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Nathan Goodyear

Natural products as important tyrosine kinase inhibitors - 0 views

dacemirror.ggws.net/...yin2019.pdf

natural therapy cancer tyrosine kinase natural therapies natural medicine tyrosine kinase inhibitors

shared by Nathan Goodyear on 16 Mar 21 - No Cached
  • Nathan Goodyear on 16 Mar 21
     
    Good review of some natural products that have been shown to inhibit tyrosine kinase activity.
Nathan Goodyear

Communication between genomic and non-genomic signaling events coordinate steroid hormo... - 0 views

www.ncbi.nlm.nih.gov/...PMC5864526

genomic signaling cancer hormones non-genomic signaling

shared by Nathan Goodyear on 10 Apr 21 - No Cached
  • steroid hormones typically interact with their cognate receptor in the cytoplasm for AR, glucocorticoid receptor (GR) and PR, but may also bind receptor in the nucleus as appears to often be the case for ERα and ERβ
  • This ligand binding results in a conformational change in the cytoplasmic NRs that leads to the dissociation of HSPs, translocation of the ligand-bound receptor to the nucleus
  • In the nucleus, the ligand-bound receptor dimerizes and then binds to DNA at specific HREs to regulate gene transcription
  • ...25 more annotations...
  • some steroid hormone-induced nuclear events can occur in minutes
  • the genomic effects of steroid hormones take longer, with changes in gene expression occurring on the timescale of hours
  • Classical steroid hormone signaling occurs when hormone binds nuclear receptors (NR) in the cytoplasm, setting off a chain of genomic events that results in, among other changes, dimerization and translocation to the nucleus where the ligand-bound receptor forms a complex with coregulators to modulate gene transcription through direct interactions with a hormone response element (HRE)
  • NRs have been found at the plasma membrane of cells, where they can propagate signal transduction often through kinase pathways
  • Membrane-localized ER, PR and AR have been reported to modulate the activity of MAPK/ERK, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), nitric oxide (NO), PKC, calcium flux and increase inositol triphosphate (IP3) levels to promote cell processes including autophagy, proliferation, apoptosis, survival, differentiation, and vasodilation
  • ERα36, a 36kDa truncated form of ERα that lacks the transcriptional activation domains of the full-length protein. Membrane-localized ERα36 can activate pathways including protein kinase C (PKC) and/or mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) to promote the progression of various cancers
  • G protein-coupled receptor 30 (GPR30), also referred to as G protein-coupled estrogen receptor (GPER), is a membrane-localized receptor that has been observed to respond to estrogen to activate rapid signaling
  • hormone-responsive G protein coupled receptor is Zip9, which androgens can activate
  • GPRC6A is another G protein-coupled membrane receptor that is responsive to androgen
  • androgen-mediated non-genomic signaling through this GPCR can modulate male fertility, hormone secretion and prostate cancer progression
  • non-NR proteins located at the cell surface can bind to steroid hormones and respond by eliciting rapid signaling events
  • Estrogens have been shown to induce rapid (i.e. seconds) calcium flux via membrane-localized ER (mER)
  • ER-calcium dynamics lead to activation of kinase pathways such as MAPK/ERK which can result in cellular effects like migration and proliferation
  • 17β-estradiol (E2) has been reported to promote angiogenesis through the activation of GPER
  • Membrane NRs may also mediate rapid signaling through crosstalk with growth factor receptors (GFR)
  • A similar crosstalk occurs between the receptor tyrosine kinase insulin-related growth factor-1 receptor (IGF-IR) and ERα. Not only does IGF-IR activate ERα, but inhibition of IGF-IR downregulates estrogen-mediated ERα activity, suggesting that IGF-IR is essential for maximal ERα signaling
    • Nathan Goodyear
      Nathan Goodyear on 10 Apr 21
       
      This is a bombshell that shatters the current right brain approach to ER. It completely shatters the concept of eat sugar, whatever you want, with cancer treatment in ER+ or hormonally responsive cancer!
  • Further, ER activates IGF-IR pathways including MAPK
  • GPER is involved in the transactivation of the EGFR independent of classical ER
  • tight interconnection between genomic and non-genomic effects of NRs.
  • non-genomic pathways can also lead to genomic effects
  • androgen-bound AR associates with the kinase Src at the plasma membrane, activating Src which then leads to a signaling cascade through MAPK/ERK
  • However, Src can also increase the expression of AR target genes by the ligand-independent transactivation of AR
  • extranuclear steroid hormone actions can potentially reprogram nuclear NR events
  • estrogen modulated the expression of several genes including endothelial nitric oxide synthase (eNOS) via rapid signaling pathways
  • epigenetic changes can then mediate genomic events in uterine tissue and breast cancer cells
Nathan Goodyear

Curcumin as tyrosine kinase inhibitor in cancer treatment - ScienceDirect - 0 views

www.sciencedirect.com/...S0223523419306361

receptor tyrosine kinase VEGF curcumin IGF-1 tyrosine kinase FGFR PDGF

shared by Nathan Goodyear on 28 Sep 20 - No Cached
  • Nathan Goodyear on 28 Sep 20
     
    Curcumin shown to be a natural TK inhibitor
Nathan Goodyear

Natural products as important tyrosine kinase inhibitors - ScienceDirect - 0 views

www.sciencedirect.com/...S0223523419308086

natural medicine natural tyrosine kinase inhibitors cancer natural therapy natural therapies

shared by Nathan Goodyear on 11 Feb 21 - No Cached
  • Nathan Goodyear on 11 Feb 21
     
    Only abstract available.
Nathan Goodyear

Branched-chain amino acids in liver diseases - 0 views

www.ncbi.nlm.nih.gov/...PMC3837260

BCAA branched chain amino acids liver cirrhosis disease

shared by Nathan Goodyear on 05 Oct 15 - No Cached
  • Serum concentrations of BCAAs are decreased, while the concentrations of the aromatic amino acids (AAAs) phenylalanine and tyrosine are increased, in patients with advanced liver diseases, resulting in a low ratio of BCAAs to AAAs, a ratio called the Fischer ratio
  • BCAAs were reported to stimulate the production of hepatocyte growth factor
  • a simplified Fischer ratio, the BCAA to tyrosine ratio (BTR), has been reported useful for predicting serum albumin concentration one year later
  • ...10 more annotations...
  • BCAA supplementation was shown to delay the progression of CCl4-induced chronic liver injury in a rat model by reducing hepatic apoptosis
  • BCAAs promoted hepatocyte regeneration in a rat model of hepatectomy
  • BCAA supplementation for advanced cirrhotic patients improves nutritional status and quality of life
  • BCAAs activate mTOR and subsequently increase the production of eukaryotic initiation factor 4E-binding protein-1 and ribosomal protein S6 kinase, which upregulate the synthesis of albumin
  • BCAAs were shown to improve homeostasis model assessment scores for insulin resistance (HOMA-IR) and beta cell function (HOMA-%B) in patients with chronic liver disease, indicating that BCAAs can ameliorate insulin resistance
  • Several clinical trials have suggested that BCAA supplementation improves the prognosis of cirrhotic patients
  • A low Fischer ratio has been associated with hepatic encephalopathy
  • Treatment with BCAAs may therefore have a beneficial effect on patients with hepatic encephalopathy mainly by compensating decreased ratio of BCAAs to AAAs, but not by reducing serum ammonia levels
  • Two randomized studies also showed that BCAAs did not clearly prevent HE in patients with advanced cirrhosis, although BCAAs prevented the progression of hepatic failure
  • a systematic review with meta-analyses on the effect of oral BCAAs for the treatment of HE was published[66]. The review has revealed that supplementation of oral BCAAs in cirrhotic patients inhibits the manifestation of HE, especially in patients with overt HE rather than those with minimal HE, but showed no effect on the survival of those patients[66]. Thus, oral administration of BCAAs is the treatment of choice in cirrhotic patients with HE
  • Nathan Goodyear on 05 Oct 15
     
    good review of BCAA and liver disease: both mechanisms and therapy.
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

How is the Immune System Suppressed by Cancer - 1 views

www.cancertutor.com/ancer-suppresses-immune-system

iNOS cancer immune system

shared by Nathan Goodyear on 23 May 18 - No Cached
  • nitric oxide (NO) released by tumor cells
  • Excellent work by Prof de Groot of Essen, indicated by adding exogenous xanthine oxidase ( XO) in hepatoma cells, hydrogen peroxide was produced to destroy the hepatoma cells
  • NO from eNOS in cancer cells can travel through membranes and over long distances in the body
  • ...43 more annotations...
  • NO also is co linked to VEGF which in turn increases the antiapoptotic gene bcl-2
  • The other important influence of NO is in its inhibition of the proapoptoic caspases cascade. This in turn protects the cells from intracellular preprogrammed death.
  • nitric oxide in immune suppression in relation to oxygen radicals is its inhibitory effect on the binding of leukocytes (PMN) at the endothelial surface
  • Inhibition of inducible Nitric Oxide Synthase (iNOS)
  • NO from the tumor cells actually suppresses the iNOS, and in addition it reduces oxygen radicals to stop the formation of peroxynitrite in these cells. But NO is not the only inhibitor of iNOS in cancer.
  • Spermine and spermidine, from the rate limiting enzyme for DNA synthases, ODC, also inhibit iNOS
  • tolerance in the immune system that decreases the immune response to antigens on the tumors
  • Freund’s adjuvant
  • increase in kinases in these cells which phosphorylate serine, and tyrosine
  • responsible for activation of many growth factors and enzymes
  • phosphorylated amino acids suppress iNOS activity
  • Hexokinase II
  • Prostaglandin E2, released from tumor cells is also an inhibitor of iNOS, as well as suppressing the immune system
  • Th-1 subset of T-cells. These cells are responsible for anti-viral and anti-cancer activities, via their cytokine production including Interleukin-2, (IL-2), and Interleukin-12 which stimulates T-killer cell replication and further activation and release of tumor fighting cytokines.
    • Nathan Goodyear
      Nathan Goodyear on 23 May 18
       
      Th1 cells stimulate NK and other tumor fighting macrophages via IL-2 and IL-12; In contrast, Th2, which is stimulated in allergies and parasitic infections, produce IL-4 and IL-10.  IL-4 and IL-10 inhibit TH-1 activation and the histamine released from mast cell degranulation upregulates T suppressor cells to further immune suppression.
  • Th-2 subset of lymphocytes, on the other hand are activated in allergies and parasitic infections to release Interleukin-4 and Interleukin-10
  • These have respectively inhibitory effects on iNOS and lymphocyte Th-1 activation
  • Mast cells contain histamine which when released increases the T suppressor cells, to lower the immune system and also acts directly on many tumor Histamine receptors to stimulate tumor growth
  • Tumor cells release IL-10, and this is thought to be one of the important areas of Th-1 suppression in cancer patients
  • IL-10 is also increased in cancer causing viral diseases such as HIV, HBV, HCV, and EBV
  • IL-10 is also a central regulator of cyclooxygenase-2 expression and prostaglandin production in tumor cells stimulating their angiogenesis and NO production
  • nitric oxide in tumor cells even prevents the activation of caspases responsible for apoptosis
    • Nathan Goodyear
      Nathan Goodyear on 23 May 18
       
      NO produced by cancer cells inhibits proapoptotic pathways such as the caspases.
  • early stages of carcinogenesis, which we call tumor promotion, one needs a strong immune system, and fewer oxygen radicals to prevent mutations but still enough to destroy the tumor cells should they develop
  • later stages of cancer development, the oxygen radicals are decreased around the tumors and in the tumor cells themselves, and the entire cancer fighting Th-1 cell replication and movement are suppressed. The results are a decrease in direct toxicity and apoptosis, which is prevented by NO, a suppression of the macrophage and leukocyte toxicity and finally, a suppression of the T-cell induced tumor toxicity
  • cGMP is increased by NO
  • NO in cancer is its ability to increase platelet-tumor cell aggregates, which enhances metastases
  • the greater the malignancies and the greater the metastatic potential of these tumors
  • The greater the NO production in many types of tumors,
  • gynecological
  • elevated lactic acid which neutralizes the toxicity and activity of Lymphocyte immune response and mobility
  • The lactic acid is also feeding fungi around tumors and that leads to elevated histamine which increases T-suppressor cells.  Histamine alone stimulates many tumor cells.
    • Nathan Goodyear
      Nathan Goodyear on 23 May 18
       
      The warburg effect in cancer cells results in the increase in local lactic acid production which suppresses lymphocyte activity and toxicity as well as stimulates histamine production with further stimulates tumor cell growth.
  • T-regulatory cells (formerly,T suppressor cells) down regulate the activity of Natural killer cells
  • last but not least, the Lactic acid from tumor cells and acidic diets shifts the lymphocyte activity to reduce its efficacy against cancer cells and pathogens in addition to altering the bacteria of the intestinal tract.
  • intestinal tract bacteria in cancer cells release sterols that suppress the immune system and down regulate anticancer activity from lymphocytes.
  • In addition to the lactic acid, adenosine is also released from tumors. Through IL-10, adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state
  • Adenosine up regulates the PD1 receptor in T-1 Lymphocytes and inhibits their activity
  • Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells
  • Adenosine appears to up-regulate the PD1 receptor in T-1 Lymphocytes and inhibits the immune system further
  • Mast cells with their release of histamine lower the immune system and also stimulate tumor growth and activate the metalloproteinases involved in angiogenesis and metastases
  • COX 2 inhibitors or all trans-retinoic acid
  • Cimetidine, an antihistamine has been actually shown to increase in apoptosis in MDSC via a separate mechanism than the antihistamine effect
    • Nathan Goodyear
      Nathan Goodyear on 23 May 18
       
      cimetidine is an H2 blocker
  • interleukin-8 (IL-8), a chemokine related to invasion and angiogenesis
  • In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNF-alpha)
  • these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-alpha-induced up-regulation of IL-8 via nuclear factor-kappaB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target
  • Nathan Goodyear on 23 May 18
     
    Great review of the immunosuppression in cancer driven by the likes of NO.
Nathan Goodyear

Insulin Resistance Induced by Hyperinsulinemia Coincides with a Persistent Alteration a... - 0 views

journals.plos.org/...article

hyperinsulinemia insulin insulin resistance

shared by Nathan Goodyear on 10 Jan 21 - No Cached
  • Nathan Goodyear on 10 Jan 21
     
    Hyperinsulinemia causes insulin resistance through an attempt to downregulates over signaling.
Nathan Goodyear

Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in... - 0 views

clincancerres.aacrjournals.org/...659.long

pharmacokinetics dosing cancer Quercetin

shared by Nathan Goodyear on 27 Aug 20 - No Cached
  • Nathan Goodyear on 27 Aug 20
     
    Great phase 1 pharmacokinetic study on Quercetin dosing.
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