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wheelchairindia9

Functional Knee Support - 0 views

www.wheelchairindia.com/...Tynor-Functional-Knee-Support

Functional Braces Best for: Sports injuries after surgery functional knee braces knee rehabilitation program knee injuries or knee surgery free movement of the knee joint decrease knee pain improve knee stability

shared by wheelchairindia9 on 19 Mar 16 - No Cached
  • wheelchairindia9 on 19 Mar 16
     
    Tynor Functional Knee Support Functional knee Support is an anterior opening device, which offers the advantage of controlled compression around the knee and a rigid lateral support and immobilization. It allows normal flexion and free movement of the knee joint. Anterio Open able Easy application Controlled compression. Perfect lateral splinting. Anatomical design. Tynor Functional Knee Support Features Bi axial heavy duty aluminum hinge Mimics the natural knee joint Ensures full weight bearing. Allows free flexion movement Four way stretchable fabric Controlled and comfortable compression No buckling No vaso constriction Enhanced comfort Open patella design Release patellar pressure Hold the patella in position Can be used for Patellofemoral diseases Wrap design with anterior closing Easy application and removal on swollen or asymmetric knees Easy application and removal for weak or geriatric patients. Allows customized compression Offers flexibility in sizing Ergonomic design Anti tourniquet effect - ensures no constriction to blood flow Better grip of the product to the body. Anatomic construction- Better functionality and Snug fit.
Nathan Goodyear

Activation of NK cells by extracellular heat shock protein 70 through induction of NKG2... - 0 views

www.ncbi.nlm.nih.gov/...PMC2935777

heat shock proteins NK cells natural killer cells cancer

shared by Nathan Goodyear on 29 Sep 18 - No Cached
  • Heat shock proteins (HSPs) are intracellular molecular chaperones that play essential roles in facilitating protein folding
  • their ability to interact with APCs and to chaperone antigenic peptides for cross-presentation to MHC class I and class II molecules on APC
  • vaccination with HSP70 was associated with increased T cell, as well as NK cell, activity in patients with CML
  • ...6 more annotations...
  • HSP70 did not activate NK cells directly. Instead, HSP70 induced the expression of an NKG2D ligand MICA on DCs, which then activated NK cells in an NKG2D-dependent manner.
  • DCs are the most powerful professional antigen presenting cells (APCs) that are instrumental in processing antigens and orchestrating antigen-specific adaptive immunity and tolerance
  • NK cells and DCs can functionally interact with each other both in vitro and in vivo
  • autologous HSP70 could stimulate significant IFN-γ production
  • The magnitude of the IFN-γ response was different from patient to patient and correlated with the number of functional NK cells
  • In addition, 10 out of 14 patients had significantly increased IFN-γ producing cells in the peripheral blood after HSP70 vaccinations, which is again in line with increased NK cell activity as reported in our original study in these patients
  • Nathan Goodyear on 29 Sep 18
     
    great review of the relationship between heat shock proteins and NK cells.
Nathan Goodyear

Anticancer mechanisms of cannabinoids - 0 views

www.ncbi.nlm.nih.gov/...PMC4791144

THC cannabinoids cancer

shared by Nathan Goodyear on 18 Sep 18 - No Cached
  • modulating key cell signalling pathways involved in the control of cancer cell proliferation and survival
  • cannabinoids inhibit angiogenesis and decrease metastasis in various tumour types in laboratory animals
  • Cannabis sativa L. (marijuana)
  • ...41 more annotations...
  • of the approximately 108 cannabinoids produced by C. sativa, Δ9-tetrahydrocannabinol (thc) is the most relevant because of its high potency and abundance in plant preparations
  • Tetrahydrocannabinol exerts a wide variety of biologic effects by mimicking endogenous substances—the endocannabinoids anandamide3 and 2-arachidonoylglycerol4,5—that engage specific cell-surface cannabinoid receptors
  • the cb2 receptor was initially described to be present in the immune system6, but was more recently shown to also be expressed in cells from other origins
  • transient receptor potential cation channel subfamily V, member 1
  • orphan G protein–coupled receptor 55
  • Most of the effects produced by cannabinoids in the nervous system and in non-neural tissues rely on cb1 receptor activation
  • two major cannabinoid-specific receptors—cb1 and cb2
  • cardiovascular tone, energy metabolism, immunity, and reproduction
  • cannabinoids are well known to exert palliative effects in cancer patients
  • best-established use is the inhibition of chemotherapy-induced nausea and vomiting
  • thc and other cannabinoids exhibit antitumour effects in a wide array of animal models of cancer
  • cannabinoid receptors and their endogenous ligands are both generally upregulated in tumour tissue compared with non-tumour tissue
  • cb2 promotes her2 (human epidermal growth factor receptor 2) pro-oncogenic signalling in breast cancer
  • pharmacologic activation of cannabinoid receptors decreases tumour growth
  • endocannabinoid signalling can also have a tumour-suppressive role
  • pharmacologic stimulation of cb receptors is, in most cases, antitumourigenic. Nonetheless, a few reports have proposed a tumour-promoting effect of cannabinoids
  • most prevalent effect is the induction of cancer cell death by apoptosis and the inhibition of cancer cell proliferation
  • impair tumour angiogenesis and block invasion and metastasis
  • thc and other cannabinoids induce the apoptotic death of glioma cells by cb1- and cb2-dependent stimulation
  • Autophagy is primarily a cytoprotective mechanism, although its activation can also lead to cell death
  • autophagy is important for cannabinoid antineoplastic activity
  • autophagy is upstream of apoptosis in the mechanism of cannabinoid-induced cell death
  • the effect of cannabinoids in hormone- dependent tumours might rely, at least in part, on the ability to interfere with the activation of growth factor receptors
  • glioma cells), pharmacologic blockade of either cb1 or cb2 prevents cannabinoid-induced cell death with similar efficacy
  • other types of cancer cells (pancreatic48, breast24, or hepatic43 carcinoma cells, for example), antagonists of cb2 but not of cb1 inhibit cannabinoid antitumour actions
  • thc promotes cancer cell death in a cb1- or cb2-dependent manner (or both) at lower concentrations
  • cannabidiol (cbd), a phytocannabinoid with a low affinity for cannabinoid receptors15, and other marijuana-derived cannabinoids57 have also been proposed to promote the apoptotic death of cancer cells acting independently of the cb1 and cb2 receptors
  • In cancer cells, cannabinoids block the activation of the vascular endothelial growth factor (vegf) pathway, an inducer of angiogenesi
  • In vascular endothelial cells, cannabinoid receptor activation inhibits proliferation and migration, and induces apoptosis
  • cb1 or cb2 receptor agonists (or both) reduce the formation of distant tumour masses in animal models of both induced and spontaneous metastasis, and inhibit adhesion, migration, and invasiveness of glioma64, breast65,66, lung67,68, and cervical68 cancer cells in culture
  • the ceramide/p8–regulated pathway plays a general role in the antitumour activity of cannabinoids targeting cb1 and cb2
  • cbd, by acting independently of the cb1 and cb2 receptors, produces a remarkable anti-tumour effect—including reduction of invasiveness and metastasis
  • cannabinoids can also enhance immune system–mediated tumour surveillance in some contexts
  • ability of thc to reduce inflammation75,76, an effect that might prevent certain types of cancer
  • recent observations suggest that the combined administration of cannabinoids with other anticancer drugs acts synergistically to reduce tumour growth
  • combined administration of gemcitabine (the benchmark agent for the treatment of pancreatic cancer) and various cannabinoid agonists synergistically reduced the viability of pancreatic cancer cells
  • Other reports indicated that anandamide and HU-210 might also enhance the anticancer activity of paclitaxel89 and 5-fluorouracil90 respectively
  • Combined administration of thc and cbd enhances the anticancer activity of thc and reduces the dose of thc needed to induce its tumour growth-inhibiting activity
  • Preclinical animal models have yielded data indicating that systemic (oral or intraperitoneal) administration of cannabinoids effectively decreases tumour growth
  • Combinations of cannabinoids with classical chemotherapeutic drugs such as the alkylating agent temozolomide (the benchmark agent for the management of glioblastoma80,84) have been shown to produce a strong anticancer action in animal models
  • pharmacologic inhibition of egfr, erk83, or akt enhances the cell-death-promoting action of thc in glioma cultures (unpublished observations by the authors), which suggests that targeting egfr and the akt and erk pathways could enhance the antitumour effect of cannabinoids
  • Nathan Goodyear on 18 Sep 18
     
    Good review of the anticancer effects of cananbinoids.
Nathan Goodyear

Omega-3 Fatty Acids and Inflammatory Processes - 0 views

www.ncbi.nlm.nih.gov/...PMC3257651

fats nutrition diet omega 3 inflammation NF-kappaB TNF-alpha omega-3 fish oil DHA EPA docosahexaenoic acid eicosapentaenoic acid

shared by Nathan Goodyear on 15 Sep 17 - No Cached
  • marine n-3 PUFAs have also been shown to alter the production of inflammatory proteins including chemokines, cytokines, growth factors and matrix proteases
  • Two transcription factors that are likely to play a role in inflammation are nuclear factor κ B (NFκB) and PPAR-γ
  • NFκB is the principal transcription factor involved in upregulation of inflammatory cytokine, adhesion molecule and cyclooxygenase-2 genes
  • ...3 more annotations...
  • PPAR-γ, is believed to act in an anti-inflammatory manner
  • PPAR-γ directly regulates inflammatory gene expression, it also interferes with the activation of NFκB creating an intriguing interaction between these two transcription factors
  • Both NFκB and PPAR-γ may be regulated by n-3 PUFAs.
  • Nathan Goodyear on 15 Sep 17
     
    great review of the anti-inflammatory effects of omega 3 DHA and EPA.  EPA inhibits COX and 5-LOX and their downstream prostaglandin and leukotrienes.  EPA/DHA inhibited endotoxin-stimulated IL-6, IL-8,TNF-alpha, and NFkappaB.
Nathan Goodyear

Niclosamide Suppresses Cancer Cell Growth By Inducing Wnt Co-Receptor LRP6 De... - 0 views

www.ncbi.nlm.nih.gov/...PMC3241710

Niclosamide cancer Wnt

shared by Nathan Goodyear on 21 Mar 18 - No Cached
  • Wnt/β-catenin signaling plays an important role in embryonic development and can lead to tumor formation when aberrantly activated.
  • Compelling evidence has indicated that there is an abnormal up-regulation of this pathway in tumorigenesis of many types of cancer
  • disruption of Wnt/β-catenin signaling represents a great opportunity to develop novel drugs for cancer chemoprevention and therapy
  • ...2 more annotations...
  • Niclosamide (trade name Niclocide) is a teniacide in the antihelmintic family that is especially effective against cestodes, which infects humans. Niclosamide has been FDA approved for such indications and has been used in humans for nearly 50 years
  • We demonstrated for the first time that niclosamide can inhibit Wnt/β-catenin signaling by inducing LRP6 degradation, and that this activity is closely associated with its antiproliferative and apoptosis inducing activity.
  • Nathan Goodyear on 21 Mar 18
     
    Niclosamide, an old anti-parasitic drug, found to inhibit the Wnt/B-catenin pathways so critical to cancer growth.  This triggers apoptosis of the cancer cell.
Nathan Goodyear

Antineoplastic Mechanisms of Niclosamide in Acute Myelogenous Leukemia Stem C... - 0 views

cancerres.aacrjournals.org/...2516

Niclosamide cancer leukemia NF-kappaB ROS TNF tumor necrosis factor

shared by Nathan Goodyear on 21 Mar 18 - No Cached
  • Here, we report on niclosamide as an antileukemic agent with two independent antineoplastic mechanisms: NF-κB pathway inactivation and ROS generation
  • In this report, we validated the inhibitory action of niclosamide against tumor necrosis factor (TNF)–induced NF-κB activation in AML cells and identified its mechanism, together with generation of reactive oxygen species (ROS), as being responsible for induced apoptosis of AML cells
  • NF-κB plays a critical role in inflammation, antiapoptotic responses, and carcinogenesis
  • ...8 more annotations...
  • pharmacologic inhibition of NF-κB was effective in killing AML cells
  • High NF-κB expression is found in primitive human AML blast cells
  • niclosamide inhibited the TNF-induced NF-κB reporter activity in a dose- and time-dependent manner
  • niclosamide inhibiting TNF-induced IKK phosphorylation (Fig. 2A), niclosamide may exert its inhibitory effect at the TAK1 step
  • Pretreatment with niclosamide completely blocked the time- and dose-dependent TNFα-induced alteration of the NF-κB–DNA complex
  • niclosamide inhibited constitutively active NF-κB binding to DNA in U266 cells
  • niclosamide completely abolished the TNFα-induced phosphorylation of IKKα/β and IκBα
  • Accordingly, the TNFα-induced degradation of IκBα was abrogated by niclosamide
  • Nathan Goodyear on 21 Mar 18
     
    Old anti-parasitic medication, niclosamide, found to have anti-leukemic acitivty through inactivation of NF-kappaB and increase in ROS production in in Vitro and in Vivo study.
Nathan Goodyear

Oncotarget | Preclinical evaluation of a nanoformulated antihelminthic, niclosamide, in... - 0 views

www.oncotarget.com/index.php

Niclosamide cancer ovarian cancer

shared by Nathan Goodyear on 16 Apr 18 - No Cached
  • Ovarian cancer is the most lethal gynecologic malignancy in the world
  • paclitaxel represents a breakthrough in the treatment of ovarian cancer, the overall 5-year survival rate of patients with stage III disease is still approximately 40%
  • Targeting cancer stem cells is an emerging concept in cancer therapy
  • ...8 more annotations...
  • Ovarian cancer stem cells play an important role in chemoresistance and cancer recurrence
  • Furthermore, recent studies indicate that niclosamide exhibits anticancer effects against various human cancer cells by acting on multiple cell signaling pathways and inducing mitochondrial uncoupling [16–21]
  • has low systemic bioavailability (~10%) when administered orally, which is beneficial for treating local parasitic infections of the intestines while minimizing systemic exposure
  • The nano-NI demonstrated significantly higher inhibitory effects on sphere formation than the original niclosamide did
  • the nano-NI formulation decreased the metabolic activity of ovarian cancer cells and caused a metabolic shift from oxidative phosphorylation to glycolysis
  • This toxicity evaluation showed that oral nano-NI had no toxic effect on either group of mice in terms of weight, plasma albumin levels, and blood cell counts, and revealed no adverse effects on vital organ function in the rodents, which suggests that nano-NI is safe for animals
  • niclosamide inhibits tumor cell growth by interrupting multiple pathways (Wnt, Notch, STAT3, NF-κB, and mTORc1) and the generation of reactive oxygen species in several cancer cells
  • The current standard therapy for ovarian cancer includes taxanes and platinum-based chemotherapy after cytoreductive surgery. Among treated patients, nearly 70 to 80% will experience disease recurrence
  • Nathan Goodyear on 16 Apr 18
     
    nano-Niclosamide more effective than traditional Niclosamide in in vitro and in vivo ovarian cancer.
Nathan Goodyear

Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer - 0 views

www.ncbi.nlm.nih.gov/...PMC4537815

cancer pancreatic cancer IV vitamin C vitamin c radiation

shared by Nathan Goodyear on 30 Jan 18 - No Cached
  • Previous studies from our laboratory have demonstrated that pharmacological ascorbate is cytotoxic to pancreatic cancer cells while normal cells are resistant
  • Ascorbate-induced cytotoxicity is mediated by the formation of H2O2 during the oxidation of ascorbate
  • the combination of IR + ascorbate increased the concentration of intracellular H2O2
  • ...17 more annotations...
  • Under steady-state conditions, intracellular GSH is maintained at millimolar concentrations, which keeps cells in a reduced environment and serves as the principal intracellular redox buffer when cells are subjected to an oxidative stressor including H2O2 (26). Glutathione peroxidase (GPx) activity catalyzes the reduction of H2O2 to water with the conversion of GSH to glutathione disulfide (GSSG). Under steady-state conditions, GSSG is recycled back to GSH by glutathione disulfide reductase using reducing equivalents from NADPH. However, under conditions of increased H2O2 flux, this recycling mechanism may become overwhelmed leading to a depletion of intracellular GSH (27, 28).
  • ascorbate radiosensitization can create an overwhelming oxidative stress to pancreatic cancer cells resulting in oxidation/depletion of the GSH intracellular redox buffer, resulting in cell death.
  • Treatment with the combination of ascorbate + IR significantly delayed tumor growth compared to controls or ascorbate alone
  • Ascorbate + IR also significantly increased overall survival compared to controls, IR alone or ascorbate alone
  • 54% of mice treated with the combination of IR + ascorbate had no measurable tumors
  • Glutathione is a measurable marker indicative of the oxidation state of the thiol redox buffer in cells. In severe systemic oxidative stress, the GSSG/2GSH couple may become oxidized, i.e. the concentration of GSH decreases and GSSG may increase because the capacity to recycle GSSG to GSH becomes rate-limiting
  • This suggests that the very high levels of pharmacological ascorbate in these experiments may have a pro-oxidant toward red blood cells as seen by a decrease in the capacity of the intracellular redox buffer
  • These data support the hypothesis that ascorbate radiosensitization does not cause an increase in oxidative damage from lipid-derived aldehydes to other organs.
  • Our current study demonstrates the potential for pharmacological ascorbate as a radiosensitizer in the treatment of pancreatic cancer.
  • pharmacological ascorbate enhances IR-induced cell killing and DNA fragmentation leading to induction of apoptosis in HL60 leukemia cells
  • pharmacological ascorbate significantly decreases clonogenic survival and inhibits the growth of all pancreatic cancer cell lines as a single agent, as well as sensitizes cancer cells to IR
  • Hurst et al. demonstrated that pharmacological ascorbate combined with IR leads to increased numbers of double-strand DNA breaks and cell cycle arrest when compared to either treatment alone
  • pharmacological ascorbate could serve as a “pro-drug” for the delivery of H2O2 to tumors
  • the double-strand breaks induced by H2O2 were more slowly repaired
  • The combination of ascorbate and IR provide two distinct mechanisms of action: ascorbate-induced toxicity due to extracellular production of H2O2 that then diffuses into cells and causes damage to DNA, protein, and lipids; and radiation-induced toxicity as a result of ROS-induced damage to DNA. In addition, redox metal metals like Fe2+ may play an important role in ascorbate-induced cytotoxicity. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of H2O2; labile iron can also react with H2O2. Recently our group has demonstrated that pharmacological ascorbate and IR increase the labile iron in tumor homogenates from this murine model of pancreatic cancer
  • we demonstrated that ascorbate or IR alone decreased tumor growth, but the combination treatment further inhibited tumor growth, indicating that pharmacological ascorbate is an effective radiosensitizer in vivo
  • data suggest that pharmacological ascorbate may protect the gut locally by decreasing IR-induced damage to the crypt cells, and systemically, by ameliorating increases in TNF-α
  • Nathan Goodyear on 30 Jan 18
     
    IV vitamin C effective as radiosensitizer in pancreatic cancer.
Nathan Goodyear

Nutrients | Free Full-Text | Vitamin C Status Correlates with Markers of Metabolic and ... - 0 views

www.mdpi.com/...htm

vitamin C health cognition

shared by Nathan Goodyear on 28 Feb 18 - No Cached
  • vitamin C deficiency is the fourth most prevalent nutrient deficiency reported in the United States
  • Hypovitaminosis C (defined as a plasma concentration ≤23 µmol/L)
  • The CHALICE (Canterbury Health, Ageing and Lifecourse) study is a unique New Zealand study comprising a comprehensive database of determinants of health
  • ...17 more annotations...
  • The CHALICE cohort of 404 individuals aged 50 years had an average vitamin C intake of ~110 mg/day, which should provide adequate plasma concentrations [14]. Despite this, a significant proportion of the participants had inadequate plasma vitamin C status
  • inadequate plasma vitamin C concentrations (i.e., <50 µmol/L)
  • adequate plasma levels (i.e., >50 µmol/L)
  • Higher plasma vitamin C status was associated with lower weight, BMI and waist circumference
  • plasma vitamin C was negatively associated with blood triglycerides, HbA1c and insulin, and positively associated with HDL levels.
  • No correlation was found between plasma vitamin C and the two indicators of heart health; blood pressure and cardiovascular risk score.
  • 2.4% of 50-year-olds were deficient in vitamin C (i.e., <11 µmol/L)
  • hypovitaminosis C (i.e., <23 µmol/L)
  • A high proportion (63%) of our participants had inadequate plasma vitamin C concentrations (i.e., <50 µmol/L)
  • The association of low vitamin C with obesity in this study replicates results in the literature [35,40,41,42,43,44], and it is apparent that individuals with higher weight require higher intakes of vitamin C to reach adequate vitamin C status
  • higher plasma vitamin C status is associated with lower circulating levels of blood triglycerides, insulin and HbA1c
  • A role for vitamin C in the prevention or management of diabetes and/or metabolic syndrome has been suggested
  • In this study, we also demonstrate lower levels of mild cognitive impairment in those with high vitamin C status
  • The odds of mild cognitive impairment were twice as high for those below 23 μmol/L plasma vitamin C concentration.
  • Vitamin C is present at very high concentrations in the brain
  • animal models have shown that the brain is the last organ to be depleted of the vitamin during prolonged deficiency
  • A recent animal study has shown that moderate vitamin C deficiency may play a role in accelerating amyloid plaque accumulation in Alzheimer’s disease
  • Nathan Goodyear on 28 Feb 18
     
    New study: vitamin C levels correlate with cognitive and metabolic health. What is your vitamin C level? Despite the adequate levels of vitamin C intake, a large % of the individuals had inadequate vitamin C levels which points to a demand issue.  Higher oxidative stress, chronic inflammation... would drive demand for vitamin C higher. Lower vitamin C levels were associated with more metabolic disease, ie. DM, and more cognitive decline.
Nathan Goodyear

Press-pulse: a novel therapeutic strategy for the metabolic management of cancer | Nutr... - 0 views

nutritionandmetabolism.biomedcentral.com/...s12986-017-0178-2

ketogenic diet ketogenic press-pulse hyperbaric oxygen therapy HBOTnutrition diet cancer HBOT IVC IV vitamin C DCA dichloracetic acid cancer therapy cancer treatment alternative cancer treatment

shared by Nathan Goodyear on 09 Jul 17 - No Cached
mamdouh_hfz liked it
  • A “press” disturbance was considered a chronic environmental stress on all organisms in an ecological community
  • “pulse” disturbances were considered acute events that disrupted biological communities to produce high mortality
  • Neoplasia involving dysregulated cell growth is the biological endpoint of the disease
  • ...84 more annotations...
  • Data from the American Cancer Society show that the rate of increase in cancer deaths/year (3.4%) was two-fold greater than the rate of increase in new cases/year (1.7%) from 2013 to 2017
  • cancer is predicted to overtake heart disease as the leading cause of death in Western societies
  • cancer can also be recognized as a metabolic disease.
  • glucose is first split into two molecules of pyruvate through the Embden–Meyerhof–Parnas glycolytic pathway in the cytosol
  • Aerobic fermentation, on the other hand, involves the production of lactic acid under normoxic conditions
  • persistent lactic acid production in the presence of adequate oxygen is indicative of abnormal respiration
  • Otto Warburg first proposed that all cancers arise from damage to cellular respiration
  • The Crabtree effect is an artifact of the in vitro environment and involves the glucose-induced suppression of respiration with a corresponding elevation of lactic acid production even under hyperoxic (pO2 = 120–160 mmHg) conditions associated with cell culture
  • the Warburg theory of insufficient aerobic respiration remains as the most credible explanation for the origin of tumor cells [2, 37, 51, 52, 53, 54, 55, 56, 57].
  • The main points of Warburg’s theory are; 1) insufficient respiration is the predisposing initiator of tumorigenesis and ultimately cancer, 2) energy through glycolysis gradually compensates for insufficient energy through respiration, 3) cancer cells continue to produce lactic acid in the presence of oxygen, and 4) respiratory insufficiency eventually becomes irreversible
  • Efraim Racker coined the term “Warburg effect”, which refers to the aerobic glycolysis that occurs in cancer cells
  • Warburg clearly demonstrated that aerobic fermentation (aerobic glycolysis) is an effect, and not the cause, of insufficient respiration
  • all tumor cells that have been examined to date contain abnormalities in the content or composition of cardiolipin
  • The evidence supporting Warburg’s original theory comes from a broad range of cancers and is now overwhelming
  • respiratory insufficiency, arising from any number mitochondrial defects, can contribute to the fermentation metabolism seen in tumor cells.
  • data from the nuclear and mitochondrial transfer experiments suggest that oncogene changes are effects, rather than causes, of tumorigenesis
  • Normal mitochondria can suppress tumorigenesis, whereas abnormal mitochondria can enhance tumorigenesis
  • In addition to glucose, cancer cells also rely heavily on glutamine for growth and survival
  • Glutamine is anapleurotic and can be rapidly metabolized to glutamate and then to α-ketoglutarate for entry into the TCA cycle
  • Glucose and glutamine act synergistically for driving rapid tumor cell growth
  • Glutamine metabolism can produce ATP from the TCA cycle under aerobic conditions
  • Amino acid fermentation can generate energy through TCA cycle substrate level phosphorylation under hypoxic conditions
  • Hif-1α stabilization enhances aerobic fermentation
  • targeting glucose and glutamine will deprive the microenvironment of fermentable fuels
  • Although Warburg’s hypothesis on the origin of cancer has created confusion and controversy [37, 38, 39, 40], his hypothesis has never been disproved
  • Warburg referred to the phenomenon of enhanced glycolysis in cancer cells as “aerobic fermentation” to highlight the abnormal production of lactic acid in the presence of oxygen
  • Emerging evidence indicates that macrophages, or their fusion hybridization with neoplastic stem cells, are the origin of metastatic cancer cells
  • Radiation therapy can enhance fusion hybridization that could increase risk for invasive and metastatic tumor cells
  • Kamphorst et al. in showing that pancreatic ductal adenocarcinoma cells could obtain glutamine under nutrient poor conditions through lysosomal digestion of extracellular proteins
  • It will therefore become necessary to also target lysosomal digestion, under reduced glucose and glutamine conditions, to effectively manage those invasive and metastatic cancers that express cannibalism and phagocytosis.
  • Previous studies in yeast and mammalian cells show that disruption of aerobic respiration can cause mutations (loss of heterozygosity, chromosome instability, and epigenetic modifications etc.) in the nuclear genome
  • The somatic mutations and genomic instability seen in tumor cells thus arise from a protracted reliance on fermentation energy metabolism and a disruption of redox balance through excess oxidative stress.
  • According to the mitochondrial metabolic theory of cancer, the large genomic heterogeneity seen in tumor cells arises as a consequence, rather than as a cause, of mitochondrial dysfunction
  • A therapeutic strategy targeting the metabolic abnormality common to most tumor cells should therefore be more effective in managing cancer than would a strategy targeting genetic mutations that vary widely between tumors of the same histological grade and even within the same tumor
  • Tumor cells are more fit than normal cells to survive in the hypoxic niche of the tumor microenvironment
  • Hypoxic adaptation of tumor cells allows for them to avoid apoptosis due to their metabolic reprograming following a gradual loss of respiratory function
  • The high rates of tumor cell glycolysis and glutaminolysis will also make them resistant to apoptosis, ROS, and chemotherapy drugs
  • Despite having high levels of ROS, glutamate-derived from glutamine contributes to glutathione production that can protect tumor cells from ROS
    • Nathan Goodyear
      Nathan Goodyear on 08 Feb 18
       
      reason to eliminate glutamine in cancer patients and even GSH with cancer patients
  • It is clear that adaptability to environmental stress is greater in normal cells than in tumor cells, as normal cells can transition from the metabolism of glucose to the metabolism of ketone bodies when glucose becomes limiting
  • Mitochondrial respiratory chain defects will prevent tumor cells from using ketone bodies for energy
  • glycolysis-dependent tumor cells are less adaptable to metabolic stress than are the normal cells. This vulnerability can be exploited for targeting tumor cell energy metabolism
  • In contrast to dietary energy reduction, radiation and toxic drugs can damage the microenvironment and transform normal cells into tumor cells while also creating tumor cells that become highly resistant to drugs and radiation
  • Drug-resistant tumor cells arise in large part from the damage to respiration in bystander pre-cancerous cells
  • Because energy generated through substrate level phosphorylation is greater in tumor cells than in normal cells, tumor cells are more dependent than normal cells on the availability of fermentable fuels (glucose and glutamine)
  • Ketone bodies and fats are non-fermentable fuels
  • Although some tumor cells might appear to oxidize ketone bodies by the presence of ketolytic enzymes [181], it is not clear if ketone bodies and fats can provide sufficient energy for cell viability in the absence of glucose and glutamine
  • Apoptosis under energy stress is greater in tumor cells than in normal cells
  • A calorie restricted ketogenic diet or dietary energy reduction creates chronic metabolic stress in the body
  • . This energy stress acts as a press disturbance
  • Drugs that target availability of glucose and glutamine would act as pulse disturbances
  • Hyperbaric oxygen therapy can also be considered another pulse disturbance
  • The KD can more effectively reduce glucose and elevate blood ketone bodies than can CR alone making the KD potentially more therapeutic against tumors than CR
  • Campbell showed that tumor growth in rats is greater under high protein (>20%) than under low protein content (<10%) in the diet
  • Protein amino acids can be metabolized to glucose through the Cori cycle
  • The fats in KDs used clinically also contain more medium chain triglycerides
  • Calorie restriction, fasting, and restricted KDs are anti-angiogenic, anti-inflammatory, and pro-apoptotic and thus can target and eliminate tumor cells through multiple mechanisms
  • Ketogenic diets can also spare muscle protein, enhance immunity, and delay cancer cachexia, which is a major problem in managing metastatic cancer
  • GKI values of 1.0 or below are considered therapeutic
  • The GKI can therefore serve as a biomarker to assess the therapeutic efficacy of various diets in a broad range of cancers.
  • It is important to remember that insulin drives glycolysis through stimulation of the pyruvate dehydrogenase complex
  • The water-soluble ketone bodies (D-β-hydroxybutyrate and acetoacetate) are produced largely in the liver from adipocyte-derived fatty acids and ketogenic dietary fat. Ketone bodies bypass glycolysis and directly enter the mitochondria for metabolism to acetyl-CoA
  • Due to mitochondrial defects, tumor cells cannot exploit the therapeutic benefits of burning ketone bodies as normal cells would
  • Therapeutic ketosis with racemic ketone esters can also make it feasible to safely sustain hypoglycemia for inducing metabolic stress on cancer cells
    • Nathan Goodyear
      Nathan Goodyear on 08 Feb 18
       
      Ketones are much more than energy adaptabilit, but actually are therapeutic.
  • ketone bodies can inhibit histone deacetylases (HDAC) [229]. HDAC inhibitors play a role in targeting the cancer epigenome
  • Therapeutic ketosis reduces circulating inflammatory markers, and ketones directly inhibit the NLRP3 inflammasome, an important pro-inflammatory pathway linked to carcinogenesis and an important target for cancer treatment response
  • Chronic psychological stress is known to promote tumorigenesis through elevations of blood glucose, glucocorticoids, catecholamines, and insulin-like growth factor (IGF-1)
  • In addition to calorie-restricted ketogenic diets, psychological stress management involving exercise, yoga, music etc. also act as press disturbances that can help reduce fatigue, depression, and anxiety in cancer patients and in animal models
  • Ketone supplementation has also been shown to reduce anxiety behavior in animal models
  • This physiological state also enhances the efficacy of chemotherapy and radiation therapy, while reducing the side effects
  • lower dosages of chemotherapeutic drugs can be used when administered together with calorie restriction or restricted ketogenic diets (KD-R)
  • Besides 2-DG, a range of other glycolysis inhibitors might also produce similar therapeutic effects when combined with the KD-R including 3-bromopyruvate, oxaloacetate, and lonidamine
    • Nathan Goodyear
      Nathan Goodyear on 08 Feb 18
       
      oxaloacetate is a glycolytic inhibitor, as is doxycycline, and IVC.
  • A synergistic interaction of the KD diet plus radiation was seen
  • It is important to recognize, however, that the radiotherapy used in glioma patients can damage the respiration of normal cells and increase availability of glutamine in the microenvironment, which can increase risk of tumor recurrence especially when used together with the steroid drug dexamethasone
  • Poff and colleagues demonstrated that hyperbaric oxygen therapy (HBOT) enhanced the ability of the KD to reduce tumor growth and metastasis
  • HBOT also increases oxidative stress and membrane lipid peroxidation of GBM cells in vitro
  • The effects of the KD and HBOT can be enhanced with administration of exogenous ketones, which further suppressed tumor growth and metastasis
  • Besides HBOT, intravenous vitamin C and dichloroacetate (DCA) can also be used with the KD to selectively increase oxidative stress in tumor cells
  • Recent evidence also shows that ketone supplementation may enhance or preserve overall physical and mental health
  • Some tumors use glucose as a prime fuel for growth, whereas other tumors use glutamine as a prime fuel [102, 186, 262, 263, 264]. Glutamine-dependent tumors are generally less detectable than glucose-dependent under FDG-PET imaging, but could be detected under glutamine-based PET imaging
  • GBM and use glutamine as a major fuel
  • Many of the current treatments used for cancer management are based on the view that cancer is a genetic disease
  • Emerging evidence indicates that cancer is a mitochondrial metabolic disease that depends on availability of fermentable fuels for tumor cell growth and survival
  • Glucose and glutamine are the most abundant fermentable fuels present in the circulation and in the tumor microenvironment
  • Low-carbohydrate, high fat-ketogenic diets coupled with glycolysis inhibitors will reduce metabolic flux through the glycolytic and pentose phosphate pathways needed for synthesis of ATP, lipids, glutathione, and nucleotides
  • Nathan Goodyear on 09 Jul 17
     
    Cancer is a mitochondrial disease? So says the well published Dr Seyfried. Glucose and glutamine drive cancer growth.
Nathan Goodyear

Curcumin Down-Regulates DNA Methyltransferase 1 and Plays an Anti-Leukemic Role in Acut... - 0 views

www.ncbi.nlm.nih.gov/...PMC3572185

aml acute myeloid leukemia cancer leukemia curcumin NF-kappaB

shared by Nathan Goodyear on 12 May 18 - No Cached
  • In a variety of solid tumors and blood cancers, aberrant hypermethylation of CpG-rich regions (>55% CG content, 0.5-4 kb in length, the so-called “CpG islands”) in the promoters of tumor suppressor genes (TSGs) results in their transcriptional silencing
  • These agents have been reported to suppress tumor growth by reversing aberrantly hypermethylation in the promoters of inactivated TSGs (e.g. p15INK4B), allowing re-expression of TSGs, thereby restoring normal cell cycle regulation, proliferation, apoptosis, and differentiation
  • groups have reported that curcumin acts as a scavenger of free radicals [13], an inhibitor of NF-κB nuclear translocation [14], and a modulator of histone deacetylase (HDAC) and histone acetyltransferase (HAT)
  • ...9 more annotations...
  • In this study, we found that curcumin down-regulated DNMT1 expression in AML cells. This occurred, at least in part, through down-modulation of two positive regulators of DNMT1: Sp1 and the NF-κB component, p65. We also found that curcumin-mediated down-regulation of DNMT1 was associated with reactivation of TSGs and tumor suppression, both in vivo and in vitro.
  • curcumin may selectively downregulate DNMT1 expression in tumor cells, but not in normal cells
  • DNMT1 expression is positively regulated by Sp1 and the NF-κB signaling component
  • indicating that curcumin may have significant anti-tumor activity in AML
  • We found that, compared to the vehicle control, curcumin treatment reduced tumor weight by 70%
  • Surprisingly, although curcumin significantly inhibited tumor growth in these mice, we were unable to find any obvious toxicity associated with curcumin treatment
  • Consistent with our observations regarding curcumin’s ability to inhibit tumor growth in vivo (Figure 4) and down-regulate DNMT1 expression in vitro and ex vivo (Figure 1), we found that decreased levels of DNMT1 protein and mRNA were expressed by tumor cells isolated from curcumin-treated mice
  • we identified curcumin as a substance which acts as an inhibitor of DNA methyltransferase enzymatic activity and induces significant global DNA hypomethylation in AML cells
  • In this study, we first demonstrated that curcumin decreases DNMT1 mRNA and protein expression levels, most likely through inhibiting expression of positive regulators of DNMT1, such as Sp1 and the p65 component of NF-κB component, and/or altering their ability to bind to the promoter region of DNMT1
  • Nathan Goodyear on 12 May 18
     
    Curcumin beneficial in AML
Nathan Goodyear

Curcumin Down-Regulates DNA Methyltransferase 1 and Plays an Anti-Leukemic Role in Acut... - 0 views

journals.plos.org/...article

aml acute myeloid leukemia curcumin cancer leukemia

shared by Nathan Goodyear on 12 May 18 - No Cached
  • Nathan Goodyear on 12 May 18
     
    curcumin beneficial in AML
Nathan Goodyear

High Progesterone Receptor Expression in Prostate Cancer Is Associated with Clinical Fa... - 0 views

www.ncbi.nlm.nih.gov/...PMC4344236

prostate cancer progesterone progesterone receptor hormones cancer prostate

shared by Nathan Goodyear on 03 Jun 18 - No Cached
  • Currently, there is a general agreement of PGR presence in the stromal cells of PCa
  • expressed in both stromal and tumor cells of the PCa tissue
  • In univariate analysis, a high density level of PGR in both TE and TS was associated with CF
  • ...17 more annotations...
  • High density level of PGR in the TE was an independent prognostic factor for CF.
  • Our large-sized study demonstrates a wide distribution of PGR in stromal and epithelial cells of both benign and malignant prostate tissue
  • there seems to be a general agreement of PGR presence in the stromal cells of PCa
  • In line with our findings, several have also reported a high PGR expression in TE of PCa [9,10,23,25]. In contrast, others have demonstrated a total lack of PGR expression in TE
  • the actions of progesterone are tissue specific
  • In our work univariate analysis demonstrated a high PGR expression in TS to be associated with clinical failure in PCa patients. So far we have not yet demonstrated the mechanism underlying this association
  • Several non-genomic proliferative actions of progesterone have been proposed in tumor cells of other organs, including breast [35–37], astrocytoma [38] and osteosarcoma [39] cell lines. However, such results are contradicted by suggestions of anti-proliferative actions of progesterone in endometrial cancer
  • Yu et al. found PGR to be negatively regulating stromal cell proliferation in vitro
  • high PGR density level in TE was associated with CF in patients with Gleason score ≥ 7
  • Bonkhoff et al. have suggested progressive emergence of PGR during PCa progression and metastasis
  • Latil and co-workers found a decreased PGR expression in clinically localized tumors and increased PGR expression in hormone-refractory tumors, when compared with normal prostate tissue
  • Our findings provide further support to these findings, indicating that PGR plays a role in the pathogenesis of PCa
  • Ki67 and PGR in TE were correlated with CF (S3 Text), indicating an association between PGR and proliferative activity
  • The mechanism behind the PGR up-regulation in PCa has not yet been elucidated
  • The PGR is, like the glucocorticoid receptor, similar to androgen receptor with 88% sequence homology in the ligand-binding domain
  • progesterone induced expression of androgen receptor-regulated genes could be a potential mechanism contributing to the development of castrate resistant PCa
  • A possibility of different roles by the two PGR isoforms in normal prostate tissue and PCa, as is suggested for the estrogen receptors [13], must also be taken into account
  • Nathan Goodyear on 03 Jun 18
     
    STudy finds that increased Progesterone receptor expression on epithelial and stromal cells is associated with increased clinical failure of therapy.  Several proposed mechanisms: 88% homologous with androgen receptor suggesting cross-stimulation and via progesterone induced increased androgen receptor gene stimulation i.e. epigenetics.
Nathan Goodyear

Development of PD-1/PD-L1 Pathway in Tumor Immune Microenvironment and Treatment for No... - 0 views

www.nature.com/...srep13110

PD-1 cancer check point inhibitors PD-L1 CLTA-4 immunotherapy

shared by Nathan Goodyear on 20 Apr 18 - No Cached
  • the lack of immunologic control is recognized as a hallmark of cancer currently
  • Programmed death-1 (PD-1) and its ligand PD-L1 play a key role in tumor immune escape and the formation of tumor microenvironment, closely related with tumor generation and development
  • Blockading the PD-1/PD-L1 pathway could reverse the tumor microenvironment and enhance the endogenous antitumor immune responses.
  • ...4 more annotations...
  • environmental factors, living habits, genetic mutations, dysfunction of the immune system and so on
  • special tumor immune microenvironment
  • cytotoxic T lymphocyte-associated antigen 4 (CLTA-4), Programmed death-1 (PD-1) and its ligands PD-L1 (B7H1) and PD-L2 (B7-DC)
  • CTLA-4 regulates T cell activity in the early stage predominantly, and PD-1 mainly limits the activity of T-cell in the tumor microenvironment at later stage of tumor growth
  • Nathan Goodyear on 20 Apr 18
     
    PD-1 to read.
Nathan Goodyear

Overall survival of cancer patients with serum lactate dehydrogenase greater ... - 0 views

www.ncbi.nlm.nih.gov/...PMC5097084

LDH lactate dehydrogenase cancer

shared by Nathan Goodyear on 08 Jun 18 - No Cached
  • catalyzes the interconversion of pyruvate and lactate during glycolysis and gluconeogenesis
  • It has long been known that many human cancers have higher LDH levels than normal tissues
  • It has long been appreciated that LDH is a prognostic factor for survival
  • ...9 more annotations...
  • The serum level of LDH correlated with tumor burden and was thought to reflect the tumor’s growth and invasive potential
  • the majority of patients with advanced or metastatic disease could be detected to have extremely high serum level of LDH
  • strong evidence to support effective chemotherapy of full dose even in patients with high LDH level
  • LDH is a key enzyme in the process of energy production in cancer cells, it catalyzes the conversion of pyruvate to lactate in hypoxic conditions
  • its function in anaerobic metabolism, cancer cells grow even after their rapid proliferation that leads to low-oxygen conditions in the tumor microenvironment
  • LDH plays an important role in tumor progression and maintenance
  • inhibition of LDH inhibits tumor progression and has been considered for the therapeutic target of cancer energy metabolism
  • LDH levels are increased in response to tissue injury or during disease states
  • LDH could be a marker of tumor burden for advanced cancer patients
  • Nathan Goodyear on 08 Jun 18
     
    High LDH, defined as >1,000, found to be maker for very poor overall survival in retrospective study.
Nathan Goodyear

Prolactin and cancer: Has the orphan finally found a home? - 0 views

www.ncbi.nlm.nih.gov/...PMC3603025

prolactin cancer

shared by Nathan Goodyear on 19 Sep 18 - No Cached
  • Nathan Goodyear on 19 Sep 18
     
    Good review on prolactin and cancer.
Nathan Goodyear

Role of IL-2 in cancer immunotherapy: OncoImmunology: Vol 5, No 6 - 1 views

www.tandfonline.com/...2162402X.2016.1163462

IL-2 cancer immune system

shared by Nathan Goodyear on 17 Apr 18 - No Cached
  • IL-2 is one of the key cytokines with pleiotropic effects on the immune system
  • IL-2 as “T-cell growth factor”
  • approved for the treatment of metastatic renal cell carcinoma (1992) and later for metastatic melanoma (1998) by FDA
  • ...13 more annotations...
  • It is produced predominately by antigen-simulated CD4+ T cells, while it can also be produced by CD8+ cells, natural killer (NK) cells, and activated dendritic cells (DC)
  • IL-2 is an important factor for the maintenance of CD4+ regulatory T cells
  • plays a critical role in the differentiation of CD4+ T cells into a variety of subsets
  • It can promote CD8+ T-cell and NK cell cytotoxicity activity, and modulate T-cell differentiation programs in response to antigen, promoting naive CD4+ T-cell differentiation into T helper-1 (Th1) and T helper-2 (Th2) cells while inhibiting T helper-17 (Th17) differentiation
  • Of note, Tregs, which act to dampen the immune response, constitutively express high levels of α chain
  • IL-2Rα is unique to IL-2 and is expressed by a number of immune cells including T regulatory cells (Treg), activated CD4+ and CD8+T cells, B cells, mature DCs, endothelial cells
  • some investigators evaluated the efficacy of regimens containing low-dose IL-2
  • IL-2 can promote the activation and cell growth of T and NK cells
  • Unfortunately, not all of patients would benefit from targeted therapy and nearly all patients who initially respond to targeted inhibitors inevitably develop acquired resistance to the treatment
  • IL-2 also stimulates T-regulatory cells that constitutively express CTLA-4 and can suppress immune reactions. Hence, IL-2 might enhance antitumor reactivity in the presence of CTLA-4 blockade
  • both HD and low-dose IL-2 therapy preferentially induce the expansion of CD4+CD25+Foxp3+ Treg and the Treg level remains elevated after each cycle of HD IL-2 therapy
  • Due to rapid elimination and metabolism via the kidney, IL-2 has a short serum half-life of several minutes
  • HD IL-2-induced severe toxicities including vascular leak syndrome (VLS), pulmonary edema, hypotension, and heart toxicities
  • Nathan Goodyear on 17 Apr 18
     
    Great historical and functional role of IL-2 in the fight against cancer.
Nathan Goodyear

Ferritin Level Is Positively Associated with Chronic Kidney Disease in Korean Men, Base... - 0 views

www.ncbi.nlm.nih.gov/...PMC5129268

ferritin Iron kidney disease nutrition health

shared by Nathan Goodyear on 27 Sep 17 - No Cached
  • The overloading of body iron plays a role as an oxidative stressor
  • active radicals can affect lipids, proteins, and deoxyribonucleic acid (DNA), resulting in tissue injury and dysfunction
  • Excess iron causes oxidative stress and induces inflammation, leading to renal disease progression
  • ...4 more annotations...
  • Serum ferritin levels correlate with total body iron storage and systemic inflammation
  • The level of serum ferritin, an acute phase protein, is increased in an inflammatory environment
  • Previous studies have reported that elevated serum ferritin levels are associated with insulin resistance syndrome, hypertension, dyslipidemia, obesity, and metabolic syndrome as risk factors of CKD
  • elevated serum ferritin levels in hemodialysis patients predict higher mortality
  • Nathan Goodyear on 27 Sep 17
     
    great review and study: finds that elevated ferritin levels (> 200 ng/ml in men) was associated with increased chronic kidney disease in Korean study.
Nathan Goodyear

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

journals.plos.org/...article

epigenetics exercise training muscle SNPs PGC-1alpha

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

An integrative analysis reveals coordinated reprogramming of the epigenome and the tran... - 0 views

www.ncbi.nlm.nih.gov/...PMC4622000

exercise epigenetics muscle

shared by Nathan Goodyear on 03 Oct 17 - No Cached
  • contribution to the training response of the epigenome as a mediator between genes and environment
  • Differential DNA methylation was predominantly observed in enhancers, gene bodies and intergenic regions and less in CpG islands or promoters
  • highly consistent and associated modifications in methylation and expression, concordant with observed health-enhancing phenotypic adaptations, are induced by a physiological stimulus
  • ...34 more annotations...
  • The health benefits following exercise training are elicited by gene expression changes in skeletal muscle, which are fundamental to the remodeling process
  • there is increasing evidence that more short-term environmental factors can influence DNA methylation
  • dietary factors have the potency to alter the degree of DNA methylation in different tissues, 9,10 including skeletal muscle
  • In one study, a single bout of endurance-type exercise was shown to affect methylation at a few promoter CpG sites
  • In the context of diabetes, exercise training has been shown to affect genome-wide methylation pattern in skeletal muscle,13 as well as in adipose tissue.
  • physiological stressors can indeed affect DNA methylation
  • training intervention reshapes the epigenome and induces significant changes in DNA methylation
  • the findings from this tightly controlled human study strongly suggest that the regulation and maintenance of exercise training adaptation is to a large degree associated to epigenetic changes, especially in regulatory enhancer regions
  • Endurance training [after training (T2) vs. before training (T1)] induced significant (false discovery rate, FDR< 0.05) methylation changes at 4919 sites across the genome in the trained leg
  • identified 4076 differentially expressed genes
  • a complementary approach revealed that over 600 CpG sites correlated to the increase in citrate synthase activity, an objective measure of training response (Figure S4 and Dataset S14). This might imply that some of these sites could influence the degree of training response.
  • As expected by a physiological environmental trigger on adult tissue, the observed effect size on DNA methylation was small in comparison to disease states such as cancer
  • a preferential localization outside of CpG Islands/Shelves/Shores
  • endurance training especially influences enhancers
  • negative correlation was more prominent for probes in promoter/5′UTR/1st exon regions, while gene bodies had a stronger peak of positive correlation
  • The significant changes in DNA methylation, that primarily occurred in enhancer regions, were to a large extent associated with relevant changes in gene expression
  • The main findings of this study were that 3 months of endurance training in healthy human volunteers induced significant methylation changes at almost 5000 sites across the genome and significant differential expression of approximately 4000 genes
  • DMPs that increased in methylation were mainly associated to structural remodeling of the muscle and glucose metabolism, while the DMPs with decreased methylation were associated to inflammatory/immunological processes and transcriptional regulation
  • This suggests that the changes in methylation seen with training were not a random effect across the genome but rather a controlled process that likely contributes to skeletal muscle adaptation to endurance training
  • Correlation of the changes in DNA methylation to the changes in gene expression showed that the majority of significant methylation/expression pairs were found in the groups representing either increases in expression with a concomitant decrease in methylation or vice versa
  • The fraction of genes showing both significant decrease in methylation and upregulation was 7.5% of the DEGs or 2.3% of all genes detected in muscle tissue with at least one measured DNA methylation position. Correspondingly, 7.0% of the DEGs or 2.1% of all genes showed both significant increase in methylation and downregulation
  • we show that DNA methylation changes are associated to gene expression changes in roughly 20% of unique genes that significantly changed with training
  • Examples of structural genes include COL4A1, COL4A2 and LAMA4. These genes have also been identified as important for differences in responsiveness to endurance training
  • methylation status could be part of the mechanism behind variable training response
  • Among the metabolic genes, MDH1 catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the citric acid cycle and NDUFA8 plays an important role in transferring electrons from NADH to the respiratory chain
  • PPP1R12A,
  • In the present study, methylation predominantly changed in enhancer regions with enrichment for binding motifs for different transcription factors suggesting that enhancer methylation may be highly relevant also in exercise biology
  • Of special interest in the biology of endurance training may be that MRFs, through binding to the PGC-1α core promoter, can regulate this well-studied co-factor for mitochondrial biogenesis
  • That endurance training led to an increased methylation in enhancer regions containing motifs for the MRFs and MEFs is somewhat counterintuitive since it should lead to the repression of the action of the above discussed transcription factors
  • decrease with training in this study, including CDCH15, MYH3, TNNT2, RYR1 and SH3GLB1
  • expression of MEF2A itself decreased with training
  • this study demonstrates that the transcriptional alterations in skeletal muscle in response to a long-term endurance exercise intervention are coupled to DNA methylation changes
  • We suggest that the training-induced coordinated epigenetic reprogramming mainly targets enhancer regions, thus contributing to differences in individual response to lifestyle interventions
  • a physiological health-enhancing stimulus can induce highly consistent modifications in DNA methylation that are associated to gene expression changes concordant with observed phenotypic adaptations
  • Nathan Goodyear on 03 Oct 17
     
    Exercise alters gene expression via methylation--the power of epigenetics.  Interestingly, the majority of the methylation was outside the CPG island regions.  This 3 month study found methylation of 5,000 sites across the genome resulting in altered expression of apps 4,000 genes.  The altered muscle changes of the endurance training was linked to DNA methylation changes.
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