For thousands
of years humans consumed fructose amounting to 16–20 grams per day
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shared by Nathan Goodyear on 17 Apr 23
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Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer ... - 0 views
www.ncbi.nlm.nih.gov/...PMC6391112
glycolytic shift LDH lactate dehydrogenase Stress immunosuppression Fear cancer
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Lactate metabolism in human health and disease | Signal Transduction and Targeted Therapy - 0 views
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shared by Nathan Goodyear on 16 Sep 13
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Nutrition & Metabolism | Full text | Fructose, insulin resistance, and metabolic dyslip... - 0 views
www.nutritionandmetabolism.com/...5
fructose metabolic syndrome metabolic syndrome insulin resistance obesity nutrition metabolism
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Of key importance is the ability of fructose to by-pass the main regulatory step of glycolysis, the conversion of glucose-6-phosphate to fructose 1,6-bisphosphate, controlled by phosphofructokinase
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Thus, while glucose metabolism is negatively regulated by phosphofructokinase, fructose can continuously enter the glycolytic pathway. Therefore, fructose can uncontrollably produce glucose, glycogen, lactate, and pyruvate, providing both the glycerol and acyl portions of acyl-glycerol molecules. These particular substrates, and the resultant excess energy flux due to unregulated fructose metabolism, will promote the over-production of TG (reviewed in [53]).
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Glycemic excursions and insulin responses were reduced by 66% and 65%, respectively, in the fructose-consuming subjects
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reduction in circulating leptin both in the short and long-term as well as a 30% reduction in ghrelin (an orexigenic gastroenteric hormone) in the fructose group compared to the glucose group.
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Both fat and fructose consumption usually results in low leptin concentrations which, in turn, leads to overeating in populations consuming energy from these particular macronutrients
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the liver takes up dietary fructose rapidly where it can be converted to glycerol-3-phosphate. This substrate favours esterification of unbound FFA to form the TG
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Although fructose does not appear to acutely increase insulin levels, chronic exposure seems to indirectly cause hyperinsulinemia and obesity through other mechanisms. One proposed mechanism involves GLUT5
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If FFA are not removed from tissues, as occurs in fructose fed insulin resistant models, there is an increased energy and FFA flux that leads to the increased secretion of TG
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In these scenarios, where there is excess hepatic fatty acid uptake, synthesis and secretion, 'input' of fats in the liver exceed 'outputs', and hepatic steatosis occurs
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Carbohydrate induced hypertriglycerolemia results from a combination of both TG overproduction, and inadequate TG clearance
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fructose-induced metabolic dyslipidemia is usually accompanied by whole body insulin resistance [100] and reduced hepatic insulin sensitivity
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Excess VLDL secretion has been shown to deliver increased fatty acids and TG to muscle and other tissues, further inducing insulin resistance
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the metabolic effects of fructose occur through rapid utilization in the liver due to the bypassing of the regulatory phosphofructokinase step in glycolysis. This in turn causes activation of pyruvate dehydrogenase, and subsequent modifications favoring esterification of fatty acids, again leading to increased VLDL secretion
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Oxidative stress has often been implicated in the pathology of insulin resistance induced by fructose feeding
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Administration of alpha-lipoic acid (LA) has been shown to prevent these changes, and improve insulin sensitivity
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LA treatment also prevents several deleterious effects of fructose feeding: the increases in cholesterol, TG, activity of lipogenic enzymes, and VLDL secretion
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PPARα is a ligand activated nuclear hormone receptor that is responsible for inducing mitochondrial and peroxisomal β-oxidation
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fructose diets altered the structure and function of VLDL particles causing and increase in the TG: protein ratio
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therefore the higher TG results in a smaller, denser, more atherogenic LDL particle, which contributes to the morbidity of the metabolic disorders associated with insulin resistance
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High fructose, which stimulates VLDL secretion, may initiate the cycle that results in metabolic syndrome long before type 2 diabetes and obesity develop
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A high flux of fructose to the liver, the main organ capable of metabolizing this simple carbohydrate, disturbs normal hepatic carbohydrate metabolism leading to two major consequences (Figure 2): perturbations in glucose metabolism and glucose uptake pathways, and a significantly enhanced rate of de novo lipogenesis and TG synthesis, driven by the high flux of glycerol and acyl portions of TG molecules coming from fructose catabolism
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shared by Nathan Goodyear on 11 Nov 14
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Role of Oxidative Stress and the Microenvironment in Breast Cancer Development and Prog... - 0 views
www.ncbi.nlm.nih.gov/...PMC3950899
cancer oxidative stress warburg effect reverse warburg effect ROS
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Oxidative stress generated by breast cancer cells activates HIF-1α and NFκB in fibroblasts, leading to autophagy and lysosomal degradation of Cav-1
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increased levels of hydrogen peroxide in exhaled breath condensate from patients with localized breast malignancy, associated with increased clinical severity
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Comparing mitochondrial metabolic activity revealed a difference between stroma and epithelial cells
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Overexpression of NOX4 in normal breast epithelial cells results in cellular senescence, resistance to apoptosis, and tumorigenic transformation, as well as increased aggressiveness of breast cancer cells
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metalloproteinases (MMP) such as MMP-2, MMP-3, and MMP-9 increase extracellular matrix turnover and are themselves activated by oxidative stress
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Lowered expression of Cav-1 not only leads to myofibroblast conversion and inflammation but also seems to impact aerobic glycolysis, leading to secretion of high energy metabolites such as pyruvate and lactate that drive mitochondrial oxidative phosphorylation in cancer cells
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secreted transforming growth factor β (TGFβ), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), fibroblast growth factor 2, and stromal-derived factor 1 (SDF1) are able to activate fibroblasts and increase cancer cell proliferation
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oxidative stress has an important role in the initiation and preservation of breast cancer progression
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the cancer cells produce hydrogen peroxide and by driving the “Reverse Warburg Effect” initiate oxidative stress in fibroblasts. As a result of this process, fibroblasts exhibited reduced mitochondrial activity, increased glucose uptake, ROS, and metabolite production.
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Oxidative stress results from an imbalance between unstable reactive species lacking one or more unpaired electrons (superoxide anion, hydrogen peroxide, hydroxyl radical, reactive nitrogen species) and antioxidants
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cancer cells are able to induce drivers of oxidative stress, autophagy and mitophagy: HIF-1α and NFκB in surrounding stroma fibro-blasts
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Studies show that loss of Cav-1 in adjacent breast cancer stroma fibroblasts can be prevented by treatment with N-acetyl cysteine, quercetin, or metformin
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hydrogen peroxide is one of the main factors that can push fibroblasts and cancer cells into senescence
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It is widely held that HIF-1α function is dependent upon its location within the tumor microenvironment. It acts as a tumor promoter in CAFs and as a tumor suppressor in cancer cells
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It was reported that overexpression of recombinant (SOD2) (Trimmer et al., 2011) or injection of SOD, catalase, or their pegylated counterparts can block recurrence and metastasis in mice
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obstructing oxidative stress in the tumor microenvironment can lead to mitophagy and promote breast cancer shutdown is a promising discovery for the development of future therapeutic interventions.
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Recent studies show that in the breast cancer microenvironment, oxidative stress causes mitochondrial dysfunction
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Really fascinating article on tumor signaling. The article points to a complex signaling between cancer cells and stromal fibroblasts that results in myofibroblast transformation that increases the microenvironment favorability of cancer. This article points to oxidative stress as the primary driving force.
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Cancer as a metabolic disease: implications for novel therapeutics - 0 views
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The Crabtree effect involves a glucose-induced suppression of respiration leading to lactate production whether or not mitochondria are damaged
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shared by Nathan Goodyear on 20 Mar 15
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Muscle Hypertrophy 2011 - 0 views
www.unm.edu/...hypertrophy2011UNM.html
resistance training weight lifting muscle exercise weight training
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mechanical tension, muscle damage and metabolic stress are the three primary factors that promote hypertrophy from exercise
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The mechanical tension is directly related to intensity of the exercise, which is the key to stimulating muscle growth
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Muscle damage, that leads to muscle soreness, from exercise training initiates an inflammatory response, which activates satellite cells growth processes
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metabolic stress that is a result of the byproducts of anaerobic metabolism (i.e., hydrogen ions, lactate, inorganic phosphates) is now also believed to promote hormonal factors leading to muscle hypertrophy
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weightlifters and powerlifters show more favorable hypertrophy of type II (fast twitch) muscle fibers
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body builders appear to have comparable hypertrophy in both the type I (slow twitch) and type II muscle fibers
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Multi-joint exercises have been shown to produce larger increases of anabolic hormones than single-joint exercises
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Intravenous Fluids and Acute Kidney Injury - FullText - Blood Purification 2017, Vol. 4... - 1 views
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Delayed-Onset Hemolytic Anemia in Patients with Travel-Associated Severe Malaria Treate... - 0 views
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delayed hemolytic events occur in ≈20% of patients with severe imported malaria, and 60% of these patients require blood transfusion
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Delayed-onset anemia (herein referred to as postartesunate delayed-onset hemolysis [PADH] pattern of anemia) has been observed to occur 2–3 weeks after initiation of IV artesunate
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The mechanism of this anemia is hemolytic, as demonstrated by high serum lactate dehydrogenase (LDH) and low plasma haptoglobin levels
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PADH occurred in 27% of patients in this study, but it was rarely associated with severe anemia and was never fatal
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This transfusion rate (<5%) is markedly lower than that previously reported for patients with severe imported malaria and delayed-onset anemia (≈60%)
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Side effects of artesunate frequently include gastrointestinal disturbances, neutropenia (1.3%), reticulocytopenia (0.6%), and elevated liver enzymes (1.1%)
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shared by Nathan Goodyear on 20 Jan 19
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The HK2 Dependent "Warburg Effect" and Mitochondrial Oxidative Phosphorylation in Cance... - 0 views
www.ncbi.nlm.nih.gov/...PMC6273842
cancer hexokinase "hexokinase 2" 3BP LDH 3-bromopyruvate "pyruvate dehydrogenase" "pyruvate dehydrogenase kinase" "lactate
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biochemistry strikes again: hexokinase 2 shown to be key step in cancer proliferation, energy metabolism and mortality. 3BP shown to be a potent glycolytic inhibitor and in animal studies shown to have significant mortality effects on cancer. Also, great review of cancer cell metabolism i.e Warburg effect, Crabtree effect, LDH, PD, PDK...
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shared by Nathan Goodyear on 02 Apr 18
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The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for ... - 0 views
nutritionandmetabolism.biomedcentral.com/...s12986-015-0009-2
cancer GKI glucose ketone index ketogenic diet nutrition
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The ‘Glucose Ketone Index’ (GKI) was created to track the zone of metabolic management for brain tumor management
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The GKI is a biomarker that refers to the molar ratio of circulating glucose over β-OHB, which is the major circulating ketone body.
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We present evidence showing that the GKI can predict success for brain cancer management in humans and mice using metabolic therapies that lower blood glucose and elevate blood ketone levels
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The GKI can be useful in determining the success of dietary therapies that shift glucose- and lactate-based metabolism to ketone-based metabolism
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Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, chronic inflammatory disease, and epilepsy
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Optimal management is predicted for values approaching 1.0, and blood glucose and ketone values should be measured 2–3 hours postprandial, twice a day if possible
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the Warburg effect (aerobic fermentation of glucose) is a common metabolic malady expressed in nearly all neoplastic cells of these and other malignant tumors
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Aerobic fermentation (Warburg effect) is necessary to compensate for the insufficiency of mitochondrial oxidative phosphorylation in the cells of most tumors
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Normal brain cells gradually transition from the metabolism of glucose to the metabolism of ketone bodies (primarily β-hydroxybutyrate and acetoacetate) for energy when circulating glucose levels become limiting
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Ketone bodies bypass the glycolytic pathway in the cytoplasm and are metabolized directly to acetyl CoA in the mitochondria
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Tumor cells are less capable than normal cells in metabolizing ketone bodies for energy due to their mitochondrial defects
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daily activities and emotional stress can cause blood glucose levels to vary making it difficult for some people to enter the predicted zone of metabolic management
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a clear association of the GKI to the therapeutic action of calorie restriction against distal invasion, proliferation, and angiogenesis in the VM-M3 model of glioblastoma
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The results suggest that GKI levels that approach 1.0 are therapeutic for managing brain tumor growth
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Therapeutic efficacy of the KD or calorie restriction is greater with lower GKI values than with higher values
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shared by Nathan Goodyear on 08 Dec 17
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Oncotarget | NADH autofluorescence, a new metabolic biomarker for cancer stem cells: Id... - 0 views
www.oncotarget.com/index.php
vitamin C IV vitamin C cancer cancer stem cells milk thistle silymarin ascorbic acid bee propolis CAPE glycolytic inhibitor natural
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Cancer stem-like cells (CSCs) are thought to be the root cause of chemotherapy-resistance and radio-resistance
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ultimately leading to treatment failure in patients with advanced disease [1-3]. They have been directly implicated mechanistically in tumor recurrence and metastasis, resulting in poor patient survival
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Our results indicate that increased mitochondrial oxidative stress and high NADH levels are both key characteristics of the CSC metabolic phenotype
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high levels of NAD(P)H auto-fluorescence are known to be a surrogate marker for mitochondrial “power”, high OXPHOS capacity and increased ATP production
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an intact NAD+ salvage pathway is strictly required for mammosphere formation, supporting our results using NAD(P)H auto-fluorescence, which enriched CSC activity by more than 5-fold.
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Since glycolysis is especially critical for maintaining the TCA cycle, OXPHOS and overall mitochondrial function, we next assessed the effects of known glycolytic inhibitors
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we show that two other natural products that function as effective glycolysis inhibitors, also inhibited mammosphere formation. More specifically, vitamin C (ascorbic acid), which induces oxidative stress and inhibits the activity of GAPDH (a key glycolytic enzyme) [17], also inhibited mammosphere formation, with an IC-50 of 1 mM (Figure 7B). Therefore, vitamin C was ~10 times more potent than 2-DG at targeting CSC propagation
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silibinin (the major active constituent of silymarin, an extract of milk thistle seeds) [18], which specifically functions as an inhibitor of glucose uptake, blocked mammosphere formation, with an IC-50 between 200 and 400 µM
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caffeic acid phenyl ester (CAPE), a key component of honey-bee propolis, has potent anti-cancer properties
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Because of it aromatic ring structure (Figure 8), we speculated that CAPE might function as a potent inhibitor of oxidative mitochondrial metabolism
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CAPE quantitatively inhibits the mitochondrial oxygen consumption rate (OCR) and, in turn, induces the onset of aerobic glycolysis (ECAR)
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CAPE shows a clear selectivity for targeting CSCs and adherent cancer cells, relative to normal fibroblasts.
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CAPE functions as a “natural” mitochondrial OXPHOS inhibitor, that preferentially targets the CSC sub-population. This could explain CAPE’s known anti-cancer properties
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Our data directly shows that a small fraction of the total cell population, characterized by increased PGC1α activity, high mitochondrial ROS/H2O2 and high NADH levels, has the ability to survive and grow under anchorage-independent conditions, driving mammosphere formation
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We highlight the utility of certain natural products, such as Silibinin, Vitamin C and CAPE, that could be used to therapeutically target CSCs. Silibinin is the major active component of silymarin, which is an extract prepared from milk thistle seeds.
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Previous studies have also shown that when non-CSCs and CSCs are both fed mitochondrial fuels (such as L-lactate or ketone bodies), that CSCs quantitatively produce more NADH in response to this stimulus
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The Noble Prize winner, Linus Pauling, was among the first to describe and clinically test the efficacy of Vitamin C, as a relatively non-toxic anti-cancer agent
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Vitamin C has two mechanisms of action. First, it is a potent pro-oxidant, that actively depletes the reduced glutathione pool, leading to cellular oxidative stress and apoptosis in cancer cells. Moreover, it also behaves as an inhibitor of glycolysis, by targeting the activity of GAPDH, a key glycolytic enzyme.
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Here, we show that Vitamin C can also be used to target the CSC population, as it is an inhibitor of energy metabolism that feeds into the mitochondrial TCA cycle and OXPHOS
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Vitamin C may prove to be promising agent for new clinical trials, aimed at testing its ability to reduce CSC activity in cancer patients, as an add-on to more conventional therapies, to prevent tumor recurrence, further disease progression and metastasis
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Interestingly, a breast cancer based clinical study has already shown that the use of Vitamin C, concurrent with or within 6 months of chemotherapy, significantly reduces both tumor recurrence and patient mortality
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CAPE quantitatively reduces mitochondrial oxygen consumption (OCR), while inducing a reactive increase in glycolysis (ECAR). As such, it potently inhibits mammosphere formation with an IC-50 of ~2.5 µM. Similarly, it also significantly inhibits cell migration
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we also demonstrate that 7 different inhibitors of key energetic pathways can be used to effectively block CSC propagation, including three natural products (silibinin, ascorbic acid and CAPE). Future studies will be necessary to test their potential for clinical benefit in cancer patients.
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The future of cancer therapy is cancer stem cells. Study finds that Vitamin C, silymarin, and bee propolis blocks mitochondrial energy pathways in cancer stem cells. Vitamin C is a known glycolytic inhbitor. Vitamin C was found to inhibit glycolysis via GAPDH targeting to inhibit the energy pathways of the mitochondria in CSCs. The authors propse that Vitamin C can be used as add on therapies for conventional therapies to specifically attack the CSCs and their contribution to recrurence, treatment resistance, and metastasis potential all in addition to the ability of vitamin C to reduce the side effects of chemotherapy.
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shared by Nathan Goodyear on 07 May 21
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Curcumin decreases Warburg effect in cancer cells by down-regulating pyruvate... - 0 views
www.ncbi.nlm.nih.gov/...PMC5974195
lactate Curcumin HIF-1 HIF-1alpha Warburg effect PKM2 oncogenic metabolism mTOR
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Balanced Crystalloids versus Saline in Noncritically Ill Adults - 0 views
Balanced Crystalloids versus Saline in Critically Ill Adults - 0 views
Macrophages are metabolically heterogeneous within the tumor microenvironment - 0 views
www.cell.com/...S2211-1247(21)01671-5
Cancer lactic acid TME lactate Tumor associate macrophages tumor microenvironment
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Monocarboxylate transporters in cancer - PMC - 0 views
Metabolic Regulation of Macrophage Polarization in Cancer - PMC - 1 views
www.ncbi.nlm.nih.gov/...PMC7187927
Tumor associate macrophages lactate M1 macrophages cancer tumor microenvironment TAMs TME M2 macrophages
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frankbkelly liked it
Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-ind... - 0 views
diigo.com/0u877k
metabolism" gut flora gut microbiome gut bacteria lactobacillus cancer gut microbiota
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