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Nathan Goodyear

Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis - 1 views

www.ncbi.nlm.nih.gov/...PMC3937164

sepsis IV vitamin C vitamin C CRP

shared by Nathan Goodyear on 11 Oct 17 - No Cached
  • Padayatty and colleagues showed that high-level ascorbic acid plasma concentrations could only be achieved by intravenous administration
  • No patient in the low or high dose ascorbic acid treatment arms of this study suffered any identifiable adverse event
  • a pharmacologic ascorbic acid treatment strategy in critically ill patients with severe sepsis appears to be safe
  • ...7 more annotations...
  • subnormal plasma ascorbic acid levels are a predictable feature in patients with severe sepsis
  • Ascorbic acid depletion in sepsis results from ascorbic acid consumption by the reduction of plasma free iron, ascorbic acid consumption by the scavenging of aqueous free radicals (peroxyl radicals), and by the destruction of the oxidized form of ascorbic acid dehydroascorbic acid
  • Sepsis further inhibits intracellular reduction of dehydroascorbic acid, producing acute intracellular ascorbic acid depletion
  • Ascorbic acid treated patients in this study exhibited rapid and sustained increases in plasma ascorbic acid levels using an intermittent every six hours administration protocol
  • Septic ascorbic acid-deficient neutrophils fail to undergo normal apoptosis. Rather, they undergo necrosis thereby releasing hydrolytic enzymes in tissue beds, thus contributing to organ injury
  • We speculate that intravenous ascorbic acid acts to restore neutrophil ascorbic acid levels
  • Repletion of ascorbic acid in this way allows for normal apoptosis, thus, preventing the release of organ damaging hydrolytic enzymes.
  • Nathan Goodyear on 11 Oct 17
     
    Study finds IV vitamin C in patients with sepsis is very safe and blunts the effects (endothelial damage, end organ damage...) of sepsis.  Of note, the IV vitamin C group reached serum levels of ascorbic acid of 1,592 to 5,722 micromol/L.  The IV groups maintained elevated serum C levels for up to 96 hours post infusion.  
Nathan Goodyear

Editorial: Cytokine-Mediated Organ Dysfunction and Tissue Damage Induced by Viruses - 1 views

www.ncbi.nlm.nih.gov/...PMC6987404

influenza TLR4 cytokine storm cytokines

shared by Nathan Goodyear on 14 May 20 - No Cached
  • Nathan Goodyear on 14 May 20
     
    Influenza and other virus' induce cytokine production i.e. cytokine storm via TLR
Nathan Goodyear

A Comparative Analysis of Low-Dose Metronomic Cyclophosphamide Reveals Absent or Low-Gr... - 0 views

cancerres.aacrjournals.org/...3994

maximum tolerated chemotherapy cancer low-dose chemotherapy

shared by Nathan Goodyear on 31 Aug 20 - No Cached
  • Nathan Goodyear on 31 Aug 20
     
    Low-dose chemotherapy significantly reduced toxicity compared to maximum tolerated dosing.
Nathan Goodyear

Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue | Reque... - 0 views

www.researchgate.net/...hrough_normal_and_tumor_tissue

tumor cancer vitamin C IV vitamin C

shared by Nathan Goodyear on 18 Jan 22 - No Cached
  • Nathan Goodyear on 18 Jan 22
     
    Plasma levels of 100 microMolar to penetrate all hypoxic areas of tumor.
Nathan Goodyear

'Spikeopathy': COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA -... - 0 views

europepmc.org/...PMC10452662

COVID COVID19 COVID-19 spike proteins spikeopathy cancer SARS-CoV-2

shared by Nathan Goodyear on 01 Sep 23 - No Cached
  • toxicity of the spike protein—both from the virus and also when produced by gene codes in the novel COVID-19 mRNA and adenovectorDNA vaccines
  • ‘spikeopathy’;
  • A central issue has been growing evidence of pathogenic effects of the SARS-CoV-2 spike protein—whether as part of the virus or produced by genetic codes in the mRNA and adenovectorDNA vaccines
  • ...10 more annotations...
  • It is apparent that the original Wuhan strain and early variants of SARS-CoV-2 in 2020 were more pathogenic than later variants. This is consistent with typical viral adaptive evolution to more infectious but less pathogenic strains, a natural phenomenon
  • SARS-CoV-2 spike protein is pathogenic, whether from the virus or created from genetic code in mRNA and adenovectorDNA vaccines.
  • Evidence suggests reverse transcription of mRNA into a DNA copy is possible
  • further suggests the possibility of intergenerational transmission if germline cells incorporate the DNA copy into the host genome
    • Nathan Goodyear
      Nathan Goodyear on 01 Sep 23
       
      Intergenerational and transgenerational!
  • (‘spikeopathy’) via several mechanisms that lead to inflammation, thrombogenesis, and endotheliitis-related tissue damage
  • Interaction of the vaccine-encoded spike protein with ACE-2, P53 and BRCA1 suggests a wide range of possible biological interference with oncological potential
  • Repeated COVID-19 vaccine booster doses appear to induce tolerance and may contribute to recurrent COVID-19 infection and ‘long COVID’.
  • spike protein is not only toxic through binding of ACE-2 receptors
  • interaction with cancer suppressor genes BRCA and P53
  • mitochondrial damage
Nathan Goodyear

NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond - PMC - 0 views

www.ncbi.nlm.nih.gov/...PMC8924116

cancer NETosis SARS-CoV-2 COVID COVID-19 COVID19 platelets

shared by Nathan Goodyear on 18 Apr 23 - No Cached
  • Pneumonia is a typical symptom of COVID-19 infection, while acute respiratory distress syndrome (ARDS) and multiple organ failure are common in severe COVID-19 patients
  • NETs are important for preventing pathogen invasion, their excessive formation can result in a slew of negative consequences, such as autoimmune inflammation and tissue damage
  • SARS-CoV-2 infection has also been linked to increased neutrophil-to-lymphocyte ratios, which is associated with disease severity and clinical prognosis
  • ...40 more annotations...
  • NETosis is a special form of programmed cell death in neutrophils, which is characterized by the extrusion of DNA, histones, and antimicrobial proteins in a web-like structure known as neutrophil extracellular traps (NETs)
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Definition
  • increased generation of reactive oxygen species (ROS) is a crucial intracellular process that causes NETosis
  • Another indirect route of SARS-CoV-2-induced NET production is platelet activation
  • When NETs are activated in the circulation, they can also induce hypercoagulability and thrombosis
  • In COVID-19, major NET protein cargos of NETs (i.e., NE, MPO, and histones) are significantly elevated.
  • SARS-CoV-2 can also infect host cells through noncanonical receptors such as C-type lectin receptors
  • Immunopathological manifestations, including cytokine storms and impaired adaptive immunity, are the primary drivers behind COVID-19, with neutrophil infiltration being suggested as a significant cause
  • NETosis and NETs are increasingly recognized as causes of vascular injury
  • SARS-CoV-2 and its components (e.g., spike proteins and viral RNA) attach to platelets and increase their activation and aggregation in COVID-19, resulting in vascular injury and thrombosis, both of which are linked to NET formation
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Connects SARS-CoV-2 to TLR on Platelets to NETosis to metastasis.
  • NET formation may be caused by activated platelets rather than SARS-CoV-2 itself
  • NETosis, leading to aberrant immunity such as cytokine storms, autoimmune disorders, and immunosuppression.
  • early bacterial coinfections were more prevalent in COVID-19 patients than those infected with other viruses
  • NETosis and NETs may also have a role in the development of post COVID-19 syndromes, including lung fibrosis, neurological disorders, tumor growth, and worsening of concomitant disease
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      NETosis-> tumor growth
  • NETs and other by-products of NETosis have been shown to act as direct inflammation amplifiers. Hyperinflammation
  • “cytokine storm”
  • SARS-CoV-2 drives NETosis and NET formation to allow for the release of free DNA and by-products (e.g., elastases and histones). This may trigger surrounding macrophages and endothelial cells to secrete excessive proinflammatory cytokines and chemokines, which, in turn, enhance NET formation and form a positive feedback of cytokine storms in COVID-19
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Cycle of hyperinflammation
  • NET release enables self-antigen exposure and autoantibody production, thereby increasing the autoinflammatory response
  • patients with COVID-19 who have higher anti-NET antibodies are more likely to be detected with positive autoantibodies [e.g., antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA)]
  • COVID-19 NETs may act as potential inducers for autoimmune responses
  • have weakened adaptive immunity as well as a high level of inflammation
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Immunomodulation
  • tumor-associated NETosis and NETs promote an immunosuppressive environment in which anti-tumor immunity is compromised
  • NETs have also been shown to enhance macrophage pyroptosis in sepsis
  • facilitating an immunosuppressive microenvironment
  • persistent immunosuppression may result in bacterial co-infection or secondary infection
  • can enhance this process by interacting with neutrophils through toll-like receptor 4 (TLR4), platelet factor 4 (PF4), and extracellular vesicle-dependent processes
  • NET-induced immunosuppression in COVID-19 in the context of co-existing bacterial infection
  • Following initial onset of COVID-19, an estimated 50% or more of COVID-19 survivors may develop multi-organ problems (e.g., pulmonary dysfunction and neurologic impairment) or have worsening concomitant chronic illness
  • NETs in the bronchoalveolar lavage fluid of severe COVID-19 patients cause EMT in lung epithelial cells
  • decreased E-cadherin (an epithelial marker) expression
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Leads to emt
  • COVID-19 also has a long-term influence on tumor progression
  • Patients with tumors have been shown to be more vulnerable to SARS-CoV-2 infection and subsequent development of severe COVID-19
  • patients who have recovered from COVID-19 may have an increased risk of developing cancer or of cancer progression and metastasis
  • awaken cancer cells
  • NETs have been shown to change the tumor microenvironment
  • enhance tumor progression and metastasis
  • vitamin C has been tested in phase 2 clinical trials aimed at reducing COVID-19-associated mortality by reducing excessive activation of the inflammatory response
  • vitamin C is an antioxidant that significantly attenuates PMA-induced NETosis in healthy neutrophils by scavenging ROS
  • vitamin C may also inhibit NETosis and NET production in COVID-19
  • Metformin
  • Vitamin C
  • Nathan Goodyear on 18 Apr 23
     
    NETosis intimately involved in progressive COVID, long COVID, autoimmunity, and cancer
Nathan Goodyear

Targeting the IDO1 pathway in cancer: from bench to bedside | Journal of Hematology & O... - 0 views

jhoonline.biomedcentral.com/...s13045-018-0644-y

tryptophan disordered tryptophan metabolism IDO2 IDO IDO1 indoleamine dioxygenase cancer NAD

shared by Nathan Goodyear on 25 Nov 22 - No Cached
  • Kyn is generated via two major routes: in peripheral tissues, controlled by the rate-limiting enzymes indoleamine 2, 3-dioxygenase 1 (IDO1) and indoleamine 2, 3-dioxygenase 2 (IDO2), and the hepatic route, in which tryptophan 2, 3-dioxygenase (TDO) is the rate-limiting enzyme
Nathan Goodyear

High-Dose Vitamin C for Cancer Therapy - PMC - 0 views

www.ncbi.nlm.nih.gov/...PMC9231292

vitamin C cancer

shared by Nathan Goodyear on 27 Jul 22 - No Cached
  • diabetes [8], atherosclerosis [9], the common cold [10], cataracts [11], glaucoma [12], macular degeneration [13], stroke [14], heart disease [15], COVID-19 [16], and cancer.
  • 1–5% of the Vit-C inside the human cells
  • interaction between Fe(II) and H2O2 produces OH− through the Fenton reaction
  • ...35 more annotations...
  • metabolic activity, oxygen transport, and DNA synthesis
  • Iron is found in the human body in the form of haemoglobin in red blood cells and growing erythroid cells.
  • macrophages contain considerable quantities of iron
  • iron is taken up by the majority of cells in the form of a transferrin (Tf)-Fe(III) complex that binds to the cell surface receptor transferrin receptor 1 (TfR1)
  • excess iron is retained in the liver cells
  • the endosomal six transmembrane epithelial antigen of the prostate 3 (STEAP3) reduces Fe(III) (ferric ion) to Fe(II) (ferrous ion), which is subsequently transferred across the endosomal membrane by divalent metal transporter 1 (DMT1)
  • labile iron pool (LIP)
  • LIP is toxic to the cells owing to the production of massive amounts of ROS.
  • DHA is quickly converted to Vit-C within the cell, by interacting with reduced glutathione (GSH) [45,46,47]. NADPH then recycles the oxidized glutathione (glutathione disulfide (GSSG)) and converts it back into GSH
  • Fe(II) catalyzes the formation of OH• and OH− during the interaction between H2O2 and O2•− (Haber–Weiss reaction)
  • Ascorbate can efficiently reduce free iron, thus recycling the cellular Fe(II)/Fe(III) to produce more OH• from H2O2 than can be generated during the Fenton reaction, which ultimately leads to lipid, protein, and DNA oxidation
  • Vit-C-stimulated iron absorption
  • reduce cellular iron efflux
  • high-dose Vit-C may elevate cellular LIP concentrations
  • ascorbate enhanced cancer cell LIP specifically by generating H2O2
  • Vit-C produces H2O2 extracellularly, which in turn inhibits tumor cells immediately
  • tumor cells have a need for readily available Fe(II) to survive and proliferate.
  • Tf has been recognized to sequester most labile Fe(II) in vivo
  • Asc•− and H2O2 were generated in vivo upon i.v Vit-C administration of around 0.5 g/kg of body weight and that the generation was Vit-C-dose reliant
  • free irons, especially Fe(II), increase Vit-C autoxidation, leading to H2O2 production
  • iron metabolism is altered in malignancies
  • increase in the expression of various iron-intake pathways or the downregulation of iron exporter proteins and storage pathways
  • Fe(II) ion in breast cancer cells is almost double that in normal breast tissues
  • macrophages in the cancer microenvironment have been revealed to increase iron shedding
  • Advanced breast tumor patients had substantially greater Fe(II) levels in their blood than the control groups without the disease
  • increased the amount of LIP inside the cells through transferrin receptor (TfR)
  • Warburg effect, or metabolic reprogramming,
  • Warburg effect is aided by KRAS or BRAF mutations
  • Vit-C is supplied, it oxidizes to DHA, and then is readily transported by GLUT-1 in mutant cells of KRAS or BRAF competing with glucose [46]. DHA is quickly converted into ascorbate inside the cell by NADPH and GSH [46,107]. This decrease reduces the concentration of cytosolic antioxidants and raises the intracellular ROS amounts
  • increased ROS inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH)
  • ROS activates poly (ADP-ribose) polymerase (PARP), which depletes NAD+ (a critical co-factor of GAPDH); thus, further reducing the GAPDH associated with a multifaceted metabolic rewiring
  • Hindering GAPDH can result in an “energy crisis”, due to the decrease in ATP production
  • high-dose Vit-C recruited metabolites and increased the enzymatic activity in the pentose phosphate pathway (PPP), blocked the tri-carboxylic acid (TCA) cycle, and increased oxygen uptake, disrupting the intracellular metabolic balance and resulting in irreversible cell death, due to an energy crisis
  • mega-dose Vit-C influences energy metabolism by producing tremendous amounts of H2O2
  • Due to its great volatility at neutral pH [76], bolus therapy with mega-dose DHA has only transitory effects on tumor cells, both in vitro and in vivo.
Nathan Goodyear

Ascorbic Acid Chemosensitizes Colorectal Cancer Cells and Synergistically Inhibits Tumo... - 0 views

www.ncbi.nlm.nih.gov/...PMC6064950

cancer vitamin C ascorbic acid colorectal cancer

shared by Nathan Goodyear on 26 Mar 22 - No Cached
  • therapeutic potential has been supported by a large and consistent body of evidences from in vitro
  • Ascorbic acid might act as a way to deliver hydrogen peroxide (H2O2) to the tissues
  • pharmacological concentrations of AA were capable of inducing anti-proliferative, cytotoxic and genotoxic effects
  • ...12 more annotations...
  • chemosensitizing
  • pharmacological concentrations of AA can sensitize cancer cells to chemotherapy, enhancing its antineoplastic effect
  • synergistic effect with conventional chemotherapeutic drugs is a fact already reported, in various types of cancer, by numerous authors, namely in pancreatic (Espey et al., 2011), prostate (Gilloteaux et al., 2014), lung (Lee et al., 2017), breast (Kurbacher et al., 1996; Wu et al., 2017) and ovarian (Ma et al., 2014) cancers.
  • chemosensitizing effect of vitamin C has already been proven by several authors in various types of cancer
  • intravenous pharmacological concentrations, may not only potentiate the effects of conventional chemotherapy, but also improve the quality of life of cancer patients
  • AA reinforced the anti-proliferative activity of 5-FU
  • Combined treatment induced a reduction of 11.5% and 43% in cell viability compared with AA or Iri therapies, respectively, emphasizing the synergistic effect
  • cytotoxic effect occurred with treatment with Iri alone, but also this effect was further potentiated by the presence of AA.
  • association of AA with Oxa showed very promising results, considering that a synergistic effect was demonstrated, in almost all conditions
  • AA and Oxa seem to act synergistically by the activation of the intrinsic pathway of apoptosis, translated on the statistically significant increase of the ratio between BAX and BCL-2 proteins, which in turn is associated with a decrease of Δψm
    • Nathan Goodyear
      Nathan Goodyear on 26 Mar 22
       
      Apoptosis -> decrease in mitochondrial membrane potential
  • Previous results obtained by our group showed that AA mediates reactive oxygen species (ROS) formation capable of irreparably damaging DNA
  • oxidative role of AA may be a key factor on the synergistic anti-cancer mechanism
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