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Topical reviews

Oxidative stress and its role in the pathogenesis of ischaemic stroke

C. L. Allen 1 * and U. Bayraktutan 1 1 Division of Stroke Medicine, University of Nottingham, Nottingham, UK

Correspondence: Claire L. Allen*, Division of Stroke Medicine, Clinical Sciences Building, University of Nottingham, Hucknall Road, Nottingham NG51PB, UK. Tel: +44 115 823 0278; Fax: +44 115 823 1767; e-mail:claire.allen@nottingham.ac.uk Conflict of interest: None.

Funding: This study was supported by grants to Dr Bayraktutan from the Stroke Association, UK.

KEYWORDSblood–brain barrier breakdown • hydrogen peroxide • ischaemia • oxidative stress • reactive oxygen species • reperfusion • stroke • superoxide

ABSTRACT

Stroke is one of the leading causes of mortality and morbidity, with astronomical financial repercussions on health systems worldwide. Ischaemic strokeaccounts for approximately 80–85% of all cases and is characterised by the disruption of cerebral blood flow and lack of oxygen to the affected area.Oxidative stress culminates due to an imbalance between pro-oxidants and antioxidants and consequent excessive production of reactive oxygenspecies. Reactive oxygen species are biphasic, playing a role in normal physiological processes and are also implicated in a number of diseaseprocesses, whereby they mediate damage to cell structures, including lipids, membranes, proteins, and DNA. The cerebral vasculature is a major target of oxidative stress playing a critical role in the pathogenesis of ischaemic brain injury following a cerebrovascular attack. Superoxide, the primaryreactive oxygen species, and its derivatives have been shown to cause vasodilatation via the opening of potassium channels and altered vascular reactivity, breakdown of the blood–brain barrier and focal destructive lesions in animal models of ischaemic stroke. However, reactive oxygen speciesare involved in normal physiological processes including cell signalling, induction of mitogenesis, and immune defence. Primarily, this review will focuson the cellular and vascular aspects of reactive oxygen and nitrogen species generation and their role in the pathogenesis of ischaemia–reperfusion

phenomena. Secondly, the proposed mechanisms of oxidative stress-related neuronal death will be reflected upon and in summation specific targetedneuroprotective therapies targetting oxidative stress and their role in the pathogenesis of stroke will be discussed.

Aging and Mitochondria (Premature Agi

Links to Degenerative Diseases

Some Premature Aging Causes Have Been Identified and These Can Be Easily ChangeInterested in Staying as “Young” and Healthy as Possible

There are many theories of aging. Some involve processes over which we presently have nohuge number yet undiscovered. Out of this highly contentious issue arose a theory involving in our cells, which shows the greatest promise to modify, reverse, and “cure” degenerative diMitochondrial Medicine may prove to be the wave of the future for medicine. It is already provin returning homeostasis to “disorders” in the body. Mitochondrial impairment has been linkeddegenerative diseases of normal aging and because these same impairments are also beingyounger aged people they are thought to be the cause of “premature aging” and therefore whpeople are developing these diseases of the aged. Identified factors that lead to mitochondria

 just happen to be factors that are adaptable to change by ourselves and with the help of sopmetabolic testing.

The Degenerative Diseases Linked to Mitochondrial ImpairmentDefects in mitochondrial function have now been linked to many of the most common diseasepopulation. These include Type II Diabetes Mellitus, Parkinson Disease, Atherosclerotic HeaStroke, Alzheimer Dementia, and Cancer. While it cannot yet be said that mitochondria are thof these problems, it is clear that mitochondria are involved because their function is “measudisturbed. Even autoimmune diseases such as Multiple Sclerosis, Systemic Lupus ErythemaRheumatoid Arthritis appear to have mitochondrial components. Each time a disease is inves

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mitochondrial impairment links are found.

Mitochondria normally become severely impaired with age. This impairment results in high leradicals that not only continually damage the mitochondria, but other important parts of the c

leading to a vicious downward spiral in overall cell function. Mitochondrial decay may also redeficits and an inability to dispose of toxins from the environment and may cause cells to die Results led to the conclusion that mitochondria can be called the "Achilles Heel" of the cell inaging.

Researchers are now wondering if mitochondrial impairment might be at the heart of many mand disorders.

Primary defects in mitochondrial function are implicated in over 100 diseases, and the list cogrow. Yet, the first mitochondrial defect--a myopathy--was demonstrated only 35 years ago.

With increased understanding of the mechanisms, underlying mitochondrial dysfunctions cambeginnings of therapeutic strategies, based mostly on the administration of antioxidants, replacofactors, vitamins and minerals, hormone balancing, and provision of nutrients. At the preseaccelerating pace of development of what may be called mitochondrial medicine, much mobe achieved within the next few years.

In 1995, the entire program of the 25th annual meeting of the American Aging Association anAmerican College of Clinical Gerontology was devoted to the role of mitochondria in the chroEven so, most physicians in America are not yet aware of the connection between chronic diabnormalities in mitochondrial function. Fortunately, this is changing through education. Howchange in medicine requires two elements - education and the availability of effective treatme

will be slow until effective treatments for mitochondrial diseases are developed.

The Really Good News? The mitochondria processes related to aging and premature agingadaptable with different (individual) interventions. What’s more, these processes can be measpecial laboratory tests. Moreover, you CAN make use of this knowledge to make significantwill and do help you to maintain your current good health or assist in reversing current healthcausing conditions – including back and neck pain conditions.

Are We Aging Prematurely?According to the federal government, Americans live an average of 73.7 years, but spend theyears in "dysfunctional life", which is marked by disease and impairment. This must mean tha

are beginning to create degenerative disease changes in our bodies long before the age of studies have shown many degenerative disease processes begin in a person’s 20s. [1] Remeage of 73.7 years is an “average.” This must then mean that there are a good number of peodegenerative diseases at even younger ages then 62. Centenarian societies are still physicahealthy, and happy long into their 80s – 90s while showing little if any western degenerative into these ages. Consider that studies have determined (without problematic genetic aspectsbiologically “set” to live well into their 120th year.

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When looking at aging and premature aging research we compiled a list of four scientifically contributors to the aging process. They are:

1. IMPAIRED MITOCHONDRIAL FUNCTION

1a) Oxidative Stress1b) Impaired or abnormal fluctuations in levels of blood sugar and insulin (Dysglycemia)1c) Increased combining of glucose andproteins (Glycation) 

1) IMPAIRED MITOCHONDRIAL FUNCTIONA quick look at the above list and it is easy to see we did not include 1a to 1c as primary factobecause while they are contributors to aging and pre-mature aging in their own right, they areknown prime contributors to impaired mitochondrial and cellular function. Impaired mitochond

functioning is looking more and more like one of the crucial candidates for all the symptoms aging and, by extension, over 100% of the leading causes of death by disease and the variousyndromes and symptoms that accompany these diseases plaguing western health.

While we are certain many more aspects of the body’s interacting metabolic systems will be causative of premature aging and the aged, this article looks at the known factors about mitofunctioning that we have control over NOW in our quest for homeostasis, health and relief fropain.

Why are Mitochondria so Important?

The mitochondria (the plural of Mitochondrion) are commonly referred to as the "powerhouseEvery cell throughout our body contains a number of these little “powerhouses”. Depending uspecific type of cell there can be one or thousands of mitochondrion in each cell.

Mitochondria consume over 80 percent of the oxygen we breathe and make over 90 perenergy our cells need to function. They use the oxygen in the air we breathe to release enfood. This process transforms food calories into chemical energy, water, and carbon dioxide.chemical energy is then stored in the form of adenosine triphosphate (ATP). ATP is the univeof energy used by all life on earth. It is like an electrical power source that drives the engines This process of burning food to make ATP is called oxidative phosphorylation. Only mitochoit. Without it, muscles could not contract and neurons could not fire. Mitochondria literally ma

for us to move and think.

Production of ATP is far from the only major function these infinitely tiny cellular componentskeep vital homeostasis on the go.

Some mitochondrial functions are performed only in specific types of cells. For example, mitoliver cells contain enzymes that allow them to detoxify ammonia, a waste product of protein mThese enzymes are not made in the mitochondria of cardiac cells. As more research is done

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information about their role is being revealed. What is known is just the “tip of the iceberg” th

What Are Some of Their Other Functions?Here is what we know today about some of the other functions these stupendously tiny cellul

have a role in:

• apoptosis (normal cell death) • Glutamate-mediated excitotoxic neuronal (Nerve) injury • Cellular reproduction • heme (iron) synthesis • steroid synthesis * - Also called steroid hormones. Synthesis of all steroids must have

begin. (*Any of numerous naturally occurring fat-soluble organic compounds such as pand bile acids, adrenocortical and sex hormones, and the precursors of certain vitamin

• heat production (enabling the organism to stay warm) 

Mitochondria are important in relation to the aging process for two reasons: their role in eneproduction and, the generation of free radicals. Yes, these little powerhouses are radicallyfor the production of free radicals in the body.

1a) Oxidative Stress (Caused by Free Radicals)Although we cannot survive without oxygen, oxygen also contributes to our death by formingwhich are unstable and highly reactive molecules that alter metabolism and damage physicaThe mitochondria are the major sites within the body for the production of free radicals. In a habout 20% of the oxygen we breathe forms free radicals. In an unhealthy state up to 80% owe breath forms free radicals.

When the mitochondria are malfunctioning, more free radicals are formed. Chemical, Metal, nutrient inadequacy, and stress adversely affect mitochondrial function by adding to increaseproduction.

Mitochondria possess their own DNA (genetic material), which unlike the DNA housed in the(center of the cell) is very vulnerable to mutation (damage) from oxidative stress (free radicalmutation of this DNA occurs, mitochondrial function may become severely damaged. It is eascycle of poor mitochondrial function, oxidative stress, mitochondrial mutation, further impairmmitochondrial function and so on.

Not only does mitochondrial impairment contribute to aging by increasing free radical producreduced generation of energy plays a role as well. We all undergo degenerative changes anormal aging; loss of normal structure and function, as our cells "run out of gas" due to mitocfailure. Degeneration and eventually death results.

While our nuclear (found in the nucleus (center) of the cell) DNA is wonderfully protected, unseem stuck with a poor mitochondrial DNA repair capacity. Each mitochondrion’s DNA can tamany free-radical "hits." For instance, mitochondrial malfunction within brain cells results in c

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impairment and death of those cells, contributing to the likes of Alzheimer and Parkinson’s di

Mitochondrial impairment is often first observed in the cells that contain greater numbers of like the cells of the heart, brain, muscles, liver, immune system, and gastrointestinal lining.

ARE YOU CONNECTING ANY DOTS TO OUR MAJOR DEGENERATIVEDISEASES YET?

What causes this “Oxidative Stress”?

Common sources of oxidative stress are: toxicity, chronic inflammation, glycation, stress, exexercise, some medications, alcohol, cigarette smoke, and dietary factors such as consumptcarbohydrates (white sugar and flour, for a start), bad fat, bad oils, fried oils, and foods cooketemperature (fried or barbequed for example). Overeating may be another source of oxidativmore food that is burned within the mitochondria the more free radicals are produced. Animaactually demonstrated that caloric restriction extends lifespan.

These are the same scientifically identified Major Contributors to aging, premature agidegenerative disease development, which we discussed in our article on Degenerative Cothe Back and Neck.

What protects and assists mitochondrial function?Many nutrients are critical for proper mitochondrial function and protection from oxidative streneeds to supply quality proteins, fats and oils, carbohydrates, and an abundance of antioxthis diet must be ingested in a healthy ratio of protein to fats to carbs. Certainly none of thfound in the Standard American Diet (Acronym: SAD)

Antioxidants are found in abundance in unprocessed, fresh, fully matured plant foods, grown

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Supplemental nutrients of particular importance to mitochondrial function include coenalpha lipoic acid, L-Acetyl Carnitine (AKA: Acetyl-L-Carnitine), and vitamin E.

Aerobic, weight bearing, and limbic exercise (no excessive exercise) also improves mitochonand increases the body’s antioxidant defenses.

There are many other nutrients and supplements that can be of assistance and may be needabove the healthy diet and those listed above. We have left them out of this list on purpose. Tonly be used after proper testing has been done, and prescribed only under the care of a nator a medical model specialist in endocrinology and mitochondrial disease. For example: peopas diabetic II, can find their blood sugar reduced to dangerously low levels with the use of R-AAcetyl Carnitine when they are also taking pharmaceutical medications that seek to produce result.

Testing for Mitochondrial HealthTwo particularly good tests for assessing mitochondrial health are the Oxidative Stress AnalyOrganic Acid Analysis. Information from both tests can be used to tailor therapy for the indiviimprove mitochondrial function. These are tests available through order of a Natural doctor. Sunder special circumstances an MD may be able to order such tests, but it is not a usual prac

The Oxidative Stress Analysis is a laboratory test performed on blood and urine specimens tlevels of oxidative stress and adequacy of the body’s antioxidants.

The Organic Acid Analysis utilizes a urine sample to measure concentrations of compounds the body’s metabolism. Several of these organic acids are produced within mitochondria. Ab

of mitochondria-derived organic acids signify altered mitochondrial function.

1b) Blood Sugar Fluctuations (Dysclycemia)Dysglycemia is basically abnormal fluctuations in levels of blood sugar resulting in high levelsAnother term is Insulin Resistance. Dysglycemia accelerates the aging process in a number impairs mitochondrial functioning and raises levels of insulin, which contributes to obesity, hyatherosclerosis, and accelerated tumor growth and produces pro-aging imbalances in other hSome of these hormonal abnormalities in turn lead to further dysglycemia. Dysglycemia impafunction, increases inflammation and leads to increased protein glycation. Dysglycemia is theprecursor of adult-onset diabetes. Diabetes complications include vascular and heart diseaseand kidney damage and other conditions.

1c) Protein GlycationGlycation is the combining of glucose with proteins, and it occurs continuously throughout thehigher the levels of glucose in the blood and the longer they stay elevated, the more glycatioInsulin resistance, which results from prolonged dysglycemia, allows blood glucose to rise to levels. Glycation results in altered structure and function of the protein. Glycation also contribinflammation and to increased oxidative stress and mitochondrial damage. The rate of proteibeen found to correlate with biological aging.

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COOKING AT HIGH TEMPERATURESEating foods cooked at high temperatures creates glycation and this is another contributor toof inflammatory cytokines. In fact, it has been shown that eating such foods leads to the form

advanced glycation end products. (AGE’s) Glycation can be described as the binding of a prto a glucose molecule, resulting in the formation of damaged protein structures. Many age-resuch as arterial stiffening, cataracts, and neurological impairment are at least partially attribuglycation. These destructive glycation reactions render proteins in the body cross-linked and functional. As these degraded proteins accumulate, they cause cells to emit signals thaproduction of inflammatory cytokines (such as IL-6 and TNF-a)

History and Current Knowledge of Mitochondria Mitochondrial medicine is a new and rapidly developing medical subspecialty. Many specialisinvolved in researching mitochondrial diseases, including physicians specializing in metabolibiologists, molecular geneticists, neurologists, biochemists, pathologists, immunologists, and

embryologists. Natural Model scientist are also looking at and participating in this research. Fprovided yet more scientific proof that the body works as a single interrelated unit.

Studies linking mitochondrial damage to the aging processes are the result of discovery of gemitochondria abnormalities “disorders” in children. The first patient was diagnosed with a genmitochondrial disorder in 1959. One thousand to 4,000 children per year are born with a typemitochondrial “disease” in the United Sates.

Many of the “diseases” associated with “aging” that would normally begin to appear in peopleof 50 to 70 showed mitochondrial damage similar to (disease) disorders suffered by those chthese, but not limited to, are type 2 diabetes, Parkinson's disease, atherosclerotic heart dis

Alzheimer's disease and cancer. Once aware of this damage, which was normal in the aged,find this same mitochondrial damage and it’s expected diseases occuring in a much youngerwell. This is now referred to as pre-mature aging.

The additional discovery that many medications can injure the mitochondria then led researcevaluating how other toxic environmental factors cause dysfunctional mitochondria and lead These include many of the 80,000 chemicals produced by industry including artificial hormon

Mitochondrial dysfunction can affect every part of the body. In some people only one organ minvolved, in others all organs may be affected. However, we want to make the strong point th

what – a problem in one area (organ or system) sooner or later upsets everything else. The lthis takes before outward, undeniable physical symptoms occur depends on too many factorhere. However, this internal upset DOES occur and WILL produce ever more negative resuThe longer one takes in starting the processes that will identify and begin to rectify such dysfgreater the danger to develop more complicated disease conditions.

Symptoms Associated with Impaired MitochondriaMedical model science supplies a list of symptoms associated with impaired and damaged m

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After reviewing these we hope you agree that they make it easy to see that this list links to, aencompasses, all major health problems in western world lifestyle countries.

Their list is as follows:

{Quote} Depending on which specific cells of the body are affected, i.e. liver, heart, brain, etcmitochondrial impairment or dysfunction within these cells may include symptoms such as:• unrelieved fatigue• Poor growth• Loss of muscle coordination, muscle weakness• Visual and/or hearing problems• Developmental delays, learning disabilities• Mental retardation• Heart, liver or kidney disease• Gastrointestinal disorders, severe constipation

• Respiratory disorders• Diabetes• Immune system dysfunction (Increased risk of infection, inflammation, cancer)• Neurological problems, seizures• Thyroid dysfunction• Steroid dysfunction• Dementia (mental disorder characterized by confusion, disorientation and memory loss) {U

Insulin and agingCentenarians, people who have lived over 100 years, don't have much in common. For examsmokers – others not. They come from all over the world without a favoring any geographic lo

particular.

However, there are 3 consistent metabolic blood indicators common to all centenarians; lowlow insulin, and low triglycerides. All 3 are relatively low vs. chronological age. Among theindicators/factors insulin is the common denominator .

The level of insulin sensitivity of the cell is one of the most important markers of lifespan.

Controlling your blood insulin level is one of the most powerful anti-aging strategies you can into action.

Insulin Resistance is being extensively studied by endocrinologists. So far, these studies havinsulin resistance with almost every life-threatening disease, and their complications - and thlooking. In many cases the link is direct (causative) to the disease, in other cases it is a resultcomplication of the disease. Metabolic Syndrome (definitely linked to Insulin Resistance) wasas a group of symptoms indicating a high risk for heart and vascular disease and diabetes II –

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only a part of an overall investigation in the possible links between insulin resistance and anydiseases. Both Metabolic Syndrome, and the Metabolic Affects of Westernized Living, loResistance’s connection to Aging and Premature Aging diseases. When we consider the infohave just read – it certainly looks like the sugar/insulin problem is ONE of the big reasons we

increasing poor health – a slippery slope to the development of all the diseases associated wmitochondrial function and premature aging for sure. And it may turn out to be the biggest cathe easiest one to change.

In Conclusion:No matter which model of medicine you favor for your back or neck pain care and treatment wkeep in mind there is no doubt the body does not work as independent parts. What affectsaffects every part. Health, and a healthy, pain free body, begin and end at the cellular-chemiwould seem that the most important part of the cellular-chemical health or metabolic diseasewe have the power to change, lies within our mitochondria. Thorough individualized tests aredetermine an overall metabolic imbalance and thereby where to begin rebalancing. We ask y

remember that orthodox testing cannot give you such definitive answers.

References:[1] Cheryl Duxbury. Aging and the Threshold of Disease, University of Waterloo, CA. Course Notes Biology and Human Aging

R Luft, Rolf Luft Research Institute, Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden “The development of mitochondriaAcad Sci U S A. 1994 September 13; 91(19): 8731–8738.

Joseph Debe, MD, "A Scientific Approach to Anti-Aging", www.drdebe.com/antiage.htm

Trifunovic, A. et al. (2004). “Premature ageing in mice expressing defective mitochondrial DNA polymerase.” Nature; 429(6990): 417–23.

Cadenas E, Davies KJ. "Mitochondrial free radical generation, oxidative stress, and aging." Free Radic Biol Med 2000 Aug;29(3-4):222-30

Ebadi M. "Introduction. Oxidative stress in mitochondria disorders of aging." Biol Signals Recept 2001 Jan-Apr;10(1-2):5-13

Kowald A. "The mitochondrial theory of aging." Biol Signals Recept 2001 May-Aug;10(3-4):162-75Allen JF, Allen CA. "A mitochondrial model for premature aging of somatically cloned mammals." IUBMB Life 1999 Oct;48(4):369-72

Van Remmen H, Richardson A. "Oxidative damage to mitochondria and aging." Exp Gerontol 2001 Jul;36(7):957-68

Wei YH, Lu CY, Wei CY, Ma YS, Lee HC. "Oxidative stress in human aging and mitochondrial disease-consequences of defective mitochondrial resantioxidant enzyme system," Chin J Physiol 2001 Mar 31;44(1):1-11

“Accumulation of deletions and point mutations in mitochondrial genome in degenerative diseases.” M. Tanaka, S. A. Kovalenko, J. S. Gong, H. J. BM. Hayakawa, M. Yoneda and T. Ozawa Department of Biomedical Chemistry, Faculty of Medicine, University of Nagoya, Japan

“Mitochondrial Medicine – Molecular Pathology of Defective Oxidative Phosphorylation. ” Egil Fosslien

Aubrey de Grey. “The Mitochondrial Free Radical Theory of Aging.” (R.G. Landes Co, 1999).

Aubrey de Grey. "The reductive hotspot hypothesis of mammalian aging: Membrane metabolism magnifies mutant mitochondrial mischief," EuropeaBiochemistry. Vol 269 : pp.2003-2009 (Apr 2002) (Minireview).

Douglas C. Wallace. "Mitochondrial Diseases in Man and Mouse," Science. pp. 1482-1488 (5 March 1999)

Douglas C. Wallace. "Mitochondrial DNA in Aging and Disease," Scientific American. pp. 40-47 (August 1997)

U.T. Brunk and A. Terman. "The mitochondrial-lysosomal axis theory of aging: Accumulation of damaged mitochondria as a result of imperfect autopEuropean Journal of Biochemistry. Vol 269 : pp.1996-2002 (Apr 2002) (Minireview).

Makiko S. Fliss, et.al. "Facile Detection of Mitochondrial DNA Mutations in Tumors and Bodily Fluids," Science. pp. 2017-2019 (17 March 2000)

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