1 1374 132 DEVELOPMENTAL PROGRAMMING OF ADULT DISEASE: REPROGRAMMING BY MELATONIN? ADULT-ONSET CHRONIC NON-COMMUNICABLE DISEASES (NCDS) CAN ORIGINATE FROM EARLY LIFE THROUGH SO-CALLED THE "DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" (DOHAD) OR "DEVELOPMENTAL PROGRAMMING". THE DOHAD CONCEPT OFFERS THE "REPROGRAMMING" STRATEGY TO SHIFT THE TREATMENT FROM ADULTHOOD TO EARLY LIFE, BEFORE CLINICAL DISEASE IS APPARENT. MELATONIN, AN ENDOGENOUS INDOLEAMINE PRODUCED BY THE PINEAL GLAND, HAS PLEIOTROPIC BIOACTIVITIES THOSE ARE BENEFICIAL IN A VARIETY OF HUMAN DISEASES. EMERGING EVIDENCE SUPPORT THAT MELATONIN IS CLOSELY INTER-RELATED TO OTHER PROPOSED MECHANISMS CONTRIBUTING TO THE DEVELOPMENTAL PROGRAMMING OF A VARIETY OF CHRONIC NCDS. RECENT ANIMAL STUDIES HAVE BEGUN TO UNRAVEL THE MULTIFUNCTIONAL ROLES OF MELATONIN IN MANY EXPERIMENTAL MODELS OF DEVELOPMENTAL PROGRAMMING. EVEN THOUGH SOME PROGRESS HAS BEEN MADE IN RESEARCH ON MELATONIN AS A REPROGRAMMING STRATEGY TO PREVENT DOHAD-RELATED NCDS, FUTURE HUMAN STUDIES SHOULD AIM AT FILLING THE TRANSLATIONAL GAP BETWEEN ANIMAL MODELS AND CLINICAL TRIALS. HERE, WE REVIEW SEVERAL KEY THEMES ON THE REPROGRAMMING EFFECTS OF MELATONIN IN DOHAD RESEARCH. WE HAVE PARTICULARLY FOCUSED ON THE FOLLOWING AREAS: MECHANISMS OF DEVELOPMENTAL PROGRAMMING; THE INTERRELATIONSHIP BETWEEN MELATONIN AND MECHANISMS UNDERLYING DEVELOPMENTAL PROGRAMMING; PATHOPHYSIOLOGICAL ROLES OF MELATONIN IN PREGNANCY AND FETAL DEVELOPMENT; AND INSIGHT PROVIDED BY ANIMAL MODELS TO SUPPORT MELATONIN AS A REPROGRAMMING THERAPY. RATES OF NCDS ARE INCREASING FASTER THAN ANTICIPATED ALL OVER THE WORLD. HENCE, THERE IS AN URGENT NEED TO UNDERSTAND REPROGRAMMING MECHANISMS OF MELATONIN AND TO TRANSLATE EXPERIMENTAL RESEARCH INTO CLINICAL PRACTICE FOR HALTING A GROWING LIST OF DOHAD-RELATED NCDS. 2017 2 5293 26 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 1366 53 DEVELOPMENTAL ORIGINS OF CHRONIC KIDNEY DISEASE: SHOULD WE FOCUS ON EARLY LIFE? CHRONIC KIDNEY DISEASE (CKD) IS BECOMING A GLOBAL BURDEN, DESPITE RECENT ADVANCES IN MANAGEMENT. CKD CAN BEGIN IN EARLY LIFE BY SO-CALLED "DEVELOPMENTAL PROGRAMMING" OR "DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" (DOHAD). EARLY-LIFE INSULTS CAUSE STRUCTURAL AND FUNCTIONAL CHANGES IN THE DEVELOPING KIDNEY, WHICH IS CALLED RENAL PROGRAMMING. EPIDEMIOLOGICAL AND EXPERIMENTAL EVIDENCE SUPPORTS THE PROPOSITION THAT EARLY-LIFE ADVERSE EVENTS LEAD TO RENAL PROGRAMMING AND MAKE SUBJECTS VULNERABLE TO DEVELOPING CKD AND ITS COMORBIDITIES IN LATER LIFE. IN ADDITION TO LOW NEPHRON ENDOWMENT, SEVERAL MECHANISMS HAVE BEEN PROPOSED FOR RENAL PROGRAMMING. THE DOHAD CONCEPT OPENS A NEW WINDOW TO OFFSET THE PROGRAMMING PROCESS IN EARLY LIFE TO PREVENT THE DEVELOPMENT OF ADULT KIDNEY DISEASE, NAMELY REPROGRAMMING. HERE, WE REVIEW THE KEY THEMES ON THE DEVELOPMENTAL ORIGINS OF CKD. WE HAVE PARTICULARLY FOCUSED ON THE FOLLOWING AREAS: EVIDENCE FROM HUMAN STUDIES SUPPORT FETAL PROGRAMMING OF KIDNEY DISEASE; INSIGHT FROM ANIMAL MODELS OF RENAL PROGRAMMING; HYPOTHETICAL MECHANISMS OF RENAL PROGRAMMING; ALTERATIONS OF RENAL TRANSCRIPTOME IN RESPONSE TO EARLY-LIFE INSULTS; AND THE APPLICATION OF REPROGRAMMING INTERVENTIONS TO PREVENT THE PROGRAMMING OF KIDNEY DISEASE. 2017 4 1302 22 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 5 3859 25 ISLET STRUCTURE AND FUNCTION IN THE GK RAT. TYPE 2 DIABETES MELLITUS (T2D) ARISES WHEN THE ENDOCRINE PANCREAS FAILS TO SECRETE SUFFICIENT INSULIN TO COPE WITH THE METABOLIC DEMAND BECAUSE OF BETA-CELL SECRETORY DYSFUNCTION AND/OR DECREASED BETA-CELL MASS. DEFINING THE NATURE OF THE PANCREATIC ISLET DEFECTS PRESENT IN T2D HAS BEEN DIFFICULT, IN PART BECAUSE HUMAN ISLETS ARE INACCESSIBLE FOR DIRECT STUDY. THIS REVIEW IS AIMED TO ILLUSTRATE TO WHAT EXTENT THE GOTO-KAKIZAKI RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2D, HAS PROVED TO BE A VALUABLE TOOL OFFERING SUFFICIENT COMMONALITIES TO STUDY THIS ASPECT. A COMPREHENSIVE COMPENDIUM OF THE MULTIPLE FUNCTIONAL GK ISLET ABNORMALITIES SO FAR IDENTIFIED IS PROPOSED IN THIS PERSPECTIVE. THE PATHOGENESIS OF DEFECTIVE BETA-CELL NUMBER AND FUNCTION IN THE GK MODEL IS ALSO DISCUSSED. IT IS PROPOSED THAT THE DEVELOPMENT OF T2D IN THE GK MODEL RESULTS FROM THE COMPLEX INTERACTION OF MULTIPLE EVENTS: (I) SEVERAL SUSCEPTIBILITY LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS (DISTINCT LOCI ENCODING IMPAIRMENT OF BETA-CELL METABOLISM AND INSULIN EXOCYTOSIS, BUT NO QUANTITATIVE TRAIT LOCUS FOR DECREASED BETA-CELL MASS); (II) GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE OFFSPRING PANCREAS (DECREASED BETA-CELL NEOGENESIS AND PROLIFERATION) TRANSMITTED OVER GENERATIONS; AND (III) LOSS OF BETA-CELL DIFFERENTIATION RELATED TO CHRONIC EXPOSURE TO HYPERGLYCAEMIA/HYPERLIPIDAEMIA, ISLET INFLAMMATION, ISLET OXIDATIVE STRESS, ISLET FIBROSIS AND PERTURBED ISLET VASCULATURE. 2010 6 6163 25 THE GK RAT BETA-CELL: A PROTOTYPE FOR THE DISEASED HUMAN BETA-CELL IN TYPE 2 DIABETES? INCREASING EVIDENCE INDICATES THAT DECREASED FUNCTIONAL BETA-CELL MASS IS THE HALLMARK OF TYPE 2 DIABETES (T2D) MELLITUS. NOWADAYS, THE DEBATE FOCUSES ON THE POSSIBLE MECHANISMS RESPONSIBLE FOR ABNORMAL ISLET MICROENVIRONMENT, DECREASED BETA-CELL NUMBER, IMPAIRED BETA-CELL FUNCTION, AND THEIR MULTIFACTORIAL AETIOLOGIES. THIS REVIEW IS AIMED TO ILLUSTRATE TO WHAT EXTEND THE GOTO-KAKIZAKI RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2D, HAS PROVED BE A VALUABLE TOOL OFFERING SUFFICIENT COMMONALITIES TO STUDY THESE ASPECTS. WE PROPOSE THAT THE DEFECTIVE BETA-CELL MASS AND FUNCTION IN THE GK MODEL REFLECT THE COMPLEX INTERACTIONS OF MULTIPLE PATHOGENIC PLAYERS: (I) SEVERAL INDEPENDENT LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS (BUT NOT DECREASED BETA-CELL MASS); (II) GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE PANCREAS (DECREASED BETA-CELL NEOGENESIS AND/OR PROLIFERATION) WHICH IS TRANSMITTED TO THE NEXT GENERATION; AND (III) LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA/HYPERLIPIDEMIA, INFLAMMATORY MEDIATORS, OXIDATIVE STRESS AND TO PERTURBED ISLET MICROARCHITECTURE. 2009 7 5250 23 PROGRAMMED DISORDERS OF BETA-CELL DEVELOPMENT AND FUNCTION AS ONE CAUSE FOR TYPE 2 DIABETES? THE GK RAT PARADIGM. NOW THAT THE REDUCTION IN BETA-MASS HAS BEEN CLEARLY ESTABLISHED IN HUMANS WITH TYPE 2 DIABETES MELLITUS (T2DM) 1-4, THE DEBATE FOCUSES ON THE POSSIBLE MECHANISMS RESPONSIBLE FOR DECREASED BETA-CELL NUMBER AND IMPAIRED BETA-CELL FUNCTION AND THEIR MULTIFACTORIAL ETIOLOGY. APPROPRIATE INBRED RODENT MODELS ARE ESSENTIAL TOOLS FOR IDENTIFICATION OF GENES AND ENVIRONMENTAL FACTORS THAT INCREASE THE RISK OF ABNORMAL BETA-CELL FUNCTION AND OF T2DM. THE INFORMATION AVAILABLE IN THE GOTO-KAKIZAKI (GK) RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2DM, ARE REVIEWED IN SUCH A PERSPECTIVE. WE PROPOSE THAT THE DEFECTIVE BETA-CELL MASS AND FUNCTION IN THE GK MODEL REFLECT THE COMPLEX INTERACTIONS OF THREE PATHOGENIC PLAYERS: (1) SEVERAL INDEPENDENT LOCI CONTAINING GENES CAUSING IMPAIRED INSULIN SECRETION; (2) GESTATIONAL METABOLIC IMPAIRMENT INDUCING A PROGRAMMING OF ENDOCRINE PANCREAS (DECREASED BETA-CELL NEOGENESIS) WHICH IS TRANSMITTED TO THE NEXT GENERATION; AND (3) SECONDARY (ACQUIRED) LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA (GLUCOTOXICITY). AN IMPORTANT MESSAGE IS THAT THE 'HERITABLE' DETERMINANTS OF T2DM ARE NOT SIMPLY DEPENDANT ON GENETIC FACTORS, BUT PROBABLY INVOLVE TRANSGENERATIONAL EPIGENETIC RESPONSES. 2005 8 6606 31 TYPE 2 DIABETES ACROSS GENERATIONS: FROM PATHOPHYSIOLOGY TO PREVENTION AND MANAGEMENT. TYPE 2 DIABETES IS NOW A PANDEMIC AND SHOWS NO SIGNS OF ABATEMENT. IN THIS SEMINAR WE REVIEW THE PATHOPHYSIOLOGY OF THIS DISORDER, WITH PARTICULAR ATTENTION TO EPIDEMIOLOGY, GENETICS, EPIGENETICS, AND MOLECULAR CELL BIOLOGY. EVIDENCE IS EMERGING THAT A SUBSTANTIAL PART OF DIABETES SUSCEPTIBILITY IS ACQUIRED EARLY IN LIFE, PROBABLY OWING TO FETAL OR NEONATAL PROGRAMMING VIA EPIGENETIC PHENOMENA. MATERNAL AND EARLY CHILDHOOD HEALTH MIGHT, THEREFORE, BE CRUCIAL TO THE DEVELOPMENT OF EFFECTIVE PREVENTION STRATEGIES. DIABETES DEVELOPS BECAUSE OF INADEQUATE ISLET BETA-CELL AND ADIPOSE-TISSUE RESPONSES TO CHRONIC FUEL EXCESS, WHICH RESULTS IN SO-CALLED NUTRIENT SPILLOVER, INSULIN RESISTANCE, AND METABOLIC STRESS. THE LATTER DAMAGES MULTIPLE ORGANS. INSULIN RESISTANCE, WHILE FORCING BETA CELLS TO WORK HARDER, MIGHT ALSO HAVE AN IMPORTANT DEFENSIVE ROLE AGAINST NUTRIENT-RELATED TOXIC EFFECTS IN TISSUES SUCH AS THE HEART. REVERSAL OF OVERNUTRITION, HEALING OF THE BETA CELLS, AND LESSENING OF ADIPOSE TISSUE DEFECTS SHOULD BE TREATMENT PRIORITIES. 2011 9 5951 33 TARGETING THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM TO PREVENT HYPERTENSION AND KIDNEY DISEASE OF DEVELOPMENTAL ORIGINS. THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) IS IMPLICATED IN HYPERTENSION AND KIDNEY DISEASE. THE DEVELOPING KIDNEY CAN BE PROGRAMMED BY VARIOUS EARLY-LIFE INSULTS BY SO-CALLED RENAL PROGRAMMING, RESULTING IN HYPERTENSION AND KIDNEY DISEASE IN ADULTHOOD. THIS THEORY IS KNOWN AS DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD). CONVERSELY, EARLY RAAS-BASED INTERVENTIONS COULD REVERSE PROGRAM PROCESSES TO PREVENT A DISEASE FROM OCCURRING BY SO-CALLED REPROGRAMMING. IN THE CURRENT REVIEW, WE MAINLY SUMMARIZE (1) THE CURRENT KNOWLEDGE ON THE RAAS IMPLICATED IN RENAL PROGRAMMING; (2) CURRENT EVIDENCE SUPPORTING THE CONNECTIONS BETWEEN THE ABERRANT RAAS AND OTHER MECHANISMS BEHIND RENAL PROGRAMMING, SUCH AS OXIDATIVE STRESS, NITRIC OXIDE DEFICIENCY, EPIGENETIC REGULATION, AND GUT MICROBIOTA DYSBIOSIS; AND (3) AN OVERVIEW OF HOW RAAS-BASED REPROGRAMMING INTERVENTIONS MAY PREVENT HYPERTENSION AND KIDNEY DISEASE OF DEVELOPMENTAL ORIGINS. TO ACCELERATE THE TRANSITION OF RAAS-BASED INTERVENTIONS FOR PREVENTION OF HYPERTENSION AND KIDNEY DISEASE, AN EXTENDED COMPREHENSION OF THE RAAS IMPLICATED IN RENAL PROGRAMMING IS NEEDED, AS WELL AS A GREATER FOCUS ON FURTHER CLINICAL TRANSLATION. 2021 10 6164 24 THE GK RAT: A PROTOTYPE FOR THE STUDY OF NON-OVERWEIGHT TYPE 2 DIABETES. TYPE 2 DIABETES MELLITUS (T2D) ARISES WHEN THE ENDOCRINE PANCREAS FAILS TO SECRETE SUFFICIENT INSULIN TO COPE WITH THE METABOLIC DEMAND BECAUSE OF BETA-CELL SECRETORY DYSFUNCTION AND/OR DECREASED BETA-CELL MASS. DEFINING THE NATURE OF THE PANCREATIC ISLET DEFECTS PRESENT IN T2D HAS BEEN DIFFICULT, IN PART BECAUSE HUMAN ISLETS ARE INACCESSIBLE FOR DIRECT STUDY. THIS REVIEW IS AIMED TO ILLUSTRATE TO WHAT EXTENT THE GOTO KAKIZAKI RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2D, HAS PROVED TO BE A VALUABLE TOOL OFFERING SUFFICIENT COMMONALITIES TO STUDY THIS ASPECT. A COMPREHENSIVE COMPENDIUM OF THE MULTIPLE FUNCTIONAL GK ABNORMALITIES SO FAR IDENTIFIED IS PROPOSED IN THIS PERSPECTIVE, TOGETHER WITH THEIR TIME-COURSE AND INTERACTIONS. A SPECIAL FOCUS IS GIVEN TOWARD THE PATHOGENESIS OF DEFECTIVE BETA-CELL NUMBER AND FUNCTION IN THE GK MODEL. IT IS PROPOSED THAT THE DEVELOPMENT OF T2D IN THE GK MODEL RESULTS FROM THE COMPLEX INTERACTION OF MULTIPLE EVENTS: (1) SEVERAL SUSCEPTIBILITY LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS; (2) GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE OFFSPRING PANCREAS AND THE MAJOR INSULIN TARGET TISSUES; AND (3) ENVIRONMENTALLY INDUCED LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA/HYPERLIPIDEMIA, INFLAMMATION, AND OXIDATIVE STRESS. 2012 11 4995 37 PERINATAL ENVIRONMENT AND ITS INFLUENCES ON METABOLIC PROGRAMMING OF OFFSPRING. THE INTRAUTERINE ENVIRONMENT SUPPORTS THE DEVELOPMENT AND HEALTH OF OFFSPRING. PERTURBATIONS TO THIS ENVIRONMENT CAN HAVE DETRIMENTAL EFFECTS ON THE FETUS THAT HAVE PERSISTENT PATHOLOGICAL CONSEQUENCES THROUGH ADOLESCENCE AND ADULTHOOD. THE DEVELOPMENTAL ORIGINS OF THE HEALTH AND DISEASE CONCEPT, ALSO KNOWN AS THE "BARKER HYPOTHESIS", HAS BEEN PUT FORTH TO DESCRIBE THE INCREASED INCIDENCE OF CHRONIC DISEASE SUCH AS CARDIOVASCULAR DISEASE AND DIABETES IN HUMANS AND ANIMALS EXPOSED TO A LESS THAN IDEAL INTRAUTERINE ENVIRONMENT. MATERNAL INFECTION, POOR OR EXCESS NUTRITION, AND STRESSFUL EVENTS CAN NEGATIVELY INFLUENCE THE DEVELOPMENT OF DIFFERENT CELL TYPES, TISSUES AND ORGAN SYSTEMS ULTIMATELY PREDISPOSING THE ORGANISM TO PATHOLOGICAL CONDITIONS. ALTHOUGH THERE ARE A VARIETY OF CONDITIONS ASSOCIATED TO EXPOSURE TO ALTERED INTRAUTERINE ENVIRONMENTS, THE FOCUS OF THIS REVIEW WILL BE ON THE CONSEQUENCES OF STRESS AND HIGH FAT DIET DURING THE PRE- AND PERINATAL PERIODS AND ASSOCIATED OUTCOMES RELATED TO OBESITY AND OTHER METABOLIC CONDITIONS. WE FURTHER DISCUSS POSSIBLE NEUROENDOCRINE AND EPIGENETIC MECHANISMS RESPONSIBLE FOR THE METABOLIC PROGRAMMING OF OFFSPRING. THE PAPER REPRESENTS AN INVITED REVIEW BY A SYMPOSIUM, AWARD WINNER OR KEYNOTE SPEAKER AT THE SOCIETY FOR THE STUDY OF INGESTIVE BEHAVIOR [SSIB] ANNUAL MEETING IN PORTLAND, JULY 2009. 2010 12 3594 41 IMPLICATIONS OF EARLY LIFE STRESS ON FETAL METABOLIC PROGRAMMING OF SCHIZOPHRENIA: A FOCUS ON EPIPHENOMENA UNDERLYING MORBIDITY AND EARLY MORTALITY. THE FETAL ORIGIN OF ADULT DISEASE HYPOTHESIS POSTULATES THAT A STRESSFUL IN UTERO ENVIRONMENT CAN HAVE DELETERIOUS CONSEQUENCES ON FETAL PROGRAMMING, POTENTIALLY LEADING TO CHRONIC DISEASE IN LATER LIFE. FACTORS KNOWN TO IMPACT FETAL PROGRAMMING INCLUDE THE TIMING, INTENSITY, DURATION AND NATURE OF THE EXTERNAL STRESSOR DURING PREGNANCY. AS SUCH, DYNAMIC MODULATION OF FETAL PROGRAMMING IS HEAVILY INVOLVED IN SHAPING HEALTH THROUGHOUT THE LIFE COURSE, POSSIBLY BY INFLUENCING METABOLIC PARAMETERS INCLUDING INSULIN ACTION, HYPOTHALAMIC-PITUITARY-ADRENAL ACTIVITY AND IMMUNE FUNCTION. THE ABILITY OF PRENATAL INSULTS TO PROGRAM ADULT DISEASE IS LIKELY TO OCCUR AS A RESULT OF REDUCED FUNCTIONAL CAPACITY IN KEY ORGANS-A "THRIFTY" PHENOTYPE-WHERE MORE RESOURCES ARE RE-ALLOCATED TO PRESERVE CRITICAL ORGANS SUCH AS THE BRAIN. NOTABLY, IT HAS BEEN POSTULATED THAT THE MANIFESTATION OF NEUROPSYCHIATRIC DISORDERS IN INDIVIDUALS PRIORLY EXPOSED TO PRENATAL STRESS MAY ARISE FROM THE INTERACTION BETWEEN HEREDITARY FACTORS AND THE INTRAUTERINE ENVIRONMENT, WHICH TOGETHER PRECIPITATE DISEASE ONSET BY DISRUPTING THE TRAJECTORY OF NORMAL BRAIN DEVELOPMENT. IN THIS REVIEW WE DISCUSS THE EVIDENCE LINKING PRENATAL PROGRAMMING TO NEUROPSYCHIATRIC DISORDERS, MAINLY SCHIZOPHRENIA, VIA A "THRIFTY PSYCHIATRIC PHENOTYPE" CONCEPT. WE START BY OUTLINING THE CONCEPTION OF THE THRIFTY PSYCHIATRIC PHENOTYPE. NEXT, WE DISCUSS THE CONVERGENCE OF POTENTIAL MECHANISTIC PATHWAYS THROUGH WHICH PRENATAL INSULTS MAY TRIGGER EPIGENETIC CHANGES THAT CONTRIBUTE TO THE INCREASED MORBIDITY AND EARLY MORTALITY OBSERVED IN NEUROPSYCHIATRIC DISORDERS. FINALLY, WE TOUCH ON THE PUBLIC HEALTH IMPORTANCE OF FETAL PROGRAMMING FOR THESE DISORDERS. WE CONCLUDE BY PROVIDING A BRIEF OUTLOOK ON THE FUTURE OF THIS EVOLVING FIELD OF RESEARCH. 2020 13 3384 22 HOFBAUER CELLS: THEIR ROLE IN HEALTHY AND COMPLICATED PREGNANCY. HOFBAUER CELLS ARE PLACENTAL VILLOUS MACROPHAGES OF FETAL ORIGIN THAT ARE PRESENT THROUGHOUT PREGNANCY. ALTHOUGH HOFBAUER CELL POPULATIONS ARE ANTIGENICALLY AND MORPHOLOGICALLY HETEROGENEOUS, THEIR EPIGENETIC, ANTIGENIC, AND FUNCTIONAL PROFILES MOST CLOSELY RESEMBLE ALTERNATIVELY ACTIVATED MACROPHAGES OR WHAT ARE REFERRED TO AS M2A, M2B, M2C, AND M2D POLARITY SUBTYPES. CONSISTENT WITH AN M2-LIKE PROFILE, THESE CELLS PLAY AN IMPORTANT ROLE IN PLACENTAL DEVELOPMENT INCLUDING VASCULOGENESIS AND ANGIOGENESIS. DURING PLACENTAL INFLAMMATION HOFBAUER CELLS MAY PRODUCE PRO-INFLAMMATORY CYTOKINES OR MEDIATORS THAT DAMAGE THE VILLOUS CELL BARRIER, AND INDUCE FIBROTIC RESPONSES WITHIN THE VILLI AS A CONTINUUM OF CHRONIC INFLAMMATION. HOWEVER, TO DATE, THERE IS NO EVIDENCE THAT HOFBAUER CELLS BECOME CLASSICALLY ACTIVATED OR ADOPT AN M1 POLARITY PHENOTYPE THAT IS ABLE TO KILL MICROBES. TO THE CONTRARY, THEIR PREDOMINANT M2 LIKE QUALITIES MAY BE WHY THESE CELLS ARE INEFFECTIVE IN CONTROLLING MOST TORCH INFECTIONS. MOREOVER, HOFBAUER CELLS MAY CONTRIBUTE TO VERTICAL TRANSMISSION OF VARIOUS PATHOGENS TO THE FETUS SINCE THEY CAN HARBOR LIVE VIRUS AND SERVE AS RESERVOIRS WITHIN THE PLACENTA. THE GOAL OF THIS REVIEW IS TO SUMMARIZE WHAT IS CURRENTLY KNOWN ABOUT THE ROLE OF HOFBAUER CELLS IN NORMAL AND COMPLICATED PREGNANCIES THAT INVOLVE IMMUNOLOGIC DISORDERS, INFLAMMATION, AND/OR INFECTION. 2018 14 4723 20 NONHUMAN PRIMATE MODELS OF POLYCYSTIC OVARY SYNDROME. WITH CLOSE GENOMIC AND PHENOTYPIC SIMILARITY TO HUMANS, NONHUMAN PRIMATE MODELS PROVIDE COMPREHENSIVE EPIGENETIC MIMICS OF POLYCYSTIC OVARY SYNDROME (PCOS), SUGGESTING EARLY LIFE TARGETING FOR PREVENTION. FETAL EXPOSURE TO TESTOSTERONE (T), OF ALL NONHUMAN PRIMATE EMULATIONS, PROVIDES THE CLOSEST PCOS-LIKE PHENOTYPES, WITH EARLY-TO-MID GESTATION T-EXPOSED FEMALE RHESUS MONKEYS EXHIBITING ADULT REPRODUCTIVE, ENDOCRINOLOGICAL AND METABOLIC DYSFUNCTIONAL TRAITS THAT ARE CO-PATHOLOGIES OF PCOS. LATE GESTATIONAL T EXPOSURE, WHILE INDUCING ADULT OVARIAN HYPERANDROGENISM AND MENSTRUAL ABNORMALITIES, HAS LESS DYSFUNCTIONAL METABOLIC ACCOMPANIMENT. FETAL EXPOSURES TO DIHYDROTESTOSTERONE (DHT) OR DIETHYLSTILBESTROL (DES) SUGGEST ANDROGENIC AND ESTROGENIC ASPECTS OF FETAL PROGRAMMING. NEONATAL EXPOSURE TO T PRODUCES NO PCOS-LIKE OUTCOME, WHILE CONTINUOUS T TREATMENT OF JUVENILE FEMALES CAUSES PRECOCIOUS WEIGHT GAIN AND EARLY MENARCHE (HIGH T), OR HIGH LH AND WEIGHT GAIN (MODERATE T). ACUTE T EXPOSURE OF ADULT FEMALES GENERATES POLYFOLLICULAR OVARIES, WHILE CHRONIC T EXPOSURE INDUCES SUBTLE MENSTRUAL IRREGULARITIES WITHOUT METABOLIC DYSFUNCTION. 2013 15 3569 43 IMPACT OF INTRA-UTERINE LIFE ON FUTURE HEALTH. SINCE THE EMERGENCE OF THE CONCEPT OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD), SUGGESTED BY BARKER IN THE 1980S, NUMEROUS EPIDEMIOLOGICAL STUDIES IN HUMANS HAVE CONFIRMED THE RELATIONSHIP BETWEEN MATERNAL OBESITY DURING PREGNANCY AND THE RISK OF OFFSPRING DEVELOPING VARIOUS CHRONIC ADULT ILLNESSES. THESE EFFECTS OF INTRAUTERINE LIFE ARE INDEPENDENT OF INHERITANCE OF DISEASE SUSCEPTIBILITY GENES AND/OR SOCIO-ECONOMIC FACTORS. REGARDING POTENTIAL MECHANISMS, RECENT DATA FROM ANIMAL MODELS SUGGESTS A ROLE OF INSULIN RESISTANCE EARLY IN DEVELOPMENT. ANOTHER POTENTIAL MECHANISM, IN THE CASE OF MATERNAL OBESITY, IS INCREASED PLACENTAL NUTRIENT TRANSFER. THE DOHAD CONCEPT ALSO INCLUDES FETAL EXPOSURE TO ENVIRONMENTAL ENDOCRINE DISRUPTORS (EEDS). A DANISH GROUP FOR THE FIRST TIME RECENTLY ANALYZED EED PASSAGE ACROSS THE PLACENTA IN HUMANS THROUGHOUT PREGNANCY. THIS STUDY SHOWED DIFFERENT LEVELS OF BIOACCUMULATION DEPENDING ON THE FETAL ORGAN, WITH GREATER VULNERABILITY IN MALE THAN FEMALE FETUSES. RECENT CLINICAL STUDIES SUGGESTED AN ASSOCIATION BETWEEN FETAL EXPOSURE TO PARTICULAR EEDS AND PRECOCIOUS PUBERTY, INCREASED INCIDENCE OF CRYPTORCHIDISM AND IMPAIRED SPERM QUALITY IN ADULTHOOD. THESE MODIFICATIONS OF THE IN-UTERO ENVIRONMENT ALSO APPEAR TO BE RESPONSIBLE FOR EPIGENETIC CHANGES THAT ARE TRANSMITTABLE OVER SEVERAL GENERATIONS. A RECENT EXAMPLE OF THIS IS THE DEMONSTRATION OF THE TRANSMISSION OF POLYCYSTIC OVARY SYNDROME (PCOS) IN MICE. IN SUMMARY, AN INCREASING NUMBER OF EXAMPLES OF THE IMPACT OF INTRAUTERINE LIFE ON THE HEALTH OF OFFSPRING HAVE APPEARED IN RECENT YEARS, ILLUSTRATING THE IMPORTANT ROLE THAT ENDOCRINOLOGISTS CAN PLAY IN PREVENTING PARTICULAR PATHOLOGIES IN FUTURE GENERATIONS. 2022 16 4007 41 LOW BIRTHWEIGHT AS A RISK FACTOR FOR NON-COMMUNICABLE DISEASES IN ADULTS. ACCORDING TO STUDIES UNDERTAKEN OVER THE PAST 40 YEARS, LOW BIRTHWEIGHT (LBW) IS NOT ONLY A SIGNIFICANT PREDICTOR OF PERINATAL DEATH AND MORBIDITY, BUT ALSO INCREASES THE RISK OF CHRONIC NON-COMMUNICABLE DISEASES (NCDS) IN ADULTHOOD. THE PURPOSE OF THIS PAPER IS TO SUMMARIZE THE RESEARCH ON LBW AS A RISK FACTOR FOR NCDS IN ADULTS. THE BARKER HYPOTHESIS WAS BASED ON THE FINDING THAT ADULTS WITH AN LBW OR AN UNHEALTHY INTRAUTERINE ENVIRONMENT, AS WELL AS A RAPID CATCH-UP, DIE DUE TO NCDS. OVER THE LAST FEW DECADES, TERMINOLOGY SUCH AS THRIFTY GENES, FETAL PROGRAMMING, DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD), AND EPIGENETIC FACTORS HAVE BEEN COINED. THE MOST COMMON NCDS INCLUDE CARDIOVASCULAR DISEASE, DIABETES MELLITUS TYPE 2 (DMT2), HYPERTENSION (HT), DYSLIPIDEMIA, PROTEINURIA, AND CHRONIC KIDNEY DISEASE (CKD). STUDIES IN MOTHERS WHO EXPERIENCED FAMINE AND THOSE THAT SOLELY REPORTED BIRTH WEIGHT AS A RISK FACTOR FOR MORTALITY SUPPORT THE CONCEPT. ALTHOUGH THE ETIOLOGY OF NCD IS UNKNOWN, BARRY BRENNER EXPLAINED THE NOTION OF A LOW GLOMERULAR NUMBER (NGLOM) IN LBW CHILDREN, FOLLOWED BY THE PROGRESSION TO HYPERFILTRATION AS THE PHYSIOPATHOLOGIC ETIOLOGY OF HT AND CKD IN ADULTS BASED ON GUYTON'S RENAL PHYSIOLOGY WORK. AUTOPSIES OF SEVERAL ETHNIC GROUPS HAVE REVEALED ANATOMOPATHOLOGIC EVIDENCE IN FETUSES AND ADULT KIDNEYS. BECAUSE OF THE RENAL RESERVE, DEMONSTRATING RENAL FUNCTION IN PROPORTION TO RENAL VOLUME IN VIVO IS MORE DIFFICULT IN ADULTS. THE GREATEST IMPACT OF THESE THEORIES CAN BE SEEN IN PEDIATRICS AND OBSTETRICS PRACTICE. 2021 17 4189 37 METABOLIC DISEASE PROGRAMMING: FROM MITOCHONDRIA TO EPIGENETICS, GLUCOCORTICOID SIGNALLING AND BEYOND. EMBRYONIC AND FOETAL DEVELOPMENT ARE CRITICAL PERIODS OF DEVELOPMENT IN WHICH SEVERAL ENVIRONMENTAL CUES DETERMINE HEALTH AND DISEASE IN ADULTHOOD. MATERNAL CONDITIONS AND AN UNFAVOURABLE INTRAUTERINE ENVIRONMENT IMPACT FOETAL DEVELOPMENT AND MAY PROGRAMME THE OFFSPRING FOR INCREASED PREDISPOSITION TO METABOLIC DISEASES AND OTHER CHRONIC PATHOLOGIC CONDITIONS THROUGHOUT ADULT LIFE. PREVIOUSLY, NON-COMMUNICABLE CHRONIC DISEASES WERE ONLY ASSOCIATED WITH GENETICS AND LIFESTYLE. NOW THE ORIGINS OF NON-COMMUNICABLE CHRONIC DISEASES ARE ASSOCIATED WITH EARLY-LIFE ADAPTATIONS THAT PRODUCE LONG-TERM DYSFUNCTION. EARLY-LIFE ENVIRONMENT SETS THE LONG-TERM HEALTH AND DISEASE RISK AND CAN SPAN THROUGH MULTIPLE GENERATIONS. RECENT RESEARCH IN DEVELOPMENTAL PROGRAMMING AIMS AT IDENTIFYING THE MOLECULAR MECHANISMS RESPONSIBLE FOR DEVELOPMENTAL PROGRAMMING OUTCOMES THAT IMPACT CELLULAR PHYSIOLOGY AND TRIGGER ADULTHOOD DISEASE. THE IDENTIFICATION OF NEW THERAPEUTIC TARGETS CAN IMPROVE OFFSPRING'S HEALTH MANAGEMENT AND PREVENT OR OVERCOME ADVERSE CONSEQUENCES OF FOETAL PROGRAMMING. THIS REVIEW SUMMARIZES RECENT BIOMEDICAL DISCOVERIES IN THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) HYPOTHESIS AND HIGHLIGHT POSSIBLE DEVELOPMENTAL PROGRAMMING MECHANISMS, INCLUDING PRENATAL STRUCTURAL DEFECTS, METABOLIC (MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, PROTEIN MODIFICATION), EPIGENETIC AND GLUCOCORTICOID SIGNALLING-RELATED MECHANISMS SUGGESTING MOLECULAR CLUES FOR THE CAUSES AND CONSEQUENCES OF PROGRAMMING OF INCREASED SUSCEPTIBILITY OF OFFSPRING TO METABOLIC DISEASE AFTER BIRTH. IDENTIFYING MECHANISMS INVOLVED IN DOHAD CAN CONTRIBUTE TO EARLY INTERVENTIONS IN PREGNANCY OR EARLY CHILDHOOD, TO RE-SET THE METABOLIC HOMEOSTASIS AND BREAK THE CHAIN OF SUBSEQUENT EVENTS THAT COULD LEAD TO THE DEVELOPMENT OF DISEASE. 2021 18 4070 27 MATERNAL DIABETES, PROGRAMMING OF BETA-CELL DISORDERS AND INTERGENERATIONAL RISK OF TYPE 2 DIABETES. A SUBSTANTIAL BODY OF EVIDENCE SUGGESTS THAT AN ABNORMAL INTRA-UTERINE MILIEU ELICITED BY MATERNAL METABOLIC DISTURBANCES AS DIVERSE AS MALNUTRITION, PLACENTAL INSUFFICIENCY, DIABETES AND OBESITY MAY BE ABLE TO PROGRAMME SUSCEPTIBILITY OF THE FOETUS TO LATER DEVELOP CHRONIC DEGENERATIVE DISEASES SUCH AS OBESITY, HYPERTENSION, CARDIOVASCULAR DISEASES AND TYPE 2 DIABETES (T2D). AS INSULIN-PRODUCING CELLS HAVE BEEN PLACED CENTRE STAGE IN THE DEVELOPMENT OF T2D, THIS REVIEW EXAMINES DEVELOPMENTAL PROGRAMMING OF THE BETA-CELL MASS (BCM) IN VARIOUS RODENT MODELS OF MATERNAL PROTEIN RESTRICTION, CALORIE RESTRICTION, OVERNUTRITION AND DIABETES. THE MAIN MESSAGE IS THAT WHATEVER THE INITIAL MATERNAL INSULT (F0 GENERATION) AND WHETHER ALONE OR IN COMBINATION, IT GIVES RISE TO THE SAME PROGRAMMED BCM OUTCOME IN THE DAUGHTER GENERATION (F1). THE ALTERED BCM PHENOTYPE IN F1 FEMALES PROHIBITS NORMAL BCM ADAPTATION DURING PREGNANCY AND, THUS, DIABETES (GESTATIONAL DIABETES) ENSUES. THIS GESTATIONAL DIABETES IS THEN PASSED FROM ONE GENERATION (F1) TO THE NEXT (F2, F3 AND SO ON). THIS REVIEW HIGHLIGHTS A NUMBER OF STUDIES THAT HAVE IDENTIFIED EPIGENETIC MECHANISMS THAT MAY CONTRIBUTE TO ALTERED BCM DEVELOPMENT AND BETA-CELL FAILURE, AS OBSERVED IN DIABETES. IN ADDITION TO THEIR ROLE IN INSTILLING THE PROGRAMMED DEFECT, THESE NON-GENOMIC MECHANISMS MAY ALSO BE INVOLVED IN ITS INTERGENERATIONAL TRANSMISSION. 2014 19 4669 27 NEW INSIGHTS INTO PATHOPHYSIOLOGY OF VESTIBULAR MIGRAINE. VESTIBULAR MIGRAINE (VM) IS A COMMON DISORDER IN WHICH GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS PROBABLY CONTRIBUTE TO ITS DEVELOPMENT. THE PATHOPHYSIOLOGY OF VM IS UNKNOWN; NEVERTHELESS IN THE LAST FEW YEARS, SEVERAL STUDIES ARE CONTRIBUTING TO UNDERSTAND THE NEUROPHYSIOLOGICAL PATHWAYS INVOLVED IN VM. THE CURRENT HYPOTHESES ARE MOSTLY BASED ON THE KNOWLEDGE OF MIGRAINE ITSELF. THE EVIDENCE OF TRIGEMINAL INNERVATION OF THE LABYRINTH VESSELS AND THE LOCALIZATION OF VASOACTIVE NEUROPEPTIDES IN THE PERIVASCULAR AFFERENT TERMINALS OF THESE TRIGEMINAL FIBERS SUPPORT THE INVOLVEMENT OF THE TRIGEMINO-VASCULAR SYSTEM. THE NEUROGENIC INFLAMMATION TRIGGERED BY ACTIVATION OF THE TRIGEMINAL-VESTIBULOCOCHLEAR REFLEX, WITH THE SUBSEQUENT INNER EAR PLASMA PROTEIN EXTRAVASATION AND THE RELEASE OF INFLAMMATORY MEDIATORS, CAN CONTRIBUTE TO A SUSTAINED ACTIVATION AND SENSITIZATION OF THE TRIGEMINAL PRIMARY AFFERENT NEURONS EXPLAINING VM SYMPTOMS. THE RECIPROCAL CONNECTIONS BETWEEN BRAINSTEM VESTIBULAR NUCLEI AND THE STRUCTURES THAT MODULATE TRIGEMINAL NOCICEPTIVE INPUTS (ROSTRAL VENTROMEDIAL MEDULLA, VENTROLATERAL PERIAQUEDUCTAL GRAY, LOCUS COERULEUS, AND NUCLEUS RAPHE MAGNUS) ARE CRITICAL TO UNDERSTAND THE PATHOPHYSIOLOGY OF VM. ALTHOUGH CORTICAL SPREADING DEPRESSION CAN AFFECT CORTICAL AREAS INVOLVED IN PROCESSING VESTIBULAR INFORMATION, FUNCTIONAL NEUROIMAGING TECHNIQUES SUGGEST A DYSMODULATION IN THE MULTIMODAL SENSORY INTEGRATION AND PROCESSING OF VESTIBULAR AND NOCICEPTIVE INFORMATION, RESULTING FROM A VESTIBULO-THALAMO-CORTICAL DYSFUNCTION, AS THE PATHOGENIC MECHANISM UNDERLYING VM. THE ELEVATED PREVALENCE OF VM SUGGESTS THAT MULTIPLE FUNCTIONAL VARIANTS MAY CONFER A GENETIC SUSCEPTIBILITY LEADING TO A DYSREGULATION OF EXCITATORY-INHIBITORY BALANCE IN BRAIN STRUCTURES INVOLVED IN THE PROCESSING OF SENSORY INFORMATION, VESTIBULAR INPUTS, AND PAIN. THE INTERACTIONS AMONG SEVERAL FUNCTIONAL AND STRUCTURAL NEURAL NETWORKS COULD EXPLAIN THE PATHOGENIC MECHANISMS OF VM. 2015 20 5011 31 PEROXIREDOXIN6, A MULTITASK ANTIOXIDANT ENZYME INVOLVED IN THE PATHOPHYSIOLOGY OF CHRONIC NONCOMMUNICABLE DISEASES. SIGNIFICANCE: CHRONIC NONCOMMUNICABLE DISEASES (NCDS) ARE THE LEADING CAUSES OF DISABILITY AND DEATH WORLDWIDE. NCDS MAINLY COMPRISE DIABETES MELLITUS, CARDIOVASCULAR DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CANCER, AND NEUROLOGICAL DEGENERATIVE DISEASES, WHICH KILL MORE THAN 80% OF POPULATION, ESPECIALLY THE ELDERLY, WORLDWIDE. RECENT ADVANCES: SEVERAL RECENT THEORIES ESTABLISHED NCDS AS MULTIFACTORIAL DISEASES, WHERE A COMBINATION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS CONTRIBUTES TO THEIR PATHOGENESIS. NEVERTHELESS, RECENT FINDINGS SUGGEST THAT THE COMMON FACTOR LINKING ALL THESE PATHOLOGIES IS AN INCREASE IN OXIDATIVE STRESS AND THE AGE-RELATED LOSS OF THE ANTIOXIDANT MECHANISMS OF DEFENSE AGAINST IT. IMPAIRMENT IN MITOCHONDRIAL HOMEOSTASIS WITH CONSEQUENT DEREGULATION IN OXIDATIVE STRESS BALANCE HAS ALSO BEEN SUGGESTED. CRITICAL ISSUES: THEREFORE, ANTIOXIDANT PROTEINS DESERVE PARTICULAR ATTENTION FOR THEIR POTENTIAL ROLE AGAINST NCDS. IN PARTICULAR, PEROXIREDOXIN(PRDX)6 IS A UNIQUE ANTIOXIDANT ENZYME, BELONGING TO THE PRDX FAMILY, WITH DOUBLE PROPERTIES, PEROXIDASE AND PHOSPHOLIPASE ACTIVITIES. THROUGH THESE ACTIVITIES, PRDX6 HAS BEEN SHOWN TO BE A POWERFUL ANTIOXIDANT ENZYME, IMPLICATED IN THE PATHOGENESIS OF DIFFERENT NCDS. RECENTLY, WE DESCRIBED A PHENOTYPE OF DIABETES MELLITUS IN PRDX6 KNOCKOUT MICE, SUGGESTING A PIVOTAL ROLE OF PRDX6 IN THE PATHOGENESIS OF CARDIOMETABOLIC DISEASES. FUTURE DIRECTIONS: INCREASING AWARENESS ON THE ROLE OF ANTIOXIDANT DEFENSES IN THE PATHOGENESIS OF NCDS MAY OPEN NOVEL THERAPEUTIC APPROACHES TO REDUCE THE BURDEN OF THIS PANDEMIC PHENOMENON. HOWEVER, KNOWLEDGE OF THE ROLE OF PRDX6 IN NCD PREVENTION AND PATHOGENESIS IS STILL NOT CLARIFIED. 2019