Glutamine : biochemistry, physiology, and clinical applications

ROLE OF GLUTAMINE IN MUSCLEGUT METABOLISMCANCER AND GLUTAMINERENAL ACID-BASE METABOLISM AND GLUCONEOGENESISANTIOXIDANT AND GLUTAMINE METABOLISMCENTRAL NERVOUS SYSTEM AND GLUTAMINE METABOLISMMICROBIOMESUMMARYREFERENCESSection I Basics of Glutamine MetabolismAn Introduction to Glutamine Metabolism. Vinicius Fernandes Cruzat and Philip NewsholmeINTRODUCTIONGLUTAMINE BIOCHEMISTRY AND METABOLISMEMERGING ROLE OF GLUTAMINE FOR CELL DEFENSECONSIDERATIONS ABOUT THE EXOGENOUS REPLACEMENT OF GLUTAMINECONCLUSION AND FUTURE PERSPECTIVESREFERENCESSection II New Data on the Biochemistry of GlutamineIntestinal Glutamine Synthetase Colocalizes with Goblet Cells and Decreases Enterocyte ProliferationINTRODUCTIONDISTRIBUTION OF GS IN THE INTESTINESEFFECT OF ENTEROCYTE-SPECIFIC DELETION OF GS ON THE INTESTINEEffect of Enterocyte-Specific Deletion of GS on Portal-Vein Amino Acid ConcentrationsEffect of Enterocyte-Specific Deletion of GS on the Number of Goblet CellsEffect of Enterocyte-Specific Deletion of GS on Enterocyte ProliferationDISCUSSIONRestriction of GS Expression to Goblet CellsEffect of Fasting and GS Deficiency on Enterocyte ProliferationEffect of Fasting and GS Deficiency on Portal Amino Acid ConcentrationsREFERENCESGlutaminase Isoforms and Glutamine MetabolismINTRODUCTIONINTERORGAN METABOLISM OF GLUTAMINEPROPERTIES OF GLUTAMINASEglsi and GLS2 GenesKinetics and Inhibitors of GlutaminaseX-ray Structure of GlutaminaseEffects of N-Acetylation of GlutaminaseTISSUE SPECIFIC FUNCTION OF GLUTAMINE METABOLISMIntestineLiverBrainKidneyCancer CellsCONCLUSIONS AND PROSPECTIVEREFERENCESSection III Molecular and Cellular Aspects of Glutamine Metabolism Importance of Glutamine to Insulin Secretion, Insulin Action, and Glycemic ControlINTRODUCTIONINSULIN ACTIONMETABOLIC STATES ASSOCIATED WITH POSITIVE EFFECTS OF GLUTAMINE SUPPLEMENTATIONGLUTAMINE SUPPLEMENTATION STUDIESTISSUE SPECIFICITY AND IMPROVEMENT IN INSULIN RESISTANCEMECHANISM OF ACTIONGLP-1Insulin ResistanceInfluences on Oxidative Stress and Associated ProcessesGlutamine and Insulin SecretionImmune Function and InflammationGlutamine Impact on Glycemia or Insulin Resistance and InflammationAdditional MechanismsStimulation of GluconeogenesisStimulation of Glucagon SecretionMitochondrial FunctionGlutamine/Glutamate CyclingSUMMARY AND CONCLUSIONREFERENCESGlutamine and AutophagyINTRODUCTION: BACKGROUND AND DRIVING FORCESTHE PUZZLING SPECTRUM OF GLUTAMINE EFFECTS ON AUTOPHAGYThe FoxO-Mediated Glutamine Synthetase-Dependent Activation PathwayThe Glutaminolysis/Ammonia-Dependent Activation PathwayThe Transcellular Ammonia-Dependent Activation PathwayThe Hexosamine-Dependent Activation PathwayThe Bidirectional Amino Acid Transport-Dependent Inhibition PathwayThe Glutaminolysis-Dependent Inhibition PathwayGENERAL MECHANISTIC CONSIDERATIONSThe GLUTAMiNE/a-KETOGLUTARATE RatioRegulation of Autophagy by MorphogensIMPLICATIONSPhysiological and Pathophysiological EffectsGlutamine, Autophagy, and AgingEffects on Cancer CellsCONCLUSION AND PERSPECTIVESREFERENCESRegulation of Hepatic Glutamine and Ammonia Metabolism by MorphogensINTRODUCTION: BACKGROUND AND DRIVING FORCESSYSTEMIC GLUTAMINE LEVELS AND THE LIVEREFFECT OF ZONATION ON HEPATIC GLUTAMINE METABOLISMREGULATION OF HEPATIC GLUTAMINE METABOLISMMetabolic RegulationThe Role of Wnt/Beta-Catenin Signaling in Controlling Glutamine SynthesisMETABOLIC CONSEQUENCES OF ZONATION AND REGULATION OF HEPATIC GLUTAMINE METABOLISMFUNCTIONAL CONSEQUENCES OF ALTERED WNT/BETA-CATENIN SIGNALINGPATHOLOGICAL AND BENEFICIAL ROLE OF GLUTAMINECONCLUSIONS AND PERSPECTIVESREFERENCESSection IV Glutamine, the Brain and Neurological Diseases Brain Glutamine. Roles in Norm and PathologyGENERAL COMMENTS: SCOPE OF THE CHAPTERGLUTAMINE IN THE HEALTHY BRAINBrain Glutamine Content and DistributionGlutamine as a Precursor of Neurotransmitters Glu and GABA: A Route from Simple Precursor/Product Demonstrations to the Visualization of the Astrocytic-Neuronal Interplay in the Gln/Glu/GABA Cycle (GGC)GLUTAMINE IN BRAIN PATHOLOGIESHyperammonemia/Hepatic EncephalopathyGeneral CharacteristicsMediation of Ammonia Neurotoxicity by GlutamineGlutamine as a Modulator of the Cyclic Guanosine Monophosphate (cGMP)/Nitric Oxide (NO) Pathway in Hyperammonemic Brain: Role of the Glutamine/Arginine Exchange Carrier, y+LAT2EpilepsyGlutamine and the Pathogenesis of Brain TumorsCONCLUDING COMMENTS: CAN MODULATION OF GLUTAMINE CONTENT OFFER TREATMENT MODALITIES FOR GLUTAMINE RELATED BRAIN DISORDERS?REFERENCESBrain Glutamine Accumulation in Liver Failure. Role in the Pathogenesis of Central Nervous System ComplicationsINTRODUCTIONGLUTAMINE: PHYSIOLOGICAL FUNCTIONS AND PATHOGENIC IMPLICATIONSBRAIN GLUTAMINE ACCUMULATION IN LIVER FAILUREBRAIN GLUTAMINE SYNTHESIS RATES IN LIVER FAILURETHE GLUTAMATE-GLUTAMINE CYCLE IN BRAINBRAIN GLUTAMINE METABOLISM IN LIVER FAILUREGlutaminaseGlutamine TransaminationCONCLUSIONSREFERENCESGlutamate/Glutamine Cycle. Evidence of Its Role in Parkinson's Disease Using In Vivo MRS TechniquesINTRODUCTIONBIOCHEMISTRY OF THE STRIATUM IN PDGlutamatergic Hyperactivity in the StriatumIn vivo MRS MeasurementsApplications in Animal Models of PDClinical Applications in PDGLUTAMATE: GLUTAMINE CYCLING INVOLVED IN PDGlutamate: Glutamine CycleGlutamate-Glutamine Cycle in PDCONCLUSIONREFERENCESSection V Glutamine and the Intestinal Tract Glutamine and Intestinal Physiology and PathologyINTRODUCTIONGLUTAMINE AND INTESTINAL PHYSIOLOGYGlutamine and Intestinal FunctionsGlutamine Metabolism in Intestinal CellsGlutamine and Gastrointestinal BacteriaGLUTAMINE AND INTESTINAL PATHOLOGYGlutamine and Intestinal Inflammation and Mucosal HealingGlutamine and Endotoxemia and SepsisGlutamine and Bacterial TranslocationCONCLUSION AND PERSPECTIVESREFERENCESGlutamine. General Facilitator of Gut Absorption and RepairINTRODUCTIONHISTORICAL OBSERVATIONSGLUTAMINE STIMULATES INTESTINAL SALT AND WATER ABSORPTIONStudies in Mammalian SpeciesH uman Studies of Gln in Oral RehydrationGLUTAMINE STIMULATES INTESTINAL RECOVERY FOLLOWING INJURYColitisEndotoxic Gut InjuryHypoxic InjuryWeanling DiarrheaIntestinal Injury Associated with Cancer and Immunosuppressant TherapyOther ModelsMECHANISTIC CONSIDERATIONS REGARDING GLN IN MUCOSAL RECOVERYGln Is a Signal to Enhance Epithelial Integrity and Cell Survival in the Intestine and Other Critical OrgansActivation of Protective HSPsAntiapoptotic EffectsERK and PI3K PathwayBarrier Function: Gln Is Necessary for Tight Junction StabilizationHUMAN STUDIES OF GLN IN GUT INJURYIn Vitro Studies of Human Biopsy MaterialsG ln and Nosocomial InfectionsGln in CancerGln in the Prevention of Necrotizing EnterocolitisGln in Short Bowel SyndromeCONCLUSIONSREFERENCESTherapeutic Role of Glutamine in Inflammatory Bowel DiseaseINTRODUCTIONMULTIFACTORIAL NATURE OF IBD PATHOGENESISEVIDENCE FOR NUTRITIONAL MODULATION OF IBD BY GLUTAMINEClinical EvidencePreclinical Evidence from Experimental IBD ModelsImproving Intestinal Barrier IntegrityRegulating Intestinal Innate ImmunityModulating Cytokine Balance and T Cell PolarizationEnhancing Intestinal Cytoprotective Heat Shock ResponseCONCLUSIONSREFERENCESSection VI Glutamine and the Catabolic State: Role of Glutamine in Critical Illness During ChildhoodGlutamine in the Critically Ill NeonateINTRODUCTIONGUT AND GLN IN NEONATESCLINICAL STUDIES OF GLNLONG-TERM FOLLOW-UP STUDY OF GLN-SUPPLEMENTED INFANTSEFFECTS OF ARGININE-GLN DIPEPTIDECONCLUSIONSREFERENCESSection VII Glutamine and the Catabolic State: Role of Glutamine in Critical Illness from AdulthoodRationale for and Efficacy of Glutamine Supplementation in Critical IllnessMETABOLIC AND PHYSIOLOGIC ROLES OF GLUTAMINE RELEVANT TO CRITICAL ILLNESSGlutamine Synthesis and Carbon MetabolismG lutamine and Glucose MetabolismGlutamine as a Precursor for Key CompoundsSplanchnic Metabolism of Dietary GlutamineGlutamine as a Nontoxic Nitrogen CarrierAdditional Roles of GlutamineCHANGES IN GLUTAMINE METABOLISM IN CRITICAL ILLNESSGLUTAMINE ROUTES OF SUPPLEMENTATION AND PHARMACOKINETICSParenteral Glutamine SupplementationEnteral Glutamine SupplementationPHYSIOLOGIC EFFECTS OF GLUTAMINE SUPPLEMENTATION IN HUMANSGlutamine Supplementation and Glucose MetabolismGlutamine Supplementation and Gut FunctionGlutamine Supplementation and Heat Shock ProteinsGlutamine Supplementation and GlutathioneEFFECTS OF GLUTAMINE ON INFECTIOUS COMPLICATIONS AND MORTALITY IN CRITICAL ILLNESSEnteral Glutamine SupplementationParenteral Glutamine SupplementationCONTROVERSIES IN GLUTAMINE SUPPLEMENTATIONCONCLUSIONSREFERENCESRole of Glutamine Oxidative Injury Pathways in Critically Ill PatientsINTRODUCTIONBASIC SCIENCE STUDIESSignificance of Glutamine LevelsRedox Functions of GlutamineImmunomodulatory Effects of GlutamineCLINICAL STUDIESBurnsSurgical and Trauma PatientsMixed ICU PopulationsMeta-AnalysesTRIALS CURRENTLY IN PROGRESSCONCLUSIONSREFERENCESGlutamine Supplementation in Critical IllnessINTRODUCTIONROUTE OF ADMINISTRATIONPATIENT GROUPSPostoperativeCritical IllnessOncology and HematologyGastrointestinalOUTCOMESProxy MeasuresMorbidityMortalityCONCLUSIONS AND PERSPECTIVESREFERENCESGlutamine Supplementation in Critical IllnessINTRODUCTIONGLUTAMINE AND GUT BARRIERGLUTAMINE AND INFLAMMATORY RESPONSEGLUTAMINE AND OXIDATIVE STRESSGLUTAMINE AND IMMUNE FUNCTIONGLUTAMINE AND HEAT SHOCK PROTEINSGLUTAMINE AND GLUCOSE HOMEOSTASISCONCLUSION AND PERSPECTIVESREFERENCESGlutamine Supplementation in Critical Illness. Focus on Renal InjuryINTRODUCTIONGLUTAMINE AS A NITROGEN SHUTTLE AND ITS ROLE DURING METABOLIC ACIDOSISGLUTAMINE: AN ESSENTIAL FACTOR FOR NATIVE KIDNEY CELLSSEPTIC AND NONSEPTIC ACUTE KIDNEY INJURY: A TARGET FOR GLUTAMINE SUPPLEMENTATION?GLUTAMINE DEPLETION IN CRITICAL ILLNESSES: DOES IT MATTER?CHRONIC KIDNEY DISEASE, WASTING, AND MORTALITYGLUTAMINE SUPPLEMENTATION IN CRITICALLY ILL PATIENTSPOSSIBLE TOXIC EFFECTS RELATED TO GLUTAMINE SUPPLEMENTATION IN ICU PATIENTS WITH AKICONCLUSIONSREFERENCESSection VIII Glutamine and the Catabolic State: Role of Glutamine in CancerGlutamine Transport and Metabolism in CancerGLUTAMINE METABOLISM: INTRODUCTIONGLUTAMINE BIOCHEMISTRY; ENZYMES AND DISPOSITIONGlutamine CyclesCELL PROLIFERATION, THE WARBURG EFFECT, AND GLUTAMINE METABOLISMTumor Glutamine Cycles and MetabolismGLUTAMINE TRANSPORTSolute Carrier Families and Glutamine TransportersGlutamine Transporters Implicated in CancerTARGETING GLUTAMINE TRANSPORT AND METABOLISM IN CANCER IMAGING AND THERAPYGlutamine-Targeted Imaging and Cancer DiagnosticsCONCLUSIONS AND FUTURE DIRECTIONSREFERENCESGlutamine as a New Therapeutic Target in Cancer. Use of Hyperpolarized Magnetic Resonance SpectroscopyHYPERPOLARIZATIONRulesSafetyAcquisitionModelingHYPERPOLARIZATION AND ONCOLOGYHyperpolarized 13C PyruvateHyperpolarized 13C BicarbonateHyperpolarized 13C GlucoseHyperpolarized 13C CholineHyperpolarized 13C FumarateINTEREST OF HYPERPOLARIZED GLUTAMINE IN THE DETECTION OF CANCERWhy Glutamine Metabolism Is Interesting in Imaging Tumor Cells?Use of Hyperpolarized 13C Glutamine in Comparison with Positron. Emission Tomography Tracers in the Detection of In Vivo CancerSUMMARY AND CONCLUSIONSREFERENCESSection IX Glutamine, Immunity, and ExerciseGlutamine and the Immune SystemINTRODUCTIONIMMUNE SYSTEMOverviewInnate ImmunityAcquired ImmunityGut-Associated Immune SystemGLUTAMINE METABOLISM BY CELLS OF THE IMMUNE SYSTEMGLUTAMINE AND THE FUNCTION OF CELLS OF THE IMMUNE SYSTEMT LymphocytesВ LymphocytesMonocytes and MacrophagesNeutrophilsGut-Associated Immune SystemPLASMA AND MUSCLE GLUTAMINE IN CATABOLIC STATESEFFECT OF EXOGENOUS GLUTAMINE ON IMMUNE FUNCTION AND SURVIVAL IN ANIMAL MODELS OF INFECTION AND INFLAMMATIONGLUTAMINE, IMMUNITY, AND INFECTION IN HOSPITALIZED PATIENTSMECHANISMS OF GLUTAMINE ACTIONMetabolic Roles of GlutamineG lutamine and Heat Shock Proteins in Immunity and InflammationHeat Shock ProteinsClinical Consequences of Upregulated HSP70 ReleaseThe Effect of HSP70 on the Inflammatory and Immune ResponseGlutamine and the Upregulation of HSP70SUMMARY AND CONCLUSIONSREFERENCESGlutamine and Exercise and Immune SystemGLUTAMINE AND ITS IMPORTANCE FOR THE IMMUNE SYSTEMGLUTAMINE AND EXERCISEGLUTAMINE, DIET, AND EXERCISE IN THE POSTEXERCISE IMMUNOMODULATIONGLUTAMINE SUPPLEMENTATION, EXERCISE, AND IMMUNE FUNCTIONCONCLUSIONREFERENCESRole of Glutamine in Exercise-Induced Immunodepression in ManROLE OF GLUTAMINE IN HUMANSEXERCISE-INDUCED ILLNESS IN HUMANSMECHANISM OF ACTION OF GLUTAMINE IN THE IMMUNE SYSTEM AND IN EXERCISE-INDUCED IMMUNODEPRESSIONGLUTAMINE AND HEAT SHOCK PROTEINS IN EXERCISEPLASMA CONCENTRATION OF GLUTAMINE IN EXERCISEGLUTAMINE AS A MARKER OF EXERCISE-INDUCED IMMUNODEPRESSION AND ILLNESSINTERACTION OF PLASMA GLUTAMINE WITH GLUTAMATEGLUTAMINE SUPPLEMENTATION IN ATHLETESGLUTAMINE SAFETYCONCLUSIONSDEDICATIONREFERENCESSection X Glutamine and AgingGlutamine Metabolism in Old AgeINTRODUCTIONPHYSIOLOGICAL IMPORTANCE AND BIOCHEMISTRY OF GLUTAMINEOVERVIEW OF MOLECULAR AND CELLULAR ASPECTS OF GLUTAMINE METABOLISM IN BOTH MAMMALS AND HUMANSEffect of Glutamine Starvation on Cell Survival and ApoptosisRegulative Potential of Glutamine: Relation to Glutathione MetabolismGlutamine Signaling in the IntestineGlutamine Signaling in the LiverIMPACT OF AGING ON THE REGULATION OF GLUTAMINE METABOLISMIs Glutamine the Cornerstone on the Protein Turnover in Skeletal Muscle with Aging?Effect of Aging on the Glutamine Metabolism in the Whole BodyImpact of Aging on Glutamine Synthesis in Skeletal Muscle: Study In Vivo by 13C SRMImpact of Aging on GS In Skeletal Muscle: Study In Vitro by BiochemistryImpact of Aging on Glutamine Synthesis in the LiverImpact of Aging on Glutamine Synthesis in the GutImpact of Aging on Glutamine Metabolism at the Cellular LevelIMPACT OF GLUTAMINE SUPPLEMENTATION IN OLD AGERatsShort SupplementationSupplementation during 5 MonthsLong-Term SupplementationHumansSUMMARY AND CONCLUSIONSREFERENCESSum Up and Future ResearchSUM UPBasics of Glutamine MetabolismNew Data on the Biochemistry of GlutamineMolecular and Cellular Aspects of Glutamine MetabolismGlutamine, the Brain, and Neurological DiseasesGlutamine and the Intestinal TractGlutamine and the Catabolic StateI: Role of Glutamine in Critical IllnessII: Role of Glutamine in CancerGlutamine, Immunity, and ExerciseGlutamine and AgingFUTURE DIRECTIONS
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