More than half of cancer patients are treated with IR at some point during their treatment
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Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer... - 0 views
www.ncbi.nlm.nih.gov/...PMC5282724
EMT TME metastasis cancer stem cells cancer MMP2 Notch MMP-9 MMP-2 radioresistance Hedgehog CSC MMP9 Snail HIF-1alpha tumor microenvironment epithelial to mesenchymal transition TGF-beta radiation
shared by Nathan Goodyear on 09 Feb 21
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Nuclear DNA is the primary target of IR; it causes DNA damage (genotoxic stress) by direct DNA ionization
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EMT, stemness, and oncogenic metabolism are known to be associated with resistance to radiotherapy and chemotherapy
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Hanahan and Weinberg proposed ten hallmarks of cancer that alter cell physiology to enhance malignant growth: 1) sustained proliferation, 2) evasion of growth suppression, 3) cell death resistance, 4) replicative immortality, 5) evasion of immune destruction, 6) tumour-promoting inflammation, 7) activation of invasion and metastasis, 8) induction of angiogenesis, 9) genome instability, and 10) alteration of metabolism
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EMT is a developmental process that plays critical roles in embryogenesis, wound healing, and organ fibrosis
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transforming growth factor-β [TGF-β], epidermal growth factor [EGF]) and their associated signalling proteins (Wnt, Notch, Hedgehog, nuclear-factor kappa B [NF-κB], extracellular signal-regulated kinase [ERK], and phosphatidylinositol 3-kinase [PI3K]/Akt
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activate EMT-inducing transcription factors, including Snail/Slug, ZEB1/δEF1, ZEB2/SIP1, Twist1/2, and E12/E47
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IR has been shown to induce EMT to enhance the motility and invasiveness of several cancer cells, including those of breast, lung, and liver cancer, and glioma cells
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IR may increase metastasis in both the primary tumour site and in normal tissues under some circumstance
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sublethal doses of IR have been shown to enhance the migratory and invasive behaviours of glioma cells
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High levels of ROS trigger cell death by causing irreversible damage to cellular components such as proteins, nucleic acids, and lipids, whereas low levels of ROS have been shown to promote tumour progression—including tumour growth, invasion, and metastasis
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Treatment with the N-acetylcysteine (NAC), a general ROS scavenger, prevents IR-induced EMT, adhesive affinity, and invasion of breast cancer cells
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IR activates the p38 MAPK pathway, which contributes to the induction of Snail expression to promote EMT and invasion
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HIF-1 is a heterodimer composed of an oxygen-sensitive α subunit and a constitutively expressed β subunit.
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Under normoxia, HIF-1α is rapidly degraded, whereas hypoxia induces stabilisation and accumulation of HIF-1α
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levels of HIF-1α mRNA are enhanced by activation of the PI3K/Akt/mammalian target of rapamycin (mTOR)
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IR is known to increase stabilisation and nuclear accumulation of HIF-1α, since hypoxia is a major condition for HIF-1 activation
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IR causes the reoxygenation of hypoxic cancer cells to increase ROS production, which leads to the stabilisation and nuclear accumulation of HIF-1
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IR increases glucose availability under reoxygenated conditions that promote HIF-1α translation by activating the Akt/mTOR pathway
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The stabilised HIF-1α then translocates to the nucleus, dimerizes with HIF-1β, and increases gene expression— including the expression of essential EMT regulators such as Snail—to induce EMT, migration, and invasion
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PAI-1 signalling is also implicated in IR-induced Akt activation that increases Snail levels to induce EMT
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EGFR activation is known to be associated with IR-induced EMT, cell migration, and invasion by activating two downstream pathways: PI3K/Akt and Raf/MEK/ERK
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IR has been shown to induce Akt activation through several signalling pathways (EGFR, C-X-C chemokine receptor type 4 [CXCR4]/C-X-C motif chemokine 12 [CXCL12], plasminogen activator inhibitor 1 [PAI-1]) and upstream regulators (Bmi1, PTEN) that promote EMT and invasion
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CSCs possess a capacity for self-renewal, and they can persistently proliferate to initiate tumours upon serial transplantation, thus enabling them to maintain the whole tumour
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Conventional cancer treatments kill most cancer cells, but CSCs survive due to their resistance to therapy, eventually leading to tumour relapse and metastasis
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identification of CSCs, three types of markers are utilised: cell surface molecules, transcription factors, and signalling pathway molecules
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CSCs express distinct and specific surface markers; commonly used ones are CD24, CD34, CD38, CD44, CD90, CD133, and ALDH
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signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, platelet-derived growth factor receptor (PDGFR), and JAK/STAT
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EMT-inducing transcription factors, such as Snail, ZEB1, and Twist1, are known to confer CSC properties
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Signalling pathways involved in EMT, including those of TGF-β, Wnt, and Notch, have been shown to play important roles in inducing the CSC phenotype
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TGF-β1 not only increases EMT markers (Slug, Twist1, β-catenin, N-cadherin), but also upregulates CSC markers (Oct4, Sox2, Nanog, Klf4) in breast and lung cancer cells
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IR has been shown to induce the CSC phenotype in many cancers, including breast, lung, and prostate cancers, as well as melanoma
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Genotoxic stress due to IR or chemotherapy promotes a CSC-like phenotype by increasing ROS production
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In prostate cancer patients, radiotherapy increases the CD44+ cell population that exhibit CSC properties
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IR also induces the re-expression of stem cell regulators, such as Sox2, Oct4, Nanog, and Klf4, to promote stemness in cancer cells
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EMT-inducing transcription factors and signalling pathways, including Snail, STAT3, Notch signalling, the PI3K/Akt pathway, and the MAPK cascade, have been shown to play important roles in IR-induced CSC properties
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STAT3 directly binds to the Snail promoter and increases Snail transcription, which induces the EMT and CSC phenotypes, in cisplatin-selected resistant cells
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Other oncogenic metabolic pathways, including glutamine metabolism, the pentose phosphate pathway (PPP), and synthesis of fatty acids and cholesterol, are also enhanced in many cancers
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cancer cells depend on mitochondrial metabolism and increase mitochondrial production of ROS that cause pseudo-hypoxia
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CAFs have defective mitochondria that lead to the cells exhibiting the Warburg effect; the cells take up glucose, and then secrete lactate to 'feed' adjacent cancer cells
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Epithelial cancer cells express MCT1, while CAFs express MCT4. MCT4-positive, hypoxic CAFs secrete lactate by aerobic glycolysis, and MCT1-expressing epithelial cancer cells then uptake and use that lactate as a substrate for the tricarboxylic acid (TCA) cycle
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MCT4-positive cancer cells depend on glycolysis and then efflux lactate, while MCT1-positive cells uptake lactate and rely on OXPHOS
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metabolic heterogeneity induces a lactate shuttle between hypoxic/glycolytic cells and oxidative/aerobic tumour cells
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bulk tumour cells exhibit a glycolytic phenotype, with increased conversion of glucose to lactate (and enhanced lactate efflux through MCT4), CSC subsets depend on oxidative phosphorylation; most of the glucose entering the cells is converted to pyruvate to fuel the TCA cycle and the electron transport chain (ETC), thereby increasing mitochondrial ROS production
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the major fraction of glucose is directed into the pentose phosphate pathway, to produce redox power through the generation of NADPH and ROS scavengers
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regulatory molecules involved in EMT and CSCs, including Snail, Dlx-2, HIF-1, STAT3, TGF-β, Wnt, and Akt, are implicated in the metabolic reprogramming of cancer cells
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HIF-1 induces the expression of glycolytic enzymes, including the glucose transporter GLUT, hexokinase, lactate dehydrogenase (LDH), and MCT, resulting in the glycolytic switch
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HIF-1 represses the expression of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), thereby inhibiting mitochondrial activity
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pyruvate kinase M2 (PKM2), LDH, and pyruvate carboxylase (PC), are implicated in the induction of the EMT and CSC phenotypes
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IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
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IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
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IR also elevates MCT1 expression that exports lactate into the extracellular environment, leading to acidification of the tumour microenvironment
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IR increases intracellular glucose, glucose 6-phosphate, fructose, and products of pyruvate (lactate and alanine), suggesting a role for IR in the upregulation of cytosolic aerobic glycolysis
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lactate stimulates cell migration and enhances secretion of hyaluronan from CAF that promote tumour metastasis
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promote tumour survival, growth, invasion, and metastasis; enhance the stiffness of the ECM; contribute to angiogenesis; and induce inflammation by releasing several growth factors and cytokines (TGF-β, VEGF, hepatocyte growth factor [HGF], PDGF, and stromal cell-derived factor 1 [SDF1]), as well as MMP
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tumours recruit the host tissue’s blood vessel network to perform four mechanisms: angiogenesis (formation of new vessels), vasculogenesis (de novo formation of blood vessels from endothelial precursor cells), co-option, and modification of existing vessels within tissues.
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immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
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immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
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The third phase, tumour escape, is mediated by antigen loss, immunosuppressive cells (TAM, MDSCs, and regulatory T cells), and immunosuppressive cytokines (TGF-β and IL-10).
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IR can elicit various changes in the TME, such as CAF activity-mediated ECM remodelling and fibrosis, cycling hypoxia, and an inflammatory response
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IR activates CAFs to promote the release of growth factors and ECM modulators, including TGF-β and MMP
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TGF-β directly influences tumour cells and CAFs, promotes tumour immune escape, and activates HIF-1 signalling
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MMPs degrade ECM that facilitates angiogenesis, tumour cell invasion, and metastasis
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IR promotes ROS production in cancer cells, which may induce the activation of oncogenes and the inactivation of tumour suppressors, which further promote oncogenic metabolism
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Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms
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JAMA Network | JAMA Neurology | Refractory Nonmotor Symptoms in Male Patients With Park... - 0 views
archneur.jamanetwork.com/article.aspx
testosterone Parkinson's Parkinson's disease therapy low T treatment inflammation neurodegenerative disease excitotoxicity neurology male
shared by Nathan Goodyear on 21 May 13
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Testosterone therapy aids symptoms of Parkinson's disease. Whether low T is an associated finding or plays a role has yet to be determined. However, we do know that androgens play an anti-inflammatory role in men and we know that inflammation plays a role in the neurodegenerative disease that is Parkinson's disease.
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Community Pharmacies 22 Million Covid-19 Jabs In One Year - 0 views
www.pharmacy.biz/lion-covid-19-jabs-in-one-year
Community-pharmacies Pharmacy-Business uk-pharmacy-news 22-Million-Covid-19-Jabs covid-19-jabs-uk covid-vaccination-programme-uk nhs-covid-vaccination
shared by pharmacybiz on 17 Jan 22
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Community pharmacies played a central role in the government's response to the Covid-19 pandemic, delivering more than 22 million jabs in the past 12 months. Besides delivering millions of jabs, latest figures from NHS England and NHS Improvement (NHSE&I) revealed a 50 per cent increase in the number of pharmacies delivering Covid boosters compared from October 2021 to January 2022. NHSE&I released the data on Friday (January 14) to thank community pharmacy teams for their work during the crisis time. Lauding the efforts made by community pharmacy teams during the pandemic, Pharmaceutical Services Negotiating Committee (PSNC) director of NHS Services Alastair Buxton said: "Just over a year ago we were fighting for Government recognition of the part community pharmacy could play in administering Covid vaccines, so a year later it is great to see the efforts of the pharmacy vaccination sites being praised by NHSE&I, with recognition of the significant role they have played in the overall programme.
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Natural Killer Cells in Pregnancy and Recurrent Pregnancy Loss: Endocrine and Immunolog... - 0 views
edrv.endojournals.org/...44.full
natural killer cells pregnancy loss recurrent immune system miscarriage NK
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NK cells have been the cells most extensively studied, primarily because they constitute the predominant leukocyte population present in the endometrium at the time of implantation and in early pregnancy
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parental chromosomal abnormalities, uterine anatomic anomalies, endometrial infections, endocrine etiologies (luteal phase defect, thyroid dysfunction, uncontrolled diabetes mellitus), antiphospholipid syndrome, inherited thrombophilias, and alloimmune causes
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In summary, in vivo animal experiments have shown an inhibitory role of estrogen on peripheral NK cell lytic activity, which is partly due to suppression of NK cell output by the bone marrow and partly due to suppression of individual NK cell cytotoxicity. However, in vitro studies so far have failed to show conclusively a direct effect of estrogen on NK cells.
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At the progesterone concentrations believed to be present in the uterus [up to 10−5 m at the maternal-fetal interface (35)], studies consistently show inhibition of lymphocyte proliferation (33) and inhibition of NK cytolytic activity in vitro
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The overall effects of estrogen on NK cells are likely multifactorial, therefore, and depend on the type of cell affected as well as the kind of ER expressed by that cell.
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It is known that progesterone can directly affect T cell differentiation in vitro, suppressing development of the Th1 pathway and enhancing differentiation along the Th2 pathway (44)
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Th1 cells predominantly produce interferon-γ (IFN-γ), IL-2, and TNF-β and are involved in cell-mediated immunity. Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13 and stimulate humoral immunity
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Furthermore, in response to progesterone, γδ T cells produce progesterone-induced blocking factor (PIBF) (54
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A defining characteristic of NK cells is their ability to lyse target cells without prior sensitization and without restriction by HLA antigens.
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IL-2 causes both NK cell proliferation and enhanced cytotoxicity. IFN-γ augments NK cytolytic activity, but does not cause NK proliferation. The two cytokines act synergistically to augment NK cytotoxicity (6).
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The largest leukocyte population in the endometrium consists of NK cells named large granulated lymphocytes
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there is a significant increase in the number of uNK cells throughout the secretory phase, which peaks in early pregnancy when uNK cells comprise about 75% of uterine leukocytes (62)
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general proinflammatory effect of estrogen, causing an influx of macrophages and neutrophils, which is antagonized by progesterone through its receptor (70, 71).
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Through promotion of a uterine Th2 environment, progesterone could indirectly affect uNK cell function
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The mechanism of this increase in uNK cell numbers has been addressed in both human and mouse models, and is likely the result of: 1) recruitment of peripheral NK cells to the uterus, and 2) proliferation of existing uNK cells
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uNK cells express a different cytokine profile, compared with resting peripheral NK cells. mRNAs for granulocyte CSF, M-CSF, GM-CSF, TNF-α, IFN-γ, TGF-β, and leukemia inhibitory factor (LIF) have been found in decidual CD56+ cells
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Their increased numbers in early pregnancy, their hormonal dependence, and their close proximity to the infiltrating trophoblast all suggest that they play an important role in the regulation of the maternal immune response to the fetal allograft and the control of trophoblast growth and invasion during human pregnancy
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Th1 immunity to trophoblast is associated with RPL, whereas Th2 immunity is associated with a successful pregnancy
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Causative role of gut microbiota in non-alcoholic fatty liver disease pathogenesis - 0 views
www.ncbi.nlm.nih.gov/...PMC3481143
metabolic endotoxemia inflammation non-alcoholic fatty liver NAFLD gut bacteria fatty liver disease
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Orexin/Hypocretin: A Neuropeptide at the Interface of Sleep, Energy Homeostasis, and Re... - 0 views
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Glutathione Redox Regulates Airway Hyperresponsiveness and Airway Inflammation in Mice ... - 0 views
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γ-GCE reduced levels of IL-4, IL-5, IL-10, and the chemokines eotaxin and RANTES (regulated on activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid, whereas it enhanced the production of IL-12 and IFN-γ.
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these findings suggest that changing glutathione redox balance, increase in GSH level, and the GSH/GSSG ratio by γ-GCE, ameliorate bronchial asthma by altering the Th1/Th2 imbalance through IL-12 production from APC and suppressing chemokine production and eosinophil migration itself.
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Through the release of Th2 cytokines, such as IL-4, IL-5, and IL-13, orchestrate the recruitment and activation of the primary effector cells of the allergic response: the mast cells and the eosinophils
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Glutathione is the most abundant nonprotein sulfhydryl compound in almost all cells. This tripeptide plays a significant role in many biological processes. It also constitutes the first line of the cellular defense mechanism against oxidative injury along with SOD, ascorbate, vitamin E, and catalase, and is the major intracellular redox buffer in ubiquitous cell types
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We have shown that glutathione redox status, namely the balance between intracellular reduced (GSH) and oxidized (GSSG) glutathione, in murine antigen-presenting cells (APC) plays a central role in determining which of the reductive and oxidative APC predominate during immune status, and the balance between reductive and oxidative APC regulates Th1/Th2 balance through production of IL-12
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we have also shown that exposure of human alveolar macrophages to the Th1 cytokine IFN-γ or the Th2 cytokine IL-4 either increases or decreases the GSH/GSSG ratio, respectively, which regulates Th1/Th2 balance through IL-12 production
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the ability to generate a Th1 or Th2 type response has turned out to depend not only on T cells but also on the intracellular glutathione redox status of APC
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Th1 cytokine IFN-γ and Th2 cytokine IL-4 increases and decreases the GSH/GSSG ratio, respectively, and that this ratio influences LPS-induced IL-12 production from alveolar macrophages
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administration of γ-GCE elevates GSH level and GSH/GSSG ratio in the lung, and ameliorates AHR and eosinophilic airway inflammation by altering the Th1/Th2 balance and suppressing chemokine production and eosinophil migration in a mouse asthma model
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Studies on activity of... [J Huazhong Univ Sci Technolog Med Sci. 2004] - PubMed - NCBI - 0 views
www.ncbi.nlm.nih.gov/...15641696
preeclampsia NK cell immune tolerance pregnancy recurrent miscarriage miscarriages
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The endocabbinoid system and the treatment of obesity - 0 views
diabesity.eu/annals.pdf
endocannabinoid endocannabinoid-mediated adiponectin obesity overweight weight-loss CB1
shared by Nathan Goodyear on 19 Mar 12
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nice review of CB1 receptors and the role they play in obesity. Endocabbinoid receptors play an important role in the hypothalamus control of metabolism and energy. CB1 is active both centrally and peripherally. Increased CB1 activity increases fat storage; decrease CB1 activity increases fatty acid oxidation through adiponectin.
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Regulation of 11beta-HSD genes in human adipose tis... [Obes Res. 2004] - PubMed - NCBI - 0 views
www.ncbi.nlm.nih.gov/...14742837
stress cortisol cortisone obesity fat cells adipocytes adipose tissue
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Testosterone deficiency: A determinant of ao... [Atherosclerosis. 2014] - PubMed - NCBI - 0 views
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low Total Testosterone associated with CAD, particularly aortic. Obviously, Testosterone, when low, is a marker of poor health in men. However, low Testosterone can likely play a role in disease development, especially when age is factored in--low Testosterone in younger men likely plays an etiology versus a lesser impact in the elder.
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Vitamin C and survival among women with breast cancer: A Meta-analysis - 0 views
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Meta-analysis finds that for every oral daily intake of 100 mg vitamin C, the risk of total mortality was decreased by 27% and the breast cancer specific mortality was decreased by 22%. A lot of potential variables that can play into this equation. However, oral vitamin C is poorly bioavailable, yet according to this meta-analysis, does provide significant health benefits and even prevention. If health and breast cancer prevention is a goal, then vitamin C needs to play a role in your daily intake.
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Estrogen and prostate cancer: an eclipsed tru... [J Cell Biochem. 2007] - PubMed - NCBI - 0 views
www.ncbi.nlm.nih.gov/...17786930
estrogen prostate cancer testosterone hormone hormones aromatase activity androgens
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Immunohistochemical Expression of Estrogen and Progesterone Receptors in Human Colorect... - 0 views
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ER and PR are suggested to play role in colon cancer. The question is do they play a role in carcinogenesis or does the expression of the receptors indicate something else i.e. attempt at differentiation through progesterone. Also, what receptors are involver here: ER alpha or beta. Likewise for the progesterone receptors
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Cambridge Journals Online - Proceedings of the Nutrition Society - Fulltext -... - 0 views
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JNK Expression by Macrophages Promotes Obesity-induced Insulin Resistance and Inflammation - 0 views
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The role of mercury and cadmi... [Altern Ther Health Med. 2007 Mar-Apr] - PubMed - NCBI - 0 views
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Promoting effects and mechanisms of action of androgen in bladder c... - PubMed - NCBI - 0 views
www.ncbi.nlm.nih.gov/...9129932
bladder cancer bladder cancer Testosterone men male hormone hormones
shared by Nathan Goodyear on 04 Jan 15
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Another animal study finds Testosterone plays a role in bladder cancer development. The study used anti androgen and 5 alpha reductase inhibitor therapy to see if these add on therapies provided anything to ADR whether via castration or pituitary suppression--the answer was no. The authors concluded that Testosterone played more of a role with AR versus the more active 5alpha-DHT metabolite.
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