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    The Root Cause in the dramatic rise of Chronic Disease & Enzymatic processes that contribute to antioxidant defense

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    Pris

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    The Root Cause in the dramatic rise of Chronic Disease & Enzymatic processes that contribute to antioxidant defense

    Post  Pris on Fri Jul 29, 2016 4:58 am

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    The Root Cause in the dramatic rise of Chronic Disease
    Richard Lear  

    NOTE to Readers: There has been a largely unrecognized explosion of chronic disease in the US. More than 170
    million Americans are currently suffering from diseases and conditions that can be vastly improved or even reversed by
    reducing levels of a single molecule called peroxynitrite. Elevated levels of peroxynitrite have been associated with more
    than 60 chronic diseases, yet can be controlled through moderate changes in lifestyle, reducing exposures to a few
    environmental toxins, improving diet plus introducing non-prescription supplementation. While thousands of scientists
    recognize the pivotal role of peroxynitrite in disease, few policy makers and physicians are aware of the opportunity they
    have to heal a nation suffering from chronic diseases. The annual economic burden of just forty fast-growing chronic
    diseases tracked in this paper is more than $2.5 trillion. With increased public awareness coupled with enlightened
    action this cost to society can be reduced to a fraction by simply implementing the knowledge we already have.  

    Growth of Chronic Disease

    There has been unprecedented growth in a new class of chronic diseases in the US since
    1990. Four categories of disease have virtually exploded: autoimmune, neurological,
    metabolic and inflammatory. Meanwhile, there has been a similar uptick in reproductive
    conditions like infertility and a half dozen psychiatric disorders.  

    While the major health threats of the 20th century: cardiovascular disease, infectious disease
    and cancer, are barely growing, at least forty chronic diseases and disorders have more than
    doubled in the past generation. Many of these new age diseases weren’t even on our radar
    until the 1980’s.

     
    In a single generation, there has been a dramatic acceleration* in the prevalence of diseases
    and disorders like
    autism (2094%),
    Alzheimer’s (299%),
    COPD (148%),
    diabetes (305%),
    sleep apnea (430%),
    celiac disease (1111%),
    ADHD (819%),
    asthma (142%),
    depression (280%),
    bipolar disease in youth (10833%),
    osteoarthritis (449%),
    lupus (787%),
    inflammatory bowel disease (IBD – 120%),
    chronic fatigue syndrome (11027%),
    fibromyalgia (7727%),
    multiple sclerosis (117%)
    and hypothyroidism (702%).
     

    The values for these increases were derived from scientific literature; that they are over-
    precise is a given. These generational increases in prevalence are offered to convey a clearer
    picture of the spectacular increase in chronic disease.

    For entire article:
    https://www.researchgate.net/publication/303673576_The_Root_Cause_in_the_dramatic_rise_of_Chronic_Disease



    Enzymatic processes that contribute to antioxidant defense


    Introduction to Integrative Medicine
    Thomas J. Morledge

    Oxidative Stress

    Processes


    Proposed mechanisms of aging as well as neurodegenerative and other organ-specific degenerative diseases have focused on the susceptibility of the cell to oxidative stress. Research in this area has demonstrated the role of oxidative stress–induced mitochondrial dysfunction and the subsequent cascade of mitochondria-initiated cellular apoptosis. Oxidative stress is also related to the development of certain cancers.

    Oxidative stress occurs when either endogenously metabolic generated reactive molecules or exogenous reactive substances in the environment interact with biologic structures, resulting in altered cellular physiology. Endogenously produced reactive oxygen species (ROS) include molecules such as superoxide, peroxynitrite, peroxyl radicals, hydroxyl, hydroxyl radicals, and singlet oxygen. Most ROS originate intracellularly in the mitochondria, which converts the energy potential from macronutrients from the diet into cellular energy currency that includes adenosine triphosphate (ATP), reduced nicotinamide adenine dinucleotide (NADH), and reduced flavin adenine dinucleotide (FADH2). Through the process of oxidative phosphorylation in the mitochondria, molecular oxygen is consumed and reduced to water. However, about 1% of the oxygen is converted to superoxide anion (O2 −). These ROS molecules, if left unchecked, damage cellular structures such as mitochondrial membranes, proteins, and DNA. Mitochondrial DNA is especially vulnerable to oxidative damage because it lacks the protective and repair mechanisms found in nuclear DNA. Repeated injury to DNA results in a cumulative loss of function. After enough hits, the mitochondria and the bioenergetics of the cell are altered in ways that can result in cellular apoptosis and loss of organ function.

    Cells have developed antioxidant defenses to protect cellular proteins, membranes, and nucleic acids. These molecules include coenzyme Q10 (CoQ10), lipoic acid, and glutathione. Enzymatic processes that also contribute to antioxidant defense include superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase.

    Oxidative stress can be assessed in the laboratory by measuring oxidized products from cellular damage. The unsaturated component of lipid membranes undergoing oxidative damage releases lipid peroxides. Oxidative injury to arachidonic acid results in the production of isoprostanes. Oxidation of guanosine molecules in DNA produces 8-hydroxydeoxyguanosine (8OHdG), which has a close relation with neuronal oxidative stress. Methods of measuring these products of oxidation are commercially available.

    The production of ATP from oxidative phosphorylation depends on organic acids generated from the Krebs cycle. To function correctly, the enzymatic processes in the Krebs cycle depend on cofactors that include nicotinamide dinucleotide derived from niacin, FAD derived from riboflavin, and thiamine pyrophosphate derived from thiamine. The production of energy from fatty acids depends on the transport of free fatty acids across the mitochondrial membrane, which requires conjugation to carnitine by the enzyme carnitine palmitoyltransferase I. The free fatty acids are then deconjugated for use in energy production.
    Antioxidants

    Today's standard American diet is poor in nutrients, rich in calories, high in glycemic load, and deficient in antioxidants. These processed foods lack the phytonutrients that provide our cells with the information to orchestrate a balanced cellular physiology to prevent cancer and inflammatory conditions. Antioxidant-rich foods in the diet are the major sources of supplemental antioxidants. The richly pigmented phytochemicals in vegetables and fruits serve antioxidant functions, and intake of vegetables and fruits has been associated with a decreased risk of some cancers. The antioxidant activity produced by whole foods, as measured by products of oxidative stress in humans, outperforms antioxidants taken as supplements. 2 Although many substances in vegetables and fruits have been identified, many remain unidentified, and the biologic effect of a parti-cular herb or plant could be related to effects of the particular plant's various phytochemicals on multiple-cell–signaling biochemical pathways.

    Green tea, rich in catechins, has demonstrated antioxidant properties related to the combination of aromatic and hydroxyl groups that make up the structure of these polyphenols. Other biologic effects of green tea include inhibition of arachidonic acid metabolites, thus reducing inflammatory responses; activation of hepatic enzymes that promote the detoxification of xenobiotic compounds; and positive effects on intestinal microflora by raising levels of Lactobacillus and Bifidobacterium while lowering levels of potential pathogenic bacteria. One of the major polyphenols in green tea, (-)-epigallocatechin-3-gallate (ECGC), has been shown to decrease lipopolysaccharide-induced tumor necrosis factor (TNF) production in a dose-dependent manner.

    Curcumin (derived from turmeric, the yellow spice in curries) has been shown to have a broad range of cellular effects in addition to its potent antioxidant activity. It has potent anti-inflammatory effects that may be related to its ability to inhibit biosynthesis of inflammatory prostaglandins from arachidonic acid and also its inhibitory effect on neutrophil aggregation. Molecular targets include the inhibition of cell-signaling pathways associated with inflammation that includes nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX). It also affects many pathways associated with cancer. 3

    Lycopene, a red carotenoid pigment, is found in a variety of plants including guava, pink grapefruit, watermelon, and tomatoes. Lycopene is a potent antioxidant that might protect vulnerable cellular components from reactive oxygen damage. Epidemiologic data show lycopene to be associated with a reduced risk of prostate cancer. Clinical trials have also demonstrated a prevention or reduction of the progression of high-grade prostate intraepithelial neoplasms into prostate cancer. Serum lycopene levels are inversely related to prostate-specific antigen (PSA) levels. Mechanisms in addition to the antioxidant effects can include inhibition of insulin-like growth factor-1 and other cell-signaling effects. 4

    In addition to whole foods, dietary supplements used to support these processes include those directed at facilitating energy production at the level of the Krebs cycle and oxidative phosphorylation. They can serve as cofactors in the processes for the generation of ATP and as antioxidants to quench aberrant ROS. Many of the substrates used in these processes are conditionally essential, which implies that under certain conditions, optimal function cannot be maintained through endogenous synthesis alone.

    CoQ10 (ubiquinone) is a potent antioxidant and also a bioenergetic enzyme that participates in electron transport during oxidative phosphorylation. CoQ10 biosynthesis is impaired by statin medications that inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, thus producing lower tissue levels of CoQ10. CoQ10 supplementation has been shown to potentially benefit a number of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and Huntington's disease. 4 Additionally, it has shown benefit in prophylaxis for migraine headache and in treating congestive heart failure, periodontal disease, and hypertension. It has also been shown to reduce doxorubicin-induced myocardial toxicity in patients receiving chemotherapy without compromising the chemotherapeutic effectiveness. Dosages as high as 1200 mg/day have been successfully used in clinical studies in patients with Parkinson's disease.

    α-Lipoic acid (ALA) is a molecule that serves as a coenzyme in several complexes in the mitochondria, including pyruvate dehydrogenase in the Krebs cycle. ALA is also a potent antioxidant in water and in lipophilic solvents. In its reduced form, dihydrolipoic acid has been demonstrated to have distinct antioxidant actions that include free radical–scavenging activity; it also can regenerate endogenous antioxidants such as glutathione, CoQ10, and vitamins E and C. Studies in patients with diabetes have shown improvement in measurements of oxidative stress. 5 ALA has also resulted in significant clinical improvement in symptom scores in patients with diabetic polyneuropathy. 6 ALA supplementation in animal models has resulted in improvement in outcomes following central nervous system reperfusion injury and protects against cataract formation in animals with induced diabetes. 7 ALA has also been used successfully to prevent liver failure in patients with amanita mushroom poisoning. Besides its direct antioxidant effects, ALA might also influence clinical outcomes through other important mechanisms and pathways such as by modulating inflammation through its inhibitory affect on NF-κB activation. 8 Therapeutic doses of ALA are in the range of 600 mg daily.

    Many foods and supplements that have primarily been believed to have antioxidant properties also play a role in modulating inflammation, have anticancer properties through cell-signaling pathways, and can influence many physiologic effects through a plethora of other mechanisms and processes. Primary prevention of cancer and degenerative diseases through the intake of a whole-foods diet seems prudent. We are beginning to have the tools available to identify persons at increased risk for oxidative damage and development of degenerative disease due to their specific genetic polymorphisms.

    For entire article:

    http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/preventive-medicine/integrative-medicine/



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