1 3359 128 HISTONE H4 LYSINE 16 ACETYLATION CONTROLS CENTRAL CARBON METABOLISM AND DIET-INDUCED OBESITY IN MICE. NONCOMMUNICABLE DISEASES (NCDS) ACCOUNT FOR OVER 70% OF DEATHS WORLD-WIDE. PREVIOUS WORK HAS LINKED NCDS SUCH AS TYPE 2 DIABETES (T2D) TO DISRUPTION OF CHROMATIN REGULATORS. HOWEVER, THE EXACT MOLECULAR ORIGINS OF THESE CHRONIC CONDITIONS REMAIN ELUSIVE. HERE, WE IDENTIFY THE H4 LYSINE 16 ACETYLTRANSFERASE MOF AS A CRITICAL REGULATOR OF CENTRAL CARBON METABOLISM. HIGH-THROUGHPUT METABOLOMICS UNVEIL A SYSTEMIC AMINO ACID AND CARBOHYDRATE IMBALANCE IN MOF DEFICIENT MICE, MANIFESTING IN T2D PREDISPOSITION. ORAL GLUCOSE TOLERANCE TESTING (OGTT) REVEALS DEFECTS IN GLUCOSE ASSIMILATION AND INSULIN SECRETION IN THESE ANIMALS. FURTHERMORE, MOF DEFICIENT MICE ARE RESISTANT TO DIET-INDUCED FAT GAIN DUE TO DEFECTS IN GLUCOSE UPTAKE IN ADIPOSE TISSUE. MOF-MEDIATED H4K16AC DEPOSITION CONTROLS EXPRESSION OF THE MASTER REGULATOR OF GLUCOSE METABOLISM, PPARG AND THE ENTIRE DOWNSTREAM TRANSCRIPTIONAL NETWORK. GLUCOSE UPTAKE AND LIPID STORAGE CAN BE RECONSTITUTED IN MOF-DEPLETED ADIPOCYTES IN VITRO BY ECTOPIC GLUT4 EXPRESSION, PPARGAMMA AGONIST THIAZOLIDINEDIONE (TZD) TREATMENT OR SIRT1 INHIBITION. HENCE, CHRONIC IMBALANCE IN H4K16AC PROMOTES A DESTABILISATION OF METABOLISM TRIGGERING THE DEVELOPMENT OF A METABOLIC DISORDER, AND ITS MAINTENANCE PROVIDES AN UNPRECEDENTED REGULATORY EPIGENETIC MECHANISM CONTROLLING DIET-INDUCED OBESITY. 2021 2 4519 19 MULTI-OMICS IN CROHN'S DISEASE: NEW INSIGHTS FROM INSIDE. CROHN'S DISEASE (CD) IS AN INFLAMMATORY BOWEL DISEASE (IBD) WITH COMPLEX CLINICAL MANIFESTATIONS SUCH AS CHRONIC DIARRHEA, WEIGHT LOSS AND HEMATOCHEZIA. DESPITE THE INCREASING INCIDENCE WORLDWIDE, CURE OF CD REMAINS EXTREMELY DIFFICULT. THE RAPID DEVELOPMENT OF HIGH-THROUGHPUT SEQUENCING TECHNOLOGY WITH INTEGRATED-OMICS ANALYSES IN RECENT YEARS HAS PROVIDED A NEW MEANS FOR EXPLORING THE PATHOGENESIS, MINING THE BIOMARKERS AND DESIGNING TARGETED PERSONALIZED THERAPEUTICS OF CD. HOST GENOMICS AND EPIGENOMICS UNVEIL HEREDITY-RELATED MECHANISMS OF SUSCEPTIBLE INDIVIDUALS, WHILE MICROBIOME AND METABOLOMICS MAP HOST-MICROBE INTERACTIONS IN CD PATIENTS. PROTEOMICS SHOWS GREAT POTENTIAL IN SEARCHING FOR PROMISING BIOMARKERS. NONETHELESS, SINGLE OMICS TECHNOLOGY CANNOT HOLISTICALLY CONNECT THE MECHANISMS WITH HETEROGENEITY OF PATHOLOGICAL BEHAVIOR IN CD. THE RISE OF MULTI-OMICS ANALYSIS INTEGRATES GENETIC/EPIGENETIC PROFILES WITH PROTEIN/MICROBIAL METABOLITE FUNCTIONALITY, PROVIDING NEW HOPE FOR COMPREHENSIVE AND IN-DEPTH EXPLORATION OF CD. HEREIN, WE EMPHASIZED THE DIFFERENT OMICS FEATURES AND APPLICATIONS OF CD AND DISCUSSED THE CURRENT RESEARCH AND LIMITATIONS OF MULTI-OMICS IN CD. THIS REVIEW WILL UPDATE AND DEEPEN OUR UNDERSTANDING OF CD FROM INTEGRATION OF BROAD OMICS SPECTRA AND WILL PROVIDE NEW EVIDENCE FOR TARGETED INDIVIDUALIZED THERAPEUTICS. 2023 3 4034 32 M6A METHYLATION PROMOTES WHITE-TO-BEIGE FAT TRANSITION BY FACILITATING HIF1A TRANSLATION. OBESITY MAINLY RESULTS FROM A CHRONIC ENERGY IMBALANCE. PROMOTING BROWNING OF WHITE ADIPOCYTES IS A PROMISING STRATEGY TO ENHANCE ENERGY EXPENDITURE AND COMBAT OBESITY. N6-METHYLADENOSINE (M6A), THE MOST ABUNDANT MRNA MODIFICATION IN EUKARYOTES, PLAYS AN IMPORTANT ROLE IN REGULATING ADIPOGENESIS. HOWEVER, WHETHER M6A REGULATES WHITE ADIPOCYTE BROWNING WAS UNKNOWN. HERE, WE REPORT THAT ADIPOSE TISSUE-SPECIFIC DELETION OF FTO, AN M6A DEMETHYLASE, PREDISPOSES MICE TO PREVENT HIGH-FAT DIET (HFD)-INDUCED OBESITY BY ENHANCING ENERGY EXPENDITURE. ADDITIONALLY, DELETION OF FTO IN VITRO PROMOTES THERMOGENESIS AND WHITE-TO-BEIGE ADIPOCYTE TRANSITION. MECHANISTICALLY, FTO DEFICIENCY INCREASES THE M6A LEVEL OF HIF1A MRNA, WHICH IS RECOGNIZED BY M6A-BINDING PROTEIN YTHDC2, FACILITATING MRNA TRANSLATION AND INCREASING HIF1A PROTEIN ABUNDANCE. HIF1A ACTIVATES THE TRANSCRIPTION OF THERMOGENIC GENES, INCLUDING PPAGGC1A, PRDM16, AND PPARG, THEREBY PROMOTING UCP1 EXPRESSION AND THE BROWNING PROCESS. COLLECTIVELY, THESE RESULTS UNVEIL AN EPIGENETIC MECHANISM BY WHICH M6A-FACILITATED HIF1A EXPRESSION CONTROLS BROWNING OF WHITE ADIPOCYTES AND THERMOGENESIS, PROVIDING A POTENTIAL TARGET TO COUNTERACT OBESITY AND METABOLIC DISEASE. 2021 4 5961 24 TELOMERE LENGTH IN PRETERM INFANTS: A PROMISING BIOMARKER OF EARLY ADVERSITY AND CARE IN THE NEONATAL INTENSIVE CARE UNIT? PRETERM INFANTS PRESENT AN IMMATURE NEUROBEHAVIORAL PROFILE AT BIRTH, EVEN IN ABSENCE OF SEVERE BRAIN INJURIES AND PERINATAL COMPLICATIONS. AS SUCH, THEY REQUIRE A LONG-LASTING HOSPITALIZATION IN THE NEONATAL INTENSIVE CARE UNIT (NICU), WHICH IS THOUGHT TO GRANT AT-RISK NEWBORNS' SURVIVAL, BUT STILL ENTAILS A NUMBER OF PHYSICAL, PAINFUL, AND SOCIO-EMOTIONAL STRESSORS. HENCE, PRETERM BIRTH AND NICU STAY REPRESENT AN EARLY ADVERSE EXPERIENCE, WHICH HAS BEEN LINKED TO DETRIMENTAL CONSEQUENCES FOR NEUROLOGICAL, NEURO-ENDOCRINAL, BEHAVIORAL, AND SOCIO-EMOTIONAL DEVELOPMENT, AS WELL AS TO DISEASE LATER IN LIFE. RECENT ADVANCES IN THE BEHAVIORAL EPIGENETIC FIELD ARE HELPING US TO UNVEIL THE POTENTIAL MECHANISMS THROUGH WHICH EARLY NICU-RELATED STRESS MAY LEAD TO NEGATIVE DEVELOPMENTAL OUTCOMES. FROM THIS PERSPECTIVE, TELOMERE REGULATION MIGHT BE A KEY PROGRAMMING MECHANISM. TELOMERES ARE THE TERMINAL PORTION OF CHROMOSOMES AND ARE KNOWN TO GET SHORTER WITH AGE. MOREOVER, TELOMERE LENGTH (TL) IS AFFECTED BY THE EXPOSURE TO STRESS DURING EARLY DEVELOPMENT. AS SUCH, TL MIGHT BE AN INNOVATIVE BIOMARKER OF EARLY ADVERSE EXPOSURES IN YOUNG INFANTS AND CHILDREN. UNFORTUNATELY, THERE IS PAUCITY OF STUDIES INVESTIGATING TL IN POPULATIONS OF PRETERM INFANTS AND ITS ASSOCIATION WITH KNOWN NICU-RELATED STRESSORS REMAINS UNEXPLORED. IN THE PRESENT PAPER, THE POTENTIAL RELEVANCE OF TL FOR RESEARCH AND CLINICAL WORK WITH PRETERM INFANTS WILL BE UNDERLINED IN THE LIGHT OF RECENT CONTRIBUTIONS LINKING PROGRESSIVE TELOMERE SHORTENING AND EARLY EXPOSURE TO ADVERSE EXPERIENCES AND STRESSFUL ENVIRONMENTS IN HUMANS. FINALLY, INSIGHTS WILL BE PROVIDED TO GUIDE CLINICALLY RELEVANT TRANSLATIONAL RESEARCH ON TL IN THE FIELD OF VPT BIRTH AND NICU STAY. 2017 5 1106 16 COMBINED TOXICITY OF ENDOCRINE-DISRUPTING CHEMICALS: A REVIEW. THE COMBINED TOXICOLOGICAL ASSESSMENT PROVIDES A REALISTIC APPROACH FOR HAZARD EVALUATION OF CHEMICAL COCKTAILS THAT CO-EXISTED IN THE ENVIRONMENT. THIS REVIEW PROVIDES A HOLISTIC INSIGHT INTO THE STUDIES HIGHLIGHTING THE MIXTURE TOXICITY OF THE ENDOCRINE-DISRUPTING CHEMICALS (EDCS), ESPECIALLY FOCUSING ON THE SCREENING OF BIOCHEMICAL PATHWAYS AND OTHER TOXICOGENETIC ENDPOINTS. REVIEWED LITERATURE SHOWED THAT NUMEROUS MULTIPLEXED TOXICOGENOMIC TECHNIQUES WERE APPLIED TO DETERMINE REPRODUCTIVE EFFECTS IN VERTEBRATES, BUT LIMITED STUDIES WERE FOUND IN NON-MAMMALIAN SPECIES AFTER MIXTURE CHEMICAL EXPOSURE. FURTHER, WE FOUND THAT THE EXPERIMENTAL DESIGN AND CONCENTRATION SELECTION ARE THE TWO IMPORTANT PARAMETERS IN MIXTURE TOXICITY STUDIES THAT SHOULD BE TIME- AND COST-EFFECTIVE, HIGHLY PRECISE, AND ENVIRONMENTALLY RELEVANT. A SUMMARY OF EDC MIXTURES AFFECTING THE THYROID AXIS, ESTROGEN AXIS, ANDROGEN AXIS, GROWTH STRESS, AND IMMUNE SYSTEM VIA IN VIVO BIOASSAYS WAS ALSO PRESENTED. IT IS INTERESTING TO MENTION THAT MAJORITY OF ESTROGENIC EFFECTS OF THE MIXTURES WERE SEX-DEPENDENT, PARTICULARLY OBSERVED IN MALE FISH AS COMPARED TO FEMALE FISH. FURTHER, THE ANDROGEN AXIS WAS PERTURBED WITH SERIOUS MALFORMATIONS IN MALE RAT TESTIS (EPIDIDYMAL OR GUBERNACULAR LESIONS, AND DECIDUOUS SPERMATIDS). ALSO, TRANSGENERATIONAL EPIGENETIC EFFECTS WERE PROMOTED IN THE F(3) AND F(4) GENERATIONS IN THE FORM OF DNA METHYLATION EPIMUTATIONS IN SPERM, INCREASING POLYCYSTIC OVARIES AND REDUCING THE OFFSPRING. SIMILARLY, INCREASED OXIDATIVE STRESS, HIGH ANTIOXIDANT ENZYMATIC ACTIVITIES, DISTURBED ESTROUS CYCLE, AND DECREASED STEROIDOGENESIS WERE THE COMMONLY FOUND EFFECTS AFTER ACUTE OR CHRONIC EXPOSURE TO EDC MIXTURES. IMPORTANTLY, THE CONCENTRATION ADDITION (CA) AND INDEPENDENT ACTION (IA) MODELS BECAME MORE PREVALENT AND SUITABLE PREDICTIVE MODELS TO UNVEIL THE PROMINENCE OF SYNERGISTIC ESTROGENIC AND ANTI-ANDROGENIC EFFECTS OF CHEMICAL MIXTURES. MORE IMPORTANTLY, THIS REVIEW ENCOMPASSES THE RESEARCH CHALLENGES AND GAPS IN THE EXISTING KNOWLEDGE AND SPECIFIC FUTURE RESEARCH PERSPECTIVES ON COMBINED TOXICITY. 2021 6 4651 25 NEUROPROGRESSION IN SCHIZOPHRENIA: PATHWAYS UNDERPINNING CLINICAL STAGING AND THERAPEUTIC COROLLARIES. OBJECTIVE: WHILST DOPAMINERGIC DYSFUNCTION REMAINS A NECESSARY COMPONENT INVOLVED IN THE PATHOGENESIS OF SCHIZOPHRENIA, OUR CURRENT PHARMACOLOGICAL ARMOURY OF DOPAMINE ANTAGONISTS DOES LITTLE TO CONTROL THE NEGATIVE SYMPTOMS OF SCHIZOPHRENIA. THIS SUGGESTS OTHER PATHOLOGICAL PROCESSES MUST BE IMPLICATED. THIS PAPER AIMS TO ELABORATE ON SUCH THEORIES. METHODS: DATA FOR THIS REVIEW WERE SOURCED FROM THE ELECTRONIC DATABASE PUBMED, AND WAS NOT LIMITED BY LANGUAGE OR DATE OF PUBLICATION. RESULTS: IT HAS BEEN SUGGESTED THAT MULTIPLE 'HITS' MAY BE REQUIRED TO UNVEIL THE CLINICAL SYNDROME IN SUSCEPTIBLE INDIVIDUALS. SUCH HITS POTENTIALLY FIRST OCCUR IN UTERO, LEADING TO NEURONAL DISRUPTION, EPIGENETIC CHANGES AND THE ESTABLISHMENT OF AN ABNORMAL INFLAMMATORY RESPONSE. THE DEVELOPMENT OF SCHIZOPHRENIA MAY THEREFORE POTENTIALLY BE VIEWED AS A NEUROPROGRESSIVE RESPONSE TO THESE EARLY STRESSORS, DRIVEN ON BY CHANGES IN TRYPTOPHAN CATABOLITE (TRYCAT) METABOLISM, REACTIVE OXYGEN SPECIES HANDLING AND N-METHYL D-ASPARTATE (NMDA) CIRCUITRY. GIVEN THE POTENTIAL FOR SUCH PROGRESSION OVER TIME, IT IS PRUDENT TO EXPLORE THE NEW TREATMENT STRATEGIES WHICH MAY BE IMPLEMENTED BEFORE SUCH CHANGES BECOME ESTABLISHED. CONCLUSIONS: OUTSIDE OF THE DOPAMINERGIC MODEL, THE POTENTIAL PATHOGENESIS OF SCHIZOPHRENIA HAS YET TO BE FULLY ELUCIDATED, BUT COMMON THEMES INCLUDE NEUROPIL SHRINKAGE, THE DEVELOPMENT OF ABNORMAL NEURONAL CIRCUITRY, AND A CHRONIC INFLAMMATORY STATE WHICH FURTHER DISRUPTS NEURONAL FUNCTION. WHILST SOME EARLY NON-DOPAMINERGIC TREATMENTS SHOW PROMISE, NONE HAVE YET TO BE FULLY STUDIED IN APPROPRIATELY STRUCTURED RANDOMIZED CONTROLLED TRIALS AND THEY REMAIN LITTLE MORE THAN POTENTIAL ATTRACTIVE TARGETS. 2014 7 665 27 BLOOD TRANSCRIPTOMICS OF DRUG-NAIVE SPORADIC PARKINSON'S DISEASE PATIENTS. BACKGROUND: PARKINSON'S DISEASE (PD) IS A CHRONIC PROGRESSIVE NEURODEGENERATIVE DISORDER THAT IS CLINICALLY DEFINED IN TERMS OF MOTOR SYMPTOMS. THESE ARE PRECEDED BY PRODROMAL NON-MOTOR MANIFESTATIONS THAT PROVE THE SYSTEMIC NATURE OF THE DISEASE. IDENTIFYING GENES AND PATHWAYS ALTERED IN LIVING PATIENTS PROVIDE NEW INFORMATION ON THE DIAGNOSIS AND PATHOGENESIS OF SPORADIC PD. METHODS: CHANGES IN GENE EXPRESSION IN THE BLOOD OF 40 SPORADIC PD PATIENTS AND 20 HEALTHY CONTROLS ("DISCOVERY SET") WERE ANALYZED BY TAKING ADVANTAGE OF THE AFFYMETRIX PLATFORM. PATIENTS WERE AT THE ONSET OF MOTOR SYMPTOMS AND BEFORE INITIATING ANY PHARMACOLOGICAL TREATMENT. DATA ANALYSIS WAS PERFORMED BY APPLYING RANKING-PRINCIPAL COMPONENT ANALYSIS, PUMA AND SIGNIFICANCE ANALYSIS OF MICROARRAYS. FUNCTIONAL ANNOTATIONS WERE ASSIGNED USING GO, DAVID, GSEA TO UNVEIL SIGNIFICANT ENRICHED BIOLOGICAL PROCESSES IN THE DIFFERENTIALLY EXPRESSED GENES. THE EXPRESSIONS OF SELECTED GENES WERE VALIDATED USING RT-QPCR AND SAMPLES FROM AN INDEPENDENT COHORT OF 12 PATIENTS AND CONTROLS ("VALIDATION SET"). RESULTS: GENE EXPRESSION PROFILING OF BLOOD SAMPLES DISCRIMINATES PD PATIENTS FROM HEALTHY CONTROLS AND IDENTIFIES DIFFERENTIALLY EXPRESSED GENES IN BLOOD. THE MAJORITY OF THESE ARE ALSO PRESENT IN DOPAMINERGIC NEURONS OF THE SUBSTANTIA NIGRA, THE KEY SITE OF NEURODEGENERATION. TOGETHER WITH NEURONAL APOPTOSIS, LYMPHOCYTE ACTIVATION AND MITOCHONDRIAL DYSFUNCTION, ALREADY FOUND IN PREVIOUS ANALYSIS OF PD BLOOD AND POST-MORTEM BRAINS, WE UNVEILED TRANSCRIPTOME CHANGES ENRICHED IN BIOLOGICAL TERMS RELATED TO EPIGENETIC MODIFICATIONS INCLUDING CHROMATIN REMODELING AND METHYLATION. CANDIDATE TRANSCRIPTS AS CBX5, TCF3, MAN1C1 AND DOCK10 WERE VALIDATED BY RT-QPCR. CONCLUSIONS: OUR DATA SUPPORT THE USE OF BLOOD TRANSCRIPTOMICS TO STUDY NEURODEGENERATIVE DISEASES. IT IDENTIFIES CHANGES IN CRUCIAL COMPONENTS OF CHROMATIN REMODELING AND METHYLATION MACHINERIES AS EARLY EVENTS IN SPORADIC PD SUGGESTING EPIGENETICS AS TARGET FOR THERAPEUTIC INTERVENTION. 2015 8 2396 23 EPIGENETIC REPROGRAMMING IN PERIODONTAL DISEASE: DYNAMIC CROSSTALK WITH POTENTIAL IMPACT IN ONCOGENESIS. PERIODONTITIS IS A CHRONIC MULTIFACTORIAL IN FL AMMATORY DISEASE ASSOCIATED WITH MICROBIAL DYSBIOSIS AND CHARACTERIZED BY PROGRESSIVE DESTRUCTION OF THE PERIODONTAL TISSUES. SUCH CHRONIC INFECTIOUS INFLAMMATORY DISEASE IS RECOGNIZED AS A MAJOR PUBLIC HEALTH PROBLEM WORLDWIDE WITH MEASURABLE IMPACT IN SYSTEMIC HEALTH. IT HAS BECOME EVIDENT THAT THE PERIODONTAL DISEASE PHENOTYPES ARE NOT ONLY DETERMINED BY THE MICROBIOME EFFECT, BUT THE EXTENT OF THE TISSUE RESPONSE IS ALSO DRIVEN BY THE HOST GENOME AND EPIGENOME PATTERNS RESPONDING TO VARIOUS ENVIRONMENTAL EXPOSURES. MORE RECENTLY THERE IS MOUNTING EVIDENCE INDICATING THAT EPIGENETIC REPROGRAMMING IN RESPONSE TO COMBINED INTRINSIC AND ENVIRONMENTAL EXPOSURES, MIGHT BE PARTICULARLY RELEVANT DUE ITS PLASTICITY AND POTENTIAL APPLICATION TOWARDS PRECISION HEALTH. THE COMPLEX EPIGENETIC CROSSTALK IS REFLECTED IN THE PROGNOSIS AND PROGRESS OF PERIODONTAL DISEASES AND MAY ALSO LEAD TO A FAVORABLE LANDSCAPE FOR CANCER DEVELOPMENT. THIS REVIEW DISCUSSES EPIGENOMICS MODIFICATIONS FOCUSING ON THE ROLE OF DNA METHYLATION AND PATHWAYS LINKING MICROBIAL INFECTION AND INFLAMMATORY PATHWAYS, WHICH ARE ALSO ASSOCIATED WITH CARCINOGENESIS. THERE IS A MORE CLEAR VISION WHEREAS 'OMICS' TECHNOLOGIES APPLIED TO UNVEIL RELEVANT EPIGENETIC FACTORS COULD PLAY A SIGNIFICANT ROLE IN THE TREATMENT OF PERIODONTAL DISEASE IN A PERSONALIZED MODE, EVIDENCING THAT PUBLIC HEALTH APPROACH SHOULD COEXIST WITH PRECISION INDIVIDUALIZED TREATMENT. 2020 9 4515 23 MULTI-OMICS APPROACHES FOR PRECISION OBESITY MANAGEMENT : POTENTIALS AND LIMITATIONS OF OMICS IN PRECISION PREVENTION, TREATMENT AND RISK REDUCTION OF OBESITY. INTRODUCTION: OBESITY IS A MULTIFACTORIAL CHRONIC DISEASE THAT CANNOT BE ADDRESSED BY SIMPLY PROMOTING BETTER DIETS AND MORE PHYSICAL ACTIVITY. TO DATE, NOT A SINGLE COUNTRY HAS SUCCESSFULLY BEEN ABLE TO CURB THE ACCUMULATING BURDEN OF OBESITY. ONE EXPLANATION FOR THE LACK OF PROGRESS IS THAT LIFESTYLE INTERVENTION PROGRAMS ARE TRADITIONALLY IMPLEMENTED WITHOUT A COMPREHENSIVE EVALUATION OF AN INDIVIDUAL'S DIAGNOSTIC BIOMARKERS. EVIDENCE FROM GENOME-WIDE ASSOCIATION STUDIES HIGHLIGHT THE IMPORTANCE OF GENETIC AND EPIGENETIC FACTORS IN THE DEVELOPMENT OF OBESITY AND HOW THEY IN TURN AFFECT THE TRANSCRIPTOME, METABOLITES, MICROBIOMES, AND PROTEOMES. OBJECTIVE: THE PURPOSE OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE DIFFERENT TYPES OF OMICS DATA: GENOMICS, EPIGENOMICS, TRANSCRIPTOMICS, PROTEOMICS, METABOLOMICS AND ILLUSTRATE HOW A MULTI-OMICS APPROACH CAN BE FUNDAMENTAL FOR THE IMPLEMENTATION OF PRECISION OBESITY MANAGEMENT. RESULTS: THE DIFFERENT TYPES OF OMICS DESIGNS ARE GROUPED INTO TWO CATEGORIES, THE GENOTYPE APPROACH AND THE PHENOTYPE APPROACH. WHEN APPLIED TO OBESITY PREVENTION AND MANAGEMENT, EACH OMICS TYPE COULD POTENTIALLY HELP TO DETECT SPECIFIC BIOMARKERS IN PEOPLE WITH RISK PROFILES AND GUIDE HEALTHCARE PROFESSIONALS AND DECISION MAKERS IN DEVELOPING INDIVIDUALIZED TREATMENT PLANS ACCORDING TO THE NEEDS OF THE INDIVIDUAL BEFORE THE ONSET OF OBESITY. CONCLUSION: INTEGRATING MULTI-OMICS APPROACHES WILL ENABLE A PARADIGM SHIFT FROM THE ONE SIZE FITS ALL APPROACH TOWARDS PRECISION OBESITY MANAGEMENT, I.E. (1) PRECISION PREVENTION OF THE ONSET OF OBESITY, (2) PRECISION MEDICINE AND TAILORED TREATMENT OF OBESITY, AND (3) PRECISION RISK REDUCTION AND PREVENTION OF SECONDARY DISEASES RELATED TO OBESITY. 2023 10 1398 25 DIET, GUT MICROBIOME AND EPIGENETICS: EMERGING LINKS WITH INFLAMMATORY BOWEL DISEASES AND PROSPECTS FOR MANAGEMENT AND PREVENTION. INFLAMMATORY BOWEL DISEASES (IBD) REPRESENT A GROWING PUBLIC HEALTH CONCERN DUE TO INCREASING INCIDENCE WORLDWIDE. THE CURRENT NOTION ON THE PATHOGENESIS OF IBD IS THAT GENETICALLY SUSCEPTIBLE INDIVIDUALS DEVELOP INTOLERANCE TO DYSREGULATED GUT MICROFLORA (DYSBIOSIS) AND CHRONIC INFLAMMATION DEVELOPS AS A RESULT OF ENVIRONMENTAL TRIGGERS. AMONG THE ENVIRONMENTAL FACTORS ASSOCIATED WITH IBD, DIET PLAYS AN IMPORTANT ROLE IN MODULATING THE GUT MICROBIOME, INFLUENCING EPIGENETIC CHANGES, AND, THEREFORE, COULD BE APPLIED AS A THERAPEUTIC TOOL TO IMPROVE THE DISEASE COURSE. NEVERTHELESS, THE CURRENT DIETARY RECOMMENDATIONS FOR DISEASE PREVENTION AND MANAGEMENT ARE SCARCE AND HAVE WEAK EVIDENCE. THIS REVIEW SUMMARISES THE CURRENT KNOWLEDGE ON THE COMPLEX INTERACTIONS BETWEEN DIET, MICROBIOME AND EPIGENETICS IN IBD. WHEREAS AN OVERABUNDANCE OF CALORIES AND SOME MACRONUTRIENTS INCREASE GUT INFLAMMATION, SEVERAL MICRONUTRIENTS HAVE THE POTENTIAL TO MODULATE IT. IMMUNONUTRITION HAS EMERGED AS A NEW CONCEPT PUTTING FORWARD THE IMPORTANCE OF VITAMINS SUCH AS VITAMINS A, C, E, AND D, FOLIC ACID, BETA CAROTENE AND TRACE ELEMENTS SUCH AS ZINC, SELENIUM, MANGANESE AND IRON. HOWEVER, WHEN ASSESSED IN CLINICAL TRIALS, SPECIFIC MICRONUTRIENTS EXERTED A LIMITED BENEFIT. BEYOND NUTRIENTS, AN ANTI-INFLAMMATORY DIETARY PATTERN AS A COMPLEX INTERVENTION APPROACH HAS BECOME POPULAR IN RECENT YEARS. HENCE, EXCLUSIVE ENTERAL NUTRITION IN PAEDIATRIC CROHN'S DISEASE IS THE ONLY NUTRITIONAL INTERVENTION CURRENTLY RECOMMENDED AS A FIRST-LINE THERAPY. OTHER NUTRITIONAL INTERVENTIONS OR SPECIFIC DIETS INCLUDING THE SPECIFIC CARBOHYDRATE DIET (SCD), THE LOW FERMENTABLE OLIGOSACCHARIDES, DISACCHARIDES, MONOSACCHARIDES, AND POLYOL (FODMAP) DIET AND, MOST RECENTLY, THE MEDITERRANEAN DIET HAVE SHOWN STRONG ANTI-INFLAMMATORY PROPERTIES AND SHOW PROMISE FOR IMPROVING DISEASE SYMPTOMS. MORE WORK IS REQUIRED TO EVALUATE THE ROLE OF INDIVIDUAL FOOD COMPOUNDS AND COMPLEX NUTRITIONAL INTERVENTIONS WITH THE POTENTIAL TO DECREASE INFLAMMATION AS A MEANS OF PREVENTION AND MANAGEMENT OF IBD. 2017 11 5025 21 PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS. PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS (CVD), ALSO REFERRED TO AS PERSONALIZED OR PRECISION CARDIOLOGY IN ACCORDANCE WITH GENERAL PRINCIPLES OF PERSONALIZED MEDICINE, IS SELECTION OF THE BEST TREATMENT FOR AN INDIVIDUAL PATIENT. IT INVOLVES THE INTEGRATION OF VARIOUS "OMICS" TECHNOLOGIES SUCH AS GENOMICS AND PROTEOMICS AS WELL AS OTHER NEW TECHNOLOGIES SUCH AS NANOBIOTECHNOLOGY. MOLECULAR DIAGNOSTICS AND BIOMARKERS ARE IMPORTANT FOR LINKING DIAGNOSIS WITH THERAPY AND MONITORING THERAPY. BECAUSE CVD INVOLVE PERTURBATIONS OF LARGE COMPLEX BIOLOGICAL NETWORKS, A SYSTEMS BIOLOGY APPROACH TO CVD RISK STRATIFICATION MAY BE USED FOR IMPROVING RISK-ESTIMATING ALGORITHMS, AND MODELING OF PERSONALIZED BENEFIT OF TREATMENT MAY BE HELPFUL FOR GUIDING THE CHOICE OF INTERVENTION. BIOINFORMATICS TOOLS ARE HELPFUL IN ANALYZING AND INTEGRATING LARGE AMOUNTS OF DATA FROM VARIOUS SOURCES. PERSONALIZED THERAPY IS CONSIDERED DURING DRUG DEVELOPMENT, INCLUDING METHODS OF TARGETED DRUG DELIVERY AND CLINICAL TRIALS. INDIVIDUALIZED RECOMMENDATIONS CONSIDER MULTIPLE FACTORS - GENETIC AS WELL AS EPIGENETIC - FOR PATIENTS' RISK OF HEART DISEASE. EXAMPLES OF PERSONALIZED TREATMENT ARE THOSE OF CHRONIC MYOCARDIAL ISCHEMIA, HEART FAILURE, AND HYPERTENSION. SIMILAR APPROACHES CAN BE USED FOR THE MANAGEMENT OF ATRIAL FIBRILLATION AND HYPERCHOLESTEROLEMIA, AS WELL AS THE USE OF ANTICOAGULANTS. PERSONALIZED MANAGEMENT INCLUDES PHARMACOTHERAPY, SURGERY, LIFESTYLE MODIFICATIONS, AND COMBINATIONS THEREOF. FURTHER PROGRESS IN UNDERSTANDING THE PATHOMECHANISM OF COMPLEX CARDIOVASCULAR DISEASES AND IDENTIFICATION OF CAUSATIVE FACTORS AT THE INDIVIDUAL PATIENT LEVEL WILL PROVIDE OPPORTUNITIES FOR THE DEVELOPMENT OF PERSONALIZED CARDIOLOGY. APPLICATION OF PRINCIPLES OF PERSONALIZED MEDICINE WILL IMPROVE THE CARE OF THE PATIENTS WITH CVD. 2017 12 4832 21 OMICS BIOMARKERS IN OBESITY: NOVEL ETIOLOGICAL INSIGHTS AND TARGETS FOR PRECISION PREVENTION. PURPOSE OF REVIEW: OMICS-BASED TECHNOLOGIES WERE SUGGESTED TO PROVIDE AN ADVANCED UNDERSTANDING OF OBESITY ETIOLOGY AND ITS METABOLIC CONSEQUENCES. THIS REVIEW HIGHLIGHTS THE RECENT DEVELOPMENTS IN "OMICS"-BASED RESEARCH AIMED TO IDENTIFY OBESITY-RELATED BIOMARKERS. RECENT FINDINGS: RECENT ADVANCES IN OBESITY AND METABOLISM RESEARCH INCREASINGLY RELY ON NEW TECHNOLOGIES TO IDENTIFY MECHANISMS IN THE DEVELOPMENT OF OBESITY USING VARIOUS "OMICS" PLATFORMS. GENETIC AND EPIGENETIC BIOMARKERS THAT TRANSLATE INTO CHANGES IN TRANSCRIPTOME, PROTEOME, AND METABOLOME COULD SERVE AS TARGETS FOR OBESITY PREVENTION. DESPITE A NUMBER OF PROMISING CANDIDATE BIOMARKERS, THERE IS AN INCREASED DEMAND FOR LARGER PROSPECTIVE COHORT STUDIES TO VALIDATE FINDINGS AND DETERMINE BIOMARKER REPRODUCIBILITY BEFORE THEY CAN FIND APPLICATIONS IN PRIMARY CARE AND PUBLIC HEALTH. "OMICS" BIOMARKERS HAVE ADVANCED OUR KNOWLEDGE ON THE ETIOLOGY OF OBESITY AND ITS LINKS WITH CHRONIC DISEASES. THEY BRING SUBSTANTIAL PROMISE IN IDENTIFYING EFFECTIVE PUBLIC HEALTH STRATEGIES THAT PAVE THE WAY TOWARDS PATIENT STRATIFICATION AND PRECISION PREVENTION. 2020 13 5792 22 STAGING IN BIPOLAR DISORDER: FROM THEORETICAL FRAMEWORK TO CLINICAL UTILITY. ILLNESS STAGING IS WIDELY UTILIZED IN SEVERAL MEDICAL DISCIPLINES TO HELP PREDICT COURSE OR PROGNOSIS, AND OPTIMIZE TREATMENT. STAGING MODELS IN PSYCHIATRY IN GENERAL, AND BIPOLAR DISORDER IN PARTICULAR, DEPEND ON THE PREMISE THAT PSYCHOPATHOLOGY MOVES ALONG A PREDICTABLE PATH: AN AT-RISK OR LATENCY STAGE, A PRODROME PROGRESSING TO A FIRST CLINICAL THRESHOLD EPISODE, AND ONE OR MORE RECURRENCES WITH THE POTENTIAL TO REVERT OR PROGRESS TO LATE OR END-STAGE MANIFESTATIONS. THE UTILITY AND VALIDITY OF A STAGING MODEL FOR BIPOLAR DISORDER DEPEND ON ITS LINKING TO CLINICAL OUTCOME, TREATMENT RESPONSE AND NEUROBIOLOGICAL MEASURES. THESE INCLUDE PROGRESSIVE BIOCHEMICAL, NEUROIMAGING AND COGNITIVE CHANGES, AND POTENTIALLY STAGE-SPECIFIC DIFFERENCES IN RESPONSE TO PHARMACOLOGICAL AND PSYCHOSOCIAL TREATMENTS. MECHANISTICALLY, STAGING MODELS IMPLY THE PRESENCE OF AN ACTIVE DISEASE PROCESS THAT, IF NOT REMEDIATED, CAN LEAD TO NEUROPROGRESSION, A MORE MALIGNANT DISEASE COURSE AND FUNCTIONAL DETERIORATION. BIOLOGICAL ELEMENTS THOUGHT TO BE OPERATIVE IN BIPOLAR DISORDER INCLUDE A GENETIC DIATHESIS, PHYSICAL AND PSYCHIC TRAUMA, EPIGENETIC CHANGES, ALTERED NEUROGENESIS AND APOPTOSIS, MITOCHONDRIAL DYSFUNCTION, INFLAMMATION, AND OXIDATIVE STRESS. MANY AVAILABLE AGENTS, SUCH AS LITHIUM, HAVE EFFECTS ON THESE TARGETS. STAGING MODELS ALSO SUGGEST THE UTILITY OF STAGE-SPECIFIC TREATMENT APPROACHES THAT MAY NOT ONLY TARGET SYMPTOM REDUCTION, BUT ALSO IMPEDE ILLNESS NEUROPROGRESSION. THESE TREATMENT APPROACHES RANGE FROM PREVENTION FOR AT-RISK INDIVIDUALS, TO EARLY INTERVENTION STRATEGIES FOR PRODROMAL AND NEWLY DIAGNOSED INDIVIDUALS, COMPLEX COMBINATION THERAPY FOR RAPIDLY RECURRENT ILLNESS, AND PALLIATIVE-TYPE APPROACHES FOR THOSE AT CHRONIC, LATE STAGES OF ILLNESS. THERE IS HOPE THAT PROMPT INITIATION OF POTENTIALLY DISEASE MODIFYING THERAPIES MAY PRECLUDE OR ATTENUATE THE COGNITIVE AND STRUCTURAL CHANGES SEEN IN THE LATER STAGES OF BIPOLAR DISORDER. THE AIMS OF THIS PAPER ARE TO: A) EXPLORE THE CURRENT LEVEL OF EVIDENCE SUPPORTING THE DESCRIPTIVE STAGING OF THE SYNDROMAL PATTERN OF BIPOLAR DISORDER; B) DESCRIBE PRELIMINARY ATTEMPTS AT VALIDATION; C) MAKE RECOMMENDATIONS FOR THE DIRECTION OF FURTHER STUDIES; AND D) PROVIDE A DISTILLATION OF THE POTENTIAL CLINICAL IMPLICATIONS OF STAGING IN BIPOLAR DISORDER WITHIN A BROADER TRANSDIAGNOSTIC FRAMEWORK. 2017 14 467 20 ARE WE FINALLY GETTING PERSONAL? MOVING TOWARDS A PERSONALIZED APPROACH IN CHRONIC LYMPHOCYTIC LEUKEMIA. WITH ITS HETEROGENEOUS BIOLOGICAL FEATURES AND CLINICAL COURSE, CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), THE MOST FREQUENT ADULT LEUKEMIA IN THE WESTERN WORLD, IS A PARADIGMATIC CONDITION REQUIRING A TAILORED APPROACH AND A PRECISE KNOWLEDGE OF THE BIOLOGY BEHIND EACH INDIVIDUAL PATIENT. THIS PERSONALIZED MANAGEMENT IS BECOMING EVEN MORE CRUCIAL, SINCE, AFTER DECADES OF PRECLINICAL WORK UNRAVELLING THE KEY ROLE OF THE B-CELL RECEPTOR (BCR) SIGNALLING PATHWAYS AND THE ANTI-APOPTOTIC MECHANISMS IN CLL CELL SURVIVAL AND PROLIFERATION, WE HAVE NOW BCR AND BCL2 INHIBITORS AVAILABLE IN CLINICAL PRACTICE. THANKS TO THIS, WE ARE NOW ABLE TO EXPLOIT SPECIFIC BIOMARKERS TO TAILOR OUR TREATMENT STRATEGIES AND IMPROVE LONG-TERM DISEASE CONTROL, PATIENT OUTCOME AND QUALITY OF LIFE. THAT NOTWITHSTANDING, AS THE DISEASE ITSELF REMAINS INCURABLE, NOVEL CHALLENGES AND UNMET CLINICAL NEEDS HAVE RISEN FROM THE INTRODUCTION OF NOVEL TARGETED AGENTS, INCLUDING MECHANISMS OF RESISTANCE AT BOTH GENETIC AND EPIGENETIC LEVELS. IN THIS REVIEW, WE SUMMARIZE THE CURRENTLY ESTABLISHED PREDICTIVE BIOMARKERS (I.E. IGHV MUTATION STATUS AND TP53 GENE DISRUPTION) THAT SHOULD BE APPLIED IN CLINICAL PRACTICE TO INFORM TREATMENT DECISION IN 2021 BUT ALSO DISCUSS THE MOST PROMISING PROGNOSTIC BIOMARKERS (B-CELL RECEPTOR STEREOTYPY, COMPLEX KARYOTYPE, SOMATIC GENE MUTATIONS, MEASURABLE RESIDUAL DISEASE - MRD) THAT MIGHT BECOME KEY TO DEFINE THE MANAGEMENT OF OUR PATIENTS IN A NEAR FUTURE. 2022 15 2731 22 EXPLORING THE COMPLEX RELATIONSHIP BETWEEN MICROBIOTA AND SYSTEMIC LUPUS ERYTHEMATOSUS. PURPOSE OF REVIEW: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY VARIOUS AUTOANTIBODIES AND MULTI-ORGAN. MICROBIOTA DYSBIOSIS IN THE GUT, SKIN, ORAL, AND OTHER SURFACES HAS A SIGNIFICANT IMPACT ON SLE DEVELOPMENT. THIS ARTICLE SUMMARIZES RELEVANT RESEARCH AND PROVIDES NEW MICROBIOME-RELATED STRATEGIES FOR EXPLORING THE MECHANISMS AND TREATING PATIENTS WITH SLE. RECENT FINDINGS: SLE PATIENTS HAVE DISRUPTIONS IN MULTIPLE MICROBIOMES, WITH THE GUT MICROBIOTA (BACTERIA, VIRUSES, AND FUNGI) AND THEIR METABOLITES BEING THE MOST THOROUGHLY RESEARCHED. THIS DYSBIOSIS CAN PROMOTE SLE PROGRESSION THROUGH MECHANISMS SUCH AS THE LEAKY GUT, MOLECULAR MIMICRY, AND EPIGENETIC REGULATION. NOTWITHSTANDING STUDY CONSTRAINTS ON THE RELATIONSHIP BETWEEN MICROBIOTA AND SLE, SPECIFIC INTERVENTIONS TARGETING THE GUT MICROBIOTA, SUCH AS PROBIOTICS, DIETARY MANAGEMENT, AND FECAL MICROBIOTA TRANSPLANTATION, HAVE EMERGED AS PROMISING SLE THERAPEUTICS. 2023 16 5214 11 PRETERM BEHAVIORAL EPIGENETICS: A SYSTEMATIC REVIEW. BEHAVIORAL EPIGENETICS IS REVEALING NEW PATHWAYS THAT LEAD INDIVIDUALS FROM EARLY ADVERSITY EXPOSURES TO LATER-IN-LIFE DETRIMENTAL OUTCOMES. PRETERM BIRTH CONSTITUTES ONE OF THE MAJOR ADVERSE EVENTS IN HUMAN DEVELOPMENT. PRETERM INFANTS ARE HOSPITALIZED IN THE NEONATAL INTENSIVE CARE UNIT (NICU) WHERE THEY ARE EXPOSED TO LIFE-SAVING YET PAIN-INDUCING PROCEDURES AND TO PROTECTIVE CARE. THE APPLICATION OF BEHAVIORAL EPIGENETICS TO THE FIELD OF PRETERM STUDIES (I.E., PRETERM BEHAVIORAL EPIGENETICS, PBE) IS RAPIDLY GROWING AND HOLDS PROMISES TO PROVIDE VALID INSIGHTS FOR RESEARCH AND CLINICAL ACTIVITY. HERE, THE EVIDENCE OF THE EPIGENETIC CORRELATES OF PRENATAL ADVERSITIES, NICU-RELATED ENVIRONMENT AND DEVELOPMENT OF PRETERM INFANTS IS SYSTEMATICALLY REVIEWED. THE FINDINGS SUGGEST THAT A NUMBER OF PRENATAL ADVERSE (E.G., MATERNAL DEPRESSION AND STRESS) AND POST-NATAL (E.G., NICU-RELATED PAIN-RELATED STRESS) EVENTS AFFECT THE DEVELOPMENTAL TRAJECTORIES OF PRETERM INFANTS AND CHILDREN VIA EPIGENETIC ALTERATIONS OF IMPRINTED AND STRESS-RELATED GENES. NONETHELESS, THE POTENTIAL EPIGENETIC VESTIGES OF EARLY CARE AND PROTECTIVE INTERVENTIONS IN NICU HAVE NOT BEEN INVESTIGATED YET AND THIS REPRESENTS A FASCINATING CHALLENGE FOR FUTURE PBE RESEARCH. 2018 17 5450 17 REPRODUCTIVE TOXICITY OF COMBINED EFFECTS OF ENDOCRINE DISRUPTORS ON HUMAN REPRODUCTION. CONFLUENCE OF ENVIRONMENTAL, GENETIC, AND LIFESTYLE VARIABLES IS RESPONSIBLE FOR DETERIORATION OF HUMAN FECUNDITY. ENDOCRINE DISRUPTORS OR ENDOCRINE DISRUPTING CHEMICALS (EDCS) MAY BE FOUND IN A VARIETY OF FOODS, WATER, AIR, BEVERAGES, AND TOBACCO SMOKE. IT HAS BEEN DEMONSTRATED IN EXPERIMENTAL INVESTIGATIONS THAT A WIDE RANGE OF ENDOCRINE DISRUPTING CHEMICALS HAVE NEGATIVE EFFECTS ON HUMAN REPRODUCTIVE FUNCTION. HOWEVER, EVIDENCE ON THE REPRODUCTIVE CONSEQUENCES OF HUMAN EXPOSURE TO ENDOCRINE DISRUPTING CHEMICALS IS SPARSE AND/OR CONFLICTING IN THE SCIENTIFIC LITERATURE. THE COMBINED TOXICOLOGICAL ASSESSMENT IS A PRACTICAL METHOD FOR ASSESSING THE HAZARDS OF COCKTAILS OF CHEMICALS, CO-EXISTING IN THE ENVIRONMENT. THE CURRENT REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF STUDIES EMPHASIZING THE COMBINED TOXICITY OF ENDOCRINE DISRUPTING CHEMICALS ON HUMAN REPRODUCTION. ENDOCRINE DISRUPTING CHEMICALS INTERACT WITH EACH OTHER TO DISRUPT THE DIFFERENT ENDOCRINE AXES, RESULTING IN SEVERE GONADAL DYSFUNCTIONS. TRANSGENERATIONAL EPIGENETIC EFFECTS HAVE ALSO BEEN INDUCED IN GERM CELLS, MOSTLY THROUGH DNA METHYLATION AND EPIMUTATIONS. SIMILARLY, AFTER ACUTE OR CHRONIC EXPOSURE TO ENDOCRINE DISRUPTING CHEMICALS COMBINATIONS, INCREASED OXIDATIVE STRESS (OS), ELEVATED ANTIOXIDANT ENZYMATIC ACTIVITY, DISRUPTED REPRODUCTIVE CYCLE, AND REDUCED STEROIDOGENESIS ARE OFTEN REPORTED CONSEQUENCES. THE ARTICLE ALSO DISCUSSES THE CONCENTRATION ADDITION (CA) AND INDEPENDENT ACTION (IA) PREDICTION MODELS, WHICH REVEAL THE IMPORTANCE OF VARIOUS SYNERGISTIC ACTIONS OF ENDOCRINE DISRUPTING CHEMICALS MIXTURES. MORE CRUCIALLY, THIS EVIDENCE-BASED STUDY ADDRESSES THE RESEARCH LIMITATIONS AND INFORMATION GAPS, AS WELL AS PARTICULARLY PRESENTS THE FUTURE RESEARCH VIEWS ON COMBINED ENDOCRINE DISRUPTING CHEMICALS TOXICITY ON HUMAN REPRODUCTION. 2023 18 1066 29 CLINICAL USE OF AMINO ACIDS AS DIETARY SUPPLEMENT: PROS AND CONS. NITROGEN SUPPLY IS PIVOTAL FOR THE MAINTENANCE OF LIFE. AMINO ACIDS CAN BE UTILIZED TO SYNTHESIZE BOTH GLUCOSE AND LIPIDS. THE OPPOSITE, I.E., PRODUCTION OF AMINO ACIDS FROM EITHER ONE OF THEM, IS NOT POSSIBLE IN THE ABSENCE OF OTHER AMINO ACIDS AS DONORS OF NITROGEN. THE QUALITY OF AMINO ACID CONTENT IN PROTEIN HAS BEEN RE-EVALUATED RECENTLY, AND THE RELEVANCE OF ESSENTIAL AMINO ACIDS HAS BEEN REPEATEDLY UNDERLINED. ESSENTIAL AMINO ACID REQUIREMENTS IN DIFFERENT MAMMALS ARE NOT IDENTICAL, AND RATIOS AMONG THEM SHOULD BE TAKEN INTO ACCOUNT WHEN PROJECTING AN EFFICIENT FORMULATION. RECENT RESEARCH HAS DEMONSTRATED THAT GENES RESPOND TO DIFFERENT QUALITIES AND QUANTITIES OF NUTRITIONAL SUPPLY, AND INCREASED PROVISION OF ESSENTIAL AMINO ACIDS INCREASES LIFESPAN IN ANIMAL EXPERIMENTS THROUGH MITOCHONDRIOGENESIS AND MAINTENANCE OF ELEVATED RATES OF SYNTHESIS OF ANTI-OXIDANT MOLECULES. MOREOVER, GENETIC EXPRESSION OF KEY CONTROLLERS OF SYNTHESIS, LIKE MTOR, MAY BE PARTICULARLY IMPORTANT FOR UNDERSTANDING SKELETAL MUSCLE MAINTENANCE. LOSSES OF MUSCLE MASS AND IMPAIRED IMMUNE FUNCTION ARE RELATED TO REDUCED PROTEIN SUPPLY, AND THERE IS INCREASING EVIDENCE THAT REGULAR ESSENTIAL AMINO ACID INTAKE AS PART OF AN ORAL DIET IS EFFECTIVE IN REVERSING MUSCLE CATABOLISM, PROMOTING MUSCLE ANABOLISM, AND RESTORING IMMUNOLOGICAL FUNCTION. THEREFORE, THE USE OF AMINO ACIDS AS SUPPLEMENTS TO DIET WOULD BE EXPANDING IN THE NEAR FUTURE. IS THIS SAFE? FEW DATA ARE AVAILABLE ON AMINO ACID TOXICITY, AND ONLY ONE ESSENTIAL AMINO ACID MAY BE CONSIDERED TO HAVE CLINICALLY RELEVANT TOXICITY: METHIONINE, BECAUSE IT IS TRANSFORMED INTO A TOXIC INTERMEDIATE, HOMOCYSTEINE, WHEN CYSTEINE SYNTHESIS IS REQUIRED BY METABOLIC NEEDS. MATCHING OF STOICHIOMETRIC RATIOS BETWEEN METHIONINE AND CYSTEINE MAY SOLVE THE PROBLEM OF SUPPLYING SUFFICIENT AMOUNTS OF SULFUR TO THE BODY. ARGININE AND GLUTAMINE ARE TWO NON-ESSENTIAL AMINO ACIDS THAN CAN BECOME "CONDITIONALLY ESSENTIAL" BECAUSE OF ELEVATED NEEDS DURING PATHOLOGICAL CONDITIONS, AND METABOLISM MAY NOT BE ABLE TO MAINTAIN THEIR CONCENTRATIONS AT SUFFICIENT LEVELS TO MATCH METABOLIC REQUIREMENTS. CHRONIC EXOGENOUS ARGININE SUPPLEMENTATION HAS NOT PROVEN TO EXERT POSITIVE CLINICAL EFFECTS IN DIFFERENT TRIALS, AND SEQUENTIAL ARTICULATION OF THE KNOWLEDGE OF INTRODUCTION OF ARGININE-DRIVEN TRANSCRIPTIONAL, TRANSLATIONAL, AND EPIGENETIC ADAPTATIONS MAY GIVE US A KEY FOR INTERPRETING THOSE PUZZLING RESULTS. 2011 19 2869 22 FUNCTIONAL FOODS AND HEALTH EFFECTS: A NUTRITIONAL BIOCHEMISTRY PERSPECTIVE. BACKGROUND: INCREASED CONSUMER S INTEREST IN HEALTH HAS DRIVEN THE DEVELOPMENT OF FOODS THAT OFFER SPECIFIC BENEFICIAL EFFECTS. THE LIST OF FOODS AND INGREDIENTS INCLUDES ESSENTIAL AND NON-ESSENTIAL NUTRIENTS, PLANT AND MARINE COMPONENTS, WHOLE FOODS, MICROORGANISMS, MICROALGAE AND TECHNOLOGICAL APPROACHES. TRADITIONALLY, HEALTH OUTCOMES FOCUSSED ON THE PREVENTION OF CHRONIC DISEASES BUT HEALTH TARGETS HAVE EXPANDED TO COVER AREAS SUCH AS BRAIN HEALTH, INFLAMMATION, EYE HEALTH, WOMEN S HEALTH, HEALTHY AGEING AND BEAUTY. OBJECTIVE: THIS REVIEW HIGHLIGHTS, FROM A NUTRITIONAL BIOCHEMISTRY PERSPECTIVE, DIFFERENTIAL ASPECTS ON DESIGNING AND INTERPRETING HUMAN STUDIES TO SUPPORT THE HEALTH EFFECTS OF FUNCTIONAL FOODS. RESULTS: DESPITE THE AVAILABLE EVIDENCE FROM IN VITRO, ANIMAL AND OBSERVATIONAL STUDIES, WELLDESIGNED HUMAN STUDIES ARE NECESSARY TO SUPPORT THE HEALTH EFFECTS OF FUNCTIONAL FOODS. INTERVENTION TRIALS WITH FOODS ARE COMPLEX AS THEY IMPLY LIMITATIONS DUE TO METHODOLOGICAL, FOOD-RELATED AND HOST-RELATED FACTORS. THE USE OF RESPONSIVE, VALIDATED AND CLINICALLY RELEVANT MARKERS BECOMES ESSENTIAL EVEN THOUGH THERE IS A LACK OF RELIABLE BIOMARKERS OF EXPOSURE FOR MANY BIOACTIVES. FURTHERMORE, THE EFFECT OF MODULATING FACTORS SUCH AS SUBCLINICAL INFLAMMATION, GUT MICROBIOTA AND GENETIC VARIABILITY SHOULD BE TAKEN INTO ACCOUNT. MULTIPLE INDICATORS MAY PROVIDE A MORE RELIABLE ALTERNATIVE TO ASSESS PHYSIOLOGICAL PROCESSES WHILE EMERGING BIOMARKERS (MICRORNAS, EPIGENETIC CHANGES) CONSTITUTE A PROMISING APPROACH. ADDITIONALLY, THE MAGNITUDE OF THE CHANGE IS CRITICAL TO SUPPORT ANY HEALTH EFFECT ALTHOUGH INTERVENTIONS MAY HAVE A LIMITED CLINICAL IMPACT BUT BE EPIDEMIOLOGICALLY RELEVANT. ALSO, BASED ON THE AVAILABLE DATA, THE PREMISE THAT BIOACTIVESCONTAINING FOODS ARE SAFE MAY BE QUESTIONABLE. CONCLUSION: AN INTEGRATED APPROACH INCLUDING MULTIPLE BIOMARKERS, GENETIC VARIABILITY, EFFECT OF GUT MICROBIOTA AND RISK/BENEFIT ASSESSMENT SHOULD BE USED TO SUPPORT THE POTENTIAL HEALTH EFFECTS OF FUNCTIONAL FOODS. 2016 20 5013 23 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AS A THERAPEUTIC TARGET FOR HEPATIC FIBROSIS: FROM BENCH TO BEDSIDE. HEPATIC FIBROSIS IS A DYNAMIC CHRONIC LIVER DISEASE OCCURRING AS A CONSEQUENCE OF WOUND-HEALING RESPONSES TO VARIOUS HEPATIC INJURIES. THIS DISORDER IS ONE OF PRIMARY PREDICTORS FOR LIVER-ASSOCIATED MORBIDITY AND MORTALITY WORLDWIDE. TO DATE, NO PHARMACOLOGICAL AGENT HAS BEEN APPROVED FOR HEPATIC FIBROSIS OR COULD BE RECOMMENDED FOR ROUTINE USE IN CLINICAL CONTEXT. CELLULAR AND MOLECULAR UNDERSTANDING OF HEPATIC FIBROSIS HAS REVEALED THAT PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA), THE FUNCTIONING RECEPTOR FOR ANTIDIABETIC THIAZOLIDINEDIONES, PLAYS A PIVOTAL ROLE IN THE PATHOBIOLOGY OF HEPATIC STELLATE CELLS (HSCS), WHOSE ACTIVATION IS THE CENTRAL EVENT IN THE PATHOGENESIS OF HEPATIC FIBROSIS. ACTIVATION OF PPARGAMMA INHIBITS HSC COLLAGEN PRODUCTION AND MODULATES HSC ADIPOGENIC PHENOTYPE AT TRANSCRIPTIONAL AND EPIGENETIC LEVELS. THESE MOLECULAR INSIGHTS INDICATE PPARGAMMA AS A PROMISING DRUG TARGET FOR ANTIFIBROTIC CHEMOTHERAPY. INTENSIVE ANIMAL STUDIES HAVE DEMONSTRATED THAT STIMULATION OF PPARGAMMA REGULATORY SYSTEM THROUGH GENE THERAPY APPROACHES AND PPARGAMMA LIGANDS HAS THERAPEUTIC PROMISE FOR HEPATIC FIBROSIS INDUCED BY A VARIETY OF ETIOLOGIES. AT THE SAME TIME, THIAZOLIDINEDIONE AGENTS HAVE BEEN INVESTIGATED FOR THEIR CLINICAL BENEFITS PRIMARILY IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS, A COMMON METABOLIC LIVER DISORDER WITH HIGH POTENTIAL TO PROGRESS TO FIBROSIS AND LIVER-RELATED DEATH. ALTHOUGH SOME STUDIES HAVE SHOWN INITIAL PROMISE, NONE HAS ESTABLISHED LONG-TERM EFFICACY IN WELL-CONTROLLED RANDOMIZED CLINICAL TRIALS. THIS COMPREHENSIVE REVIEW COVERS THE 10-YEAR DISCOVERIES OF THE MOLECULAR BASIS FOR PPARGAMMA REGULATION OF HSC PATHOPHYSIOLOGY AND THEN FOCUSES ON THE ANIMAL INVESTIGATIONS AND CLINICAL TRIALS OF VARIOUS THERAPEUTIC MODALITIES TARGETING PPARGAMMA FOR HEPATIC FIBROSIS. 2013