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Nathan Goodyear

Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2... - 0 views

  • Chen et al. have revealed that ascorbate at pharmacologic concentrations (0.3–20 mM) achieved only by intravenously (i.v.) administration selectively kills a variety of cancer cell lines in vitro, but has little cytotoxic effect on normal cells.
  • Ascorbic acid (the reduced form of vitamin C) is specifically transported into cells by sodium-dependent vitamin C transporters (SVCTs)
  • SVCT-1 is predominantly expressed in epithelial tissues
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  • whereas the expression of SVCT-2 is ubiquitous
  • differential sensitivity to VC may result from variations in VC flow into cells, which is dependent on SVCT-2 expression.
  • high-dose VC significantly impaired both the tumorspheres initiation (Fig. 4d, e) and the growth of established tumorspheres derived from HCC cells (Fig. 4f, g) in a time-dependent and dose-dependent manner.
  • Hepatocellular carcinoma (HCC)
  • The antioxidant, N-acetyl-L-cysteine (NAC), preventing VC-induced ROS production (a ROS scavenger), completely restored the viability and colony formation among VC-treated cells
  • DNA double-strand damage was found following VC treatment
  • DNA damage was prevented by NAC
  • Interestingly, the combination of VC and cisplatin was even more effective in reducing tumor growth and weight
  • Consistent with the in vitro results, stemness-related genes expressions in tumor xenograft were remarkably reduced after VC or VC+cisplatin treatment, whereas conventional cisplatin therapy alone led to the increase of CSCs
  • VC is one of the numerous common hepatoprotectants.
  • Interestingly, at extracellular concentrations greater than 1 mM, VC induces strong cytotoxicity to cancer cells including liver cancer cells
  • we hypothesized that intravenous VC might reduce the risk of recurrence in HCC patients after curative liver resection.
  • Intriguingly, the 5-year disease-free survival (DFS) for patients who received intravenous VC was 24%, as opposed to 15% for no intravenous VC-treated patients
  • Median DFS time for VC users was 25.2 vs. 18 months for VC non-users
  • intravenous VC use is linked to improved DFS in HCC patients.
  • In this study, based on the elevated expression of SVCT-2, which is responsible for VC uptake, in liver CSCs, we revealed that clinically achievable concentrations of VC preferentially eradicated liver CSCs in vitro and in vivo
    • Nathan Goodyear
       
      the authors here made similar mistakes to the Mayo authors i.e. under doses here in this study.  They dosed at only 2 grams IVC.  A woefully low dose of IVC.
  • Additionally, we found that intravenous VC reduced the risk of post-surgical HCC progression in a retrospective cohort study.
    • Nathan Goodyear
       
      positive results despite a low dose used.
    • Nathan Goodyear
       
      Their comfort zone was 1mM.  They should have targeted 20-40 mM.
  • Three hundred thirty-nine participants (55.3%) received 2 g intravenous VC for 4 or more days after initial hepatectomy
  • As the key protein responsible for VC uptake in the liver, SVCT-2 played crucial roles in regulating the sensitivity to ascorbate-induced cytotoxicity
  • we also observed that SVCT-2 was highly expressed in human HCC samples and preferentially elevated in liver CSCs
  • SVCT-2 might serve as a potential CSC marker and therapeutic target in HCC
  • CSCs play critical roles in regulating tumor initiation, relapse, and chemoresistance
  • we revealed that VC treatment dramatically reduced the self-renewal ability, expression levels of CSC-associated genes, and percentages of CSCs in HCC, indicating that CSCs were more susceptible to VC-induced cell death
  • as a drug for eradicating CSCs, VC may represent a promising strategy for treatment of HCC, alone or particularly in combination with chemotherapeutic drugs
  • In HCC, we found that VC-generated ROS caused genotoxic stress (DNA damage) and metabolic stress (ATP depletion), which further activated the cyclin-dependent kinase inhibitor p21, leading to G2/M phase cell cycle arrest and caspase-dependent apoptosis in HCC cells
  • we demonstrated a synergistic effect of VC and chemotherapeutic drug cisplatin on killing HCC both in vitro and in vivo
  • Intravenous VC has also been reported to reduce chemotherapy-associated toxicity of carboplatin and paclitaxel in patients,38 but the specific mechanism needs further investigation
    • Nathan Goodyear
       
      so, exclude the benefit to patients until the exact mechanism of action, which will never be fully elicited?!?!?
  • Our retrospective cohort study also showed that intravenous VC use (2 g) was related to the improved DFS in HCC patients after initial hepatectomy
    • Nathan Goodyear
       
      Terribly inadequate dose.  Target is 20-40 mM which other studies have found occur with 50-75 grams of IVC.
  • several clinical trials of high-dose intravenous VC have been conducted in patients with advanced cancer and have revealed improved quality of life and prolonged OS
  • high-dose VC was not toxic to immune cells and major immune cell subpopulations in vivo
  • high recurrence rate and heterogeneity
  • tumor progression, metastasis, and chemotherapy-resistance
  • SVCT-2 was highly expressed in HCC samples in comparison to peri-tumor tissues
  • high expression (grade 2+/3+) of SVCT-2 was in agreement with poorer overall survival (OS) of HCC patients (Fig. 1c) and more aggressive tumor behavior
  • SVCT-2 is enriched in liver CSCs
  • these data suggest that SVCT-2 is preferentially expressed in liver CSCs and is required for the maintenance of liver CSCs.
  • pharmacologic concentrations of plasma VC higher than 0.3 mM are achievable only from i.v. administration
  • The viabilities of HCC cells were dramatically decreased after exposure to VC in dose-dependent manner
  • VC and cisplatin combination further caused cell apoptosis in tumor xenograft
  • These results verify that VC inhibits tumor growth in HCC PDX models and SVCT-2 expression level is associated with VC response
  • qPCR and IHC analysis demonstrated that expression levels of CSC-associated genes and percentages of CSCs in PDXs dramatically declined after VC treatment, confirming the inhibitory role of VC in liver CSCs
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    IV vitamin C in vitro and in vivo found to "preferentially" eradicate cancer stem cells.  In addition, IV vitamin C was found to be adjunctive to chemotherapy, found to be hepatoprotectant.  This study also looked at SVCT-2, which is the transport protein important in liver C uptake.
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

Endothelial cell damage is the central part of COVID-19 and a mouse model induced by in... - 0 views

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    It is concluded that ACE2+ endothelial damage is a central part of SARS-CoV2 pathology and may be induced by the spike protein alone.
babajemofficial

How To Your Bleached Hair At Home - BabaJem - 0 views

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    You might require more than simple lifestyle changes and DIY remedies to improve your hair if it has been seriously damaged by bleach or any other environmental factors.
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    You might require more than simple lifestyle changes and DIY remedies to improve your hair if it has been seriously damaged by bleach or any other environmental factors.
Nathan Goodyear

Effect of Arnica D30 in marathon runners. Pooled ... [Homeopathy. 2003] - PubMed - NCBI - 0 views

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    Arnica found to lower muscle soreness after marathons, but not found to lower cell damage markers.
Nathan Goodyear

Experimental study on the effect of vitamin C administration on lipid peroxidation and ... - 0 views

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    Rat model shows that vitamin C reduces oxidative damage from lead.  Thus, vitamin C provides antioxidant effect.
Nathan Goodyear

Run for your life … at a comfortable speed and not too far -- O'Keefe and Lav... - 0 views

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    Running beyond 25 miles weekly is damaging to the heart according to this editorial.  
Nathan Goodyear

Running: the risk of coronary events † - 0 views

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    This study shows that "healthy marathon" runners may not be as healthy as once thought.  Basically, current strategies to assess coronary artery calcification is inadequate.  Point: damage is being done that is not being detected.
Nathan Goodyear

Chylomicron formation and glucagon-like peptide 1 receptor are involved in activation o... - 0 views

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    Inflammatory foods coupled with elevated glucose levels and hypertriglyceridemia induces endotoxemia, oxidative damage and immune,inflammatory dysfunction; thus activated chylomicrons
Nathan Goodyear

Roundup Disrupted Male Reproductive Func... [Free Radic Biol Med. 2013] - PubMed - NCBI - 0 views

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    Glyphosate, component of Roundup is well known to be an endocrine disruptor.  This rat study describes the mechanism  of disruption of the Sertoli cells resulting in male infertility.  In addition to the disruption of spermatogenesis, Glyphosate was shown to deplete glutathione levels compromising detoxification.  If that is not enough, oxidative damage marker TBARS was elevated.  
Nathan Goodyear

Pesticide-induced decrease in rat tes... [Ecotoxicol Environ Saf. 2013] - PubMed - NCBI - 0 views

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    Pesticides disrupt the testicular function, in part, through oxidative damage.  This study found Alpha lipoic acid  to be a promising, effective mechanism to reduce the oxidative stress.  They also found tocopherols to be effect, but to a lesser extent.
vrocky

Top skincare tips for working women - 0 views

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    Working Women Skincare Tips If you are able to run away from fast food fast sufficient, you might be doing a enormous favour to your skin. The ingredients in fast food can damage your health and your skin too. At work, have a some of almonds, berries or some fruits handy. You need habitually eat all types and colours of organic, fresh vegetables, particularly green and leafy ones. Be necessary at least one cup of two-three dissimilar types of berries thrice a week. Take in veggie juices in your diet. These types of foods are sure to improvement your antioxidant
Nathan Goodyear

Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations - 0 views

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    Adjuvants in vaccines are dangerous.  ASIA and macrophages myofasciitis are implicated in the damage caused by adjuvants, of which aluminum is the most widely known.  I love what the author says here: "safe assessments for vaccines have often not included appropriate toxicity studies because vaccines have not been viewed as inherently toxic".  This is not political but scientific.
wheelchairindia9

Tynor Elbow Support - 0 views

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    Tynor Wrist Brace with Double Lock is designed with a double lock that will make it simple to apply and remove. Its double lock feature gives rigid support to the wrist. It partially keeps the wrist immobilized. It can easily adjust the compression around the affected area as per the desire. It provides the warming feel to the injured area to allay the local pain and inflammation. It has a high modulus of elasticity which works for a long time, even if use this on a regularl basis. It has striped elastic webbing which is of high quality material. This double lock wrist brace is strong, rigid and comfortable to wear. Its material is porous in nature which keeps the affected area air ventilated. It can adjust the compression pressure according to the will. Its double hook loop locking system is easy to apply and remove as well as comes with universal sizing. This wrist brace provides strength and support to the wrist and keep the wrist protected against the further injury or damage. Tynor Wrist Brace with Double Lock Wrist brace with double lock is designed to support, protect and partially immobilize the wrist. It compresses the area and retain the body heat to allay local pain and inflammation. Extra grip. Extra porous Controlled compression. Easy application. Tynor Wrist Brace with Double Lock Features High quality, striped elastic webbing Strong and durable Porous and comfortable High modulus of elasticity- Retains shape and size for a long time. Excellent compressive strength, better support Hook loop Double locking Easy to apply and remove Ensures optimal compression Better fitting and universal sizing. Tynor Elbow Support Elbow support provides firm compression, warmth & support to the forearm and the elbow joint, to allay pain inflammation and stiffness, generally associated with old age, arthritis, sports injury etc. Light weight Four way stretch Freely breathable Soft and comfortable Tynor Elbow Support Features Anatom
wheelchairindia9

Tynor Foot Drop Splint Right-Left - 0 views

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    Tynor Foot Drop Splint Right/Left Applications Prevention and correction of foot drop. Peripheral nerve paralysis. Nerve/Muscle damage. Ankle or Plantar flexion contracture. Functional Alignment of the foot. Post operative care. Burn patients. Tynor Foot Drop Splint Right/Left Features Effective foot lift. Strong leaf spring action. Customizable. Thin walled, worn in a shoe. Tynor Foot Drop Splint Right/Left Measurements Measure shoe size Size Chart - Sizes European American Small 34-36 2.8-4.4 Medium 37-39 5.3-6.8 Large 40-42 7.5-9.0
Nathan Goodyear

Normal Fasting Plasma Glucose Levels and Type 2 Diabetes in Young Men - NEJM - 0 views

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    Fasting glucose levels >90 require treatment.  Don't wait until they increase above 100, damage is actively occurring in the kidneys at levels above 90.  institute dietary/lifestyle changes at any point above 84.
Nathan Goodyear

Allopregnanolone, a progesterone metabolite, i... [Ann Emerg Med. 2006] - PubMed - NCBI - 0 views

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    again an animal model; but progesterone and allopregnanolone shown to reduce brain damage.  Allopregnanolone was more effective in this animal model.
Nathan Goodyear

Glyphosate Formulations Induce Apoptosis and Necrosis in Human Umbilical, Embryonic, an... - 0 views

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    Glyphosate-based herbicides (commonly found in roundup) shown to cause damage to placenta cells.  This has major implications in infertility and pregnancy health
Nathan Goodyear

Physiologic progesterone reduces mitochondrial dysfunction and hippocampal cell loss af... - 0 views

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    Bioidentical progesterone shown to reduce post TBI mitochondrial dysfunction. This has significant implications on the ability of the damaged brain to heal and recover, thus limiting post-injury cognitive deficits.
Nathan Goodyear

Does stress damage the brain? [Biol Psychiatry. 1999] - PubMed - NCBI - 1 views

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    stress results in shrinkage of the hippocampus of the brain.  This would result in deficiency in serotonin and thus contribute to many of the symptoms found in those with PTSD.
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