and neurotransmission. Free radicals are very unstable and react
quickly with other compounds, and try to capture the needed electron to gain stability. A chain reaction thus gets
started. Once the process is started, it can cascade, and finally results in the disruption of a living cell. Generally,
harmful effects of reactive oxygen species on the cell are most often like damage of DNA, oxidations of
polydesaturated fatty acids in lipids, oxidations of amino acids in proteins, oxidatively inactivate specific
enzymes by oxidation of co-factors. Free radicals cause many human diseases like cancer Alzheimer’s disease,
cardiac reperfusion abnormalities, kidney disease, fibrosis, etc. The free radicals formed in our body are
combated by antioxidants that safely interact with free radicals and terminate the chain reaction before vital
molecules are damaged. Excessive exercise has been found to increase the free radical level in the body and
causes intense damage to the Regular physical exercise enhances the antioxidant defense system and protects
against exercise induced free radical damage. Apart from the destructive effects of free radical they are also
responsible for some vital actions like destroy the bacteria and other cells of foreign matter, kill cancer cells,
turning on and off of genes and fight infection, to keep our brain alert and in focus.
Keywords
Radicals, Free Radicals, Reactive oxygen species, Anti-oxidant, Redox signaling
Introduction
Free Radicals are molecules with an unpaired electron. Due to the presence of a free electron, these molecules
are highly reactive. They are important intermediates in natural processes involved in cytotoxicity, control of
vascular tone, and neurotransmission. Radiolysis is a powerful method to generate specific free radicals and
measure their reactivity [1].
Types of long lived radicals
Stable radicals: The prime example of a stable radical is molecular oxygen O2. Organic radicals can be long
lived if they occur in a conjugated π system, such as the radical derived from α-tocopherol & vitamin E. Thiazyl
radicals show remarkable kinetic and thermodynamic stability, with only a very limited extent of π resonance
stabilization.
Persistent radicals: Compounds with persistent radicals are long lived due to steric crowding around the radical
center and makes them physically difficult to react with another molecule. Examples of these include-Gomberg's
triphenylmethyl radical, Fremy's salt (Potassium nitrosodisulfonate, Nitroxides, such as TEMPO(2,2,6,6-
Tetramethylpiperidine-1-oxyl ),verdazyls, nitronyl nitroxides, azephenylenyls , radicals derived from PTM
(perchlorophenylmethyl radical) and TTM (tris(2,4,6-trichlorophenylmethyl radical). The longest-lived free
radical is melanin, which may persist for millions of years.
Diradicals: Molecules containing two radical centers are called diradical. Multiple radical centers can also exist
in a molecule. Molecular oxygen naturally (i.e. atmospheric oxygen) exists as a diradical (in its ground state as
triplet oxygen). The high reactivity of atmospheric oxygen is owed somewhat to its diradical state (although
non-radical states of oxygen are actually less stable). The existence of atmospheric molecular oxygen as a
triplet-state radical is the cause of its paramagnetic character, which can be easily demonstrated by attraction of
oxygen to an external magnet [2-7].
Production route of free radicals
Production of free radicals in the body is continuous and inescapable. The basic causes include the following
[8]:
Abheri Das Sarma et. al. / International Journal of Pharma Sciences and Research (IJPSR)
Vol.1(3), 2010, 185-192
The immune system: Immune system cells deliberately create oxy-radicals and ROS (Reactive oxygen species)
as weapons.
Energy production: During energy-producing cell generates continuously and abundantly oxy-radicals and
ROS as toxic waste. The cell includes a number of metabolic processes, each of which can produce different
free radicals. Thus, even a single cell can produce many different kinds of free radicals.
Stress: The pressures common in industrial societies can trigger the body's stress response to mass produce free
radicals. The stress response races the body's energy-creating apparatus, increasing the number of free radicals
as a toxic by-product. Moreover, the hormones that mediate the stress reaction in the body - cortisol and
catecholamine - themselves degenerate into particularly destructive free radicals.
Pollution and other external substances: Air pollutants such as asbestos, benzene, carbon monoxide, chlorine,
formaldehyde, ozone, tobacco smoke, and toluene ,Chemical solvents such as cleaning products, glue, paints,
and paint thinners , Over-the-counter and prescribed medications , Perfumes , Pesticides , Water pollutants such
as chloroform and other trihalomethanes caused by chlorination ,Cosmic radiation, Electromagnetic fields,
Medical and dental x-rays, Radon gas, Solar radiation ,the food containing farm chemicals, like fertilizers and
pesticides, processed foods containing high levels of lipid peroxides, are all potent generator of free radicals.
General factors: Aging, Metabolism, Stress
Dietary factors: Additives, alcohol, coffee, foods of animal origin, foods that have been barbecued, broiled,
fried, grilled, or otherwise cooked at high, temperatures, foods that have been browned or burned, herbicides,
hydrogenated vegetable oils, pesticides, sugar.
Toxins: Carbon tetrachloride, Paraquat, Benzo (a) pyrene, Aniline dyes, Toluene
Drugs: Adriamycin, Bleomycin, Mitomycin C, Nitrofurantoin, Chlorpromazine
Formation of free radicals
Normally, bonds don’t split to leave a molecule with an odd, unpaired electron. But when weak bonds split, free
radicals are formed. Free radicals are very unstable and react quickly with other compounds, trying to capture
the needed electron to gain stability. When the "attacked" molecule loses its electron, it becomes a free radical
itself, beginning a chain reaction. All this happens in nanoseconds. Once the process is started, it can cascade,
finally resulting in the disruption of a living cell. Some free radicals may arise normally during metabolism and
by immune system’s cells purposefully to neutralize viruses and bacteria. Normally, the body can handle free
radicals, but if antioxidants are unavailable, or if the free radical production becomes excessive, damage can
occur [8].
Figure 1: Free radical formation [8]
Steps involving free radical generation
In chemistry, free radicals take part in radical addition and radical substitution as reactive intermediates. Chain
reactions involving free radicals can usually be divided into three distinct processes: initiation, propagation, and
termination.
Initiation reactions are those, which result in a net increase in the number of free radicals. They may involve the
formation of free radicals from stable species or they may involve reactions of free radicals with stable species
to form more free radicals.
Propagation reactions involve free radicals in which the total number of free radicals remains the same.
Termination reactions are those reactions resulting in a net decrease in the number of free radicals. Typically
two free radicals combine to form a more stable species, for example: 2Cl· Cl2
Abheri Das Sarma et. al. / International Journal of Pharma Sciences and Research (IJPSR)
Vol.1(3), 2010, 185-192
The formation of radicals may involve breaking of covalent bonds homolytically, a process that requires
significant amounts of energy. For example, splitting H2 into 2H· has a ΔH° of +435 kJ/mol, and Cl2 into 2Cl·
has a ΔH° of +243 kJ/mol. This is known as the homolytic bond dissociation energy, and is usually abbreviated
as the symbol DH°. The bond energy between two covalently bonded atoms is affected by the structure of the
molecule. Homolytic bond cleavage most often happens between two atoms of similar electronegativity.
However, propagation is a very exothermic reaction.
Radicals may also be formed by single electron oxidation or reduction of an atom or molecule. An example is
the production of superoxide by the electron transport chain.
Free radical-targets
Free radicals attack three main cellular components.
Lipids
Peroxidation of lipids in cell membranes can damage cell membranes by disrupting fluidity and permeability.
Lipid peroxidation can also adversely affect the function of membrane bound proteins such as enzymes and
receptors.
Proteins
Direct damage to proteins can be caused by free radicals. This can affect many kinds of protein, interfering with
enzyme activity and the function of structural proteins.
DNA
Fragmentation of DNA caused by free radical attack causes activation of the poly (ADP-ribose) synthetase
enzyme. This splits NAD+ to aid the repair of DNA. However, if the damage is extensive, NAD+ levels may
become depleted to the extent that the cell may no longer be able to function and dies.
The site of tissue damage by free radicals is dependent on the tissue and the reactive species involved. Extensive
damage can lead to death of the cell; this may be by necrosis or apoptosis depending on the type of cellular
damage. When a cell membrane or an organelle membrane is damaged by free radicals, it loses its protective
properties. This puts the health of the entire cell at risk.
Damaging effects
Cells normally defend themselves against ROS damage through the use of enzymes such as superoxide
dismutase and catalase. Small molecule antioxidants such as ascorbic acid (vitamin C), uric acid, and
glutathione also play important roles as cellular antioxidants. Similarly, polyphenol antioxidants assist in
preventing ROS damage by scavenging free radicals. The negative effects of ROS on cell metabolism include
roles in programmed cell death and apoptosis, whereas positive effects include induction of host defense genes
and mobilization of ion transport systems. In particular, platelets involved in wound repair and blood
homeostasis release ROS to recruit additional platelets to sites of injury. These also provide a link to the
adaptive immune system via the recruitment of leukocytes. Reactive oxygen species are involved in
cardiovascular disease, hearing impairment via cochlear damage induced by elevated sound levels, ototoxicity
of drugs such as cisplatin, and in congenital deafness in both animals and humans. [2-5]
Generally, harmful effects of reactive oxygen species on the cell are most often:
Damage of DNA
Oxidations of polydesaturated fatty acids in lipids
Oxidations of amino acids in proteins
Oxidatively inactivate specific enzymes by oxidation of co-factors
Fig.2. Cellular damage due to free radicals [9]
Abheri Das Sarma et. al. / International Journal of Pharma Sciences and Research (IJPSR)
Vol.1(3), 2010, 185-192
Reactive oxygen species (ROS)
Reactive oxygen species (ROS) are very small molecules and are highly reactive due to the presence of unpaired
valence shell electrons. ROS is formed as a natural byproduct of the normal metabolism of oxygen and have
important roles in cell signaling. However, during times of environmental stress ROS levels can increase
dramatically, which can result in significant damage to cell structures. Platelets involved in wound repair and
blood homeostasis release ROS to recruit additional platelets to sites of injury. Generally, harmful effects of
reactive oxygen species on the cell are most often like -Damage of DNA, oxidations of polydesaturated fatty
acids in lipids, oxidations of amino acids in proteins, oxidatively inactivates specific enzymes by oxidation of
co-factors. [10-14]
Figure 3: Effects of ROS [8]
Free radicals in beneficial role
Free radicals perform many critical functions in our bodies in controlling the flow of blood through our
arteries, to fight infection, to keep our brain alert and in focus.
Phagocytic cells involved in body defense produce and mobilize oxygen free radicals to destroy the bacteria
and other cells of foreign matter which they ingest.
Similar to antioxidants, some free radicals at low levels are signaling molecules, i.e. they are responsible for
turning on and off of genes.
Some free radicals such as nitric oxide and superoxide are produced in very high amount by immune cells
to poison viruses and bacteria.
Some free radicals kill cancer cells. In fact certain cancer drugs aim in increasing the free radical amount in
body.
Defensive systems against free radicals
All aerobic forms of life maintain elaborate anti-free-radical defense systems, also known as antioxidant
systems.
Enzymes: The defense enzyme, superoxide dismutase (SOD), takes hold of molecules of superoxide - a
particularly destructive free radical-and changes them to a much less reactive form. SOD and another important
antioxidant enzyme set, the glutathione system, work within the cell. Circulating biochemical’s like uric acid
and ceruloplasmin react with free radicals in the intercellular spaces and bloodstream.
Self repair: The body also has systems to repair or replace damaged building blocks of cells. Most protein
constituents in the cell are completely replaced every few days. Scavenger enzymes break used and damaged
proteins into their component parts for reuse by the cell.
Nutrients: Vitamins and other nutrients neutralize the oxy radicals' and serves as second line of defense.
Among the many substances used are Vitamins C and E, beta-carotene, and bioflavonoids. [15].
Free radical diagnosis-
Free radical can be diagnosed by certain techniques that includes [16]:
i. Electron Spin resonance
ii. Nuclear magnetic resonance using a phenomenon called CIDNP
iii. Chemical labeling-
This includes the use of X-ray photoelectron spectroscopy (XPS) or Absorption spectroscopy.
iv. Use of free radical markers-
Stable, specifc, or nonspecific derivatives of physiological substances can be measured e.g lipid
peroxidation products (isoprostanes), amino acid oxidation products (meta-tyrosine, ortho-tyrosine,
hydroxyl-Leu dityrosine) , peptide oxidation products (oxidized glutathione).
Abheri Das Sarma et. al. / International Journal of Pharma Sciences and Research (IJPSR)
Vol.1(3), 2010, 185-192
v. Indirect method-
Measurement of the decrease in the amount of antioxidants(,reduced glutathione-GSH)
Free radicals and human disease
Cancer: Like radiation and carcinogens, free-radical oxidation breaks strands of DNA. The breaks are repaired,
but some mistakes occurs leading mutations. These genetic mutations can cause cancers. The age-related
increase in cancer rates might have something to do with an age-related rise in oxidative damage to DNA.
Alzheimer’s disease: The brain in Alzheimer's disease (AD) is under increased oxidative stress and this may
have a role in the pathogenesis of neuron degeneration and death in this disorder. The direct evidence supporting
increased oxidative stress in AD is: (1) increased brain Fe, Al, and Hg in AD, capable of stimulating free radical
generation; (2) increased lipid peroxidation and decreased polyunsaturated fatty acids in the AD brain, and
increased 4-hydroxynonenal, an aldehyde product of lipid peroxidation in AD ventricular fluid; (3) increased
protein and DNA oxidation in the AD brain; (4) diminished energy metabolism and decreased cytochrome c
oxidase in the brain in AD; (5) advanced glycation end products (AGE), malondialdehyde, carbonyls,
peroxynitrite, heme oxygenase-1 and SOD-1 in neurofibrillary tangles and AGE, heme oxygenase-1, SOD-1 in
senile plaques; and (6) that amyloid beta peptide is capable of generating free radicals. So free radicals are
possibly involved in the pathogenesis of neuron death in Alzheimer's disease (AD).
Cardiac Reperfusion Abnormalities: Oxygen free radicals are highly reactive compounds causing per
oxidation of lipids and proteins and are thought to play an important role in the pathogenesis of reperfusion
abnormalities including myocardial stunning, irreversible injury, and reperfusion arrhythmias. Free radical
accumulation has been measured in ischemic and reperfused myocardium directly using techniques such as
electron paramagnetic resonance spectroscopy and tissue chemiluminescence and indirectly using biochemical
assays of lipid per oxidation products. Potential sources of free radicals during ischemia and reperfusion have
been identified in myocytes, vascular endothelium, and leukocytes. Injury to processes involved in regulation of
the intracellular Ca2+ concentration may be a common mechanism underlying both free radical- induced and
reperfusion abnormalities.
Kidney: Mitochondrial free radical production induces lipid peroxidation during myohemoglobinuria. Iron
catalyzed free radical formation and lipid peroxidation are accepted mechanisms of heme protein-induced acute
renal failure. However, the source(s) of those free radicals which trigger lipid peroxidation in proximal tubular
cells remains unknown. In conclusion, the terminal mitochondrial respiratory chain is the dominant source of
free radical.
Fibrosis: Oxygen, paraquat, nitrofurantoins, and bleomycin, produces pulmonary fibrosis. Radical-generating
agents such as iron and copper are also associated with liver fibrosis (cirrhosis) and fibrotic changes in other
organs such as the heart. The induction of vitreous scarring by interocular iron or copper is also well known, as
is the association of homocystinuria with fibrotic lesions of the arteries. Adult Respiratory Distress Syndrome
(ARDS) occurs due to production of active oxygen species by inflammatory cells.
Figure 4: Overview of free radical damage [16]
Abheri Das Sarma et. al. / International Journal of Pharma Sciences and Research (IJPSR)
Vol.1(3), 2010, 185-192
Anti-oxidant
Substances that inhibit oxidation, and are capable of counteracting the damaging effects of oxidation in body
tissue are termed antioxidants. They prevent damage caused by free radicals. They create a barrier from free
radial damage that results in decaying process of oxidation. Oxidation causes aging in the skin, so antioxidants
like pomegranate, vitamin C, vitamin E, goji berry, ellagic acid, and green tea can reduce the process of aging
Antioxidants are intimately involved in the prevention of cellular damage -- the common pathway for cancer,
aging, and a variety of diseases. [6-13]. Although there are several enzyme systems within the body that
scavenge free radicals, the principle micronutrient (vitamin) antioxidants are vitamin E, beta-carotene, and
vitamin C. Additionally, selenium, a trace metal that is required for proper function of one of the body's
antioxidant enzyme systems, is sometimes included in this category. The body cannot manufacture these
micronutrients so they must be supplied in the diet [1]. The ideal antioxidants should bear certain properties
like; they must be effective in low concentration. They must be adequately soluble in oxidizable product. They
must be non-toxic and non-irritant at the effective concentration even after prolong storage .They must be
odorless, tasteless and should not impart color to the product. Their decomposition product should be non- toxic
and non-irritant. They must be stable and effective over wide range of pH. They must be neutral and should not
react chemically with other constituent present [9].
Some natural and synthetic antioxidant: Vitamin E d-alpha tocopherol a fat-soluble vitamin present in nuts,
seeds, vegetable and fish oils, whole grains (esp. wheat germ), fortified cereals, and apricots. Vitamin C
Ascorbic acid is a water-soluble vitamin present in citrus fruits and juices, green peppers, cabbage, spinach,
broccoli, kale, cantaloupe, kiwi, and strawberries. Beta-carotene is a precursor to vitamin A (retinol) and is
present in liver, egg yolk, milk, butter, spinach, carrots, squash, broccoli, yams, tomato, cantaloupe, peaches,
and grains. Because beta-carotene is converted to vitamin A by the body there is no set requirement. [17-24].
Butylated hydroxy Toluene (BHT), butylated hydroxy Anisole (BHA), gallic acid are synthetic antioxidants.
Antioxidants preventing against free radical damage
The vitamins C and E are thought to protect the body against the destructive effects of free radicals.
Antioxidants neutralize free radicals by donating one of their own electrons, ending the electron-"stealing"
reaction. The antioxidant nutrients themselves don’t become free radicals by donating an electron because they
are stable in either form. They act as scavengers, helping to prevent cell and tissue damage that could lead to
cellular damage and disease.
Vitamin E – The most abundant fat-soluble antioxidant in the body. It is one of the most efficient chain-breaking
antioxidants available, is the primary defender against oxidation, and is the primary defender against lipid per
oxidation (creation of unstable molecules containing more oxygen than is usual). Vitamin C – The most
abundant water-soluble antioxidant in the body. It acts primarily in cellular fluid. It combats free-radical
formation caused by pollution and cigarette smoke. Also helps return vitamin E to its active form [1].
Role of antioxidant in preventing cancer and heart disease
Epidemiological observations show lower cancer rates in people whose diets are rich in fruits and vegetables.
This has lead to the theory that these diets contain substances, possibly antioxidants, which protect against the
development of cancer. There is currently intense scientific investigation into this topic. Thus far, none of the
large, well designed studies have shown that dietary supplementation with extra antioxidants reduces the risk of
developing cancer. Antioxidants are also thought to have a role in slowing the aging process and preventing
heart disease and strokes. Therefore from a public health perspective it is premature to make recommendations
regarding antioxidant supplements and disease prevention. [25-27].
Exercise and oxidative damage
Endurance exercise can increase oxygen utilization from 10 to 20 times over the resting state. This greatly
increases the generation of free radicals, prompting concern about enhanced damage to muscles, and other
tissues. As it is not possible to directly measure free radicals in the body, the by-products that result from free
radical reactions can be measured. If the generation of free radicals exceeds the antioxidant defenses then one
would expect to see more of these by-products. Regular physical exercise enhances the antioxidant defense
system and protects against exercise induced free radical damage. These changes occur slowly over time and
appear to parallel other adaptations to exercise. On the other hand, intense exercise in untrained individuals
overwhelms defenses resulting in increased free radical damage. Thus, the "weekend warrior" who is
predominantly sedentary during the week but engages in vigorous bouts of exercise during the weekend may be
doing more harm than good. [28-30].
Abheri Das Sarma et. al. / International Journal of Pharma Sciences and Research (IJPSR)
Vol.1(3), 2010, 185-192
Antioxidant supplements prevent exercise-induced damage
Vitamin deficiencies can create difficulties due to increased level of free radical in the body. It is hypothesized
that vitamin E is involved in the recovery process following exercise. Currently, the amount of vitamin E needed
to produce these effects is unknown. So, adequate amount of these vitamins must be regularly taken to reduce
damages caused by free radicals.
Amount of antioxidant required
Antioxidants supplements were once thought to be harmless but increasingly we are becoming aware of
interactions and potential toxicity. It is interesting to note that, in the normal concentrations found in the body,
vitamin C and beta-carotene are antioxidants; but at higher concentrations they are pro-oxidants and, thus,
harmful. Also, very little is known about the long-term consequences of mega doses of antioxidants. The body's
finely tuned mechanisms are carefully balanced to withstand a variety of insults. Taking chemicals without a
complete understanding of all of their effects may disrupt this balance [31 and 32].
Some recommendations regarding usage of antioxidants
One should follow balanced training program that emphasizes regular exercise and should include 5 servings of
fruit or vegetables per day. This may help to develop inherent antioxidant systems.
For extremely demanding races (such as an ultra distance event), or when adapting to high altitude, a vitamin E
supplement can be taken. One should carefully take the antioxidants so that over supplement does not occur
because it is extremely hazardous [33].
Conclusion
Monitoring and rapid detection of free radical is necessary to combat the spread of various diseases. Difficulty
in producing free radical scavengers in dosage from illustrates the need for more research about the chemical
nature and behavior of free radicals. So if we can intensify our knowledge regarding free radicals & go deep into
it we can easily prove the proverb “PREVENTION IS BETTER THAN CURE” but at the same time we should
remember, “AN APPLE A DAY KEEPS A DOCTOR AWAY”.
So detailed knowledge regarding the benefits and hazard of free radicals must be known so that in a busy life
where everyone is involved in a rat race one can easily combat against the deadly effect of free radicals and can
live a healthy life. Moreover this would serve as a concise knowledge about free radicals for the study of
students as well as researchers.
Reference
[1] R. T. Oakley, Prog. Inorg. Chem., 1998, 36, 299.
[2] A. J. Banister, et. al., Adv. Hetero. Chem., 1995, 62, 137.
[3] P. Pacher, J. S. Beckman, L. Liaudet, ("Nitric oxide and peroxynitrite in health and disease". Physiol. Rev., 2997, 87 (1): 315
424.
[4] C. J. Rhodes, An overview of the role of free radicals in biology and of the use of electron spin resonance in their detection may
be found in a recent book.
[5] Taylor and Francis, Toxicology of the Human Environment - the critical role of free radicals, , London, 2000.
[6] G. Herzberg, "The spectra and structures of simple free radicals", 1971.
[7] 28th International Symposium on Free Radicals, 2008.
[8] Lippincott Williams & Wilkins Instructor’s Resource, Parth’s Pathophysiology: Concepts of Altered Health States, Seventh
edition, 2008.
[9] C. K. Sen, The general case for redox control of wound repair, Wound Repair and Regeneration, 2003, 11, 431-438.
[10] F. Krötz, H. Y. Sohn, T. Gloe, et. al., Oxidase-dependent platelet superoxide anion release increases platelet recruitment, Blood,
2002, 100, 917-924.
[11] P. Pignatelli, F. M. Pulcinelli, L. Lenti, et. al., Hydrogen Peroxide Is Involved in Collagen-Induced Platelet Activation, Blood,
1998, 91 (2), 484-490.
[12] T. J. Guzik, R. Korbut, T. Adamek-Guzik, Nitric oxide and superoxide in inflammation and immune regulation, Journal of
Physiology and Pharmacology, 2003, 54 (4), 469-487.
[13] The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers New England
Journal of Medicine (NEJM), 1994, 230 (15) 14, 1029-1035.
[14] A Clinical Trial of Antioxidant Vitamins to Prevent Colorectal Adenoma NEJM, 1994, 231 (3), 141-147.
[15] Antioxidant Vitamins Benefits Not Yet Proved (editorial) NEJM, 1994, 230 (15) 1080 – 1081.
[16] Antioxidants and Physical Performance, Critical Reviews in Food Science and Nutrition, 1995, 35(1&2): 131-141.
[17] Increased blood antioxidant systems of runners in response to training load. Clinical Science, 1991, 80, 611-618.
[18] Exercise, Oxidative Damage and Effects of Antioxidant Manipulation (review). Journal of Nutrition, 1992, 122(3): 766-73.
[19] Antioxidants: role of supplementation to prevent exercise-induced oxidative stress (review). Medicine and Science in Sports and
Exercise, 1993, 25(2): 232-6.
[20] Prospects for the use of antioxidant therapies, Drugs, 1995, 49(3): 345-61.
[21] CRC Handbook of Free Radicals and Antioxidants, 1989, 1: 209-221.
[22] E. Cadenas, K. J. Davies, Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med, 2000, 29:222-
230.
[23] S. Z. Imam, B. Karahalil, B. A. Hogue, et. al., Mitochondrial and nuclear DNA-repair capacity of various brain regions in mouse
is altered in an age-dependent manner. Neurobiol Aging. In press, 2008.
Abheri Das Sarma et. al. / International Journal of Pharma Sciences and Research (IJPSR)
Vol.1(3), 2010, 185-192
[24] A. Navarro, Mitochondrial enzyme activities as biochemical markers of aging. Mol Aspects Med., 2004, 25:37-48.
[25] L. A. MacMillan-Crow, J. A.Thompson, Peroxynitrite-mediated inactivation of manganese superoxide dismutase involves
nitration and oxidation of critical tyrosine residues. Biochemistry, 1998, 37:1613-1622.
[26] J. J. Chen, B. P. Yu, Alterations in mitochondrial membrane fluidity by lipid peroxidation products. Free Radic Biol Med., 1994,
17:411-418.
[27] S. Laganiere, B. P. Yu, Modulation of membrane phospholipid fatty acid composition by age and food restriction. Gerontology,
1993, 39:7-18.
[28] CRC Handbook of Free Radicals and Antioxidants, 1989, 1: 209-221.
[29] D. Harman, "A biologic clock: the mitochondria?” J. Am. Geriatrics Society, 1972, 20 (4): 145-147.
[30] T. Parkes, K. Kirby, J Phillips, et. al., "Transgenic analysis of the cSOD-null phenotypic syndrome in Drosophila". Genome,
1998, 41: 642–651.
[31] P, Larsen, "Aging and resistance to oxidative damage in Caenorhabditis elegans". Proc Natl Acad Sci U S A, 1993, 90 (19):
8905-9.
[32] S. Helfand, B. Rogina, "Genetics of aging in the fruit fly, Drosophila melanogaster". Annu Rev Genet, 2008, 37: 329-48.
[33] R. Sohal, R. Mockett, W. Orr, "Mechanisms of aging: an appraisal of the oxidative stress hypothesis". Free Radic Biol Med.,
2002, 33 (5): 575-86.
... Anti-oxidant nutrients won't be free radicals through donating the electron since they were considered stable in either form, also they are acting as scavengers, help preventing cell as well as tissue damage which might result in cellular damage and diseases (42) . Based on the literature, the endogenous anti-oxidants might not be enough, the contributions regarding external anti-oxidants as one of the secondary defense systems against the free radicals was thus vital. ...
... In spite of the massive damage resulting from an increase in the accumulation regarding free radicals, there was a positive side or significant role free radicals (42) . ...
... Canlı organizmalardaki serbest radikaller hem endojen hem de eksojen kaynaklı olabilmektedir. Serbest radikaller hücrede ve çevrede daima üretilmektedirler [2,6,10,24,29,30,31]. ...
Conference Paper
Full-text available
Rapid growth of technology, enviromental pollution, agricultural pesticides, heavy metals uncontrolled industrialization and the pollution of waste water discharges changes (damages) the structure of each cell and tissue of organisms. Free radicals that occur in tissues damage dna, proteins, carbonhydrates and lipids which are biologically important. So living organisms have developed various mechanisms to protect themselves from the potantial detsroying effects of free radicals. Free radicals can move away from the living structure with the help of inrtacellular system, extracellular defence system and nutrition taken from outside in other words antioxydanst. For prevention form the illnesses cause by free radicals, oxydants and antioxydants have to be balances.
... At physiological concentration, ROS plays essential roles in physiological process such as gene expression, signal transduction, and redox regulation. However, during some pathological conditions, the excessive ROS production has harmful effects for human body, such as damages of proteins, DNA, and lipids [8]. In addition, many etiological factors associated with liver disease are commonly highly productive under excessive ROS. ...
Article
Full-text available
Polydatin, one of the natural active small molecules, was commonly applied in protecting and treating liver disorders in preclinical studies. Oxidative stress plays vital roles in liver injury caused by various factors, such as alcohol, viral infections, dietary components, drugs, and other chemical reagents. It is reported that oxidative stress might be one of the main reasons in the progressive development of alcohol liver diseases (ALDs), nonalcoholic liver diseases (NAFLDs), liver injury, fibrosis, hepatic failure (HF), and hepatocellular carcinoma (HCC). In this paper, we comprehensively summarized the pharmacological effects and potential molecular mechanisms of polydatin for protecting and treating liver disorders via regulation of oxidative stress. According to the previous studies, polydatin is a versatile natural compound and exerts significantly protective and curative effects on oxidative stress-associated liver diseases via various molecular mechanisms, including amelioration of liver function and insulin resistance, inhibition of proinflammatory cytokines, lipid accumulation, endoplasmic reticulum stress and autophagy, regulation of PI3K/Akt/mTOR, and activation of hepatic stellate cells (HSCs), as well as increase of antioxidant enzymes (such as catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), superoxide dismutase (SOD), glutathione reductase (GR), and heme oxygenase-1 (HO-1)). In addition, polydatin acts as a free radical scavenger against reactive oxygen species (ROS) by its phenolic and ethylenic bond structure. However, further clinical investigations are still needed to explore the comprehensive molecular mechanisms and confirm the clinical treatment effect of polydatin in liver diseases related to regulation of oxidative stress.
... Birçok mikroorganizma, insan-hayvan vücudunda ve yaşam alanlarında biyolojik bir denge halinde yaşamlarını sürdürmektedirler, fakat bu mikroorganizmaların hızlı ve kontrolsüz bir şekilde büyümeleri çeşitli tehlikeli sorunlara yol açabilmektedir. İnsan ve hayvan vücudundaki enfeksiyonları kontrol altına almak için antibiyotikler kullanılmakta, ancak insan vücudunda, başta serbest radikallerin artışı olmak üzere birçok yan etkiye neden olabilmektedirler (Parham et al., 2020;Sarma, Mallick, & Ghosh, 2010). Serbest radikaller başta kanser olmak üzere insan sağlığı açısından birçok tehlikeli hastalığı tetiklenmesinden sorumlu ajanlar olarak kabul edilmektedir. ...
... Again, the free radical attacks the C4-C5 double bond of both pyrimidines and purines, and the poly (ADP-ribose) synthetize enzyme is activated, resulting in the cleavage of NAD+ to aid in DNA fragmentation and repair. Finally, when degradation is widespread, NAD+ levels can drop drastically and cell death can occur (23,24). ...
Chapter
Full-text available
In this review, an extensive current literature review has been brought together and the effects of the liver in terms of oxidative stress antioxidant interaction and the ways in which it is affected have been tried to be revealed.
Article
Beta-cryptoxanthin (β-CRX), a pro vitamin A carotenoid was extracted from Kocuria marina DAGII, a gram positive bacteria isolated from soil. To determine the antioxidant activity of β-CRX against free radicals, DPPH, ABTS, H2O2 and TAC assay were performed. The scavenging results showed antioxidant activity of beta-cryptoxanthin. The scavenging activity increased with increased pigment concentration. The IC50 value of beta-cryptoxanthin for DPPH, ABTS and H2O2 were found to be 32.51 ± 1.15 µg/ml, 41.91 ± 0.33 µg/ml and 38.30 ± 1.13 µg/ml respectively. The TAC assay value of beta cryptoxanthin was 872.0101 ± 1.84 µg BHT/mg of sample. This showed that beta-cryptoxanthin extracted from K.marina DAGII cells can serve as economical pigment with antioxidant property.
Article
Sea cucumbers are marine organism that have interesting biological activities and generally used for food, cosmetics, and medicine. The use of sea cucumbers in cosmetics due to sea cucumbers have good antioxidant and antibacterial activity. There have not been many studies on sea cucumbers in Indonesia that show sea cucumbers as antibacterial (especially bacteria that cause acne. This study was conducted on sixteen species of sea cucumber from genus Actinopyga, Bohadscia, Holothuria, Pseudocolochirus, and Stichopus to select sea cucumber species that have the best activity in counteracting free radicals (antioxidant) and inhibits acne bacterial growth (anti-acne activities) on Propionibacterium acnes, Staphylococcus epidermidis, and Staphylococcus aureus . Antioxidant test is carried out using DPPH (2,2-diphenyl-1-picrylhydrazil) method while antibacterial test uses Plate Bioassay method with resazurin indicator . Test results on the sixteen samples of methanol extract of sea cucumber species showed that H. leucospilota was the species with the highest antioxidant activity with an IC 50 value of 9.66 ± 0.15 mg.mL-1 and with an inhibition of 53.09 ± 1.20 % at a concentration of 10 mg.mL-1. Five species of sea cucumbers that have antibacterial activity in the three bacteria tested were Holothuria impatiens, Holothuria scabra, Pseudocolochirus sp., Stichopus vastus , and Holothuria atra .
Article
Full-text available
In this study, we investigated whether (1) collagen-induced platelet aggregation is associated with a burst of H2O2, (2) this oxidant species is involved in the activation of platelets, and (3) the pathways of platelet activation are stimulated by H2O2. Collagen-induced platelet aggregation was associated with production of H2O2, which was abolished by catalase, an enzyme that destroys H2O2. H2O2 production was not observed when ADP or thrombin were used as agonists. Catalase inhibited dose-dependently thromboxane A2 production, release of arachidonic acid from platelet membrane, and Inositol 1,4,5P3 (IP3) formation. In aspirin-treated platelets stimulated with high concentrations of collagen, catalase inhibited platelet aggregation, calcium mobilization, and IP3 production. This study suggests that collagen-induced platelet aggregation is associated with a burst of H2O2 that acts as a second messenger by stimulating the arachidonic acid metabolism and phospholipase C pathway.
Article
In this study, we investigated whether (1) collagen-induced platelet aggregation is associated with a burst of H2O2, (2) this oxidant species is involved in the activation of platelets, and (3) the pathways of platelet activation are stimulated by H2O2. Collagen-induced platelet aggregation was associated with production of H2O2, which was abolished by catalase, an enzyme that destroys H2O2. H2O2 production was not observed when ADP or thrombin were used as agonists. Catalase inhibited dose-dependently thromboxane A2 production, release of arachidonic acid from platelet membrane, and Inositol 1,4,5P3 (IP3) formation. In aspirin-treated platelets stimulated with high concentrations of collagen, catalase inhibited platelet aggregation, calcium mobilization, and IP3 production. This study suggests that collagen-induced platelet aggregation is associated with a burst of H2O2 that acts as a second messenger by stimulating the arachidonic acid metabolism and phospholipase C pathway.
Chapter
IntroductionExperimental Methods DihydridesMonohydridesNonhydridesConclusion
Article
Mitochondria have been described as “the powerhouses of the cell” because they link the energy-releasing activities of electron transport and proton pumping with the energy conserving process of oxidative phosphorylation, to harness the value of foods in the form of ATP. Such energetic processes are not without dangers, however, and the electron transport chain has proved to be somewhat “leaky.” Such side reactions of the mitochondrial electron transport chain with molecular oxygen directly generate the superoxide anion radical (O2•−), which dismutates to form hydrogen peroxide (H2O2), which can further react to form the hydroxyl radical (HO). In addition to these toxic electron transport chain reactions of the inner mitochondrial membrane, the mitochondrial outer membrane enzyme monoamine oxidase catalyzes the oxidative deamination of biogenic amines and is a quantitatively large source of H2O2 that contributes to an increase in the steady state concentrations of reactive species within both the mitochondrial matrix and cytosol. In this article we review the mitochondrial rates of production and steady state levels of these reactive oxygen species. Reactive oxygen species generated by mitochondria, or from other sites within or outside the cell, cause damage to mitochondrial components and initiate degradative processes. Such toxic reactions contribute significantly to the aging process and form the central dogma of “The Free Radical Theory of Aging.” In this article we review current understandings of mitochondrial DNA, RNA, and protein modifications by oxidative stress and the enzymatic removal of oxidatively damaged products by nucleases and proteases. The possible contributions of mitochondrial oxidative polynucleotide and protein turnover to apoptosis and aging are explored.
Article
1. Blood antioxidants were measured in venous blood samples from 20 runners and six sedentary individuals. All subjects were male, between 20 and 40 years old, and in steady state with respect to body weight and physical activity patterns. Dietary analysis was undertaken using a 7-day weighed food intake. Correlations were sought between antioxidants in blood and (1) weekly training distance and (2) maximum oxygen uptake. In addition, 12 runners could be classified into two groups undertaking either low (range 16–43 km, n = 6) or high (80–147 km, n = 6) weekly training. 2. Body weight (range 55.3–90.0 kg) and percentage body fat (range 7–19%) both showed negative correlations with the weekly training distance (both P < 0.001). Energy intake and maximum oxygen uptake were both correlated with the weekly training distance (both P < 0.001). 3. Plasma creatine kinase activity, an indicator of muscle damage, was significantly correlated with the weekly training distance (P < 0.01), whereas the plasma concentration of thiobarbituric acid-reactive substances, an indicator of free-radical-mediated lipid peroxidation, decreased with increased maximum oxygen uptake (P < 0.01). 4. Erythrocyte α-tocopherol content was greater in the two running groups (P < 0.05) compared with the sedentary group, and lymphocyte ascorbic acid concentration was significantly elevated in the high-training group (P < 0.01) compared with the low-training group. 5. Erythrocyte activities of the antioxidant enzymes, glutathione peroxidase and catalase, were significantly and positively correlated with the weekly training distance (P < 0.01 and P < 0.05, respectively). Total erythrocyte glutathione content was higher in the two training groups, and was accounted for by an increase in reduced glutathione content. 6. These results indicate that there is an increase in blood antioxidant defence mechanisms associated with endurance training or the related life style, but despite this there is a degree of muscle damage in the training individuals.
Article
:The author suggests that the maximal life span of a given mammalian species is largely an expression of genetic control over the rate of oxygen utilization. The latter determines the rate of accumulation of mitochondrial damage produced by free radical reactions, the rate increasing with the rate of oxygen consumption, which ultimately causes death.
Article
Age-related damage to the mitochondrial membrane, including decreased membrane fluidity, has been attributed to free radical reactions. Our previous studies point to lipid peroxidation as a primary cause in age-related changes in membrane fluidity. This report offers new evidence that lipid peroxidation-modulated decreases in membrane fluidity are mediated through two aldehydic lipid peroxidation products, 4-hydroxynonenal (HNE) and malondialdehyde (MDA). Hepatic mitochondria were isolated from both ad libitum fed (AL) and dietary restricted (DR) rats of different ages. Introduction of the aldehydes was found to decrease mitochondrial membrane fluidity, although the fluidity decrease induced by HNE was more pronounced than that induced by MDA. It seems likely that HNE modifies membrane fluidity by direct interaction with membrane phospholipids, as shown by the generation of a fluorescent complex between HNE and membrane phospholipids. Finally, HNE and MDA were isolated and quantitated in mitochondria. Their levels clearly differentiated between animals of different age and dietary groups. These data indicate that the reactive products of lipid peroxidation, especially HNE, may play an important role in mediating the decreased mitochondrial membrane fluidity observed in aging animals.
Article
Phospholipids from liver mitochondrial and microsomal membrane preparations were analyzed to further assess the effects of age and lifelong calorie restriction on membrane lipid composition. Results showed that the major phospholipid classes, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol and cardiolipin did not vary significantly with age or diet. The fatty acid composition of the phospholipids was determined in PC and PE and ages of 6, 12 and 24 months. The data revealed characteristic patterns of age-related changes in ad libitum (AL) fed rats: membrane levels of long-chain polyunsaturated fatty acids, 22:4 and 22:5, increased progressively, while membrane linoleic acid (18:2) decreased steadily with age. Levels of 18:2 fell by approximately 40%, and 22:5 content almost doubled making the peroxidizability index increase with age. In addition, levels of 16:1 and 18:1 decreased significantly with age, indicating a possible change in delta 9-desaturase activity coefficient. Food restriction resulted in a significant increase in levels of essential fatty acids while attenuating levels of 22:4, 22:5, 22:6 and peroxidizability. We concluded that the membrane-stabilizing action of long-term calorie restriction relates to the selective modification of membrane long-chain polyunsaturated fatty acids during aging.
Article
Previous studies from our laboratory have demonstrated that the mitochondrial protein manganese superoxide dismutase is inactivated, tyrosine nitrated, and present as higher molecular mass species during human renal allograft rejection. To elucidate mechanisms whereby tyrosine modifications might result in loss of enzymatic activity and altered structure, the effects of specific biological oxidants on recombinant human manganese superoxide dismutase in vitro have been evaluated. Hydrogen peroxide or nitric oxide had no effect on enzymatic activity, tyrosine modification, or electrophoretic mobility. Exposure to either hypochlorous acid or tetranitromethane (pH 6) inhibited (approximately 50%) enzymatic activity and induced the formation of dityrosine and higher mass species. Treatment with tetranitromethane (pH 8) inhibited enzymatic activity 67% and induced the formation of nitrotyrosine. In contrast, peroxynitrite completely inhibited enzymatic activity and induced formation of both nitrotyrosine and dityrosine along with higher molecular mass species. Combination of real-time spectral analysis and electrospray mass spectroscopy revealed that only three (Y34, Y45, and Y193) of the nine total tyrosine residues in manganese superoxide dismutase were nitrated by peroxynitrite. Inspection of X-ray crystallographic data suggested that neighboring glutamate residues associated with two of these tyrosines may promote targeted nitration by peroxynitrite. Tyr34, which is present in the active site, appeared to be the most susceptible residue to peroxynitrite-mediated nitration. Collectively, these observations are consistent with previous results using chronically rejecting human renal allografts and provide a compelling argument supporting the involvement of peroxynitrite during this pathophysiologic condition.