1 4209 158 METALLOTHIONEIN 2A GENE POLYMORPHISMS IN RELATION TO DISEASES AND TRACE ELEMENT LEVELS IN HUMANS. HUMAN METALLOTHIONEINS ARE A SUPERFAMILY OF LOW MOLECULAR WEIGHT INTRACELLULAR PROTEINS, WHOSE SYNTHESIS CAN BE INDUCED BY ESSENTIAL ELEMENTS (PRIMARILY ZN AND CU), TOXIC ELEMENTS AND CHEMICAL AGENTS, AND STRESS-PRODUCING CONDITIONS. OF THE FOUR KNOWN ISOFORMS IN THE HUMAN BODY MT2 IS THE MOST COMMON. THE EXPRESSION OF METALLOTHIONEINS IS ENCODED BY A MULTIGENE FAMILY OF LINKED GENES AND CAN BE INFLUENCED BY SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) IN THESE GENES. TO DATE, 24 SNPS IN THE MT2A GENE HAVE BEEN IDENTIFIED WITH THE INCIDENCE OF ABOUT 1 % IN VARIOUS POPULATION GROUPS, AND THREE OF THEM WERE SHOWN TO AFFECT PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL PROCESSES. THIS REVIEW SUMMARISES CURRENT KNOWLEDGE ABOUT THESE THREE SNPS IN THE MT2A GENE AND THEIR ASSOCIATIONS WITH ELEMENT CONCENTRATIONS IN THE BODY OF HEALTHY AND DISEASED PERSONS. THE MOST INVESTIGATED SNP IS RS28366003 (MT2A -5 A/G). REPORTS ASSOCIATE IT WITH LONGEVITY, CANCER (BREAST, PROSTATE, LARYNGEAL, AND IN PARANASAL SINUSES), AND CHRONIC RENAL DISEASE. THE SECOND MOST INVESTIGATED SNP, RS10636 (MT2A +838G/C), IS ASSOCIATED WITH BREAST CANCER, CARDIOVASCULAR DISEASE, AND TYPE 2 DIABETES. BOTH ARE ALSO ASSOCIATED WITH SEVERAL METAL/METALLOID CONCENTRATIONS IN THE ORGANISM. THE THIRD SNP, RS1610216 (MT2A -209A/G), HAS BEEN STUDIED FOR ASSOCIATION WITH TYPE 2 DIABETES, CARDIOMYOPATHY, HYPERGLYCAEMIA, AND ZN CONCENTRATIONS. METALLOTHIONEIN CONCENTRATIONS AND MT2A POLYMORPHISMS HAVE A POTENTIAL TO BE USED AS BIOMARKERS OF METAL EXPOSURE AND CLINICAL MARKERS OF A NUMBER OF CHRONIC DISEASES. THIS POTENTIAL NEEDS TO BE STUDIED AND VERIFIED IN A LARGE NUMBER OF WELL-DEFINED GROUPS OF PARTICIPANTS (SEVERAL HUNDREDS AND THOUSANDS) WITH A FOCUS ON PARTICULAR PHYSIOLOGICAL OR PATHOLOGICAL CONDITION AND TAKING INTO CONSIDERATION OTHER CONTRIBUTING FACTORS, SUCH AS ENVIRONMENTAL EXPOSURE AND INDIVIDUAL GENETIC AND EPIGENETIC MAKEUP. 2020 2 6137 36 THE EPIGENETICS OF PSYCHOSIS: A STRUCTURED REVIEW WITH REPRESENTATIVE LOCI. THE EVIDENCE FOR AN ENVIRONMENTAL COMPONENT IN CHRONIC PSYCHOTIC DISORDERS IS STRONG AND RESEARCH ON THE EPIGENETIC MANIFESTATIONS OF THESE ENVIRONMENTAL IMPACTS HAS COMMENCED IN EARNEST. IN REVIEWING THIS RESEARCH, THE FOCUS IS ON THREE GENES AS MODELS FOR DIFFERENTIAL METHYLATION, MCHR1, AKT1 AND TDO2, EACH OF WHICH HAVE BEEN INVESTIGATED FOR GENETIC ASSOCIATION WITH PSYCHOTIC DISORDERS. ENVIRONMENTAL FACTORS ASSOCIATED WITH PSYCHOTIC DISORDERS, AND WHICH INTERACT WITH THESE MODEL GENES, ARE EXPLORED IN DEPTH. THE LOCATION OF TRANSCRIPTION FACTOR MOTIFS RELATIVE TO KEY METHYLATION SITES IS EVALUATED FOR PREDICTED GENE EXPRESSION RESULTS, AND FOR OTHER SITES, EVIDENCE IS PRESENTED FOR METHYLATION DIRECTING ALTERNATIVE SPLICING. EXPERIMENTAL RESULTS FROM KEY STUDIES SHOW DIFFERENTIAL METHYLATION: FOR MCHR1, IN PSYCHOSIS CASES VERSUS CONTROLS; FOR AKT1, AS A PRE-EXISTING METHYLATION PATTERN INFLUENCING BRAIN ACTIVATION FOLLOWING ACUTE ADMINISTRATION OF A PSYCHOSIS-ELICITING ENVIRONMENTAL STIMULUS; AND FOR TDO2, IN A PATTERN ASSOCIATED WITH A DEVELOPMENTAL FACTOR OF RISK FOR PSYCHOSIS, IN ALL CASES THE PREDICTED EXPRESSION IMPACT BEING HIGHLY DEPENDENT ON LOCATION. METHYLATION INDUCED BY SMOKING, A CONFOUNDING VARIABLE, EXHIBITS AN INTRIGUING PATTERN FOR ALL THREE GENES. FINALLY, HOW DIFFERENTIAL METHYLATION MESHES WITH DARWINIAN PRINCIPLES IS EXAMINED, IN PARTICULAR AS IT RELATES TO THE "FLEXIBLE STEM" THEORY OF EVOLUTION. 2022 3 3418 35 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 4 1567 38 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D. 2018 5 6720 27 VITAMIN D METABOLISM GENES ARE DIFFERENTIALLY METHYLATED IN INDIVIDUALS WITH CHRONIC KNEE PAIN. CONTEXT: RECENT EVIDENCE SUGGESTS THAT VITAMIN D MAY INTERACT WITH THE EPIGENOME AND PLAY A ROLE IN THE PAIN EXPERIENCE. IN ORDER FOR PROPER FUNCTIONING TO OCCUR, THERE MUST BE AN ADEQUATE LEVEL OF VITAMIN D PRESENT, MADE POSSIBLE BY ENZYMATIC REACTIONS THAT ALLOW VITAMIN D TO BE BIOLOGICALLY ACTIVE. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE EPIGENETIC LANDSCAPE OF GENES INVOLVED IN VITAMIN D METABOLISM IN INDIVIDUALS WITH AND WITHOUT CHRONIC KNEE PAIN. PROCEDURES: COMMUNITY-DWELLING INDIVIDUALS RECRUITED AS PART OF A LARGER STUDY FOCUSED ON KNEE PAIN PROVIDED DEMOGRAPHIC, CLINICAL AND PAIN-RELATED INFORMATION, AS WELL AS AN INTRAVENOUS BLOOD SAMPLE TO DETERMINE DNA METHYLATION LEVELS AT CPG SITES. MAIN FINDINGS: THERE WERE DIFFERENCES IN DNA METHYLATION BETWEEN THOSE WITH AND WITHOUT PAIN IN GENES THAT CODE FOR ENZYMES RELATED TO VITAMIN D METABOLISM: CYP24A1 (24-HYDROXYLASE) AND CYP27B1 (1-?-HYDROXYLASE). THERE WAS ALSO HYPERMETHYLATION ON THE GENE THAT CODES FOR THE VITAMIN D RECEPTOR (VDR). PRINCIPAL CONCLUSIONS: THE PRESENCE OF CHRONIC PAIN IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS IN GENES RESPONSIBLE FOR THE EXPRESSION OF ENZYMES INVOLVED IN VITAMIN D METABOLISM AND CELLULAR FUNCTION. THESE RESULTS LAY GROUNDWORK IN UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION BETWEEN VITAMIN D AND CHRONIC PAIN. 2023 6 5737 48 SMOKING AND HEALTH: ASSOCIATION BETWEEN TELOMERE LENGTH AND FACTORS IMPACTING ON HUMAN DISEASE, QUALITY OF LIFE AND LIFE SPAN IN A LARGE POPULATION-BASED COHORT UNDER THE EFFECT OF SMOKING DURATION. REACTIVE OXYGEN SPECIES (ROS) ARE OF PRIMARY IMPORTANCE AS THEY CAUSE DAMAGE TO LIPIDS, PROTEINS, AND DNA EITHER ENDOGENOUSLY BY CELLULAR MECHANISM, OR THROUGH EXOGENOUS EXPOSURE TO ENVIRONMENTAL INJURY FACTORS, INCLUDING OXIDATION INSULT FACTORS, SUCH AS TOBACCO SMOKE. CURRENTLY 46.3 MILLION ADULTS (25.7 PERCENT OF THE POPULATION) ARE SMOKERS. THIS INCLUDES 24 MILLION MEN (28.1 PERCENT OF THE TOTAL) AND MORE THAN 22 MILLION WOMEN (23.5 PERCENT). THE PREVALENCE IS HIGHEST AMONG PERSONS 25-44 YEARS OF AGE. CIGARETTE SMOKERS HAVE A HIGHER RISK OF DEVELOPING SEVERAL CHRONIC DISORDERS. THESE INCLUDE FATTY BUILDUPS IN ARTERIES, SEVERAL TYPES OF CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (LUNG PROBLEMS). AS PERIPHERAL LEUKOCYTES HAVE BEEN THE MAIN TARGET OF HUMAN TELOMERE RESEARCH, MOST OF WHAT IS KNOWN ABOUT HUMAN TELOMERE DYNAMICS IN VIVO IS BASED ON THESE CELLS. LEUKOCYTE TELOMERE LENGTH (TL) IS A COMPLEX TRAIT THAT IS SHAPED BY GENETIC, EPIGENETIC, AND ENVIRONMENTAL DETERMINANTS. IN THIS ARTICLE, WE CONSIDER THAT SMOKING MODIFIES LEUKOCYTE TL IN HUMANS AND CONTRIBUTES TO ITS VARIABILITY AMONG INDIVIDUALS, ALTHOUGH THE SMOKING EFFECT ON TL AND ITS RELATION WITH OTHER METABOLIC INDICES MAY ACCELERATE BIOLOGICAL AGING AND DEVELOPMENT OF SMOKING-INDUCED CHRONIC DISEASES IN A LARGE HUMAN POPULATION-BASED COHORTS WITH SMOKING BEHAVIOR. RECENT STUDIES CONFIRMED THAT INDIVIDUALS WITH SHORTER TELOMERES PRESENT A HIGHER PREVALENCE OF ARTERIAL LESIONS AND HIGHER RISK OF CARDIOVASCULAR DISEASE MORTALITY. THIS STUDY ORIGINALLY SUGGESTS THAT EFFICIENT THERAPEUTIC PROTECTION OF TL AND STRUCTURE IN RESPONSE TO STRESSES THAT ARE KNOWN TO REDUCE TL, SUCH AS OXIDATIVE DAMAGE OR INFLAMMATION ASSOCIATED WITH TOBACCO SMOKING, WOULD LEAD TO BETTER TELOMERE MAINTENANCE. RECENTLY, WE HAVE DISCOVERED THE POTENTIAL USE OF TELOMERE-RESTORATIVE IMIDAZOLE-CONTAINING DIPEPTIDE (NON-HYDROLIZED CARNOSINE, CARCININE) BASED THERAPY FOR BETTER SURVIVAL OF SMOKERS. WE CONCLUDE THAT A BETTER THERAPEUTIC OR NUTRITIONAL MAINTENANCE OF TL MAY CONFER HEALTHY AGING IN SMOKERS AND EXCEPTIONAL LONGEVITY IN REGULARLY ROS-EXPOSED HUMAN SURVIVORS. 2011 7 1524 26 DNA METHYLATION CHANGES IN CYSTIC FIBROSIS: CAUSE OR CONSEQUENCE? TWIN AND SIBLING STUDIES HAVE SHOWN THAT LUNG DISEASE SEVERITY IS VARIABLE AMONG CYSTIC FIBROSIS (CF) PATIENTS AND AFFECTED TO THE SAME EXTENT BY GENETIC AND NONHERITABLE FACTORS. GENETIC FACTORS HAVE BEEN THOROUGHLY ASSESSED, WHEREAS THE MOLECULAR MECHANISMS WHEREBY NONHERITABLE FACTORS CONTRIBUTE TO THE PHENOTYPIC VARIABILITY OF CF PATIENTS ARE STILL UNKNOWN. EPIGENETIC MODIFICATIONS MAY REPRESENT THE MISSING LINK BETWEEN NONHERITABLE FACTORS AND PHENOTYPIC VARIATION IN CF. HEREIN, WE REVIEW RECENT STUDIES SHOWING THAT DNA METHYLATION IS ALTERED IN CF AND WE ADDRESS THREE POSSIBLE FACTORS RESPONSIBLE FOR THESE VARIATIONS: (I) OVERPRODUCTION OF REACTIVE OXYGEN SPECIES, (II) DEPLETION OF DNA METHYLATION COFACTORS AND (III) SUSCEPTIBILITY TO ACUTE AND CHRONIC BACTERIAL INFECTIONS. ALSO, WE HYPOTHESIZE THAT THE UNIQUE DNA METHYLATION PROFILE OF EACH PATIENT CAN MODULATE THE PHENOTYPE AND DISCUSS THE INTEREST OF IMPLEMENTING INTEGRATED GENOMIC, EPIGENOMIC AND TRANSCRIPTOMIC STUDIES TO FURTHER UNDERSTAND THE CLINICAL DIVERSITY OF CF PATIENTS (GRAPHICAL ABSTRACT). 2020 8 6334 31 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 9 4198 35 METABOLIC PROFILING DISTINGUISHES THREE SUBTYPES OF ALZHEIMER'S DISEASE. THE CAUSE OF ALZHEIMER'S DISEASE IS INCOMPLETELY DEFINED, AND NO TRULY EFFECTIVE THERAPY EXISTS. HOWEVER, MULTIPLE STUDIES HAVE IMPLICATED METABOLIC ABNORMALITIES SUCH AS INSULIN RESISTANCE, HORMONAL DEFICIENCIES, AND HYPERHOMOCYSTEINEMIA. OPTIMIZING METABOLIC PARAMETERS IN A COMPREHENSIVE WAY HAS YIELDED COGNITIVE IMPROVEMENT, BOTH IN SYMPTOMATIC AND ASYMPTOMATIC INDIVIDUALS. THEREFORE, EXPANDING THE STANDARD LABORATORY EVALUATION IN PATIENTS WITH DEMENTIA MAY BE REVEALING. HERE I REPORT THAT METABOLIC PROFILING REVEALS THREE ALZHEIMER'S DISEASE SUBTYPES. THE FIRST IS INFLAMMATORY, IN WHICH MARKERS SUCH AS HS-CRP AND GLOBULIN:ALBUMIN RATIO ARE INCREASED. THE SECOND TYPE IS NON-INFLAMMATORY, IN WHICH THESE MARKERS ARE NOT INCREASED, BUT OTHER METABOLIC ABNORMALITIES ARE PRESENT. THE THIRD TYPE IS A VERY DISTINCTIVE CLINICAL ENTITY THAT AFFECTS RELATIVELY YOUNG INDIVIDUALS, EXTENDS BEYOND THE TYPICAL ALZHEIMER'S DISEASE INITIAL DISTRIBUTION TO AFFECT THE CORTEX WIDELY, IS CHARACTERIZED BY EARLY NON-AMNESTIC FEATURES SUCH AS DYSCALCULIA AND APHASIA, IS OFTEN MISDIAGNOSED OR LABELED ATYPICAL ALZHEIMER'S DISEASE, TYPICALLY AFFECTS APOE4-NEGATIVE INDIVIDUALS, AND IS ASSOCIATED WITH STRIKING ZINC DEFICIENCY. GIVEN THE INVOLVEMENT OF ZINC IN MULTIPLE ALZHEIMER'S-RELATED METABOLIC PROCESSES, SUCH AS INSULIN RESISTANCE, CHRONIC INFLAMMATION, ADAM10 PROTEOLYTIC ACTIVITY, AND HORMONAL SIGNALING, THIS SYNDROME OF ALZHEIMER'S-PLUS WITH LOW ZINC (APLZ) WARRANTS FURTHER METABOLIC, GENETIC, AND EPIGENETIC CHARACTERIZATION. 2015 10 4399 37 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 11 2533 33 EPIGENETICS IN AUTOIMMUNE CONNECTIVE TISSUE DISEASES. BACKGROUND. AUTOIMMUNE CONNECTIVE TISSUE DISEASES (ACTDS) ENCOMPASS A HETEROGENEOUS GROUP OF CHRONIC IMMUNE-MEDIATED INFLAMMATORY DISORDERS, PRIMARILY AFFECTING CONNECTIVE TISSUES AND CLINICALLY CHARACTERIZED BY VARIABLE MULTISYSTEM MANIFESTATIONS, FREQUENTLY OVERLAPPING. ENVIRONMENTAL FACTORS ARE THOUGHT TO PROMOTE ACTD DEVELOPMENT IN GENETIC PREDISPOSING/ENDOCRINE PERMISSIVE BACKGROUND THROUGH THE INDUCTION OF EPIGENETIC MODIFICATIONS, CONSISTING OF STABLE, HERITABLE, BUT POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION, OCCURRING WITHOUT ALTERATIONS OF THE DNA SEQUENCE. ACTUALLY, EPIGENETIC MECHANISMS (SUCH AS HISTONE MODIFICATIONS, DNA METHYLATION, NUCLEOSOME POSITIONING, AND RNA INTERFERENCE) LINK GENOTYPE UPSTREAM AND PHENOTYPE DOWNSTREAM, AND, IF PERSISTENTLY ABERRANT, MAY CAUSE A VARIETY OF HUMAN DISEASES, INCLUDING ACTDS. WE AIMED TO REVIEW THE RECENT ADVANCES IN THE KNOWLEDGE OF THE ACTD EPIGENETIC ALTERATIONS. METHODS: A DETAILED SEARCH OF THE AVAILABLE LITERATURE WAS PERFORMED IN THE PUBMED (U.S. NATIONAL LIBRARY OF MEDICINE) DATABASE. RESULTS: GROWING EVIDENCE UNDERLINES THE RELEVANT ROLE OF EPIGENETIC DEFECTS IN THE ACTD PATHOGENESIS, AND SPECIFIC EPIGENETIC PATTERNS CAN REPRESENT DISEASE BIOMARKERS. IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA), EPIGENETIC VARIATIONS INTERACT DETERMINING THE TYPICAL "AGGRESSIVE" PHENOTYPE DISPLAYED BY RA SYNOVIAL FIBROBLASTS. EPIGENETIC MODIFICATIONS ARE INVOLVED IN THE PROFIBROTIC PROCESS THAT CHARACTERIZES SYSTEMIC SCLEROSIS. IN SYSTEMIC LUPUS ERYTHEMATOSUS AND SJOGREN'S SYNDROME, COMPLEX EPIGENETIC CHANGES ALTERING GENE EXPRESSION HAVE BEEN DEMONSTRATED. CONCLUSIONS: COMPREHENSIVE STUDIES WILL CONTRIBUTE TO FURTHER DEFINE THE ABERRANT EPIGENETIC MECHANISMS INVOLVED IN THE ACTDS ETIOPATHOGENESIS. MOREOVER, BEING EPIGENETIC CHANGES POTENTIALLY REVERSIBLE, THE IDENTIFICATION OF ACTDS EPIGENETIC BIOMARKERS WILL ALLOW THE DEVELOPMENT OF THERAPEUTIC STRATEGIES ADDRESSED TO TARGET DYSREGULATED GENES AND CORRECT ABERRANT EPIGENOMIC ALTERATIONS. 2014 12 4187 52 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 6141 40 THE ETIOLOGY OF PEYRONIE'S DISEASE: PATHOGENESIS AND GENETIC CONTRIBUTIONS. INTRODUCTION: PEYRONIE'S DISEASE (PD) IS A CHRONIC FIBROSING CONDITION THAT CONTRIBUTES TO PENILE DEFORMITY, CURVATURE, AND PAIN. INITIAL FAMILIAL STUDIES DEMONSTRATED POTENTIAL GENETIC LINKS TO PD. SINCE THAT TIME, VERY FEW INVESTIGATIONS HAVE SIGNIFICANTLY ADVANCED THE SCIENCE IN THIS AREA. HENCE, THERE IS A LARGE OPPORTUNITY AND SIGNIFICANT NEED TO BETTER STUDY THE UNDERLYING GENOMICS AND PATHOGENESIS OF PD. AIM: TO SUMMARIZE THE CURRENT GENOMIC LITERATURE RELEVANT TO PD. METHODS: A REVIEW WAS PERFORMED OF ALL PUBMED-INDEXED LITERATURE FROM 1970-2018 RELATING TO THE PATHOPHYSIOLOGY AND GENETICS OF PD. KEY FINDINGS WERE CATEGORICALLY SUMMARIZED TO INCLUDE EPIDEMIOLOGY, RISK FACTORS, INHERITANCE PATTERNS, CHROMOSOMAL INSTABILITY, GENETIC ASSOCIATIONS, EPIGENETICS, DIFFERENTIAL GENE EXPRESSION, AND PRECLINICAL MODELS OF PD. MAIN OUTCOME MEASURES: SUMMARY OF THE CURRENT LITERATURE ON THE GENETICS OF PD. RESULTS: PD IS A COMMON CONDITION AND HAS SEVERAL KNOWN RISK FACTORS AND COMORBID DISEASE ASSOCIATIONS. ALTHOUGH MEN WITH PD ARE BELIEVED TO BE GENETICALLY PREDISPOSED, THERE ARE LIKELY SEVERAL SUBTYPES OF THE CONDITION, EACH WITH VARIED PATHOPHYSIOLOGICAL DISORDERS AND CONTRIBUTING FACTORS. AVAILABLE DATA SUGGEST THAT PD IS ASSOCIATED WITH UNDERLYING GENETIC INSTABILITY, INCLUDING DYSREGULATION OF GENES RELATING TO FIBROSIS AND CELLULAR DEGRADATION, THUS, RESULTING IN ABNORMAL PLAQUE DEVELOPMENT AND PENILE DEFORMITY. PRECLINICAL MODELS, INCLUDING CELL CULTURES AND RAT MODELS, DEMONSTRATE SEVERAL CONSISTENCIES WITH PD CLINICAL AND HISTOPATHOLOGIC CHARACTERISTICS; HOWEVER, AN IDEAL MODEL WITH SPONTANEOUS DEVELOPMENT OF PD IS LACKING. CONCLUSION: BASED ON LIMITED DATA, PD LIKELY REPRESENTS A HETEROGENEOUS CONDITION, WITH BOTH HERITABLE AND ENVIRONMENTALLY-DRIVEN EPIGENETIC FACTORS CONTRIBUTING TO ITS DEVELOPMENT AND PROGRESSION. HOWEVER, THERE REMAINS A SIGNIFICANT GAP IN THE LITERATURE ON THE UNDERLYING CAUSE AND PATHOPHYSIOLOGY OF THE CONDITION, SUGGESTING A SUBSTANTIAL NEED FOR FURTHER INVESTIGATION AND STUDY. SHARMA KL, ALOM M, TROST L. THE ETIOLOGY OF PEYRONIE'S DISEASE: PATHOGENESIS AND GENETIC CONTRIBUTIONS. SEX MED REV 2020;8:314-323. 2020 14 276 30 AGE-RELATED DIFFERENCES IN MONOCYTE DNA METHYLATION AND IMMUNE FUNCTION IN HEALTHY KENYAN ADULTS AND CHILDREN. BACKGROUND: AGE-RELATED CHANGES IN ADAPTIVE AND INNATE IMMUNE CELLS HAVE BEEN ASSOCIATED WITH A DECLINE IN EFFECTIVE IMMUNITY AND CHRONIC, LOW-GRADE INFLAMMATION. EPIGENETIC, TRANSCRIPTIONAL, AND FUNCTIONAL CHANGES IN MONOCYTES OCCUR WITH AGING, THOUGH MOST STUDIES TO DATE HAVE FOCUSED ON DIFFERENCES BETWEEN YOUNG ADULTS AND THE ELDERLY IN POPULATIONS WITH EUROPEAN ANCESTRY; FEW DATA EXIST REGARDING CHANGES THAT OCCUR IN CIRCULATING MONOCYTES DURING THE FIRST FEW DECADES OF LIFE OR IN AFRICAN POPULATIONS. WE ANALYZED DNA METHYLATION PROFILES, CYTOKINE PRODUCTION, AND INFLAMMATORY GENE EXPRESSION PROFILES IN MONOCYTES FROM YOUNG ADULTS AND CHILDREN FROM WESTERN KENYA. RESULTS: WE IDENTIFIED SEVERAL HYPO- AND HYPER-METHYLATED CPG SITES IN MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN THAT REPLICATED FINDINGS IN THE CURRENT LITERATURE OF DIFFERENTIAL DNA METHYLATION IN MONOCYTES FROM ELDERLY PERSONS VS. YOUNG ADULTS ACROSS DIVERSE POPULATIONS. DIFFERENTIALLY METHYLATED CPG SITES WERE ALSO NOTED IN GENE REGIONS IMPORTANT TO INFLAMMATION AND INNATE IMMUNE RESPONSES. MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN DISPLAYED INCREASED PRODUCTION OF IL-8, IL-10, AND IL-12P70 IN RESPONSE TO TLR4 AND TLR2/1 STIMULATION AS WELL AS DISTINCT INFLAMMATORY GENE EXPRESSION PROFILES. CONCLUSIONS: THESE FINDINGS COMPLEMENT PREVIOUS REPORTS OF AGE-RELATED METHYLATION CHANGES IN ISOLATED MONOCYTES AND PROVIDE NOVEL INSIGHTS INTO THE ROLE OF AGE-ASSOCIATED CHANGES IN INNATE IMMUNE FUNCTIONS. 2021 15 705 35 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 16 3801 40 INTERPLAY OF VITAMIN D AND SIRT1 IN TISSUE-SPECIFIC METABOLISM-POTENTIAL ROLES IN PREVENTION AND TREATMENT OF NON-COMMUNICABLE DISEASES INCLUDING CANCER. THE IMPORTANCE OF THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES, INCLUDING OBESITY, METABOLIC SYNDROME, TYPE 2 DIABETES, CARDIOVASCULAR DISEASES, AND CANCER, IS INCREASING AS A REQUIREMENT OF THE AGING POPULATION IN DEVELOPED COUNTRIES AND THE SUSTAINABILITY OF HEALTHCARE. SIMILARLY, THE 2013-2030 ACTION PLAN OF THE WHO FOR THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES SEEKS THESE ACHIEVEMENTS. ADEQUATE LIFESTYLE CHANGES, ALONE OR WITH THE NECESSARY TREATMENTS, COULD REDUCE THE RISK OF MORTALITY OR THE DETERIORATION OF QUALITY OF LIFE. IN OUR RECENT WORK, WE SUMMARIZED THE ROLE OF TWO CENTRAL FACTORS, I.E., APPROPRIATE LEVELS OF VITAMIN D AND SIRT1, WHICH ARE CONNECTED TO ADEQUATE LIFESTYLES WITH BENEFICIAL EFFECTS ON THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES. BOTH OF THESE FACTORS HAVE RECEIVED INCREASED ATTENTION IN RELATION TO THE COVID-19 PANDEMIC AS THEY BOTH TAKE PART IN REGULATION OF THE MAIN METABOLIC PROCESSES, I.E., LIPID/GLUCOSE/ENERGY HOMEOSTASIS, OXIDATIVE STRESS, REDOX BALANCE, AND CELL FATE, AS WELL AS IN THE HEALTHY REGULATION OF THE IMMUNE SYSTEM. VITAMIN D AND SIRT1 HAVE DIRECT AND INDIRECT INFLUENCE OF THE REGULATION OF TRANSCRIPTION AND EPIGENETIC CHANGES AND ARE RELATED TO CYTOPLASMIC SIGNALING PATHWAYS SUCH AS PLC/DAG/IP3/PKC/MAPK, MEK/ERK, INSULIN/MTOR/CELL GROWTH, PROLIFERATION; LEPTIN/PI3K-AKT-MTORC1, AKT/NFKB/COX-2, NFKB/TNFALPHA, IL-6, IL-8, IL-1BETA, AND AMPK/PGC-1ALPHA/GLUT4, AMONG OTHERS. THROUGH THEIR PROPER REGULATION, THEY MAINTAIN NORMAL BODY WEIGHT, LIPID PROFILE, INSULIN SECRETION AND SENSITIVITY, BALANCE BETWEEN THE PRO- AND ANTI-INFLAMMATORY PROCESSES UNDER NORMAL CONDITIONS AND INFECTIONS, MAINTAIN ENDOTHELIAL HEALTH; BALANCE CELL DIFFERENTIATION, PROLIFERATION, AND FATE; AND BALANCE THE CIRCADIAN RHYTHM OF THE CELLULAR METABOLISM. THE ROLE OF THESE TWO MOLECULES IS INTERCONNECTED IN THE MOLECULAR NETWORK, AND THEY REGULATE EACH OTHER IN SEVERAL LAYERS OF THE HOMEOSTASIS OF ENERGY AND THE CELLULAR METABOLISM. BOTH HAVE A CENTRAL ROLE IN THE MAINTENANCE OF HEALTHY AND BALANCED IMMUNE REGULATION AND REDOX REACTIONS; THEREFORE, THEY COULD CONSTITUTE PROMISING TARGETS EITHER FOR PREVENTION OR AS COMPLEMENTARY THERAPIES TO ACHIEVE A BETTER QUALITY OF LIFE, AT ANY AGE, FOR HEALTHY PEOPLE AND PATIENTS UNDER CHRONIC CONDITIONS. 2023 17 6772 40 [ADVANCES IN EPIGENETIC MARKERS OF DERMATOMYOSITIS/POLYMYOSITIS]. IDIOPATHIC INFLAMMATORY MYOPATHY (IIM) IS A RARE GROUP OF AUTOIMMUNE DISEASES, CHARACTERIZED BY CHRONIC MUSCLE WEAKNESS, MUSCLE FATIGUE AND INFILTRATION OF SINGLE NUCLEAR CELLS IN SKELETAL MUSCLE. ITS SUBTYPES INCLUDE DERMATOMYOSITIS (DM), POLYMYOSITIS (PM), INCLUSION BODY MYOSITIS (IBM) AND IMMUNE-MEDIATED NECROTIZING MYOSITIS (IMNM), AND THE MOST COMMON SUBTYPES ARE DM AND PM. PM IS AN AUTOIMMUNE DISEASE MAINLY MANIFESTED BY MUSCLE DAMAGE. WHEN THE SKIN IS INVOLVED, IT IS CALLED DM. THE INCIDENCE OF IIM WAS RELATIVELY LOW, WHICH WAS 1.16-19 PER MILLION PEOPLE/YEAR, BUT THE MORTALITY WAS HIGH AND THE PROGNOSIS WAS POOR. THE PATHOGENESIS OF IIM IS STILL UNCLEAR. PREVIOUS STUDIES SUGGEST THAT BOTH IMMUNE AND NON-IMMUNE MECHANISMS ARE INVOLVED IN ITS PATHOGENESIS, ESPECIALLY CELLULAR AND HUMORAL IMMUNITY. IN RECENT YEARS, RESEARCHERS HAVE CONDUCTED A NUMBER OF STUDIES ON THE PATHOGENESIS OF IIM, ESPECIALLY IN THE STUDY OF DM/PM WITH THE APPLICATION OF HIGH-THROUGHPUT BIOMETRICS. EPIGENETICS IS A DISCIPLINE THAT REFERS TO THE GENETIC PHENOMENA OF DNA METHYLATION SPECTRUM, CHROMATIN STRUCTURE STATE AND GENE EXPRESSION SPECTRUM TRANSFERRED BETWEEN CELLS WITHOUT ANY CHANGES IN DNA SEQUENCE, INCLUDING DNA METHYLATION, CHROMATIN MODIFICATION AND NON-CODING RNA CHANGES. A LARGE NUMBER OF STUDIES HAVE SHOWN THAT EPIGENETIC MODIFICATION PLAYS AN IMPORTANT ROLE IN MANY DISEASES, ESPECIALLY IN CANCER. RECENT STUDIES HAVE ALSO FOUND A SERIES OF EPIGENETIC MARKERS RELATED TO THE OCCURRENCE AND DEVELOPMENT OF DM/PM, MAINLY IN THE ASPECT OF NON-CODING RNA CHANGES, SUCH AS MIR-10A, MIR-206, ETC. AND THERE HAS ALSO BEEN SOME RESEARCH ON DNA METHYLATION. HOWEVER, NO STUDIES HAVE BEEN REPORTED ON WHETHER CHROMATIN MODIFICATION IS INVOLVED IN THE PATHOGENESIS OF DM/PM. THE PATHOGENESIS OF DM/PM IS COMPLEX AND DIVERSE. WITH THE DEVELOPMENT OF RESEARCH, CERTAIN MICRORNAS (MIRNAS) AND LONG NON-CODING RNAS (LNCRNAS) MAY BECOME BIOLOGICAL MARKERS FOR THE EARLY DIAGNOSIS OF DM/PM. THEREFORE, THIS PAPER MAINLY EXPOUNDS THE RESEARCH PROGRESS OF THE BIOMARKERS OF DM/PM FROM THE ASPECT OF EPIGENETICS. 2019 18 2901 34 GENDER DIFFERENCES IN GERM-CELL MUTAGENESIS AND GENETIC RISK. CURRENT INTERNATIONAL CLASSIFICATION SYSTEMS FOR CHEMICAL MUTAGENS ARE HAZARD-BASED RATHER THAN AIMED AT ASSESSING RISKS QUANTITATIVELY. IN THE PAST, GERM-CELL TESTS HAVE BEEN MAINLY PERFORMED WITH A LIMITED NUMBER OF SOMATIC CELL MUTAGENS, AND RARELY UNDER CONDITIONS AIMED AT COMPARING GENDER-SPECIFIC DIFFERENCES IN SUSCEPTIBILITY TO MUTAGEN EXPOSURES. THERE ARE PROFOUND DIFFERENCES IN THE GENETIC CONSTITUTION, AND IN HORMONAL, STRUCTURAL, AND FUNCTIONAL ASPECTS OF DIFFERENTIATION AND CONTROL OF GAMETOGENESIS BETWEEN THE SEXES. A CRITICAL REVIEW OF THE LITERATURE SUGGESTS THAT THESE DIFFERENCES MAY HAVE A PROFOUND IMPACT ON THE RELATIVE SUSCEPTIBILITY, STAGE OF HIGHEST SENSITIVITY AND THE RELATIVE RISK FOR THE GENESIS OF GENE MUTATION, AS WELL AS STRUCTURAL AND NUMERICAL CHROMOSOMAL ABERRATIONS IN MALE AND FEMALE GERM CELLS. TRANSMISSION OF GERM-CELL MUTATIONS TO THE OFFSPRING MAY ALSO ENCOUNTER GENDER-SPECIFIC INFLUENCES. GENDER DIFFERENCES IN SUSCEPTIBILITY TO CHEMICALLY DERIVED ALTERATIONS IN IMPRINTING PATTERNS MAY POSE A THREAT FOR THE HEALTH OF THE OFFSPRING AND MAY ALSO BE TRANSMITTED TO FUTURE GENERATIONS. RECENT REPORTS ON DIFFERENT GENETIC EFFECTS FROM HIGH ACUTE AND FROM CHRONIC LOW-DOSE EXPOSURES CHALLENGE THE VALIDITY OF CONCLUSIONS DRAWN FROM STANDARD METHODS OF MUTAGENICITY TESTING. IN CONCLUSION, RESEARCH IS URGENTLY NEEDED TO IDENTIFY GENETIC HAZARDS FOR A LARGER RANGE OF CHEMICAL COMPOUNDS, INCLUDING THOSE SUSPECTED TO DISTURB PROPER CHROMOSOME SEGREGATION. ALTERATIONS IN EPIGENETIC PROGRAMMING AND THEIR HEALTH CONSEQUENCES WILL HAVE TO BE INVESTIGATED. MORE ATTENTION SHOULD BE PAID TO GENDER-SPECIFIC GENETIC EFFECTS. FINALLY, THE DATABASE FOR GERM-CELL MUTAGENS SHOULD BE ENLARGED USING MOLECULAR METHODOLOGIES, AND GENETIC EPIDEMIOLOGY STUDIES SHOULD BE PERFORMED WITH THESE TECHNIQUES TO VERIFY HUMAN GENETIC RISK. 2007 19 49 36 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 20 6468 29 TISSUE-SPECIFIC ENRICHMENT OF LYMPHOMA RISK LOCI IN REGULATORY ELEMENTS. THOUGH NUMEROUS POLYMORPHISMS HAVE BEEN ASSOCIATED WITH RISK OF DEVELOPING LYMPHOMA, HOW THESE VARIANTS FUNCTION TO PROMOTE TUMORIGENESIS IS POORLY UNDERSTOOD. HERE, WE REPORT THAT LYMPHOMA RISK SNPS, ESPECIALLY IN THE NON-HODGKIN'S LYMPHOMA SUBTYPE CHRONIC LYMPHOCYTIC LEUKEMIA, ARE SIGNIFICANTLY ENRICHED FOR CO-LOCALIZATION WITH EPIGENETIC MARKS OF ACTIVE GENE REGULATION. THESE ENRICHMENTS WERE SEEN IN A LYMPHOID-SPECIFIC MANNER FOR NUMEROUS ENCODE DATASETS, INCLUDING DNASE-HYPERSENSITIVITY AS WELL AS MULTIPLE SEGMENTATION-DEFINED ENHANCER REGIONS. FURTHERMORE, WE IDENTIFY PUTATIVELY FUNCTIONAL SNPS THAT ARE BOTH IN REGULATORY ELEMENTS IN LYMPHOCYTES AND ARE ASSOCIATED WITH GENE EXPRESSION CHANGES IN BLOOD. WE DEVELOPED AN ALGORITHM, UES, THAT USES A MONTE CARLO SIMULATION APPROACH TO CALCULATE THE ENRICHMENT OF PREVIOUSLY IDENTIFIED RISK SNPS IN VARIOUS FUNCTIONAL ELEMENTS. THIS MULTISCALE APPROACH INTEGRATING MULTIPLE DATASETS HELPS DISENTANGLE THE UNDERLYING BIOLOGY OF LYMPHOMA, AND MORE BROADLY, IS GENERALLY APPLICABLE TO GWAS RESULTS FROM OTHER DISEASES AS WELL. 2015