1 1127 83 COMPOUND COMBINATIONS TARGETING LONGEVITY: CHALLENGES AND PERSPECTIVES. AGING IS ONE OF THE WORLD'S GREATEST CONCERNS, REQUIRING URGENT, EFFECTIVE, LARGE-SCALE INTERVENTIONS TO DECREASE THE NUMBER OF LATE-LIFE CHRONIC DISEASES AND IMPROVE HUMAN HEALTHSPAN. ANTI-AGING DRUG THERAPY IS ONE OF THE MOST PROMISING STRATEGIES TO COMBAT THE EFFECTS OF AGING. HOWEVER, MOST GEROPROTECTIVE COMPOUNDS ARE KNOWN TO SUCCESSFULLY AFFECT ONLY A FEW AGING-RELATED TARGETS. GIVEN THIS, THERE IS A GREAT BIOLOGICAL RATIONALE FOR THE USE OF COMBINATIONS OF ANTI-AGING INTERVENTIONS. IN THIS REVIEW, WE CHARACTERIZE THE VARIOUS TYPES OF COMPOUND COMBINATIONS USED TO MODULATE LIFESPAN, DISCUSS THE EXISTING EVIDENCE ON THEIR ROLE IN LIFE EXTENSION, AND PRESENT SOME KEY POINTS ABOUT CURRENT CHALLENGES AND FUTURE PROSPECTS FOR THE DEVELOPMENT OF COMBINATION DRUG ANTI-AGING THERAPY. 2023 2 372 21 AN EMERGING EPIDEMIC OF NONCOMMUNICABLE DISEASES IN DEVELOPING POPULATIONS DUE TO A TRIPLE EVOLUTIONARY MISMATCH. WITH THEIR TRANSITION FROM ADVERSE TO AFFLUENT ENVIRONMENTS, DEVELOPING POPULATIONS EXPERIENCE A RAPID INCREASE IN THE NUMBER OF INDIVIDUALS WITH NONCOMMUNICABLE DISEASES. HERE, WE EMPHASIZE THAT DEVELOPING POPULATIONS ARE MORE SUSCEPTIBLE THAN WESTERN POPULATIONS TO ACQUIRE THESE CHRONIC DISEASES, BECAUSE THEIR GENETIC, CULTURAL, AND EPIGENETIC CHARACTERISTICS DO NOT MATCH WITH THE EAGERLY AWAITED AFFLUENT ENVIRONMENTS. IN REGARD TO THIS, THERE IS AN URGENT NEED FOR PUBLIC HEALTH ORGANIZATIONS TO REORGANIZE CURRENT ENVIRONMENTS IN DEVELOPING POPULATIONS SO AS TO FIT THEIR INHERITED CHARACTERISTICS. UNFORTUNATELY, THIS NEED IS NEGLECTED AS AN ESSENTIAL PART OF THE SUSTAINABLE DEVELOPMENT GOALS THAT FORM THE CORE OF THE UNITED NATIONS' POST-2015 DEVELOPMENT AGENDA. ONLY THROUGH GLOBAL COLLABORATIVE EFFORTS CAN THE ENVIRONMENTS IN DEVELOPING POPULATIONS BE REORGANIZED AND, THEREBY, THE EMERGING EPIDEMIC OF NONCOMMUNICABLE DISEASES BE STALLED. 2016 3 3105 25 GENOMICS AND PROTEOMICS IN LIVER FIBROSIS AND CIRRHOSIS. GENOMICS AND PROTEOMICS HAVE BECOME INCREASINGLY IMPORTANT IN BIOMEDICAL SCIENCE IN THE PAST DECADE, AS THEY PROVIDE AN OPPORTUNITY FOR HYPOTHESIS-FREE EXPERIMENTS THAT CAN YIELD MAJOR INSIGHTS NOT PREVIOUSLY FORESEEN WHEN SCIENTIFIC AND CLINICAL QUESTIONS ARE BASED ONLY ON HYPOTHESIS-DRIVEN APPROACHES. USE OF THESE TOOLS, THEREFORE, OPENS NEW AVENUES FOR UNCOVERING PHYSIOLOGICAL AND PATHOLOGICAL PATHWAYS. LIVER FIBROSIS IS A COMPLEX DISEASE PROVOKED BY A RANGE OF CHRONIC INJURIES TO THE LIVER, AMONG WHICH ARE VIRAL HEPATITIS, (NON-) ALCOHOLIC STEATOHEPATITIS AND AUTOIMMUNE DISORDERS. SOME CHRONIC LIVER PATIENTS WILL NEVER DEVELOP FIBROSIS OR CIRRHOSIS, WHEREAS OTHERS RAPIDLY PROGRESS TOWARDS CIRRHOSIS IN A FEW YEARS. THIS VARIETY CAN BE CAUSED BY DISEASE-RELATED FACTORS (FOR EXAMPLE, VIRAL GENOTYPE) OR HOST-FACTORS (GENETIC/EPIGENETIC). IT IS VITAL TO ESTABLISH ACCURATE TOOLS TO IDENTIFY THOSE PATIENTS AT HIGHEST RISK FOR DISEASE SEVERITY OR PROGRESSION IN ORDER TO DETERMINE WHO ARE IN NEED OF IMMEDIATE THERAPIES. MOREOVER, THERE IS AN URGENT IMPERATIVE TO IDENTIFY NON-INVASIVE MARKERS THAT CAN ACCURATELY DISTINGUISH MILD AND INTERMEDIATE STAGES OF FIBROSIS. IDEALLY, BIOMARKERS CAN BE USED TO PREDICT DISEASE PROGRESSION AND TREATMENT RESPONSE, BUT THESE STUDIES WILL TAKE MANY YEARS DUE TO THE REQUIREMENT FOR LENGTHY FOLLOW-UP PERIODS TO ASSESS OUTCOMES. CURRENT GENOMIC AND PROTEOMIC RESEARCH PROVIDES MANY CANDIDATE BIOMARKERS, BUT INDEPENDENT VALIDATION OF THESE BIOMARKERS IS LACKING, AND REPRODUCIBILITY IS STILL A KEY CONCERN. THUS, GREAT OPPORTUNITIES AND CHALLENGES LIE AHEAD IN THE FIELD OF GENOMICS AND PROTEOMICS, WHICH, IF SUCCESSFUL, COULD TRANSFORM THE DIAGNOSIS AND TREATMENT OF CHRONIC FIBROSING LIVER DISEASES. 2012 4 4712 16 NON-ALCOHOLIC FATTY LIVER DISEASE: METABOLIC, GENETIC, EPIGENETIC AND ENVIRONMENTAL RISK FACTORS. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST FREQUENT CAUSES OF CHRONIC LIVER DISEASE IN THE WESTERN WORLD, PROBABLY DUE TO THE GROWING PREVALENCE OF OBESITY, METABOLIC DISEASES, AND EXPOSURE TO SOME ENVIRONMENTAL AGENTS. IN CERTAIN PATIENTS, SIMPLE HEPATIC STEATOSIS CAN PROGRESS TO NON-ALCOHOLIC STEATOHEPATITIS (NASH), WHICH CAN SOMETIMES LEAD TO LIVER CIRRHOSIS AND ITS COMPLICATIONS INCLUDING HEPATOCELLULAR CARCINOMA. UNDERSTANDING THE MECHANISMS THAT CAUSE THE PROGRESSION OF NAFLD TO NASH IS CRUCIAL TO BE ABLE TO CONTROL THE ADVANCEMENT OF THE DISEASE. THE MAIN HYPOTHESIS CONSIDERS THAT IT IS DUE TO MULTIPLE FACTORS THAT ACT TOGETHER ON GENETICALLY PREDISPOSED SUBJECTS TO SUFFER FROM NAFLD INCLUDING INSULIN RESISTANCE, NUTRITIONAL FACTORS, GUT MICROBIOTA, AND GENETIC AND EPIGENETIC FACTORS. IN THIS ARTICLE, WE WILL DISCUSS THE EPIDEMIOLOGY OF NAFLD, AND WE OVERVIEW SEVERAL TOPICS THAT INFLUENCE THE DEVELOPMENT OF THE DISEASE FROM SIMPLE STEATOSIS TO LIVER CIRRHOSIS AND ITS POSSIBLE COMPLICATIONS. 2021 5 4326 20 MICRORNAS IN THE PATHOGENESIS OF NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), OR, MORE ACCURATELY, METABOLIC ASSOCIATED FATTY LIVER DISEASE, ACCOUNTS FOR A LARGE PROPORTION OF CHRONIC LIVER DISORDERS WORLDWIDE AND IS CLOSELY ASSOCIATED WITH OTHER CONDITIONS SUCH AS CARDIOVASCULAR DISEASE, OBESITY, AND TYPE 2 DIABETES MELLITUS. NAFLD RANGES FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS (NASH) AND CAN PROGRESS TO CIRRHOSIS AND, EVENTUALLY, ALSO HEPATOCELLULAR CARCINOMA. THE MORBIDITY AND MORTALITY ASSOCIATED WITH NAFLD ARE INCREASING RAPIDLY YEAR ON YEAR. CONSEQUENTLY, THERE IS AN URGENT NEED TO UNDERSTAND THE ETIOLOGY AND PATHOGENESIS OF NAFLD AND IDENTIFY EFFECTIVE THERAPEUTIC TARGETS. MICRORNAS (MIRNAS), IMPORTANT EPIGENETIC FACTORS, HAVE RECENTLY BEEN PROPOSED TO PARTICIPATE IN NAFLD PATHOGENESIS. HERE, WE REVIEW THE ROLES OF MIRNAS IN LIPID METABOLISM, INFLAMMATION, APOPTOSIS, FIBROSIS, HEPATIC STELLATE CELL ACTIVATION, INSULIN RESISTANCE, AND OXIDATIVE STRESS, KEY FACTORS THAT CONTRIBUTE TO THE OCCURRENCE AND PROGRESSION OF NAFLD. ADDITIONALLY, WE SUMMARIZE THE ROLE OF MIRNA-ENRICHED EXTRACELLULAR VESICLES IN NAFLD. THESE MIRNAS MAY COMPRISE SUITABLE THERAPEUTIC TARGETS FOR THE TREATMENT OF THIS CONDITION. 2021 6 5807 20 STRATEGIES, MODELS AND BIOMARKERS IN EXPERIMENTAL NON-ALCOHOLIC FATTY LIVER DISEASE RESEARCH. NON-ALCOHOLIC FATTY LIVER DISEASE ENCOMPASSES A SPECTRUM OF LIVER DISEASES, INCLUDING SIMPLE STEATOSIS, STEATOHEPATITIS, LIVER FIBROSIS AND CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. NON-ALCOHOLIC FATTY LIVER DISEASE IS CURRENTLY THE MOST DOMINANT CHRONIC LIVER DISEASE IN WESTERN COUNTRIES DUE TO THE FACT THAT HEPATIC STEATOSIS IS ASSOCIATED WITH INSULIN RESISTANCE, TYPE 2 DIABETES MELLITUS, OBESITY, METABOLIC SYNDROME AND DRUG-INDUCED INJURY. A VARIETY OF CHEMICALS, MAINLY DRUGS, AND DIETS IS KNOWN TO CAUSE HEPATIC STEATOSIS IN HUMANS AND RODENTS. EXPERIMENTAL NON-ALCOHOLIC FATTY LIVER DISEASE MODELS RELY ON THE APPLICATION OF A DIET OR THE ADMINISTRATION OF DRUGS TO LABORATORY ANIMALS OR THE EXPOSURE OF HEPATIC CELL LINES TO THESE DRUGS. MORE RECENTLY, GENETICALLY MODIFIED RODENTS OR ZEBRAFISH HAVE BEEN INTRODUCED AS NON-ALCOHOLIC FATTY LIVER DISEASE MODELS. CONSIDERABLE INTEREST NOW LIES IN THE DISCOVERY AND DEVELOPMENT OF NOVEL NON-INVASIVE BIOMARKERS OF NON-ALCOHOLIC FATTY LIVER DISEASE, WITH SPECIFIC FOCUS ON HEPATIC STEATOSIS. EXPERIMENTAL DIAGNOSTIC BIOMARKERS OF NON-ALCOHOLIC FATTY LIVER DISEASE, SUCH AS (EPI)GENETIC PARAMETERS AND '-OMICS'-BASED READ-OUTS ARE STILL IN THEIR INFANCY, BUT SHOW GREAT PROMISE. IN THIS PAPER, THE ARRAY OF TOOLS AND MODELS FOR THE STUDY OF LIVER STEATOSIS IS DISCUSSED. FURTHERMORE, THE CURRENT STATE-OF-ART REGARDING EXPERIMENTAL BIOMARKERS SUCH AS EPIGENETIC, GENETIC, TRANSCRIPTOMIC, PROTEOMIC AND METABONOMIC BIOMARKERS WILL BE REVIEWED. 2015 7 264 15 ADVANCING ASTHMA CARE: THE GLASS IS ONLY HALF FULL! OVER THE PAST 20 YEARS, THERE HAS BEEN A CONCERTED EFFORT IN THE UNITED STATES TO REDUCE MORBIDITY RELATED TO CHRONIC DISEASE, INCLUDING ASTHMA. ATTENTION WAS INITIALLY DIRECTED TOWARD ASTHMA IN RESPONSE TO THE RECOGNITION THAT ASTHMA MORTALITY WAS INCREASING AND THAT THE BURDEN OF DISEASE WAS SIGNIFICANT. THESE EFFORTS TO ADDRESS ASTHMA MORTALITY LED TO MANY NEW INITIATIVES TO DEVELOP CLINICAL PRACTICE GUIDELINES, IMPLEMENT THE ASTHMA GUIDELINES INTO CLINICAL PRACTICE, CONDUCT RESEARCH TO FILL THE GAPS IN THE GUIDELINES, AND CONTINUOUSLY REVISE THE ASTHMA GUIDELINES AS MORE INFORMATION BECAME AVAILABLE. AN ASSESSMENT OF OUR PROGRESS SHOWS SIGNIFICANT ACCOMPLISHMENTS IN RELATION TO REDUCING ASTHMA MORTALITY AND HOSPITALIZATIONS. CONSEQUENTLY, WE ARE NOW AT A CROSSROADS IN ASTHMA CARE. ALTHOUGH WE HAVE RECOGNIZED SOME REMARKABLE ACCOMPLISHMENTS IN REDUCING ASTHMA MORTALITY AND MORBIDITY, THE AVAILABILITY OF NEW TOOLS TO MONITOR DISEASE ACTIVITY, INCLUDING BIOMARKERS AND EPIGENETIC MARKERS, ALONG WITH INFORMATION TECHNOLOGY SYSTEMS TO MONITOR ASTHMA CONTROL HOLD SOME PROMISE IN IDENTIFYING GAPS IN DISEASE MANAGEMENT. THESE ADVANCES SHOULD PROMPT THE EVOLUTION OF NEW STRATEGIES AND NEW TREATMENTS TO FURTHER REDUCE DISEASE BURDEN. IT NOW BECOMES IMPERATIVE TO CONTINUE A FOCUS ON WAYS TO FURTHER REDUCE THE BURDEN OF ASTHMA AND PREVENT ITS ONSET. 2011 8 3022 20 GENETICS AND EPIGENETICS PURPOSE IN NONALCOHOLIC FATTY LIVER DISEASE. INTRODUCTION: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) COMPRISES A BROAD SPECTRUM OF DISEASES, WHICH CAN PROGRESS FROM BENIGN STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS, LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. NAFLD IS THE MOST COMMON CHRONIC LIVER DISEASE IN DEVELOPED COUNTRIES, AFFECTING APPROXIMATELY 25% OF THE GENERAL POPULATION. INSULIN RESISTANCE, ADIPOSE TISSUE DYSFUNCTION, MITOCHONDRIAL AND ENDOPLASMIC RETICULUM STRESS, CHRONIC INFLAMMATION, GENETIC AND EPIGENETIC FACTORS ARE NAFLD TRIGGERS THAT CONTROL THE DISEASE SUSCEPTIBILITY AND PROGRESSION. AREAS COVERED: IN RECENT YEARS A LARGE NUMBER OF INVESTIGATIONS HAVE BEEN CARRIED OUT TO ELUCIDATE GENETIC AND EPIGENETIC FACTORS IN THE DISEASE PATHOGENESIS, AS WELL AS THE SEARCH FOR DIAGNOSTIC MARKERS AND THERAPEUTIC TARGETS. THIS PAPER OBJECTIVE IS TO REPORT THE MOST STUDIED GENETIC AND EPIGENETIC VARIANTS AROUND NAFLD. EXPERT OPINION: NAFLD LEAD TO VARIOUS COMORBIDITIES, WHICH HAVE A CONSIDERABLE IMPACT ON THE PATIENT WELLNESS AND LIFE QUALITY, AS WELL AS ON THE COSTS THEY GENERATE FOR THE COUNTRY'S HEALTH SERVICES. IT IS ESSENTIAL TO CONTINUE WITH MOLECULAR RESEARCH, SINCE IT COULD BE USED AS A CLINICAL TOOL FOR PROGNOSIS AND DISEASE SEVERITY. SPECIFICALLY, IN THE FIELD OF HEPATOLOGY, PLASMA MIRNAS COULD PROVIDE A NOVEL TOOL IN LIVER DISEASES DIAGNOSIS AND MONITORING, REPRESENTING AN ALTERNATIVE TO INVASIVE DIAGNOSTIC PROCEDURES. 2020 9 5161 27 PRECISION AND PERSONALIZED MEDICINE: HOW GENOMIC APPROACH IMPROVES THE MANAGEMENT OF CARDIOVASCULAR AND NEURODEGENERATIVE DISEASE. LIFE EXPECTANCY HAS GRADUALLY GROWN OVER THE LAST CENTURY. THIS HAS DEEPLY AFFECTED HEALTHCARE COSTS, SINCE THE GROWTH OF AN AGING POPULATION IS CORRELATED TO THE INCREASING BURDEN OF CHRONIC DISEASES. THIS REPRESENTS THE INTERESTING CHALLENGE OF HOW TO MANAGE PATIENTS WITH CHRONIC DISEASES IN ORDER TO IMPROVE HEALTH CARE BUDGETS. EFFECTIVE PRIMARY PREVENTION COULD REPRESENT A PROMISING ROUTE. TO THIS END, PRECISION, TOGETHER WITH PERSONALIZED MEDICINE, ARE USEFUL INSTRUMENTS IN ORDER TO INVESTIGATE PATHOLOGICAL PROCESSES BEFORE THE APPEARANCE OF CLINICAL SYMPTOMS AND TO GUIDE PHYSICIANS TO CHOOSE A TARGETED THERAPY TO MANAGE THE PATIENT. CARDIOVASCULAR AND NEURODEGENERATIVE DISEASES REPRESENT SUITABLE MODELS FOR TAKING FULL ADVANTAGE OF PRECISION MEDICINE TECHNOLOGIES APPLIED TO ALL STAGES OF DISEASE DEVELOPMENT. THE AVAILABILITY OF HIGH TECHNOLOGY INCORPORATING ARTIFICIAL INTELLIGENCE AND ADVANCEMENT PROGRESS MADE IN THE FIELD OF BIOMEDICAL RESEARCH HAVE BEEN SUBSTANTIAL TO UNDERSTAND HOW GENES, EPIGENETIC MODIFICATIONS, AGING, NUTRITION, DRUGS, MICROBIOME AND OTHER ENVIRONMENTAL FACTORS CAN IMPACT HEALTH AND CHRONIC DISORDERS. THE AIM OF THE PRESENT REVIEW IS TO ADDRESS HOW PRECISION AND PERSONALIZED MEDICINE CAN BRING GREATER CLARITY TO THE CLINICAL AND BIOLOGICAL COMPLEXITY OF THESE TYPES OF DISORDERS ASSOCIATED WITH HIGH MORTALITY, INVOLVING TREMENDOUS HEALTH CARE COSTS, BY DESCRIBING IN DETAIL THE METHODS THAT CAN BE APPLIED. THIS MIGHT OFFER PRECIOUS TOOLS FOR PREVENTIVE STRATEGIES AND POSSIBLE CLUES ON THE EVOLUTION OF THE DISEASE AND COULD HELP IN PREDICTING MORBIDITY, MORTALITY AND DETECTING CHRONIC DISEASE INDICATORS MUCH EARLIER IN THE DISEASE COURSE. THIS, OF COURSE, WILL HAVE A MAJOR EFFECT ON BOTH IMPROVING THE QUALITY OF CARE AND QUALITY OF LIFE OF THE PATIENTS AND REDUCING TIME EFFORTS AND HEALTHCARE COSTS. 2020 10 1859 24 EMBEDDING THE COMMUNITY AND INDIVIDUALS IN DISEASE PREVENTION. THE PRIMARY PREVENTION OF NON-COMMUNICABLE DISEASES IS ONE OF THE MOST CHALLENGING AND EXCITING ASPECTS OF MEDICINE AND PRIMARY CARE THIS CENTURY. FOR CANCER, IT IS AN URGENT MATTER IN LIGHT OF THE INCREASING BURDEN OF THE DISEASE AMONG YOUNGER PEOPLE AND THE HIGHER FREQUENCY OF MORE AGGRESSIVE FORMS OF THE DISEASE FOR ALL AGES. MOST CHRONIC DISORDERS RESULT FROM THE INFLUENCE OF THE ENVIRONMENT ON THE EXPRESSION OF GENES WITHIN AN INDIVIDUAL. THE ENVIRONMENT AT-LARGE ENCOMPASSES LIFESTYLE (INCLUDING NUTRITION), AND CHEMICAL/PHYSICAL AND SOCIAL EXPOSURES. IN CANCER, THE INTERACTION BETWEEN THE (EPI)GENETIC MAKEUP OF AN INDIVIDUAL AND A MULTIPLICITY OF ENVIRONMENTAL RISK AND PROTECTING FACTORS IS CONSIDERED KEY TO DISEASE ONSET. THUS, LIKE FOR PRECISION THERAPY DEVELOPED FOR PATIENTS, PERSONALIZED OR PRECISION PREVENTION IS ENVISIONED FOR INDIVIDUALS AT RISK. PREVENTION MEANS IDENTIFYING PEOPLE AT HIGHER RISK AND INTERVENING TO REDUCE THE RISK. IT REQUIRES BIOLOGICAL MARKERS OF RISK AND NON-AGGRESSIVE PREVENTIVE ACTIONS FOR THE INDIVIDUAL, BUT IT ALSO INVOLVES ACTING ON THE ENVIRONMENT AND THE COMMUNITY. SOCIAL SCIENTISTS ARE CONSIDERING MICRO (INDIVIDUAL/FAMILY), MESO (COMMUNITY), AND MACRO (COUNTRY POPULATION) LEVELS OF CARE TO ILLUSTRATE THAT PROBLEMS AND SOLUTIONS EXIST ON DIFFERENT SCALES. IDEALLY, THE DESIGN OF INTERVENTIONS IN PREVENTION SHOULD INTEGRATE ALL THESE LEVELS. IN THIS PERSPECTIVE ARTICLE, USING THE EXAMPLE OF BREAST CANCER, WE ARE DISCUSSING CHALLENGES AND POSSIBLE SOLUTIONS FOR A MULTIDISCIPLINARY COMMUNITY OF SCIENTISTS, PRIMARY HEALTH CARE PRACTITIONERS AND CITIZENS TO DEVELOP A HOLISTIC APPROACH OF PRIMARY PREVENTION, KEEPING IN MIND EQUITABLE ACCESS TO CARE. 2022 11 6264 16 THE MULTIPLE-HIT PATHOGENESIS OF NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD). NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS INCREASINGLY PREVALENT AND REPRESENTS A GROWING CHALLENGE IN TERMS OF PREVENTION AND TREATMENT. DESPITE ITS HIGH PREVALENCE, ONLY A SMALL MINORITY OF AFFECTED PATIENTS DEVELOPS INFLAMMATION AND SUBSEQUENTLY FIBROSIS AND CHRONIC LIVER DISEASE, WHILE MOST OF THEM ONLY EXHIBIT SIMPLE STEATOSIS. IN THIS CONTEXT, THE FULL UNDERSTANDING OF THE MECHANISMS UNDERLYING THE DEVELOPMENT OF NAFLD AND NON-ALCOHOLIC STEATOHEPATITIS (NASH) IS OF EXTREME IMPORTANCE; DESPITE ADVANCES IN THIS FIELD, KNOWLEDGE ON THE PATHOGENESIS OF NAFLD IS STILL INCOMPLETE. THE 'TWO-HIT' HYPOTHESIS IS NOW OBSOLETE, AS IT IS INADEQUATE TO EXPLAIN THE SEVERAL MOLECULAR AND METABOLIC CHANGES THAT TAKE PLACE IN NAFLD. THE "MULTIPLE HIT" HYPOTHESIS CONSIDERS MULTIPLE INSULTS ACTING TOGETHER ON GENETICALLY PREDISPOSED SUBJECTS TO INDUCE NAFLD AND PROVIDES A MORE ACCURATE EXPLANATION OF NAFLD PATHOGENESIS. SUCH HITS INCLUDE INSULIN RESISTANCE, HORMONES SECRETED FROM THE ADIPOSE TISSUE, NUTRITIONAL FACTORS, GUT MICROBIOTA AND GENETIC AND EPIGENETIC FACTORS. IN THIS ARTICLE, WE REVIEW THE FACTORS THAT FORM THIS HYPOTHESIS. 2016 12 2544 18 EPIGENETICS IN LIVER DISEASE: FROM BIOLOGY TO THERAPEUTICS. KNOWLEDGE OF THE FUNDAMENTAL EPIGENETIC MECHANISMS GOVERNING GENE EXPRESSION AND CELLULAR PHENOTYPE ARE SUFFICIENTLY ADVANCED THAT NOVEL INSIGHTS INTO THE EPIGENETIC CONTROL OF CHRONIC LIVER DISEASE ARE NOW EMERGING. HEPATOLOGISTS ARE IN THE PROCESS OF SHEDDING LIGHT ON THE ROLES PLAYED BY DNA METHYLATION, HISTONE/CHROMATIN MODIFICATIONS AND NON-CODING RNAS IN SPECIFIC LIVER PATHOLOGIES. ALONGSIDE THESE DISCOVERIES ARE ADVANCES IN THE TECHNOLOGIES FOR THE DETECTION AND QUANTIFICATION OF EPIGENETIC BIOMARKERS, EITHER DIRECTLY FROM PATIENT TISSUE OR FROM BODY FLUIDS. THE PREMISE FOR THIS REVIEW IS TO SURVEY THE RECENT ADVANCES IN THE FIELD OF LIVER EPIGENETICS AND TO EXPLORE THEIR POTENTIAL FOR TRANSLATION BY INDUSTRY AND CLINICAL HEPATOLOGISTS FOR THE DESIGN OF NOVEL THERAPEUTICS AND DIAGNOSTIC/PROGNOSTIC BIOMARKERS. IN PARTICULAR, WE PRESENT FINDINGS IN THE CONTEXT OF HEPATOCELLULAR CARCINOMA, FIBROSIS AND NON-ALCOHOLIC FATTY LIVER DISEASE, WHERE THERE IS URGENT UNMET NEED FOR NEW CLINICAL INTERVENTIONS AND BIOMARKERS. 2016 13 3270 13 HEPATOCELLULAR CARCINOMA IN THE CONTEXT OF NON-ALCOHOLIC STEATOHEPATITIS (NASH): RECENT ADVANCES IN THE PATHOGENIC MECHANISMS. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON TYPE OF LIVER CANCER. HCC IS PARTICULARLY AGGRESSIVE AND IS ONE OF THE LEADING CAUSES OF CANCER MORTALITY. IN RECENT DECADES, THE EPIDEMIOLOGICAL LANDSCAPE OF HCC HAS UNDERGONE SIGNIFICANT CHANGES. WHILE CHRONIC VIRAL HEPATITIS AND EXCESSIVE ALCOHOL CONSUMPTION HAVE LONG BEEN IDENTIFIED AS THE MAIN RISK FACTORS FOR HCC, NON-ALCOHOLIC STEATOHEPATITIS (NASH), PARALLELING THE WORLDWIDE EPIDEMIC OF OBESITY AND TYPE 2 DIABETES, HAS BECOME A GROWING CAUSE OF HCC IN THE US AND EUROPE. HERE, WE REVIEW THE RECENT ADVANCES IN EPIDEMIOLOGICAL, GENETIC, EPIGENETIC AND PATHOGENIC MECHANISMS AS WELL AS EXPERIMENTAL MOUSE MODELS THAT HAVE IMPROVED THE UNDERSTANDING OF NASH PROGRESSION TOWARD HCC. WE ALSO DISCUSS THE CLINICAL MANAGEMENT OF PATIENTS WITH NASH-RELATED HCC AND POSSIBLE THERAPEUTIC APPROACHES. 2020 14 5163 18 PRECISION/PERSONALIZED MEDICINE IN ALLERGIC DISEASES AND ASTHMA. LIKE MANY OTHER CHRONIC DISEASES, EVERY ALLERGIC PATIENT HAS DIFFERENT CHARACTERISTICS BASED ON CLINICAL COURSE, TREATMENT RESPONSIVENESS AND DISEASE OUTCOMES, WHICH ARE ASSOCIATED WITH THE GENETIC AND EPIGENETIC CONTROL OF MOLECULAR MECHANISMS AND ENVIRONMENT. THIS VARIABILITY NECESSITATES THE ESTABLISHMENT OF PATIENT-TAILORED AND PRECISION APPROACHES IN HANDLING ALLERGIC DISORDERS. BETTER UNDERSTANDING OF THE UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS FOR THE DEVELOPMENT OF ALLERGIC DISORDERS WILL PROVIDE MORE RATIONALE STRATEGIES BASED ON INDIVIDUAL CASES IN CONTROLLING AND TREATING THESE DISORDERS. ENDOTYPING, PHENOTYPING, GENOTYPING AND THERATYPING, AND BIOMARKERS ARE KEYWORDS IN THIS AREA AND HAVE BEEN GAINING LOTS OF ATTENTION IN THE FIELD OF PRECISION MEDICINE, WHICH AIMS TO REVOLUTIONIZE PATIENT CARE AND DEVELOP BETTER PREVENTION AND TREATMENT STRATEGIES. IN ADDITION, PRECISION HEALTH IS A NEW CONCEPT THAT BRINGS PRECISE APPROACHES TO THE SCENE FOR BEING HEALTHY AND PREVENTION OF ALLERGIC DISEASE AND ASTHMA. THE SPECIALTY OF ALLERGY HAS A LEADING ROLE IN THE FIELD, BECAUSE ALLERGEN-SPECIFIC IMMUNOTHERAPY STARTED 105 YEARS AGO, AND IS HISTORICALLY A LEADING PERSONALIZED/PRECISION MEDICINE APPROACH IN ALL MEDICINE DISCIPLINES PROVIDING THE POSSIBILITY OF CURE IN AN INDIVIDUALIZED MANNER INSTEAD OF CONVENTIONAL SYMPTOMATIC TREATMENTS. 2018 15 13 33 360-DEGREE PERSPECTIVES ON OBESITY. ALARMING STATISTICS SHOW THAT THE NUMBER OF PEOPLE AFFECTED BY EXCESSIVE WEIGHT HAS SURPASSED 2 BILLION, REPRESENTING APPROXIMATELY 30% OF THE WORLD'S POPULATION. THE AIM OF THIS REVIEW IS TO PROVIDE A COMPREHENSIVE OVERVIEW OF ONE OF THE MOST SERIOUS PUBLIC HEALTH PROBLEMS, CONSIDERING THAT OBESITY REQUIRES AN INTEGRATIVE APPROACH THAT TAKES INTO ACCOUNT ITS COMPLEX ETIOLOGY, INCLUDING GENETIC, ENVIRONMENTAL, AND LIFESTYLE FACTORS. ONLY AN UNDERSTANDING OF THE CONNECTIONS BETWEEN THE MANY CONTRIBUTORS TO OBESITY AND THE SYNERGY BETWEEN TREATMENT INTERVENTIONS CAN ENSURE SATISFACTORY OUTCOMES IN REDUCING OBESITY. MECHANISMS SUCH AS OXIDATIVE STRESS, CHRONIC INFLAMMATION, AND DYSBIOSIS PLAY A CRUCIAL ROLE IN THE PATHOGENESIS OF OBESITY AND ITS ASSOCIATED COMPLICATIONS. COMPOUNDING FACTORS SUCH AS THE DELETERIOUS EFFECTS OF STRESS, THE NOVEL CHALLENGE POSED BY THE OBESOGENIC DIGITAL (FOOD) ENVIRONMENT, AND THE STIGMA ASSOCIATED WITH OBESITY SHOULD NOT BE OVERLOOKED. PRECLINICAL RESEARCH IN ANIMAL MODELS HAS BEEN INSTRUMENTAL IN ELUCIDATING THESE MECHANISMS, AND TRANSLATION INTO CLINICAL PRACTICE HAS PROVIDED PROMISING THERAPEUTIC OPTIONS, INCLUDING EPIGENETIC APPROACHES, PHARMACOTHERAPY, AND BARIATRIC SURGERY. HOWEVER, MORE STUDIES ARE NECESSARY TO DISCOVER NEW COMPOUNDS THAT TARGET KEY METABOLIC PATHWAYS, INNOVATIVE WAYS TO DELIVER THE DRUGS, THE OPTIMAL COMBINATIONS OF LIFESTYLE INTERVENTIONS WITH ALLOPATHIC TREATMENTS, AND, LAST BUT NOT LEAST, EMERGING BIOLOGICAL MARKERS FOR EFFECTIVE MONITORING. WITH EACH PASSING DAY, THE OBESITY CRISIS TIGHTENS ITS GRIP, THREATENING NOT ONLY INDIVIDUAL LIVES BUT ALSO BURDENING HEALTHCARE SYSTEMS AND SOCIETIES AT LARGE. IT IS HIGH TIME WE TOOK ACTION AS WE CONFRONT THE URGENT IMPERATIVE TO ADDRESS THIS ESCALATING GLOBAL HEALTH CHALLENGE HEAD-ON. 2023 16 6048 23 THE CONCEPTS OF ASTHMA ENDOTYPES AND PHENOTYPES TO GUIDE CURRENT AND NOVEL TREATMENT STRATEGIES. ASTHMA, A COMMON, NON-COMMUNICABLE CHRONIC DISEASE AFFECTS OVER 300 MILLION INDIVIDUALS WORLDWIDE. THE WESTERN WORLD LIFESTYLE IS CLAIMED TO BE RESPONSIBLE FOR THIS HIGH AND INCREASING PREVALENCE. ASTHMA HAS BEEN DEFINED AS A SYNDROME WITH VARIOUS PHENOTYPES AND ENDOTYPES, ALLERGIC ASTHMA AND TYPE 2 ASTHMA BEING THE MOST FREQUENT. A GREAT INCREASE IN PREVALENCE OF ALLERGIC DISEASES HAS NECESSITATED INTENSIVE INVESTIGATIONS BOTH FOR UNDERSTANDING THE UNDERLYING MECHANISMS AND FOR THE DEVELOPMENT OF NOVEL THERAPY OPTIONS WITH LONG-TERM EFFICACY AND LIMITED SIDE-EFFECTS. ALLERGIC PATIENTS DEMONSTRATE UNIQUE PRESENTATIONS WITH VARIABLE VISIBLE CHARACTERISTICS AND DISEASE OUTCOMES DEPENDING ON DIFFERENT MOLECULAR MECHANISMS, RELATED TO INFLUENCE OF GENES AND EPIGENETIC CONTROL BY MICRO- AND MACRO-ENVIRONMENT. AREAS COVERED: THIS ARTICLE REVIEWS THE DEFINITION OF ASTHMA PHENOTYPES AND POSSIBLE ENDOTYPES, ADVANCES IN ALLERGY-IMMUNOLOGY FIELD AND CONTEMPORARY PERSONALIZED THERAPY OPTIONS FOR ASTHMA. EXPERT COMMENTARY: BETTER UNDERSTANDING OF THE COMPLEX IMMUNE NETWORK OF ALLERGIC INFLAMMATION AND KEY PLAYERS OF IMMUNITY IS CONTINUOUSLY BEING PROVIDED FOR CLARIFICATION OF ASTHMA SUB-TYPES. SUCCESSFUL THERAPY OF ASTHMA REQUIRES BETTER DEFINITION OF UNDERLYING PATHOGENESIS, WHICH SEQUENTIALLY COULD END UP WITH 'CUSTOM-TAILORED' INDIVIDUALIZED, EVIDENCE-BASED AND MORE PRECISE THERAPY OPTIONS; A NEW ERA TERMED AS 'PRECISION MEDICINE'. ENDOTYPE, PHENOTYPE, THERATYPE AND BIOMARKER TERMS ARISE AS MAJOR KEYWORDS IN PRECISION/PERSONALIZED MEDICINE. 2018 17 4832 22 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 18 1374 26 DEVELOPMENTAL PROGRAMMING OF ADULT DISEASE: REPROGRAMMING BY MELATONIN? ADULT-ONSET CHRONIC NON-COMMUNICABLE DISEASES (NCDS) CAN ORIGINATE FROM EARLY LIFE THROUGH SO-CALLED THE "DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" (DOHAD) OR "DEVELOPMENTAL PROGRAMMING". THE DOHAD CONCEPT OFFERS THE "REPROGRAMMING" STRATEGY TO SHIFT THE TREATMENT FROM ADULTHOOD TO EARLY LIFE, BEFORE CLINICAL DISEASE IS APPARENT. MELATONIN, AN ENDOGENOUS INDOLEAMINE PRODUCED BY THE PINEAL GLAND, HAS PLEIOTROPIC BIOACTIVITIES THOSE ARE BENEFICIAL IN A VARIETY OF HUMAN DISEASES. EMERGING EVIDENCE SUPPORT THAT MELATONIN IS CLOSELY INTER-RELATED TO OTHER PROPOSED MECHANISMS CONTRIBUTING TO THE DEVELOPMENTAL PROGRAMMING OF A VARIETY OF CHRONIC NCDS. RECENT ANIMAL STUDIES HAVE BEGUN TO UNRAVEL THE MULTIFUNCTIONAL ROLES OF MELATONIN IN MANY EXPERIMENTAL MODELS OF DEVELOPMENTAL PROGRAMMING. EVEN THOUGH SOME PROGRESS HAS BEEN MADE IN RESEARCH ON MELATONIN AS A REPROGRAMMING STRATEGY TO PREVENT DOHAD-RELATED NCDS, FUTURE HUMAN STUDIES SHOULD AIM AT FILLING THE TRANSLATIONAL GAP BETWEEN ANIMAL MODELS AND CLINICAL TRIALS. HERE, WE REVIEW SEVERAL KEY THEMES ON THE REPROGRAMMING EFFECTS OF MELATONIN IN DOHAD RESEARCH. WE HAVE PARTICULARLY FOCUSED ON THE FOLLOWING AREAS: MECHANISMS OF DEVELOPMENTAL PROGRAMMING; THE INTERRELATIONSHIP BETWEEN MELATONIN AND MECHANISMS UNDERLYING DEVELOPMENTAL PROGRAMMING; PATHOPHYSIOLOGICAL ROLES OF MELATONIN IN PREGNANCY AND FETAL DEVELOPMENT; AND INSIGHT PROVIDED BY ANIMAL MODELS TO SUPPORT MELATONIN AS A REPROGRAMMING THERAPY. RATES OF NCDS ARE INCREASING FASTER THAN ANTICIPATED ALL OVER THE WORLD. HENCE, THERE IS AN URGENT NEED TO UNDERSTAND REPROGRAMMING MECHANISMS OF MELATONIN AND TO TRANSLATE EXPERIMENTAL RESEARCH INTO CLINICAL PRACTICE FOR HALTING A GROWING LIST OF DOHAD-RELATED NCDS. 2017 19 4464 15 MOLECULAR MECHANISMS OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)/NONALCOHOLIC STEATOHEPATITIS (NASH). NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST COMMON CHRONIC LIVER DISEASES WORLDWIDE AND HAS GARNERED INCREASING ATTENTION IN RECENT DECADES. NAFLD IS CHARACTERIZED BY A WIDE RANGE OF LIVER CHANGES, FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS (NASH), CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. THE PATHOGENESIS OF NAFLD/NASH IS VERY COMPLICATED AND INVOLVES LIPID ACCUMULATION, INSULIN RESISTANCE, INFLAMMATION, AND FIBROGENESIS. IN ADDITION, NAFLD IS CLOSELY ASSOCIATED WITH COMPLICATIONS SUCH AS OBESITY, DYSLIPIDEMIA, AND TYPE 2 DIABETES. IN PARTICULAR, THE CLINICAL SPECTRUM, PATHOPHYSIOLOGY, AND THERAPEUTIC OPTIONS OF NAFLD SHARE MANY THINGS IN COMMON WITH DIABETES. INSULIN RESISTANCE IS AN UNDERLYING BASIS FOR THE PATHOGENESIS OF DIABETES AND NAFLD. THIS CHAPTER FOCUSES ON THE MOLECULAR MECHANISM INVOLVED IN THE PATHOGENESIS OF INSULIN RESISTANCE, DIABETES, AND NASH/NAFLD INCLUDING THOSE THAT DRIVE DISEASE PROGRESSION SUCH AS OXIDATIVE STRESS, GENETIC AND EPIGENETIC MECHANISMS, ADIPONECTIN, CYTOKINES, AND IMMUNE CELLS. 2021 20 6860 21 [OBESITY EPIDEMIC: CURRENT EVIDENCE, CHALLENGES AND FUTURE DIRECTIONS]. THE OBESITY EPIDEMIC IS A PHENOMENON THAT HAS BEEN WIDELY STUDIED IN RECENT DECADES BUT IS STILL INCOMPLETELY UNDERSTOOD, AND ITS CONTROL IS FAR FROM THE DESIRABLE LEVEL IN VIEW OF THE INCREASING PREVALENCE FIGURES OBSERVED WORLDWIDE. THIS PAPER CONDUCTS A NARRATIVE REVIEW WITH THE AIM OF PROVIDING UPDATED EVIDENCE ON THE GLOBAL OBESITY EPIDEMIC, AND PARTICULARLY ON THE SITUATION IN LATIN AMERICA AND ARGENTINA, IDENTIFYING THE MAIN CHALLENGES AND FUTURE DIRECTIONS FOR ADDRESSING THIS PUBLIC HEALTH PROBLEM. IT FIRST DESCRIBES THE CURRENT BURDEN AND INCREASING TRENDS IN THE PREVALENCE OF OBESITY, IN THE OVERALL POPULATION AND BY POPULATION GROUPS, AND ITS POSSIBLE ASSOCIATION WITH GENETIC AND EPIGENETIC ASPECTS. IT ALSO SUMMARIZES THE DIRECT AND INDIRECT SOCIOECONOMIC CONSEQUENCES OF THIS EPIDEMIC, AS WELL AS RECENT STRATEGIES AND INITIATIVES FOCUSED ON OBESITY PREVENTION, WITH SPECIAL ATTENTION TO THOSE REPORTED AS THE MOST EFFICIENT IN THE LATIN AMERICAN CONTEXT. THIS REVIEW IDENTIFIED SOME PENDING CHALLENGES IN THE REGION, THE INTEGRATED APPROACH TO THE DOUBLE BURDEN OF MALNUTRITION AND THE GROWING CHILDHOOD OVERWEIGHT; AND IT POINTS OUT SOME EMERGING APPROACHES, SUCH AS THE SYNDEMIC APPROACH, AS POTENTIALLY USEFUL TO UNDERSTAND AND ADDRESS THIS COMPLEX PROBLEM IN THE CURRENT CONTEXT. IN CONCLUSION, IT HIGHLIGHTS THE IMPORTANCE OF IMPLEMENTING RENEWED, MORE EFFICIENT AND EVIDENCE-BASED STRATEGIES TO CONTROL THE GROWING PREVALENCE OF OBESITY, WHICH WOULD ALSO IMPACT ON THE BURDEN OF RELATED CHRONIC DISEASES, AND THUS ON THE ECONOMY AND WELL-BEING OF LATIN AMERICAN SOCIETIES. 2023