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Introduction
There was an era when people were worried about the disease
processes and its treatment. But off late, tremendous efforts
are being made to find out the ways of prevention of important
diseases. The important research studies are rightly to be
repeated with other populations, but nevertheless give an
opportunity to consider the integrated actions of the known
reducing (Antioxidant) systems. Inadequacy of certain internally
produced reducing systems has been postulated as being at the
core of some disease processes. It is believed that life has
originated from basic chemicals by free radical reaction,
largely initialed by ionizing radiation from sun. Paradoxically
the same reactions creating life may also be responsible for
many diseases, ageing and death.
Free Radicals (FRs)
These are highly reactive chemical entities that have a
single unpaired electron in their outer most orbits. Under
certain conditions can be highly toxic to the cells. Generally
unstable and try to become stable, either by accepting or
donating an electron. Therefore if two FRs react, they
neutralize each other. However, if the FRs react with stable
molecules, there is generation of more free radicals. This
characteristic enables the FRs to participate in autocatalytic
chain reactions,
Molecules with which they react are themselves converted to free
radicals to propagate the chain of damages.
Reactive Oxygen Species (ROS): -
These are free radicals derived initially from oxygen. But
as they do not contain unpaired electrons in their outermost
orbit, they do not qualify as free radicals and so are referred
to separately as ROS. E.g.- H2O2, HOCL, NO. Free radicals are
formed in side our body by both PHYSIOLOGICAL (Natural) and
PATHOLOGICAL stimuli.
Mechanism of Action of FRs :
They act on the cell membranes and membranes of different
organelles of cells and cause cell injury and death by oxidative
reactions. So FRs are also called OXIDANTS. FRs cause lipid
peroxidation. The PUFA of cell membrane are more vulnerable for
this injury. By lipid peroxidation FR increases the permeability
of cells, leading to calcium influx and altered PH of the cell.
FRs alter the enzyme and receptor proteins. FRs cause –
cross-linking of proteins and fragmentation of protein strands,
oxidation of amino acids like cystene, Methionine. These
alterations in the enzymes and receptors inside the cell lead to
abnormal cell behavior. FRs cause fracturing on the cell nucleus
resulting in single strand DNA damage. This oxidative injury may
be lethal leading to cell death and ultimately removed by phagocytosis.
It may also be sub lethal - which may result in increased cell
permeability leading to mutation of cells. FRs Induce chain
reactions during the process of oxidant damage resulting in
tissue destruction & degeneration, some electrons may escape
oxidation and become FRs.
This chain reaction may produce diseases like: -
Antioxidants (AOs)
These are substances, which protect us against potentially
harmful free radicals derived from oxygen. To combat the
injurious effects of FRs our body has its own system of ‘in
vivo’ Antioxidants’. In normal healthy state a balance is
maintained between FRs & Aos The ‘AO’ activity of serum is
measured as - % inhibition of lipid peroxidation in a
standardized brain homogenate. Moreover we can as well
supplement these from outside (in vitro Antioxidants).
Oxidative Stress: -
Under normal conditions body maintains an equilibrium between
its own FR’s and Antioxidants. When this equilibrium breaks, a
state called oxidation stress arises with in, due to FR
formation or AO system.
AO Status in Normal Pregnancy:
-
There is increased need for AOs as there is increased production
of FRs due to Pregnancy being a stressful condition. Because of
the rapidly growing fetus there is increased cellular activity.
Thus AO activity during normal pregnancy progressively increases
as demonstrated by Serum tocopherol. However, there is no
evidence to suggest the need for administration of ‘AOs’ during
normal pregnancy but drugs that lead to ‘FR’ formation must be
avoided.
AOs & Diabetic Embryopathy: -
Oxidative stress has been suggested to contribute to the
increased risk of fetal malformations in poorly controlled
diabetics. There are reports of lipid peroxidation in cell
membranes in diabetic pregnancies Periods of maternal
hyperglycemia & hypoglycemia may cause marked changes in the
availability of glucose to the fetus. Also conc. of lipids,
notably the ketone bodies and branched chain amino acids in the
maternal circulation contribute to altered nutrition for the
embryo leading to FR conc. & fetal malformation in embryo.
During later part of pregnancy load of glucose in the
mitochondria may accelerate the flow of electrons through
respiratory chain including mitochondrial leakage of free
radicals. This leads to production of FR in embryonic tissues to
cause congenital malformations. Thus maintenance of normal
concentration of metabolites of all nutrient class may be
important for prevention of adverse fetal outcome. But the
question is will dietary supplements alone hold the key to the
future in diabetic embryopathy? However, maintenance of blood
glucose level at euglycemic level is always important for
prevention of Diabetic embryopathy.
AOs & Down syndrome: -
Free radicals being the hallmark of aging are greatly increased
with maternal age. So FRs play a role in pathogenesis of Down’s
syndrome. Administration of AOs may help in preventing this
disease.
FRs & AOs in Preterm Delivery: -
Sub clinical chorioamnionitis leads to libe
ration of bacterial
antitoxins (polysaccharide in nature) and inflammatory
cytokines. These cause stimulation of inflammatory cells and
cells of CX. which in turn produce NO2. Evidence: There is N2O
in vaginal samples of females having preterm delivery. So
antioxidants may play a part in the treatment of preterm
delivery.
FRs & AOs in New Born Babies: -
In recent years experimental and clinical data have provided
compelling evidences for involvement of oxygen derived ‘FRs’ in
disorders of prematurity like Chronic lung disease, Retinopathy,
Intra ventricular hemorrhages. Narcotizing Enterocolitis: - FRs
cause microvascular injury and cell permeability leading to
narcotizing enterocolitis.
Carcinogenesis: -
Basics of cancer formation: -
A normal cell can undergo malignant transformation in presence
of procarcinogens and carcinogens. However, in early stages, it
can revert back to normal cell when detected and corrected by
our body immune system. Without immune system detection a normal
cell is converted to malignant cell. Free radicals are formed
from stimulants like –Radiation, Xenobiotics, Inflammatory
cells, Respiration etc, which act on cellular targets to cause
oxidant DNA damage in form of mutagenesis & clostogenesis, which
cause initiation of carcinogenesis by activation of proto-oncogens.
Procarcinogens are metabolically activated by FRs, which cause
promotion and progression of these initiated cells to cancer and
ultimately carcinogenesis sets in
AOs in Cancer Prevention: -
DEFENCE: - enzymes with antioxidant property cause first line of
defence by: -
Protecting the lipids and enzymes against oxidation retarding
the generation of free radicals and creating a balance of ‘AOs’
against FRs in the body prevents cell pathology, metabolic
disturbances, changes in cell permeability, formation of toxic
products and resultant prevention of initiation of
carcinogenesis. Majority of epidemiological data suggest
supplementation with antioxidants- Vit.- A, E, C; beta carotene
& selenium, decreases the incidence of various cancers.
FRs & AOs in Infertility - Male
Various studies have suggested Conc. of Malondialdehyde (MDA) is
inversely proportional to fertility in case of males. In
asthenospermic and oligoasthenospermic males there is increased
serum concentration of MDA. Even in normospermic males if there
is concentration of MDA there is reduced fertility. Addition of
vitamin E causes decreased concentration of MDA and improves
fertility.
FRs & AOs in Infertility - Female
FRs cause short luteal phase and LPDS. In IVF arrest the cell
growth (div) at 2, 4, 8 cell stages hamper the regulation of
corpus luteum. Addition of ‘AOs’ improves the results.
CONCLUSION
Traffic lights are to cars, what ‘AOs’ are to the cells. Oxidant
generation is a part of human life. Every O2 atom we breath in
,is converted to water inside our body by addition of four
electrons sequentially. When four electrons are added three ‘FRs’-
O2, H2 O2 & OH are formed along with water. So where there is
life there are oxidants. But when produced in excess, they can
cause any disease. So our concern should be to FRs in systemic
circulation. However, careful use of ‘AOs’ and newer and more
accurate methods to measure oxidant generation in humans will go
a long way to find out the exact contribution of oxidants in
disease processes and the role of ‘AOs’ to prevent it.
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