Long-chain polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are highly enriched in neuronal synaptosomal plasma membranes and vesicles
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Stuck at the bench: Potential natural neuroprotective compounds for concussion - 0 views
www.ncbi.nlm.nih.gov/...PMC3205506
concussions concussion natural therapies brain curcumin omega 3 resveratrol green tea EGCG EPA DHA vitamin E vitamin c vitamin D
shared by Nathan Goodyear on 20 Feb 16
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effective supplementation and/or increased ingestion of dietary sources rich in EPA and DHA, such as cold-water fish species and fish oil, may help improve a multitude of neuronal functions, including long-term potentiation and cognition.
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multiple preclinical studies have suggested that DHA and/or EPA supplementation may have potential benefit through a multitude of diverse, but complementary mechanisms
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pre-injury dietary supplementation with fish oil effectively reduces post-traumatic elevations in protein oxidation
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The benefits of pre-traumatic DHA supplementation have not only been independently confirmed,[150] but DHA supplementation has been shown to significantly reduce the number of swollen, disconnected and injured axons when administered following traumatic brain injury.
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DHA has provided neuroprotection in experimental models of both focal and diffuse traumatic brain injury
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potential mechanisms of neuroprotection, in addition to DHA and EPA's well-established anti-oxidant and anti-inflammatory properties
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Despite abundant laboratory evidence supporting its neuroprotective effects in experimental models, the role of dietary DHA and/or EPA supplementation in human neurological diseases remains uncertain
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Several population-based, observational studies have suggested that increased dietary fish and/or omega-3 polyunsaturated fatty acid consumption may reduce risk for ischemic stroke in several populations
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Randomized control trials have also demonstrated significant reductions in ischemic stroke recurrence,[217] relative risk for ischemic stroke,[2] and reduced incidence of both symptomatic vasospasm and mortality following subarachnoid hemorrhage
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curcumin has gained much attention from Western researchers for its potential therapeutic benefits in large part due to its potent anti-oxidant[128,194,236] and anti-inflammatory properties
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Curcumin is highly lipophilic and crosses the blood-brain barrier enabling it to exert a multitude of different established neuroprotective effects
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in the context of TBI, a series of preclinical studies have suggested that pre-traumatic and post-traumatic curcumin supplementation may bolster the brain's resilience to injury and serve as a valuable therapeutic option
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Curcumin may confer significant neuroprotection because of its ability to act on multiple deleterious post-traumatic, molecular cascades
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studies demonstrated that both pre- and post-traumatic curcumin administration resulted in a significant reduction of neuroinflammation via inhibition of the pro-inflammatory molecules interleukin 1β and nuclear factor kappa B (NFκB)
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no human studies have been conducted with respect to the effects of curcumin administration on the treatment of TBI, subarachnoid or intracranial hemorrhage, epilepsy or stroke
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studies have demonstrated that resveratrol treatment reduces brain edema and lesion volume, as well as improves neurobehavioral functional performance following TBI
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green tea consumption or supplementation with its derivatives may bolster cognitive function acutely and may slow cognitive decline
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At least one population based study, though, did demonstrate that increased green tea consumption was associated with a reduced risk for Parkinson's disease independent of total caffeine intake
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a randomized, placebo-controlled trial demonstrated that administration of green tea extract and L-theanine, over 16 weeks of treatment, improved indices of memory and brain theta wave activity on electroencephalography, suggesting greater cognitive alertness
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Other animal studies have also demonstrated that theanine, another important component of green tea extract, exerts a multitude of neuroprotective benefits in experimental models of ischemic stroke,[63,97] Alzheimer's disease,[109] and Parkinson's disease
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Theanine, like EGCG, contains multiple mechanisms of neuroprotective action including protection from excitotoxic injury[97] and inhibition of inflammation
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More recent research has suggested that vitamin D supplementation and the prevention of vitamin D deficiency may serve valuable roles in the treatment of TBI and may represents an important and necessary neuroprotective adjuvant for post-TBI progesterone therapy
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Progesterone is one of the few agents to demonstrate significant reductions in mortality following TBI in human patients in preliminary trials
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in vitro and in vivo studies have suggested that vitamin D supplementation with progesterone administration may significantly enhance neuroprotection
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Vitamin D deficiency may increase inflammatory damage and behavioral impairment following experimental injury and attenuate the protective effects of post-traumatic progesterone treatment.[37]
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emerging evidence has suggested that daily intravenous administration of vitamin E following TBI significantly decreases mortality and improves patient outcomes
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high dose vitamin C administration following injury stabilized or reduced peri-lesional edema and infarction in the majority of patients receiving post-injury treatment
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it has been speculated that combined vitamin C and E therapy may potentiate CNS anti-oxidation and act synergistically with regards to neuroprotection
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one prospective human study has found that combined intake of vitamin C and E displays significant treatment interaction and reduces the risk of stroke
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Pycnogenol has demonstrated the ability to slow or reduce the pathological processes associated with Alzheimer's disease
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Pcynogenol administration, in a clinical study of elderly patients, led to improved cognition and reductions in markers of lipid peroxidase
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One other point of consideration is that in neurodegenerative disease states like Alzheimer's disease and Parkinson's disease, where there are high levels of reactive oxygen species generation, vitamin E can tend to become oxidized itself. For maximal effectiveness and to maintain its anti-oxidant capacity, vitamin E must be given in conjunction with other anti-oxidants like vitamin C or flavonoids
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These various factors might account for the null effects of alpha-tocopherol supplementation in patients with MCI and Alzheimer's disease
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preliminary results obtained in a pediatric population have suggested that post-traumatic oral creatine administration (0.4 g/kg) given within four hours of traumatic brain injury and then daily thereafter, may improve both acute and long-term outcomes
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Acutely, post-traumatic creatine administration seemed to reduce duration of post-traumatic amnesia, length of time spent in the intensive care unit, and duration of intubation
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At three and six months post-injury, subjects in the creatine treatment group demonstrated improvement on indices of self care, communication abilities, locomotion, sociability, personality or behavior and cognitive function when compared to untreated controls
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patients in the creatine-treatment group were less likely to experience headaches, dizziness and fatigue over six months of follow-up
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CNS creatine is derived from both its local biosynthesis from the essential amino acids methionine, glycine and arginine
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Studies of patients with CNS creatine deficiency and/or murine models with genetic ablation of creatine kinase have consistently demonstrated significant neurological impairment in the absence of proper creatine, phosphocreatine, or creatine kinase function; thus highlighting its functional importance
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chronic dosing may partially reverse neurological impairments in human CNS creatine deficiency syndromes
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Several studies have suggested that creatine supplementation may also reduce oxidative DNA damage and brain glutamate levels in Huntington disease patients
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Another study highlighted that creatine supplementation marginally improved indices of mood and reduced the need for increased dopaminergic therapy in patients with Parkinson's disease
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AHA: HDL - the waters grow muddier : Clinical Endocrinology News - 0 views
www.clinicalendocrinologynews.com/...d2b497c21aa780dcb35cd9f6c.html
HDL cholesterol CVD cardiovascular disease
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Normalization of testosterone level is associated with reduced incidence of myocardial ... - 0 views
eurheartj.oxfordjournals.org/...2706
low T low Testosterone Testosterone Testosterone therapy mortality MI stroke heart men male hormones
shared by Nathan Goodyear on 18 Jan 16
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In this study of men with low TT levels and without prior MI or stroke, normalization of TT levels using TRT is associated with lower all-cause mortality, fewer MIs, and ischaemic strokes.
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It can be postulated that the beneficial effect of normal T levels on adipose tissue, insulin sensitivity, and lipid profiles or by its anti-inflammatory and anticoagulant properties, as reported by other investigators, might have contributed to our findings
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Recent FDA analyses suggest that currently only half of the men on TRT had been diagnosed with hypogonadism
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men without a history of previous MI or stroke who have low TT levels, TRT might be associated with decreased risks of MI, ischaemic stroke, and all-cause mortality in long-term follow-up
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TRT should aim for doses resulting in normalization of TT level as this was shown to be associated with reduction in adverse CV events
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Inborn-like errors of metabolism are determinants of breast cancer risk, clinical respo... - 0 views
www.ncbi.nlm.nih.gov/...PMC6114970
cancer metabolism breast cancer glutamine glutamate aspartate oncogenes
shared by Nathan Goodyear on 24 Sep 18
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We now recognize that human cancers evolve in an environment of metabolic stress. Rapidly proliferating tumor cells deprived of adequate oxygen, nutrients, hormones and growth factors up-regulate pathways that address these deficiencies to overcome hypoxia (HIF), vascular insufficiency (VEGF), growth factor deprivation (EGFR, HER2) and the loss of hormonal support (ER, PR, AR) all to enhance survival and proliferation
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The results suggest that breast cancer could be preceded by systemic subclinical disturbances in glucose-insulin homeostasis characterized by mild, likely asymptomatic, IEM-like biochemical changes
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The process would include variable periods of hyperinsulinemia with the consequent systemic MYC activation of glycolysis, glutaminolysis, structural lipidogenesis and further exacerbation of hypoglycemia, the result of MYC's known role as an inhibitor of liver gluconeogenesis
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The metabolic changes we describe in breast cancer arise in concert with IEM-like changes in oxidative phosphorylation as detected by increased values of the ratio lactate/pyruvate (Supplementary Table 2A, 2B) characteristic of Ox/Phos deficiency [25]. In our study, 76% (70/92) of the European breast cancer patients had lactate/pyruvate ratios values higher than the normal value of 25.8
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four-fold higher frequency of cancer (including breast) in patients with energy metabolism disorders
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growing recognition that cancer cells differ from their normal counterparts in their use of nutrients, synthesis of biomolecules and generation of energy
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glutamine concentrations in the cancer patients were reduced to nearly 1/8 of the levels observed in the normal population
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blood concentrations of aspartate (p = 1.7e-67, FDR = 8.3e-67) (Figure (Figure1E)1E) and glutamate (p = 6.4e-96, FDR = 6.2e-95) (Figure (Figure1F)1F) were nearly 10 fold higher than the normal ranges of 0–5 μM/L and 40 μM/L, respectively
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glutamine consumption associated with parallel increases in glutamate and aspartate (Figure (Figure1A1A red arrows) is considered a hallmark of MYC-driven “glutaminolysis”
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Gln/Glu ratio inversely correlates with i- late stage metabolic syndrome and with ii- increased chance of death
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changes in glutamine consumption, reflected by the Gln/Glu ratio could provide a metabolic link between breast cancer initiation and diabetes, reflective of a systemic metabolic reprogramming from glucose to glutamine as the preferred source of precursors for biosynthetic reactions and cellular energy
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the metabolic dependencies of cancer characterized by excessive glycolysis, glutaminolysis and malignant lipidogenesis, previously considered a consequence of local tumor DNA aberration [23] could, instead, represent a systemic biochemical aberration that predates and very likely promotes tumorigenesis
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accumulation of very long chain acylcarnitines such as C14:1-OH (p = 0.0, FDR = 0.0), C16 (p = 0.0, FDR = 0.0), C18 (p = 0.0, FDR = 0.0) and C18:1 (p = 1.73e-322, FDR = 1.16-321) and lipids containing VLCFA (lysoPC a C28:0) (p = 1.14-e95, FDR = 1.65e-95) in the blood of breast and colon cancer patients
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Among the most powerful metabolic equations for MYC-activation is that which links the widely used MYC-driven desaturation marker ratio of SFA/MUFA to the MYC glutaminolysis-associated ratio of (Asp/Gln)
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liver dysfunction shares many features with both IEM and cancer suggesting a role for hepatic dysfunction in carcinogenesis
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cancer “conscripts” the human genome to meet its needs under conditions of systemic metabolic stress
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Lipid metabolism is associated with developmental epigenetic programming | Scientific R... - 0 views
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The Pharmacokinetics and Interactions of Ivermectin in Humans-A Mini-review - 0 views
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second rise in plasma levels (mostly occurring between 6 and 12 h after the dose) suggesting an enterohepatic recycling of the drug
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the optimal dose of ivermectin is 150 μg/kg, but the frequency of administration is still controversial, ranging from 150 μg/kg once to three times yearly.
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To interrupt the transmission of onchocerciasis in humans, the combination of ivermectin and doxycycline is highly effective as, in infested patients, the ingestion of the anthelmintic (200 μg/kg, single dose) and the antibacterial (100 mg/kg, daily for 6 weeks)
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This issue becames important, as combination chemotherapy is being used with increasing frequency as resistance to antiparasitic agents is becoming more widespread.
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prothrombin times were significantly above baseline by one week to one month after drug ingestion, suggesting an antagonist effect against vitamin K
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prolonged prothrombin ratios were observed in 148 subjects given ivermectin orally. Although no patients suffered bleeding complications, factor II and VII levels were reduced in most of them, suggesting interference with vitamin K metabolism
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Ivermectin has a minimal effect on coagulation and concern about mass treatment for this reason appears to be unjustified
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Baseline and On-Treatment High-Density Lipoprotein Cholesterol and the Risk of Cancer i... - 0 views
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Ascorbic acid: Chemistry, biology and the treatment of cancer - 0 views
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iron and ascorbate has long been used as an oxidizing system; the combination of these two reagents is referred to as the Udenfriend system
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pharmacokinetic data indicate that intravenous administration of ascorbate can bypass this tight control resulting in highly elevated plasma levels
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ascorbate readily oxidizes to produce H2O2, pharmacological ascorbate has been proposed as a prodrug for the delivery of H2O2 to tumors
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Ascorbate is an excellent reducing agent and readily undergoes two consecutive, one-electron oxidations to form ascorbate radical (Asc•−) and dehydroascorbic acid (DHA)
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Ascorbate oxidizes readily. The rate of oxidation is dependent on pH and is accelerated by catalytic metals
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In near-neutral buffers with contaminating metals, the oxidation and subsequent loss of ascorbate can be very rapid
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Ascorbate is an excellent one-electron reducing agent that can reduce ferric (Fe3+) to ferrous (Fe2+) iron, while being oxidized to ascorbate radical
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In a classic Fenton reaction, Fe2+ reacts with H2O2 to generate Fe3+ and the very oxidizing hydroxyl radical
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e presence of ascorbate can allow the recycling of Fe3+ back to Fe2+, which in turn will catalyze the formation of highly reactive oxidants from H2O2
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Depending on concentrations, the effects of ascorbate on models of lipid peroxidation can be pro- or antioxidant
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Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by... - 0 views
www.researchgate.net/...r_by_a_dual_COX-2sEH_inhibitor
chemotherapy COX2 ovarian cancer COX-2 cytokine storm
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Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by... - 0 views
1More
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease - NEJM - 0 views
www.nejm.org/...NEJMoa1707914
inflammation lipids cholesterol atherothrombosis cardiovascular disease CRP myocardial infarction stroke cardiovascular death
shared by Nathan Goodyear on 05 Sep 17
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new study challenges the cholesterol = cardiovascular event story? Good science asks questions and challenges dogma. The authors claim the inflammatory hypothesis of atherothrombosis is yet unproven? Maybe they need to get out and read more. The point here Is not the drug in question, but the fact that a reduction in inflammation reduced recurrent cardiovascular events independent of cholesterol.
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Effects of transdermal application of DHEA on the levels of steroids, gonadotropins and... - 0 views
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Ferritin Level Is Positively Associated with Chronic Kidney Disease in Korean Men, Base... - 0 views
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active radicals can affect lipids, proteins, and deoxyribonucleic acid (DNA), resulting in tissue injury and dysfunction
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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
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[Malondialdehyde (MDA) as a lipid peroxidation marker]. - PubMed - NCBI - 0 views
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Hypercholesterolemia and apolipoprotein B expression: Regulation by selenium status | L... - 0 views
lipidworld.biomedcentral.com/...1476-511X-4-28
selenium Apolipoprotein B apo B cardiovascular disease
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Lipid metabolism in cancer cells under metabolic stress | British Journal of Cancer - 0 views
128More
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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