1  3889 146 KLOTHO RECOVERY BY GENISTEIN VIA PROMOTER HISTONE ACETYLATION AND DNA DEMETHYLATION MITIGATES RENAL FIBROSIS IN MICE. RENAL FIBROSIS IS A COMMON HISTOMORPHOLOGICAL FEATURE OF RENAL AGING AND CHRONIC KIDNEY DISEASES OF ALL ETIOLOGIES, AND ITS INITIATION AND PROGRESSION ARE SUBSTANTIALLY INFLUENCED BY ABERRANT EPIGENETIC MODIFICATIONS OF FIBROSIS-SUSCEPTIBLE GENES, YET WITHOUT EFFECTIVE THERAPY. "EPIGENETIC DIETS" EXHIBIT TISSUE-PROTECTIVE AND EPIGENETIC-MODULATING PROPERTIES; HOWEVER, THEIR ANTI-RENAL FIBROSIS FUNCTIONS AND THE UNDERLYING MECHANISMS ARE LESS UNDERSTOOD. IN THIS STUDY, WE SHOW THAT GENISTEIN, A PHYTOESTROGENIC ISOFLAVONE ENRICHED IN DIETARY SOY PRODUCTS, EXHIBITS IMPRESSIVE ANTI-RENAL FIBROSIS ACTIVITIES BY RECOVERING EPIGENETIC LOSS OF KLOTHO, A KIDNEY-ENRICHED ANTI-AGING AND FIBROSIS-SUPPRESSING PROTEIN. MOUSE FIBROTIC KIDNEYS INDUCED BY UUO (UNILATERAL URETERAL OCCLUSION) DISPLAYED SEVERER KLOTHO SUPPRESSION AND ADVERSE EXPRESSION OF RENAL FIBROSIS-ASSOCIATED PROTEINS, BUT GENISTEIN ADMINISTRATION MARKEDLY RECOVERED THE KLOTHO LOSS AND ATTENUATED RENAL FIBROSIS AND THE PROTEIN EXPRESSION ABNORMALITIES. THE EXAMINATION OF POSSIBLE CAUSES OF THE KLOTHO RECOVERY REVEALED THAT GENISTEIN SIMULTANEOUSLY INHIBITED HISTONE 3 DEACETYLATION OF KLOTHO PROMOTER AND NORMALIZED THE PROMOTER DNA HYPERMETHYLATION BY SUPPRESSING ELEVATED DNA METHYLTRANSFERASE DNMT1 AND DNMT3A. MORE IMPORTANTLY, GENISTEIN'S ANTI-RENAL FIBROSIS EFFECTS ON THE RENAL FIBROTIC LESIONS AND THE ABNORMAL EXPRESSIONS OF FIBROSIS-ASSOCIATED PROTEINS WERE ABROGATED WHEN KLOTHO IS KNOCKDOWN BY RNA INTERFERENCES IN UUO MICE. THUS, OUR RESULTS IDENTIFY KLOTHO RESTORATION VIA EPIGENETIC HISTONE ACETYLATION AND DNA DEMETHYLATION AS A CRITICAL MECHANISM OF GENISTEIN'S ANTI-FIBROSIS FUNCTION AND SHED NEW LIGHTS ON THE POTENTIALS OF EPIGENETIC DIETS IN PREVENTING OR TREATING AGING OR RENAL FIBROSIS-ASSOCIATED KIDNEY DISEASES. KEY MESSAGES: GENISTEIN PREVENTS RENAL FIBROSIS AND THE ASSOCIATED KLOTHO SUPPRESSION IN UUO MICE. GENISTEIN UPREGULATES KLOTHO IN PART BY REVERSING THE PROMOTER HISTONE 3 HYPOACETYLATION. GENISTEIN ALSO PRESERVES KLOTHO VIA RELIEVING KLOTHO PROMOTER HYPERMETHYLATION. GENISTEIN DEMETHYLATES KLOTHO PROMOTER BY INHIBITING ABERRANT DNMT1/3A EXPRESSION. GENISTEIN RESTORATION OF KLOTHO IS ESSENTIAL FOR ITS ANTI-RENAL FIBROSIS FUNCTION.	2019	
                                                                                                                                                                                                                                                                                                                                          
2   426  30 ANTI-DIABETIC FUNCTIONS OF SOY ISOFLAVONE GENISTEIN: MECHANISMS UNDERLYING ITS EFFECTS ON PANCREATIC BETA-CELL FUNCTION. TYPE 2 DIABETES IS A RESULT OF CHRONIC INSULIN RESISTANCE AND LOSS OF FUNCTIONAL PANCREATIC BETA-CELL MASS. STRATEGIES TO PRESERVE BETA-CELL MASS AND A GREATER UNDERSTANDING OF THE MECHANISMS UNDERLYING BETA-CELL TURNOVER ARE NEEDED TO PREVENT AND TREAT THIS DEVASTATING DISEASE. GENISTEIN, A NATURALLY OCCURRING SOY ISOFLAVONE, IS REPORTED TO HAVE NUMEROUS HEALTH BENEFITS ATTRIBUTED TO MULTIPLE BIOLOGICAL FUNCTIONS. OVER THE PAST 10 YEARS, NUMEROUS STUDIES HAVE DEMONSTRATED THAT GENISTEIN HAS ANTI-DIABETIC EFFECTS, IN PARTICULAR, DIRECT EFFECTS ON BETA-CELL PROLIFERATION, GLUCOSE-STIMULATED INSULIN SECRETION AND PROTECTION AGAINST APOPTOSIS, INDEPENDENT OF ITS FUNCTIONS AS AN ESTROGEN RECEPTOR AGONIST, ANTIOXIDANT, OR TYROSINE KINASE INHIBITOR. EFFECTS ARE STRUCTURE-SPECIFIC AND NOT COMMON TO ALL FLAVONOIDS. WHILE THERE ARE LIMITED DATA ON THE EFFECTS OF GENISTEIN CONSUMPTION IN HUMANS WITH DIABETES, THERE ARE A PLETHORA OF ANIMAL AND CELL-CULTURE STUDIES THAT DEMONSTRATE A DIRECT EFFECT OF GENISTEIN ON BETA-CELLS AT PHYSIOLOGICALLY RELEVANT CONCENTRATIONS (<10 MUM). THE EFFECTS APPEAR TO INVOLVE CAMP/PKA SIGNALING AND THERE ARE SOME STUDIES THAT SUGGEST AN EFFECT ON EPIGENETIC REGULATION OF GENE EXPRESSION. THIS REVIEW FOCUSES ON THE ANTI-DIABETIC EFFECTS OF GENISTEIN IN BOTH IN VITRO AND IN VIVO MODELS AND POTENTIAL MECHANISMS UNDERLYING ITS DIRECT EFFECTS ON BETA-CELLS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3  2040  30 EPIGENETIC CHANGES WITH DIETARY SOY IN CYNOMOLGUS MONKEYS. NUTRITIONAL INTERVENTIONS ARE IMPORTANT ALTERNATIVES FOR REDUCING THE PREVALENCE OF MANY CHRONIC DISEASES. SOY IS A GOOD SOURCE OF PROTEIN THAT CONTAINS ISOFLAVONES, INCLUDING GENISTEIN AND DAIDZEIN, AND MAY ALTER THE RISK OF OBESITY, TYPE 2 DIABETES, OSTEOPOROSIS, CARDIOVASCULAR DISEASE, AND REPRODUCTIVE CANCERS. WE HAVE SHOWN PREVIOUSLY IN NONHUMAN PRIMATES THAT SOY PROTEIN CONTAINING ISOFLAVONES LEADS TO IMPROVED BODY WEIGHT, INSULIN SENSITIVITY, LIPID PROFILES, AND ATHEROSCLEROSIS COMPARED TO PROTEIN WITHOUT SOY ISOFLAVONES (CASEIN), AND DOES NOT INCREASE THE RISK OF CANCER. SINCE GENISTEIN HAS BEEN SHOWN TO ALTER DNA METHYLATION, WE COMPARED THE METHYLATION PROFILES OF CYNOMOLGUS MONKEYS, FROM MULTIPLE TISSUES, EATING TWO HIGH-FAT, TYPICAL AMERICAN DIETS (TAD) WITH SIMILAR MACRONUTRIENT CONTENTS, WITH OR WITHOUT SOY PROTEIN. DNA METHYLATION STATUS WAS SUCCESSFULLY DETERMINED FOR 80.6% OF THE PROBES IN AT LEAST ONE TISSUE USING ILLUMINA'S HUMANMETHYLATION27 BEADCHIP. OVERALL METHYLATION INCREASED IN LIVER AND MUSCLE TISSUE WHEN MONKEYS SWITCHED FROM THE TAD-SOY TO THE TAD-CASEIN DIETS. GENES INVOLVED IN EPIGENETIC PROCESSES, SPECIFICALLY HOMEOBOX GENES (HOXA5, HOXA11, AND HOXB1), AND ABCG5 WERE AMONG THOSE THAT CHANGED BETWEEN DIETS. THESE DATA SUPPORT THE USE OF THE HUMANMETHYLATION27 BEADCHIP IN CYNOMOLGUS MONKEYS AND IDENTIFY EPIGENETIC CHANGES ASSOCIATED WITH DIETARY INTERVENTIONS WITH SOY PROTEIN THAT MAY POTENTIALLY AFFECT THE ETIOLOGY OF COMPLEX DISEASES.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4  3036  61 GENISTEIN AMELIORATES RENAL FIBROSIS THROUGH REGULATION SNAIL VIA M6A RNA DEMETHYLASE ALKBH5. RENAL TUBULE-INTERSTITIAL FIBROSIS IS RELATED TO CHRONIC KIDNEY DISEASE PROGRESSION AND A TYPICAL FEATURE OF THE AGING KIDNEY. EPIGENETIC MODIFICATIONS OF FIBROSIS-PRONE GENES REGULATE THE DEVELOPMENT OF RENAL FIBROSIS. AS A KIND OF "EPIGENETIC DIET", SOY ISOFLAVONE GENISTEIN WAS REPORTED TO HAVE RENAL PROTECTIVE ACTION AND EPIGENETIC-MODULATING EFFECTS. HOWEVER, ITS RENAL PROTECTION ROLE AND UNDERLYING MECHANISMS ARE YET TO BE FULLY CLARIFIED. HEREIN, WE SHOWED THAT GENISTEIN EXHIBITS A DEMONSTRABLE ANTI-FIBROTIC EFFECT ON KIDNEY IN VIVO UUO (UNILATERAL URETERAL OCCLUSION) MODEL AND RENAL EPITHELIAL CELLS IN VITRO MODEL. THE MECHANISM IS STRONGLY ASSOCIATED WITH EPITHELIAL-TO-MESENCHYMAL TRANSITION AND M6A RNA DEMETHYLASE ALKBH5. MOUSE FIBROTIC KIDNEYS INDUCED BY UUO EXHIBITED ADVERSE EXPRESSION OF RENAL FIBROSIS-RELATED PROTEINS AND SIGNIFICANT INCREASES IN THE TOTAL M6A LEVEL. AS AN ERASER, ALKBH5 SHOWED SEVERER SUPPRESSION IN THE RENAL FIBROSIS PROCESS. HOWEVER, GENISTEIN PRETREATMENT RESTORED ALKBH5 LOSS REMARKABLY AND REDUCED RENAL FIBROSIS, ABNORMAL PROTEIN, AND INFLAMMATORY MARKERS. THE EXAMINATION OF POSSIBLE MECHANISMS REVEALED THAT GENISTEIN PROMOTED ALKBH5 AND MAYBE INDUCED THE LEVEL OF MRNA M6A METHYLATION IN SOME EPITHELIAL-TO-MESENCHYMAL TRANSITION-RELATED TRANSCRIPTION FACTORS. WE FOUND SNAIL WAS THE CRITICAL REGULATOR AND CRITICAL FOR THE PROTECTIVE ROLE OF GENISTEIN. TO VERIFY THE RELATIONSHIP BETWEEN ALKBH5 AND SNAIL, WE GENERATED KNOCKDOWN AND OVEREXPRESSION OF ALKBH5 CELLS IN VITRO. ALKBH5 KNOCKDOWN ENHANCED THE MESENCHYMAL PHENOTYPE MARKER ALPHA-SMOOTH MUSCLE ACTIN AND SNAIL EXPRESSION. IN AGREEMENT, OVEREXPRESSION ALKBH5 INCREASED EPITHELIAL ADHESION MOLECULE E-CADHERIN AND REDUCED SNAIL EXPRESSION. IN CONCLUSION, GENISTEIN INCREASED RENAL ALKBH5 EXPRESSION IN UUO-INDUCED RENAL FIBROSIS AND REDUCED RNA M6A LEVELS AND AMELIORATES RENAL DAMAGES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  4792  38 NUTRITIONAL EPIGENETICS AND PHYTOCHEMICALS IN CANCER FORMATION. NUTRIGENETICS AND NUTRIGENOMICS ARE TWO CONCEPTS IN THE AREA OF NUTRITIONAL GENOMICS. EPIGENETICS IS A NEW DISCIPLINE WITH SIGNIFICANT POTENTIAL IN THE PREVENTION AND MANAGEMENT OF CERTAIN CARCINOMAS AND DISEASES. EPIGENETICS CONSISTS OF DNA METHYLATION, HISTONE MODIFICATION, NON-CODING RNAS, AND TELOMERASE ACTIVITY. EPIGENETIC-BASED MECHANISMS ACT ON THE INHIBITION OF CANCER CELLS BY MODULATING ENZYMES SUCH AS DNA METHYLTRANSFERASE AND HISTONE DEACETYLASE, AS WELL AS NON-CODING RNAS. PHYTOCHEMICALS ARE NATURAL BIOACTIVE COMPONENTS OF PLANT ORIGIN THAT HAVE ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTI-ANGIOGENIC EFFECTS ON VARIOUS DISEASES, ESPECIALLY CANCER. THE EPIGENETIC DIET IS A NUTRITIONAL MODEL BASED ON THE CONSUMPTION OF VARIOUS PHYTOCHEMICALS SUCH AS EPIGALLOCATECHIN-3-GALLATE, MORIN, CAFFEIC ACID PHENYL ESTER, APIGENIN, GENISTEIN, CURCUMIN, RESVERATROL, AND SULFORAPHANE. PHYTOCHEMICALS EXERT THEIR EFFECTS ON CANCER-BASED BY REDUCING CELL PROLIFERATION, INVASION, AND METASTASIS AND INCREASING CELL APOPTOSIS. SIMULTANEOUSLY, IT HAS FUNCTIONS SUCH AS REDUCING ONCOGENES THAT HAVE EFFECTS ON CANCER ETIOLOGY AND INCREASING TUMOR SUPPRESSOR GENES.KEY TEACHING POINTSCANCER IS A CHRONIC DISEASE WITH A HIGH MORTALITY RATE, IN WHICH VARIOUS GENETIC AND ENVIRONMENTAL FACTORS ARE INVOLVED IN ITS ETIOLOGY.PROTOONCOGENES, TUMOR SUPPRESSOR GENES, AND DNA REPAIR GENES ARE AMONG THE GENE GROUPS THAT FORM THE BASIS OF CANCER AND GENETIC STRUCTURE.THE BIDIRECTIONAL INTERACTION BETWEEN NUTRITION AND THE HUMAN GENOME HAS BEEN EFFECTIVE IN THE EMERGENCE OF THE CONCEPTS OF NUTRIGENETICS AND NUTRIGENOMICS.EPIGENETIC DIET IS A DIET BASED ON THE CONSUMPTION OF FOODS SUCH AS SOY, GRAPES, BLUEBERRIES, TURMERIC, CRUCIFEROUS VEGETABLES, AND GREEN TEA, WHICH INDUCE EPIGENETIC MECHANISMS THAT PROTECT AGAINST CANCER AND AGING.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6   617  28 BIOACTIVE FOOD COMPOUNDS, EPIGENETICS AND CHRONIC DISEASE PREVENTION: FOCUS ON EARLY-LIFE INTERVENTIONS WITH POLYPHENOLS. CONSUMPTION OF BIOACTIVE COMPOUNDS SUCH AS POLYPHENOLS, ISOTHIOCYANATES, SULFUR-CONTAINING COMPOUNDS AND TERPENOIDS, FOUND IN FRUITS AND VEGETABLES, IS ASSOCIATED WITH PREVENTION OF CHRONIC DISEASE. THESE BIOACTIVE FOOD COMPOUNDS ELICIT THEIR PROTECTIVE EFFECTS THROUGH COMPLEX MECHANISMS AT THE CELLULAR AND MOLECULAR, INCLUDING EPIGENETIC LEVELS. ACCORDING TO THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) PARADIGM, IN UTERO EXPOSURE TO STRESSORS SUCH AS MALNUTRITION THROUGH MATERNAL DIET WOULD IMPAIR FETAL DEVELOPMENT AND EPIGENETICALLY PROGRAM INCREASED RISK OF METABOLIC DISEASES AND SOME CANCERS IN ADULT LIFE. IN ADDITION, A ROLE FOR FATHERS DIET DURING PRECONCEPTION ON THEIR OFFSPRING HEALTH AND CHRONIC DISEASE SUSCEPTIBILITY HAS ALSO EMERGED. THIS HIGHLIGHTS EARLY LIFE AS A PROMISING WINDOW OF OPPORTUNITY FOR STARTING DIETARY INTERVENTIONS FOCUSING ON PREVENTING CHRONIC DISEASES. HOWEVER, KNOWLEDGE ON THE POTENTIAL BENEFICIAL IMPACT OF EARLY LIFE EXPOSURE TO BIOACTIVE FOOD COMPOUNDS IS LIMITED. AMONG THE STUDIES THAT HAVE INVESTIGATED BIOACTIVE FOOD COMPOUNDS IN THE CONTEXT OF DOHAD, MOST HAVE FOCUSED ON THE IMPACT OF DIETARY POLYPHENOLS. THUS, IN THIS REVIEW WE DISCUSS EXPERIMENTAL EVIDENCE SUPPORTING A ROLE FOR THE DIETARY POLYPHENOLS RESVERATROL, GENISTEIN, EPIGALLOCATECHIN-3-GALLATE AND ANTHOCYANINS IN CHRONIC DISEASE PREVENTION CONSIDERING A PERSPECTIVE FROM EARLY-LIFE INTERVENTIONS THROUGH MATERNAL AND PATERNAL DIETS AND FOCUSING ON EPIGENETICS AS A POTENTIAL UNDERLYING MECHANISM.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7  1744  32 EARLY LIFE ADVERSE ENVIRONMENTAL EXPOSURES INCREASE THE RISK OF UTERINE FIBROID DEVELOPMENT: ROLE OF EPIGENETIC REGULATION. UTERINE FIBROIDS [UF(S), AKA: LEIOMYOMA] ARE THE MOST IMPORTANT BENIGN NEOPLASTIC THREAT TO WOMEN'S HEALTH. THEY ARE THE MOST COMMON CAUSE OF HYSTERECTOMY IMPOSING UNTOLD PERSONAL CONSEQUENCES AND 100S OF BILLIONS OF HEALTHCARE DOLLARS, WORLDWIDE. CURRENTLY, THERE IS NO LONG TERM EFFECTIVE FDA-APPROVED MEDICAL TREATMENT AVAILABLE, AND SURGERY IS THE MAINSTAY. THE ETIOLOGY OF UFS IS NOT FULLY UNDERSTOOD. IN THIS REGARD, WE AND OTHERS HAVE RECENTLY REPORTED THAT SOMATIC MUTATIONS IN THE GENE ENCODING THE TRANSCRIPTIONAL MEDIATOR SUBUNIT MED12 ARE FOUND TO OCCUR AT A HIGH FREQUENCY ( APPROXIMATELY 85%) IN UFS. UFS LIKELY ORIGINATE WHEN A MED12 MUTATION OCCURS IN A MYOMETRIAL STEM CELL CONVERTING IT INTO A TUMOR-FORMING STEM CELL LEADING TO A CLONAL FIBROID LESION. ALTHOUGH THE MOLECULAR ATTRIBUTES UNDERLYING THE MECHANISTIC FORMATION OF UFS IS LARGELY UNKNOWN, A GROWING BODY OF LITERATURE IMPLICATES UNFAVORABLE EARLY LIFE ENVIRONMENTAL EXPOSURES AS POTENTIALLY IMPORTANT CONTRIBUTORS. EARLY LIFE EXPOSURE TO EDCS DURING SENSITIVE WINDOWS OF DEVELOPMENT CAN REPROGRAM NORMAL PHYSIOLOGICAL RESPONSES AND ALTER DISEASE SUSCEPTIBILITY LATER IN LIFE. NEONATAL EXPOSURE TO THE EDCS SUCH AS DIETHYLSTILBESTROL (DES) AND GENISTEIN DURING REPRODUCTIVE TRACT DEVELOPMENT HAS BEEN SHOWN TO INCREASE THE INCIDENCE, MULTIPLICITY AND OVERALL SIZE OF UFS IN THE EKER RAT MODEL, CONCOMITANTLY REPROGRAMMING ESTROGEN-RESPONSIVE GENE EXPRESSION. IMPORTANTLY, EDC EXPOSURE REPRESSES ENHANCER OF ZESTE 2 (EZH2) AND REDUCES LEVELS OF HISTONE 3 LYSINE 27 TRIMETHYLATION (H3K27ME3) REPRESSIVE MARK THROUGH ESTROGEN RECEPTOR/PHOSPHATIDYLINOSITIDE 3-KINASES/PROTEIN KINASE B NON-GENOMIC SIGNALING IN THE DEVELOPING UTERUS. CONSIDERING THE FACT THAT DISTINCT MEDIATOR COMPLEX SUBUNIT 12 (MED12) MUTATIONS ARE DETECTED IN DIFFERENT FIBROID LESIONS IN THE SAME UTERUS, THE EMERGENCE OF EACH MED12 MUTATION IS LIKELY AN INDEPENDENT EVENT IN AN ALTERED MYOMETRIAL STEM CELL. IT IS THEREFORE POSSIBLE THAT A CHRONIC REDUCTION IN DNA REPAIR CAPACITY EVENTUALLY CAUSES THE EMERGENCE OF MUTATIONS SUCH AS MED12 IN MYOMETRIAL STEM CELLS CONVERTING THEM INTO FIBROID TUMOR-FORMING STEM CELLS, AND THEREBY LEADS TO THE DEVELOPMENT OF UFS. ADVANCING OUR UNDERSTANDING OF THE MECHANISTIC ROLE EPIGENETIC REGULATION OF STEM CELLS PLAYS IN MEDIATING RISK AND TUMORIGENESIS WILL HELP IN POINTING THE WAY TOWARD THE DEVELOPMENT OF NOVEL THERAPEUTIC OPTIONS.	2016	
                                                                                                                                            
8  1396  31 DIET INDUCED EPIGENETIC CHANGES AND THEIR IMPLICATIONS FOR HEALTH. DIETARY EXPOSURES CAN HAVE CONSEQUENCES FOR HEALTH YEARS OR DECADES LATER AND THIS RAISES QUESTIONS ABOUT THE MECHANISMS THROUGH WHICH SUCH EXPOSURES ARE 'REMEMBERED' AND HOW THEY RESULT IN ALTERED DISEASE RISK. THERE IS GROWING EVIDENCE THAT EPIGENETIC MECHANISMS MAY MEDIATE THE EFFECTS OF NUTRITION AND MAY BE CAUSAL FOR THE DEVELOPMENT OF COMMON COMPLEX (OR CHRONIC) DISEASES. EPIGENETICS ENCOMPASSES CHANGES TO MARKS ON THE GENOME (AND ASSOCIATED CELLULAR MACHINERY) THAT ARE COPIED FROM ONE CELL GENERATION TO THE NEXT, WHICH MAY ALTER GENE EXPRESSION, BUT WHICH DO NOT INVOLVE CHANGES IN THE PRIMARY DNA SEQUENCE. THESE INCLUDE THREE DISTINCT, BUT CLOSELY INTER-ACTING, MECHANISMS INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING MICRORNAS (MIRNA) WHICH, TOGETHER, ARE RESPONSIBLE FOR REGULATING GENE EXPRESSION NOT ONLY DURING CELLULAR DIFFERENTIATION IN EMBRYONIC AND FOETAL DEVELOPMENT BUT ALSO THROUGHOUT THE LIFE-COURSE. THIS REVIEW SUMMARIZES THE GROWING EVIDENCE THAT NUMEROUS DIETARY FACTORS, INCLUDING MICRONUTRIENTS AND NON-NUTRIENT DIETARY COMPONENTS SUCH AS GENISTEIN AND POLYPHENOLS, CAN MODIFY EPIGENETIC MARKS. IN SOME CASES, FOR EXAMPLE, EFFECTS OF ALTERED DIETARY SUPPLY OF METHYL DONORS ON DNA METHYLATION, THERE ARE PLAUSIBLE EXPLANATIONS FOR THE OBSERVED EPIGENETIC CHANGES, BUT TO A LARGE EXTENT, THE MECHANISMS RESPONSIBLE FOR DIET-EPIGENOME-HEALTH RELATIONSHIPS REMAIN TO BE DISCOVERED. IN ADDITION, RELATIVELY LITTLE IS KNOWN ABOUT WHICH EPIGENOMIC MARKS ARE MOST LABILE IN RESPONSE TO DIETARY EXPOSURES. GIVEN THE PLASTICITY OF EPIGENETIC MARKS AND THEIR RESPONSIVENESS TO DIETARY FACTORS, THERE IS POTENTIAL FOR THE DEVELOPMENT OF EPIGENETIC MARKS AS BIOMARKERS OF HEALTH FOR USE IN INTERVENTION STUDIES.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9  4786  28 NUTRITION AND HEALTH DURING MID-LIFE: SEARCHING FOR SOLUTIONS AND MEETING CHALLENGES FOR THE AGING POPULATION. INTERACTIONS BETWEEN GENETIC (GENOME) AND ENVIRONMENTAL FACTORS (EPIGENOME) OPERATE DURING A PERSON'S ENTIRE LIFESPAN. THE AGING PROCESS IS ASSOCIATED WITH SEVERAL CELLULAR AND ORGANIC FUNCTIONAL ALTERATIONS THAT, AT THE END, CAUSE MULTI-ORGANIC CELL FAILURE. EPIGENETIC MECHANISMS OF AGING ARE MODIFIABLE BY APPROPRIATE PREVENTIVE ACTIONS MEDIATED BY SIRTUINS, CALORIC INPUT, DIET COMPONENTS, ADIPOSE TISSUE-RELATED INFLAMMATORY REACTIONS, AND PHYSICAL ACTIVITY. THE MEDITERRANEAN LIFESTYLE HAS BEEN FOR MANY MILLENNIA A DAILY HABIT FOR PEOPLE IN WESTERN CIVILIZATIONS LIVING AROUND THE MEDITERRANEAN SEA WHO WORKED INTENSIVELY AND SURVIVED WITH VERY FEW SEASONAL FOODS. A HIGH ADHERENCE TO THE TRADITIONAL MEDITERRANEAN DIET IS ASSOCIATED WITH LOW MORTALITY (HIGHER LONGEVITY) AND REDUCED RISK OF DEVELOPING CHRONIC DISEASES, INCLUDING CANCER, THE METABOLIC SYNDROME, DEPRESSION AND CARDIOVASCULAR AND NEURODEGENERATIVE DISEASES. REPORTS INDICATE THAT SOME DIETARY COMPONENTS, SUCH AS OLIVE OIL, ANTIOXIDANTS, OMEGA-3 AND -6 POLYUNSATURATED ACIDS, POLYPHENOLS AND FLAVONOIDS, MEDIATE BENEFICIAL ANTI-AGING EFFECTS (ANTI-CHRONIC DISEASES AND INCREASED LONGEVITY). EQUALLY, PHYSICAL ACTIVITY DISPLAYS A POSITIVE EFFECT, PRODUCING CALORIC CONSUMPTION AND REGULATION OF ADIPOSE AND PANCREATIC FUNCTION. THE PREDICTIVE STRENGTH OF SOME FOOD PATTERNS MAY BE A WAY OF DEVELOPING RECOMMENDATIONS FOR FOOD AND HEALTH POLICIES. THIS PAPER WILL DISCUSS SEVERAL WAYS OF IMPROVING HEALTH DURING MID-LIFE, FOCUSING ON CERTAIN GROUPS OF FUNCTIONAL FOODS AND HEALTHY HABITS WHICH MAY REDUCE OR PREVENT AGE-RELATED CHRONIC DISEASES.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10  3174  35 H19 LNCRNA IDENTIFIED AS A MASTER REGULATOR OF GENES THAT DRIVE UTERINE LEIOMYOMAS. UTERINE LEIOMYOMAS OR FIBROIDS (UFS) ARE BENIGN TUMORS CHARACTERIZED BY HYPERPLASTIC SMOOTH MUSCLE CELLS AND EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX (ECM). AFFLICTING ~80% OF WOMEN, AND SYMPTOMATIC IN 25%, UFS BRING TREMENDOUS SUFFERING AND ARE AN ECONOMIC BURDEN WORLDWIDE; THEY CAUSE SEVERE PAIN AND BLEEDING, AND ARE THE LEADING CAUSE OF HYSTERECTOMY. YET, UFS ARE SEVERELY UNDERSTUDIED WITH FEW EFFECTIVE TREATMENT OPTIONS AVAILABLE; THOSE THAT ARE AVAILABLE FREQUENTLY HAVE SIGNIFICANT SIDE EFFECTS SUCH AS MENOPAUSAL SYMPTOMS. RECENTLY, INTEGRATED GENOME-SCALE STUDIES HAVE REVEALED MUTATIONS AND FIBROID SUBTYPE-SPECIFIC EXPRESSION CHANGES IN KEY DRIVER GENES, WITH MED12 AND HMGA2 TOGETHER CONTRIBUTING TO NEARLY 90% OF ALL UFS, BUT THEIR REGULATION OF EXPRESSION IS POORLY CHARACTERIZED. HERE WE REPORT THAT THE EXPRESSION OF H19 LONG NONCODING RNA (LNCRNA) IS ABERRANTLY INCREASED IN UFS. USING CELL CULTURE AND GENOME-WIDE TRANSCRIPTOME AND METHYLATION PROFILING ANALYSES, WE DEMONSTRATE THAT H19 PROMOTES EXPRESSION OF MED12, HMGA2, AND KEY ECM-REMODELING GENES VIA MULTIPLE MECHANISMS INCLUDING A NEW CLASS OF EPIGENETIC MODIFICATION BY TET3. OUR RESULTS MARK THE FIRST EXAMPLE OF AN EVOLUTIONARILY CONSERVED LNCRNA IN PATHOGENESIS OF UFS AND REGULATION OF TET EXPRESSION. GIVEN THE LINK BETWEEN A H19 SINGLE-NUCLEOTIDE POLYMORPHISM (SNP) AND INCREASED RISK AND TUMOR SIZE OF UFS, AND THE EXISTENCE OF MULTIPLE FIBROID SUBTYPES DRIVEN BY KEY PATHWAY GENES REGULATED BY H19, WE PROPOSE A UNIFYING MECHANISM FOR PATHOGENESIS OF UTERINE FIBROIDS MEDIATED BY H19 AND IDENTIFY A PATHWAY FOR FUTURE EXPLORATION OF NOVEL TARGET THERAPIES FOR UTERINE LEIOMYOMAS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11  4147  27 MECHANISMS UNDERLYING BIOLOGICAL EFFECTS OF CRUCIFEROUS GLUCOSINOLATE-DERIVED ISOTHIOCYANATES/INDOLES: A FOCUS ON METABOLIC SYNDROME. AN INVERSE CORRELATION BETWEEN VEGETABLE CONSUMPTION AND THE INCIDENCE OF CANCER HAS LONG BEEN DESCRIBED. THIS PROTECTIVE EFFECT IS STRONGER WHEN CRUCIFEROUS VEGETABLES ARE SPECIFICALLY CONSUMED. THE BENEFICIAL PROPERTIES OF VEGETABLES ARE ATTRIBUTED TO THEIR BIOACTIVE COMPONENTS LIKE FIBER, ANTIOXIDANTS VITAMINS, ANTIOXIDANTS, MINERALS, AND PHENOLIC COMPOUNDS. CRUCIFEROUS VEGETABLES CONTAIN ALL THESE MOLECULES; HOWEVER, WHAT MAKES THEM DIFFERENT ARE THEIR SULFUROUS COMPONENTS, CALLED GLUCOSINOLATES, RESPONSIBLE FOR THEIR SPECIAL SMELL AND TASTE. GLUCOSINOLATES ARE INACTIVE BIOLOGICALLY IN THE ORGANISM BUT ARE HYDROLYZED BY THE ENZYME MYROSINASE RELEASED AS A RESULT OF CHEWING, LEADING TO THE FORMATION OF ACTIVE DERIVATIVES SUCH AS ISOTHIOCYANATES AND INDOLES. A CONSIDERABLE NUMBER OF IN VITRO AND IN VIVO STUDIES HAVE REPORTED THAT ISOTHIOCYANATES AND INDOLES ELICIT CHEMOPREVENTIVE POTENCY THROUGH MULTIPLE MECHANISMS THAT INCLUDE MODULATION OF PHASES I AND II DETOXIFICATION PATHWAY ENZYMES, REGULATION OF CELL CYCLE ARREST, AND CONTROL OF CELL GROWTH, INDUCTION OF APOPTOSIS, ANTIOXIDANT ACTIVITY, ANTI-ANGIOGENIC EFFECTS, AND EPIGENETIC REGULATION. NUCLEAR ERYTHROID 2-RELATED FACTOR 2 (NRF2) AND NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) ARE KEY AND CENTRAL REGULATORS IN ALL THESE PROCESSES WITH A MAIN ROLE IN OXIDATIVE STRESS AND INFLAMMATION CONTROL. IT HAS BEEN DESCRIBED THAT ISOTHIOCYANATES AND INDOLES REGULATE THEIR ACTIVITY DIRECTLY AND INDIRECTLY. TODAY, THE METABOLIC SYNDROME (CENTRAL OBESITY, INSULIN RESISTANCE, HYPERLIPIDEMIA, AND HYPERTENSION) IS RESPONSIBLE FOR A MAJORITY OF DEATHS WORLDWIDE. ALL COMPONENTS OF METABOLIC SYNDROME ARE CHARACTERIZED BY CHRONIC INFLAMMATION WITH DEREGULATION OF THE PI3K/AKT/MTOR, MAPK/EKR/JNK, NRF2, AND NF-KAPPAB SIGNALING PATHWAYS. THE EFFECTS OF GLSS DERIVATIVES CONTROLLING THESE PATHWAYS HAVE BEEN WIDELY DESCRIBED IN RELATION TO CANCER. CHANGES IN FOOD CONSUMPTION PATTERNS OBSERVED IN THE LAST DECADES TO HIGHER CONSUMPTION OF ULTRA-PROCESSED FOODS, WITH ELEVATION IN SIMPLE SUGAR AND SATURATED FAT CONTENTS AND LOWER CONSUMPTION OF VEGETABLES AND FRUITS HAVE BEEN DIRECTLY CORRELATED WITH METABOLIC SYNDROME PREVALENCE. IN THIS REVIEW, IT IS SUMMARIZED THE KNOWLEDGE REGARDING THE MECHANISMS BY WHICH CRUCIFEROUS GLUCOSINOLATE DERIVATIVES (ISOTHIOCYANATES AND INDOLES) DIRECTLY AND INDIRECTLY REGULATE THESE PATHWAYS. HOWEVER, THE REVIEW PLACES A SPECIAL FOCUS ON THE KNOWLEDGE OF THE EFFECTS OF GLUCOSINOLATES DERIVATIVES IN METABOLIC SYNDROME, SINCE THIS HAS NOT BEEN REVIEWED BEFORE.	2020	

12  6338  23 THE ROLE OF ENDOCRINE-DISRUPTING CHEMICALS IN UTERINE FIBROID PATHOGENESIS. PURPOSE OF REVIEW: UTERINE LEIOMYOMA (FIBROIDS) IS A GYNECOLOGIC DISORDER IMPACTING THE MAJORITY OF WOMEN IN THE UNITED STATES. WHEN SYMPTOMATIC, THESE NONCANCEROUS TUMORS CAN CAUSE SEVERE MORBIDITY INCLUDING PELVIC PAIN, MENORRHAGIA, AND INFERTILITY. ENDOCRINE-DISRUPTING CHEMICALS (EDCS) MAY REPRESENT A MODIFIABLE RISK FACTOR. THE AIM OF THIS REVIEW IS TO SUMMARIZE RECENT HUMAN AND EXPERIMENTAL EVIDENCE ON EDCS EXPOSURES AND FIBROIDS. RECENT FINDINGS: MULTIPLE EDCS ARE ASSOCIATED WITH FIBROID OUTCOMES AND/OR PROCESSES INCLUDING PHTHALATES, PARABENS, ENVIRONMENTAL PHENOLS, ALTERNATE PLASTICIZERS, DIETHYLSTILBESTROL, ORGANOPHOSPHATE ESTERS, AND TRIBUTYLTIN. EPIDEMIOLOGIC STUDIES SUGGEST EXPOSURE TO CERTAIN EDCS, SUCH AS DI-(2-ETHYLHXYL)-PHTHALATE (DEHP), ARE ASSOCIATED WITH INCREASED FIBROID RISK AND SEVERITY. BOTH HUMAN AND EXPERIMENTAL STUDIES INDICATE THAT EPIGENETIC PROCESSES MAY PLAY AN IMPORTANT ROLE IN LINKING EDCS TO FIBROID PATHOGENESIS. IN-VITRO AND IN-VIVO STUDIES SHOW THAT DEHP, BISPHENOL A, AND DIETHYLSTILBESTROL CAN IMPACT BIOLOGICAL PATHWAYS CRITICAL TO FIBROID PATHOGENESIS. SUMMARY: WHILE RESEARCH ON EDCS AND FIBROIDS IS STILL EVOLVING, RECENT EVIDENCE SUGGESTS EDC EXPOSURES MAY CONTRIBUTE TO FIBROID RISK AND PROGRESSION. FURTHER RESEARCH IS NEEDED TO EXAMINE THE IMPACTS OF EDC MIXTURES AND TO IDENTIFY CRITICAL BIOLOGICAL PATHWAYS AND WINDOWS OF EXPOSURE. THESE RESULTS COULD OPEN THE DOOR TO NEW PREVENTION STRATEGIES FOR FIBROIDS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13  1836  21 EFFECTS OF NUTRIENT AND BIOACTIVE FOOD COMPONENTS ON ALZHEIMER'S DISEASE AND EPIGENETIC. ALZHEIMER'S DISEASE (AD) IS THE MOST COMMON FORM OF DEMENTIA IN THE ELDERLY AND IS A CHRONIC NEURODEGENERATIVE DISEASE THAT IS BECOMING WIDESPREAD. FOR THIS REASON, IN RECENT YEARS FACTORS AFFECTING THE DEVELOPMENT, PROGRESSION AND COGNITIVE FUNCTION OF THE AD HAVE BEEN EMPHASIZED. NUTRIENTS AND OTHER BIOACTIVE NUTRIENTS ARE AMONG THE FACTORS THAT ARE EFFECTIVE IN AD. IN PARTICULAR, VITAMINS A, C AND E, VITAMINS B(1), B(6) AND B(12), FOLATE, MAGNESIUM, CHOLINE, INOSITOL, ANTHOCYANINS, ISOFLAVONES ETC. NUTRIENTS AND BIOACTIVE NUTRIENTS ARE KNOWN TO BE EFFECTIVE IN THE DEVELOPMENT OF AD. NUTRIENTS AND NUTRIENT COMPONENTS MAY ALSO HAVE AN EPIGENETIC EFFECT ON AD. AT THE SAME TIME, NUTRIENTS AND BIOACTIVE FOOD COMPONENTS SLOW DOWN THE PROGRESSION OF THE DISEASE. FOR THIS REASON, THE EFFECT OF NUTRIENTS AND FOOD COMPONENTS ON AD WAS EXAMINED IN THIS REVIEW.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
14  6436  30 THERAPEUTIC ACTIONS OF TEA PHENOLIC COMPOUNDS AGAINST OXIDATIVE STRESS AND INFLAMMATION AS CENTRAL MEDIATORS IN THE DEVELOPMENT AND PROGRESSION OF HEALTH PROBLEMS: A REVIEW FOCUSING ON MICRORNA REGULATION. MANY HEALTH PROBLEMS INCLUDING CHRONIC DISEASES ARE CLOSELY ASSOCIATED WITH OXIDATIVE STRESS AND INFLAMMATION. TEA HAS ABUNDANT PHENOLIC COMPOUNDS WITH VARIOUS HEALTH BENEFITS INCLUDING ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES. THIS REVIEW FOCUSES ON THE PRESENT UNDERSTANDING OF THE IMPACT OF TEA PHENOLIC COMPOUNDS ON THE EXPRESSION OF MIRNAS, AND ELUCIDATES THE BIOCHEMICAL AND MOLECULAR MECHANISMS UNDERLYING THE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL PROTECTIVE ACTIONS OF TEA PHENOLIC COMPOUNDS AGAINST OXIDATIVE STRESS- AND/OR INFLAMMATION-MEDIATED DISEASES. CLINICAL STUDIES SHOWED THAT DRINKING TEA OR TAKING CATECHIN SUPPLEMENT ON A DAILY BASIS PROMOTED THE ENDOGENOUS ANTIOXIDANT DEFENSE SYSTEM OF THE BODY WHILE INHIBITING INFLAMMATORY FACTORS. THE REGULATION OF CHRONIC DISEASES BASED ON EPIGENETIC MECHANISMS, AND THE EPIGENETIC-BASED THERAPIES INVOLVING DIFFERENT TEA PHENOLIC COMPOUNDS, HAVE BEEN INSUFFICIENTLY STUDIED. THE MOLECULAR MECHANISMS AND APPLICATION STRATEGIES OF MIR-27 AND MIR-34 INVOLVED IN OXIDATIVE STRESS RESPONSE AND MIR-126 AND MIR-146 INVOLVED IN INFLAMMATION PROCESS WERE PRELIMINARILY INVESTIGATED. SOME EMERGING EVIDENCE SUGGESTS THAT TEA PHENOLIC COMPOUNDS MAY PROMOTE EPIGENETIC CHANGES, INVOLVING NON-CODING RNA REGULATION, DNA METHYLATION, HISTONE MODIFICATION, UBIQUITIN AND SUMO MODIFICATIONS. HOWEVER, EPIGENETIC MECHANISMS AND EPIGENETIC-BASED DISEASE THERAPIES INVOLVING PHENOLIC COMPOUNDS FROM DIFFERENT TEAS, AND THE POTENTIAL CROSS-TALKS AMONG THE EPIGENETIC EVENTS, REMAIN UNDERSTUDIED.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15  4396  24 MODULATION OF CHRONIC INFLAMMATION BY QUERCETIN: THE BENEFICIAL EFFECTS ON OBESITY. OBESITY HAS BECOME A MAJOR RISK FACTOR FOR THE DEVELOPMENT OF CHRONIC DISEASES SUCH AS INSULIN RESISTANCE, TYPE 2 DIABETES MELLITUS, AND CARDIOVASCULAR DISEASE. MOREOVER, OBESITY INDUCES CHRONIC INFLAMMATION IN ADIPOSE TISSUE, LIVER, SKELETAL MUSCLE, AND THE VASCULAR SYSTEM. QUERCETIN IS THE MAJOR REPRESENTATIVE OF THE FLAVONOID SUBCLASS OF FLAVONOLS, WHICH IS UBIQUITOUSLY CONTAINED WITHIN NATURAL PLANTS SUCH AS GREEN TEA, AND VEGETABLES, INCLUDING ONIONS AND APPLES. RESEARCHERS HAVE FOCUSED GREATER ATTENTION TO THE BENEFICIAL PHYSIOLOGICAL ROLES OF QUERCETIN, WHICH HAS ANTI-OXIDATIVE, ANTI-INFLAMMATORY, AND ANTI-FIBROTIC EFFECTS ON INSULIN RESISTANCE AND ATHEROSCLEROSIS IN OBESITY-RELATED DISEASES. ALSO, THE ANTI-INFLAMMATORY EFFECTS OF QUERCETIN ON INTESTINAL MICROBIOTA HAVE BEEN DEMONSTRATED IN OBESITY. IN ADDITION, THERE IS INCREASING EVIDENCE THAT QUERCETIN IS ASSOCIATED WITH EPIGENETIC ACTIVITIES IN CANCER, AND IN MATERNAL UNDERNUTRITION DURING GESTATION AND LACTATION. IN THIS REVIEW, WE FOCUS ON THE CHEMICAL PROPERTIES OF QUERCETIN, ITS DIETARY SOURCES IN OBESITY, AND ITS ANTI-INFLAMMATORY EFFECTS ON INSULIN RESISTANCE, ATHEROSCLEROSIS, INTESTINAL MICROBIOTA, AND MATERNAL UNDER-NUTRITION WITH EPIGENETIC ACTIVITY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  2295  25 EPIGENETIC REGULATION IN UTERINE FIBROIDS-THE ROLE OF TEN-ELEVEN TRANSLOCATION ENZYMES AND THEIR POTENTIAL THERAPEUTIC APPLICATION. UTERINE FIBROIDS (UFS) ARE MONOCLONAL, BENIGN TUMORS THAT CONTAIN ABNORMAL SMOOTH MUSCLE CELLS AND THE ACCUMULATION OF EXTRACELLULAR MATRIX (ECM). ALTHOUGH BENIGN, UFS ARE A MAJOR SOURCE OF GYNECOLOGIC AND REPRODUCTIVE DYSFUNCTION, RANGING FROM MENORRHAGIA AND PELVIC PAIN TO INFERTILITY, RECURRENT MISCARRIAGE, AND PRETERM LABOR. MANY RISK FACTORS ARE INVOLVED IN THE PATHOGENESIS OF UFS VIA GENETIC AND EPIGENETIC MECHANISMS. THE LATTER INVOLVING DNA METHYLATION AND DEMETHYLATION REACTIONS PROVIDE SPECIFIC DNA METHYLATION PATTERNS THAT REGULATE GENE EXPRESSION. ACTIVE DNA DEMETHYLATION REACTIONS MEDIATED BY TEN-ELEVEN TRANSLOCATION PROTEINS (TETS) AND ELEVATED LEVELS OF 5-HYDROXYMETHYLCYTOSINE HAVE BEEN SUGGESTED TO BE INVOLVED IN UF FORMATION. THIS REVIEW PAPER SUMMARIZES THE MAIN FINDINGS REGARDING THE FUNCTION OF TET ENZYMES AND THEIR ACTIVITY DYSREGULATION THAT MAY TRIGGER THE DEVELOPMENT OF UFS. UNDERSTANDING THE ROLE THAT EPIGENETICS PLAYS IN THE PATHOGENESIS OF UFS MAY POSSIBLY LEAD TO A NEW TYPE OF PHARMACOLOGICAL FERTILITY-SPARING TREATMENT METHOD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17  4805  25 OBESITY AND METABOLIC COMORBIDITIES: ENVIRONMENTAL DISEASES? OBESITY AND METABOLIC COMORBIDITIES REPRESENT INCREASING HEALTH PROBLEMS. ENDOCRINE DISRUPTING COMPOUNDS (EDCS) ARE EXOGENOUS AGENTS THAT CHANGE ENDOCRINE FUNCTION AND CAUSE ADVERSE HEALTH EFFECTS. MOST EDCS ARE SYNTHETIC CHEMICALS; SOME ARE NATURAL FOOD COMPONENTS AS PHYTOESTROGENS. PEOPLE ARE EXPOSED TO COMPLEX MIXTURES OF CHEMICALS THROUGHOUT THEIR LIVES. EDCS IMPACT HORMONE-DEPENDENT METABOLIC SYSTEMS AND BRAIN FUNCTION. LABORATORY AND HUMAN STUDIES PROVIDE COMPELLING EVIDENCE THAT HUMAN CHEMICAL CONTAMINATION CAN PLAY A ROLE IN OBESITY EPIDEMIC. CHEMICAL EXPOSURES MAY INCREASE THE RISK OF OBESITY BY ALTERING THE DIFFERENTIATION OF ADIPOCYTES. EDCS CAN ALTER METHYLATION PATTERNS AND NORMAL EPIGENETIC PROGRAMMING IN CELLS. OXIDATIVE STRESS MAY BE INDUCED BY MANY OF THESE CHEMICALS, AND ACCUMULATING EVIDENCE INDICATES THAT IT PLAYS IMPORTANT ROLES IN THE ETIOLOGY OF CHRONIC DISEASES. THE INDIVIDUAL SENSITIVITY TO CHEMICALS IS VARIABLE, DEPENDING ON ENVIRONMENT AND ABILITY TO METABOLIZE HAZARDOUS CHEMICALS. A NUMBER OF GENES, ESPECIALLY THOSE REPRESENTING ANTIOXIDANT AND DETOXIFICATION PATHWAYS, HAVE POTENTIAL APPLICATION AS BIOMARKERS OF RISK ASSESSMENT. THE POTENTIAL HEALTH EFFECTS OF COMBINED EXPOSURES MAKE THE RISK ASSESSMENT PROCESS MORE COMPLEX COMPARED TO THE ASSESSMENT OF SINGLE CHEMICALS. TECHNIQUES AND METHODS NEED TO BE FURTHER DEVELOPED TO FILL DATA GAPS AND INCREASE THE KNOWLEDGE ON HARMFUL EXPOSURE COMBINATIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
18  3576  31 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	
                                                                                                                                                                                                                                         
19  1802  23 EFFECT OF PATERNAL DIET ON SPERMATOGENESIS AND OFFSPRING HEALTH: FOCUS ON EPIGENETICS AND INTERVENTIONS WITH FOOD BIOACTIVE COMPOUNDS. INFERTILITY IS A GROWING PUBLIC HEALTH PROBLEM. CONSUMPTION OF ANTIOXIDANT BIOACTIVE FOOD COMPOUNDS (BFCS) THAT INCLUDE MICRONUTRIENTS AND NON-NUTRIENTS HAS BEEN HIGHLIGHTED AS A POTENTIAL STRATEGY TO PROTECT AGAINST OXIDATIVE AND INFLAMMATORY DAMAGE IN THE MALE REPRODUCTIVE SYSTEM INDUCED BY OBESITY, ALCOHOL, AND TOXICANTS AND, THUS, IMPROVE SPERMATOGENESIS AND THE FERTILITY PARAMETERS. PATERNAL CONSUMPTION OF SUCH DIETARY COMPOUNDS COULD NOT ONLY BENEFIT THE FATHERS BUT THEIR OFFSPRING AS WELL. STUDIES IN THE NEW FIELD OF PATERNAL ORIGINS OF HEALTH AND DISEASE SHOW THAT PATERNAL MALNUTRITION CAN ALTER SPERM EPIGENOME, AND THIS CAN ALTER FETAL DEVELOPMENT AND PROGRAM AN INCREASED RISK OF METABOLIC DISEASES AND BREAST CANCER IN ADULTHOOD. BFCS, SUCH AS ASCORBIC ACID, ALPHA-TOCOPHEROL, POLYUNSATURATED FATTY ACIDS, TRACE ELEMENTS, CARNITINES, N-ACETYLCYSTEINE, AND COENZYME Q10, HAVE BEEN SHOWN TO IMPROVE MALE GAMETOGENESIS, MODULATE EPIGENETICS OF GERM CELLS, AND THE EPIGENETIC SIGNATURE OF THE OFFSPRING, RESTORING OFFSPRING METABOLIC HEALTH INDUCED BY STRESSORS DURING EARLY LIFE. THIS INDICATES THAT, FROM A FATHER'S PERSPECTIVE, PRECONCEPTION IS A VALUABLE WINDOW OF OPPORTUNITY TO START POTENTIAL NUTRITIONAL INTERVENTIONS WITH THESE BFCS TO MAXIMIZE SPERM EPIGENETIC INTEGRITY AND PROMOTE ADEQUATE FETAL GROWTH AND DEVELOPMENT, THUS PREVENTING CHRONIC DISEASE IN ADULTHOOD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20  6290  27 THE POTENTIAL ROLE OF NUTRITIONAL GENOMICS TOOLS IN VALIDATING HIGH HEALTH FOODS FOR CANCER CONTROL: BROCCOLI AS EXAMPLE. NUTRITIONAL GENOMICS REFLECTS GENE/NUTRIENT INTERACTIONS, UTILISING HIGH-THROUGHPUT GENOMIC TOOLS IN NUTRITION RESEARCH. THE FIELD ALSO CONSIDERS THE CONTRIBUTION OF INDIVIDUAL GENOTYPES TO WELLNESS AND THE RISK OF CHRONIC DISEASE (NUTRIGENETICS), AND HOW SUCH GENETIC PREDISPOSITION MAY BE MODIFIED BY APPROPRIATE DIETS. FOR EXAMPLE, HIGH CONSUMPTION OF BRASSICACEOUS VEGETABLES, INCLUDING BROCCOLI, HAS REGULARLY ASSOCIATED WITH LOW CANCER RISK. BIOACTIVE CHEMICALS IN BROCCOLI INCLUDE GLUCOSINOLATES, PLANT PIGMENTS INCLUDING KAEMPFEROL, QUERCETIN, LUTEIN AND CAROTENOIDS, VARIOUS VITAMINS, MINERALS AND AMINO ACIDS. CANCER PREVENTION IS HYPOTHESISED TO ACT THROUGH VARIOUS MECHANISMS INCLUDING MODULATION OF XENOBIOTIC METABOLISING ENZYMES, NF-E2 P45-RELATED FACTOR-2 (NRF2)-MEDIATED STRESS-RESPONSE MECHANISMS, AND PROTECTION AGAINST GENOMIC INSTABILITY. BROCCOLI AND BROCCOLI EXTRACTS ALSO REGULATE THE PROGRESSION OF CANCER THROUGH ANTI-INFLAMMATORY EFFECTS, EFFECTS ON SIGNAL TRANSDUCTION, EPIGENETIC EFFECTS AND MODULATION OF THE COLONIC MICROFLORA. HUMAN INTERVENTION STUDIES WITH BROCCOLI AND RELATED FOODS, USING STANDARD BIOMARKER METHODOLOGIES, REVEAL PART OF A COMPLEX PICTURE. NUTRIGENOMIC APPROACHES, ESPECIALLY TRANSCRIPTOMICS, ENABLE SIMULTANEOUS STUDY OF VARIOUS SIGNALLING PATHWAYS AND NETWORKS. PHENOTYPIC, GENETIC AND/OR METABOLIC STRATIFICATION MAY IDENTIFY INDIVIDUALS MOST LIKELY TO RESPOND POSITIVELY TO FOODS OR DIETS. JOINTLY, THESE TECHNOLOGIES CAN PROVIDE PROOF OF HUMAN EFFICACY, AND MAY BE ESSENTIAL TO ENSURE EFFECTIVE MARKET TRANSFER AND UPTAKE OF BROCCOLI AND RELATED FOODS.	2012