It is important to note that, although the blood level of glucose drops, it still remains at a physiological level (23), which is maintained through gluconeogenesis involving glucogenic amino acids and also glycerol released from triglycerides
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The therapeutic imp... [Prostaglandins Leukot Essent Fatty Acids. 2004] - PubMed - NCBI - 0 views
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Ketone bodies as a therapeutic for Alzheim... [Neurotherapeutics. 2008] - PubMed - NCBI - 0 views
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The Ketogenic Diet and Sport: A Possible Marriage? : Exercise and Sport Sciences Reviews - 0 views
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“physiological ketosis” where KB levels may rise to 7 to 8 mmol L-1 (but without any pH change). In “pathological diabetic ketoacidosis,” on the other hand, ketonemia can exceed 20 mmol L-1 and also cause lowering of blood pH
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in the initial phase of KD, about 16% of glucose comes from glycerol (released from triglyceride hydrolysis) and the bulk (60–65 g) from proteins via gluconeogenesis (proteins may be of either dietary or endogenous origin
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The importance of glycerol as a glucose source increases progressively during ketosis; in fact, glycerol passes from supplying 16% of total glucose to an average of 60% after many days (>7 d) of complete fasting (from 38% in lean individual to 79% in the obese).
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The possible reasons for the effectiveness of KD for weight loss may be listed as follows, in order of evidence, strongest first: Figure 3Image Tools 1. Appetite reduction: protein satiety, effects on appetite-related hormones such as ghrelin, and possibly a sort of direct appetite-blocking effect of KB 2. Reduced lipogenesis and increased fat oxidation 3. A reduction in respiratory quotient may indicate a greater metabolic efficiency in fat oxidation 4. A thermic effect of proteins and increased energy usage by gluconeogenesis
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all data regarding biochemical and molecular mechanisms suggest that it is very difficult to increase muscle mass during a KD; use of which really should be limited to the few days immediately before competition in bodybuilding.
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a long-term KD can interfere with some muscle hypertrophy mechanisms and this could be counterproductive if the aim of the athlete is to gain muscle mass
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Fasting is neuroprotective following traumatic brain injury - Davis - 2008 - Journal of... - 0 views
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Ketogenic Diet for Obesity: Friend or Foe? - 0 views
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Press-pulse: a novel therapeutic strategy for the metabolic management of cancer | Nutr... - 0 views
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A “press” disturbance was considered a chronic environmental stress on all organisms in an ecological community
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“pulse” disturbances were considered acute events that disrupted biological communities to produce high mortality
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Data from the American Cancer Society show that the rate of increase in cancer deaths/year (3.4%) was two-fold greater than the rate of increase in new cases/year (1.7%) from 2013 to 2017
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glucose is first split into two molecules of pyruvate through the Embden–Meyerhof–Parnas glycolytic pathway in the cytosol
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Aerobic fermentation, on the other hand, involves the production of lactic acid under normoxic conditions
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persistent lactic acid production in the presence of adequate oxygen is indicative of abnormal respiration
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The Crabtree effect is an artifact of the in vitro environment and involves the glucose-induced suppression of respiration with a corresponding elevation of lactic acid production even under hyperoxic (pO2 = 120–160 mmHg) conditions associated with cell culture
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the Warburg theory of insufficient aerobic respiration remains as the most credible explanation for the origin of tumor cells [2, 37, 51, 52, 53, 54, 55, 56, 57].
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The main points of Warburg’s theory are; 1) insufficient respiration is the predisposing initiator of tumorigenesis and ultimately cancer, 2) energy through glycolysis gradually compensates for insufficient energy through respiration, 3) cancer cells continue to produce lactic acid in the presence of oxygen, and 4) respiratory insufficiency eventually becomes irreversible
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Efraim Racker coined the term “Warburg effect”, which refers to the aerobic glycolysis that occurs in cancer cells
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Warburg clearly demonstrated that aerobic fermentation (aerobic glycolysis) is an effect, and not the cause, of insufficient respiration
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all tumor cells that have been examined to date contain abnormalities in the content or composition of cardiolipin
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The evidence supporting Warburg’s original theory comes from a broad range of cancers and is now overwhelming
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respiratory insufficiency, arising from any number mitochondrial defects, can contribute to the fermentation metabolism seen in tumor cells.
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data from the nuclear and mitochondrial transfer experiments suggest that oncogene changes are effects, rather than causes, of tumorigenesis
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Normal mitochondria can suppress tumorigenesis, whereas abnormal mitochondria can enhance tumorigenesis
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Glutamine is anapleurotic and can be rapidly metabolized to glutamate and then to α-ketoglutarate for entry into the TCA cycle
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Amino acid fermentation can generate energy through TCA cycle substrate level phosphorylation under hypoxic conditions
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Although Warburg’s hypothesis on the origin of cancer has created confusion and controversy [37, 38, 39, 40], his hypothesis has never been disproved
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Warburg referred to the phenomenon of enhanced glycolysis in cancer cells as “aerobic fermentation” to highlight the abnormal production of lactic acid in the presence of oxygen
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Emerging evidence indicates that macrophages, or their fusion hybridization with neoplastic stem cells, are the origin of metastatic cancer cells
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Radiation therapy can enhance fusion hybridization that could increase risk for invasive and metastatic tumor cells
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Kamphorst et al. in showing that pancreatic ductal adenocarcinoma cells could obtain glutamine under nutrient poor conditions through lysosomal digestion of extracellular proteins
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It will therefore become necessary to also target lysosomal digestion, under reduced glucose and glutamine conditions, to effectively manage those invasive and metastatic cancers that express cannibalism and phagocytosis.
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Previous studies in yeast and mammalian cells show that disruption of aerobic respiration can cause mutations (loss of heterozygosity, chromosome instability, and epigenetic modifications etc.) in the nuclear genome
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The somatic mutations and genomic instability seen in tumor cells thus arise from a protracted reliance on fermentation energy metabolism and a disruption of redox balance through excess oxidative stress.
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According to the mitochondrial metabolic theory of cancer, the large genomic heterogeneity seen in tumor cells arises as a consequence, rather than as a cause, of mitochondrial dysfunction
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A therapeutic strategy targeting the metabolic abnormality common to most tumor cells should therefore be more effective in managing cancer than would a strategy targeting genetic mutations that vary widely between tumors of the same histological grade and even within the same tumor
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Tumor cells are more fit than normal cells to survive in the hypoxic niche of the tumor microenvironment
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Hypoxic adaptation of tumor cells allows for them to avoid apoptosis due to their metabolic reprograming following a gradual loss of respiratory function
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The high rates of tumor cell glycolysis and glutaminolysis will also make them resistant to apoptosis, ROS, and chemotherapy drugs
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Despite having high levels of ROS, glutamate-derived from glutamine contributes to glutathione production that can protect tumor cells from ROS
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It is clear that adaptability to environmental stress is greater in normal cells than in tumor cells, as normal cells can transition from the metabolism of glucose to the metabolism of ketone bodies when glucose becomes limiting
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Mitochondrial respiratory chain defects will prevent tumor cells from using ketone bodies for energy
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glycolysis-dependent tumor cells are less adaptable to metabolic stress than are the normal cells. This vulnerability can be exploited for targeting tumor cell energy metabolism
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In contrast to dietary energy reduction, radiation and toxic drugs can damage the microenvironment and transform normal cells into tumor cells while also creating tumor cells that become highly resistant to drugs and radiation
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Drug-resistant tumor cells arise in large part from the damage to respiration in bystander pre-cancerous cells
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Because energy generated through substrate level phosphorylation is greater in tumor cells than in normal cells, tumor cells are more dependent than normal cells on the availability of fermentable fuels (glucose and glutamine)
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Although some tumor cells might appear to oxidize ketone bodies by the presence of ketolytic enzymes [181], it is not clear if ketone bodies and fats can provide sufficient energy for cell viability in the absence of glucose and glutamine
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A calorie restricted ketogenic diet or dietary energy reduction creates chronic metabolic stress in the body
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The KD can more effectively reduce glucose and elevate blood ketone bodies than can CR alone making the KD potentially more therapeutic against tumors than CR
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Campbell showed that tumor growth in rats is greater under high protein (>20%) than under low protein content (<10%) in the diet
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Calorie restriction, fasting, and restricted KDs are anti-angiogenic, anti-inflammatory, and pro-apoptotic and thus can target and eliminate tumor cells through multiple mechanisms
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Ketogenic diets can also spare muscle protein, enhance immunity, and delay cancer cachexia, which is a major problem in managing metastatic cancer
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The GKI can therefore serve as a biomarker to assess the therapeutic efficacy of various diets in a broad range of cancers.
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It is important to remember that insulin drives glycolysis through stimulation of the pyruvate dehydrogenase complex
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The water-soluble ketone bodies (D-β-hydroxybutyrate and acetoacetate) are produced largely in the liver from adipocyte-derived fatty acids and ketogenic dietary fat. Ketone bodies bypass glycolysis and directly enter the mitochondria for metabolism to acetyl-CoA
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Due to mitochondrial defects, tumor cells cannot exploit the therapeutic benefits of burning ketone bodies as normal cells would
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Therapeutic ketosis with racemic ketone esters can also make it feasible to safely sustain hypoglycemia for inducing metabolic stress on cancer cells
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ketone bodies can inhibit histone deacetylases (HDAC) [229]. HDAC inhibitors play a role in targeting the cancer epigenome
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Therapeutic ketosis reduces circulating inflammatory markers, and ketones directly inhibit the NLRP3 inflammasome, an important pro-inflammatory pathway linked to carcinogenesis and an important target for cancer treatment response
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Chronic psychological stress is known to promote tumorigenesis through elevations of blood glucose, glucocorticoids, catecholamines, and insulin-like growth factor (IGF-1)
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In addition to calorie-restricted ketogenic diets, psychological stress management involving exercise, yoga, music etc. also act as press disturbances that can help reduce fatigue, depression, and anxiety in cancer patients and in animal models
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This physiological state also enhances the efficacy of chemotherapy and radiation therapy, while reducing the side effects
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lower dosages of chemotherapeutic drugs can be used when administered together with calorie restriction or restricted ketogenic diets (KD-R)
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Besides 2-DG, a range of other glycolysis inhibitors might also produce similar therapeutic effects when combined with the KD-R including 3-bromopyruvate, oxaloacetate, and lonidamine
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It is important to recognize, however, that the radiotherapy used in glioma patients can damage the respiration of normal cells and increase availability of glutamine in the microenvironment, which can increase risk of tumor recurrence especially when used together with the steroid drug dexamethasone
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Poff and colleagues demonstrated that hyperbaric oxygen therapy (HBOT) enhanced the ability of the KD to reduce tumor growth and metastasis
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The effects of the KD and HBOT can be enhanced with administration of exogenous ketones, which further suppressed tumor growth and metastasis
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Besides HBOT, intravenous vitamin C and dichloroacetate (DCA) can also be used with the KD to selectively increase oxidative stress in tumor cells
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Recent evidence also shows that ketone supplementation may enhance or preserve overall physical and mental health
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Some tumors use glucose as a prime fuel for growth, whereas other tumors use glutamine as a prime fuel [102, 186, 262, 263, 264]. Glutamine-dependent tumors are generally less detectable than glucose-dependent under FDG-PET imaging, but could be detected under glutamine-based PET imaging
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Many of the current treatments used for cancer management are based on the view that cancer is a genetic disease
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Emerging evidence indicates that cancer is a mitochondrial metabolic disease that depends on availability of fermentable fuels for tumor cell growth and survival
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Glucose and glutamine are the most abundant fermentable fuels present in the circulation and in the tumor microenvironment
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Low-carbohydrate, high fat-ketogenic diets coupled with glycolysis inhibitors will reduce metabolic flux through the glycolytic and pentose phosphate pathways needed for synthesis of ATP, lipids, glutathione, and nucleotides
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Frontiers | Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic M... - 0 views
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The SOC for GBM was modified in this patient to initiate KMT prior to surgical resection, to eliminate steroid medication, and to include HBOT as part of the therapy
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The observed reduction in blood glucose in our patient would reduce lactic acid fermentation in the tumor cells, while the elevation of ketone bodies would fuel normal cells thus protecting them from hypoglycemia and oxidative stress
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Evidence indicates that glioma cells cannot effectively use ketone bodies for energy due to defects in the number, structure, and function of their mitochondria
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The accuracy of the GKI as a predictor for therapeutic efficacy, however, is better when ketone bodies are measured from the blood than when measured from the urine
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A reduction of glucose-driven lactic acid fermentation would not only increase tumor cell apoptosis, but would also reduce inflammation and edema in the tumor microenvironment thus reducing tumor cell angiogenesis and invasion
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Besides serving as a metabolic fuel for GBM, glutamine is also an essential metabolite for normal immune cells
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therapies that inhibit glutamine availability and utilization must be strategically employed to avoid inadvertent impairment of immune cell functions
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we used the non-toxic green tea extract, EGCG, and chloroquine in an attempt to limit glutamine availability to the tumor cells
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EGCG is thought to target the glutamate dehydrogenase activity that facilitates glutamine metabolism in GBM cells
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Chloroquine, on the other hand, will inhibit lysosomal digestion thus restricting fermentable amino acids and carbohydrates from phagocytosed materials in the tumor microenvironment
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As glucose and glutamine fermentation protect tumor cells from oxidative stress, reduced availability of these metabolites under ketosis could enhance the therapeutic action of HBOT, as we recently described
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Prior to subtotal tumor resection and standard of care (SOC), the patient conducted a 72-h water-only fast
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Following the fast, the patient initiated a vitamin/mineral-supplemented ketogenic diet (KD) for 21 days that delivered 900 kcal/day
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the patient received metformin (1,000 mg/day), methylfolate (1,000 mg/day), chloroquine phosphate (150 mg/day), epigallocatechin gallate (400 mg/day), and hyperbaric oxygen therapy (HBOT) (60 min/session, 5 sessions/week at 2.5 ATA)
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Biomarkers showed reduced blood glucose and elevated levels of urinary ketones with evidence of reduced metabolic activity (choline/N-acetylaspartate ratio) and normalized levels of insulin, triglycerides, and vitamin D
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This is the first report of confirmed GBM treated with a modified SOC together with KMT and HBOT, and other targeted metabolic therapies
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glucose and glutamine are the primary fuels that drive the rapid growth of most tumors including GBM
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Glucose drives tumor growth through aerobic fermentation (Warburg effect), while glutamine drives tumor growth through glutaminolysis
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The fermentation waste products of these molecules, i.e., lactic acid and succinic acid, respectively, acidify the tumor microenvironment thus contributing further to tumor progression
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Glucose and glutamine metabolism is also responsible for the high antioxidant capacity of the tumor cells thus making them resistant to chemo- and radiotherapies
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The reliance on glucose and glutamine for tumor cell malignancy comes largely from the documented defects in the number, structure, and function of mitochondria and mitochondrial-associated membranes
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These abnormalities cause the neoplastic GBM cells to rely more heavily on substrate level phosphorylation than on oxidative phosphorylation for energy
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dexamethasone not only increases blood glucose levels but also increases glutamine levels through its induction of glutamine synthetase activity
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Calorie restriction and restricted KD are anti-angiogenic, anti-inflammatory, anti-invasive, and also kill tumor cells through a proapoptotic mechanism
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Evidence also shows that therapeutic ketosis can act synergistically with several drugs and procedures to enhance cancer management improving both progression free and overall survival
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hyperbaric oxygen therapy (HBOT) increases oxidative stress on tumor cells especially when used alongside therapies that reduce blood glucose and raise blood ketones
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The glutamine dehydrogenase inhibitor, epigallocatechin gallate (EGCG) is also proposed to target glutamine metabolism
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The therapeutic implications of ketone bodies: the effects of ketone bodies in patholog... - 0 views
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The human metabolic response to chronic ketosis without caloric restriction: preservati... - 0 views
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effects of beta-hydroxybutyrate on cognition in memory-impaired adults - 0 views
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Those with Alzheimer's disease have associated dysfunction of glucose metabolism in the brain, particularly in the hippocampus. It has been reported that a ketogenic diet can improve cognitive function in these individuals. In this study, the ketone bodies were initiated through a diet high in medium chain fatty acids. The ketone bodies served as an alternative fuel source for the brain.
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Ketoacids? Good medicine? - 0 views
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Beta-hydroxybutyrate brain neurology neuroplasticity neurogenesis inflammation calorie restriction ketosis ketoacids
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PLOS ONE: The Ketogenic Diet and Hyperbaric Oxygen Therapy Prolong Survival in Mice wit... - 0 views
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This finding strongly supports the efficacy of the KD and HBO2T as therapies to inhibit tumor progression and prolong survival in animals with metastatic cancer.
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We found that the KD fed ad libitum significantly increased mean survival time in mice with metastatic cancer
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Ketogenic diets are also known to have an appetite suppressing effect which may contribute to body weight loss
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KD with HBO2T. Combining these therapies nearly doubled survival time in mice with metastatic cancer,
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low carbohydrate or ketogenic diets promote weight loss in overweight individuals, they are also known to spare muscle wasting during conditions of energy restriction and starvation
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dietary-induced therapeutic ketosis in a cancer patient would prevent muscle wasting similarly as it does with athletes undergoing intense exercise
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when given as an adjuvant treatment to advanced cancer patients, the KD improves quality of life and enhances the efficacy of chemotherapy treatment in the clinic
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mouse study finds that ketogenic diet plus hyperbaric O2 treatment prolongs survival.
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Frontiers | Increasing Superoxide Production and the Labile Iron Pool in Tumor Cells ma... - 0 views
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High dose IV vitamin C HBOT DCA high-dose IV vitamin C prooxidative high dose vitamin C ketosis cancer hyperthermia vitamin C IV vitamin C ascorbic acid
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Cancer Metabolism: Fasting Reset, the Keto-Paradox and Drugs for Undoing - PMC - 0 views
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