Five branched chain and aromatic amino acids (isoleucine, leucine, valine, tyrosine, and phenylalanine) showed significant associations with future diabetes
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Dose- and Schedule-Dependent Inhibition of the Mammalian Target of Rapamycin Pathway Wi... - 0 views
Evaluation of off-label rapamycin use to promote healthspan in 333 adults | GeroScience - 0 views
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Nutritional Modulation of Insulin Resistance - 0 views
www.hindawi.com/...424780
macronutrient macronutrients nutrition insulin resistance glucose protein carbohydrates metabolism fats
shared by Nathan Goodyear on 21 Oct 13
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there is increasing evidence that longer term high-protein intake may have detrimental effects on insulin resistance [68, 117–123], diabetes risk [69], and the risk of developing cardiovascular disease
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significant and clinically relevant worsening of insulin sensitivity with an isoenergetic plant-based high-protein diet
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longer term high-protein intake has been shown to result in whole-body insulin resistance [68, 118], associated with upregulation of factors involved in the mammalian target of rapamycin (mTOR)/S6K1 signalling pathway [68], increased stimulation of glucagon and insulin within the endocrine pancreas, high glycogen turnover [118] and stimulation of gluconeogenesis [68, 118].
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it was recently shown in a large prospective cohort with 10 years followup that consuming 5% of energy from both animal and total protein at the expense of carbohydrates or fat increases diabetes risk by as much as 30% [69]. This reinforces the theory that high-protein diets can have adverse effects on glucose metabolism.
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Another recent study showed that low-carbohydrate high-protein diets, used on a regular basis and without consideration of the nature of carbohydrates or the source of proteins, are also associated with increased risk of cardiovascular disease [70], thereby indicating a potential link between high-protein Western diets, T2DM, and cardiovascular risk.
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Branched-Chain Amino Acid Supplementation in Patients with Liver Diseases - 0 views
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BCAAs not only provide substrates for protein synthesis but also accelerate the biochemical machinery, which facilitates liver regeneration, compensating for progressive liver-cell death
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rapamycin signaling in the liver, a well-demonstrated effect of BCAAs, promotes albumin synthesis in the liver
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Branched Chain Amino Acid Supplementation for Patients with Cirrhosis | Clinical Correl... - 0 views
www.clinicalcorrelations.org/?p=3544
BCCA branched chain amino acids liver cirrhosis hepatitis amino acids
shared by Nathan Goodyear on 05 Oct 15
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low level of BCAAs in patients with cirrhosis is hypothesized to be one of multiple factors responsible for development of hepatic encephalopathy
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supplementation of BCAAs is thought to facilitate ammonia detoxification by supporting synthesis of glutamine, one of the non-branched chain amino acids, in skeletal muscle and in the brain as well as diminishing the influx of AAAs across the blood-brain barrier
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oral BCAA supplementation is more useful in chronic encephalopathic patients than is parenteral BCAA supplementation in patients with acute encephalopathy
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Studies show that administration of amino acid formulas enriched with BCAAs can reduce protein loss, support protein synthesis, and improve nutritional status of patients with chronic liver disease
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Leucine has been shown to be the most effective of the BCAAs because it acts via multiple pathways to stimulate protein synthesis
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BCAAs (particularly leucine) help to reverse the catabolic, hyperglucagonemic state of cirrhosis both by stimulating insulin release from the pancreatic β cells and by decreasing insulin resistance allowing for better glucose utilization
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BCAA supplementation improves protein-energy malnutrition by improving utilization of glucose, thereby diminishing the drive for proteolysis, inhibiting protein breakdown, and stimulating protein synthesis
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Cirrhotic patients have impaired immune defense, characterized by defective phagocytic activity and impaired intracellular killing activity
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another effect of BCAA supplementation is improvement of phagocytic function of neutrophils and possibly improvement in natural killer T (NKT) cell lymphocyte activity
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BCAA supplementation may reduce the risk of infection in patients with advanced cirrhosis not only through improvement in protein-energy malnutrition but also by directly improving the function of the immune cells themselves
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A proposed mechanism for improved liver regeneration is the stimulatory effect of BCAAs (particularly leucine) on the secretion of hepatocyte growth factor by hepatic stellate cells
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BCAAs activate rapamycin signaling pathways which promotes albumin synthesis in the liver as well as protein and glycogen synthesis in muscle tissue
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Chemical improvement with BCAA treatment is demonstrated by recovery of serum albumin and lowering of serum bilirubin levels
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long-term oral BCAA supplementation was useful in staving off malnutrition and improving survival by preventing end-stage fatal complications of cirrhosis such as hepatic failure and gastrointestinal bleeding
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The incidence of death by any cause, development of liver cancer, rupture of esophageal varices, or progression to hepatic failure was decreased in the group that received BCAA supplementation
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Patients receiving BCAA supplementation also have a lower average hospital admission rate, better nutritional status, and better liver function tests
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BCAAs have been shown to mitigate hepatic encephalopathy, cachexia, and infection rates, complications associated with the progression of hepatic cirrhosis
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Highest levels are found in casein whey protein of dairy products and vegetables, such as corn and mushrooms. Other sources include egg albumin, beans, peanuts and brown rice bran
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Oral supplementation tends to provide a better hepatic supply of BCAAs for patients able to tolerate PO nutrition as compared with IV supplementation, especially when treating symptoms of hepatic encephalopathy
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Coadministration of BCAAs with carnitine and zinc has also been shown to increase ammonia metabolism further reducing the encephalopathic symptoms
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Cirrhotic patients benefit from eating frequent, small meals that prevent long fasts which place the patient in a catabolic state
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the best time for BCAA supplementation is at bedtime to improve the catabolic state during starvation in early morning fasting
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A late night nutritional snack reduces symptoms of weakness and fatigability, lowers postprandial hyperglycemia, increases skeletal muscle mass,[25] improves nitrogen balance, and increases serum albumin levels.[26] Nocturnal BCAAs even improve serum albumin in cirrhotic patients who show no improvement with daytime BCAAs
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Protein-energy malnutrition (PEM), with low serum albumin and low muscle mass, occurs in 65-90% of cases of advanced cirrhosis
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BCAAs are further depleted from the circulation due to increased uptake by skeletal muscles that use the BCAAs in the synthesis of glutamine, which is produced in order to clear the ammonia that is not cleared by the failing liver
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patients with chronic liver disease, particularly cirrhosis, routinely have decreased BCAAs and increased aromatic amino acids (AAAs) in their circulation
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Maintaining a higher serum albumin in patients with cirrhosis is associated with decreased mortality and improved quality of life
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Niclosamide, an old antihelminthic agent, demonstrates antitumor activity by blocking m... - 0 views
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Accumulating evidence suggests that niclosamide targets multiple signaling pathways such as nuclear factor-kappaB (NF-kB), Wnt/β-catenin, and Notch, most of which are closely involved with cancer stem cell proliferation
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The transcription factor NF-κB has been demonstrated to promote cancer growth, angiogenesis, escape from apoptosis, and tumorigenesis
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Niclosamide blocked TNFα-induced IκBα phosphorylation, translocation of p65, and the expression of NF-κB-regulated genes
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The Wnt signaling pathway plays fundamental roles in directing tissue patterning in embryonic development, in maintaining tissue homeostasis in differentiated tissue, and in tumorigenesis
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The Notch signaling pathway plays important roles in a variety of cellular processes such as proliferation, differentiation, apoptosis, cell fate decisions, and maintenance of stem cells
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niclosamide potently suppresses the luciferase activity of a CBF-1-dependent reporter gene in both a dose-dependent and a time-dependent manners in K562 leukemia cells
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niclosamide treatment abrogated the epidermal growth factor (EGF)-stimulated dimerization and nuclear translocation and transcriptional activity of Stat3, and induced cell growth inhibition and apoptosis in several types of cancer cells (e.g. Du145, Hela, A549) that exhibit relatively higher levels of Stat3 constitutive activation
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Niclosamide is active against cancer cells such as AML and colorectal cancer cells, not only as a monotherapy but also as part of combination therapy, in which it has been found to be synergistic with frontline chemotherapeutic agents (e.g., oxaliplatin, cytarabine, etoposide, and daunorubicin)
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Because niclosamide targets multiple signaling pathways (e.g., NF-κB, Wnt/β-catenin, and Notch), most of which are closely involved with cancer stem cells, it holds promise in eradicating cancer stem cells
Anti-Breast Cancer Potential of Quercetin via the Akt/AMPK/Mammalian Target of Rapamyci... - 0 views
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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