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Basics of Oxidative Stress

1) Free radicals such as reactive oxygen species are formed during a
variety of biochemical reactions and cellular functions (such as
mitochondria metabolism). The steady-state formation of pro-oxidants
(free radicals) is normally balanced by a similar rate of consumption
by antioxidants. Oxidative stress results from an imbalance between
formation and neutralization of pro-oxidants. Various pathologic
processes disrupt this balance by increasing the formation of free
radicals in proportion to the available antioxidants (thus, oxidative
stress). Examples of increased free radical formation are immune cell
activation, inflammation, ischemia, infection, cancer and so on. Free
radical formation and the effect of these toxic molecules on cell
function (which can result in cell death) are collectively called
"oxidative stress." These free radicals are highly reactive, unstable
molecules that have an unpaired electron in their outer shell. They
react with (oxidize) various cellular components including DNA,
proteins, lipids / fatty acids and advanced glycation end products
(e.g. carbonyls). These reactions between cellular components and free
radicals lead to DNA damage, mitochondrial malfunction, cell membrane
damage and eventually cell death (apoptosis - which is the term for
programmed cell death).

2) Free radicals are generally reactive oxygen or nitrogen species.
Examples of free radicals (oxidizing molecules) are hydrogen peroxide,
hydroxyl radical, nitric oxide, peroxynitrite, singlet oxygen,
superoxide anion and peroxyl radical. Superoxide is generated via
several cellular oxidase systems (enzyme reactions). Once formed, it
participates in several reactions yielding various free radicals such
as hydrogen peroxide, peroxynitrite, etc. In turn, these can lead to
chain reaction byproducts that also act to damage cells (example: lipid
peroxidation products). An example of a very potent free radical is
peroxynitrite which is 1000X more potent as an oxidizing compound than
hydrogen peroxide. Markers of peroxynitrite formation (such as
nitrotyrosines or isoprostanes) can be found in many disease states
including Alzheimer's brains, Parkinson's disease, chronic heart
disease, liver disease, areas of inflammation, and so on. Thus, excess
free radical formation is associated with many disease states.
Inflammation, poor blood flow, degenerative diseases, and toxin
exposures among other mechanisms all lead to oxidative stress.

A wide variety of diseases have evidence of excess generation of free
radicals, oxidative stress and inadequate antioxidant activity. Some
examples are neuro-degenerative diseases (see below), heart disease,
HIV disease, chronic fatigue syndrome, hepatitis, cancer, autoimmune
diseases, etc.

3) Antioxidants are molecules or compounds that act as free radical
scavengers. Most antioxidants are electron donors and react with the
free radicals to form innocuous end products such as water. These
antioxidants bind and inactivate the free radicals. Thus, antioxidants
protect against oxidative stress and prevent damage to cells. By
definition oxidative stress results when free radical formation is
unbalanced in proportion to the protective antioxidants. There are many
examples of antioxidants:
Intracellular enzymes: superoxide dismutase (SOD), glutathione
peroxidase
Endogenous molecules: glutathione (GSH), sufhydryl groups, alpha lipoic
acid, CoQ 10, thioredoxin
Essential nutrients: vitamin C, vitamin E, selenium, N-acetly cysteine
(NAC)
Dietary compounds: bioflavonoids, proanthocyanidans
4) All cells have intracellular antioxidants (such as superoxide
dismutase and glutathione) which are very important for protecting all
cells from oxidative stress at all times. Glutathione (GSH) is very
important as an intracellular antioxidant. GSH has been found to be low
in many disease states (including virtually all those noted above)
indicating oxidative stress and inadequate antioxidant activity to
"keep up" with the free radicals. Maintaining and improving GSH levels
may be important in these illnesses.

There are several ways to increase GSH levels. GSH can be given as a
supplement but it is not absorbed very well from the gastrointestinal
tract (secondary to an enzyme that inactivates it). Cysteine is the
main (rate limiting) precursor of GSH production. N-acetyl cysteine
(NAC) is probably the best way to administer cysteine since it is more
stable and is very effective in increasing GSH levels. Alpha lipoic
acid and vitamin C both increase internal recycling of GSH, thus
increase the GSH levels.

5) GSH is important in the normal functioning of immune cells. Low GSH
levels have been associated with impaired immune function. Decreased
GSH impairs T cell proliferation and activation. Other abnormalities of
immune function associated with decreased GSH levels are impaired IL-2
production, impaired IL-2 responses and a shift to TH2 response as
compared to TH1. Restoring GSH levels to normal may be important in
normalizing immune function.

TNF alpha (a major pro-inflammatory cytokine) impairs GSH production by
several mechanisms, resulting in lowered GSH levels. Furthermore,
oxidative stress increases TNF alpha production. Therefore, GSH
disturbances and enhanced TNF alpha production / activation lead to a
pathogenic "loop" or vicious cycle.

Oxidative Stress in Neurologic Diseases
Oxidative stress has been extensively studied in neurologic disease
including Alzheimer's disease, Parkinson's disease, multiple
sclerosis, ALS, AIDS dementia and so on. This is not surprising since
the brain (neural cells) is especially susceptible to oxidative stress
and subsequent damage to cells (including cell death). In a disease
such as Alzheimer's, oxidative stress / oxidative damage is felt to
play a key role in the loss of neurons and the progression to dementia
(See Dementia).

Antioxidants which effectively enter the nervous system, improve GSH
levels, act as antioxidants themselves and are well absorbed from the
GI tract would be ideal candidates for protection of the brain and
nervous system from oxidative stress / damage. NAC, alpha lipoic acid
and probably CoQ 10 fulfill such characteristics of these important
properties. A prime example is the use of these antioxidants in the
protection / prevention of Alzheimer's disease, Parkinson's disease
and so on. Certain trace minerals are necessary for certain
antioxidants to function (e.g. selenium and zinc).

Oxidative Stress and Chronic Fatigue Syndrome
Below is an example of a potential sequence of events in which free
radicals are excessively formed and play a role in chronic fatigue
syndrome.
Active HHV-6 infection occurs in CFS patients
Active HHV-6 infection of various cells (such as white blood cells) is
a potent inducer of tumor necrosis factor alpha (a potent
pro-inflammatory cytokine)
TNF alpha leads to formation of excess free radicals, particularly
peroxynitrite
TNF alpha also lowers levels of GSH
The free radicals that are formed (such as peroxynitrite) can damage
cells, reduce immune function, lead to significant cell malfunction and
cell death
Increased free radicals and low GSH levels have been reported in CFS
The free radicals can also lead to formation of other oxidative
molecules. An example in CFS is the formation of isoprostanes (reaction
of peroxynitrite with prostaglandins). Increased levels of isoprostanes
have been reported in CFS patients. The isoprostanes can act as free
radicals themselves but are also very potent vasoconstrictors (thus can
impair blood flow). This can then result in a vicious cycle (cytokine
production and poor blood flow / free radical formation / cell damage /
reduced immune function / reduced internal antioxidant activity /
isoprostane formation which causes further free radical damage and
reduce blood flow / resultant cytokine (TNF alpha) production / more
free radicals / repeat the cycle).

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