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Nathan Goodyear

Peripheral oxidative stress in relapsing-remitting multiple sclerosis - 0 views

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    Relapsing remitting MS patients found to have in increased 8OHdG, reduced glutathione, reduced glutathione to oxidized glutathione ratio, super oxidized disumutase, glutathione reductase, and global oxidative stress.  In contrast, decreased total antioxidant capacity, oxidized glutathione, glutathione perioxidase, and glutathione transferase were found in relapsing remitting MS patients.
Nathan Goodyear

Deficient Glutathione in the Pathophysiology of Mycotoxin-Related Illness - 0 views

  • Decreased function of the enzymes of glutathione production results in a microenvironment depleted of glutathione on a chronic basis
  • In humans, deficiency of glutathione can lead to chronic conditions [97], including chronic asthma
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    Mycotoxins deplete glutathione production and this depletion of glutathione is a portion go the toxicity/ill effects related to mycotoxins.  This article also points to evidence that glutathione can actually be employed in the treatment of mycotoxin related conditions/illnesses.
Nathan Goodyear

Glutathione Redox Regulates Airway Hyperresponsiveness and Airway Inflammation in Mice ... - 0 views

  • γ-GCE reduced levels of IL-4, IL-5, IL-10, and the chemokines eotaxin and RANTES (regulated on activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid, whereas it enhanced the production of IL-12 and IFN-γ.
  • γ-GCE suppressed eosinophils infiltration
  • γ-GCE directly inhibited chemokine-induced eosinophil chemotaxis
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  • these findings suggest that changing glutathione redox balance, increase in GSH level, and the GSH/GSSG ratio by γ-GCE, ameliorate bronchial asthma by altering the Th1/Th2 imbalance through IL-12 production from APC and suppressing chemokine production and eosinophil migration itself.
  • Bronchial asthma is a typical helper T cell type 2 (Th2) disease
  • Through the release of Th2 cytokines, such as IL-4, IL-5, and IL-13, orchestrate the recruitment and activation of the primary effector cells of the allergic response: the mast cells and the eosinophils
  • Glutathione is the most abundant nonprotein sulfhydryl compound in almost all cells. This tripeptide plays a significant role in many biological processes. It also constitutes the first line of the cellular defense mechanism against oxidative injury along with SOD, ascorbate, vitamin E, and catalase, and is the major intracellular redox buffer in ubiquitous cell types
  • We have shown that glutathione redox status, namely the balance between intracellular reduced (GSH) and oxidized (GSSG) glutathione, in murine antigen-presenting cells (APC) plays a central role in determining which of the reductive and oxidative APC predominate during immune status, and the balance between reductive and oxidative APC regulates Th1/Th2 balance through production of IL-12
  • we have also shown that exposure of human alveolar macrophages to the Th1 cytokine IFN-γ or the Th2 cytokine IL-4 either increases or decreases the GSH/GSSG ratio, respectively, which regulates Th1/Th2 balance through IL-12 production
  • the ability to generate a Th1 or Th2 type response has turned out to depend not only on T cells but also on the intracellular glutathione redox status of APC
  • Th1 cytokine IFN-γ and Th2 cytokine IL-4 increases and decreases the GSH/GSSG ratio, respectively, and that this ratio influences LPS-induced IL-12 production from alveolar macrophages
  • the ability to generate a Th1 or Th2 response is dependent on glutathione redox status of APC
  • administration of γ-GCE elevates GSH level and GSH/GSSG ratio in the lung, and ameliorates AHR and eosinophilic airway inflammation by altering the Th1/Th2 balance and suppressing chemokine production and eosinophil migration in a mouse asthma model
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    glutathione redox reaction plays an important role in the ability to balance Th1 and Th2 and thus disease potential i.e. asthma as this study example.  
Nathan Goodyear

MR spectroscopic imaging of glutathione in the white and gray matter at 7 T with an app... - 0 views

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    Interesting study on glutathione.  The study looked at glutathione levels in the brain using MR.  The authors found lower glutathione levels in the Grey matter versus normal controls and lower glutathione levels in white matter lesions.
Nathan Goodyear

Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a p... - 0 views

  • Taken together, these data indicate that ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H2O2, and that blood can be a delivery system of the pro-drug to tissues.
  • These findings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H2O2 may be beneficial
  • pharmacologic concentrations of ascorbate killed cancer but not normal cells, that cell death was dependent only on extracellular but not intracellular ascorbate, and that killing was dependent on extracellular hydrogen peroxide (H2O2) formation with ascorbate radical as an intermediate
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  • Our data show that ascorbic acid selectively killed cancer but not normal cells, using concentrations that could only be achieved by i.v. administration
  • Ascorbate-mediated cell death was due to protein-dependent extracellular H2O2 generation, via ascorbate radical formation from ascorbate as the electron donor. Like glucose, when ascorbate is infused i.v., the resulting pharmacologic concentrations should distribute rapidly in the extracellular water space (42). We showed that such pharmacologic ascorbate concentrations in media, as a surrogate for extracellular fluid, generated ascorbate radical and H2O2. In contrast, the same pharmacologic ascorbate concentrations in whole blood generated little detectable ascorbate radical and no detectable H2O2. These findings can be accounted for by efficient and redundant H2O2 catabolic pathways in whole blood (e.g., catalase and glutathione peroxidase) relative to those in media or extracellular fluid
  • ascorbic acid administered i.v. in pharmacologic concentrations may serve as a pro-drug for H2O2 delivery to the extracellular milieu
  • H2O2 generated in blood is normally removed by catalase and glutathione peroxidase within red blood cells, with internal glutathione providing reducing equivalents
  • The electron source for glutathione is NADPH from the pentose shunt, via glucose-6-phosphate dehydrogenase. If activity of this enzyme is diminished, the predicted outcome is impaired H2O2 removal causing intravascular hemolysis, the observed clinical finding.
    • Nathan Goodyear
       
      The mechansism here is inadequate recycling of GSH due to lack of G6PD, build up of intracellular H2O2 and RBC lysis--hemolysis.
  • Only recently has it been understood that the discordant clinical findings can be explained by previously unrecognized fundamental pharmacokinetics properties of ascorbate
  • Intracellular transport of ascorbate is tightly controlled in relation to extracellular concentration
  • Intravenous ascorbate infusion is expected to drastically change extracellular but not intracellular concentrations
  • For i.v. ascorbate to be clinically useful in killing cancer cells, pharmacologic but not physiologic extracellular concentrations should be effective, independent of intracellular ascorbate concentrations.
    • Nathan Goodyear
       
      accumulation of extracellular vitamin C is the effect.
  • It is unknown why ascorbate, via H2O2, killed some cancer cells but not normal cells.
  • There was no correlation with ascorbate-induced cell death and glutathione, catalase activity, or glutathione peroxidase activity.
  • H2O2, as the product of pharmacologic ascorbate concentrations, has potential therapeutic uses in addition to cancer treatment, especially in infections
  • Neutrophils generate H2O2 from superoxide,
  • i.v. ascorbate is effective in some viral infections
  • H2O2 is toxic to hepatitis C
  • Use of ascorbate as an H2O2-delivery system against sensitive pathogens, viral or bacterial, has substantial clinical implications that deserve rapid exploration.
  • Recent pharmacokinetics studies in men and women show that 10 g of ascorbate given i.v. is expected to produce plasma concentrations of nearly 6 mM, which are >25-fold higher than those concentrations from the same oral dose
  • As much as a 70-fold difference in plasma concentrations is expected between oral and i.v. administration,
  • Complementary and alternative medicine practitioners worldwide currently use ascorbate i.v. in some patients, in part because there is no apparent harm
  • Human Burkitt's lymphoma cells
  • We first investigated whether ascorbate in pharmacologic concentrations selectively affected the survival of cancer cells by studying nine cancer cell lines
  • Clinical pharmacokinetics analyses show that pharmacologic concentrations of plasma ascorbate, from 0.3 to 15 mM, are achievable only from i.v. administration
  • plasma ascorbate concentrations from maximum possible oral doses cannot exceed 0.22 mM because of limited intestinal absorption
  • For five of the nine cancer cell lines, ascorbate concentrations causing a 50% decrease in cell survival (EC50 values) were less than 5 mM, a concentration easily achievable from i.v. infusion
  • All tested normal cells were insensitive to 20 mM ascorbate.
    • Nathan Goodyear
       
      meaning safe.
  • Lymphoma cells were selected because of their sensitivity to ascorbate
  • As ascorbate concentration increased, the pattern of death changed from apoptosis to pyknosis/necrosis, a pattern suggestive of H2O2-mediated cell death
  • Apoptosis occurred by 6 h after exposure, and cell death by pyknosis was ≈90% at 14 h after exposure
    • Nathan Goodyear
       
      work continued beyond the IVC therapy itself
  • In contrast to lymphoma cells, there was little or no killing of normal lymphocytes and monocytes by ascorbate
  • Ascorbate is transported into cells as such by sodium-dependent transporters, whereas dehydroascorbic acid is transported into cells by glucose transporters and then immediately reduced internally to ascorbate
  • Whether or not intracellular ascorbate was preloaded, extracellular ascorbate induced the same amount and type of death.
  • extracellular ascorbate in pharmacologic concentrations mediates death of lymphoma cells by apoptosis and pyknosis/necrosis, independently of intracellular ascorbate.
  • H2O2 as the effector species mediating pharmacologic ascorbate-induced cell death
  • Superoxide dismutase was not protective
  • Because these data implicated H2O2 in cell killing, we added H2O2 to lymphoma cells and studied death patterns using nuclear staining (19, 28). The death patterns found with exogenous H2O2 exposure were similar to those found with ascorbate
  • For both ascorbate and H2O2, death changed from apoptosis to pyknosis/necrosis as concentrations increased
  • Sensitivity to direct exposure to H2O2 was greater in lymphoma cells compared with normal lymphocytes and normal monocytes
  • There was no association between the EC50 for ascorbate-mediated cell death and intracellular glutathione concentrations, catalase activity, or glutathione peroxidase activity
  • H2O2 generation was dependent on time, ascorbate concentration, and the presence of trace amounts of serum in media
  • ascorbate radical is a surrogate marker for H2O2 formation.
  • whatever H2O2 is generated should be removed by glutathione peroxidase and catalase within red blood cells, because H2O2 is membrane permeable
  • The data are consistent with the hypothesis that ascorbate in pharmacologic concentrations is a pro-drug for H2O2 generation in the extracellular milieu but not in blood.
  • The occurrence of one predicted complication, oxalate kidney stones, is controversial
  • In patients with glucose-6-phosphate dehydrogenase deficiency, i.v. ascorbate is contraindicated because it causes intravascular hemolysis
  • ascorbate at pharmacologic concentrations in blood is a pro-drug for H2O2 delivery to tissues.
  • ascorbate, an electron-donor in such reactions, ironically initiates pro-oxidant chemistry and H2O2 formation
  • data here showed that ascorbate initiated H2O2 formation extracellularly, but H2O2 targets could be either intracellular or extracellular, because H2O2 is membrane permeant
    • Nathan Goodyear
       
      the conversion of ascorbate to H2O2 occurs extracellular
  • More than 100 patients have been described, presumably without glucose-6-phosphate dehydrogenase deficiency, who received 10 g or more of i.v. ascorbate with no reported adverse effects other than tumor lysis
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    IV vitamin C benefits cancer patients
Nathan Goodyear

Unveiling the Mechanisms for Decreased Glutathione in Individuals with HIV Infection - 0 views

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    men with HIV have GSH depleted macrophages.  GSH is the reduced, ready to act form of Glutathione.  In contrast, the macrophages were high in the oxidized form of Glutathione--GSSG.  In HIV, the high inflammation increased oxidative stress, likely overwhelmed Nrf2 activation and resulted in decreased GSH synthase transcription and thus decreased Glutathione production balance.
Nathan Goodyear

Glutathione prevents the early asthmatic reaction and airway hyperresponsiveness in gui... - 0 views

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    animal model finds that glutathione depletion increases hyperactivity of bronchioles.  Early exposure to glutathione ethyl ester, a precursor to glutathione, blunted the airway hyperactivity.
Nathan Goodyear

Activity of superoxide dismutase, catalase, glutathione peroxidase, and glutathione red... - 0 views

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    "Glutathione reductase activity is lower in all colorectal carcinoma groups than in control, and a significant decrease in glutathione reductase activity was obtained between patients in tumor stage II and III compared to tumor stage IV." Same is see with SOD in study.
Nathan Goodyear

- Cancer Network - 0 views

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    Glutathione shown to provide longer survival in Ovarian cancer.  They describe glutathione as "novel".  Glutathione, in this study, was used as an adjunct in therapy.
Nathan Goodyear

Glutathione in multiple sclerosis: More than just an antioxidant? - 0 views

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    good read on glutathione in MS.  Glutathione is depleted in MS.  
Nathan Goodyear

Nebulized Glutathione Induces Bronchoconstriction in Patients with Mild Asthma (ATS Jou... - 0 views

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    Study finds that nebulizer glutathione in mild asthma induces bronchoconstriction.  This despite the knowledge that glutathione peroxidase activity is known to be depressed in those with asthma.  The severity of the asthma of the individuals included in this study might explain the finding.
Nathan Goodyear

Aluminum decreases the glutathione regeneration by the inhibition of NADP-isocitrate de... - 0 views

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    Aluminum decreases the regeneration of reduced glutathione, leading to depletion of glutathione.
Nathan Goodyear

Effects of estrogen on gene expression profiles in mouse hypothalamus and whi... - 0 views

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    obesity causes oxidative stress, which depletes glutathione.  Lower weight and increase glutathione
Nathan Goodyear

Glutathione supplementation improves macrophage functions in HIV. - PubMed - NCBI - 0 views

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    reduced glutathione, via increased oxidative stress, levels lost in HIV.  NAC and liposomal Glutathione increased innate immune function--macrophages.
Nathan Goodyear

Cancer-preventing attributes of probioti... [Int J Food Sci Nutr. 2010] - PubMed - NCBI - 0 views

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    The evidence of probiotics in cancer is limited.  The limited evidence points to an increase in anti-oxidative enzymes i.e. glutathion-S-transferase, glutathione perioxidase, catalase, SOD.
Nathan Goodyear

Glutathione S-transferase activity in epithelial ovarian cancer: Association with respo... - 0 views

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    higher glutathione S-transferase activity associated with improved survival and response with chemotherapy.
Nathan Goodyear

Role of certain trace minerals in oxidative stress, inflammation, CD4/CD8 lymphocyte ra... - 0 views

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    Asthma associated with low selenium, low zinc, high copper, low glutathione peroxidase, glutathione reductase, and catalase activity; in contrast, increased hs-CRP, and TBARS was  noted.  Interesting that FEV1 and FVC positively correlated with Se levels.
Nathan Goodyear

The role of S-adenosyl methionine in preventing FOLFOX-induced liver toxicity: a retros... - 0 views

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    SAMe shown to lower liver toxicity in chemotherapy treatment.  SAMe could be a powerful chemotherapeutic adjuvant.  This makes since, because cancer is known to be a hypomethylated state.  Low methyl donors will reduce CBS activity and thus lower glutathione.  This will result in increased oxidative stress and inflammation in the liver.  SAMe will open the CBS activity up and increase glutathione production.
Nathan Goodyear

Randomized, double-blind, pilot evaluation of int... [Mov Disord. 2009] - PubMed - NCBI - 0 views

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    IV glutathione shown to be same and provide mild improvement in Parkinson's disease.  This is a small pilot study, but a good place to start.  The likelyhood is that glutathione is more beneficial early in Parkinson's disease to slow disease progression.
Nathan Goodyear

Glutathione and Parkinson's Disease - ACAM Integrative Medicine (IM) Blog - 0 views

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    IV glutathione therapy as adjuvant in people with Parkinson's disease
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