1 2702 118 EXCITOTOXICITY AND OVERNUTRITION ADDITIVELY IMPAIR METABOLIC FUNCTION AND IDENTITY OF PANCREATIC BETA-CELLS. A SUSTAINED INCREASE IN INTRACELLULAR CA(2+) CONCENTRATION (REFERRED TO HEREAFTER AS EXCITOTOXICITY), BROUGHT ON BY CHRONIC METABOLIC STRESS, MAY CONTRIBUTE TO PANCREATIC BETA-CELL FAILURE. TO DETERMINE THE ADDITIVE EFFECTS OF EXCITOTOXICITY AND OVERNUTRITION ON BETA-CELL FUNCTION AND GENE EXPRESSION, WE ANALYZED THE IMPACT OF A HIGH-FAT DIET (HFD) ON ABCC8 KNOCKOUT MICE. EXCITOTOXICITY CAUSED BETA-CELLS TO BE MORE SUSCEPTIBLE TO HFD-INDUCED IMPAIRMENT OF GLUCOSE HOMEOSTASIS, AND THESE EFFECTS WERE MITIGATED BY VERAPAMIL, A CA(2+) CHANNEL BLOCKER. EXCITOTOXICITY, OVERNUTRITION, AND THE COMBINATION OF BOTH STRESSES CAUSED SIMILAR BUT DISTINCT ALTERATIONS IN THE BETA-CELL TRANSCRIPTOME, INCLUDING ADDITIVE INCREASES IN GENES ASSOCIATED WITH MITOCHONDRIAL ENERGY METABOLISM, FATTY ACID BETA-OXIDATION, AND MITOCHONDRIAL BIOGENESIS AND THEIR KEY REGULATOR PPARGC1A OVERNUTRITION WORSENED EXCITOTOXICITY-INDUCED MITOCHONDRIAL DYSFUNCTION, INCREASING METABOLIC INFLEXIBILITY AND MITOCHONDRIAL DAMAGE. IN ADDITION, EXCITOTOXICITY AND OVERNUTRITION, INDIVIDUALLY AND TOGETHER, IMPAIRED BOTH BETA-CELL FUNCTION AND IDENTITY BY REDUCING EXPRESSION OF GENES IMPORTANT FOR INSULIN SECRETION, CELL POLARITY, CELL JUNCTION, CILIA, CYTOSKELETON, VESICULAR TRAFFICKING, AND REGULATION OF BETA-CELL EPIGENETIC AND TRANSCRIPTIONAL PROGRAM. SEX HAD AN IMPACT ON ALL BETA-CELL RESPONSES, WITH MALE ANIMALS EXHIBITING GREATER METABOLIC STRESS-INDUCED IMPAIRMENTS THAN FEMALES. TOGETHER, THESE FINDINGS INDICATE THAT A SUSTAINED INCREASE IN INTRACELLULAR CA(2+), BY ALTERING MITOCHONDRIAL FUNCTION AND IMPAIRING BETA-CELL IDENTITY, AUGMENTS OVERNUTRITION-INDUCED BETA-CELL FAILURE. 2020 2 5293 28 PROTEASOMAL DEGRADATION OF THE HISTONE ACETYL TRANSFERASE P300 CONTRIBUTES TO BETA-CELL INJURY IN A DIABETES ENVIRONMENT. IN TYPE 2 DIABETES, AMYLOID OLIGOMERS, CHRONIC HYPERGLYCEMIA, LIPOTOXICITY, AND PRO-INFLAMMATORY CYTOKINES ARE DETRIMENTAL TO BETA-CELLS, CAUSING APOPTOSIS AND IMPAIRED INSULIN SECRETION. THE HISTONE ACETYL TRANSFERASE P300, INVOLVED IN REMODELING OF CHROMATIN STRUCTURE BY EPIGENETIC MECHANISMS, IS A KEY UBIQUITOUS ACTIVATOR OF THE TRANSCRIPTIONAL MACHINERY. IN THIS STUDY, WE REPORT THAT LOSS OF P300 ACETYL TRANSFERASE ACTIVITY AND EXPRESSION LEADS TO BETA-CELL APOPTOSIS, AND MOST IMPORTANTLY, THAT STRESS SITUATIONS KNOWN TO BE ASSOCIATED WITH DIABETES ALTER P300 LEVELS AND FUNCTIONAL INTEGRITY. WE FOUND THAT PROTEASOMAL DEGRADATION IS THE MECHANISM SUBSERVING P300 LOSS IN BETA-CELLS EXPOSED TO HYPERGLYCEMIA OR PRO-INFLAMMATORY CYTOKINES. WE ALSO REPORT THAT MELATONIN, A HORMONE PRODUCED IN THE PINEAL GLAND AND KNOWN TO PLAY KEY ROLES IN BETA-CELL HEALTH, PRESERVES P300 LEVELS ALTERED BY THESE TOXIC CONDITIONS. COLLECTIVELY, THESE DATA IMPLY AN IMPORTANT ROLE FOR P300 IN THE PATHOPHYSIOLOGY OF DIABETES. 2018 3 6205 37 THE INFLUENCE OF PLANT EXTRACTS AND PHYTOCONSTITUENTS ON ANTIOXIDANT ENZYMES ACTIVITY AND GENE EXPRESSION IN THE PREVENTION AND TREATMENT OF IMPAIRED GLUCOSE HOMEOSTASIS AND DIABETES COMPLICATIONS. DIABETES IS A COMPLEX METABOLIC DISORDER RESULTING EITHER FROM INSULIN RESISTANCE OR AN IMPAIRED INSULIN SECRETION. PROLONGED ELEVATED BLOOD GLUCOSE CONCENTRATION, THE KEY CLINICAL SIGN OF DIABETES, INITIATES AN ENHANCEMENT OF REACTIVE OXYGEN SPECIES DERIVED FROM GLUCOSE AUTOXIDATION AND GLYCOSYLATION OF PROTEINS. CONSEQUENTLY, CHRONIC OXIDATIVE STRESS OVERWHELMS CELLULAR ENDOGENOUS ANTIOXIDANT DEFENSES AND LEADS TO THE ACUTE AND LONG-STANDING STRUCTURAL AND FUNCTIONAL CHANGES OF MACROMOLECULES RESULTING IN IMPAIRED CELLULAR FUNCTIONING, CELL DEATH AND ORGAN DYSFUNCTION. THE OXIDATIVE STRESS PROVOKED CHAIN OF PATHOLOGICAL EVENTS OVER TIME CAUSE DIABETIC COMPLICATIONS SUCH AS NEPHROPATHY, PERIPHERAL NEUROPATHY, CARDIOMYOPATHY, RETINOPATHY, HYPERTENSION, AND LIVER DISEASE. UNDER DIABETIC CONDITIONS, ACCOMPANYING GENOME/EPIGENOME AND METABOLITE MARKERS ALTERATIONS MAY ALSO AFFECT GLUCOSE HOMEOSTASIS, PANCREATIC BETA-CELLS, MUSCLE, LIVER, AND ADIPOSE TISSUE. BY PROVIDING DEEPER GENETIC/EPIGENETIC INSIGHT OF DIRECT OR INDIRECT DIETARY EFFECTS, NUTRIGENOMICS OFFERS A PROMISING OPPORTUNITY TO IMPROVE THE QUALITY OF LIFE OF DIABETIC PATIENTS. NATURAL PLANT EXTRACTS, OR THEIR NATURALLY OCCURRING COMPOUNDS, WERE SHOWN TO BE VERY PROFICIENT IN THE PREVENTION AND TREATMENT OF DIFFERENT PATHOLOGIES ASSOCIATED WITH OXIDATIVE STRESS INCLUDING DIABETES AND ITS COMPLICATIONS. CONSIDERING THAT FOOD INTAKE IS ONE OF THE CRUCIAL COMPONENTS IN DIABETES' PREVALENCE, PROGRESSION AND COMPLICATIONS, THIS REVIEW SUMMARIZES THE EFFECT OF THE MAJOR PLANT SECONDARY METABOLITE AND PHYTOCONSTITUENTS ON THE ANTIOXIDANT ENZYMES ACTIVITY AND GENE EXPRESSION UNDER DIABETIC CONDITIONS. 2021 4 3643 32 INCREASED INFLAMMATORY RESPONSE IN AGED MICE IS ASSOCIATED WITH AGE-RELATED ZINC DEFICIENCY AND ZINC TRANSPORTER DYSREGULATION. AGING IS A COMPLEX PROCESS ASSOCIATED WITH PHYSIOLOGICAL CHANGES IN NUMEROUS ORGAN SYSTEMS. IN PARTICULAR, AGING OF THE IMMUNE SYSTEM IS CHARACTERIZED BY PROGRESSIVE DYSREGULATION OF IMMUNE RESPONSES, RESULTING IN INCREASED SUSCEPTIBILITY TO INFECTIOUS DISEASES, IMPAIRED VACCINATION EFFICACY AND SYSTEMIC LOW-GRADE CHRONIC INFLAMMATION. INCREASING EVIDENCE SUGGEST THAT INTRACELLULAR ZINC HOMEOSTASIS, REGULATED BY ZINC TRANSPORTER EXPRESSION, IS CRITICALLY INVOLVED IN THE SIGNALING AND ACTIVATION OF IMMUNE CELLS. WE HYPOTHESIZE THAT EPIGENETIC ALTERATIONS AND NUTRITIONAL DEFICITS ASSOCIATED WITH AGING MAY LEAD TO ZINC TRANSPORTER DYSREGULATION, RESULTING IN DECREASES IN CELLULAR ZINC LEVELS AND ENHANCED INFLAMMATION WITH AGE. THE GOAL OF THIS STUDY WAS TO EXAMINE THE CONTRIBUTION OF AGE-RELATED ZINC DEFICIENCY AND ZINC TRANSPORTER DYSREGULATION ON THE INFLAMMATORY RESPONSE IN IMMUNE CELLS. THE EFFECTS OF ZINC DEFICIENCY AND AGE ON THE INDUCTION OF INFLAMMATORY RESPONSES WERE DETERMINED USING AN IN VITRO CELL CULTURE SYSTEM AND AN AGED MOUSE MODEL. WE SHOWED THAT ZINC DEFICIENCY, PARTICULARLY THE REDUCTION IN INTRACELLULAR ZINC IN IMMUNE CELLS, WAS ASSOCIATED WITH INCREASED INFLAMMATION WITH AGE. FURTHERMORE, REDUCED ZIP 6 EXPRESSION ENHANCED PROINFLAMMATORY RESPONSE, AND AGE-SPECIFIC ZIP 6 DYSREGULATION CORRELATED WITH AN INCREASE IN ZIP 6 PROMOTER METHYLATION. FURTHERMORE, RESTORING ZINC STATUS VIA DIETARY SUPPLEMENTATION REDUCED AGED-ASSOCIATED INFLAMMATION. OUR DATA SUGGESTED THAT AGE-RELATED EPIGENETIC DYSREGULATION IN ZINC TRANSPORTER EXPRESSION MAY INFLUENCE CELLULAR ZINC LEVELS AND CONTRIBUTE TO INCREASED SUSCEPTIBILITY TO INFLAMMATION WITH AGE. 2013 5 2026 22 EPIGENETIC CHANGES IN BONE MARROW PROGENITOR CELLS INFLUENCE THE INFLAMMATORY PHENOTYPE AND ALTER WOUND HEALING IN TYPE 2 DIABETES. CLASSICALLY ACTIVATED (M1) MACROPHAGES ARE KNOWN TO PLAY A ROLE IN THE DEVELOPMENT OF CHRONIC INFLAMMATION ASSOCIATED WITH IMPAIRED WOUND HEALING IN TYPE 2 DIABETES (T2D); HOWEVER, THE MECHANISM RESPONSIBLE FOR THE DOMINANT PROINFLAMMATORY (M1) MACROPHAGE PHENOTYPE IN T2D WOUNDS IS UNKNOWN. SINCE EPIGENETIC ENZYMES CAN DIRECT MACROPHAGE PHENOTYPES, WE ASSESSED THE ROLE OF HISTONE METHYLATION IN BONE MARROW (BM) STEM/PROGENITOR CELLS IN THE PROGRAMMING OF MACROPHAGES TOWARD A PROINFLAMMATORY PHENOTYPE. WE HAVE FOUND THAT A REPRESSIVE HISTONE METHYLATION MARK, H3K27ME3, IS DECREASED AT THE PROMOTER OF THE IL-12 GENE IN BM PROGENITORS AND THIS EPIGENETIC SIGNATURE IS PASSED DOWN TO WOUND MACROPHAGES IN A MURINE MODEL OF GLUCOSE INTOLERANCE (DIET-INDUCED OBESE). THESE EPIGENETICALLY "PREPROGRAMMED" MACROPHAGES RESULT IN POISED MACROPHAGES IN PERIPHERAL TISSUE AND NEGATIVELY IMPACT WOUND REPAIR. WE FOUND THAT IN DIABETIC CONDITIONS THE H3K27 DEMETHYLASE JMJD3 DRIVES IL-12 PRODUCTION IN MACROPHAGES AND THAT IL-12 PRODUCTION CAN BE MODULATED BY INHIBITING JMJD3. USING HUMAN T2D TISSUE AND MURINE MODELS, WE HAVE IDENTIFIED A PREVIOUSLY UNRECOGNIZED MECHANISM BY WHICH MACROPHAGES ARE PROGRAMMED TOWARD A PROINFLAMMATORY PHENOTYPE, ESTABLISHING A PATTERN OF UNRESTRAINED INFLAMMATION ASSOCIATED WITH NONHEALING WOUNDS. HENCE, HISTONE DEMETHYLASE INHIBITOR-BASED THERAPY MAY REPRESENT A NOVEL TREATMENT OPTION FOR DIABETIC WOUNDS. 2015 6 4974 23 PATHOPHYSIOLOGICAL MECHANISMS LEADING TO MUSCLE LOSS IN CHRONIC KIDNEY DISEASE. LOSS OF MUSCLE PROTEINS IS A DELETERIOUS CONSEQUENCE OF CHRONIC KIDNEY DISEASE (CKD) THAT CAUSES A DECREASE IN MUSCLE STRENGTH AND FUNCTION, AND CAN LEAD TO A REDUCTION IN QUALITY OF LIFE AND INCREASED RISK OF MORBIDITY AND MORTALITY. THE EFFECTIVENESS OF CURRENT TREATMENT STRATEGIES IN PREVENTING OR REVERSING MUSCLE PROTEIN LOSSES IS LIMITED. THE LIMITATIONS LARGELY STEM FROM THE SYSTEMIC NATURE OF DISEASES SUCH AS CKD, WHICH STIMULATE SKELETAL MUSCLE PROTEIN DEGRADATION PATHWAYS WHILE SIMULTANEOUSLY ACTIVATING MECHANISMS THAT IMPAIR MUSCLE PROTEIN SYNTHESIS AND REPAIR. STIMULI THAT INITIATE MUSCLE PROTEIN LOSS INCLUDE METABOLIC ACIDOSIS, INSULIN AND IGF1 RESISTANCE, CHANGES IN HORMONES, CYTOKINES, INFLAMMATORY PROCESSES AND DECREASED APPETITE. A GROWING BODY OF EVIDENCE SUGGESTS THAT SIGNALLING MOLECULES SECRETED FROM MUSCLE CAN ENTER THE CIRCULATION AND SUBSEQUENTLY INTERACT WITH RECIPIENT ORGANS, INCLUDING THE KIDNEYS, WHILE CONVERSELY, PATHOLOGICAL EVENTS IN THE KIDNEY CAN ADVERSELY INFLUENCE PROTEIN METABOLISM IN SKELETAL MUSCLE, DEMONSTRATING THE EXISTENCE OF CROSSTALK BETWEEN KIDNEY AND MUSCLE. TOGETHER, THESE SIGNALS, WHETHER DIRECT OR INDIRECT, INDUCE CHANGES IN THE LEVELS OF REGULATORY AND EFFECTOR PROTEINS VIA ALTERATIONS IN MRNAS, MICRORNAS AND CHROMATIN EPIGENETIC RESPONSES. ADVANCES IN OUR UNDERSTANDING OF THE SIGNALS AND PROCESSES THAT MEDIATE MUSCLE LOSS IN CKD AND OTHER MUSCLE WASTING CONDITIONS WILL SUPPORT THE FUTURE DEVELOPMENT OF THERAPEUTIC STRATEGIES TO REDUCE MUSCLE LOSS. 2022 7 4891 28 OXIDATIVE STRESS AND INFLAMMATORY MARKERS IN PREDIABETES AND DIABETES. PREDIABETES IS A STATE OF ELEVATED PLASMA GLUCOSE IN WHICH THE THRESHOLD FOR DIABETES HAS NOT YET BEEN REACHED AND CAN PREDISPOSE TO THE DEVELOPMENT OF TYPE 2 DIABETES AND CARDIOVASCULAR DISEASES. INSULIN RESISTANCE AND IMPAIRED BETA-CELL FUNCTION ARE OFTEN ALREADY PRESENT IN PREDIABETES. HYPERGLYCEMIA CAN UPREGULATE MARKERS OF CHRONIC INFLAMMATION AND CONTRIBUTE TO INCREASED REACTIVE OXYGEN SPECIES (ROS) GENERATION, WHICH ULTIMATELY CAUSE VASCULAR DYSFUNCTION. CONVERSELY, INCREASED OXIDATIVE STRESS AND INFLAMMATION CAN LEAD TO INSULIN RESISTANCE AND IMPAIRED INSULIN SECRETION. PROPER TREATMENT OF HYPERGLYCEMIA AND INHIBITION OF ROS OVERPRODUCTION IS CRUCIAL FOR DELAYING ONSET OF DIABETES AND FOR PREVENTION OF CARDIOVASCULAR COMPLICATIONS. THUS, IT IS IMPERATIVE TO DETERMINE THE MECHANISMS INVOLVED IN THE PROGRESSION FROM PREDIABETES TO DIABETES INCLUDING A CLARIFICATION OF HOW OLD AND NEW MEDICATIONS AFFECT OXIDATIVE AND IMMUNE MECHANISMS OF DIABETES. IN THIS REVIEW, WE DISCUSS THE RELATIONSHIP BETWEEN OXIDATIVE STRESS AND HYPERGLYCEMIA ALONG WITH LINKS BETWEEN INFLAMMATION AND PREDIABETES. ADDITIONALLY, THE EFFECTS OF HYPERGLYCEMIC MEMORY, MICROVESICLES, MICRO-RNA, AND EPIGENETIC REGULATION ON INFLAMMATION, OXIDATIVE STATE, AND GLYCEMIC CONTROL ARE HIGHLIGHTED. ADIPOSE TISSUE AND THEIR INFLUENCE ON CHRONIC INFLAMMATION ARE ALSO BRIEFLY REVIEWED. FINALLY, THE ROLE OF IMMUNE-TARGETED THERAPIES AND ANTI-DIABETIC MEDICATION ON GLYCEMIC CONTROL AND OXIDATIVE STRESS ARE DISCUSSED. 2019 8 6374 33 THE ROLE OF MITOCHONDRIA IN MYOCARDIAL DAMAGE CAUSED BY ENERGY METABOLISM DISORDERS: FROM MECHANISMS TO THERAPEUTICS. MYOCARDIAL DAMAGE IS THE MOST SERIOUS PATHOLOGICAL CONSEQUENCE OF CARDIOVASCULAR DISEASES AND AN IMPORTANT REASON FOR THEIR HIGH MORTALITY. IN RECENT YEARS, BECAUSE OF THE HIGH PREVALENCE OF SYSTEMIC ENERGY METABOLISM DISORDERS (E.G., OBESITY, DIABETES MELLITUS, AND METABOLIC SYNDROME), COMPLICATIONS OF MYOCARDIAL DAMAGE CAUSED BY THESE DISORDERS HAVE ATTRACTED WIDESPREAD ATTENTION. ENERGY METABOLISM DISORDERS ARE INDEPENDENT OF TRADITIONAL INJURY-RELATED RISK FACTORS, SUCH AS ISCHEMIA, HYPOXIA, TRAUMA, AND INFECTION. AN IMBALANCE OF MYOCARDIAL METABOLIC FLEXIBILITY AND MYOCARDIAL ENERGY DEPLETION ARE USUALLY THE INITIAL CHANGES OF MYOCARDIAL INJURY CAUSED BY ENERGY METABOLISM DISORDERS, AND ABNORMAL MORPHOLOGY AND FUNCTIONAL DESTRUCTION OF THE MITOCHONDRIA ARE THEIR IMPORTANT FEATURES. SPECIFICALLY, MITOCHONDRIA ARE THE CENTERS OF ENERGY METABOLISM, AND RECENT EVIDENCE HAS SHOWN THAT DECREASED MITOCHONDRIAL FUNCTION, CAUSED BY AN IMBALANCE IN MITOCHONDRIAL QUALITY CONTROL, MAY PLAY A KEY ROLE IN MYOCARDIAL INJURY CAUSED BY ENERGY METABOLISM DISORDERS. UNDER CHRONIC ENERGY STRESS, MITOCHONDRIA UNDERGO PATHOLOGICAL FISSION, WHILE MITOPHAGY, MITOCHONDRIAL FUSION, AND BIOGENESIS ARE INHIBITED, AND MITOCHONDRIAL PROTEIN BALANCE AND TRANSFER ARE DISTURBED, RESULTING IN THE ACCUMULATION OF NONFUNCTIONAL AND DAMAGED MITOCHONDRIA. CONSEQUENTLY, DAMAGED MITOCHONDRIA LEAD TO MYOCARDIAL ENERGY DEPLETION AND THE ACCUMULATION OF LARGE AMOUNTS OF REACTIVE OXYGEN SPECIES, FURTHER AGGRAVATING THE IMBALANCE IN MITOCHONDRIAL QUALITY CONTROL AND FORMING A VICIOUS CYCLE. IN ADDITION, IMPAIRED MITOCHONDRIA COORDINATE CALCIUM HOMEOSTASIS IMBALANCE, AND EPIGENETIC ALTERATIONS PARTICIPATE IN THE PATHOGENESIS OF MYOCARDIAL DAMAGE. THESE PATHOLOGICAL CHANGES INDUCE RAPID PROGRESSION OF MYOCARDIAL DAMAGE, EVENTUALLY LEADING TO HEART FAILURE OR SUDDEN CARDIAC DEATH. TO INTERVENE MORE SPECIFICALLY IN THE MYOCARDIAL DAMAGE CAUSED BY METABOLIC DISORDERS, WE NEED TO UNDERSTAND THE SPECIFIC ROLE OF MITOCHONDRIA IN THIS CONTEXT IN DETAIL. ACCORDINGLY, PROMISING THERAPEUTIC STRATEGIES HAVE BEEN PROPOSED. WE ALSO SUMMARIZE THE EXISTING THERAPEUTIC STRATEGIES TO PROVIDE A REFERENCE FOR CLINICAL TREATMENT AND DEVELOPING NEW THERAPIES. 2023 9 1895 26 ENDOTHELIAL DYSFUNCTION IN INDIVIDUALS BORN AFTER FETAL GROWTH RESTRICTION: CARDIOVASCULAR AND RENAL CONSEQUENCES AND PREVENTIVE APPROACHES. INDIVIDUALS BORN AFTER INTRAUTERINE GROWTH RESTRICTION (IUGR) HAVE AN INCREASED RISK OF PERINATAL MORBIDITY/MORTALITY, AND THOSE WHO SURVIVE FACE LONG-TERM CONSEQUENCES SUCH AS CARDIOVASCULAR-RELATED DISEASES, INCLUDING SYSTEMIC HYPERTENSION, ATHEROSCLEROSIS, CORONARY HEART DISEASE AND CHRONIC KIDNEY DISEASE. IN ADDITION TO THE DEMONSTRATED LONG-TERM EFFECTS OF DECREASED NEPHRON ENDOWMENT AND HYPERACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, INDIVIDUALS BORN AFTER IUGR ALSO EXHIBIT EARLY ALTERATIONS IN VASCULAR STRUCTURE AND FUNCTION, WHICH HAVE BEEN IDENTIFIED AS KEY FACTORS OF THE DEVELOPMENT OF CARDIOVASCULAR-RELATED DISEASES. THE ENDOTHELIUM PLAYS A MAJOR ROLE IN MAINTAINING VASCULAR FUNCTION AND HOMEOSTASIS. THEREFORE, IT IS NOT SURPRISING THAT IMPAIRED ENDOTHELIAL FUNCTION CAN LEAD TO THE LONG-TERM DEVELOPMENT OF VASCULAR-RELATED DISEASES. ENDOTHELIAL DYSFUNCTION, PARTICULARLY IMPAIRED ENDOTHELIUM-DEPENDENT VASODILATION AND VASCULAR REMODELING, INVOLVES DECREASED NITRIC OXIDE (NO) BIOAVAILABILITY, IMPAIRED ENDOTHELIAL NO SYNTHASE FUNCTIONALITY, INCREASED OXIDATIVE STRESS, ENDOTHELIAL PROGENITOR CELLS DYSFUNCTION AND ACCELERATED VASCULAR SENESCENCE. PREVENTIVE APPROACHES SUCH AS BREASTFEEDING, SUPPLEMENTATION WITH FOLATE, VITAMINS, ANTIOXIDANTS, L-CITRULLINE, L-ARGININE AND TREATMENT WITH NO MODULATORS REPRESENT PROMISING STRATEGIES FOR IMPROVING ENDOTHELIAL FUNCTION, MITIGATING LONG-TERM OUTCOMES AND POSSIBLY PREVENTING IUGR OF VASCULAR ORIGIN. MOREOVER, THE IDENTIFICATION OF EARLY BIOMARKERS OF ENDOTHELIAL DYSFUNCTION, ESPECIALLY EPIGENETIC BIOMARKERS, COULD ALLOW EARLY SCREENING AND FOLLOW-UP OF INDIVIDUALS AT RISK OF DEVELOPING CARDIOVASCULAR AND RENAL DISEASES, THUS CONTRIBUTING TO THE DEVELOPMENT OF PREVENTIVE AND THERAPEUTIC STRATEGIES TO AVERT THE LONG-TERM EFFECTS OF ENDOTHELIAL DYSFUNCTION IN INFANTS BORN AFTER IUGR. 2017 10 4386 27 MITOCHONDRIAL STRESS INDUCED BY CONTINUOUS STIMULATION UNDER HYPOXIA RAPIDLY DRIVES T CELL EXHAUSTION. CANCER AND CHRONIC INFECTIONS INDUCE T CELL EXHAUSTION, A HYPOFUNCTIONAL FATE CARRYING DISTINCT EPIGENETIC, TRANSCRIPTOMIC AND METABOLIC CHARACTERISTICS. HOWEVER, DRIVERS OF EXHAUSTION REMAIN POORLY UNDERSTOOD. AS INTRATUMORAL EXHAUSTED T CELLS EXPERIENCE SEVERE HYPOXIA, WE HYPOTHESIZED THAT METABOLIC STRESS ALTERS THEIR RESPONSES TO OTHER SIGNALS, SPECIFICALLY, PERSISTENT ANTIGENIC STIMULATION. IN VITRO, ALTHOUGH CD8(+) T CELLS EXPERIENCING CONTINUOUS STIMULATION OR HYPOXIA ALONE DIFFERENTIATED INTO FUNCTIONAL EFFECTORS, THE COMBINATION RAPIDLY DROVE T CELL DYSFUNCTION CONSISTENT WITH EXHAUSTION. CONTINUOUS STIMULATION PROMOTED BLIMP-1-MEDIATED REPRESSION OF PGC-1ALPHA-DEPENDENT MITOCHONDRIAL REPROGRAMMING, RENDERING CELLS POORLY RESPONSIVE TO HYPOXIA. LOSS OF MITOCHONDRIAL FUNCTION GENERATED INTOLERABLE LEVELS OF REACTIVE OXYGEN SPECIES (ROS), SUFFICIENT TO PROMOTE EXHAUSTED-LIKE STATES, IN PART THROUGH PHOSPHATASE INHIBITION AND THE CONSEQUENT ACTIVITY OF NUCLEAR FACTOR OF ACTIVATED T CELLS. REDUCING T CELL-INTRINSIC ROS AND LOWERING TUMOR HYPOXIA LIMITED T CELL EXHAUSTION, SYNERGIZING WITH IMMUNOTHERAPY. THUS, IMMUNOLOGIC AND METABOLIC SIGNALING ARE INTRINSICALLY LINKED: THROUGH MITIGATION OF METABOLIC STRESS, T CELL DIFFERENTIATION CAN BE ALTERED TO PROMOTE MORE FUNCTIONAL CELLULAR FATES. 2021 11 948 27 CHRONIC METABOLIC DERANGEMENT-INDUCED COGNITIVE DEFICITS AND NEUROTOXICITY ARE ASSOCIATED WITH REST INACTIVATION. CHRONIC METABOLIC ALTERATIONS MAY REPRESENT A RISK FACTOR FOR THE DEVELOPMENT OF COGNITIVE IMPAIRMENT, DEMENTIA, OR NEURODEGENERATIVE DISEASES. HYPERGLYCEMIA AND OBESITY ARE KNOWN TO IMPRINT EPIGENETIC MARKERS THAT COMPROMISE THE PROPER EXPRESSION OF CELL SURVIVAL GENES. HERE, WE SHOWED THAT CHRONIC HYPERGLYCEMIA (60 DAYS) INDUCED BY A SINGLE INTRAPERITONEAL INJECTION OF STREPTOZOTOCIN COMPROMISED COGNITION BY REDUCING HIPPOCAMPAL ERK SIGNALING AND BY INDUCING NEUROTOXICITY IN RATS. THE MECHANISMS APPEAR TO BE LINKED TO REDUCED ACTIVE DNA DEMETHYLATION AND DIMINISHED EXPRESSION OF THE NEUROPROTECTIVE TRANSCRIPTION FACTOR REST. THE IMPACT OF THE RELATIONSHIP BETWEEN ADIPOSITY AND DNA HYPERMETHYLATION ON REST EXPRESSION WAS ALSO DEMONSTRATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN OBESE CHILDREN WITH REDUCED LEVELS OF BLOOD ASCORBATE. THE REVERSIBLE NATURE OF EPIGENETIC MODIFICATIONS AND THE COGNITIVE IMPAIRMENT REPORTED IN OBESE CHILDREN, ADOLESCENTS, AND ADULTS SUGGEST THAT THE CORRECTION OF THE ANTHROPOMETRY AND THE PERIPHERAL METABOLIC ALTERATIONS WOULD PROTECT BRAIN HOMEOSTASIS AND REDUCE THE RISK OF DEVELOPING NEURODEGENERATIVE DISEASES. 2019 12 5693 19 SILENCING OF MATERNAL HEPATIC GLUCOCORTICOID RECEPTOR IS ESSENTIAL FOR NORMAL FETAL DEVELOPMENT IN MICE. EXCESSIVE OR CHRONIC STRESS CAN LEAD TO A VARIETY OF DISEASES DUE TO ABERRANT ACTIVATION OF THE GLUCOCORTICOID RECEPTOR (GR), A LIGAND ACTIVATED TRANSCRIPTION FACTOR. PREGNANCY REPRESENTS A PARTICULAR WINDOW OF SENSITIVITY IN WHICH EXCESSIVE STRESS CAN HAVE ADVERSE OUTCOMES, PARTICULARLY ON THE DEVELOPING FETUS. HERE WE SHOW MATERNAL HEPATIC STRESS HORMONE RESPONSIVENESS IS DIMINISHED VIA EPIGENETIC SILENCING OF THE GLUCOCORTICOID RECEPTOR DURING PREGNANCY. PROVOCATIVELY, REINSTALLATION OF GR TO HEPATOCYTES DURING PREGNANCY BY ADENO-ASSOCIATED VIRAL TRANSDUCTION DYSREGULATES GENES INVOLVED IN PROLIFERATION, RESULTING IN IMPAIRED PREGNANCY-INDUCED HEPATOMEGALY. DISRUPTION OF THE MATERNAL HEPATIC ADAPTATION TO PREGNANCY RESULTS IN IN UTERO GROWTH RESTRICTION (IUGR). THESE DATA DEMONSTRATE PREGNANCY ANTAGONIZES THE LIVER-SPECIFIC EFFECTS OF STRESS HORMONE SIGNALING IN THE MATERNAL COMPARTMENT TO ULTIMATELY SUPPORT THE HEALTHY DEVELOPMENT OF EMBRYOS. 2019 13 1302 25 DEFECTIVE FUNCTIONAL BETA-CELL MASS AND TYPE 2 DIABETES IN THE GOTO-KAKIZAKI RAT MODEL. INCREASING EVIDENCE INDICATES THAT DECREASED FUNCTIONAL BETA-CELL MASS IS THE HALLMARK OF TYPE 2 DIABETES MELLITUS. THEREFORE, THE DEBATE FOCUSES ON THE POSSIBLE MECHANISMS RESPONSIBLE FOR ABNORMAL ISLET MICROENVIRONMENT, DECREASED BETA-CELL NUMBER, IMPAIRED BETA-CELL FUNCTION AND THEIR MULTIFACTORIAL ETIOLOGIES. THE INFORMATION AVAILABLE ON THE GOTO-KAKIZAKI/PAR RAT LINE, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS TYPE 2 DIABETES MELLITUS, ARE REVIEWED IN SUCH A PERSPECTIVE. WE PROPOSE THAT THE DEFECTIVE BETA-CELL MASS AND FUNCTION IN THE GOTO-KAKIZAKI/PAR MODEL REFLECT THE COMPLEX INTERACTIONS OF MULTIPLE PATHOGENIC PLAYERS, INCLUDING SEVERAL INDEPENDENT LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS (BUT NOT DECREASED BETA-CELL MASS), GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE PANCREAS (DECREASED BETA-CELL NEOGENESIS), WHICH IS TRANSMITTED TO THE NEXT GENERATION, AND LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA, INFLAMMATORY MEDIATORS, OXIDATIVE STRESS AND PERTURBED ISLET MICROARCHITECTURE. 2007 14 1383 26 DIABETES AND ITS CARDIOVASCULAR COMPLICATIONS: POTENTIAL ROLE OF THE ACETYLTRANSFERASE P300. DIABETES HAS BEEN SHOWN TO ACCELERATE VASCULAR SENESCENCE, WHICH IS ASSOCIATED WITH CHRONIC INFLAMMATION AND OXIDATIVE STRESS, BOTH IMPLICATED IN THE DEVELOPMENT OF ENDOTHELIAL DYSFUNCTION. THIS CONDITION REPRESENTS THE INITIAL ALTERATION LINKING DIABETES TO RELATED CARDIOVASCULAR (CV) COMPLICATIONS. RECENTLY, IT HAS BEEN HYPOTHESISED THAT THE ACETYLTRANSFERASE, P300, MAY CONTRIBUTE TO ESTABLISHING AN EARLY VASCULAR SENESCENT PHENOTYPE, PLAYING A RELEVANT ROLE IN DIABETES-ASSOCIATED INFLAMMATION AND OXIDATIVE STRESS, WHICH DRIVE ENDOTHELIAL DYSFUNCTION. SPECIFICALLY, P300 CAN MODULATE VASCULAR INFLAMMATION THROUGH EPIGENETIC MECHANISMS AND TRANSCRIPTION FACTORS ACETYLATION. INDEED, IT REGULATES THE INFLAMMATORY PATHWAY BY INTERACTING WITH NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS P65 SUBUNIT (NF-KAPPAB P65) OR BY INDUCING ITS ACETYLATION, SUGGESTING A CRUCIAL ROLE OF P300 AS A BRIDGE BETWEEN NF-KAPPAB P65 AND THE TRANSCRIPTIONAL MACHINERY. ADDITIONALLY, P300-MEDIATED EPIGENETIC MODIFICATIONS COULD BE UPSTREAM OF THE ACTIVATION OF INFLAMMATORY CYTOKINES, AND THEY MAY INDUCE OXIDATIVE STRESS BY AFFECTING THE PRODUCTION OF REACTIVE OXYGEN SPECIES (ROS). BECAUSE SEVERAL IN VITRO AND IN VIVO STUDIES SHED LIGHT ON THE POTENTIAL USE OF ACETYLTRANSFERASE INHIBITORS, A BETTER UNDERSTANDING OF THE MECHANISMS UNDERLYING THE ROLE OF P300 IN DIABETIC VASCULAR DYSFUNCTION COULD HELP IN FINDING NEW STRATEGIES FOR THE CLINICAL MANAGEMENT OF CV DISEASES RELATED TO DIABETES. 2023 15 5471 29 RESPIRATORY MUSCLE SENESCENCE IN AGEING AND CHRONIC LUNG DISEASES. AGEING IS A PROGRESSIVE CONDITION THAT USUALLY LEADS TO THE LOSS OF PHYSIOLOGICAL PROPERTIES. THIS PROCESS IS ALSO PRESENT IN RESPIRATORY MUSCLES, WHICH ARE AFFECTED BY BOTH SENESCENT CHANGES OCCURRING IN THE WHOLE ORGANISM AND THOSE THAT ARE MORE SPECIFIC FOR MUSCLES. THE MECHANISMS OF THE LATTER CHANGES INCLUDE OXIDATIVE STRESS, DECREASE IN NEUROTROPHIC FACTORS AND DNA ABNORMALITIES. AGEING NORMALLY COEXISTS WITH COMORBIDITIES, INCLUDING RESPIRATORY DISEASES, WHICH FURTHER DETERIORATE THE STRUCTURE AND FUNCTION OF RESPIRATORY MUSCLES. IN THIS CONTEXT, CHANGES INTRINSIC TO AGEING BECOME ENHANCED BY MORE SPECIFIC FACTORS SUCH AS THE IMPAIRMENT IN LUNG MECHANICS AND GAS EXCHANGE, EXACERBATIONS AND HYPOXIA. HYPOXIA IN PARTICULAR HAS A DIRECT EFFECT ON MUSCLES, MAINLY THROUGH THE EXPRESSION OF INDUCIBLE FACTORS (HYPOXIC-INDUCIBLE FACTOR), AND CAN RESULT IN OXIDATIVE STRESS AND CHANGES IN DNA, DECREASE IN MITOCHONDRIAL BIOGENESIS AND DEFECTS IN THE TISSUE REPAIR MECHANISMS. INTENSE EXERCISE CAN ALSO CAUSE DAMAGE IN RESPIRATORY MUSCLES OF ELDERLY RESPIRATORY PATIENTS, BUT THIS CAN BE FOLLOWED BY TISSUE REPAIR AND REMODELLING. HOWEVER, AGEING INTERFERES WITH MUSCLE REPAIR BY TAMPERING WITH THE FUNCTION OF SATELLITE CELLS, MAINLY DUE TO OXIDATIVE STRESS, DNA DAMAGE AND EPIGENETIC MECHANISMS. IN ADDITION TO THE NORMAL PROCESS OF AGEING, STRESS-INDUCED PREMATURE SENESCENCE CAN ALSO OCCUR, INVOLVING CHANGES IN THE EXPRESSION OF MULTIPLE GENES BUT WITHOUT MODIFICATIONS IN TELOMERE LENGTH. 2020 16 3436 24 HYPERGLYCEMIC MEMORY OF INNATE IMMUNE CELLS PROMOTES IN VITRO PROINFLAMMATORY RESPONSES OF HUMAN MONOCYTES AND MURINE MACROPHAGES. IT HAS BEEN WELL ESTABLISHED THAT THE PRESENCE OF DIABETES IS ACCOMPANIED BY A CHRONIC INFLAMMATORY STATE PROMOTING VARIOUS DIABETES-ASSOCIATED COMPLICATIONS. ONE POTENTIAL DRIVER OF THIS ENHANCED INFLAMMATORY STATE IN PATIENTS WITH DIABETES IS HYPERGLYCEMIA. EVEN AFTER BLOOD GLUCOSE CONTROL IS ACHIEVED, DIABETES-ASSOCIATED COMPLICATIONS PERSIST, SUGGESTING THE PRESENCE OF A "HYPERGLYCEMIC MEMORY." INNATE IMMUNE CELLS, CRITICALLY INVOLVED IN VARIOUS COMPLICATIONS ASSOCIATED WITH DIABETES, CAN BUILD NONSPECIFIC, IMMUNOLOGICAL MEMORY (TRAINED IMMUNITY) VIA EPIGENETIC REGULATION. WE EXAMINE THE POTENTIAL INVOLVEMENT OF HYPERGLYCEMIA-INDUCED TRAINED IMMUNITY IN PROMOTING INFLAMMATION. OUR RESULTS SHOW THAT HYPERGLYCEMIA INDUCES A TRAINED PHENOTYPE IN VIVO IN MICE AND IN VITRO IN HUMAN MONOCYTES, REPRESENTATIVE BY AN INCREASED TNF-ALPHA SECRETION AFTER EX VIVO STIMULATION WITH LPS. THESE EFFECTS WERE LARGELY MEDIATED BY EPIGENETIC CHANGES CONTROLLED BY THE MIXED LINEAGE LEUKEMIA (MLL) FAMILY BECAUSE TREATMENT WITH THE MLL INHIBITOR MENIN-MLL DURING THE PROCESS OF TRAINED IMMUNITY ACQUISITION REPRESSED THE PROINFLAMMATORY PHENOTYPE. COLLECTIVELY, OUR RESULTS IDENTIFY A NOVEL LINK BETWEEN HYPERGLYCEMIA AND INFLAMMATION IN INNATE IMMUNE CELLS THAT MIGHT EXPLAIN THE INCREASED PROINFLAMMATORY STATE DURING DIABETES POTENTIALLY CONTRIBUTING TO THE DEVELOPMENT OF VARIOUS DIABETES-ASSOCIATED COMPLICATIONS. 2021 17 3341 28 HISTONE DEACETYLASE-2 IS INVOLVED IN STRESS-INDUCED COGNITIVE IMPAIRMENT VIA HISTONE DEACETYLATION AND PI3K/AKT SIGNALING PATHWAY MODIFICATION. EXPOSURE TO CHRONIC STRESS UPREGULATES BLOOD GLUCOCORTICOID LEVELS AND IMPAIRS COGNITION VIA DIVERSE EPIGENETIC MECHANISMS, SUCH AS HISTONE DEACETYLATION. HISTONE DEACETYLATION CAN LEAD TO TRANSCRIPTIONAL SILENCING OF MANY PROTEINS INVOLVED IN COGNITION AND MAY ALSO CAUSE LEARNING AND MEMORY DYSFUNCTION. HISTONE DEACETYLASE?2 (HDAC2) HAS BEEN DEMONSTRATED TO EPIGENETICALLY BLOCK COGNITION VIA A REDUCTION IN THE HISTONE ACETYLATION LEVEL; HOWEVER, IT IS UNKNOWN WHETHER HDAC2 IS INVOLVED IN THE COGNITIVE DECLINE INDUCED BY CHRONIC STRESS. TO THE BEST OF AUTHORS' KNOWLEDGE, THIS IS THE FIRST STUDY TO DEMONSTRATE THAT THE STRESS HORMONE CORTICOSTEROID UPREGULATE HDAC2 PROTEIN LEVELS IN NEURO?2A CELLS AND CAUSE CELL INJURIES. HDAC2 KNOCKDOWN RESULTED IN A SIGNIFICANT AMELIORATION OF THE PATHOLOGICAL CHANGES IN N2A CELLS VIA THE UPREGULATION OF HISTONE ACETYLATION AND MODIFICATIONS IN THE PHOSPHOINOSITIDE 3?KINASE/PROTEIN KINASE B SIGNALING PATHWAY. IN ADDITION, THE HDAC2 PROTEIN LEVELS WERE UPREGULATED IN 12?MONTH?OLD FEMALE C57BL/6J MICE UNDER CHRONIC STRESS IN VIVO. TAKEN TOGETHER, THESE FINDINGS SUGGESTED THAT HDAC2 MAY BE AN IMPORTANT NEGATIVE REGULATOR INVOLVED IN CHRONIC STRESS?INDUCED COGNITIVE IMPAIRMENT. 2017 18 6357 28 THE ROLE OF HYPERGLYCAEMIA IN THE DEVELOPMENT OF DIABETIC CARDIOMYOPATHY. DIABETES MELLITUS IS A METABOLIC DISORDER WITH A CHRONIC HYPERGLYCAEMIC STATE. CARDIOVASCULAR DISEASES ARE THE PRIMARY CAUSE OF MORTALITY IN PATIENTS WITH DIABETES. INCREASING EVIDENCE SUPPORTS THE EXISTENCE OF DIABETIC CARDIOMYOPATHY, A CARDIAC DYSFUNCTION WITH IMPAIRED CARDIAC CONTRACTION AND RELAXATION, INDEPENDENT OF CORONARY AND/OR VALVULAR COMPLICATIONS. DIABETIC CARDIOMYOPATHY CAN LEAD TO HEART FAILURE. SEVERAL PRECLINICAL AND CLINICAL STUDIES HAVE AIMED TO DECIPHER THE UNDERLYING MECHANISMS OF DIABETIC CARDIOMYOPATHY. AMONG ALL THE CO-FACTORS, HYPERGLYCAEMIA SEEMS TO PLAY AN IMPORTANT ROLE IN THIS PATHOLOGY. HYPERGLYCAEMIA HAS BEEN SHOWN TO ALTER CARDIAC METABOLISM AND FUNCTION THROUGH SEVERAL DELETERIOUS MECHANISMS, SUCH AS OXIDATIVE STRESS, INFLAMMATION, ACCUMULATION OF ADVANCED GLYCATED END-PRODUCTS AND UPREGULATION OF THE HEXOSAMINE BIOSYNTHESIS PATHWAY. THESE MECHANISMS ARE RESPONSIBLE FOR THE ACTIVATION OF HYPERTROPHIC PATHWAYS, EPIGENETIC MODIFICATIONS, MITOCHONDRIAL DYSFUNCTION, CELL APOPTOSIS, FIBROSIS AND CALCIUM MISHANDLING, LEADING TO CARDIAC STIFFNESS, AS WELL AS CONTRACTILE AND RELAXATION DYSFUNCTION. THIS REVIEW AIMS TO DESCRIBE THE HYPERGLYCAEMIC-INDUCED ALTERATIONS THAT PARTICIPATE IN DIABETIC CARDIOMYOPATHY, AND THEIR CORRELATION WITH THE SEVERITY OF THE DISEASE AND PATIENT MORTALITY, AND TO PROVIDE AN OVERVIEW OF CARDIAC OUTCOMES OF GLUCOSE-LOWERING THERAPY. 2021 19 799 24 CELLULAR SIGNALING AND POTENTIAL NEW TREATMENT TARGETS IN DIABETIC RETINOPATHY. DYSFUNCTION AND DEATH OF MICROVASCULAR CELLS AND IMBALANCE BETWEEN THE PRODUCTION AND THE DEGRADATION OF EXTRACELLULAR MATRIX (ECM) PROTEINS ARE A CHARACTERISTIC FEATURE OF DIABETIC RETINOPATHY (DR). GLUCOSE-INDUCED BIOCHEMICAL ALTERATIONS IN THE VASCULAR ENDOTHELIAL CELLS MAY ACTIVATE A CASCADE OF SIGNALING PATHWAYS LEADING TO INCREASED PRODUCTION OF ECM PROTEINS AND CELLULAR DYSFUNCTION/DEATH. CHRONIC DIABETES LEADS TO THE ACTIVATION OF A NUMBER OF SIGNALING PROTEINS INCLUDING PROTEIN KINASE C, PROTEIN KINASE B, AND MITOGEN-ACTIVATED PROTEIN KINASES. THESE SIGNALING CASCADES ARE ACTIVATED IN RESPONSE TO HYPERGLYCEMIA-INDUCED OXIDATIVE STRESS, POLYOL PATHWAY, AND ADVANCED GLYCATION END PRODUCT FORMATION AMONG OTHERS. THE ABERRANT SIGNALING PATHWAYS ULTIMATELY LEAD TO ACTIVATION OF TRANSCRIPTION FACTORS SUCH AS NUCLEAR FACTOR-KAPPAB AND ACTIVATING PROTEIN-1. THE ACTIVITY OF THESE TRANSCRIPTION FACTORS IS ALSO REGULATED BY EPIGENETIC MECHANISMS THROUGH TRANSCRIPTIONAL COACTIVATOR P300. THESE COMPLEX SIGNALING PATHWAYS MAY BE INVOLVED IN GLUCOSE-INDUCED ALTERATIONS OF ENDOTHELIAL CELL PHENOTYPE LEADING TO THE PRODUCTION OF INCREASED ECM PROTEINS AND VASOACTIVE EFFECTOR MOLECULES CAUSING FUNCTIONAL AND STRUCTURAL CHANGES IN THE MICROVASCULATURE. UNDERSTANDING OF SUCH MECHANISTIC PATHWAYS WILL HELP TO DEVELOP FUTURE ADJUVANT THERAPIES FOR DIABETIC RETINOPATHY. 2007 20 5816 25 STRESS AND STEM CELLS. THE UNIQUE PROPERTIES AND FUNCTIONS OF STEM CELLS MAKE THEM PARTICULARLY SUSCEPTIBLE TO STRESSES AND ALSO LEAD TO THEIR REGULATION BY STRESS. STEM CELL DIVISION MUST RESPOND TO THE DEMAND TO REPLENISH CELLS DURING NORMAL TISSUE TURNOVER AS WELL AS IN RESPONSE TO DAMAGE. OXIDATIVE STRESS, MECHANICAL STRESS, GROWTH FACTORS, AND CYTOKINES SIGNAL STEM CELL DIVISION AND DIFFERENTIATION. MANY OF THE CONSERVED PATHWAYS REGULATING STEM CELL SELF-RENEWAL AND DIFFERENTIATION ARE ALSO STRESS-RESPONSE PATHWAYS. THE LONG LIFE SPAN AND DIVISION POTENTIAL OF STEM CELLS CREATE A PROPENSITY FOR TRANSFORMATION (CANCER) AND SPECIFIC STRESS RESPONSES SUCH AS APOPTOSIS AND SENESCENCE ACT AS ANTITUMOR MECHANISMS. QUIESCENCE REGULATED BY CDK INHIBITORS AND A HYPOXIC NICHE REGULATED BY FOXO TRANSCRIPTION FACTOR FUNCTION TO REDUCE STRESS FOR SEVERAL TYPES OF STEM CELLS TO FACILITATE LONG-TERM MAINTENANCE. AGING IS A PARTICULARLY RELEVANT STRESS FOR STEM CELLS, BECAUSE REPEATED DEMANDS ON STEM CELL FUNCTION OVER THE LIFE SPAN CAN HAVE CUMULATIVE CELL-AUTONOMOUS EFFECTS INCLUDING EPIGENETIC DYSREGULATION, MUTATIONS, AND TELOMERE EROSION. IN ADDITION, AGING OF THE ORGANISM IMPAIRS FUNCTION OF THE STEM CELL NICHE AND SYSTEMIC SIGNALS, INCLUDING CHRONIC INFLAMMATION AND OXIDATIVE STRESS. 2012