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Nathan Goodyear

Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skelet... - 0 views

  • short-term HFO introduces DNA methylation changes on a genome-wide scale in human skeletal muscle
  • These changes were only partly reversed after 6–8 weeks
  • The induction of DNA methylation changes after 5 days of HFO supports the growing awareness of DNA methylation as a dynamic signal that is possibly relevant to short-term day-to-day metabolic adaptations, including acute exercise
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  • Diverging DNA methylation levels between elderly, but not young, genetically identical twins indicate that environmental exposures throughout life may permanently influence DNA methylation, suggesting some preservation of de novo DNA methylation in adults
  • our finding of a slow reversibility rate indicates the demethylation process may be somewhat impeded compared with the induction of methylation changes by diet, which could have implications for the preservation or build-up of CpG methylation over time
  • A slow reversibility of DNA methylation induced by carcinogenic agents has likewise been observed due to ingestion of high-fat diets in rodents
  • the relationship between DNA methylation and gene expression is not always straightforward
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    Study finds variability of methylation and some genetic expression alteration with high fat diet.  Restated, what you eat interacts with your DNA to alter genetic expression.  This has implications on initiation of therapy as well as response to therapy.
Nathan Goodyear

Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde... - 0 views

  • Hydroxyl radicals cause oxidative damage to cells because they unspecifically attack biomolecules [22] located less than a few nanometres from its site of generation and are involved in cellular disorders such as neurodegeneration [23, 24], cardiovascular disease [25], and cancer [26, 27].
  • It is generally assumed that in biological systems is formed through redox cycling by Fenton reaction, where free iron (Fe2+) reacts with hydrogen peroxide (H2O2) and the Haber-Weiss reaction that results in the production of Fe2+ when superoxide reacts with ferric iron (Fe3+)
  • other transition-metal including Cu, Ni, Co, and V can be responsible for formation in living cells
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  • The hydroperoxyl radical () plays an important role in the chemistry of lipid peroxidation
  • The is a much stronger oxidant than superoxide anion-radical
  • Lipid peroxidation can be described generally as a process under which oxidants such as free radicals or nonradical species attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs) that involve hydrogen abstraction from a carbon, with oxygen insertion resulting in lipid peroxyl radicals and hydroperoxides as described previously
  • under medium or high lipid peroxidation rates (toxic conditions) the extent of oxidative damage overwhelms repair capacity, and the cells induce apoptosis or necrosis programmed cell death
  • The overall process of lipid peroxidation consists of three steps: initiation, propagation, and termination
  • Once lipid peroxidation is initiated, a propagation of chain reactions will take place until termination products are produced.
  • The main primary products of lipid peroxidation are lipid hydroperoxides (LOOH)
  • Among the many different aldehydes which can be formed as secondary products during lipid peroxidation, malondialdehyde (MDA), propanal, hexanal, and 4-hydroxynonenal (4-HNE) have been extensively studied
  • MDA has been widely used for many years as a convenient biomarker for lipid peroxidation of omega-3 and omega-6 fatty acids because of its facile reaction with thiobarbituric acid (TBA)
  • MDA is one of the most popular and reliable markers that determine oxidative stress in clinical situations [53], and due to MDA’s high reactivity and toxicity underlying the fact that this molecule is very relevant to biomedical research community
  • 4-HNE is considered as “second toxic messengers of free radicals,” and also as “one of the most physiologically active lipid peroxides,” “one of major generators of oxidative stress,” “a chemotactic aldehydic end-product of lipid peroxidation,” and a “major lipid peroxidation product”
  • MDA is an end-product generated by decomposition of arachidonic acid and larger PUFAs
  • Identifying in vivo MDA production and its role in biology is important as indicated by the extensive literature on the compound (over 15 800 articles in the PubMed database using the keyword “malondialdehyde lipid peroxidation” in December 2013)
  • MDA reactivity is pH-dependent
  • When pH decreases MDA exists as beta-hydroxyacrolein and its reactivity increases
  • MAA adducts are shown to be highly immunogenic [177–181]. MDA adducts are biologically important because they can participate in secondary deleterious reactions (e.g., crosslinking) by promoting intramolecular or intermolecular protein/DNA crosslinking that may induce profound alteration in the biochemical properties of biomolecules and accumulate during aging and in chronic diseases
  • MDA is an important contributor to DNA damage and mutation
  • This MDA-induced DNA alteration may contribute significantly to cancer and other genetic diseases.
  • Dietary intake of certain antioxidants such as vitamins was associated with reduced levels of markers of DNA oxidation (M1dG and 8-oxodG) measured in peripheral white blood cells of healthy subjects, which could contribute to the protective role of vitamins on cancer risk
  • 4-HNE is an extraordinarily reactive compound
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    Great review of lipid peroxidation
Nathan Goodyear

The acute effect of high-dose intravenous vitamin C and other nutrients on blood pressu... - 0 views

  • the reduction in BP within the first 10–20 min may be primarily attributed to a direct vasodilatory physiological effect, described as venodilation
  • BP reduction observed after 70–90 min is likely attributable to pharmacokinetically plausible vitamin C absorption and vasodilation because of nitric oxide release
  • Pharmacokinetic studies of IVC administration observed peak plasma levels within the first 90 min, with plasma levels reaching 13350 μmol/l for 50 g of IVC
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  • Essential hypertension, associated with endothelial dysfunction because of an impaired nitric oxide/l-arginine pathway and impaired vasodilation can be restored by vitamin C
  • marked increase in BP response when IVB12 is administered
  • The mean BP increased significantly up to 12–16 mmHg systolic and diastolic independent of the dosage of vitamin B12
  • The production of norepinephrine, which can stimulate angiotensin-II production, which in turn influences BP, has been suggested as a possible mechanism for the increase in BP with IVB12
  • excess norephinephrine levels stimulate the sympathetic nervous system, leading to increased cortisol production, which has also been linked to increases in BP
  • Animal studies have found higher serum levels of norepinephrine (noradrenaline) in the adrenal medulla of rats receiving methylcobalamin (methyl-vitamin B12)
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    IV vitamin C in mostly normotensive patients (> 30 grams) reduced blood pressure.  Some of the patients were pre-hypertensive. Vitamin B12 increase the blood pressure.
jessicaewing

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Nathan Goodyear

Maximum Tolerable Dose and Low-Dose Metronomic Chemotherapy Have Opposite Effects on th... - 0 views

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    Only pdf available here. Start difference in the MTD to metronomic dosing of chemotherapy.
Nathan Goodyear

IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SA... - 0 views

  • These mRNA vaccines represented a new type of vaccine that comprises synthetic mRNA molecules that contain the coding sequence necessary to build the SARS-CoV-2 Spike protein, which is encased in the lipid nanoparticles (LNPs) to allow for the delivery of mRNA to cells.
  • proteins are synthesized within the host cells
  • they can induce significant neutralizing anti-spike IgG and IgA response
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  • Lethal COVID-19 cases have been linked to higher levels of IgG4 antibodies
  • mRNA vaccines trigger their synthesis
  • provide the scientific rationale suggesting that repeated vaccination with mRNA vaccines could generate an immune tolerance mechanism, thereby favoring unopposed SARS-CoV-2 replication.
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