1 1066 197 CLINICAL USE OF AMINO ACIDS AS DIETARY SUPPLEMENT: PROS AND CONS. NITROGEN SUPPLY IS PIVOTAL FOR THE MAINTENANCE OF LIFE. AMINO ACIDS CAN BE UTILIZED TO SYNTHESIZE BOTH GLUCOSE AND LIPIDS. THE OPPOSITE, I.E., PRODUCTION OF AMINO ACIDS FROM EITHER ONE OF THEM, IS NOT POSSIBLE IN THE ABSENCE OF OTHER AMINO ACIDS AS DONORS OF NITROGEN. THE QUALITY OF AMINO ACID CONTENT IN PROTEIN HAS BEEN RE-EVALUATED RECENTLY, AND THE RELEVANCE OF ESSENTIAL AMINO ACIDS HAS BEEN REPEATEDLY UNDERLINED. ESSENTIAL AMINO ACID REQUIREMENTS IN DIFFERENT MAMMALS ARE NOT IDENTICAL, AND RATIOS AMONG THEM SHOULD BE TAKEN INTO ACCOUNT WHEN PROJECTING AN EFFICIENT FORMULATION. RECENT RESEARCH HAS DEMONSTRATED THAT GENES RESPOND TO DIFFERENT QUALITIES AND QUANTITIES OF NUTRITIONAL SUPPLY, AND INCREASED PROVISION OF ESSENTIAL AMINO ACIDS INCREASES LIFESPAN IN ANIMAL EXPERIMENTS THROUGH MITOCHONDRIOGENESIS AND MAINTENANCE OF ELEVATED RATES OF SYNTHESIS OF ANTI-OXIDANT MOLECULES. MOREOVER, GENETIC EXPRESSION OF KEY CONTROLLERS OF SYNTHESIS, LIKE MTOR, MAY BE PARTICULARLY IMPORTANT FOR UNDERSTANDING SKELETAL MUSCLE MAINTENANCE. LOSSES OF MUSCLE MASS AND IMPAIRED IMMUNE FUNCTION ARE RELATED TO REDUCED PROTEIN SUPPLY, AND THERE IS INCREASING EVIDENCE THAT REGULAR ESSENTIAL AMINO ACID INTAKE AS PART OF AN ORAL DIET IS EFFECTIVE IN REVERSING MUSCLE CATABOLISM, PROMOTING MUSCLE ANABOLISM, AND RESTORING IMMUNOLOGICAL FUNCTION. THEREFORE, THE USE OF AMINO ACIDS AS SUPPLEMENTS TO DIET WOULD BE EXPANDING IN THE NEAR FUTURE. IS THIS SAFE? FEW DATA ARE AVAILABLE ON AMINO ACID TOXICITY, AND ONLY ONE ESSENTIAL AMINO ACID MAY BE CONSIDERED TO HAVE CLINICALLY RELEVANT TOXICITY: METHIONINE, BECAUSE IT IS TRANSFORMED INTO A TOXIC INTERMEDIATE, HOMOCYSTEINE, WHEN CYSTEINE SYNTHESIS IS REQUIRED BY METABOLIC NEEDS. MATCHING OF STOICHIOMETRIC RATIOS BETWEEN METHIONINE AND CYSTEINE MAY SOLVE THE PROBLEM OF SUPPLYING SUFFICIENT AMOUNTS OF SULFUR TO THE BODY. ARGININE AND GLUTAMINE ARE TWO NON-ESSENTIAL AMINO ACIDS THAN CAN BECOME "CONDITIONALLY ESSENTIAL" BECAUSE OF ELEVATED NEEDS DURING PATHOLOGICAL CONDITIONS, AND METABOLISM MAY NOT BE ABLE TO MAINTAIN THEIR CONCENTRATIONS AT SUFFICIENT LEVELS TO MATCH METABOLIC REQUIREMENTS. CHRONIC EXOGENOUS ARGININE SUPPLEMENTATION HAS NOT PROVEN TO EXERT POSITIVE CLINICAL EFFECTS IN DIFFERENT TRIALS, AND SEQUENTIAL ARTICULATION OF THE KNOWLEDGE OF INTRODUCTION OF ARGININE-DRIVEN TRANSCRIPTIONAL, TRANSLATIONAL, AND EPIGENETIC ADAPTATIONS MAY GIVE US A KEY FOR INTERPRETING THOSE PUZZLING RESULTS. 2011 2 4788 44 NUTRITION, EPIGENETICS, AND METABOLIC SYNDROME. SIGNIFICANCE: EPIDEMIOLOGICAL AND ANIMAL STUDIES HAVE DEMONSTRATED A CLOSE LINK BETWEEN MATERNAL NUTRITION AND CHRONIC METABOLIC DISEASE IN CHILDREN AND ADULTS. COMPELLING EXPERIMENTAL RESULTS ALSO INDICATE THAT ADVERSE EFFECTS OF INTRAUTERINE GROWTH RESTRICTION ON OFFSPRING CAN BE CARRIED FORWARD TO SUBSEQUENT GENERATIONS THROUGH COVALENT MODIFICATIONS OF DNA AND CORE HISTONES. RECENT ADVANCES: DNA METHYLATION IS CATALYZED BY S-ADENOSYLMETHIONINE-DEPENDENT DNA METHYLTRANSFERASES. METHYLATION, DEMETHYLATION, ACETYLATION, AND DEACETYLATION OF HISTONE PROTEINS ARE PERFORMED BY HISTONE METHYLTRANSFERASE, HISTONE DEMETHYLASE, HISTONE ACETYLTRANSFERASE, AND HISTONE DEACETYLTRANSFERASE, RESPECTIVELY. HISTONE ACTIVITIES ARE ALSO INFLUENCED BY PHOSPHORYLATION, UBIQUITINATION, ADP-RIBOSYLATION, SUMOYLATION, AND GLYCOSYLATION. METABOLISM OF AMINO ACIDS (GLYCINE, HISTIDINE, METHIONINE, AND SERINE) AND VITAMINS (B6, B12, AND FOLATE) PLAYS A KEY ROLE IN PROVISION OF METHYL DONORS FOR DNA AND PROTEIN METHYLATION. CRITICAL ISSUES: DISRUPTION OF EPIGENETIC MECHANISMS CAN RESULT IN OXIDATIVE STRESS, OBESITY, INSULIN RESISTANCE, DIABETES, AND VASCULAR DYSFUNCTION IN ANIMALS AND HUMANS. DESPITE A RECOGNIZED ROLE FOR EPIGENETICS IN FETAL PROGRAMMING OF METABOLIC SYNDROME, RESEARCH ON THERAPIES IS STILL IN ITS INFANCY. POSSIBLE INTERVENTIONS INCLUDE: 1) INHIBITION OF DNA METHYLATION, HISTONE DEACETYLATION, AND MICRORNA EXPRESSION; 2) TARGETING EPIGENETICALLY DISTURBED METABOLIC PATHWAYS; AND 3) DIETARY SUPPLEMENTATION WITH FUNCTIONAL AMINO ACIDS, VITAMINS, AND PHYTOCHEMICALS. FUTURE DIRECTIONS: MUCH WORK IS NEEDED WITH ANIMAL MODELS TO UNDERSTAND THE BASIC MECHANISMS RESPONSIBLE FOR THE ROLES OF SPECIFIC NUTRIENTS IN FETAL AND NEONATAL PROGRAMMING. SUCH NEW KNOWLEDGE IS CRUCIAL TO DESIGN EFFECTIVE THERAPEUTIC STRATEGIES FOR PREVENTING AND TREATING METABOLIC ABNORMALITIES IN OFFSPRING BORN TO MOTHERS WITH A PREVIOUS EXPERIENCE OF MALNUTRITION. 2012 3 6715 43 VITAMIN A AND THE EPIGENOME. THE EPIGENETIC PHENOMENA REFER TO HERITABLE CHANGES IN GENE EXPRESSION OTHER THAN THOSE IN THE DNA SEQUENCE, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS. MAJOR RESEARCH PROGRESS IN THE LAST FEW YEARS HAS PROVIDED FURTHER PROOF THAT ENVIRONMENTAL FACTORS, INCLUDING DIET AND NUTRITION, CAN INFLUENCE PHYSIOLOGIC AND PATHOLOGIC PROCESSES THROUGH EPIGENETIC ALTERATIONS, WHICH IN TURN INFLUENCE GENE EXPRESSION. THIS INFLUENCE IS TERMED NUTRITIONAL EPIGENETICS, AND ONE PROMINENT EXAMPLE IS THE REGULATION OF GENE TRANSCRIPTION BY VITAMIN A THROUGH INTERACTION TO ITS NUCLEAR RECEPTOR. VITAMIN A IS CRITICAL THROUGHOUT LIFE. TOGETHER WITH ITS DERIVATIVES, IT REGULATES DIVERSE PROCESSES INCLUDING REPRODUCTION, EMBRYOGENESIS, VISION, GROWTH, CELLULAR DIFFERENTIATION AND PROLIFERATION, MAINTENANCE OF EPITHELIAL CELLULAR INTEGRITY AND IMMUNE FUNCTION. HERE WE REVIEW THE EPIGENETIC ROLE OF VITAMIN A IN CANCER, STEM CELLS DIFFERENTIATION, PROLIFERATION, AND IMMUNITY. THE DATA PRESENTED HERE SHOW THAT RETINOIC ACID IS A POTENT AGENT CAPABLE OF INDUCING ALTERATIONS IN EPIGENETIC MODIFICATIONS THAT PRODUCE VARIOUS EFFECTS ON THE PHENOTYPE. MEDICAL BENEFITS OF VITAMIN A AS AN EPIGENETIC MODULATOR, ESPECIALLY WITH RESPECT TO ITS CHRONIC USE AS NUTRITIONAL SUPPLEMENT, SHOULD RELY ON OUR FURTHER UNDERSTANDING OF ITS EPIGENETIC EFFECTS DURING HEALTH AND DISEASE, AS WELL AS THROUGH DIFFERENT GENERATIONS. 2017 4 5110 40 POLYPHENOLS AND THE MODULATION OF GENE EXPRESSION PATHWAYS: CAN WE EAT OUR WAY OUT OF THE DANGER OF CHRONIC DISEASE? PLANT-DERIVED DIETARY POLYPHENOLS MAY IMPROVE SOME DISEASE STATES AND PROMOTE HEALTH. EXPERIMENTAL EVIDENCE SUGGESTS THAT THIS IS PARTIALLY ATTRIBUTABLE TO CHANGES IN GENE EXPRESSION. THE RATIONAL USE OF BIOACTIVE FOOD COMPONENTS MAY THEREFORE PRESENT AN OPPORTUNITY TO ACTIVATE OR REPRESS SELECTED GENE EXPRESSION PATHWAYS AND, CONSEQUENTLY, TO MANAGE OR PREVENT DISEASE. IT REMAINS TO BE DETERMINED WHETHER THIS USE OF BIOACTIVE FOOD COMPONENTS CAN BE DONE SAFELY. THIS ARTICLE REVIEWS THE ASSOCIATED CONTROVERSIES AND LIMITATIONS OF POLYPHENOL THERAPY. THERE IS A PAUCITY OF CLINICAL DATA ON THE RATIONAL USE OF POLYPHENOLS, INCLUDING A LACK OF KNOWLEDGE ON EFFECTIVE DOSAGE, ACTUAL CHEMICAL FORMULATIONS, BIOAVAILABILITY, DISTRIBUTION IN TISSUES, THE EFFECT OF GENETIC VARIATIONS, DIFFERENCES IN GUT MICROFLORA, THE SYNERGISTIC (OR ANTAGONISTIC) EFFECTS OBSERVED IN EXTRACTS, AND THE POSSIBLE INTERACTION BETWEEN POLYPHENOLS AND LIPID DOMAINS OF CELL MEMBRANES THAT MAY ALTER THE FUNCTION OF RELEVANT RECEPTORS. THE SEMINAL QUESTION OF WHY PLANTS MAKE SUBSTANCES THAT BENEFIT HUMANS REMAINS UNANSWERED, AND THERE IS STILL MUCH TO LEARN IN TERMS OF CORRELATIVE VERSUS CAUSAL EFFECTS OF HUMAN EXPOSURE TO VARIOUS NUTRIENTS. THE AVAILABLE DATA STRONGLY SUGGEST SIGNIFICANT EFFECTS AT THE MOLECULAR LEVEL THAT REPRESENT INTERACTIONS WITH THE EPIGENOME. THE ADVENT OF RELATIVELY SIMPLE TECHNOLOGIES IS HELPING THE FIELD OF EPIGENETICS PROGRESS AND FACILITATING THE ACQUISITION OF MULTIPLE TYPES OF DATA THAT WERE PREVIOUSLY DIFFICULT TO OBTAIN. IN THIS REVIEW, WE SUMMARIZE THE MOLECULAR BASIS OF THE EPIGENETIC REGULATION OF GENE EXPRESSION AND THE EPIGENETIC CHANGES ASSOCIATED WITH THE CONSUMPTION OF POLYPHENOLS THAT ILLUSTRATE HOW MODIFICATIONS IN HUMAN NUTRITION MAY BECOME RELEVANT TO HEALTH AND DISEASE. 2014 5 6342 41 THE ROLE OF EPIGENETIC REGULATOR SIRT1 IN BALANCING THE HOMEOSTASIS AND PREVENTING THE FORMATION OF SPECIFIC "SOIL" OF METABOLIC DISORDERS AND RELATED CANCERS. SIRT1 WAS DISCOVERED IN 1979 BUT GROWING INTEREST IN THIS PROTEIN OCCURRED ONLY 20 YEARS LATER WHEN ITS OVEREXPRESSION WAS REPORTED TO PROLONG THE LIFESPAN OF YEAST. SINCE THEN, SEVERAL STUDIES HAVE SHOWN THE BENEFITS OF ITS INCREASED EXPRESSION IN PREVENTING OR DELAYING OF MANY DISEASES. SIRT1, AS A HISTONE DEACETYLASE, IS AN EPIGENETIC REGULATOR BUT IT HAS WIDE RANGE OF NON-HISTONE TARGETS WHICH ARE INVOLVED IN METABOLISM, ENERGY SENSING PATHWAYS, CIRCADIAN MACHINERY AND IN INFLAMMATORY REGULATION. DISTURBANCES IN THESE INTERCONNECTED PROCESSES CAUSE DIFFERENT DISEASES, HOWEVER IT SEEMS THEY HAVE COMMON ROOTS IN UNBALANCED INFLAMMATORY PROCESSES AND LOWER LEVEL OR INACTIVATION OF SIRT1. SIRT1 INACTIVATION WAS IMPLICATED IN CORONAVIRUS DISEASE (COVID-19) SEVERITY AS WELL AND ITS LOW LEVEL COUNTED AS A PREDICTOR OF UNCONTROLLED COVID-19. SEVERAL OTHER DISEASES SUCH AS METABOLIC DISEASE, OBESITY, DIABETES, ALZHEIMER'S DISEASE, CARDIOVASCULAR DISEASE OR DEPRESSION ARE RELATED TO CHRONIC INFLAMMATION AND SIMILARLY SHOW DECREASED SIRT1 LEVEL. IT HAS RECENTLY BEEN KNOWN THAT SIRT1 IS INDUCIBLE BY CALORIE RESTRICTION/PROPER DIET, PHYSICAL ACTIVITY AND APPROPRIATE EMOTIONAL STATE. INDEED, A HEALTHIER METABOLIC STATE BELONGS TO HIGHER LEVEL OF SIRT1 EXPRESSION. THESE SUGGEST THAT APPROPRIATE LIFESTYLE AS NON-PHARMACOLOGICAL TREATMENT MAY BE A BENEFICIAL TOOL IN THE PREVENTION OF INFLAMMATION OR METABOLIC DISTURBANCE-RELATED DISEASES AS WELL AS COULD BE A PART OF THE COMPLEMENTARY THERAPY IN MEDICAL PRACTICE TO REACH BETTER THERAPEUTIC RESPONSE AND QUALITY OF LIFE. WE AIMED IN THIS REVIEW TO LINK THE BENEFICIAL EFFECT OF SIRT1 WITH THOSE DISEASES, WHERE ITS LEVEL DECREASED. MOREOVER, WE AIMED TO COLLECT EVIDENCES OF INTERVENTIONS OR TREATMENTS, WHICH INCREASE SIRT1 EXPRESSION AND THUS, OPEN THE POSSIBILITY TO USE THEM AS PREVENTIVE OR COMPLEMENTARY THERAPIES IN MEDICAL PRACTICE. 2022 6 6257 33 THE MOLECULAR BASIS OF TOLERANCE. TOLERANCE IS DEFINED AS THE DIMINISHED RESPONSE TO ALCOHOL OR OTHER DRUGS OVER THE COURSE OF REPEATED OR PROLONGED EXPOSURE. THIS MECHANISM ALLOWS PHYSIOLOGICAL PROCESSES TO ACHIEVE STABILITY IN A CONSTANTLY CHANGING ENVIRONMENT. THE ONSET OF TOLERANCE MAY OCCUR WITHIN MINUTES, DURING A SINGLE EXPOSURE TO ALCOHOL (I.E., ACUTE TOLERANCE), OR OVER LONGER TIMEFRAMES AND WITH PROLONGED EXPOSURE TO ALCOHOL (I.E., RAPID OR CHRONIC TOLERANCE). CHANGES IN TOLERANCE INDUCED BY ALCOHOL MAY AFFECT SEVERAL PROCESSES AT THE MOLECULAR, CELLULAR, OR BEHAVIORAL LEVEL. THESE EFFECTS OFTEN ARE INTERRELATED AND MAY BE DIFFICULT TO SEPARATE. THIS ARTICLE DESCRIBES CHANGES AT THE MOLECULAR LEVEL THAT ARE RELATED TO THE ONSET OF ACUTE, RAPID, OR CHRONIC TOLERANCE. IT FOCUSES ON NEURONAL MEMBRANE-BOUND CHANNELS AND THE FACTORS THAT AFFECT THEIR FUNCTION AND PRODUCTION, SUCH AS MODIFICATION OF PROTEIN SYNTHESIS AND ACTIVITY, INTERACTION WITH THE MEMBRANE LIPID MICROENVIRONMENT, EPIGENETIC EFFECTS ON CYTOPLASMIC REGULATION, AND GENE TRANSCRIPTION. ALSO CONSIDERED IS THE GENETICS OF TOLERANCE. 2008 7 5373 43 RECENT ADVANCES IN UNDERSTANDING THE ROLE OF DIET AND OBESITY IN THE DEVELOPMENT OF COLORECTAL CANCER. COLORECTAL CANCER (CRC) IS A MAJOR CAUSE OF PREMATURE DEATH IN THE UK AND MANY DEVELOPED COUNTRIES. HOWEVER, THE RISK OF DEVELOPING CRC IS WELL RECOGNISED TO BE ASSOCIATED NOT ONLY WITH DIET BUT ALSO WITH OBESITY AND LACK OF EXERCISE. WHILE EPIDEMIOLOGICAL EVIDENCE SHOWS AN ASSOCIATION WITH FACTORS SUCH AS HIGH RED MEAT INTAKE AND LOW INTAKE OF VEGETABLES, FIBRE AND FISH, THE MECHANISMS UNDERLYING THESE EFFECTS ARE ONLY NOW BEING ELUCIDATED. CRC DEVELOPS OVER MANY YEARS AND IS TYPICALLY CHARACTERISED BY AN ACCUMULATION OF MUTATIONS, WHICH MAY ARISE AS A CONSEQUENCE OF INHERITED POLYMORPHISMS IN KEY GENES, BUT MORE COMMONLY AS A RESULT OF SPONTANEOUSLY ARISING MUTATIONS AFFECTING GENES CONTROLLING CELL PROLIFERATION, DIFFERENTIATION, APOPTOSIS AND DNA REPAIR. EPIGENETIC CHANGES ARE OBSERVED THROUGHOUT THE PROGRESS FROM NORMAL MORPHOLOGY THROUGH FORMATION OF ADENOMA, AND THE SUBSEQUENT DEVELOPMENT OF CARCINOMA. THE REASONS WHY THIS ACCUMULATION OF LOSS OF HOMOEOSTATIC CONTROLS ARISES ARE UNCLEAR BUT CHRONIC INFLAMMATION HAS BEEN PROPOSED TO PLAY A CENTRAL ROLE. OBESITY IS ASSOCIATED WITH INCREASED PLASMA LEVELS OF CHEMOKINES AND ADIPOKINES CHARACTERISTIC OF CHRONIC SYSTEMIC INFLAMMATION, AND DIETARY FACTORS SUCH AS FISH OILS AND PHYTOCHEMICALS HAVE BEEN SHOWN TO HAVE ANTI-INFLAMMATORY PROPERTIES AS WELL AS MODULATING ESTABLISHED RISK FACTORS SUCH AS APOPTOSIS AND CELL PROLIFERATION. THERE IS ALSO SOME EVIDENCE THAT DIET CAN MODIFY EPIGENETIC CHANGES. THIS PAPER BRIEFLY REVIEWS THE CURRENT STATE OF KNOWLEDGE IN RELATION TO CRC DEVELOPMENT AND CONSIDERS EVIDENCE FOR POTENTIAL MECHANISMS BY WHICH DIET MAY MODIFY RISK. 2011 8 4974 36 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 9 3546 45 IMMUNOMODULATORY DIET IN PEDIATRIC AGE. IN THE LAST FEW DECADES, THE IMPORTANCE OF A FUNCTIONING IMMUNE SYSTEM AND HEALTH STATUS HAS BECOME MORE EVIDENT. MULTIPLE FACTORS ARE ABLE TO INFLUENCE THE DEVELOPMENT OF CHRONIC DISEASES AND DIET IS ONE OF THE MOST IMPORTANT ENVIRONMENTAL FACTORS. EVIDENCE DEMONSTRATES THAT DIETARY PATTERNS HIGH IN FAT AND LOW IN FIBER ARE ASSOCIATED WITH THE DEVELOPMENT OF NON-COMMUNICABLE DISEASES. MOREOVER, OPTIMAL NUTRITIONAL STATUS CAN MODULATE IMMUNE MATURATION AND RESPONSE TO INFLAMMATION. DURING INFLAMMATORY CONDITIONS, NUTRITIONAL DEFICIENCIES MAY OCCUR, ESTABLISHING A VICIOUS CIRCLE, CONSEQUENTLY A BALANCED NUTRITIONAL STATUS IS ESSENTIAL TO PREVENT AND COUNTERACT INFECTIONS. DIETARY DIVERSITY CAN PREVENT ALLERGIC DISEASES AND NUTRIENTS SUCH AS DHA, ARGININE, VITAMINS AND TRACE ELEMENTS HAVE AN IMPACT ON PHYSICAL BARRIERS (SUCH AS GUT MUCOSAL BARRIER AND SKIN), ON THE IMMUNE SYSTEM RESPONSE AND ON MICROBIOME MODULATION. PROTEIN DEFICIENCIES CAN COMPROMISE INNATE AND ADAPTIVE IMMUNE FUNCTIONS; ARGININE AVAILABILITY CAN AFFECT THE IMMUNE RESPONSE IN INJURED STATES AND OTHER DISEASE PROCESSES; EPA AND DHA CAN MODULATE BOTH INNATE AND ADAPTIVE IMMUNITY; PREBIOTICS HAVE A BENEFICIAL EFFECT ON THE FUNCTIONING OF THE IMMUNE SYSTEM. ZINC, COPPER, SELENIUM AND IRON ARE INVOLVED IN THE CORRECT DEVELOPMENT AND FUNCTION OF THE IMMUNE SYSTEM. VITAMINS D, E, A, B AND C HAVE A ROLE ON IMMUNE SYSTEM THROUGH DIFFERENT MECHANISMS OF ACTION. SINCE A COMPLEX INTERPLAY EXISTS BETWEEN DIET, MICROBIOME AND EPIGENETIC FACTORS WHICH DETERMINE NUTRIENT-INDUCED CHANGES ON THE IMMUNE FUNCTION, THE EFFECT OF EACH SINGLE NUTRIENT MAY BE DIFFICULT TO STUDY. WELL-DESIGNED INTERVENTION STUDIES, INVESTIGATING THE EFFECTS OF WHOLE DIETARY PATTERN, SHOULD BE PERFORMED TO CLARIFY IMPACT OF FOODS ON THE IMMUNE FUNCTION AND DISEASE RISK. 2021 10 2617 48 EPIGENOME TARGETING BY PROBIOTIC METABOLITES. BACKGROUND: THE INTESTINAL MICROBIOTA PLAYS AN IMPORTANT ROLE IN IMMUNE DEVELOPMENT AND HOMEOSTASIS. A DISTURBED MICROBIOTA DURING EARLY INFANCY IS ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING INFLAMMATORY AND ALLERGIC DISEASES LATER IN LIFE. THE MECHANISMS UNDERLYING THESE EFFECTS ARE POORLY UNDERSTOOD BUT ARE LIKELY TO INVOLVE ALTERATIONS IN MICROBIAL PRODUCTION OF FERMENTATION-DERIVED METABOLITES, WHICH HAVE POTENT IMMUNE MODULATING PROPERTIES AND ARE REQUIRED FOR MAINTENANCE OF HEALTHY MUCOSAL IMMUNE RESPONSES. PROBIOTICS ARE BENEFICIAL BACTERIA THAT HAVE THE CAPACITY TO ALTER THE COMPOSITION OF BACTERIAL SPECIES IN THE INTESTINE THAT CAN IN TURN INFLUENCE THE PRODUCTION OF FERMENTATION-DERIVED METABOLITES. PRINCIPAL AMONG THESE METABOLITES ARE THE SHORT-CHAIN FATTY ACIDS BUTYRATE AND ACETATE THAT HAVE POTENT ANTI-INFLAMMATORY ACTIVITIES IMPORTANT IN REGULATING IMMUNE FUNCTION AT THE INTESTINAL MUCOSAL SURFACE. THEREFORE STRATEGIES AIMED AT RESTORING THE MICROBIOTA PROFILE MAY BE EFFECTIVE IN THE PREVENTION OR TREATMENT OF ALLERGIC AND INFLAMMATORY DISEASES. PRESENTATION OF THE HYPOTHESIS: PROBIOTIC BACTERIA HAVE DIVERSE EFFECTS INCLUDING ALTERING MICROBIOTA COMPOSITION, REGULATING EPITHELIAL CELL BARRIER FUNCTION AND MODULATING OF IMMUNE RESPONSES. THE PRECISE MOLECULAR MECHANISMS MEDIATING THESE PROBIOTIC EFFECTS ARE NOT WELL UNDERSTOOD. SHORT-CHAIN FATTY ACIDS SUCH AS BUTYRATE ARE A CLASS OF HISTONE DEACETYLASE INHIBITORS IMPORTANT IN THE EPIGENETIC CONTROL OF HOST CELL RESPONSES. IT IS HYPOTHESIZED THAT THE BIOLOGICAL FUNCTION OF PROBIOTICS MAY BE A RESULT OF EPIGENETIC MODIFICATIONS THAT MAY EXPLAIN THE WIDE RANGE OF EFFECTS OBSERVED. STUDIES DELINEATING THE EFFECTS OF PROBIOTICS ON SHORT-CHAIN FATTY ACID PRODUCTION AND THE EPIGENETIC ACTIONS OF SHORT-CHAIN FATTY ACIDS WILL ASSIST IN UNDERSTANDING THE ASSOCIATION BETWEEN MICROBIOTA AND ALLERGIC OR AUTOIMMUNE DISORDERS. TESTING THE HYPOTHESIS: WE PROPOSE THAT TREATMENT WITH SPECIFIC PROBIOTIC BACTERIA UNDER IN VIVO CONDITIONS WOULD OFFER THE IDEAL CONDITIONS TO EXAMINE THE MICROBIOLOGICAL, IMMUNOLOGICAL AND EPIGENETIC MECHANISMS OF ACTION. ADVANCES IN EPIGENETIC TECHNOLOGY NOW ALLOW INVESTIGATORS TO BETTER UNDERSTAND THE COMPLEX BIOLOGICAL PROPERTIES OF PROBIOTICS AND THEIR METABOLITES. IMPLICATIONS OF THE HYPOTHESIS: DETERMINING THE PRECISE MECHANISMS OF PROBIOTIC ACTION WILL LEAD TO MORE SPECIFIC AND EFFICACIOUS THERAPEUTIC STRATEGIES IN THE PREVENTION OR TREATMENT OF CHRONIC INFLAMMATORY CONDITIONS. 2010 11 6259 26 THE MOLECULAR MECHANISMS BY WHICH VITAMIN D PREVENTS INSULIN RESISTANCE AND ASSOCIATED DISORDERS. NUMEROUS STUDIES HAVE SHOWN THAT VITAMIN D DEFICIENCY IS VERY COMMON IN MODERN SOCIETIES AND IS PERCEIVED AS AN IMPORTANT RISK FACTOR IN THE DEVELOPMENT OF INSULIN RESISTANCE AND RELATED DISEASES SUCH AS OBESITY AND TYPE 2 DIABETES (T2DM). WHILE IT IS GENERALLY ACCEPTED THAT VITAMIN D IS A REGULATOR OF BONE HOMEOSTASIS, ITS ABILITY TO COUNTERACT INSULIN RESISTANCE IS SUBJECT TO DEBATE. THE GOAL OF THIS COMMUNICATION IS TO REVIEW THE MOLECULAR MECHANISM BY WHICH VITAMIN D REDUCES INSULIN RESISTANCE AND RELATED COMPLICATIONS. THE UNIVERSITY LIBRARY, PUBMED, AND GOOGLE SCHOLAR WERE SEARCHED TO FIND RELEVANT STUDIES TO BE SUMMARIZED IN THIS REVIEW ARTICLE. INSULIN RESISTANCE IS ACCOMPANIED BY CHRONIC HYPERGLYCAEMIA AND INFLAMMATION. RECENT STUDIES HAVE SHOWN THAT VITAMIN D EXHIBITS INDIRECT ANTIOXIDATIVE PROPERTIES AND PARTICIPATES IN THE MAINTENANCE OF NORMAL RESTING ROS LEVEL. APPEALINGLY, VITAMIN D REDUCES INFLAMMATION AND REGULATES CA(2+) LEVEL IN MANY CELL TYPES. THEREFORE, THE BENEFICIAL ACTIONS OF VITAMIN D INCLUDE DIMINISHED INSULIN RESISTANCE WHICH IS OBSERVED AS AN IMPROVEMENT OF GLUCOSE AND LIPID METABOLISM IN INSULIN-SENSITIVE TISSUES. 2020 12 3576 50 IMPACT OF NUTRITION ON POLLUTANT TOXICITY: AN UPDATE WITH NEW INSIGHTS INTO EPIGENETIC REGULATION. EXPOSURE TO ENVIRONMENTAL POLLUTANTS IS A GLOBAL HEALTH PROBLEM AND IS ASSOCIATED WITH THE DEVELOPMENT OF MANY CHRONIC DISEASES, INCLUDING CARDIOVASCULAR DISEASE, DIABETES AND METABOLIC SYNDROME. THERE IS A GROWING BODY OF EVIDENCE THAT NUTRITION CAN BOTH POSITIVELY AND NEGATIVELY MODULATE THE TOXIC EFFECTS OF POLLUTANT EXPOSURE. DIETS HIGH IN PROINFLAMMATORY FATS, SUCH AS LINOLEIC ACID, CAN EXACERBATE POLLUTANT TOXICITY, WHEREAS DIETS RICH IN BIOACTIVE AND ANTI-INFLAMMATORY FOOD COMPONENTS, INCLUDING OMEGA-3 FATTY ACIDS AND POLYPHENOLS, CAN ATTENUATE TOXICANT-ASSOCIATED INFLAMMATION. PREVIOUSLY, RESEARCHERS HAVE ELUCIDATED DIRECT MECHANISMS OF NUTRITIONAL MODULATION, INCLUDING ALTERATION OF NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB) SIGNALING, BUT RECENTLY, INCREASED FOCUS HAS BEEN GIVEN TO THE WAYS IN WHICH NUTRITION AND POLLUTANTS AFFECT EPIGENETICS. NUTRITION HAS BEEN DEMONSTRATED TO MODULATE EPIGENETIC MARKERS THAT HAVE BEEN LINKED EITHER TO INCREASED DISEASE RISKS OR TO PROTECTION AGAINST DISEASES. OVERNUTRITION (I.E. OBESITY) AND UNDERNUTRITION (I.E. FAMINE) HAVE BEEN OBSERVED TO ALTER PRENATAL EPIGENETIC TAGS THAT MAY INCREASE THE RISK OF OFFSPRING DEVELOPING DISEASE LATER IN LIFE. CONVERSELY, BIOACTIVE FOOD COMPONENTS, INCLUDING CURCUMIN, HAVE BEEN SHOWN TO ALTER EPIGENETIC MARKERS THAT SUPPRESS THE ACTIVATION OF NF-KAPPAB, THUS REDUCING INFLAMMATORY RESPONSES. EXPOSURE TO POLLUTANTS ALSO ALTERS EPIGENETIC MARKERS AND MAY CONTRIBUTE TO INFLAMMATION AND DISEASE. IT HAS BEEN DEMONSTRATED THAT POLLUTANTS, VIA EPIGENETIC MODULATIONS, CAN INCREASE THE ACTIVATION OF NF-KAPPAB AND UPREGULATE MICRORNAS ASSOCIATED WITH INFLAMMATION, CARDIAC INJURY AND OXIDATIVE DAMAGE. IMPORTANTLY, RECENT EVIDENCE SUGGESTS THAT NUTRITIONAL COMPONENTS, INCLUDING EPIGALLOCATECHIN GALLATE (EGCG), CAN PROTECT AGAINST POLLUTANT-INDUCED INFLAMMATION THROUGH EPIGENETIC REGULATION OF PROINFLAMMATORY TARGET GENES OF NF-KAPPAB. FURTHER RESEARCH IS NEEDED TO BETTER UNDERSTAND HOW NUTRITION CAN MODULATE POLLUTANT TOXICITY THROUGH EPIGENETIC REGULATION. THEREFORE, THE OBJECTIVE OF THIS REVIEW IS TO ELUCIDATE THE CURRENT EVIDENCE LINKING EPIGENETIC CHANGES TO POLLUTANT-INDUCED DISEASES AND HOW THIS REGULATION MAY BE MODULATED BY NUTRIENTS ALLOWING FOR THE DEVELOPMENT OF FUTURE PERSONALIZED LIFESTYLE INTERVENTIONS. 2017 13 3848 28 IS EPIGENETICS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE? BACKGROUND: EPIGENETIC MECHANISMS PROVIDE ONE POTENTIAL EXPLANATION FOR HOW ENVIRONMENTAL INFLUENCES IN EARLY LIFE CAUSE LONG-TERM CHANGES IN CHRONIC DISEASE SUSCEPTIBILITY. WHEREAS EPIGENETIC DYSREGULATION IS INCREASINGLY IMPLICATED IN VARIOUS RARE DEVELOPMENTAL SYNDROMES AND CANCER, THE ROLE OF EPIGENETICS IN COMPLEX CHRONIC DISEASES, SUCH AS CARDIOVASCULAR DISEASE, TYPE 2 DIABETES AND OBESITY, REMAINS LARGELY UNCHARACTERIZED. EXTENSIVE WORK IN ANIMAL MODELS IS REQUIRED TO DEVELOP SPECIFIC HYPOTHESES THAT CAN BE PRACTICABLY TESTED IN HUMANS. ANIMAL MODELS: WE HAVE DEVELOPED A MOUSE MODEL SHOWING THAT METHYL DONOR SUPPLEMENTATION PREVENTS TRANSGENERATIONAL AMPLIFICATION OF OBESITY, SUGGESTING A ROLE FOR DNA METHYLATION IN THE DEVELOPMENTAL ESTABLISHMENT OF BODY WEIGHT REGULATION. CONCLUSIONS: COUPLING SUCH MODELS WITH RECENTLY DEVELOPED EPIGENOMIC TECHNOLOGIES SHOULD ULTIMATELY ENABLE US TO DETERMINE IF EPIGENETICS IS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE. 2009 14 397 44 AN UPDATE ON FETAL ALCOHOL SYNDROME-PATHOGENESIS, RISKS, AND TREATMENT. ALCOHOL IS A WELL-ESTABLISHED TERATOGEN THAT CAN CAUSE VARIABLE PHYSICAL AND BEHAVIORAL EFFECTS ON THE FETUS. THE MOST SEVERE CONDITION IN THIS SPECTRUM OF DISEASES IS KNOWN AS FETAL ALCOHOL SYNDROME (FAS). THE DIFFERENCES IN MATERNAL AND FETAL ENZYMES, IN TERMS OF ABUNDANCE AND EFFICIENCY, IN ADDITION TO REDUCED ELIMINATION, ALLOW FOR ALCOHOL TO HAVE A PROLONGED EFFECT ON THE FETUS. THIS CAN ACT AS A TERATOGEN THROUGH NUMEROUS METHODS INCLUDING REACTIVE OXYGEN SPECIES (GENERATED AS BY PRODUCTS OF CYP2E1), DECREASED ENDOGENOUS ANTIOXIDANT LEVELS, MITOCHONDRIAL DAMAGE, LIPID PEROXIDATION, DISRUPTED NEURONAL CELL-CELL ADHESION, PLACENTAL VASOCONSTRICTION, AND INHIBITION OF COFACTORS REQUIRED FOR FETAL GROWTH AND DEVELOPMENT. MORE RECENTLY, ALCOHOL HAS ALSO BEEN SHOWN TO HAVE EPIGENETIC EFFECTS. INCREASED FETAL EXPOSURE TO ALCOHOL AND SUSTAINED ALCOHOL INTAKE DURING ANY TRIMESTER OF PREGNANCY IS ASSOCIATED WITH AN INCREASED RISK OF FAS. OTHER RISK FACTORS INCLUDE GENETIC INFLUENCES, MATERNAL CHARACTERISTICS, FOR EXAMPLE, LOWER SOCIOECONOMIC STATUSES AND SMOKING, AND PATERNAL CHRONIC ALCOHOL USE. THE TREATMENT OPTIONS FOR FAS HAVE RECENTLY STARTED TO BE EXPLORED ALTHOUGH NONE ARE CURRENTLY APPROVED CLINICALLY. THESE INCLUDE PRENATAL ANTIOXIDANT ADMINISTRATION FOOD SUPPLEMENTS, FOLIC ACID, CHOLINE, NEUROACTIVE PEPTIDES, AND NEUROTROPHIC GROWTH FACTORS. TACKLING THE WIDER IMPACTS OF FAS, SUCH AS COMORBIDITIES, AND THE FAMILY SYSTEM HAVE BEEN SHOWN TO IMPROVE THE QUALITY OF LIFE OF FAS PATIENTS. THIS REVIEW AIMED TO FOCUS ON THE PATHOGENESIS, ESPECIALLY MECHANISMS OF ALCOHOL TERATOGENICITY, AND RISKS OF DEVELOPING FAS. RECENT DEVELOPMENTS IN POTENTIAL MANAGEMENT STRATEGIES, INCLUDING PRENATAL INTERVENTIONS, ARE DISCUSSED. 2016 15 6133 38 THE EPIGENETIC ROLE OF VITAMIN C IN NEURODEVELOPMENT. THE MATERNAL DIET DURING PREGNANCY IS A KEY DETERMINANT OF OFFSPRING HEALTH. EARLY STUDIES HAVE LINKED POOR MATERNAL NUTRITION DURING GESTATION WITH A PROPENSITY FOR THE DEVELOPMENT OF CHRONIC CONDITIONS IN OFFSPRING. THESE CONDITIONS INCLUDE CARDIOVASCULAR DISEASE, TYPE 2 DIABETES AND EVEN COMPROMISED MENTAL HEALTH. WHILE MULTIPLE FACTORS MAY CONTRIBUTE TO THESE OUTCOMES, DISTURBED EPIGENETIC PROGRAMMING DURING EARLY DEVELOPMENT IS ONE POTENTIAL BIOLOGICAL MECHANISM. THE EPIGENOME IS PROGRAMMED PRIMARILY IN UTERO, AND DURING THIS TIME, THE DEVELOPING FETUS IS HIGHLY SUSCEPTIBLE TO ENVIRONMENTAL FACTORS SUCH AS NUTRITIONAL INSULTS. DURING NEURODEVELOPMENT, EPIGENETIC PROGRAMMING COORDINATES THE FORMATION OF PRIMITIVE CENTRAL NERVOUS SYSTEM STRUCTURES, NEUROGENESIS, AND NEUROPLASTICITY. DYSREGULATED EPIGENETIC PROGRAMMING HAS BEEN IMPLICATED IN THE AETIOLOGY OF SEVERAL NEURODEVELOPMENTAL DISORDERS SUCH AS TATTON-BROWN-RAHMAN SYNDROME. ACCORDINGLY, THERE IS GREAT INTEREST IN DETERMINING HOW MATERNAL NUTRIENT AVAILABILITY IN PREGNANCY MIGHT AFFECT THE EPIGENETIC STATUS OF OFFSPRING, AND HOW SUCH INFLUENCES MAY PRESENT PHENOTYPICALLY. IN RECENT YEARS, A NUMBER OF EPIGENETIC ENZYMES THAT ARE ACTIVE DURING EMBRYONIC DEVELOPMENT HAVE BEEN FOUND TO REQUIRE VITAMIN C AS A COFACTOR. THESE ENZYMES INCLUDE THE TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASES (TETS) AND THE JUMONJI C DOMAIN-CONTAINING HISTONE LYSINE DEMETHYLASES THAT CATALYSE THE OXIDATIVE REMOVAL OF METHYL GROUPS ON CYTOSINES AND HISTONE LYSINE RESIDUES, RESPECTIVELY. THESE ENZYMES ARE INTEGRAL TO EPIGENETIC REGULATION AND HAVE FUNDAMENTAL ROLES IN CELLULAR DIFFERENTIATION, THE MAINTENANCE OF PLURIPOTENCY AND DEVELOPMENT. THE DEPENDENCE OF THESE ENZYMES ON VITAMIN C FOR OPTIMAL CATALYTIC ACTIVITY ILLUSTRATES A POTENTIALLY CRITICAL CONTRIBUTION OF THE NUTRIENT DURING MAMMALIAN DEVELOPMENT. THESE INSIGHTS ALSO HIGHLIGHT A POTENTIAL RISK ASSOCIATED WITH VITAMIN C INSUFFICIENCY DURING PREGNANCY. THE LINK BETWEEN VITAMIN C INSUFFICIENCY AND DEVELOPMENT IS PARTICULARLY APPARENT IN THE CONTEXT OF NEURODEVELOPMENT AND HIGH VITAMIN C CONCENTRATIONS IN THE BRAIN ARE INDICATIVE OF IMPORTANT FUNCTIONAL REQUIREMENTS IN THIS ORGAN. ACCORDINGLY, THIS REVIEW CONSIDERS THE EVIDENCE FOR THE POTENTIAL IMPACT OF MATERNAL VITAMIN C STATUS ON NEURODEVELOPMENTAL EPIGENETICS. 2022 16 6211 31 THE INTERPLAY BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN IN HEALTH AND DISEASE: POTENTIAL ROLE OF AUTONOMIC REGULATION AND EPIGENETIC MECHANISMS. OXIDATIVE STRESS CAN BE INDUCED BY VARIOUS STIMULI AND ALTERED IN CERTAIN CONDITIONS, INCLUDING EXERCISE AND PAIN. ALTHOUGH MANY STUDIES HAVE INVESTIGATED OXIDATIVE STRESS IN RELATION TO EITHER EXERCISE OR PAIN, THE LITERATURE PRESENTS CONFLICTING RESULTS. THEREFORE, THIS REVIEW CRITICALLY DISCUSSES EXISTING LITERATURE ABOUT THIS TOPIC, AIMING TO PROVIDE A CLEAR OVERVIEW OF KNOWN INTERACTIONS BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN IN HEALTHY PEOPLE AS WELL AS IN PEOPLE WITH CHRONIC PAIN, AND TO HIGHLIGHT POSSIBLE CONFOUNDING FACTORS TO KEEP IN MIND WHEN REFLECTING ON THESE INTERACTIONS. IN ADDITION, AUTONOMIC REGULATION AND EPIGENETIC MECHANISMS ARE PROPOSED AS POTENTIAL MECHANISMS OF ACTION UNDERLYING THE INTERPLAY BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN. THIS REVIEW HIGHLIGHTS THAT THE RELATION BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN IS POORLY UNDERSTOOD AND NOT STRAIGHTFORWARD, AS IT IS DEPENDENT ON THE CHARACTERISTICS OF EXERCISE, BUT ALSO ON WHICH POPULATION IS INVESTIGATED. TO BE ABLE TO COMPARE STUDIES ON THIS TOPIC, STRICT GUIDELINES SHOULD BE DEVELOPED TO LIMIT THE EFFECT OF SEVERAL CONFOUNDING FACTORS. THIS WAY, THE TRUE INTERPLAY BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN, AND THE UNDERLYING MECHANISMS OF ACTION CAN BE REVEALED AND VALIDATED VIA INDEPENDENT STUDIES. 2020 17 1010 31 CHRONICALLY ELEVATED PROLIFERATION AS A RISK FACTOR FOR NEOPLASIA. CHRONIC DISEASE CONDITIONS THAT ARE ASSOCIATED WITH ELEVATED PROLIFERATION ARE WELL ESTABLISHED AS RISK FACTORS FOR CANCER DEVELOPMENT. THESE MAY BE DUE TO VIRUSES (FOR EXAMPLE, IN THE CASE OF HEPATITIS AND LIVER CANCER), BACTERIAL INFECTIONS, PARASITE INFESTATION OR PHYSICAL TRAUMA. IN ADDITION TO THESE EXOGENOUS AGENTS THERE ARE ALSO METABOLIC ABNORMALITIES THAT CAN CONTRIBUTE, CAUSED BY GENETIC OR EPIGENETIC INFLUENCE. IN THE LATTER CASE, AN INCREASE IN SERUM LEVELS OF THE HORMONES OESTROGEN, TESTOSTERONE AND INSULIN MAY BE OF SPECIAL IMPORTANCE. THE PRESENT REVIEW CONCENTRATES ATTENTION ON FACTORS THAT INDUCE ELEVATED CELL TURNOVER AND FOR WHICH THERE IS EPIDEMIOLOGICAL AND/OR EXPERIMENTAL EVIDENCE OF A LINK WITH NEOPLASIA, WITH PARTICULAR STRESS ON THE INDIVIDUAL ORGAN OR TISSUE LEVEL. 1998 18 4625 50 NEUROBIOLOGY OF VITAMIN C: EXPANDING THE FOCUS FROM ANTIOXIDANT TO ENDOGENOUS NEUROMODULATOR. ASCORBIC ACID (AA) IS A WATER-SOLUBLE VITAMIN (C) FOUND IN ALL BODILY ORGANS. MOST MAMMALS SYNTHESIZE IT, HUMANS ARE REQUIRED TO EAT IT, BUT ALL MAMMALS NEED IT FOR HEALTHY FUNCTIONING. AA REACHES ITS HIGHEST CONCENTRATION IN THE BRAIN WHERE BOTH NEURONS AND GLIA RELY ON TIGHTLY REGULATED UPTAKE FROM BLOOD VIA THE GLUCOSE TRANSPORT SYSTEM AND SODIUM-COUPLED ACTIVE TRANSPORT TO ACCUMULATE AND MAINTAIN AA AT MILLIMOLAR LEVELS. AS A PROTOTYPE ANTIOXIDANT, AA IS NOT ONLY NEUROPROTECTIVE, BUT ALSO FUNCTIONS AS A COFACTOR IN REDOX-COUPLED REACTIONS ESSENTIAL FOR THE SYNTHESIS OF NEUROTRANSMITTERS (E.G., DOPAMINE AND NOREPINEPHRINE) AND PARACRINE LIPID MEDIATORS (E.G., EPOXIECOISATRIENOIC ACIDS) AS WELL AS THE EPIGENETIC REGULATION OF DNA. ALTHOUGH REDOX CAPACITY LED TO THE PROMOTION OF AA IN HIGH DOSES AS POTENTIAL TREATMENT FOR VARIOUS NEUROPATHOLOGICAL AND PSYCHIATRIC CONDITIONS, AMPLE EVIDENCE HAS NOT SUPPORTED THIS THERAPEUTIC STRATEGY. HERE, WE FOCUS ON SOME LONG-NEGLECTED ASPECTS OF AA NEUROBIOLOGY, INCLUDING ITS MODULATORY ROLE IN SYNAPTIC TRANSMISSION AS DEMONSTRATED BY THE LONG-ESTABLISHED LINK BETWEEN RELEASE OF ENDOGENOUS AA IN BRAIN EXTRACELLULAR FLUID AND THE CLEARANCE OF GLUTAMATE, AN EXCITATORY AMINO ACID. EVIDENCE THAT THIS LINK CAN BE DISRUPTED IN ANIMAL MODELS OF HUNTINGTON S DISEASE IS REVEALING OPPORTUNITIES FOR NEW RESEARCH PATHWAYS AND THERAPEUTIC APPLICATIONS (E.G., EPILEPSY AND PAIN MANAGEMENT). IN FACT, WE SUGGEST THAT IMPROVED UNDERSTANDING OF THE REGULATION OF ENDOGENOUS AA AND ITS INTERACTION WITH KEY BRAIN NEUROTRANSMITTER SYSTEMS, RATHER THAN ADMINISTRATION OF AA IN EXCESS, SHOULD BE THE TARGET OF FUTURE BRAIN-BASED THERAPIES. 2019 19 2700 46 EXCESS IRON: CONSIDERATIONS RELATED TO DEVELOPMENT AND EARLY GROWTH. WHAT EFFECTS MIGHT ARISE FROM EARLY LIFE EXPOSURES TO HIGH IRON? THIS REVIEW CONSIDERS THE SPECIFIC EFFECTS OF HIGH IRON ON THE BRAIN, STEM CELLS, AND THE PROCESS OF ERYTHROPOIESIS AND IDENTIFIES GAPS IN OUR KNOWLEDGE OF WHAT MOLECULAR DAMAGE MAY BE INCURRED BY OXIDATIVE STRESS THAT IS IMPARTED BY HIGH IRON STATUS IN EARLY LIFE. SPECIFIC AREAS TO ENHANCE RESEARCH ON THIS TOPIC INCLUDE THE FOLLOWING: LONGITUDINAL BEHAVIORAL STUDIES OF CHILDREN TO TEST ASSOCIATIONS BETWEEN IRON EXPOSURES AND MOOD, EMOTION, COGNITION, AND MEMORY; ANIMAL STUDIES TO DETERMINE EPIGENETIC CHANGES THAT REPROGRAM BRAIN DEVELOPMENT AND METABOLIC CHANGES IN EARLY LIFE THAT COULD BE FOLLOWED THROUGH THE LIFE COURSE; AND THE ESTABLISHMENT OF HUMAN EPIGENETIC MARKERS OF IRON EXPOSURES AND OXIDATIVE STRESS THAT COULD BE MONITORED FOR EARLY ORIGINS OF ADULT CHRONIC DISEASES. IN ADDITION, EFFORTS TO UNDERSTAND HOW IRON EXPOSURE INFLUENCES STEM CELL BIOLOGY COULD BE ENHANCED BY ESTABLISHING PLATFORMS TO COLLECT BIOLOGICAL SPECIMENS, INCLUDING UMBILICAL CORD BLOOD AND AMNIOTIC FLUID, TO BE MADE AVAILABLE TO THE RESEARCH COMMUNITY. AT THE MOLECULAR LEVEL, THERE IS A NEED TO BETTER UNDERSTAND STRESS ERYTHROPOIESIS AND CHANGES IN IRON METABOLISM DURING PREGNANCY AND DEVELOPMENT, ESPECIALLY WITH RESPECT TO REGULATORY CONTROL UNDER HIGH IRON CONDITIONS THAT MIGHT PROMOTE INEFFECTIVE ERYTHROPOIESIS AND IRON-LOADING ANEMIA. THESE INVESTIGATIONS SHOULD FOCUS NOT ONLY ON FACTORS SUCH AS HEPCIDIN AND ERYTHROFERRONE BUT SHOULD ALSO INCLUDE NEWLY IDENTIFIED INTERACTIONS BETWEEN TRANSFERRIN RECEPTOR-2 AND THE ERYTHROPOIETIN RECEPTOR. FINALLY, DESPITE OUR UNDERSTANDING THAT SEVERAL KEY MICRONUTRIENTS (E.G., VITAMIN A, COPPER, MANGANESE, AND ZINC) SUPPORT IRON'S FUNCTION IN ERYTHROPOIESIS, HOW THESE NUTRIENTS INTERACT REMAINS, TO OUR KNOWLEDGE, UNKNOWN. IT IS NECESSARY TO CONSIDER MANY FACTORS WHEN FORMULATING RECOMMENDATIONS ON IRON SUPPLEMENTATION. 2017 20 3547 38 IMMUNOMODULATORY ROLE OF NUTRIENTS: HOW CAN PULMONARY DYSFUNCTIONS IMPROVE? NUTRITION IS AN IMPORTANT TOOL THAT CAN BE USED TO MODULATE THE IMMUNE RESPONSE DURING INFECTIOUS DISEASES. IN ADDITION, THROUGH DIET, IMPORTANT SUBSTRATES ARE ACQUIRED FOR THE BIOSYNTHESIS OF REGULATORY MOLECULES IN THE IMMUNE RESPONSE, INFLUENCING THE PROGRESSION AND TREATMENT OF CHRONIC LUNG DISEASES, SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). IN THIS WAY, NUTRITION CAN PROMOTE LUNG HEALTH STATUS. A RANGE OF NUTRIENTS, SUCH AS VITAMINS (A, C, D, AND E), MINERALS (ZINC, SELENIUM, IRON, AND MAGNESIUM), FLAVONOIDS AND FATTY ACIDS, PLAY IMPORTANT ROLES IN REDUCING THE RISK OF PULMONARY CHRONIC DISEASES AND VIRAL INFECTIONS. THROUGH THEIR ANTIOXIDANT AND ANTI-INFLAMMATORY EFFECTS, NUTRIENTS ARE ASSOCIATED WITH BETTER LUNG FUNCTION AND A LOWER RISK OF COMPLICATIONS SINCE THEY CAN DECREASE THE HARMFUL EFFECTS FROM THE IMMUNE SYSTEM DURING THE INFLAMMATORY RESPONSE. IN ADDITION, BIOACTIVE COMPOUNDS CAN EVEN CONTRIBUTE TO EPIGENETIC CHANGES, INCLUDING HISTONE DEACETYLASE (HDAC) MODIFICATIONS THAT INHIBIT THE TRANSCRIPTION OF PROINFLAMMATORY CYTOKINES, WHICH CAN CONTRIBUTE TO THE MAINTENANCE OF HOMEOSTASIS IN THE CONTEXT OF INFECTIONS AND CHRONIC INFLAMMATORY DISEASES. THESE NUTRIENTS ALSO PLAY AN IMPORTANT ROLE IN ACTIVATING IMMUNE RESPONSES AGAINST PATHOGENS, WHICH CAN HELP THE IMMUNE SYSTEM DURING INFECTIONS. HERE, WE PROVIDE AN UPDATED OVERVIEW OF THE ROLES PLAYED BY DIETARY FACTORS AND HOW THEY CAN AFFECT RESPIRATORY HEALTH. THEREFORE, WE WILL SHOW THE ANTI-INFLAMMATORY ROLE OF FLAVONOIDS, FATTY ACIDS, VITAMINS AND MICROBIOTA, IMPORTANT FOR THE CONTROL OF CHRONIC INFLAMMATORY DISEASES AND ALLERGIES, IN ADDITION TO THE ANTIVIRAL ROLE OF VITAMINS, FLAVONOIDS, AND MINERALS DURING PULMONARY VIRAL INFECTIONS, ADDRESSING THE MECHANISMS INVOLVED IN EACH FUNCTION. THESE MECHANISMS ARE INTERESTING IN THE DISCUSSION OF PERSPECTIVES ASSOCIATED WITH SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2) INFECTION AND ITS PULMONARY COMPLICATIONS SINCE PATIENTS WITH SEVERE DISEASE HAVE VITAMINS DEFICIENCY, ESPECIALLY VITAMIN D. IN ADDITION, RESEARCHES WITH THE USE OF FLAVONOIDS HAVE BEEN SHOWN TO DECREASE VIRAL REPLICATION IN VITRO. THIS WAY, A FULL UNDERSTANDING OF DIETARY INFLUENCES CAN IMPROVE THE LUNG HEALTH OF PATIENTS. 2021