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Nathan Goodyear

Inflammation and insulin resistance 10.1016/j.febslet.2007.11.057 : FEBS Letters | ScienceDirect.com - 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
  • In the liver, insulin inhibits the expression of key gluconeogenic enzymes and, therefore, insulin resistance in liver leads to elevated hepatic glucose production
  • 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.
  • saturated fatty acids are the most potent inducers of this inflammatory response
  • 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

Effects of supplementation with fish oil-derived n−3 fatty acids and γ-linolenic acid on circulating plasma lipids and fatty acid profiles in women - 0 views

www.ajcn.org/37.full

Omega-3 n-3 GLA fish oil cholesterol LDL fatty acids fish oil

shared by Nathan Goodyear on 23 Jul 12 - No Cached
  • Nathan Goodyear on 23 Jul 12
     
    mixture of omega-3 and GLA shown to statistically lower LDL.  The mixture that was statistically significant was 4:2.
Nathan Goodyear

Lowered testosterone in male obesity: Mechanisms, morbidity and management Tang Fui MN, Dupuis P, Grossmann M - Asian J Androl - 0 views

www.ajandrology.com/article.asp

Testosterone male obesity overweight men hormone hormones low T Low T

shared by Nathan Goodyear on 15 Jan 14 - No Cached
  • The number of overweight people is expected to increase from 937 million in 2005 to 1.35 billion in 2030
  • Similarly the number of obese people is projected to increase from 396 million in 2005 to 573 million in 2030
  • By 2030, China alone is predicted to have more overweight men and women than the traditional market economies combined
  • ...37 more annotations...
  • diacylglycerol O-acyltransferase 2 (DGAT2), mechanistically implicated in this differential storage, [10] is regulated by dihydrotestosterone, [11] suggesting a potential role for androgens to influence the genetic predisposition to either the MHO or MONW phenotype.
  • bariatric surgery achieves 10%-30% long-term weight loss in controlled studies
  • The fact that obese men have lower testosterone compared to lean men has been recognized for more than 30 years
  • Reductions in testosterone levels correlate with the severity of obesity and men
  • epidemiological data suggest that the single most powerful predictor of low testosterone is obesity, and that obesity is a major contributor of the age-associated decline in testosterone levels.
  • healthy ageing by itself is uncommonly associated with marked reductions in testosterone levels
  • obesity blunts this LH rise, obesity leads to hypothalamic-pituitary suppression irrespective of age which cannot be compensated for by physiological mechanisms
  • Reductions in total testosterone levels are largely a consequence of reductions in sex hormone binding globulin (SHBG) due to obesity-associated hyperinsulinemia
  • although controversial, measurement of free testosterone levels may provide a more accurate assessment of androgen status than the (usually preferred) measurement of total testosterone in situations where SHBG levels are outside the reference range
  • SHBG increases with age
  • marked obesity however is associated with an unequivocal reduction of free testosterone levels, where LH and follicle stimulating hormone (FSH) levels are usually low or inappropriately normal, suggesting that the dominant suppression occurs at the hypothalamic-pituitary level
  • adipose tissue, especially when in the inflamed, insulin-resistant state, expresses aromatase which converts testosterone to estradiol (E 2 ). Adipose E 2 in turn may feedback negatively to decrease pituitary gonadotropin secretion
  • diabetic obesity is associated with decreases in circulatory E 2
  • In addition to E 2 , increased visceral fat also releases increased amounts of pro-inflammatory cytokines, insulin and leptin; all of which may inhibit the activity of the HPT axis at multiple levels
  • In the prospective Massachusetts Male Aging Study (MMAS), moving from a non-obese to an obese state resulted in a decline of testosterone levels
  • weight loss, whether by diet or surgery, increases testosterone levels proportional to the amount of weight lost
  • fat is androgen-responsive
  • low testosterone may augment the effects of a hypercaloric diet
  • In human male ex vivo adipose tissue, testosterone decreased adipocyte differentiation by 50%.
  • Testosterone enhances catecholamine-induced lipolysis in vitro and reduces lipoprotein lipase activity and triglyceride uptake in human abdominal adipose tissue in vivo
  • in men with prostate cancer receiving 12 months of androgen deprivation therapy, fat mass increased by 3.4 kg and abdominal VAT by 22%, with the majority of these changes established within 6 months
  • severe sex steroid deficiency can increase fat mass rapidly
  • bidirectional relationship between testosterone and obesity
  • increasing body fat suppresses the HPT axis by multiple mechanisms [30] via increased secretion of pro-inflammatory cytokines, insulin resistance and diabetes; [19],[44] while on the other hand low testosterone promotes further accumulation of total and visceral fat mass, thereby exacerbating the gonadotropin inhibition
  • androgens may play a more significant role in VAT than SAT
  • men undergoing androgen depletion for prostate cancer show more marked increases in visceral compared to subcutaneous fat following treatment
    • Nathan Goodyear
      Nathan Goodyear on 16 Jan 14
       
      Interesting: low T increases VAT, yet T therapy does not reduce VAT, yet T therapy reduces SAT.
  • irisin, derived from muscle, induces brown fat-like properties in rodent white fat
  • androgens can act via the PPARg-pathway [37] which is implicated in the differentiation of precursor fat cells to the energy-consuming phenotype
  • low testosterone may compound the effect of increasing fat mass by making it more difficult for obese men to lose weight via exercise
  • pro-inflammatory cytokines released by adipose tissue may contribute to loss of muscle mass and function, leading to inactivity and further weight gain in a vicious cycle
  • Sarcopenic obesity, a phenotype recapitulated in men receiving ADT for prostate cancer, [55] may not only be associated with functional limitations, but also aggravate the metabolic risks of obesity;
  • observational evidence associating higher endogenous testosterone with reduced loss of muscle mass and crude measures of muscle function in men losing weight
  • genuine reactivation of the HPT axis in obese men requires more substantial weight-loss
  • A number of intervention studies have confirmed that both diet- and surgically-induced weight losses are associated with increased testosterone, with the rise in testosterone generally proportional to the amount of weight lost
  • men, regardless of obesity level, can benefit from the effect of weight loss.
  • inconsistent effect of testosterone on VAT
  • Nathan Goodyear on 15 Jan 14
     
    to be read
Nathan Goodyear

Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy - 0 views

erc.endocrinology-journals.org/...R175.full

prostate cancer DHT 3-beta-diol 3-alpha-diol metabolites metabolite male men hormone hormones androgen deprivation therapy

shared by Nathan Goodyear on 03 Feb 14 - No Cached
  • Additional studies have similarly found that prostate tissue levels of DHT in PCa patients treated with ADT therapy before prostatectomy declined by only ∼75% versus declines of ∼95% in serum levels
  • In a recent study in healthy men, treatment for 1 month with a GnRH antagonist to suppress testicular androgen synthesis caused a 94% decline in serum testosterone, but only a 70–80% decline in prostate tissue testosterone and DHT
  • progression to CRPC was associated with increased intratumoral accumulation or synthesis of testosterone.
  • ...9 more annotations...
  • the intraprostatic synthesis of testosterone from adrenal-derived precursors likely accounts for the relatively high testosterone levels in prostate after ADT
  • In addition, AR activity in these cells is likely further enhanced by multiple mechanisms that sensitize AR to low levels of androgens
  • higher affinity ligand DHT (approximately eightfold higher affinity
  • type 2 5α-reductase (SRD5A2) being the major enzyme in prostate
  • reduce DHT to 5α-androstane-3α,17β-diol (3α-androstanediol; Ji et al. 2003, Rizner et al. 2003), which is then glucuronidated to form 3α-androstanediol glucuronide by the enzymes UDP glycosyltransferase 2, B15 (UGT2B15) or UGT2B17
  • DHT in prostate is inactivated by the enzyme AKR1C2, which is also termed 3α-hydroxysteroid dehydrogenase type 3 (3α-HSD type 3
    • Nathan Goodyear
      Nathan Goodyear on 03 Feb 14
       
      The metabolite 3-alpha androstanediol is NOT inactive as this author states.  This DHT metabolite actually can stimulate  ER alpha receptors in the prostate.
  • AKR1C1, is also expressed in prostate. However, in contrast to AKR1C2, it converts DHT primarily to 5α-androstane-3β,17β-diol (3β-androstanediol; Steckelbroeck et al. 2004), which is a potential endogenous ligand for the estrogen receptor β
  • Significantly, intraprostatic testosterone levels were not substantially reduced relative to controls with normal serum androgen levels, although DHT levels were reduced to 18% of controls
  • testosterone levels in many of the CRPC samples were actually increased relative to control tissues (Montgomery et al. 2008). While DHT levels were less markedly increased, this may have reflected DHT catabolism
  • Nathan Goodyear on 03 Feb 14
     
    This article discusses the failure of androgen deprivation therapy and prostate cancer.  This failure is quite common.  The authors point to alpha-DHT as the primary mechanism through AR stimulation.  However, we know that DHT metabolites also stimulate estrogen receptors.
Nathan Goodyear

The Androgen Derivative 5α-Androstane-3β,17β-Diol Inhibits Prostate Cancer Cell Migration Through Activation of the Estrogen Receptor β Subtype - 0 views

cancerres.aacrjournals.org/...5445.short

prostate cancer DHT metabolite 3-alpha androstanediol ER beta ER-beta E-cadherin male hormone hormones men

shared by Nathan Goodyear on 27 Jan 14 - No Cached
  • the dihydrotestosterone metabolite 5α-androstane-3β,17β-diol (3β-Adiol), a steroid which does not bind androgen receptors, but efficiently binds the estrogen receptor β (ERβ), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERβ signaling
  • estradiol is not active
  • 3β-Adiol, through ERβ, induces the expression of E-cadherin, a protein known to be capable of blocking metastasis formation in breast and prostate cancer cells
  • Nathan Goodyear on 27 Jan 14
     
    DHT metabolite 3-beta androstanediol inhibits prostate cancer via its interaction with ER beta not AR.  This study finds increased E-cadherin transcription to reduce metastasis.  Estrogen was not active, according to this study.  This implies that estrogen in early disease may have a different signal than late.
Nathan Goodyear

PLOS ONE: Effect of Marine-Derived n-3 Polyunsaturated Fatty Acids on C-Reactive Protein, Interleukin 6 and Tumor Necrosis Factor α: A Meta-Analysis - 0 views

www.plosone.org/...10.1371%2Fjournal.pone.0088103

inflammation omega 3 omega-3 n-3 CRP IL-6 TNF-alpha

shared by Nathan Goodyear on 14 Feb 14 - No Cached
  • Nathan Goodyear on 14 Feb 14
     
    meta-analysis finds that omega-3 fatty acids decrease CRP, IL-6, and TNF-alpha.
Nathan Goodyear

Metabolic influences on neuroendocrine regulation of reproduction - 0 views

www.ncbi.nlm.nih.gov/...PMC3898855

metabolism metabolic regulation reproduction Leptin Ghrelin Insulin Kisspeptin GNRH

shared by Nathan Goodyear on 17 Feb 14 - No Cached
  • Energy storage occurs mainly at the level of white adipose tissue, where adipocytes secrete the anorexigenic adipokine leptin
  • humans and laboratory animals with leptin or insulin deficiency or resistance and/or increased ghrelin levels exhibit delayed or absent puberty and frequently display hypogonadotropic hypogonadism, which prevents fertility
  • Ghrelin suppresses pulsatile gonadotropin-releasing hormone (GnRH) release [14,15], thus serving as a signal to suppress reproduction in times of famine
  • ...4 more annotations...
  • GnRH neurons have been shown to express insulin receptor mRNA and protein [27] and are activated by insulin
  • AgRP and NPY have the opposite (orexigenic) effect, inducing food intake.
  • Neuropeptides derived from POMC/CART neurons exert a potent anorectic action, thus decreasing food intake and body weight
  • Kisspeptins (encoded by KISS1) have been identified in the last decade as the most potent secretagogues of GnRH release.
  • Nathan Goodyear on 17 Feb 14
     
    Good, although brief, discussion of the interaction between metabolism and hormones.  Kisspeptin is a GNRH secreatagogue "upstream".   Insulin, Leptin, and Gherlin can inhibit GNRH through resistance and low levels.  Probably a U shaped graph of optimal activity.
Nathan Goodyear

Inflammatory cause of metabolic syndrome via brain stress and NF-κB - 0 views

www.ncbi.nlm.nih.gov/...PMC3314172

metabolic syndrome TLR cytokines hypothalamus brain neurology metabolic syndrome NF-kappaB DIO diet induced obesity over nutrition nutrition inflammation

shared by Nathan Goodyear on 09 Jul 13 - No Cached
  • Mechanistic studies further showed that such metabolic inflammation is related to the induction of various intracellular stresses such as mitochondrial oxidative stress, endoplasmic reticulum (ER) stress, and autophagy defect under prolonged nutritional excess
  • intracellular stress-inflammation process for metabolic syndrome has been established in the central nervous system (CNS) and particularly in the hypothalamus
  • the CNS and the comprised hypothalamus are known to govern various metabolic activities of the body including appetite control, energy expenditure, carbohydrate and lipid metabolism, and blood pressure homeostasis
  • ...56 more annotations...
  • Reactive oxygen species (ROS) refer to a class of radical or non-radical oxygen-containing molecules that have high oxidative reactivity with lipids, proteins, and nucleic acids
  • a large measure of intracellular ROS comes from the leakage of mitochondrial electron transport chain (ETC)
  • Another major source of intracellular ROS is the intentional generation of superoxides by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
  • there are other ROS-producing enzymes such as cyclooxygenases, lipoxygenases, xanthine oxidase, and cytochrome p450 enzymes, which are involved with specific metabolic processes
  • To counteract the toxic effects of molecular oxidation by ROS, cells are equipped with a battery of antioxidant enzymes such as superoxide dismutases, catalase, peroxiredoxins, sulfiredoxin, and aldehyde dehydrogenases
  • intracellular oxidative stress has been indicated to contribute to metabolic syndrome and related diseases, including T2D [72; 73], CVDs [74-76], neurodegenerative diseases [69; 77-80], and cancers
  • intracellular oxidative stress is highly associated with the development of neurodegenerative diseases [69] and brain aging
  • dietary obesity was found to induce NADPH oxidase-associated oxidative stress in rat brain
  • mitochondrial dysfunction in hypothalamic proopiomelanocortin (POMC) neurons causes central glucose sensing impairment
  • Endoplasmic reticulum (ER) is the cellular organelle responsible for protein synthesis, maturation, and trafficking to secretory pathways
  • unfolded protein response (UPR) machinery
  • ER stress has been associated to obesity, insulin resistance, T2D, CVDs, cancers, and neurodegenerative diseases
  • brain ER stress underlies neurodegenerative diseases
  • under environmental stress such as nutrient deprivation or hypoxia, autophagy is strongly induced to breakdown macromolecules into reusable amino acids and fatty acids for survival
  • intact autophagy function is required for the hypothalamus to properly control metabolic and energy homeostasis, while hypothalamic autophagy defect leads to the development of metabolic syndrome such as obesity and insulin resistance
  • prolonged oxidative stress or ER stress has been shown to impair autophagy function in disease milieu of cancer or aging
  • TLRs are an important class of membrane-bound pattern recognition receptors in classical innate immune defense
  • Most hypothalamic cell types including neurons and glia cells express TLRs
  • overnutrition constitutes an environmental stimulus that can activate TLR pathways to mediate the development of metabolic syndrome related disorders such as obesity, insulin resistance, T2D, and atherosclerotic CVDs
  • Isoforms TLR1, 2, 4, and 6 may be particularly pertinent to pathogenic signaling induced by lipid overnutrition
  • hypothalamic TLR4 and downstream inflammatory signaling are activated in response to central lipid excess via direct intra-brain lipid administration or HFD-feeding
  • overnutrition-induced metabolic derangements such as central leptin resistance, systemic insulin resistance, and weight gain
  • these evidences based on brain TLR signaling further support the notion that CNS is the primary site for overnutrition to cause the development of metabolic syndrome.
  • circulating cytokines can limitedly travel to the hypothalamus through the leaky blood-brain barrier around the mediobasal hypothalamus to activate hypothalamic cytokine receptors
  • significant evidences have been recently documented demonstrating the role of cytokine receptor pathways in the development of metabolic syndrome components
  • entral administration of TNF-α at low doses faithfully replicated the effects of central metabolic inflammation in enhancing eating, decreasing energy expenditure [158;159], and causing obesity-related hypertension
  • Resistin, an adipocyte-derived proinflammatory cytokine, has been found to promote hepatic insulin resistance through its central actions
  • both TLR pathways and cytokine receptor pathways are involved in central inflammatory mechanism of metabolic syndrome and related diseases.
  • In quiescent state, NF-κB resides in the cytoplasm in an inactive form due to inhibitory binding by IκBα protein
  • IKKβ activation via receptor-mediated pathway, leading to IκBα phosphorylation and degradation and subsequent release of NF-κB activity
  • Research in the past decade has found that activation of IKKβ/NF-κB proinflammatory pathway in metabolic tissues is a prominent feature of various metabolic disorders related to overnutrition
  • it happens in metabolic tissues, it is mainly associated with overnutrition-induced metabolic derangements, and most importantly, it is relatively low-grade and chronic
  • this paradigm of IKKβ/NF-κB-mediated metabolic inflammation has been identified in the CNS – particularly the comprised hypothalamus, which primarily accounts for to the development of overnutrition-induced metabolic syndrome and related disorders such as obesity, insulin resistance, T2D, and obesity-related hypertension
  • evidences have pointed to intracellular oxidative stress and mitochondrial dysfunction as upstream events that mediate hypothalamic NF-κB activation in a receptor-independent manner under overnutrition
  • In the context of metabolic syndrome, oxidative stress-related NF-κB activation in metabolic tissues or vascular systems has been implicated in a broad range of metabolic syndrome-related diseases, such as diabetes, atherosclerosis, cardiac infarct, stroke, cancer, and aging
  • intracellular oxidative stress seems to be a likely pathogenic link that bridges overnutrition with NF-κB activation leading to central metabolic dysregulation
  • overnutrition is an environmental inducer for intracellular oxidative stress regardless of tissues involved
  • excessive nutrients, when transported into cells, directly increase mitochondrial oxidative workload, which causes increased production of ROS by mitochondrial ETC
  • oxidative stress has been shown to activate NF-κB pathway in neurons or glial cells in several types of metabolic syndrome-related neural diseases, such as stroke [185], neurodegenerative diseases [186-188], and brain aging
  • central nutrient excess (e.g., glucose or lipids) has been shown to activate NF-κB in the hypothalamus [34-37] to account for overnutrition-induced central metabolic dysregulations
  • overnutrition can present the cell with a metabolic overload that exceeds the physiological adaptive range of UPR, resulting in the development of ER stress and systemic metabolic disorders
  • chronic ER stress in peripheral metabolic tissues such as adipocytes, liver, muscle, and pancreatic cells is a salient feature of overnutrition-related diseases
  • recent literature supports a model that brain ER stress and NF-κB activation reciprocally promote each other in the development of central metabolic dysregulations
  • when intracellular stresses remain unresolved, prolonged autophagy upregulation progresses into autophagy defect
  • autophagy defect can induce NF-κB-mediated inflammation in association with the development of cancer or inflammatory diseases (e.g., Crohn's disease)
  • The connection between autophagy defect and proinflammatory activation of NF-κB pathway can also be inferred in metabolic syndrome, since both autophagy defect [126-133;200] and NF-κB activation [20-33] are implicated in the development of overnutrition-related metabolic diseases
  • Both TLR pathway and cytokine receptor pathways are closely related to IKKβ/NF-κB signaling in the central pathogenesis of metabolic syndrome
  • Overnutrition, especially in the form of HFD feeding, was shown to activate TLR4 signaling and downstream IKKβ/NF-κB pathway
  • TLR4 activation leads to MyD88-dependent NF-κB activation in early phase and MyD88-indepdnent MAPK/JNK pathway in late phase
  • these studies point to NF-κB as an immediate signaling effector for TLR4 activation in central inflammatory response
  • TLR4 activation has been shown to induce intracellular ER stress to indirectly cause metabolic inflammation in the hypothalamus
  • central TLR4-NF-κB pathway may represent one of the early receptor-mediated events in overnutrition-induced central inflammation.
  • cytokines and their receptors are both upstream activating components and downstream transcriptional targets of NF-κB activation
  • central administration of TNF-α at low dose can mimic the effect of obesity-related inflammatory milieu to activate IKKβ/NF-κB proinflammatory pathways, furthering the development of overeating, energy expenditure decrease, and weight gain
  • the physiological effects of IKKβ/NF-κB activation seem to be cell type-dependent, i.e., IKKβ/NF-κB activation in hypothalamic agouti-related protein (AGRP) neurons primarily leads to the development of energy imbalance and obesity [34]; while in hypothalamic POMC neurons, it primarily results in the development of hypertension and glucose intolerance
  • the hypothalamus, is the central regulator of energy and body weight balance [
  • Nathan Goodyear on 09 Jul 13
     
    Great article chronicles the biochemistry of "over nutrition" and inflammation through NF-kappaB activation and its impact on the brain.
Nathan Goodyear

Modulation of arachidonic acid metabolism by curcumin and related β-diketone derivatives: effects on cytosolic phospholipase A2, cyclooxygenases and 5-lipoxygenase - 0 views

carcin.oxfordjournals.org/...1671.long

curcumin tumeric inflammation

shared by Nathan Goodyear on 13 Sep 13 - No Cached
  • Nathan Goodyear on 13 Sep 13
     
    Full text of curmin's inhibition of COX and LOX.
Nathan Goodyear

SpringerPlus | Full text | Testosterone-derived estradiol production by male endothelium is robust and dependent on p450 aromatase via estrogen receptor alpha - 0 views

www.springerplus.com/...214

aromatase activity aromatase estradiol estrogen atherosclerosis hormone hormones male ER-alpha ER alpha

shared by Nathan Goodyear on 04 Oct 13 - No Cached
  • Nathan Goodyear on 04 Oct 13
     
    Mouse study, but aromatase activity and ER alpha required for atherosclerosis in male mice.
Nathan Goodyear

Therapy in the Early Stage: Incretins - 0 views

care.diabetesjournals.org/...S264.full

incretins glucose diabetes

shared by Nathan Goodyear on 11 Dec 13 - No Cached
  • Increased resistance to insulin action in the skeletal muscle and liver associated with enhanced hepatic glucose output and impaired insulin secretion due to a progressive decline of β-cell function are long-recognized core defects
  • in addition, other mechanisms/organs are involved, augmenting the pathological pathways: adipocytes (altered fat metabolism due to insulin resistance), gastrointestinal tract (incretin deficiency and/or resistance), pancreatic α-cells (hyperglucagonemia and increased hepatic sensitivity to glucagon), kidneys (enhanced glucose reabsorption), and central nervous system (insulin resistance)
  • β-cell failure
    • Nathan Goodyear
      Nathan Goodyear on 11 Dec 13
       
      and studies have shown that a reduction in insulin function will decrease LH production and thus lead to a decrease in Testosterone production in men.
  • ...2 more annotations...
  • Incretins are gut-derived hormones, members of the glucagon superfamily, released in response to nutrient ingestion (mainly glucose and fat)
  • They exert a wide range of effects, including stimulation of pancreatic insulin secretion in a glucose-dependent manner and play an important role in the local gastrointestinal and whole-body physiology
  • Nathan Goodyear on 11 Dec 13
     
    good discussion on incretins and their role in glucose homeostasis. 
Nathan Goodyear

Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle - 0 views

brain.oxfordjournals.org/...1821.full

macrophagic myofasciitis aluminum vaccines vaccinations macrophagic myofasciitis

shared by Nathan Goodyear on 09 Oct 13 - No Cached
  • Nathan Goodyear on 09 Oct 13
     
    Macrophagic myofasciitis is the result of aluminum component in vaccines.
Nathan Goodyear

Long-term persistence of vaccine-derived alu... [J Inorg Biochem. 2009] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...19748679

aluminum vaccine vaccinations neurologic brain cognition

shared by Nathan Goodyear on 09 Oct 13 - No Cached
  • Nathan Goodyear on 09 Oct 13
     
    Migration and long-term neurologic dysfunction as a result of aluminum hydroxide.
Nathan Goodyear

Role of Pancreatic Cancer-derived Exosomes in Salivary Biomarker Development - 0 views

www.jbc.org/26888

saliva testing salivary pancreatic cancer

shared by Nathan Goodyear on 16 Oct 13 - No Cached
  • Nathan Goodyear on 16 Oct 13
     
    Saliva is proving to be an exciting medium for functional testing.  Recently, studies have found saliva as a great medium to evaluate for cancer biomarkers.  This study find pancreatic cancer biomarkers in saliva.
Nathan Goodyear

Graviola: A Novel Promising Natural-Derived Drug That Inhibits Tumorigenicity and Metastasis of Pancreatic Cancer Cells In Vitro and In Vivo Through Altering Cell Metabolism - 0 views

www.ncbi.nlm.nih.gov/...PMC3371140

pancreatic cancer pancreatic cancer HIF-1alpha NF-kappaB GLUT4 GLUT1 Graviola Soursop Annona Muricata

shared by Nathan Goodyear on 17 Oct 13 - No Cached
  • Nathan Goodyear on 17 Oct 13
     
    New insight to new therapy for Pancreatic cancer.  This article/study does a great job of reviewing the biochemistry by which Graviola works against pancreatic cancer.  Graviola was shown to downregulate HIF-1alpha, NF-kappaB, GLUT1, GLUT4, HKII, and LDHA.  Complex 1 of the electron transport was also inhibited.
Nathan Goodyear

Effect of dehydroepiandrosterone derivatives... [Bioorg Med Chem. 2014] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...25261928

5alpha reductase DHEA metabolites hormone hormones

shared by Nathan Goodyear on 06 Oct 14 - No Cached
  • Nathan Goodyear on 06 Oct 14
     
    Interesting abstract of study of DHEA metabolites.  In vivo study finds some DHEA metabolites inhibit 5-alpha-reductase activity.  The opening sentence implies that 5alpha-reductase and conversion of T to DHT promotes androgen dependent disease.  The inference here is cancer, however, what they fail to mention is that this activity is via the estrogen receptors.
Nathan Goodyear

Low-T3 Syndrome - 0 views

circ.ahajournals.org/...708.long

T3 low T3 cardiac heart disease CVD cardiovascular thyroid hormone hormones hypothyroid hypothyroidism

shared by Nathan Goodyear on 03 Jul 12 - No Cached
  • More than 80% of the biologically active hormone triiodothyronine (T3) derives from peripheral conversion of prohormone thyroxine (T4) secreted by the thyroid gland
  • Low thyroid hormone concentrations, in particular low serum T3 concentrations, are a common finding in patients with nonthyroidal illnesses, including cardiac disorders
  • a direct relationship between low circulating levels of T3 and adverse prognosis of cardiac patients
  • ...4 more annotations...
  • The present study clearly shows the existence of a strong association between the reduction of biologically active T3 and mortality in a large population of cardiac hospitalized patients
  • highly significant increase in the incidence of cardiac and cumulative deaths in patients with low T3 compared with patients with normal T3 levels
  • the relevance of the low T3 state as a strong, independent predictor of mortality in cardiac patients
  • low T3 concentrations are a strong independent predictive marker of poor prognosis in cardiac patients
  • Nathan Goodyear on 03 Jul 12
     
    low T3 associated with poor prognosis in cardiac patients.   Poor prognosis = death.  T3 is important in cardiac remodeling, which is inherently important with cardiac disease.
Nathan Goodyear

PLOS ONE: Mast Cell-Derived Histamine Mediates Cystitis Pain - 0 views

journals.plos.org/...article

IC interstitial cystitis mast cells inflammation bladder

shared by Nathan Goodyear on 12 May 15 - No Cached
  • Nathan Goodyear on 12 May 15
     
    Mast cells contribute/cause the pro inflammatory response that results in pain in people with interstitial cystitis.  This is mediated via Histamine type I and type II receptors.
Nathan Goodyear

Diet-induced obesity and low testosterone increase neuroinflammation and impair neural function - 0 views

www.ncbi.nlm.nih.gov/...PMC4190446

Testosterone neuroinflammation glia insulin resistance obesity diabetes brain CNS PNS inflammation low T low Testosterone TNF-alpha IL-1beta

shared by Nathan Goodyear on 28 Apr 15 - No Cached
  • both obesity and low testosterone are also risk factors for neural dysfunction, including cognitive impairment [58–61] and development of AD
  • Levels of obesity and testosterone are often inversely correlated
  • diet-induced obesity causes significant metabolic disturbances and impairs central and peripheral nervous systems.
  • ...23 more annotations...
  • both obesity and low testosterone are linked with promotion of inflammatory pathways [70–72] and exert harmful actions on the central [73–75] and peripheral [29,76] nervous systems
  • In general, obesity-related changes were worsened by low testosterone and improved by testosterone treatment; however, this relationship was not statistically significant in several instances. Further, our data suggest that a common pathway that may contribute to obesity and testosterone effects is regulation of inflammation
  • fasting blood glucose levels were independently and additively increased by GDX-induced testosterone depletion and high-fat diet
  • testosterone treatment significantly reduced fasting glucose under both the normal and high-fat diets, demonstrating potential therapeutic efficacy of testosterone supplementation
  • fasting insulin, insulin resistance (HOMA index), and glucose tolerance, low testosterone tended to exacerbate and or testosterone treatment improved outcomes.
  • testosterone status did not significantly affect body weight
  • testosterone’s effects likely do not indicate an indirect result on adiposity but rather regulatory action(s) on other aspects of metabolic homeostasis
  • Prior work in rodents has shown diet-induced obesity induces insulin resistance in rat brain [63] and that testosterone replacement improves insulin sensitivity in obese rats [64]. Our findings are consistent with the human literature, which indicates that (i) testosterone levels are inversely correlated to insulin resistance and T2D in healthy [30,65] as well as obese men [66], and (ii) androgen therapy can improve some metabolic measures in overweight men with low testosterone
  • it has been shown that TNFα has inhibitory effects on neuron survival, differentiation, and neurite outgrowth
  • Our data demonstrate that low testosterone and obesity independently increased cerebrocortical mRNA levels of both TNFα and IL-1β
  • Testosterone status also affected metabolic and neural measures
  • many beneficial effects of testosterone, including inhibition of proinflammatory cytokine expression
  • neuroprotection [80,81], are dependent upon androgen receptors, the observed effects of testosterone in this study may involve androgen receptor activation
  • testosterone can be converted by the enzyme aromatase into estradiol, which is also known to exert anti-inflammatory [82] and neuroprotective [83] actions
  • glia are the primary sources of proinflammatory molecules in the CNS
  • poorer survival of neurons grown on glia from mice maintained on high-fat diet
  • Since testosterone can affect glial function [86] and improve neuronal growth and survival [87–89], it was unexpected that testosterone status exhibited rather modest effects on neural health indices with the only significant response being an increase in survival in the testosterone-treated, high-fat diet group
  • significantly increased expression of TNFα and IL-1β in glia cultures derived from obese mice
  • testosterone treatment significantly lowered TNFα and IL-1β expression to near basal levels even in obese mice, indicating a protective benefit of testosterone across diet conditions
  • IL-1β treatment has been shown to induce synapse loss and inhibit differentiation of neurons
  • Testosterone status and diet-induced obesity were associated with significant regulation of macrophage infiltration
  • testosterone prevented and/or restored thermal nociception in both diet groups
  • a possible mechanism by which obesity and testosterone levels may affect the health of both CNS and PNS
  • Nathan Goodyear on 28 Apr 15
     
    Study points to obesity and low Testosterone contribution of neuroinflammation.  No effect of body weight was seen with TRT.  This animal model found similar positive effects of TRT in insulin sensitivity.  Obesity and low T increase inflammatory cytokine production: this study found an increase in TNF-alpha and IL-1beta and TRT reduced TNF-alpha and IL-1beta to near base-line.  Testosterone is neuroprotective and this study reviewed the small volume of evaded that pointed to benefit from estradiol.  Testosterone's effect on glial survival was positive but not significant.  Obesity and low T were found to be associated with increased macrophage infiltration in the PNS with increased TNF-alpha and IL-1beta.   Testosterone therapy improved peripheral neuropathy via its positive effects on nocicieption.
wheelchairindia9

Hand Driven Tricycle India - 0 views

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Various Types Of Tricycle For Handicapped tricycle for handicapped children special needs tricycles strength and coordination hand driven tricycle india

shared by wheelchairindia9 on 18 Apr 15 - No Cached
  • wheelchairindia9 on 18 Apr 15
     
    Tricycle is also better and will enable the rider to make sharper turns on roads. Every time a person needs to be seated in a conventional tricycle or disembark from it, the needs help. But attached footrests to help the rider. With a bigger seat and stronger tyres, the vehicle will also help vendors. And every part of the cycle can be dismantled too, which makes it easier to transport. Although tricycles are often associated with toddlers, they are also widely ridden by adults. 'Trikes' are often ridden by older adults or people with disabilities who prefer the extra balance offered by a third wheel. Characteristics of Tricycles: Three wheels. Easily balanced. Brakes. Gears. Often have a storage basket at the rear. Can buy electric powered tricycles. In tricycles distinct types of pedal-driven motion. The tricycle was conceived and produced especially for children from the outset, however bicycles for children were derived by a simple reduction of the scale of the adult counterpart. Standard Single Hand Drive Tricycle: Frame : Made by E.R.W. Tubes 22.22 mm- 18 G. Seat & Back : MS, CRC Sheet Seat Size 18"x 16" Wheel Size : Wheel Diameter 28"x 1 1/2" Tyre and Tube Standard Company. Parts : Standard Quality Color : Black Painted Brake : Front Wheel liver System Drive : Rear Wheel Right Side Tricycle with rear wheel chain-driven transmission and a diamond shaped frame, it quickly entered into widespread use for transportation, work, and leisure purposes. Tricycles are available to accommodate a vast array of special needs. Hand-pedaled recumbent tricycles make it possible for those without the use of their legs. Children, teens and adults with cerebral palsy and similar disorders can select tricycles specially designed to increase strength and coordination. Caregivers to autistic children can ride with their child on tandem special needs tricycles built to accommodate one adult and one child rider.
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