1 5112 88 POLYUNSATURATED FATTY ACIDS: BIOCHEMICAL, NUTRITIONAL AND EPIGENETIC PROPERTIES. DIETARY POLYUNSATURATED FATTY ACIDS (PUFA) HAVE EFFECTS ON DIVERSE PHYSIOLOGICAL PROCESSES IMPACTING NORMAL HEALTH AND CHRONIC DISEASES, SUCH AS THE REGULATION OF PLASMA LIPID LEVELS, CARDIOVASCULAR AND IMMUNE FUNCTION, INSULIN ACTION AND NEURONAL DEVELOPMENT AND VISUAL FUNCTION. INGESTION OF PUFA WILL LEAD TO THEIR DISTRIBUTION TO VIRTUALLY EVERY CELL IN THE BODY WITH EFFECTS ON MEMBRANE COMPOSITION AND FUNCTION, EICOSANOID SYNTHESIS, CELLULAR SIGNALING AND REGULATION OF GENE EXPRESSION. CELL SPECIFIC LIPID METABOLISM, AS WELL AS THE EXPRESSION OF FATTY ACID-REGULATED TRANSCRIPTION FACTORS, LIKELY PLAY AN IMPORTANT ROLE IN DETERMINING HOW CELLS RESPOND TO CHANGES IN PUFA COMPOSITION. THIS REVIEW WILL FOCUS ON RECENT ADVANCES ON THE ESSENTIALITY OF THESE MOLECULES AND ON THEIR INTERPLAY IN CELL PHYSIOLOGY, LEADING TO NEW PERSPECTIVE IN DIFFERENT THERAPEUTIC FIELDS. 2004 2 2320 30 EPIGENETIC REGULATION OF GENE EXPRESSION AND M2 MACROPHAGE POLARIZATION AS NEW POTENTIAL OMEGA-3 POLYUNSATURATED FATTY ACID TARGETS IN COLON INFLAMMATION AND CANCER. INTRODUCTION: IT HAS BECOME INCREASINGLY CLEAR THAT DIETARY HABITS MAY AFFECT THE RISK/PROGRESSION OF CHRONIC DISEASES WITH A PATHOGENIC INFLAMMATORY COMPONENT, SUCH AS COLORECTAL CANCER. CONSIDERABLE ATTENTION HAS BEEN DIRECTED TOWARD THE ABILITY OF NUTRITIONAL AGENTS TO TARGET KEY MOLECULAR PATHWAYS INVOLVED IN THESE INFLAMMATORY-RELATED DISEASES. AREAS COVERED: OMEGA-3 POLYUNSATURATED FATTY ACIDS (PUFA) AND THEIR OXIDATIVE METABOLITES HAVE ATTRACTED CONSIDERABLE INTEREST AS POSSIBLE ANTI-INFLAMMATORY AND ANTI-CANCER AGENTS, ESPECIALLY IN AREAS SUCH AS THE LARGE BOWEL, WHERE THE INFLUENCE OF ORALLY INTRODUCED SUBSTANCES IS HIGH AND TUMORS SHOW DERANGED PUFA PATTERNS. ON THIS BASIS, WE HAVE ANALYZED PRE-CLINICAL FINDINGS THAT HAVE RECENTLY REVEALED NEW INSIGHT INTO THE MOLECULAR PATHWAYS TARGETED BY OMEGA-3 PUFA. EXPERT OPINION: THE FINDINGS ANALYZED HEREIN DEMONSTRATE THAT OMEGA-3 PUFA MAY EXERT BENEFICIAL EFFECTS BY TARGETING THE EPIGENETIC REGULATION OF GENE EXPRESSION AND ALTERING M2 MACROPHAGE POLARIZATION DURING THE INFLAMMATORY RESPONSE. THESE MECHANISMS NEED TO BE BETTER EXPLORED IN THE LARGE BOWEL, AND FURTHER STUDIES COULD BETTER CLARIFY THEIR ROLE AND THE POTENTIAL OF DIETARY INTERVENTIONS WITH OMEGA-3 PUFA IN THE LARGE BOWEL. THE EPIGENOMIC MECHANISM IS DISCUSSED IN VIEW OF THE POTENTIAL OF OMEGA-3 PUFA TO ENHANCE THE EFFICACY OF OTHER AGENTS USED IN THE THERAPY OF COLORECTAL CANCER. 2016 3 4110 37 MECHANISMS BY WHICH PLEIOTROPIC AMPHIPHILIC N-3 PUFA REDUCE COLON CANCER RISK. COLORECTAL CANCER IS ONE OF THE MAJOR CAUSES OF CANCER-RELATED MORTALITY IN BOTH MEN AND WOMEN WORLDWIDE. GENETIC SUSCEPTIBILITY AND DIET ARE PRIMARY DETERMINANTS OF CANCER RISK AND TUMOR BEHAVIOR. EXPERIMENTAL, EPIDEMIOLOGICAL, AND CLINICAL DATA SUBSTANTIATE THE BENEFICIAL ROLE OF N-3 POLYUNSATURATED FATTY ACIDS (PUFA) IN PREVENTING CHRONIC INFLAMMATION AND COLON CANCER. FROM A MECHANISTIC PERSPECTIVE, N-3 PUFA ARE PLEIOTROPIC AND MULTIFACETED WITH RESPECT TO THEIR MOLECULAR MECHANISMS OF ACTION. FOR EXAMPLE, THIS CLASS OF DIETARY LIPID UNIQUELY ALTERS MEMBRANE STRUCTURE/ CYTOSKELETAL FUNCTION, IMPACTING MEMBRANE RECEPTOR FUNCTION AND DOWNSTREAM SIGNALING CASCADES, INCLUDING GENE EXPRESSION PROFILES AND CELL PHENOTYPE. IN ADDITION, N-3 PUFA CAN SYNERGIZE WITH OTHER POTENTIAL ANTI-TUMOR AGENTS, SUCH AS FERMENTABLE FIBER AND CURCUMIN. WITH THE RISING PREVALENCE OF DIET-INDUCED OBESITY, THERE IS ALSO AN URGENT NEED TO ELUCIDATE THE LINK BETWEEN CHRONIC INFLAMMATION IN ADIPOSE TISSUE AND COLON CANCER RISK IN OBESITY. IN THIS REVIEW, WE WILL SUMMARIZE RECENT DEVELOPMENTS LINKING N-3 PUFA INTAKE, MEMBRANE ALTERATIONS, EPIGENETIC MODULATION, AND EFFECTS ON OBESITY-ASSOCIATED COLON CANCER RISK. 2014 4 3546 31 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 5 4273 32 MICROBIOTA AND EPIGENETICS: HEALTH IMPACT. EPIGENETIC CHANGES ASSOCIATED WITH DISEASE DEVELOPMENT AND PROGRESSIONS ARE OF INCREASING IMPORTANCE BECAUSE OF THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. SEVERAL EPIGENETIC CHANGES ASSOCIATED WITH CHRONIC METABOLIC DISORDERS HAVE BEEN STUDIED IN VARIOUS DISEASES. EPIGENETIC CHANGES ARE MOSTLY MODULATED BY ENVIRONMENTAL FACTORS, INCLUDING THE HUMAN MICROBIOTA LIVING IN DIFFERENT PARTS OF OUR BODIES. THE MICROBIAL STRUCTURAL COMPONENTS AND THE MICROBIALLY DERIVED METABOLITES DIRECTLY INTERACT WITH HOST CELLS, THEREBY MAINTAINING HOMEOSTASIS. MICROBIOME DYSBIOSIS, ON THE OTHER HAND, IS KNOWN TO PRODUCE ELEVATED LEVELS OF DISEASE-LINKED METABOLITES, WHICH MAY DIRECTLY AFFECT A HOST METABOLIC PATHWAY OR INDUCE EPIGENETIC CHANGES THAT CAN LEAD TO DISEASE DEVELOPMENT. DESPITE THEIR IMPORTANT ROLE IN HOST PHYSIOLOGY AND SIGNAL TRANSDUCTION, THERE HAS BEEN LITTLE RESEARCH INTO THE MECHANICS AND PATHWAYS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. THIS CHAPTER FOCUSES ON THE RELATIONSHIP BETWEEN MICROBES AND THEIR EPIGENETIC EFFECTS IN DISEASED PATHOLOGY, AS WELL AS ON THE REGULATION AND METABOLISM OF THE DIETARY OPTIONS AVAILABLE TO THE MICROBES. FURTHERMORE, THIS CHAPTER ALSO PROVIDES A PROSPECTIVE LINK BETWEEN THESE TWO IMPORTANT PHENOMENA, TERMED "MICROBIOME AND EPIGENETICS." 2023 6 3547 35 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 7 3576 34 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 8 6715 33 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 9 4453 31 MOLECULAR MECHANISMS AND PATHWAYS AS TARGETS FOR CANCER PREVENTION AND PROGRESSION WITH DIETARY COMPOUNDS. A UNIQUE FEATURE OF BIOACTIVE FOOD INGREDIENTS IS THEIR BROAD ANTIOXIDANT FUNCTION. ANTIOXIDANTS HAVING A WIDE SPECTRUM OF CHEMICAL STRUCTURE AND ACTIVITY BEYOND BASIC NUTRITION; DISPLAY DIFFERENT HEALTH BENEFITS BY THE PREVENTION AND PROGRESSION OF CHRONIC DISEASES. FUNCTIONAL FOOD COMPONENTS ARE CAPABLE OF ENHANCING THE NATURAL ANTIOXIDANT DEFENSE SYSTEM BY SCAVENGING REACTIVE OXYGEN AND NITROGEN SPECIES, PROTECTING AND REPAIRING DNA DAMAGE, AS WELL AS MODULATING THE SIGNAL TRANSDUCTION PATHWAYS AND GENE EXPRESSION. MAJOR PATHWAYS AFFECTED BY BIOACTIVE FOOD INGREDIENTS INCLUDE THE PRO-INFLAMMATORY PATHWAYS REGULATED BY NUCLEAR FACTOR KAPPA B (NF-KAPPAB), AS WELL AS THOSE ASSOCIATED WITH CYTOKINES AND CHEMOKINES. THE PRESENT REVIEW SUMMARIZES THE IMPORTANCE OF PLANT BIOACTIVES AND THEIR ROLES IN THE REGULATION OF INFLAMMATORY PATHWAYS. BIOACTIVES INFLUENCE SEVERAL PHYSIOLOGICAL PROCESSES SUCH AS GENE EXPRESSION, CELL CYCLE REGULATION, CELL PROLIFERATION, CELL MIGRATION, ETC., RESULTING IN CANCER PREVENTION. CANCER INITIATION IS ASSOCIATED WITH CHANGES IN METABOLIC PATHWAYS SUCH AS GLUCOSE METABOLISM, AND THE EFFECT OF BIOACTIVES IN NORMALIZING THIS PROCESS HAS BEEN PROVIDED. INITIATION AND PROGRESSION OF INFLAMMATORY BOWEL DISEASES (IBD) WHICH INCREASE THE CHANCES OF DEVELOPING OF COLORECTAL CANCERS CAN BE DOWNREGULATED BY PLANT BIOACTIVES. SEVERAL ASPECTS OF THE POTENTIAL ROLES OF MICRORNAS AND EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT OF CANCERS HAVE ALSO BEEN PRESENTED. 2017 10 6183 28 THE IMPACT OF ENVIRONMENTAL FACTORS IN INFLUENCING EPIGENETICS RELATED TO OXIDATIVE STATES IN THE CARDIOVASCULAR SYSTEM. OXIDATIVE STATES EXERT A SIGNIFICANT INFLUENCE ON A WIDE RANGE OF BIOLOGICAL AND MOLECULAR PROCESSES AND FUNCTIONS. WHEN THEIR BALANCE IS SHIFTED TOWARDS ENHANCED AMOUNTS OF FREE RADICALS, PATHOLOGICAL PHENOMENA CAN OCCUR, AS THE GENERATION OF REACTIVE OXYGEN SPECIES (ROS) IN TISSUE MICROENVIRONMENT OR IN THE SYSTEMIC CIRCULATION CAN BE DETRIMENTAL. EPIDEMIC CHRONIC DISEASES OF WESTERN SOCIETIES, SUCH AS CARDIOVASCULAR DISEASE, OBESITY, AND DIABETES CORRELATE WITH THE IMBALANCE OF REDOX HOMEOSTASIS. CURRENT ADVANCES IN OUR UNDERSTANDING OF EPIGENETICS HAVE REVEALED A PARALLEL SCENARIO SHOWING THE INFLUENCE OF OXIDATIVE STRESS AS A MAJOR REGULATOR OF EPIGENETIC GENE REGULATION VIA MODIFICATION OF DNA METHYLATION, HISTONES, AND MICRORNAS. THIS HAS PROVIDED BOTH THE BIOLOGICAL LINK AND A POTENTIAL MOLECULAR EXPLANATION BETWEEN OXIDATIVE STRESS AND CARDIOVASCULAR/METABOLIC PHENOMENA. ACCORDINGLY, IN THIS REVIEW, WE WILL PROVIDE CURRENT INSIGHTS ON THE PHYSIOLOGICAL AND PATHOLOGICAL IMPACT OF CHANGES IN OXIDATIVE STATES ON CARDIOVASCULAR DISORDERS, BY SPECIFICALLY FOCUSING ON THE INFLUENCE OF EPIGENETIC REGULATION. A SPECIAL EMPHASIS WILL HIGHLIGHT THE EFFECT ON EPIGENETIC REGULATION OF HUMAN'S CURRENT LIFE HABITS, EXTERNAL AND ENVIRONMENTAL FACTORS, INCLUDING FOOD INTAKE, TOBACCO, AIR POLLUTION, AND ANTIOXIDANT-BASED APPROACHES. ADDITIONALLY, THE STRATEGY TO QUANTIFY OXIDATIVE STATES IN HUMANS IN ORDER TO DETERMINE WHICH BIOLOGICAL MARKER COULD BEST MATCH A SUBJECT'S PROFILE WILL BE DISCUSSED. 2017 11 2855 30 FROM INFLAMMAGING TO HEALTHY AGING BY DIETARY LIFESTYLE CHOICES: IS EPIGENETICS THE KEY TO PERSONALIZED NUTRITION? THE PROGRESSIVELY OLDER POPULATION IN DEVELOPED COUNTRIES IS REFLECTED IN AN INCREASE IN THE NUMBER OF PEOPLE SUFFERING FROM AGE-RELATED CHRONIC INFLAMMATORY DISEASES SUCH AS METABOLIC SYNDROME, DIABETES, HEART AND LUNG DISEASES, CANCER, OSTEOPOROSIS, ARTHRITIS, AND DEMENTIA. THE HETEROGENEITY IN BIOLOGICAL AGING, CHRONOLOGICAL AGE, AND AGING-ASSOCIATED DISORDERS IN HUMANS HAVE BEEN ASCRIBED TO DIFFERENT GENETIC AND ENVIRONMENTAL FACTORS (I.E., DIET, POLLUTION, STRESS) THAT ARE CLOSELY LINKED TO SOCIOECONOMIC FACTORS. THE COMMON DENOMINATOR OF THESE FACTORS IS THE INFLAMMATORY RESPONSE. CHRONIC LOW-GRADE SYSTEMIC INFLAMMATION DURING PHYSIOLOGICAL AGING AND IMMUNOSENESCENCE ARE INTERTWINED IN THE PATHOGENESIS OF PREMATURE AGING ALSO DEFINED AS 'INFLAMMAGING.' THE LATTER HAS BEEN ASSOCIATED WITH FRAILTY, MORBIDITY, AND MORTALITY IN ELDERLY SUBJECTS. HOWEVER, IT IS UNKNOWN TO WHAT EXTENT INFLAMMAGING OR LONGEVITY IS CONTROLLED BY EPIGENETIC EVENTS IN EARLY LIFE. TODAY, HUMAN DIET IS BELIEVED TO HAVE A MAJOR INFLUENCE ON BOTH THE DEVELOPMENT AND PREVENTION OF AGE-RELATED DISEASES. MOST PLANT-DERIVED DIETARY PHYTOCHEMICALS AND MACRO- AND MICRONUTRIENTS MODULATE OXIDATIVE STRESS AND INFLAMMATORY SIGNALING AND REGULATE METABOLIC PATHWAYS AND BIOENERGETICS THAT CAN BE TRANSLATED INTO STABLE EPIGENETIC PATTERNS OF GENE EXPRESSION. THEREFORE, DIET INTERVENTIONS DESIGNED FOR HEALTHY AGING HAVE BECOME A HOT TOPIC IN NUTRITIONAL EPIGENOMIC RESEARCH. INCREASING EVIDENCE HAS REVEALED THAT COMPLEX INTERACTIONS BETWEEN FOOD COMPONENTS AND HISTONE MODIFICATIONS, DNA METHYLATION, NON-CODING RNA EXPRESSION, AND CHROMATIN REMODELING FACTORS INFLUENCE THE INFLAMMAGING PHENOTYPE AND AS SUCH MAY PROTECT OR PREDISPOSE AN INDIVIDUAL TO MANY AGE-RELATED DISEASES. REMARKABLY, HUMANS PRESENT A BROAD RANGE OF RESPONSES TO SIMILAR DIETARY CHALLENGES DUE TO BOTH GENETIC AND EPIGENETIC MODULATIONS OF THE EXPRESSION OF TARGET PROTEINS AND KEY GENES INVOLVED IN THE METABOLISM AND DISTRIBUTION OF THE DIETARY CONSTITUENTS. HERE, WE WILL SUMMARIZE THE EPIGENETIC ACTIONS OF DIETARY COMPONENTS, INCLUDING PHYTOCHEMICALS, AND MACRO- AND MICRONUTRIENTS AS WELL AS METABOLITES, THAT CAN ATTENUATE INFLAMMAGING. WE WILL DISCUSS THE CHALLENGES FACING PERSONALIZED NUTRITION TO TRANSLATE HIGHLY VARIABLE INTERINDIVIDUAL EPIGENETIC DIET RESPONSES TO POTENTIAL INDIVIDUAL HEALTH BENEFITS/RISKS RELATED TO AGING DISEASE. 2015 12 6067 28 THE DIABETES MELLITUS-ATHEROSCLEROSIS CONNECTION: THE ROLE OF LIPID AND GLUCOSE METABOLISM AND CHRONIC INFLAMMATION. DIABETES MELLITUS COMPRISES A GROUP OF CARBOHYDRATE METABOLISM DISORDERS THAT SHARE A COMMON MAIN FEATURE OF CHRONIC HYPERGLYCEMIA THAT RESULTS FROM DEFECTS OF INSULIN SECRETION, INSULIN ACTION, OR BOTH. INSULIN IS AN IMPORTANT ANABOLIC HORMONE, AND ITS DEFICIENCY LEADS TO VARIOUS METABOLIC ABNORMALITIES IN PROTEINS, LIPIDS, AND CARBOHYDRATES. ATHEROSCLEROSIS DEVELOPS AS A RESULT OF A MULTISTEP PROCESS ULTIMATELY LEADING TO CARDIOVASCULAR DISEASE ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY. ALTERATION OF LIPID METABOLISM IS A RISK FACTOR AND CHARACTERISTIC FEATURE OF ATHEROSCLEROSIS. POSSIBLE LINKS BETWEEN THE TWO CHRONIC DISORDERS DEPENDING ON ALTERED METABOLIC PATHWAYS HAVE BEEN INVESTIGATED IN NUMEROUS STUDIES. IT WAS SHOWN THAT BOTH TYPES OF DIABETES MELLITUS CAN ACTUALLY INDUCE ATHEROSCLEROSIS DEVELOPMENT OR FURTHER ACCELERATE ITS PROGRESSION. ELEVATED GLUCOSE LEVEL, DYSLIPIDEMIA, AND OTHER METABOLIC ALTERATIONS THAT ACCOMPANY THE DISEASE DEVELOPMENT ARE TIGHTLY INVOLVED IN THE PATHOGENESIS OF ATHEROSCLEROSIS AT ALMOST EVERY STEP OF THE ATHEROGENIC PROCESS. CHRONIC INFLAMMATION IS CURRENTLY CONSIDERED AS ONE OF THE KEY FACTORS IN ATHEROSCLEROSIS DEVELOPMENT AND IS PRESENT STARTING FROM THE EARLIEST STAGES OF THE PATHOLOGY INITIATION. IT MAY ALSO BE REGARDED AS ONE OF THE POSSIBLE LINKS BETWEEN ATHEROSCLEROSIS AND DIABETES MELLITUS. HOWEVER, THE DATA AVAILABLE SO FAR DO NOT ALLOW FOR DEVELOPING EFFECTIVE ANTI-INFLAMMATORY THERAPEUTIC STRATEGIES THAT WOULD STOP ATHEROSCLEROTIC LESION PROGRESSION OR INDUCE LESION REDUCTION. IN THIS REVIEW, WE SUMMARIZE THE MAIN ASPECTS OF DIABETES MELLITUS THAT POSSIBLY AFFECT THE ATHEROGENIC PROCESS AND ITS RELATIONSHIP WITH CHRONIC INFLAMMATION. WE ALSO DISCUSS THE ESTABLISHED PATHOPHYSIOLOGICAL FEATURES THAT LINK ATHEROSCLEROSIS AND DIABETES MELLITUS, SUCH AS OXIDATIVE STRESS, ALTERED PROTEIN KINASE SIGNALING, AND THE ROLE OF CERTAIN MIRNA AND EPIGENETIC MODIFICATIONS. 2020 13 2562 26 EPIGENETICS IN THE PRIMARY AND SECONDARY PREVENTION OF CARDIOVASCULAR DISEASE: INFLUENCE OF EXERCISE AND NUTRITION. INCREASING EVIDENCE LINKS CHANGES IN EPIGENETIC SYSTEMS, SUCH AS DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA EXPRESSION, TO THE OCCURRENCE OF CARDIOVASCULAR DISEASE (CVD). THESE EPIGENETIC MODIFICATIONS CAN CHANGE GENETIC FUNCTION UNDER INFLUENCE OF EXOGENOUS STIMULI AND CAN BE TRANSFERRED TO NEXT GENERATIONS, PROVIDING A POTENTIAL MECHANISM FOR INHERITANCE OF BEHAVIOURAL INTERVENTION EFFECTS. THE BENEFITS OF EXERCISE AND NUTRITIONAL INTERVENTIONS IN THE PRIMARY AND SECONDARY PREVENTION OF CVD ARE WELL ESTABLISHED, BUT THE MECHANISMS ARE NOT COMPLETELY UNDERSTOOD. IN THIS REVIEW, WE DESCRIBE THE ACUTE AND CHRONIC EPIGENETIC EFFECTS OF PHYSICAL ACTIVITY AND DIETARY CHANGES. WE PROPOSE EXERCISE AND NUTRITION AS POTENTIAL TRIGGERS OF EPIGENETIC SIGNALS, PROMOTING THE RESHAPING OF TRANSCRIPTIONAL PROGRAMMES WITH EFFECTS ON CVD PHENOTYPES. FINALLY, WE HIGHLIGHT RECENT DEVELOPMENTS IN EPIGENETIC THERAPEUTICS WITH IMPLICATIONS FOR PRIMARY AND SECONDARY CVD PREVENTION. 2022 14 5069 26 PHYSICAL ACTIVITY IN THE PREVENTION OF HUMAN DISEASES: ROLE OF EPIGENETIC MODIFICATIONS. EPIGENETIC MODIFICATION REFERS TO HERITABLE CHANGES IN GENE FUNCTION THAT CANNOT BE EXPLAINED BY ALTERATIONS IN THE DNA SEQUENCE. THE CURRENT LITERATURE CLEARLY DEMONSTRATES THAT THE EPIGENETIC RESPONSE IS HIGHLY DYNAMIC AND INFLUENCED BY DIFFERENT BIOLOGICAL AND ENVIRONMENTAL FACTORS SUCH AS AGING, NUTRIENT AVAILABILITY AND PHYSICAL EXERCISE. AS SUCH, IT IS WELL ACCEPTED THAT PHYSICAL ACTIVITY AND EXERCISE CAN MODULATE GENE EXPRESSION THROUGH EPIGENETIC ALTERNATIONS ALTHOUGH THE TYPE AND DURATION OF EXERCISE ELICITING SPECIFIC EPIGENETIC EFFECTS THAT CAN RESULT IN HEALTH BENEFITS AND PREVENT CHRONIC DISEASES REMAINS TO BE DETERMINED. THIS REVIEW HIGHLIGHTS THE MOST SIGNIFICANT FINDINGS FROM EPIGENETIC STUDIES INVOLVING PHYSICAL ACTIVITY/EXERCISE INTERVENTIONS KNOWN TO BENEFIT CHRONIC DISEASES SUCH AS METABOLIC SYNDROME, DIABETES, CANCER, CARDIOVASCULAR AND NEURODEGENERATIVE DISEASES. 2017 15 6034 30 THE CHALLENGE BY MULTIPLE ENVIRONMENTAL AND BIOLOGICAL FACTORS INDUCE INFLAMMATION IN AGING: THEIR ROLE IN THE PROMOTION OF CHRONIC DISEASE. THE AGING PROCESS IS DRIVEN BY MULTIPLE MECHANISMS THAT LEAD TO CHANGES IN ENERGY PRODUCTION, OXIDATIVE STRESS, HOMEOSTATIC DYSREGULATION AND EVENTUALLY TO LOSS OF FUNCTIONALITY AND INCREASED DISEASE SUSCEPTIBILITY. MOST AGED INDIVIDUALS DEVELOP CHRONIC LOW-GRADE INFLAMMATION, WHICH IS AN IMPORTANT RISK FACTOR FOR MORBIDITY, PHYSICAL AND COGNITIVE IMPAIRMENT, FRAILTY, AND DEATH. AT ANY AGE, CHRONIC INFLAMMATORY DISEASES ARE MAJOR CAUSES OF MORBIMORTALITY, AFFECTING UP TO 5-8% OF THE POPULATION OF INDUSTRIALIZED COUNTRIES. SEVERAL ENVIRONMENTAL FACTORS CAN PLAY AN IMPORTANT ROLE FOR MODIFYING THE INFLAMMATORY STATE. GENETICS ACCOUNTS FOR ONLY A SMALL FRACTION OF CHRONIC-INFLAMMATORY DISEASES, WHEREAS ENVIRONMENTAL FACTORS APPEAR TO PARTICIPATE, EITHER WITH A CAUSATIVE OR A PROMOTIONAL ROLE IN 50% TO 75% OF PATIENTS. SEVERAL OF THOSE CHANGES DEPEND ON EPIGENETIC CHANGES THAT WILL FURTHER MODIFY THE INDIVIDUAL RESPONSE TO ADDITIONAL STIMULI. THE INTERACTION BETWEEN INFLAMMATION AND THE ENVIRONMENT OFFERS IMPORTANT INSIGHTS ON AGING AND HEALTH. THESE CONDITIONS, OFTEN DEPENDING ON THE INDIVIDUAL'S SEX, APPEAR TO LEAD TO DECREASED LONGEVITY AND PHYSICAL AND COGNITIVE DECLINE. IN ADDITION TO BIOLOGICAL FACTORS, THE ENVIRONMENT IS ALSO INVOLVED IN THE GENERATION OF PSYCHOLOGICAL AND SOCIAL CONTEXT LEADING TO STRESS. POOR PSYCHOLOGICAL ENVIRONMENTS AND OTHER SOURCES OF STRESS ALSO RESULT IN INCREASED INFLAMMATION. HOWEVER, THE MECHANISMS UNDERLYING THE ROLE OF ENVIRONMENTAL AND PSYCHOSOCIAL FACTORS AND NUTRITION ON THE REGULATION OF INFLAMMATION, AND HOW THE RESPONSE ELICITED FOR THOSE FACTORS INTERACT AMONG THEM, ARE POORLY UNDERSTOOD. WHEREAS CERTAIN DELETERIOUS ENVIRONMENTAL FACTORS RESULT IN THE GENERATION OF OXIDATIVE STRESS DRIVEN BY AN INCREASED PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES, ENDOPLASMIC RETICULUM STRESS, AND INFLAMMATION, OTHER FACTORS, INCLUDING NUTRITION (POLYUNSATURATED FATTY ACIDS) AND BEHAVIORAL FACTORS (EXERCISE) CONFER PROTECTION AGAINST INFLAMMATION, OXIDATIVE AND ENDOPLASMIC RETICULUM STRESS, AND THUS AMELIORATE THEIR DELETERIOUS EFFECT. HERE, WE DISCUSS PROCESSES AND MECHANISMS OF INFLAMMATION ASSOCIATED WITH ENVIRONMENTAL FACTORS AND BEHAVIOR, THEIR LINKS TO SEX AND GENDER, AND THEIR OVERALL IMPACT ON AGING. 2020 16 2617 40 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 17 5558 23 ROLE OF GUT MICROBIOTA IN THE AETIOLOGY OF OBESITY: PROPOSED MECHANISMS AND REVIEW OF THE LITERATURE. THE AETIOLOGY OF OBESITY HAS BEEN ATTRIBUTED TO SEVERAL FACTORS (ENVIRONMENTAL, DIETARY, LIFESTYLE, HOST, AND GENETIC FACTORS); HOWEVER NONE OF THESE FULLY EXPLAIN THE INCREASE IN THE PREVALENCE OF OBESITY WORLDWIDE. GUT MICROBIOTA LOCATED AT THE INTERFACE OF HOST AND ENVIRONMENT IN THE GUT ARE A NEW AREA OF RESEARCH BEING EXPLORED TO EXPLAIN THE EXCESS ACCUMULATION OF ENERGY IN OBESE INDIVIDUALS AND MAY BE A POTENTIAL TARGET FOR THERAPEUTIC MANIPULATION TO REDUCE HOST ENERGY STORAGE. SEVERAL MECHANISMS HAVE BEEN SUGGESTED TO EXPLAIN THE ROLE OF GUT MICROBIOTA IN THE AETIOLOGY OF OBESITY SUCH AS SHORT CHAIN FATTY ACID PRODUCTION, STIMULATION OF HORMONES, CHRONIC LOW-GRADE INFLAMMATION, LIPOPROTEIN AND BILE ACID METABOLISM, AND INCREASED ENDOCANNABINOID RECEPTOR SYSTEM TONE. HOWEVER, EVIDENCE FROM ANIMAL AND HUMAN STUDIES CLEARLY INDICATES CONTROVERSIES IN DETERMINING THE CAUSE OR EFFECT RELATIONSHIP BETWEEN THE GUT MICROBIOTA AND OBESITY. METAGENOMICS BASED STUDIES INDICATE THAT FUNCTIONALITY RATHER THAN THE COMPOSITION OF GUT MICROBIOTA MAY BE IMPORTANT. FURTHER MECHANISTIC STUDIES CONTROLLING FOR ENVIRONMENTAL AND EPIGENETIC FACTORS ARE THEREFORE REQUIRED TO HELP UNRAVEL OBESITY PATHOGENESIS. 2016 18 996 20 CHRONIC STRESS, EPIGENETICS, AND ADIPOSE TISSUE METABOLISM IN THE OBESE STATE. IN OBESITY, ENDOCRINE AND METABOLIC PERTURBATIONS, INCLUDING THOSE INDUCED BY CHRONIC ACTIVATION OF THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS, ARE ASSOCIATED WITH THE ACCUMULATION OF ADIPOSE TISSUE AND INFLAMMATION. SUCH CHANGES ARE ATTRIBUTABLE TO A COMBINATION OF GENETIC AND EPIGENETIC FACTORS THAT ARE INFLUENCED BY THE ENVIRONMENT AND EXACERBATED BY CHRONIC ACTIVATION OF THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS. STRESS EXPOSURE AT DIFFERENT LIFE STAGES CAN ALTER ADIPOSE TISSUE METABOLISM DIRECTLY THROUGH EPIGENETIC MODIFICATION OR INDIRECTLY THROUGH THE MANIPULATION OF HYPOTHALAMIC APPETITE REGULATION, AND THEREBY CONTRIBUTE TO ENDOCRINE CHANGES THAT FURTHER DISRUPT WHOLE-BODY ENERGY BALANCE. THIS REVIEW SYNTHESIZES CURRENT KNOWLEDGE, WITH AN EMPHASIS ON HUMAN CLINICAL TRIALS, TO DESCRIBE METABOLIC CHANGES IN ADIPOSE TISSUE AND ASSOCIATED ENDOCRINE, GENETIC AND EPIGENETIC CHANGES IN THE OBESE STATE. IN PARTICULAR, WE DISCUSS EPIGENETIC CHANGES INDUCED BY STRESS EXPOSURE AND THEIR CONTRIBUTION TO APPETITE AND ADIPOCYTE DYSFUNCTION, WHICH COLLECTIVELY PROMOTE THE PATHOGENESIS OF OBESITY. SUCH KNOWLEDGE IS CRITICAL FOR PROVIDING FUTURE DIRECTIONS OF METABOLISM RESEARCH AND TARGETS FOR TREATING METABOLIC DISORDERS. 2020 19 2930 27 GENES AND DIET IN THE PREVENTION OF CHRONIC DISEASES IN FUTURE GENERATIONS. NUTRITION IS A MODIFIABLE KEY FACTOR THAT IS ABLE TO INTERACT WITH BOTH THE GENOME AND EPIGENOME TO INFLUENCE HUMAN HEALTH AND FERTILITY. IN PARTICULAR, SPECIFIC GENETIC VARIANTS CAN INFLUENCE THE RESPONSE TO DIETARY COMPONENTS AND NUTRIENT REQUIREMENTS, AND CONVERSELY, THE DIET ITSELF IS ABLE TO MODULATE GENE EXPRESSION. IN THIS CONTEXT AND THE ERA OF PRECISION MEDICINE, NUTRIGENETIC AND NUTRIGENOMIC STUDIES OFFER SIGNIFICANT OPPORTUNITIES TO IMPROVE THE PREVENTION OF METABOLIC DISTURBANCES, SUCH AS TYPE 2 DIABETES, GESTATIONAL DIABETES, HYPERTENSION, AND CARDIOVASCULAR DISEASES, EVEN WITH TRANSGENERATIONAL EFFECTS. THE PRESENT REVIEW TAKES INTO ACCOUNT THE INTERACTIONS BETWEEN DIET, GENES AND HUMAN HEALTH, AND PROVIDES AN OVERVIEW OF THE ROLE OF NUTRIGENETICS, NUTRIGENOMICS AND EPIGENETICS IN THE PREVENTION OF NON-COMMUNICABLE DISEASES. MOREOVER, WE FOCUS OUR ATTENTION ON THE MECHANISM OF INTERGENERATIONAL OR TRANSGENERATIONAL TRANSMISSION OF THE SUSCEPTIBILITY TO METABOLIC DISTURBANCES, AND UNDERLINE THAT THE REVERSIBILITY OF EPIGENETIC MODIFICATIONS THROUGH DIETARY INTERVENTION COULD COUNTERACT PERTURBATIONS INDUCED BY LIFESTYLE AND ENVIRONMENTAL FACTORS. 2020 20 5821 20 STRESS IN OBESITY AND ASSOCIATED METABOLIC AND CARDIOVASCULAR DISORDERS. OBESITY HAS SIGNIFICANT IMPLICATIONS FOR HEALTHCARE, SINCE IT IS A MAJOR RISK FACTOR FOR BOTH TYPE 2 DIABETES AND THE METABOLIC SYNDROME. THIS SYNDROME IS A COMMON AND COMPLEX DISORDER COMBINING OBESITY, DYSLIPIDEMIA, HYPERTENSION, AND INSULIN RESISTANCE. IT IS ASSOCIATED WITH HIGH ATHEROSCLEROTIC CARDIOVASCULAR RISK, WHICH CAN ONLY PARTIALLY BE EXPLAINED BY ITS COMPONENTS. THEREFORE, TO EXPLAIN HOW OBESITY CONTRIBUTES TO THE DEVELOPMENT OF METABOLIC AND CARDIOVASCULAR DISORDERS, MORE AND BETTER INSIGHT IS REQUIRED INTO THE EFFECTS OF PERSONAL AND ENVIRONMENTAL STRESS ON DISEASE PROCESSES. IN THIS PAPER, WE SHOW THAT OBESITY IS A CHRONIC INFLAMMATORY DISEASE, WHICH HAS MANY MOLECULAR MECHANISMS IN COMMON WITH ATHEROSCLEROSIS. FURTHERMORE, WE FOCUS ON THE ROLE OF OXIDATIVE STRESS ASSOCIATED WITH OBESITY IN THE DEVELOPMENT OF THE METABOLIC SYNDROME. WE DISCUSS HOW SEVERAL STRESS CONDITIONS ARE RELATED TO INFLAMMATION AND OXIDATIVE STRESS IN ASSOCIATION WITH OBESITY AND ITS COMPLICATIONS. WE ALSO EMPHASIZE THE RELATION BETWEEN STRESS CONDITIONS AND THE DEREGULATION OF EPIGENETIC CONTROL MECHANISMS BY MEANS OF MICRORNAS AND SHOW HOW THIS IMPAIRMENT FURTHER CONTRIBUTES TO THE DEVELOPMENT OF OBESITY, CLOSING THE VICIOUS CIRCLE. FINALLY, WE DISCUSS THE LIMITATIONS OF CURRENT ANTI-INFLAMMATION AND ANTIOXIDANT THERAPY TO TREAT OBESITY. 2012