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Nathan Goodyear

A potential role of endogenous progesterone in mod... [Clin Endocrinol (Oxf). 2009] - P... - 0 views

www.ncbi.nlm.nih.gov/...19222493

progesterone HGH human growth hormone

shared by Nathan Goodyear on 20 May 11 - No Cached
  • These data also suggest that endogenous progesterone could play a modulation role on pituitary hormone secretion, stimulating GH and PRL release and enhancing the inhibitory action of sleep on TSH secretion.
  • normally cycling young women, daytime GH and PRL secretions are increased in luteal phase
  • Nathan Goodyear on 20 May 11
     
    normal luteal progesterone production stimulate HGH release
Nathan Goodyear

Does Cortisol Inhibit Pulsatile Luteinizing Hormone Secretion at the Hypothalamic or Pi... - 0 views

press.endocrine.org/...en.2003-1114

cortisol stress LH pituitary hypothalamus GnRH hormone hormones

shared by Nathan Goodyear on 02 Apr 15 - No Cached
  • Nathan Goodyear on 02 Apr 15
     
    Cortisol inhbits LH secretion at the level of the Pituitary.  The result is a decreased pulse amplitude as a result of decreased pituitary response to GNRH.
Nathan Goodyear

Olive Component Oleuropein Promotes β-Cell Insulin Secretion and Protects β-C... - 0 views

pubs.acs.org/...acs.biochem.7b00199

olive oil diabetes metabolism insulin Oleuropein

shared by Nathan Goodyear on 18 Sep 17 - No Cached
  • Nathan Goodyear on 18 Sep 17
     
    Only abstract available here.  Study finds oleuropein, compound in olive oil, increases insulin secretion in response to glucose via unregulated ERK/MAPK signaling.  Oleuropein also blocked the cytotoxicity induced by amyloids i.e. beta amyloid plaques are well known hallmarks of Alzheimer's disease.
Nathan Goodyear

Dichloroacetate improves immune dysfunction caused by tumor-secreted lactic acid and in... - 0 views

pubmed.ncbi.nlm.nih.gov/23420584

tumor microenvironment TME immunosuppression cancer immunomodulation DCA lactic acid

shared by Nathan Goodyear on 13 Mar 21 - No Cached
  • Nathan Goodyear on 13 Mar 21
     
    The title tells all: Dichloroacetate improves immune dysfunction caused by tumor-secreted lactic acid and increases antitumor immunoreactivity
Nathan Goodyear

Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer... - 0 views

www.ncbi.nlm.nih.gov/...PMC5282724

EMT TME metastasis cancer stem cells cancer MMP2 Notch MMP-9 MMP-2 radioresistance Hedgehog CSC MMP9 Snail HIF-1alpha tumor microenvironment epithelial to mesenchymal transition TGF-beta radiation

shared by Nathan Goodyear on 09 Feb 21 - No Cached
  • More than half of cancer patients are treated with IR at some point during their treatment
  • fractionation schedule is the delivery of 1.8–2.0 Gy per day, five days per week
  • Nuclear DNA is the primary target of IR; it causes DNA damage (genotoxic stress) by direct DNA ionization
  • ...121 more annotations...
  • IR also indirectly induces DNA damage by stimulating reactive oxygen species (ROS) production
  • IR is known to induce EMT in vitro
  • p53 is activated in response to IR-induced DNA damage
  • IR paradoxically also promotes tumour recurrence and metastasis
  • DNA double-strand breaks (DSBs)
  • cancer cells undergoing EMT acquire invasive and metastatic properties
  • changes in the tumour microenvironment (TME)
  • IR seems to induce EMT and CSC phenotypes by regulating cellular metabolism
  • EMT, stemness, and oncogenic metabolism are known to be associated with resistance to radiotherapy and chemotherapy
  • Hanahan and Weinberg proposed ten hallmarks of cancer that alter cell physiology to enhance malignant growth: 1) sustained proliferation, 2) evasion of growth suppression, 3) cell death resistance, 4) replicative immortality, 5) evasion of immune destruction, 6) tumour-promoting inflammation, 7) activation of invasion and metastasis, 8) induction of angiogenesis, 9) genome instability, and 10) alteration of metabolism
  • EMT is a developmental process that plays critical roles in embryogenesis, wound healing, and organ fibrosis
  • IR is known to induce stemness and metabolic alterations in cancer cells
  • transforming growth factor-β [TGF-β], epidermal growth factor [EGF]) and their associated signalling proteins (Wnt, Notch, Hedgehog, nuclear-factor kappa B [NF-κB], extracellular signal-regulated kinase [ERK], and phosphatidylinositol 3-kinase [PI3K]/Akt
  • activate EMT-inducing transcription factors, including Snail/Slug, ZEB1/δEF1, ZEB2/SIP1, Twist1/2, and E12/E47
  • Loss of E-cadherin is considered a hallmark of EMT
  • IR has been shown to induce EMT to enhance the motility and invasiveness of several cancer cells, including those of breast, lung, and liver cancer, and glioma cells
  • IR may increase metastasis in both the primary tumour site and in normal tissues under some circumstance
  • sublethal doses of IR have been shown to enhance the migratory and invasive behaviours of glioma cells
  • ROS are known to play an important role in IR-induced EMT
  • High levels of ROS trigger cell death by causing irreversible damage to cellular components such as proteins, nucleic acids, and lipids, whereas low levels of ROS have been shown to promote tumour progression—including tumour growth, invasion, and metastasis
  • hypoxia-inducible factor-1 (HIF-1) is involved in IR-induced EMT
  • Treatment with the N-acetylcysteine (NAC), a general ROS scavenger, prevents IR-induced EMT, adhesive affinity, and invasion of breast cancer cells
    • Nathan Goodyear
      Nathan Goodyear on 09 Feb 21
       
      NAC for all patients receiving radiation therapy
  • Snail has been shown to play a crucial role in IR-induced EMT, migration, and invasion
  • IR activates the p38 MAPK pathway, which contributes to the induction of Snail expression to promote EMT and invasion
  • NF-κB signalling that promotes cell migration
  • ROS promote EMT to allow cancer cells to avoid hostile environments
  • HIF-1 is a heterodimer composed of an oxygen-sensitive α subunit and a constitutively expressed β subunit.
  • Under normoxia, HIF-1α is rapidly degraded, whereas hypoxia induces stabilisation and accumulation of HIF-1α
  • levels of HIF-1α mRNA are enhanced by activation of the PI3K/Akt/mammalian target of rapamycin (mTOR)
  • IR is known to increase stabilisation and nuclear accumulation of HIF-1α, since hypoxia is a major condition for HIF-1 activation
  • IR induces vascular damage that causes hypoxia
  • ROS is implicated in IR-induced HIF-1 activation
  • IR causes the reoxygenation of hypoxic cancer cells to increase ROS production, which leads to the stabilisation and nuclear accumulation of HIF-1
  • IR increases glucose availability under reoxygenated conditions that promote HIF-1α translation by activating the Akt/mTOR pathway
  • The stabilised HIF-1α then translocates to the nucleus, dimerizes with HIF-1β, and increases gene expression— including the expression of essential EMT regulators such as Snail—to induce EMT, migration, and invasion
  • TGF-β signalling has been shown to play a crucial role in IR-induced EMT
  • AP-1 transcription factor is involved in IR-induced TGF-β1 expression
  • Wnt/β-catenin signalling is also implicated in IR-induced EMT
  • Notch signalling is known to be involved in IR-induced EMT
  • IR also increases Notch-1 expression [99]. Notch-1 is known to induce EMT by upregulating Snail
  • PAI-1 signalling is also implicated in IR-induced Akt activation that increases Snail levels to induce EMT
  • EGFR activation is known to be associated with IR-induced EMT, cell migration, and invasion by activating two downstream pathways: PI3K/Akt and Raf/MEK/ERK
  • ROS and RNS are also implicated in IR-induced EGFR activation
  • IR has also been shown to activate Hedgehog (Hh) signalling to induce EMT
  • IR has been shown to induce Akt activation through several signalling pathways (EGFR, C-X-C chemokine receptor type 4 [CXCR4]/C-X-C motif chemokine 12 [CXCL12], plasminogen activator inhibitor 1 [PAI-1]) and upstream regulators (Bmi1, PTEN) that promote EMT and invasion
  • CSCs possess a capacity for self-renewal, and they can persistently proliferate to initiate tumours upon serial transplantation, thus enabling them to maintain the whole tumour
  • Conventional cancer treatments kill most cancer cells, but CSCs survive due to their resistance to therapy, eventually leading to tumour relapse and metastasis
  • identification of CSCs, three types of markers are utilised: cell surface molecules, transcription factors, and signalling pathway molecules
  • CSCs express distinct and specific surface markers; commonly used ones are CD24, CD34, CD38, CD44, CD90, CD133, and ALDH
  • Transcription factors, including Oct4, Sox2, Nanog, c-Myc, and Klf4,
  • signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, platelet-derived growth factor receptor (PDGFR), and JAK/STAT
  • microRNAs (miRNAs), including let-7, miR-22, miR-34a, miR-128, the miR-200 family, and miR-451
  • Non-CSCs can be reprogrammed to become CSCs by epigenetic and genetic changes
  • EMT-inducing transcription factors, such as Snail, ZEB1, and Twist1, are known to confer CSC properties
  • Signalling pathways involved in EMT, including those of TGF-β, Wnt, and Notch, have been shown to play important roles in inducing the CSC phenotype
  • TGF-β1 not only increases EMT markers (Slug, Twist1, β-catenin, N-cadherin), but also upregulates CSC markers (Oct4, Sox2, Nanog, Klf4) in breast and lung cancer cells
  • some CSC subpopulations arise independently of EMT
  • IR has been shown to induce the CSC phenotype in many cancers, including breast, lung, and prostate cancers, as well as melanoma
  • Genotoxic stress due to IR or chemotherapy promotes a CSC-like phenotype by increasing ROS production
  • IR has been shown to induce reprogramming of differentiated cancer cells into CSCs
  • In prostate cancer patients, radiotherapy increases the CD44+ cell population that exhibit CSC properties
  • IR also induces the re-expression of stem cell regulators, such as Sox2, Oct4, Nanog, and Klf4, to promote stemness in cancer cells
  • EMT-inducing transcription factors and signalling pathways, including Snail, STAT3, Notch signalling, the PI3K/Akt pathway, and the MAPK cascade, have been shown to play important roles in IR-induced CSC properties
  • STAT3 directly binds to the Snail promoter and increases Snail transcription, which induces the EMT and CSC phenotypes, in cisplatin-selected resistant cells
  • Other oncogenic metabolic pathways, including glutamine metabolism, the pentose phosphate pathway (PPP), and synthesis of fatty acids and cholesterol, are also enhanced in many cancers
  • metabolic reprogramming
  • HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
  • metabolic reprogramming
  • tumour cells exhibit high mitochondrial metabolism as well as aerobic glycolysis
  • occurring within the same tumour
  • CSCs can be highly glycolytic-dependent or oxidative phosphorylation (OXPHOS)-dependen
  • mitochondrial function is crucial for maintaining CSC functionality
  • cancer cells depend on mitochondrial metabolism and increase mitochondrial production of ROS that cause pseudo-hypoxia
  • HIF-1 then enhances glycolysis
  • CAFs have defective mitochondria that lead to the cells exhibiting the Warburg effect; the cells take up glucose, and then secrete lactate to 'feed' adjacent cancer cells
  • lactate transporter, monocarboxylate transporter (MCT)
  • nutrient microenvironment
  • Epithelial cancer cells express MCT1, while CAFs express MCT4. MCT4-positive, hypoxic CAFs secrete lactate by aerobic glycolysis, and MCT1-expressing epithelial cancer cells then uptake and use that lactate as a substrate for the tricarboxylic acid (TCA) cycle
  • MCT4-positive cancer cells depend on glycolysis and then efflux lactate, while MCT1-positive cells uptake lactate and rely on OXPHOS
  • metabolic heterogeneity induces a lactate shuttle between hypoxic/glycolytic cells and oxidative/aerobic tumour cells
  • bulk tumour cells exhibit a glycolytic phenotype, with increased conversion of glucose to lactate (and enhanced lactate efflux through MCT4), CSC subsets depend on oxidative phosphorylation; most of the glucose entering the cells is converted to pyruvate to fuel the TCA cycle and the electron transport chain (ETC), thereby increasing mitochondrial ROS production
  • the major fraction of glucose is directed into the pentose phosphate pathway, to produce redox power through the generation of NADPH and ROS scavengers
  • HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
  • regulatory molecules involved in EMT and CSCs, including Snail, Dlx-2, HIF-1, STAT3, TGF-β, Wnt, and Akt, are implicated in the metabolic reprogramming of cancer cells
  • HIF-1 induces the expression of glycolytic enzymes, including the glucose transporter GLUT, hexokinase, lactate dehydrogenase (LDH), and MCT, resulting in the glycolytic switch
  • HIF-1 represses the expression of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), thereby inhibiting mitochondrial activity
  • STAT3 has been implicated in EMT-induced metabolic changes as well
  • TGF-β and Wnt play important roles in the metabolic alteration of cancer cells
  • Akt is also implicated in the glycolytic switch and in promoting cancer cell invasiveness
  • EMT, invasion, metastasis, and stemness
  • pyruvate kinase M2 (PKM2), LDH, and pyruvate carboxylase (PC), are implicated in the induction of the EMT and CSC phenotypes
  • decreased activity of PKM2 is known to promote an overall shift in metabolism to aerobic glycolysis
  • LDH catalyses the bidirectional conversion of lactate to pyruvate
  • High levels of LDHA are positively correlated with the expression of EMT and CSC markers
  • IR has been shown to induce metabolic changes in cancer cells
  • IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
  • IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
  • IR also elevates MCT1 expression that exports lactate into the extracellular environment, leading to acidification of the tumour microenvironment
  • IR increases intracellular glucose, glucose 6-phosphate, fructose, and products of pyruvate (lactate and alanine), suggesting a role for IR in the upregulation of cytosolic aerobic glycolysis
  • Lactate can activate latent TGF-
  • lactate stimulates cell migration and enhances secretion of hyaluronan from CAF that promote tumour metastasis
  • promote tumour survival, growth, invasion, and metastasis; enhance the stiffness of the ECM; contribute to angiogenesis; and induce inflammation by releasing several growth factors and cytokines (TGF-β, VEGF, hepatocyte growth factor [HGF], PDGF, and stromal cell-derived factor 1 [SDF1]), as well as MMP
  • tumours recruit the host tissue’s blood vessel network to perform four mechanisms: angiogenesis (formation of new vessels), vasculogenesis (de novo formation of blood vessels from endothelial precursor cells), co-option, and modification of existing vessels within tissues.
  • immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
  • immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
  • intrinsic immunogenicity or induce tolerance
  • cancer immunoediting’
  • three phases: 1) elimination, 2) equilibrium, and 3) escape.
  • The third phase, tumour escape, is mediated by antigen loss, immunosuppressive cells (TAM, MDSCs, and regulatory T cells), and immunosuppressive cytokines (TGF-β and IL-10).
  • IR can elicit various changes in the TME, such as CAF activity-mediated ECM remodelling and fibrosis, cycling hypoxia, and an inflammatory response
  • IR activates CAFs to promote the release of growth factors and ECM modulators, including TGF-β and MMP
  • TGF-β directly influences tumour cells and CAFs, promotes tumour immune escape, and activates HIF-1 signalling
    • Nathan Goodyear
      Nathan Goodyear on 09 Feb 21
       
      And now the receipts
  • MMPs degrade ECM that facilitates angiogenesis, tumour cell invasion, and metastasis
    • Nathan Goodyear
      Nathan Goodyear on 09 Feb 21
       
      Receipts and mechanisms
  • IR also promotes MMP-2/9 activation in cancer cells to promote EMT, invasion, and metastasis
  • IR-induced Snail increases MMP-2 expression to promote EMT
  • Radiotherapy has the paradoxical side-effect of increasing tumour aggressiveness
  • IR promotes ROS production in cancer cells, which may induce the activation of oncogenes and the inactivation of tumour suppressors, which further promote oncogenic metabolism
  • Metabolic alterations
  • oncogenic metabolism
  • elicit various changes in the TME
  • Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms
  • Nathan Goodyear on 09 Feb 21
     
    Important review article.
Nathan Goodyear

TGF-β1 secreted by M2 phenotype macrophages enhances the stemness and migrati... - 0 views

www.spandidos-publications.com/...ijmm.2018.3923

TGF-beta M2 cancer M2 macrophages

shared by Nathan Goodyear on 02 Oct 20 - No Cached
  • Nathan Goodyear on 02 Oct 20
     
    T-regulator cells secrete TGF-beta to promote M2 polarization in the TME to promote tumor progression and spread.
Nathan Goodyear

Tumor necrosis factor-α and muscle wasting: a cellular perspective - 0 views

www.ncbi.nlm.nih.gov/...PMC59514

muscle loss wasting TNF-alpha inflammation

shared by Nathan Goodyear on 12 Nov 12 - No Cached
  • Nathan Goodyear on 12 Nov 12
     
    TNF-alpha associated with muscle loss and weakness.  TNF-alpha may also decrease testosterone production/secretion resulting in muscle loss.  
Nathan Goodyear

Suppression of Rat Thyrotroph and Thyroid Cell Function by Tumor Necrosis Factor-&#x3b1... - 0 views

online.liebertpub.com/...thy.1993.3.325

TNF-alpha inflammation inflammatory cytokines TSH TSH suppression thyroid

shared by Nathan Goodyear on 01 Feb 13 - No Cached
  • Nathan Goodyear on 01 Feb 13
     
    TNF-alpha inhibits TSH secretion in response to TRH stimulus.
Nathan Goodyear

Thyrotropin suppression by metformin in a cohort of patients with differentiated thyroi... - 0 views

www.endocrine-abstracts.org/...ea0020p141.htm

TSH thyroid metformin

shared by Nathan Goodyear on 31 Jan 13 - No Cached
  • Nathan Goodyear on 31 Jan 13
     
    Again, showing that metformin suppresses TSH secretion without change in actual thyroid hormone levels.  We know that inflammation plays a role in HPA suppression, why not with TSH?
Nathan Goodyear

Thyrotropin Suppression by Metformin - 0 views

jcem.endojournals.org/...225.long

TSH thyroid metformin

shared by Nathan Goodyear on 31 Jan 13 - No Cached
  • Nathan Goodyear on 31 Jan 13
     
    Metformin shown to suppress TSH secretion without change in free t4 or free t3 levels.  This again, shows the lack of reliability of the test TSH.  With the suppression of TSH indicated in this study, the free t4 and t3 should have been elevated, but were obviously not.
Nathan Goodyear

Gender and sex hormones in multiple sclerosis pathology and therapy - 0 views

www.ncbi.nlm.nih.gov/...PMC2689399

hormones MS multiple Sclerosis Estriol progesterone

shared by Nathan Goodyear on 11 Jan 17 - No Cached
  • It is now well recognized that the disease manifestation is reduced in pregnant women with relapsing-remitting MS
  • This occurs particularly during the third trimester when levels of estrogens (estradiol and estriol) and progesterone (see Table 2) are elevated up to about 20 times
  • This seems well correlated with a decrease in active white matter lesions detected by MRI
  • ...12 more annotations...
  • This clinical improvement is however followed by temporary rebound exacerbations at post-partum, when the hormone levels decline
  • a shift from Th1 to Th2 immune response, expansion of suppressive regulatory T lymphocytes and decrease in the number of circulating CD16+ natural killer (NK)-cells
  • Th1 lymphocytes secrete proinflammatory cytokines (e.g. IL-2, IFNgamma, lymphotoxin) while Th2 cells secrete anti-inflammatory cytokines (e.g. IL-4, IL-5, IL-10), which favor humoral-mediated responses
  • Th2 cytokines are associated with down-regulation of Th1 cytokines and this Th2 shift is believed to provide protection from allograft rejection during pregnancy as well as from Th1-mediated autoimmune disease
  • it is worth noting that the levels of other hormones with anti-inflammatory activity (1,25-dihydroxy-vitamin D3, norepinephrine, cortisol) also increase by 2 to 4 times during late pregnancy
  • 1,25-dihydroxy vitamin D3 induces regulatory T-cell function important for development of self-tolerance
  • breast-feeding does not alter the relapse rate in women with MS
  • Leptin is a pleiotropic hormone produced primarily by adipocytes but also by T lymphocytes and neurons
  • Several lines of evidence indicate that leptin contributes to EAE/MS pathogenesis, influencing its onset and clinical severity, by acting as a proinflammatory cytokine which promotes regulatory T cell (Treg) anergy and hyporesponsiveness, resulting in increased Th1 (TNFalpha, INFgamma) and reduced Th2 (IL-4) cytokine production
  • circulating leptin levels are increased in relapsing-remitting MS patients (men and women analyzed together) while the CD4+CD25+Treg population decreases
  • As the leptin plasma concentrations are proportional to the amount of fat tissue, obese/overweight individuals produce higher levels of leptin
  • Nielsen et al found that estradiol and progesterone exert neuroprotection against glutamate neurotoxicity, while MPA antagonizes the neuroprotective effect of estradiol and exacerbated neuron death induced by glutamate excitotoxicity
  • Nathan Goodyear on 11 Jan 17
     
    very good review of the differences in MS and hormones between the sexes.
Nathan Goodyear

Differential Regulation of Gonadotropin Secretion by Testosterone in the Human Male: Ab... - 0 views

jcem.endojournals.org/...53.long

Testosterone men T E2 estradiol FSH LH HPA male hormone regulation

shared by Nathan Goodyear on 25 Apr 12 - No Cached
  • Nathan Goodyear on 25 Apr 12
     
    In men, Testosterone is shown to provide negative feedback on LH; but FSH is primarily regulated by estradiol.
Nathan Goodyear

Reduction of Inflammatory Cytokine Concentrations and Improvement of Endothelial Functi... - 0 views

circ.ahajournals.org/...804

obesity overweight visceral adiposity adipose tissue cytokines adipocytokines TNF-alpha IL-6 P-selectin ICAM-1 VCAM-1 CVD cardiovascular disease weight loss weight loss

shared by Nathan Goodyear on 30 Mar 12 - No Cached
  • Nathan Goodyear on 30 Mar 12
     
    adipose tissue releases inflammatory markers (cytokines IL-6, TNF-alpha, V-CAM-1, ICAM-1, and P-selectin). Associated endovascular disfunction and eventually cardiovascular disease.  A direct link between obesity induced inflammation and endovascular dysfunction.  Weight loss in these obese women reduced secretion of the associated inflammatory cytokines and thus decreased vascular dysfunction.
Nathan Goodyear

Exercise and Testosterone - 0 views

www.sast.org.tw/...FI1112060008_aO.pdf

testosterone training athletic performance athlete athletic muscle

shared by Nathan Goodyear on 26 Jun 12 - No Cached
  • Nathan Goodyear on 26 Jun 12
     
    type and length of training effects testosterone secretion. Testosterone plays an important role in muscle performance and mass. Prolonged training can result in a decrease in testosterone level. This has significance with highly trained athletes. One pitfall of this study was the assessment of testosterone via serum.
Nathan Goodyear

Inflammation and insulin resistance 10.1016/j.febslet.2007.11.057 : FEBS Letters | Scie... - 0 views

www.sciencedirect.com/...S0014579307012082

inflammation insulin resistance IR PPAR TNF-alpha IL-6 IL-10 IL-1Beta JNK GLT-4 Resistin adiponectin Gherlin NF-kapppB iNOS lkkb obesity TLR-4

shared by Nathan Goodyear on 10 Jan 12 - No Cached
  • A subsequent study by Yuan et al. showed that Tnf treatment of 3T3L1 adipocytes induces insulin resistance and that this could be prevented by pretreatment of cells with aspirin
  • Activation of the Tnf receptor results in stimulation of NFκB signaling via Ikkb
  • Insulin is a pleiotropic hormone
  • ...25 more annotations...
  • the percentage of macrophages in a given adipose tissue depot is positively correlated with adiposity and adipocyte size
  • Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes
  • Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NFκB activation by reducing IKK activity [38]
  • adipose tissue macrophages are responsible for nearly all adipose tissue Tnf expression and a significant portion of Nos2 and Il6 expression
  • One theory holds that the expansion of adipose tissue leads to adipocyte hypertrophy and hyperplasia and that large adipocytes outstrip the local oxygen supply leading to cell autonomous hypoxia with activation of cellular stress pathways
  • The use of the anti-inflammatory compounds, salicylate and its derivative aspirin, for treating symptoms of T2DM dates back over 100 years
  • elevated levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin (IL-8) have all been reported in various diabetic and insulin resistant states
  • overnutrition and obesity are often accompanied by elevations in tissue and circulating FFA concentrations, and saturated FFAs can directly activate pro-inflammatory responses
  • Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity
  • In skeletal muscle insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter
  • macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the “classically activated” pro-inflammatory macrophage, to the M2 state or the “alternatively activated” non-inflammatory cell
  • saturated fatty acids are the most potent inducers of this inflammatory response
  • Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes iNOS (reviewed in [33]
  • Adipose tissue insulin signaling results in decreased hormone sensitive lipase activity and this anti-lipolytic effect inhibits free fatty acid (FFA) efflux out of adipocytes.
  • In the liver, insulin inhibits the expression of key gluconeogenic enzymes and, therefore, insulin resistance in liver leads to elevated hepatic glucose production
  • elevated JNK activity in liver, adipose tissue and skeletal muscle of obese insulin resistant mice, and knockout of Jnk1 (Jnk1−/−) leads to amelioration of insulin resistance in high fat diet
  • Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance
  • C-reactive protein (CRP)
  • these studies highlight the possibility that increased iNOS activity plays a direct role in the pathogenesis of insulin resistance
  • the important role of Ikkb in the development of obesity and inflammation-induced insulin resistance.
  • It is probable that local concentrations of inflammatory mediators, such as FFAs, Tnf or other cytokines/adipokines contribute to this polarity switch
  • Tnf and other cytokines/chemokines are symptomatic of inflammation, and while they propagate and/or maintain the inflammatory state, they are not the initial cause(s) of inflammation
  • Tlr4, in particular, is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria
  • Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system.
  • Tlr4 stimulation results in the activation of both Ikkb/NFκB and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1, etc. (reviewed in [57
  • Nathan Goodyear on 10 Jan 12
     
    Great review of all the known components in the inflammation, insulin resistance link
Nathan Goodyear

PPARs, Obesity, and Inflammation - 0 views

www.ncbi.nlm.nih.gov/...PMC1783744

obesity inflammation PPARs perioxisome proliferator-activated receptor

shared by Nathan Goodyear on 16 Jan 12 - No Cached
  • increase of 61% within 10 years
  • Many of the inflammatory markers found in plasma of obese individuals appear to originate from adipose tissue
  • obesity is a state of chronic low-grade inflammation that is initiated by morphological changes in the adipose tissue.
  • ...19 more annotations...
  • secretion of MCP-1, resistin, and other proinflammatory cytokines is increased by obesity, the adipose secretion of the anti-inflammatory protein adiponectin is decreased
  • the peroxisome proliferators- activated receptor (PPAR) family are involved in the regulation of inflammation and energy homestasis
  • natural agonists, including unsaturated fatty acids and eicosanoids
  • PPARα also regulates inflammatory processes, mainly by inhibiting inflammatory gene expression
  • upregulation of COX-2 is seen in alcoholic steatohepatitis and nonalcoholic steatohepatitis and has been directly linked to the progression of steatosis to steatohepatitis, the inhibitory effect of PPARα on COX-2 may reduce steatohepatitis
  • PPARα agonists have a clear anorexic effect resulting in decreased food intake, evidence is accumulating that PPARα may also directly influence adipose tissue function, including its inflammatory status.
  • PPARα may govern adipose tissue inflammation in three different ways: (1) by decreasing adipocyte hypertrophy, which is known to be connected with a higher inflammatory status of the tissue [3, 11, 59], (2) by direct regulation of inflammatory gene expression via locally expressed PPARα, or (3) by systemic events likely originating from liver
  • PPARγ is considered the master regulator of adipogenesis
  • Unsaturated fatty acids and several eicosanoids serve as endogenous agonists of PPARγ
  • PPARγ2, which is adipose-tissue specific
  • two different molecular mechanisms have been proposed by which anti-inflammatory actions of PPARγ are effectuated: (1) via interference with proinflammatory transcription factors including STAT, NF-κB, and AP-1
  • and (2) by preventing removal of corepressor complexes from gene promoter regions resulting in suppression of inflammatory gene transcription
  • diet-induced obesity is associated with increased inflammatory gene expression in adipose tissue via adipocyte hypertrophy and macrophage infiltration
  • PPARγ is able to reverse macrophage infiltration, and subsequently reduces inflammatory gene expression
  • Inflammatory adipokines mainly originate from macrophages which are part of the stromal vascular fraction of adipose tissue [18, 19], and accordingly, the downregulation of inflammatory adipokines in WAT by PPARγ probably occurs via effects on macrophages
  • By interfering with NF-κB signaling pathways, PPARγ is known to decrease inflammation in activated macrophages
  • Recent data suggest that activation of PPARγ in fatty liver may protect against inflammation
  • PPARs may influence the inflammatory response either by direct transcriptional downregulation of proinflammatory genes
  • anti-inflammatory properties of PPARs in human obesity
  • Nathan Goodyear on 16 Jan 12
     
    PPARs play pivotal in obesity.  PPARs appear to reduce the inflammatory cascade associated with obesity.  Downregulation of PPARs are associated with increased inflammation.  Natural PPARs include unsaturated fats and eicosanoids.
Nathan Goodyear

Thyroid function and thyroid hormone metabol... [Klin Wochenschr. 1981] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...7241955

hypothyroid hypothyroidism TSH T3 syndrome low aging thyroid hormone

shared by Nathan Goodyear on 07 Feb 12 - No Cached
  • Nathan Goodyear on 07 Feb 12
     
    This study doesn't find evidence of low t3-syndrome, but suggests the impairment of TSH secretion (low TSH)is the first potential sign of thyroid dysfunction.
Nathan Goodyear

Caloric restriction increases adiponectin expression by adipose tissue and prevents the... - 0 views

www.jnutbio.com/...abstract

calorie restriction adiponectin insulin resistance adipocytes fat tissue cells overweight obesity

shared by Nathan Goodyear on 31 Jul 12 - No Cached
  • Nathan Goodyear on 31 Jul 12
     
    Calorie restriction increases adiponectin secretion from adipocytes.  Another plus of calorie restriction.  Remember, adiponectin and insulin are inversely associated.  Granted, this is in a rat model, but still supporting the overall health benefits of calorie restriction.
Nathan Goodyear

Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy... - 1 views

www.nature.com/...nm.2890.html

chemotherapy cancer CA WNT16B prostate tumor resistance

shared by Nathan Goodyear on 11 Aug 12 - No Cached
  • Nathan Goodyear on 11 Aug 12
     
    study shows how chemotherapy can contribute to treatment resistance by the growing cancer.  This is done through the secretion of a protein called WNT16B.  This protective protein increases tumor growth.
Nathan Goodyear

Uncoupling between insulin and rele... [Metab Syndr Relat Disord. 2010] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...20156067

Obesity obese PCOS women insulin resistance IR D-chiro-inositiol

shared by Nathan Goodyear on 19 Nov 11 - No Cached
  • Nathan Goodyear on 19 Nov 11
     
    Obese women with PCOS found to have uncoupled insulin and d-chiro-inositol secretion thus worsening insulin resistance
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