1 2616 88 EPIGENOME MODULATION INDUCED BY KETOGENIC DIETS. KETOGENIC DIETS (KD) ARE DIETARY STRATEGIES LOW IN CARBOHYDRATES, NORMAL IN PROTEIN, AND HIGH, NORMAL, OR REDUCED IN FAT WITH OR WITHOUT (VERY LOW-CALORIES KETOGENIC DIET, VLCKD) A REDUCED CALORIC INTAKE. KDS HAVE BEEN SHOWN TO BE USEFUL IN THE TREATMENT OF OBESITY, METABOLIC DISEASES AND RELATED DISORDERS, NEUROLOGICAL DISEASES, AND VARIOUS PATHOLOGICAL CONDITIONS SUCH AS CANCER, NONALCOHOLIC LIVER DISEASE, AND CHRONIC PAIN. SEVERAL STUDIES HAVE INVESTIGATED THE INTRACELLULAR METABOLIC PATHWAYS THAT CONTRIBUTE TO THE BENEFICIAL EFFECTS OF THESE DIETS. ALTHOUGH EPIGENETIC CHANGES ARE AMONG THE MOST IMPORTANT DETERMINANTS OF AN ORGANISM'S ABILITY TO ADAPT TO ENVIRONMENTAL CHANGES, DATA ON THE EPIGENETIC CHANGES ASSOCIATED WITH THESE DIETARY PATHWAYS ARE STILL LIMITED. THIS REVIEW PROVIDES AN OVERVIEW OF THE MAJOR EPIGENETIC CHANGES ASSOCIATED WITH KDS. 2022 2 4399 32 MODULATION OF GENOMIC AND POSTGENOMIC ALTERATIONS IN NONCANCER DISEASES AND CRITICAL PERIODS OF LIFE. GENOMIC AND POSTGENOMIC CHANGES ARE EXTENSIVELY INVESTIGATED IN CANCER RESEARCH. SIMILAR ALTERATIONS, AFFECTING GENOME, TRANSCRIPTOME, MIRNOME AND/OR PROTEOME END-POINTS, HAVE BEEN DETECTED IN A VARIETY OF OTHER CHRONIC DEGENERATIVE DISEASES, SUCH AS ATHEROSCLEROSIS, DEGENERATIVE HEART DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEUROLOGICAL DISORDERS, EYE DISEASES, DIABETES, METABOLIC SYNDROME, SKIN AGEING AND ALOPECIA. NO GENERALIZATION CAN BE MADE DUE TO THE MYRIAD OF DIVERSE CLINICAL ENTITIES CLASSIFIED AS CHRONIC DEGENERATIVE DISEASES. MOREOVER, THE DETECTION OF MOLECULAR CHANGES DOES NOT AUTOMATICALLY IMPLY THEIR CAUSAL ROLE. NEVERTHELESS, COMMON MECHANISMS, SUCH AS DNA DAMAGE, EPIGENETIC ALTERATIONS, OXIDATIVE STRESS, AND CHRONIC INFLAMMATION, IN ADDITION TO GENETIC PREDISPOSITION, ARE OFTEN INVOLVED IN NONCANCER DISEASES. WE DEBATE HERE IN MORE DETAIL THE SUBJECTS OF CARDIOVASCULAR DISEASES AND OF SKIN DISEASES. MOREOVER, WE DISCUSS OUR EXPERIMENTAL STUDIES SUGGESTING THAT GENOMIC AND POSTGENOMIC CHANGES DO ALSO OCCUR DURING CRITICAL PERIODS OF LIFE, INCLUDING THE PRENATAL LIFE, THE PERINATAL PERIOD, AND AGEING. IN ADDITION, WE COMMENT ON THE FINDING THAT STEM-DERIVED CELLS ARE MORE SUSCEPTIBLE TO MOLECULAR DAMAGE THAN MORE DIFFERENTIATED CELLS. ALL THESE DATA ARE VIEWED IN THE PERSPECTIVE OF PREVENTIVE MEDICINE. IN FACT, THERE IS EVIDENCE THAT THE GENOMIC AND POSTGENOMIC ALTERATIONS OCCURRING NOT ONLY IN SEVERAL PATHOLOGICAL CONDITIONS BUT ALSO IN PARAPHYSIOLOGICAL SITUATIONS THAT AFFECT CRITICAL PERIODS OF LIFE CAN BE MODULATED BY MEANS OF DIETARY AND PHARMACOLOGICAL AGENTS. THE DISCOVERY THAT CHEMOPREVENTIVE AGENTS ARE ALSO ABLE TO ATTENUATE NUCLEOTIDE DAMAGE IN STEM-DERIVED CELLS WARRANTS FURTHER STUDIES IN VIEW OF POSSIBLE CLINICAL APPLICATIONS. 2009 3 3591 26 IMPAIRED ONE CARBON METABOLISM AND DNA METHYLATION IN ALCOHOL TOXICITY. EXCESSIVE ALCOHOL CONSUMPTION IS A PROMINENT PROBLEM AND ONE OF THE MAJOR CAUSES OF MORTALITY AND MORBIDITY AROUND THE WORLD. LONG-TERM, HEAVY ALCOHOL CONSUMPTION IS ASSOCIATED WITH A NUMBER OF DELETERIOUS HEALTH CONSEQUENCES, SUCH AS CANCER, HEART AND LIVER DISEASE, A VARIETY OF NEUROLOGICAL, COGNITIVE, AND BEHAVIORAL DEFICITS. ALCOHOL CONSUMPTION IS ALSO ASSOCIATED WITH DEVELOPMENTAL DEFECTS. THE CAUSES OF ALCOHOL-INDUCED TOXICITY ARE PRESENTLY UNCLEAR. ONE OF THE MECHANISMS UNDERLYING ALCOHOL TOXICITY HAS TO DO WITH ITS INTERACTION WITH FOLIC ACID/HOMOCYSTEINE OR ONE-CARBON METABOLISM (OCM). OCM IS A MAJOR DONOR OF METHYL GROUPS FOR METHYLATION, PARTICULARLY DNA METHYLATION CRITICAL FOR EPIGENETIC REGULATION OF GENE EXPRESSION, AND ITS DISTURBANCE MAY COMPROMISE DNA METHYLATION, THEREBY AFFECTING GENE EXPRESSION. OCM DISTURBANCE MEDIATED BY NUTRIENT DEFICITS IS A WELL-KNOWN RISK FACTOR FOR VARIOUS DISORDERS AND DEVELOPMENTAL DEFECTS (E.G., NEURAL TUBE DEFECTS). IN THIS REVIEW, WE SUMMARIZE THE ROLE OF OCM DISTURBANCE AND ASSOCIATED EPIGENETIC ABERRATIONS IN CHRONIC ALCOHOL-INDUCED TOXICITY. IN THIS REVIEW, WE SUMMARIZE THE ROLE OF ONE-CARBON METABOLISM (OCM) ABERRATIONS IN CHRONIC ALCOHOL-INDUCED TOXICITY. OCM IS A MAJOR DONOR OF METHYL GROUPS FOR METHYLATION REACTIONS, PARTICULARLY DNA METHYLATION CRITICAL FOR EPIGENETIC REGULATION OF GENE EXPRESSION. ALCOHOL INTERFERENCE WITH OCM AND CONSEQUENT REDUCED AVAILABILITY OF METHYL GROUPS, IMPROPER DNA METHYLATION, AND ABERRANT GENE EXPRESSION CAN PLAY A CAUSATIVE ROLE IN ALCOHOL TOXICITY. 2014 4 5890 31 SYSTEMS BIOLOGY ELUCIDATES COMMON PATHOGENIC MECHANISMS BETWEEN NONALCOHOLIC AND ALCOHOLIC-FATTY LIVER DISEASE. THE ABNORMAL ACCUMULATION OF FAT IN THE LIVER IS OFTEN RELATED EITHER TO METABOLIC RISK FACTORS ASSOCIATED WITH METABOLIC SYNDROME IN THE ABSENCE OF ALCOHOL CONSUMPTION (NONALCOHOLIC FATTY LIVER DISEASE, NAFLD) OR TO CHRONIC ALCOHOL CONSUMPTION (ALCOHOLIC FATTY LIVER DISEASE, AFLD). CLINICAL AND HISTOLOGICAL STUDIES SUGGEST THAT NAFLD AND AFLD SHARE PATHOGENIC MECHANISMS. NEVERTHELESS, CURRENT DATA ARE STILL INCONCLUSIVE AS TO WHETHER THE UNDERLYING BIOLOGICAL PROCESS AND DISEASE PATHWAYS OF NAFLD AND AFLD ARE ALIKE. OUR PRIMARY AIM WAS TO INTEGRATE OMICS AND PHYSIOLOGICAL DATA TO ANSWER THE QUESTION OF WHETHER NAFLD AND AFLD SHARE MOLECULAR PROCESSES THAT LEAD TO DISEASE DEVELOPMENT. WE ALSO EXPLORED THE EXTENT TO WHICH INSULIN RESISTANCE (IR) IS A DISTINCTIVE FEATURE OF NAFLD. TO ANSWER THESE QUESTIONS, WE USED SYSTEMS BIOLOGY APPROACHES, SUCH AS GENE ENRICHMENT ANALYSIS, PROTEIN-PROTEIN INTERACTION NETWORKS, AND GENE PRIORITIZATION, BASED ON MULTI-LEVEL DATA EXTRACTED BY COMPUTATIONAL DATA MINING. WE OBSERVED THAT THE LEADING DISEASE PATHWAYS ASSOCIATED WITH NAFLD DID NOT SIGNIFICANTLY DIFFER FROM THOSE OF AFLD. HOWEVER, SYSTEMS BIOLOGY REVEALED THE IMPORTANCE OF EACH MOLECULAR PROCESS BEHIND EACH OF THE TWO DISEASES, AND DISSECTED DISTINCTIVE MOLECULAR NAFLD AND AFLD-SIGNATURES. COMPARATIVE CO-ANALYSIS OF NAFLD AND AFLD CLARIFIED THE PARTICIPATION OF NAFLD, BUT NOT AFLD, IN CARDIOVASCULAR DISEASE, AND SHOWED THAT INSULIN SIGNALING IS IMPAIRED IN FATTY LIVER REGARDLESS OF THE NOXA, BUT THE PUTATIVE REGULATORY MECHANISMS ASSOCIATED WITH NAFLD SEEM TO ENCOMPASS A COMPLEX NETWORK OF GENES AND PROTEINS, PLAUSIBLE OF EPIGENETIC MODIFICATIONS. GENE PRIORITIZATION SHOWED A CANCER-RELATED FUNCTIONAL MAP THAT SUGGESTS THAT THE FATTY TRANSFORMATION OF THE LIVER TISSUE IS REGARDLESS OF THE CAUSE, AN EMERGING MECHANISM OF UBIQUITOUS ONCOGENIC ACTIVATION. IN CONCLUSION, SIMILAR UNDERLYING DISEASE MECHANISMS LEAD TO NAFLD AND AFLD, BUT SPECIFIC ONES DEPICT A PARTICULAR DISEASE SIGNATURE THAT HAS A DIFFERENT IMPACT ON THE SYSTEMIC CONTEXT. 2013 5 2597 30 EPIGENETICS OF SUBCELLULAR STRUCTURE FUNCTIONING IN THE ORIGIN OF RISK OR RESILIENCE TO COMORBIDITY OF NEUROPSYCHIATRIC AND CARDIOMETABOLIC DISORDERS. MECHANISMS CONTROLLING MITOCHONDRIAL FUNCTION, PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM (ER) AND NUCLEAR PROCESSES SUCH AS TELOMERE LENGTH AND DNA REPAIR MAY BE SUBJECT TO EPIGENETIC CUES THAT RELATE THE GENOMIC EXPRESSION AND ENVIRONMENTAL EXPOSURES IN EARLY STAGES OF LIFE. THEY MAY ALSO BE INVOLVED IN THE COMORBID APPEARANCE OF CARDIOMETABOLIC (CMD) AND NEUROPSYCHIATRIC DISORDERS (NPD) DURING ADULTHOOD. MITOCHONDRIAL FUNCTION AND PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM ARE ASSOCIATED WITH OXIDATIVE STRESS AND ELEVATED INTRACELLULAR CALCIUM LEVELS AND MAY ALSO UNDERLIE THE VULNERABILITY FOR COMORBID CMD AND NPD. MITOCHONDRIA PROVIDE KEY METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+), ATP, ALPHA-KETOGLUTARATE AND ACETYL COENZYME A THAT ARE REQUIRED FOR MANY TRANSCRIPTIONAL AND EPIGENETIC PROCESSES. THEY ARE ALSO A SOURCE OF FREE RADICALS. ON THE OTHER HAND, EPIGENETIC MARKERS IN NUCLEAR DNA DETERMINE MITOCHONDRIAL BIOGENESIS. THE ER IS THE SUBCELLULAR ORGANELLE IN WHICH SECRETORY PROTEINS ARE FOLDED. MANY ENVIRONMENTAL FACTORS STOP THE ABILITY OF CELLS TO PROPERLY FOLD PROTEINS AND MODIFY POST-TRANSLATIONALLY SECRETORY AND TRANSMEMBRANE PROTEINS LEADING TO ENDOPLASMIC RETICULUM STRESS AND OXIDATIVE STRESS. ER FUNCTIONING MAY BE EPIGENETICALLY DETERMINED. CHRONIC ER STRESS IS EMERGING AS A KEY CONTRIBUTOR TO A GROWING LIST OF HUMAN DISEASES, INCLUDING CMD AND NPD. TELOMERE LOSS CAUSES CHROMOSOMAL FUSION, ACTIVATION OF THE CONTROL OF DNA DAMAGE-RESPONSES, UNSTABLE GENOME AND ALTERED STEM CELL FUNCTION, WHICH MAY UNDERLIE THE COMORBIDITY OF CMD AND NPD. THE LENGTH OF TELOMERES IS RELATED TO OXIDATIVE STRESS AND MAY BE EPIGENETICALLY PROGRAMMED. PATHWAYS INVOLVED IN DNA REPAIR MAY BE EPIGENETICALLY PROGRAMMED AND MAY CONTRIBUTE TO DISEASES. IN THIS PAPER, WE DESCRIBE SUBCELLULAR MECHANISMS THAT ARE DETERMINED BY EPIGENETIC MARKERS AND THEIR POSSIBLE RELATION TO THE DEVELOPMENT OF INCREASED SUSCEPTIBILITY TO DEVELOP CMD AND NPD. 2018 6 49 28 A CURRENT GENETIC AND EPIGENETIC VIEW ON HUMAN AGING MECHANISMS. THE PROCESS OF AGING IS ONE OF THE MOST COMPLEX AND INTRIGUING BIOLOGICAL PHENOMENONS. AGING IS A GENETICALLY REGULATED PROCESS IN WHICH THE ORGANISM'S MAXIMUM LIFESPAN POTENTIAL IS PRE-DETERMINED, WHILE THE RATE OF AGING IS INFLUENCED BY ENVIRONMENTAL FACTORS AND LIFESTYLE. CONSIDERING THE COMPLEXITY OF MECHANISMS INVOLVED IN THE REGULATION OF AGING PROCESS, UP TO THIS DATE THERE ISN'T A MAJOR, UNIFYING THEORY WHICH COULD EXPLAIN THEM. AS GENETIC/EPIGENETIC AND ENVIRONMENTAL FACTORS BOTH INEVITABLY INFLUENCE THE AGING PROCESS, HERE WE PRESENT A REVIEW ON THE GENETIC AND EPIGENETIC REGULATION OF THE MOST IMPORTANT MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE PROCESS OF AGING. BASED ON THE STUDIES ON OXIDATIVE STRESS, METABOLISM, GENOME STABILITY, EPIGENETIC MODIFICATIONS AND CELLULAR SENESCENCE IN ANIMAL MODELS AND HUMANS, WE GIVE AN OVERVIEW OF KEY GENETIC AND MOLECULAR PATHWAYS RELATED TO AGING. AS MOST OF GENETIC MANIPULATIONS WHICH INFLUENCE THE AGING PROCESS ALSO AFFECT REPRODUCTION, WE DISCUSS AGING IN HUMANS AS A POST-REPRODUCTIVE GENETICALLY DETERMINED PROCESS. AFTER THE AGE OF REPRODUCTIVE SUCCESS, AGING CONTINOUSLY PROGRESSES WHICH CLINICALLY COINCIDES WITH THE ONSET OF MOST CHRONIC DISEASES, CANCERS AND DEMENTIONS. AS EVOLUTION SHAPES THE GENOMES FOR REPRODUCTIVE SUCCESS AND NOT FOR POST-REPRODUCTIVE SURVIVAL, AGING COULD BE DEFINED AS A PROTECTIVE MECHANISM WHICH ENSURES THE PRESERVATION AND PROGRESS OF SPECIES THROUGH THE MODIFICATION, TRASMISSION AND IMPROVEMENT OF GENETIC MATERIAL. 2009 7 6398 28 THE ROLE OF VITAMIN D AND VDR IN CARCINOGENESIS: THROUGH EPIDEMIOLOGY AND BASIC SCIENCES. IN THE LAST TWO DECADES VITAMIN D (VD) RESEARCH HAS DEMONSTRATED NEW EXTRASKELETAL ACTIONS OF THIS PRE-HORMONE, SUGGESTING A PROTECTIVE ROLE OF THIS SECOSTEROID IN THE ONSET, PROGRESSION AND PROGNOSIS OF SEVERAL CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS CARDIOVASCULAR DISEASE, DIABETES MELLITUS OR CANCER. REGARDING CARCINOGENESIS, BOTH PRECLINICAL AND EPIDEMIOLOGICAL EVIDENCE AVAILABLE SHOW ONCOPROTECTIVE ACTIONS OF VD AND ITS RECEPTOR, THE VDR. HOWEVER, IN LATE NEOPLASTIC STAGES THE VD SYSTEM (VDS) SEEMS TO BE LESS FUNCTIONAL, WHICH APPEARS TO BE DUE TO AN EPIGENETIC SILENCING OF THE SYSTEM. IN PRECLINICAL EXPERIMENTAL STUDIES, VD PRESENTS ONCOPROTECTIVE ACTIONS THROUGH MODULATION OF INFLAMMATION, CELL PROLIFERATION, CELL DIFFERENTIATION, ANGIOGENESIS, INVASIVE AND METASTATIC POTENTIAL, APOPTOSIS, MIRNA EXPRESSION REGULATION AND MODULATION OF THE HEDGEHOG SIGNALLING PATHWAY. MOREOVER, EPIDEMIOLOGICAL EVIDENCE POINTS TOWARDS AN ONCOPROTECTIVE ROLE OF VITAMIN D AND VDR IN COLORECTAL CANCER. THIS ASSOCIATION IS MORE CONTROVERSIAL WITH BREAST, OVARIAN AND PROSTATE CANCERS, ALTHOUGH WITH A FEW ADVERSE EFFECTS. NONETHELESS, WE SHOULD CONSIDER OTHER FACTORS TO DETERMINE THE BENEFIT OF INCREASED SERUM CONCENTRATION OF VD. MUCH OF THE EPIDEMIOLOGICAL EVIDENCE IS STILL INCONCLUSIVE, AND WE WILL HAVE TO WAIT FOR NEW, BETTER-DESIGNED ONGOING RCTS AND THEIR RESULTS TO DISCERN THE REAL EFFECT OF VITAMIN D IN CANCER RISK REDUCTION AND THERAPY. THE OBJECTIVE OF THIS LITERATURE REVIEW IS TO OFFER AN UP-TO-DATE ANALYSIS OF THE ROLE OF THE VD AND VDR, IN THE ONSET, PROGRESSION AND PROGNOSIS OF ALL TYPES OF CANCER. WE FURTHER DISCUSS THE AVAILABLE LITERATURE AND SUGGEST NEW HYPOTHESES AND FUTURE CHALLENGES IN THE FIELD OF VD RESEARCH. 2017 8 2000 21 EPIGENETIC AND NON-CODING REGULATION OF ALCOHOL ABUSE AND ADDICTION. ALCOHOL USE DISORDER IS A CHRONIC DEBILITATED CONDITION ADVERSELY AFFECTING THE LIVES OF MILLIONS OF INDIVIDUALS THROUGHOUT THE MODERN WORLD. INDIVIDUALS SUFFERING FROM AN ALCOHOL USE DISORDER DIAGNOSIS FREQUENTLY HAVE SERIOUS COOCCURRING CONDITIONS, WHICH OFTEN FURTHER EXACERBATES PROBLEMATIC DRINKING BEHAVIOR. COMPREHENDING THE BIOCHEMICAL PROCESSES UNDERLYING THE PROGRESSION AND PERPETUATION OF DISEASE IS ESSENTIAL FOR MITIGATING MALADAPTIVE BEHAVIOR IN ORDER TO RESTORE BOTH PHYSIOLOGICAL AND PSYCHOLOGICAL HEALTH. THE RANGE OF CELLULAR AND BIOLOGICAL SYSTEMS CONTRIBUTING TO, AND AFFECTED BY, ALCOHOL USE DISORDER AND OTHER COMORBID DISORDERS NECESSITATES A FUNDAMENTAL GRASP OF INTRICATE FUNCTIONAL RELATIONSHIPS THAT GOVERN MOLECULAR BIOLOGY. EPIGENETIC FACTORS ARE RECOGNIZED AS ESSENTIAL MEDIATORS OF CELLULAR BEHAVIOR, ORCHESTRATING A SYMPHONY OF GENE EXPRESSION CHANGES WITHIN MULTICELLULAR ENVIRONMENTS THAT ARE ULTIMATELY RESPONSIBLE FOR DIRECTING HUMAN BEHAVIOR. UNDERSTANDING THE EPIGENETIC AND TRANSCRIPTIONAL REGULATORY MECHANISMS INVOLVED IN THE PATHOGENESIS OF DISEASE IS IMPORTANT FOR IMPROVING AVAILABLE PHARMACOTHERAPIES AND REDUCING THE INCIDENCE OF ALCOHOL ABUSE AND COOCCURRING CONDITIONS. 2021 9 650 17 BISPHENOL A AND HUMAN CHRONIC DISEASES: CURRENT EVIDENCES, POSSIBLE MECHANISMS, AND FUTURE PERSPECTIVES. BISPHENOL-A (BPA) IS ONE OF THE HIGHEST VOLUME CHEMICALS PRODUCED WORLDWIDE, WITH OVER 6BILLION POUNDS PRODUCED AND OVER 100T RELEASED INTO THE ATMOSPHERE EACH YEAR. RECENT EXTENSIVE LITERATURE HAS RAISED CONCERNS ABOUT ITS POSSIBLE IMPLICATION IN THE ETIOLOGY OF SOME HUMAN CHRONIC DISEASES SUCH AS DIABETES, OBESITY, REPRODUCTIVE DISORDERS, CARDIOVASCULAR DISEASES, BIRTH DEFECTS, CHRONIC RESPIRATORY AND KIDNEY DISEASES AND BREAST CANCER. IN THIS REVIEW, WE PRESENT THE HIGHLIGHTED EVIDENCES ON THE RELATIONSHIP BETWEEN BPA EXPOSURE AND HUMAN CHRONIC DISEASES AND WE DISCUSS ITS EVENTUAL MECHANISMS OF ACTION, ESPECIALLY GENETIC, EPIGENETIC AND ENDOCRINE DISRUPTION MECHANISMS WITH THE POSSIBLE INVOLVEMENT OF OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION AND CELL SIGNALING. 2014 10 705 27 BUILDING RISK-ON-A-CHIP MODELS TO IMPROVE BREAST CANCER RISK ASSESSMENT AND PREVENTION. PREVENTIVE ACTIONS FOR CHRONIC DISEASES HOLD THE PROMISE OF IMPROVING LIVES AND REDUCING HEALTHCARE COSTS. FOR SEVERAL DISEASES, INCLUDING BREAST CANCER, MULTIPLE RISK AND PROTECTIVE FACTORS HAVE BEEN IDENTIFIED BY EPIDEMIOLOGISTS. THE IMPACT OF MOST OF THESE FACTORS HAS YET TO BE FULLY UNDERSTOOD AT THE ORGANISM, TISSUE, CELLULAR AND MOLECULAR LEVELS. IMPORTANTLY, COMBINATIONS OF EXTERNAL AND INTERNAL RISK AND PROTECTIVE FACTORS INVOLVE COOPERATIVITY THUS, SYNERGIZING OR ANTAGONIZING DISEASE ONSET. MODELS ARE NEEDED TO MECHANISTICALLY DECIPHER CANCER RISKS UNDER DEFINED CELLULAR AND MICROENVIRONMENTAL CONDITIONS. HERE, WE BRIEFLY REVIEW BREAST CANCER RISK MODELS BASED ON 3D CELL CULTURE AND PROPOSE TO IMPROVE RISK MODELING WITH LAB-ON-A-CHIP APPROACHES. WE SUGGEST EPITHELIAL TISSUE POLARITY, DNA REPAIR AND EPIGENETIC PROFILES AS ENDPOINTS IN RISK ASSESSMENT MODELS AND DISCUSS THE DEVELOPMENT OF 'RISKS-ON-CHIPS' INTEGRATING BIOSENSORS OF THESE ENDPOINTS AND OF GENERAL TISSUE HOMEOSTASIS. RISKS-ON-CHIPS WILL HELP IDENTIFY BIOMARKERS OF RISK, SERVE AS SCREENING PLATFORMS FOR CANCER PREVENTIVE AGENTS, AND PROVIDE A BETTER UNDERSTANDING OF RISK MECHANISMS, HENCE RESULTING IN NOVEL DEVELOPMENTS IN DISEASE PREVENTION. 2013 11 3777 21 INTERACTOME OF OBESITY: OBESIDOME : GENETIC OBESITY, STRESS INDUCED OBESITY, PATHOGENIC OBESITY INTERACTION. OBESITY IS A CHRONIC DISEASE OF INCREASING PREVALENCE REACHING EPIDEMIC PROPORTIONS. GENETIC DEFECTS AS WELL AS EPIGENETIC EFFECTS CONTRIBUTE TO THE OBESITY PHENOTYPE. INVESTIGATING GENE (E.G. MC4R DEFECTS)-ENVIRONMENT (BEHAVIOR, INFECTIOUS AGENTS, STRESS) INTERACTIONS IS A RELATIVE NEW FIELD OF GREAT RESEARCH INTEREST. IN THIS STUDY, WE HAVE MADE AN EFFORT TO CREATE AN INTERACTOME (HENCEFORTH REFERRED TO AS "OBESIDOME"), WHERE EXTRINSIC STRESSORS RESPONSE, INTRINSIC PREDISPOSITION, IMMUNITY RESPONSE TO INFLAMMATION AND AUTONOMOUS NERVOUS SYSTEM IMPLICATIONS ARE INTEGRATED. THESE PATHWAYS ARE PRESENTED IN ONE INTERACTOME NETWORK FOR THE FIRST TIME. IN OUR STUDY, OBESITY-RELATED GENES/GENE PRODUCTS WERE FOUND TO FORM A COMPLEX INTERACTIONS NETWORK. 2017 12 4187 35 METABOLIC AND VASCULAR EFFECT OF THE MEDITERRANEAN DIET. SEVERAL STUDIES INDICATED HOW DIETARY PATTERNS THAT WERE OBTAINED FROM NUTRITIONAL CLUSTER ANALYSIS CAN PREDICT DISEASE RISK OR MORTALITY. LOW-GRADE CHRONIC INFLAMMATION REPRESENTS A BACKGROUND PATHOGENETIC MECHANISM LINKING METABOLIC RISK FACTORS TO INCREASED RISK OF CHRONIC DEGENERATIVE DISEASES. A MEDITERRANEAN DIET (MEDI) STYLE HAS BEEN REPORTED AS ASSOCIATED WITH A LOWER DEGREE OF INFLAMMATION BIOMARKERS AND WITH A PROTECTIVE ROLE ON CARDIOVASCULAR AND CEREBROVASCULAR EVENTS. THERE IS HETEROGENEITY IN DEFINING THE MEDDIET, AND IT CAN, OWING TO ITS COMPLEXITY, BE CONSIDERED AS AN EXPOSOME WITH THOUSANDS OF NUTRIENTS AND PHYTOCHEMICALS. RECENTLY, IT HAS BEEN REPORTED A NOVEL POSITIVE ASSOCIATION BETWEEN BASELINE PLASMA CERAMIDE CONCENTRATIONS AND CARDIOVASCULAR EVENTS AND HOW ADHERENCE TO A MEDITERRANEAN DIET-STYLE MAY INFLUENCE THE POTENTIAL NEGATIVE RELATIONSHIP BETWEEN ELEVATED PLASMA CERAMIDE CONCENTRATIONS AND CARDIOVASCULAR DISEASES (CVD). SEVERAL RANDOMIZED CONTROLLED TRIALS (RCTS) SHOWED THE POSITIVE EFFECTS OF THE MEDI DIET STYLE ON SEVERAL CARDIOVASCULAR RISK FACTORS, SUCH AS BODY MASS INDEX, WAIST CIRCUMFERENCE, BLOOD LIPIDS, BLOOD PRESSURE, INFLAMMATORY MARKERS AND ADHESION MOLECULES, AND DIABETES AND HOW THESE ADVANTAGES OF THE MEDI ARE MAINTAINED IN COMPARISON OF A LOW-FAT DIET. SOME STUDIES REPORTED A POSITIVE EFFECT OF ADHERENCE TO A MEDITERRANEAN DIET AND HEART FAILURE INCIDENCE, WHEREAS SOME RECENT STUDIES, SUCH AS THE PREDIMED STUDY, SHOWED THAT THE INCIDENCE OF MAJOR CARDIOVASCULAR EVENTS WAS LOWER AMONG THOSE ASSIGNED TO MEDI SUPPLEMENTED WITH EXTRA-VIRGIN OLIVE OIL OR NUTS THAN AMONG THOSE ASSIGNED TO A REDUCED-FAT DIET. NEW STUDIES ARE NEEDED TO BETTER UNDERSTAND THE MOLECULAR MECHANISMS, WHEREBY THE MEDDIET MAY EXERCISE ITS EFFECTS. HERE, WE PRESENT RECENT ADVANCES IN UNDERSTANDING THE MOLECULAR BASIS OF MEDDIET EFFECTS, MAINLY FOCUSING ON CARDIOVASCULAR DISEASES, BUT ALSO DISCUSSING OTHER RELATED DISEASES. WE REVIEW MEDDIET COMPOSITION AND ASSESSMENT AS WELL AS THE LATEST ADVANCES IN THE GENOMIC, EPIGENOMIC (DNA METHYLATION, HISTONE MODIFICATIONS, MICRORNAS, AND OTHER EMERGING REGULATORS), TRANSCRIPTOMIC (SELECTED GENES AND WHOLE TRANSCRIPTOME), AND METABOLOMIC AND METAGENOMIC ASPECTS OF THE MEDDIET EFFECTS (AS A WHOLE AND FOR ITS MOST TYPICAL FOOD COMPONENTS). WE ALSO PRESENT A REVIEW OF THE CLINICAL EFFECTS OF THIS DIETARY STYLE UNDERLYING THE BIOCHEMICAL AND MOLECULAR EFFECTS OF THE MEDITERRANEAN DIET. OUR PURPOSE IS TO REVIEW THE MAIN FEATURES OF THE MEDITERRANEAN DIET IN PARTICULAR ITS BENEFITS ON HUMAN HEALTH, UNDERLING THE ANTI-INFLAMMATORY, ANTI-OXIDANT AND ANTI-ATHEROSCLEROTIC EFFECTS TO WHICH NEW KNOWLEDGE ABOUT EPIGENETIC AND GUT-MICROBIOTA RELATIONSHIP IS RECENTLY ADDED. 2019 13 4999 22 PERINATAL PROGRAMMING OF CIRCADIAN CLOCK-STRESS CROSSTALK. AN INTACT COMMUNICATION BETWEEN CIRCADIAN CLOCKS AND THE STRESS SYSTEM IS IMPORTANT FOR MAINTAINING PHYSIOLOGICAL HOMEOSTASIS UNDER RESTING CONDITIONS AND IN RESPONSE TO EXTERNAL STIMULI. THERE IS ACCUMULATING EVIDENCE FOR A RECIPROCAL INTERACTION BETWEEN BOTH-FROM THE SYSTEMIC TO THE MOLECULAR LEVEL. DISRUPTION OF THIS INTERACTION BY EXTERNAL FACTORS SUCH AS SHIFTWORK, JETLAG, OR CHRONIC STRESS INCREASES THE RISK OF DEVELOPING METABOLIC, IMMUNE, OR MOOD DISORDERS. FROM EXPERIMENTS IN RODENTS, WE KNOW THAT BOTH SYSTEMS MATURATE DURING THE PERINATAL PERIOD. DURING THAT TIME, EXOGENOUS FACTORS SUCH AS STRESS OR ALTERATIONS IN THE EXTERNAL PHOTOPERIOD MAY CRITICALLY AFFECT-OR PROGRAM-PHYSIOLOGICAL FUNCTIONS LATER IN LIFE. THIS DEVELOPMENTAL PROGRAMMING PROCESS HAS BEEN ATTRIBUTED TO MATERNAL STRESS SIGNALS REACHING THE EMBRYO, WHICH LASTINGLY CHANGE GENE EXPRESSION THROUGH THE INDUCTION OF EPIGENETIC MECHANISMS. DESPITE THE WELL-KNOWN FUNCTION OF THE ADULT CIRCADIAN SYSTEM IN TEMPORAL COORDINATION OF PHYSIOLOGY AND BEHAVIOR, THE ROLE OF MATERNAL AND EMBRYONIC CIRCADIAN CLOCKS DURING PREGNANCY AND POSTNATAL DEVELOPMENT IS STILL POORLY DEFINED. A BETTER UNDERSTANDING OF THE CIRCADIAN-STRESS CROSSTALK AT DIFFERENT PERIODS OF DEVELOPMENT MAY HELP TO IMPROVE STRESS RESISTANCE AND DEVISE PREVENTIVE AND THERAPEUTIC STRATEGIES AGAINST CHRONIC STRESS-ASSOCIATED DISORDERS. 2018 14 6334 18 THE ROLE OF DNA METHYLATION AND HYDROXYMETHYLATION IN IMMUNOSENESCENCE. A HEALTHY FUNCTIONING IMMUNE SYSTEM IS CRITICAL TO STAVE OFF INFECTIOUS DISEASES, BUT AS HUMANS AND OTHER ORGANISMS AGE, THEIR IMMUNE SYSTEMS DECLINE. AS A RESULT, DISEASES THAT WERE READILY THWARTED IN EARLY LIFE POSE NONTRIVIAL HARM AND CAN EVEN BE DEADLY IN LATE LIFE. IMMUNOSENESCENCE IS DEFINED AS THE GENERAL DETERIORATION OF THE IMMUNE SYSTEM WITH AGE, AND IT IS CHARACTERIZED BY FUNCTIONAL CHANGES IN HEMATOPOIETIC STEM CELLS (HSCS) AND SPECIFIC BLOOD CELL TYPES AS WELL AS CHANGES IN LEVELS OF NUMEROUS FACTORS, PARTICULARLY THOSE INVOLVED IN INFLAMMATION. POTENTIAL MECHANISMS UNDERLYING IMMUNOSENESCENCE INCLUDE EPIGENETIC CHANGES SUCH AS CHANGES IN DNA METHYLATION (DNAM) AND DNA HYDROXYMETHYLATION (DNAHM) THAT OCCUR WITH AGE. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE WHAT IS CURRENTLY KNOWN ABOUT THE RELATIONSHIP BETWEEN IMMUNOSENESCENCE AND THE AGE-RELATED CHANGES TO DNAM AND DNAHM, AND TO DISCUSS EXPERIMENTAL APPROACHES BEST SUITED TO FILL GAPS IN OUR UNDERSTANDING. 2019 15 4992 21 PEELING THE ONION: ANOTHER LAYER IN THE REGULATION OF INSULIN SECRETION. INSULIN SECRETION BY PANCREATIC BETA CELLS IS A DYNAMIC AND HIGHLY REGULATED PROCESS DUE TO THE CENTRAL IMPORTANCE OF INSULIN IN ENABLING EFFICIENT UTILIZATION AND STORAGE OF GLUCOSE. MULTIPLE REGULATORY LAYERS ENABLE BETA CELLS TO ADAPT TO ACUTE CHANGES IN NUTRIENT AVAILABILITY AS WELL AS CHRONIC CHANGES IN METABOLIC DEMAND. WHILE EPIGENETIC FACTORS HAVE BEEN WELL ESTABLISHED AS REGULATORS OF CHRONIC BETA CELL ADAPTATIONS TO INSULIN RESISTANCE, THEIR ROLE IN ACUTE ADAPTATIONS IN RESPONSE TO NUTRIENT STIMULATION HAS BEEN RELATIVELY UNEXPLORED. IN THIS ISSUE OF THE JCI, WORTHAM ET AL. REPORT THAT SHORT-TERM DYNAMIC CHANGES IN HISTONE MODIFICATIONS REGULATED INSULIN SECRETION AND ACUTE BETA CELL ADAPTATIONS IN RESPONSE TO FASTING AND FEEDING CYCLES. THESE FINDINGS HIGHLIGHT THE IMPORTANCE OF INVESTIGATING WHETHER OTHER EPIGENETIC MECHANISMS MAY CONTRIBUTE TO ACUTE PHYSIOLOGIC ADAPTATIONS IN BETA CELLS. 2023 16 1749 30 EARLY LIFE INTERVENTIONS CAN SHAPE AGING. IT IS WELL DOCUMENTED THAT THE ENVIRONMENT OF THE DEVELOPING FETUS, INCLUDING AVAILABILITY OF NUTRIENTS AND PRESENCE OF TOXINS, CAN HAVE MAJOR IMPACT ON ADULT PHENOTYPE, AGE-RELATED TRAITS AND RISK OF CHRONIC DISEASE. THERE IS ALSO ACCUMULATING EVIDENCE THAT POSTNATAL ENVIRONMENT CAN IMPACT ADULT CHARACTERISTICS RELATED TO EVOLUTIONARY FITNESS, HEALTH, AND AGING. TO DETERMINE WHETHER EARLY LIFE HORMONAL INTERVENTIONS CAN ALTER TRAJECTORY OF AGING, WE HAVE EXAMINED THE EFFECTS OF EARLY LIFE GROWTH HORMONE (GH) REPLACEMENT THERAPY IN PROP1(DF) (AMES DWARF) MICE WHICH ARE GH DEFICIENT AND REMARKABLY LONG LIVED. TWICE-DAILY GH INJECTIONS BETWEEN THE AGES OF TWO AND EIGHT WEEKS COMPLETELY NORMALIZED ("RESCUED") A NUMBER OF ADULT METABOLIC CHARACTERISTICS BELIEVED TO CONTRIBUTE TO EXTENDED LONGEVITY OF THESE MUTANTS. IMPORTANTLY, LONGEVITY OF AMES DWARF MICE WAS REDUCED BY EARLY LIFE GH TREATMENT. THIS WAS ASSOCIATED WITH HISTONE H3 MODIFICATIONS. WE CONCLUDE THAT THE TRAJECTORY OF MAMMALIAN AGING CAN BE MODIFIED BY EARLY LIFE INTERVENTIONS. MECHANISTIC LINKS AMONG INTERVENTIONS DURING POSTNATAL DEVELOPMENT, ADULT METABOLIC CHARACTERISTICS, AGING, AND LONGEVITY, APPARENTLY INVOLVE EPIGENETIC PHENOMENA. 2022 17 3899 28 LATE NEUROLOGICAL CONSEQUENCES OF ZIKA VIRUS INFECTION: RISK FACTORS AND PHARMACEUTICAL APPROACHES. ZIKA VIRUS (ZIKV) INFECTION WAS HISTORICALLY CONSIDERED A DISEASE WITH MILD SYMPTOMS AND NO MAJOR CONSEQUENCES TO HUMAN HEALTH. HOWEVER, SEVERAL LONG-TERM, LATE ONSET, AND CHRONIC NEUROLOGICAL COMPLICATIONS, BOTH IN CONGENITALLY-EXPOSED BABIES AND IN ADULT PATIENTS, HAVE BEEN REPORTED AFTER ZIKV INFECTION, ESPECIALLY AFTER THE 2015 EPIDEMICS IN THE AMERICAN CONTINENT. THE DEVELOPMENT OR SEVERITY OF THESE CONDITIONS CANNOT BE FULLY PREDICTED, BUT IT IS POSSIBLE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO DETERMINE ZIKV INFECTION OUTCOMES. THIS REINFORCES THE IMPORTANCE THAT INDIVIDUALS EXPOSED TO ZIKV ARE SUBMITTED TO LONG-TERM CLINICAL SURVEILLANCE AND HIGHLIGHTS THE URGENT NEED FOR THE DEVELOPMENT OF THERAPEUTIC APPROACHES TO REDUCE OR ELIMINATE THE NEUROLOGICAL BURDEN OF INFECTION. HERE, WE REVIEW THE EPIDEMIOLOGY OF ZIKV-ASSOCIATED NEUROLOGICAL COMPLICATIONS AND THE ROLE OF FACTORS THAT MAY INFLUENCE DISEASE OUTCOME. MOREOVER, WE DISCUSS EXPERIMENTAL AND CLINICAL EVIDENCE OF DRUGS THAT HAVE SHOWN PROMISING RESULTS IN VITRO OR IN VITRO AGAINST VIRAL REPLICATION AND AND/OR ZIKV-INDUCED NEUROTOXICITY. 2019 18 2568 23 EPIGENETICS OF ALCOHOL-RELATED LIVER DISEASES. ALCOHOL-RELATED LIVER DISEASE (ARLD) IS A PRIMARY CAUSE OF CHRONIC LIVER DISEASE IN THE UNITED STATES. DESPITE ADVANCES IN THE DIAGNOSIS AND MANAGEMENT OF ARLD, IT REMAINS A MAJOR PUBLIC HEALTH PROBLEM ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY, EMPHASISING THE NEED TO ADOPT NOVEL APPROACHES TO THE STUDY OF ARLD AND ITS COMPLICATIONS. EPIGENETIC CHANGES ARE INCREASINGLY BEING RECOGNISED AS CONTRIBUTING TO THE PATHOGENESIS OF MULTIPLE DISEASE STATES. HARNESSING THE POWER OF INNOVATIVE TECHNOLOGIES FOR THE STUDY OF EPIGENETICS (E.G., NEXT-GENERATION SEQUENCING, DNA METHYLATION ASSAYS, HISTONE MODIFICATION PROFILING AND COMPUTATIONAL TECHNIQUES LIKE MACHINE LEARNING) HAS RESULTED IN A SEISMIC SHIFT IN OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF ARLD. KNOWLEDGE OF THESE TECHNIQUES AND ADVANCES IS OF PARAMOUNT IMPORTANCE FOR THE PRACTICING HEPATOLOGIST AND RESEARCHERS ALIKE. ACCORDINGLY, IN THIS REVIEW ARTICLE WE WILL SUMMARISE THE CURRENT KNOWLEDGE ABOUT ALCOHOL-INDUCED EPIGENETIC ALTERATIONS IN THE CONTEXT OF ARLD, INCLUDING BUT NOT LIMITED TO, DNA HYPER/HYPO METHYLATION, HISTONE MODIFICATIONS, CHANGES IN NON-CODING RNA, 3D CHROMATIN ARCHITECTURE AND ENHANCER-PROMOTER INTERACTIONS. ADDITIONALLY, WE WILL DISCUSS THE STATE-OF-THE-ART TECHNIQUES USED IN THE STUDY OF ARLD (E.G. SINGLE-CELL SEQUENCING). WE WILL ALSO HIGHLIGHT THE EPIGENETIC REGULATION OF CHEMOKINES AND THEIR PROINFLAMMATORY ROLE IN THE CONTEXT OF ARLD. LASTLY, WE WILL EXAMINE THE CLINICAL APPLICATIONS OF EPIGENETICS IN THE DIAGNOSIS AND MANAGEMENT OF ARLD. 2022 19 2610 24 EPIGENETICS: A POTENTIAL MECHANISM INVOLVED IN THE PATHOGENESIS OF VARIOUS ADVERSE CONSEQUENCES OF OBSTRUCTIVE SLEEP APNEA. EPIGENETICS IS DEFINED AS THE HERITABLE PHENOTYPIC CHANGES WHICH DO NOT INVOLVE ALTERATIONS IN THE DNA SEQUENCE, INCLUDING HISTONE MODIFICATIONS, NON-CODING RNAS, AND DNA METHYLATION. RECENTLY, MUCH ATTENTION HAS BEEN PAID TO THE ROLE OF HYPOXIA-MEDIATED EPIGENETIC REGULATION IN CANCER, PULMONARY HYPERTENSION, ADAPTATION TO HIGH ALTITUDE, AND CARDIORENAL DISEASE. IN CONTRAST TO SUSTAINED HYPOXIA, CHRONIC INTERMITTENT HYPOXIA WITH RE-OXYGENATION (IHR) PLAYS A MAJOR ROLE IN THE PATHOGENESIS OF VARIOUS ADVERSE CONSEQUENCES OF OBSTRUCTIVE SLEEP APNEA (OSA), RESEMBLING ISCHEMIA RE-PERFUSION INJURY. NEVERTHELESS, THE ROLE OF EPIGENETICS IN THE PATHOGENESIS OF OSA IS CURRENTLY UNDEREXPLORED. THIS REVIEW PROPOSES THAT EPIGENETIC PROCESSES ARE INVOLVED IN THE DEVELOPMENT OF VARIOUS ADVERSE CONSEQUENCES OF OSA BY INFLUENCING ADAPTIVE POTENTIAL AND PHENOTYPIC VARIABILITY UNDER CONDITIONS OF CHRONIC IHR. IMPROVED UNDERSTANDING OF THE INTERACTION BETWEEN GENETIC AND ENVIRONMENTAL FACTORS THROUGH EPIGENETIC REGULATIONS HOLDS GREAT VALUE TO GIVE DEEPER INSIGHT INTO THE MECHANISMS UNDERLYING IHR-RELATED LOW-GRADE INFLAMMATION, OXIDATIVE STRESS, AND SYMPATHETIC HYPERACTIVITY, AND CLARIFY THEIR IMPLICATIONS FOR BIOMEDICAL RESEARCH. 2019 20 3418 27 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000