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Nathan Goodyear

Oncotarget | Vitamin C and Doxycycline: A synthetic lethal combination therapy targetin... - 0 views

www.impactjournals.com/...index.php

cancer doxycycline IV vitamin C vitamin C

shared by Nathan Goodyear on 14 Jun 17 - No Cached
  • These eight distinct cancer types included: DCIS, breast (ER(+) and ER(-)), ovarian, prostate, lung, and pancreatic carcinomas, as well as melanoma and glioblastoma. Doxycycline was also effective in halting the propagation of primary cultures of CSCs from breast cancer patients, with advanced metastatic disease (isolated from ascites fluid and/or pleural effusions)
  • Doxycycline behaves as a strong radio-sensitizer, successfully overcoming radio-resistance in breast CSCs
  • cancer cells can indeed escape the effects of Doxycycline, by reverting to a purely glycolytic phenotype. Fortunately, the metabolic inflexibility conferred by this escape mechanism allows Doxycycline-resistant (DoxyR) CSCs to be more effectively targeted with many other metabolic inhibitors, including Vitamin C, which functionally blocks aerobic glycolysis
  • ...36 more annotations...
  • Vitamin C inhibits GAPDH (a glycolytic enzyme) and depletes the cellular pool of glutathione, resulting in high ROS production and oxidative stress
  • DoxyR CSCs are between 4- to 10-fold more susceptible to the effects of Vitamin C
  • Doxycycline and Vitamin C may represent a new synthetic lethal drug combination for eradicating CSCs, by ultimately targeting both mitochondrial and glycolytic metabolism
  • inhibiting their propagation in the range of 100 to 250 µM
  • metabolic flexibility in cancer cells allows them to escape therapeutic eradication, leading to chemo- and radio-resistance
  • used doxycycline to pharmacologically induce metabolic inflexibility in CSCs, by chronically inhibiting mitochondrial biogenesis
  • This treatment resulted in a purely glycolytic population of surviving cancer cells
  • DoxyR cells are mainly glycolytic
  • MCF7 cells survive and develop Doxycycline-resistance, by adopting a purely glycolytic phenotype
  • Cancer stem cells (CSCs) are thought to be the “root cause” of tumor recurrence, distant metastasis and therapy-resistance
  • the conserved evolutionary similarities between aerobic bacteria and mitochondria, certain classes of antibiotics inhibit mitochondrial protein translation, as an off-target side-effect
  • Vitamin C was more potent than 2-DG; it inhibited DoxyR CSC propagation by > 90% at 250 µM and 100% at 500 µM
  • IC-50
  • DoxyR CSCs are between 4- to 10-fold more sensitive to Vitamin C than control MCF7 CSCs
  • Berberine, which is a naturally occurring antibiotic that also behaves as an OXPHOS inhibitor
  • treatment with Berberine effectively inhibited the propagation of the DoxyR CSCs by > 50% at 1 µM and > 80% at 10 µM.
  • Doxycycline, a clinically approved antibiotic, induces metabolic stress in cancer cells. This allows the remaining cancer cells to be synchronized towards a purely glycolytic phenotype, driving a form of metabolic inflexibility
  • Doxycycline-driven aerobic glycolysis
  • new synthetic lethal strategy for eradicating CSCs, by employing i) Doxycycline (to target mitochondria) and ii) Vitamin C (to target glycolysis)
  • Doxycycline inhibits mitochondrial biogenesis and OXPHOS,
  • hibits glycolytic metabolism by targeting and inhibiting the enzyme GAPDH
  • CSCs act as the main promoter of tumor recurrence and patient relapse
  • a metabolic shift from oxidative to glycolytic metabolism represents an escape mechanism for breast cancer cells chronically-treated with a mitochondrial stressor like Doxycycline, as mitochondrial dys-function leads to a stronger dependence on glucose
  • Vitamin C has been demonstrated to selectively kill cancer cells in vitro and to inhibit tumor growth in experimental mouse models
  • many of these actions have been attributed to the ability of Vitamin C to act as a glycolysis inhibitor, by targeting GAPDH and depleting the NAD pool
  • here we show that DoxyR CSCs are more vulnerable to the inhibitory effects of Vitamin C, at 4- to 10-fold lower concentrations, between 100 to 250 μM
  • concurrent use of Vitamin C, with standard chemotherapy, reduces tumor recurrence and patient mortality
  • after oral administration, Vitamin C plasma levels reach concentrations of ~70-220 μM
  • intravenous administration results in 30- to 70- fold higher plasma concentrations of Vitamin C
  • pro-oxidant activity results from Vitamin C’s action on metal ions, which generates free radicals and hydrogen peroxide, and is associated with cell toxicity
  • it has been shown that high-dose Vitamin C is more cytotoxic to cancer cells than to normal cells
  • This selectivity appears to be due to the higher catalase content observed in normal cells (~10-100 fold greater), as compared to tumor cells. Hence, Vitamin C may be regarded as a safe agent that selectively targets cancer cells
  • the concurrent use of Doxycycline and Vitamin C, in the context of this infectious disease, appeared to be highly synergistic in patients
  • Goc et al., 2016, showed that Doxycycline is synergistic in vitro with certain phytochemicals and micronutrients, including Vitamin C, in the in vitro killing of the vegetative spirochete form of Borrelia spp., the causative agent underlying Lyme disease
  • Doxycycline, an FDA-approved antibiotic, behaves as an inhibitor of mitochondrial protein translation
  • CSCs successfully escape from the anti-mitochondrial effects of Doxycycline, by assuming a purely glycolytic phenotype. Therefore, DoxyR CSCs are then more susceptible to other metabolic perturbations, because of their metabolic inflexibility
  • Nathan Goodyear on 14 Jun 17
     
    Not especially new, but IV vitamin C + daily doxycycline found to kill cancer stem cells.
Nathan Goodyear

Immune responses to malignancies - 0 views

www.ncbi.nlm.nih.gov/...PMC3721350

cancer immune system

shared by Nathan Goodyear on 18 Apr 18 - No Cached
  • increased densities of T-cell infiltrates with a high proportion of CD8+ T cells within primary colorectal carcinomas were associated with a significant protection against tumor recurrence
  • coexpression of genes mediating cytotoxicity and TH1 adaptive immune responses accurately predicted survival in patients with colorectal carcinoma independently of the metastatic status.
  • tumor-specific cytolytic T lymphocytes (CTLs)
  • ...10 more annotations...
  • tumor-associated antigens (TAs)
  • Proinflammatory cytokines secreted by inflammatory cells can contribute to tumor progression, and soluble factors produced by the tumor in response to nonspecific or tumor-specific signals, such as prostaglandin E2 (PGE2), adenosine, or TGF-β, downregulate functions of immune cells
  • they are largely ineffective in arresting tumor growth, although they can proliferate and mediate antitumor cytotoxicity on their removal from the tumor bed and ex vivo IL-2 activation.42
  • DCs (HLA-DR+CD86+CD80+CD14−) are nature’s best APCs
  • They are a common component of tumor immune infiltrates and are responsible for the uptake, processing, and cross-presentation of TAs to naive or memory T cells, thus playing a crucial role in the generation of tumor-specific effector T cells
  • DCs control the induction of Treg cells. In patients with cancer, cellular interactions between antigen-presenting DCs and T cells lead to expansion and accumulation of Treg cells at the tumor site and in the periphery
  • NK cells (CD3−CD56+CD16+), which mediate innate immunity and contain both perforin-rich and granzyme-rich granules, are well equipped to mediate lysis of tumor cells
  • B cells (CD19+, CD20+) are also rare in most human tumors, with the exception of breast cancer and melanoma
  • The initial acute inflammation involving the recruitment and influx of antitumor effector cells is replaced by chronic inflammation in later stages of tumor progression
  • Tissue hypoxia plays a major role in shaping the nature of immune infiltrates in tumors
  • Nathan Goodyear on 18 Apr 18
     
    Another great review of the immune system during different stages of carcinogenesis; how the cancer manipulates the immue system to cloak itself from the immune system.
Nathan Goodyear

Gleason Score and Lethal Prostate Cancer: Does 3 + 4 = 4 + 3? - 0 views

www.ncbi.nlm.nih.gov/...PMC2717753

prostate cancer cancer prostate Gleason score

shared by Nathan Goodyear on 16 May 18 - No Cached
  • The Gleason system, introduced in 1974
  • is an architectural grading system that ranges from 1 (well differentiated) to 5 (poorly differentiated)
  • The Gleason score (GS) is the sum of the primary and secondary patterns with a range of 2 to 10
  • ...2 more annotations...
  • patients with GS ≥ 7 are at greater risk for extraprostatic extension and biochemical recurrence
  • It is widely accepted that Gleason grade from biopsy is frequently upgraded at prostatectomy, resulting in a reluctance to assign a low GS at diagnosis
  • Nathan Goodyear on 16 May 18
     
    Review of Gleason score in prostate cancer.
Nathan Goodyear

An Overview of Melatonin and Breast Cancer | Natural Medicine Journal - 0 views

www.naturalmedicinejournal.com/...ew-melatonin-and-breast-cancer

melatonin cancer

shared by Nathan Goodyear on 31 May 18 - No Cached
  • Overall its effect on cancer cells is oncostatic at physiological levels, or cytotoxic at higher concentrations
  • direct antioxidant, antimitotic, antiestrogenic, prodifferentiating and antimetastatic effects have been well characterized
  • hypothalamic-pituitary axis (HPA) and immune system
  • ...2 more annotations...
  • On a cellular level, melatonin acts as a selective estrogen receptor modulator (SERM) through decreased expression of estrogen receptor alpha and reduction in the ability of estrogen-estrogen receptor alpha (ERα) complex to bind to the estrogen response element (ERE) on DNA
  • Melatonin also acts as a selective estrogen enzyme modulator (SEEM), reducing the activity of aromatase in cells
  • Nathan Goodyear on 31 May 18
     
    review of melatonins activity in cancer battle.
Nathan Goodyear

Broad targeting of angiogenesis for cancer prevention and therapy - 0 views

www.ncbi.nlm.nih.gov/...PMC4737670

cancer curcumin VEGF EGCG green tea melatonin quercetin Resveratrol silymarin flavonoids HIF-1alpha

shared by Nathan Goodyear on 01 Jun 18 - No Cached
  • vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), interleukin-8 (IL-8), placental growth factor (PlGF), transforming growth factor-beta (TGFbeta), platelet derived growth factor (PDGF), angiopoietins (Angs) and others (reviewed in [4])
  • The switch may also involve down-regulation of endogenous inhibitors of angiogenesis such as endostatin, angiostatin or thrombospondin (reviewed in [5]) and has thus been regarded as the result of tipping the net balance between positive and negative regulators
  • There is a complex interrelationship between tumor hypoxia and tumor angiogenesis
  • ...17 more annotations...
  • chronic hypoxia
  • acute hypoxia
  • Environmental stress as a result of low oxygen and proper nutrient deprivation, such as glucose deprivation, are capable of inducing VEGF mRNA stabilization resulting in increased levels of the secreted ligand and angiogenic growth
  • HIFalpha subunits accumulate in the cytoplasm where they bind HIFbeta to form a heterodimer that subsequently translocates to the nucleus to activate transcription of target genes, including genes important for various processes such as metabolism (glucose transporter (GLUT)-1, hexokinase (HK)-1), cell growth (cyclin (CCN)-D1 [23]) and also angiogenesis, such as erythropoietin, VEGF and PDGF [24] (summarized in Fig. 1)
  • When oxygen levels are low (hypoxia; red arrow) PHDs cannot hydroxylate HIFalphas thereby allowing them to escape pVHL-mediated degradation. HIFalpha subunits accumulate and bind to their heterodimeric partner, HIFbeta, translocate into the nucleus and activate a cascade of hypoxic signaling first by the transcription of various target genes including microRNAs that are important for tumor promoting pathways
  • c-Src is also capable of activating HIFs by indirectly inhibiting PHD activity via the NADPH oxidase/Rac pathway.
  • mTOR can also promote stabilization and HIF transcriptional activity
  • hypoxia inducible factors (HIFs), heterodimeric transcription factors composed from alpha and beta subunits, which can be rapidly stabilized to fluidly adapt to and overcome the effects of a hypoxic environment
  • Curcumin inhibits the expression of epidermal growth factor receptor (EGFR), VEGFR-1, VEGFR-2 and VEGFR-3, and the kinase activity of Src and FAK, which are responsible for the induction of angiogenic genes as well as endothelial cell polarity and migration
  • Curcumin also reduces the MMP-2 and MMP-9 expression, along with the suppression of growth and invasion potential of tumor cells in culture and xenograft experiments
  • The expression of angiogenic biomarkers COX-2 and serum levels of VEGF were significantly reduced in the curcumin-treated group
  • Resveratrol inhibits capillary endothelial cell growth and new blood vessel growth in animals
  • interrupting cell proliferation, inducing apoptosis
  • [155] and impeding angiogenesis by suppressing VEGF expression through down-regulation of HIF-1alpha
  • resveratrol was reported to inhibit cell proliferation of human ovarian cancer cells and human osteosarcoma cells by attenuating HIF-1alpha
  • prevents cytokine-induced vascular leakage and tumor metastasis
  • The underlying molecular mechanisms include: blocking VEGF- and FGF-receptor-mediated MAPK activation, inhibiting Akt- and MAPK-driven HIF-1alpha basal expression and its induction by IGF-1, stimulating the proteasomal degradation of HIF-1alpha, inhibiting phosphatidyl inositol (PI)-3K/Akt and Ras/mitogen/extracellular signal-regulated kinase (MEK)/ERK pathways, and activation of forkhead box (FOX)O transcription factors
  • Nathan Goodyear on 01 Jun 18
     
    natural compounds to attach cancer explained.
trungtamnamkhoa

Pimples In The Penis - What Is The Cause? - 1 views

trungtamnamkhoa.com/noi-mun-o-duong-vat.html

hormones cancer hormone Testosterone Men Health healthy Disease Male

shared by trungtamnamkhoa on 25 Jun 19 - No Cached
  • trungtamnamkhoa on 25 Jun 19
     
    The penis gets pimples, white or red items make men worried because they don't know the cause. In most of the causes of penile acne, the group of causes of sexually transmitted diseases is the most dangerous. Genital skin is very sensitive, especially in the penis. Only a small change can cause abnormal symptoms such as tumors, irritation, irritation and discomfort. Men need to understand the reasons for effective prevention and treatment. Group of allergy causes: Men with acne in the penis due to local allergies, for example, the penis skin has been exposed to "strange" substances from poor quality condoms. In addition, wearing underwear that is too tight, fabric material is not guaranteed or new clothes bought without washing well and many dust and dirt also cause irritation and penile pimples. Eating allergenic foods can also irritate the skin and, if unfortunately, the skin is as delicate as the "genital area".
Nathan Goodyear

Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial A... - 0 views

www.ncbi.nlm.nih.gov/...PMC3228295

cancer artesunate

shared by Nathan Goodyear on 08 May 20 - No Cached
  • Nathan Goodyear on 08 May 20
     
    Great, great review of anti-cancer mechanisms of artemisinin(s).
anastasiadaunne

Thought Elevators - 0 views

www.thoughtelevatorsinfo.com

brain waves Thought Elevators Eric Taller theta meditation guided relaxation self improvement

shared by anastasiadaunne on 15 Mar 17 - No Cached
  • anastasiadaunne on 15 Mar 17
     
    Full review of Thought Elevators Program by Eric Taller
  • anastasiadaunne on 15 Mar 17
     
    Please read this information on a wonderful program I have found that helps me find peace and mental wellness in my life!
pearlgwenson

Questions to Ask When Choosing the Best Day Spa as a Gift - 1 views

bestspagift.wordpress.com/...ing-the-best-day-spa-as-a-gift

spa gift massage wellness health

shared by pearlgwenson on 19 May 17 - No Cached
  • pearlgwenson on 19 May 17
     
    Spa gift card is another unique gift you can give to friends or loved ones on special occasions or holidays.
Nathan Goodyear

Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years after Mild Traumat... - 0 views

www.ncbi.nlm.nih.gov/...PMC3829860

hbot hyperbaric therapy hyperbaric brain concussion post concussion syndrome TBI traumatic brain injury

shared by Nathan Goodyear on 17 May 17 - No Cached
  • The changes in SPECT images after treatment indicate that HBOT led to reactivation of neuronal activity in stunned areas that seemed normal under CT and MRI imaging. While SPECT imaging has a limited spatial resolution (compared, for example, to fMRI), the changes in activity were sufficiently robust to be clearly detected by the SPECT images.
  • HBOT might initiate a cellular and vascular repair mechanism and improve cerebral vascular flow
  • HBOT induces regeneration of axonal white matter [61], [62], [63], [64], has positive effect upon the myelinization and maturation of injured neural fibers [65], and can stimulate axonal growth and increase the ability of neurons to function and communicate with each other
  • ...6 more annotations...
  • HBOT was found to have a role in initiation and/or facilitation of angiogenesis and cell proliferation processes needed for axonal regeneration [67].
  • The observed reactivation of neuronal activity in the stunned areas found here, along with similar results in post-stroke patients
  • At the cellular level, HBOT can improve cellular metabolism, reduce apoptosis, alleviate oxidative stress and increase levels of neurotrophins and nitric oxide through enhancement of mitochondrial function (in both neurons and glial cells)
  • HBOT may promote the neurogenesis of endogenous neural stem cells
  • With regard to secondary injury mechanisms in mTBI, HBOT can initiate vascular repair mechanism and improve cerebral vascular flow [58], [59], [68], [69], promote blood brain barrier integrity and reduce inflammatory reactions [28] as well as brain edema
  • It might be possible that HBOT enables the metabolic change simply by supplying the missing energy/oxygen needed for those regeneration processes.
  • Nathan Goodyear on 17 May 17
     
    Hbot therapy, according to study, induces neuroplasticity and improves brain function in post concussion syndrome and those with mTBI.  The important point about this study was that the study was done years after the injury; what if the therapy was employed immediately after...
Nathan Goodyear

The Single Nucleotide Polymorphism Gly482Ser in the PGC-1α Gene Impairs Exerc... - 0 views

journals.plos.org/...article

epigenetics exercise training muscle SNPs PGC-1alpha

shared by Nathan Goodyear on 30 Nov 17 - No Cached
  • Oxidative slow-twitch type I fibres (henceforth briefly called ‘slow fibres’) contain MHC-Iβ. They use oxidative phosphorylation (OXPHOS) to generate ATP and are thus highly fatigue resistant and preferentially activated during endurance exercise. Slow fibres comprise high amounts of mitochondria, myoglobin and lipid droplets, and are well supplied by capillaries
  • there are three types of fast-twitch fibres (types IIA, IID/X, IIB, with the corresponding MHC isoforms IIa, IId/x, IIb) which are all used for rapid high-force generation. Oxidative-glycolytic fast-twitch type IIA fibres have intermediate amounts of mitochondria, lipid droplets and capillaries, and are intermediately resistant to fatigue (as compared to type I and types IIB and IID/X). Glycolytic fast-twitch type IID/X fibres are poor in mitochondria, lipids and capillaries and more susceptible to fatique than type IIA. Glycolytic fast-twitch type IIB fibres have the lowest amounts of mitochondria, lipid droplets and capillaries, but generate the highest contraction velocities
  • Several studies have shown that PGC-1α is upregulated after endurance training
  • ...3 more annotations...
  • upregulation of PGC-1α expression enhances and/or maintains mitochondrial biogenesis, eventually leading to an increased mitochondrial content of the muscle fibres.
  • PGC-1α also plays an important role in the pathogenesis of insulin resistance and T2D
  • carriers of the Gly482Ser SNP have a reduced cardiorespiratory fitness and a higher risk for metabolic syndrome and T2D
  • Nathan Goodyear on 30 Nov 17
     
    Those that carry the risk SNP for Gly482Ser for the PGC-1alpha gene dont' transform type II to type I and thus decrease the effectiveness of aeorbic exercise training, decreased oxidative phosphorylation, decreased lipid oxidation, increased lipid accumulaiton in muscle, and increased risk of IR, obesity, and diabetes.
Nathan Goodyear

Towards ageing well: Use it or lose it: Exercise, epigenetics and cognition | SpringerLink - 0 views

link.springer.com/...s10522-017-9719-3

exercise ageing epigenetics

shared by Nathan Goodyear on 21 Nov 17 - No Cached
  • Nathan Goodyear on 21 Nov 17
     
    Exercise reshapes your DNA expression through epigenetics. Age knows no limitations.
srireddy17

Effects of Skipping Breakfast | Telugu Health Tips 2017 - YouTube - 0 views

www.youtube.com/watch

health healthcare teluguhealth healthcaretips telugutips healthyliving healthtips healthycaretips breakfasttips breakfasttimings

shared by srireddy17 on 01 Dec 17 - No Cached
  • srireddy17 on 01 Dec 17
     
    Get the latest 2017 healthy tips of diet, benefits, effects, healthcare, nutrition, fitness, wellness and more from Pranay Healthcare. Subscribe to Pranay Healthcare and get more updates.
chrismance

Best Strains For Anxiety - Getmarijuananearme.com - Strains for anxiety - 0 views

getmarijuananearme.com/t-cannabis-strains-for-anxiety

cancer hormones hormone Testosterone inflammation disease Obesity anxiety depression stress pain PTSD

shared by chrismance on 01 Jun 21 - No Cached
  • chrismance on 01 Jun 21
     
    An educating article about how cannabis can help with anxiety as well as many other defects
snfilms

Well Wishes for Mahalaya - 0 views

#HappyMahalaya #SubhoMahalaya #snfilms #JalpariTheNaiad #SayaniDas

shared by snfilms on 21 Sep 20 - No Cached
  • snfilms on 21 Sep 20
     
    Mahalaya - the climactic point of Pitru Paksha and the beginning of Devi Paksha | সময় চেতনার জাগরণের, সময় দেবীশক্তির সম্বর্ধনার, সময় নারীসম্মান বিকাশের । https://youtu.be/QsadtbB4HwQ
Nathan Goodyear

Low-dose Interleukin-2 in the Treatment of Autoimmune Disease | touchONCOLOGY - 0 views

www.touchoncology.com/...2-treatment-autoimmune-disease

cancer autoimmune disease Tregs Treg cells Treg immune system disease IL-2

shared by Nathan Goodyear on 04 Apr 18 - No Cached
Amol kashikar liked it
  • affect approximately 5 to 8 % of the US population
  • the incidence and prevalence of autoimmune diseases are rising
  • Type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD) account for the majority of the patients with autoimmune diseases
  • ...9 more annotations...
  • Autoimmune diseases are characterized by a breakdown of mechanisms that allow the immune system to distinguish between self and nonself and maintain immunologic self-tolerance
  • Tregs, which are important in the maintenance of peripheral immune tolerance.
  • Several subtypes of Tregs exist, the most well studied being CD4+ cells that express high-level CD25 and the transcription factor forkhead box P3 (FOXP3)
  • Treg deficiency or dysfunction is associated with autoimmune disease
  • In clinical studies, decreased levels of circulating CD25+CD4+ T cells have been reported in patients with autoimmune disease
  • These data have led to the hypothesis that augmentation of Tregs may be a useful therapeutic strategy in autoimmune disease
  • Treg augmentation has resulted in clinical improvements in numerous animal models of autoimmune diseases
  • the administration of in vitro expanded CD4+CD25highCD127-Tregs has been found to be safe and may help to preserve β-cell function in children with T1D
  • ability of IL-2 to augment the numbers and function of CD4+ Tregs.
  • Nathan Goodyear on 04 Apr 18
     
    Great article.  Immune dysfunction plays role in autoimmune disease and cancer.  Treg cells sit at the center of autoimmunity.  This artice highlights the different uses: low dose IL2 therapy to augment Tregs and reduce autoinflammation and high dose IL2 to augment Treg cells in the fight against cancer.
Nathan Goodyear

ALIVE AND WELL by Philip E. Binzel, Jr., M.D. - 1 views

whale.to/binzel.html

cancer amygdalin vitamin B17 laetrile Dr. Binzel

shared by Nathan Goodyear on 16 Apr 18 - No Cached
  • Nathan Goodyear on 16 Apr 18
     
    The end report of Dr. Binzel's experience with the use of Laetril in cancer.
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

Repurposing Drugs in Oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer ... - 0 views

www.ncbi.nlm.nih.gov/...PMC5718030

chloroquine hydroxychloroquine cancer repurposed drugs

shared by Nathan Goodyear on 03 May 21 - No Cached
  • HCQ, doses for long-term use range between 200 and 400 mg per day.
  • Short-term administration of CQ or HCQ rarely causes severe side effects
  • Short-term administration of CQ or HCQ rarely causes severe side effects
  • ...24 more annotations...
  • bone marrow suppression
  • cardiomyopathy
  • irreversible retinal toxicity
  • hypoglycaemia
  • daily doses up to 400 mg of HCQ or 250 mg CQ for several years are considered to carry an acceptable risk for CQ-induced retinopathies, with the exception of individuals of short stature
  • chronic CQ or HCQ therapy be monitored through regular ophthalmic examinations (3–6 month intervals), full blood counts and blood glucose level checks
  • long-term HCQ exposure, skeletal muscle function and tendon reflexes should be monitored for weakness
  • both CQ and HCQ, specific caution is advised in patients suffering from impaired hepatic function (especially when associated with cirrhosis), porphyria, renal disease, epilepsy, psoriasis, glucose-6-phosphate dehydrogenase deficiency and known hypersensitivity to 4-aminoquinoline compounds
  • CQ and HCQ can effectively increase the efficacy of various anti-cancer drugs
  • CQ can prevent the entrapment of protonated chemotherapeutic drugs by buffering the extracellular tumour environment and intracellular acidic spaces
  • This study recommends an adjuvant HCQ dose of 600 mg, twice daily.
  • HCQ addition was shown to produce metabolic stress in the tumours
  • HCQ (400 mg/day)
  • important effects of CQ and HCQ on the tumour microenvironment
  • The main and most studied anti-cancer effect of CQ and HCQ is the inhibition of autophagy
  • the expression levels of TLR9 are higher in hepatocellular carcinoma, oesophageal, lung, breast, gastric and prostate cancer cells as compared with adjacent noncancerous cells, and high expression is often linked with poor prognosis
  • TLR9-mediated activation of the NF-κB signalling pathway and the associated enhanced expression of matrix metalloproteinase-2 (MMP-2), MMP-7 and cyclo-oxygenase 2 mRNA
  • HCQ can activate caspase-3 and modulate the Bcl-2/Bax ratio inducing apoptosis in CLL, B-cell CLL and glioblastoma cells
  • In triple-negative breast cancer, CQ was shown to eliminate cancer stem cells through reduction of the expression of Janus-activated kinase 2 and DNA methyl transferase 1 [106] or through induction of mitochondrial dysfunction, subsequently causing oxidative DNA damage and impaired repair of double-stranded DNA breaks
  • CQ or HCQ would be considered for use in combination with immunomodulation anti-cancer therapies
  • Therapies used in combination with CQ or HCQ include chemotherapeutic drugs, tyrosine kinase inhibitors, various monoclonal antibodies, hormone therapies and radiotherapy
  • Most studies hypothesise that CQ and HCQ could increase the efficacy of other anti-cancer drugs by blocking pro-survival autophagy.
  • daily doses between 400 and 1200 mg for HCQ are safe and well tolerated, but two studies identified 600-mg HCQ daily as the MTD
  • HCQ is often administered twice daily to limit plasma fluctuations and toxicity
Nathan Goodyear

Cannabigerol is a novel, well-tolerated appetite stimulant in pre-satiated rats - PMC - 0 views

www.ncbi.nlm.nih.gov/...PMC5021742

cannabigerol appetite phytocannabinoids CBG

shared by Nathan Goodyear on 20 Apr 24 - No Cached
  • Nathan Goodyear on 20 Apr 24
     
    Appetite stimulation at 120 to 240 mg/kg
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