1 84 114 A NOVEL EPIGENETIC MECHANISM OF FXR INHIBITING GLP-1 SECRETION VIA MIR-33 AND ITS DOWNSTREAM TARGETS. TYPE II DIABETES IS A COMPLEX, CHRONIC, AND PROGRESSIVE DISEASE. PREVIOUSLY, WE DEMONSTRATE THAT FXR INHIBITS GLP-1 SECRETION VIA INTERACTING WITH CREB TO INHIBIT THE TRANSCRIPTIONAL ACTIVITY OF CREB, THUS PROMOTING THE DEVELOPMENT OF TYPE II DIABETES. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, HISTONE ACETYLATION, AND POST-TRANSCRIPTIONAL RNA REGULATION, ARE ESSENTIAL MEDIATORS CONTRIBUTING TO DIABETES-ASSOCIATED MORBIDITY AND MORTALITY. THUS, WE ATTEMPTED TO INVESTIGATE THE EPIGENETIC MECHANISMS OF FXR MODULATING GLP-1 SECRETION. FIRSTLY, THE INVOLVEMENT OF HISTONE ACETYLATION, DNA METHYLATION, AND POST-TRANSCRIPTIONAL REGULATION IN FXR INHIBITING GLP-1 SECRETION WAS VERIFIED. AS FXR OVEREXPRESSION SIGNIFICANTLY INHIBITED THE ACTIVITY OF GCG 3'-UTR, WE HYPOTHESIZE THAT MIRNA MIGHT PARTICIPATE IN THE MECHANISM. TWO ONLINE TOOLS AND REAL-TIME PCR REVEALED THAT FXR PROMOTED MIR-33 EXPRESSION. MOREOVER, MIR-33 INHIBITED THE EXPRESSION OF GCG AND CREB1 THROUGH DIRECT TARGETING IN STC-1 CELLS. FXR OVEREXPRESSION IN STC-1 CELLS SIGNIFICANTLY REDUCED THE MRNA EXPRESSION AND PROTEIN LEVELS OF BOTH GCG AND CREB1, AS WELL AS THE SECRETION OF GLP-1; MIR-33 INHIBITION EXERTED OPPOSING EFFECTS. MORE IMPORTANTLY, THE EFFECTS OF FXR OVEREXPRESSION WERE SIGNIFICANTLY REVERSED BY MIR-33 INHIBITION, INDICATING THAT FXR INHIBITED GLP-1 SECRETION THROUGH PROMOTING MIR-33 EXPRESSION, THEREFORE INHIBITING THE EXPRESSION OF MIR-33 TARGETS, GCG AND CREB1. IN CONCLUSION, WE PROVIDE A NOVEL EPIGENETIC MECHANISM BY WHICH FXR INHIBITS THE SECRETION OF GLP-1 THROUGH MIR-33 AND ITS TWO DOWNSTREAM TARGETS, GCG AND CREB1. THESE FINDINGS MIGHT PROVIDE INNOVATIVE STRATEGIES FOR IMPROVING TYPE II DIABETES, WHICH NEEDS FURTHER IN VIVO AND CLINICAL INVESTIGATION. 2019 2 4514 31 MULTI-OMICS ANALYSIS REVEALS CHANGES IN THE INTESTINAL MICROBIOME, TRANSCRIPTOME, AND METHYLOME IN A RAT MODEL OF CHRONIC NON-BACTERIAL PROSTATITIS: INDICATIONS FOR THE EXISTENCE OF THE GUT-PROSTATE AXIS. CHRONIC NON-BACTERIAL PROSTATITIS (CNP) IS ONE OF THE MOST PREVALENT DISEASES IN HUMAN MALES WORLDWIDE. IN 2005, THE PROSTATE-GUT AXIS WAS FIRST PROPOSED TO INDICATE THE CLOSE RELATIONSHIP BETWEEN THE PROSTATE AND THE INTESTINE. THIS STUDY INVESTIGATED CNP-INDUCED CHANGES OF THE GUT MICROBIOTA, GENE EXPRESSION AND DNA METHYLATION IN A RAT MODEL BY USING MULTI-OMICS ANALYSIS. FIRSTLY, 16S RDNA SEQUENCING PRESENTED AN ALTERED STRUCTURE OF THE MICROBIOTA IN CECUM OF CNP RATS. THEN, TRANSCRIPTOMIC ANALYSIS REVEALED THAT THE EXPRESSION OF 185 GENES IN INTESTINAL EPITHELIUM WAS SIGNIFICANTLY CHANGED BY CNP. THESE CHANGES CAN PARTICIPATE IN THE IMMUNE SYSTEM, DIGESTIVE SYSTEM, METABOLIC PROCESS, ETC. FINALLY, METHYLC-CAPTURE SEQUENCING (MCC-SEQ) FOUND 73,232 DIFFERENTIALLY METHYLATED SITES (DMSS) IN THE DNA OF INTESTINAL EPITHELIUM BETWEEN CONTROL AND CNP RATS. A COMBINED ANALYSIS OF METHYLOMICS AND TRANSCRIPTOMICS SUGGESTED AN EPIGENETIC MECHANISM FOR CNP-INDUCED DIFFERENTIAL EXPRESSION GENES CORRELATED WITH INTESTINAL BARRIER FUNCTION, IMMUNITY, METABOLISM, ENTERIC INFECTIOUS DISEASE, ETC. MORE IMPORTANTLY, THE TRANSCRIPTOMIC, METHYLOMIC AND GUT MICROBIAL CHANGES WERE HIGHLY CORRELATED WITH MULTIPLE PROCESSES INCLUDING INTESTINAL IMMUNITY, METABOLISM AND EPITHELIAL BARRIER FUNCTION. IN THIS STUDY, DISRUPTED HOMEOSTASIS IN THE GUT MICROBIOTA, GENE EXPRESSION AND DNA METHYLATION WERE REPORTED IN CNP, WHICH SUPPORTS THE EXISTENCE OF THE GUT-PROSTATE AXIS. 2021 3 1341 29 DETANGLING THE INTERRELATIONS BETWEEN MAFLD, INSULIN RESISTANCE, AND KEY HORMONES. METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASE (MAFLD) HAS INCREASINGLY BECOME A SIGNIFICANT AND HIGHLY PREVALENT CAUSE OF CHRONIC LIVER DISEASE, DISPLAYING A WIDE ARRAY OF RISK FACTORS AND PATHOPHYSIOLOGIC MECHANISMS OF WHICH ONLY A FEW HAVE SO FAR BEEN CLEARLY ELUCIDATED. A BIDIRECTIONAL INTERACTION BETWEEN HORMONAL DISCREPANCIES AND METABOLIC-RELATED DISORDERS, INCLUDING OBESITY, TYPE 2 DIABETES MELLITUS (T2DM), AND POLYCYSTIC OVARIAN SYNDROME (PCOS) HAS BEEN DESCRIBED. SINCE THE CHANGE IN NOMENCLATURE FROM NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) TO MAFLD IS BASED ON THE CLEAR IMPACT OF METABOLIC ELEMENTS ON THE DISEASE, THE RECIPROCAL INTERACTIONS OF HORMONES SUCH AS INSULIN, ADIPOKINES (LEPTIN AND ADIPONECTIN), AND ESTROGENS HAVE STRONGLY POINTED TO THE INTRINSIC LINKS THAT LEAD TO THE HETEROGENEOUS EPIDEMIOLOGY, CLINICAL PRESENTATIONS, AND RISK FACTORS INVOLVED IN MAFLD IN DIFFERENT POPULATIONS. THE OBJECTIVE OF THIS WORK IS TWOFOLD. FIRSTLY, THERE IS A BRIEF DISCUSSION REGARDING THE CHANGE IN NOMENCLATURE AS WELL AS EPIDEMIOLOGY, RISK FACTORS, AND PATHOPHYSIOLOGIC MECHANISMS OTHER THAN HORMONAL EFFECTS, WHICH INCLUDE NUTRITION AND THE GUT MICROBIOME, AS WELL AS GENETIC AND EPIGENETIC INFLUENCES. SECONDLY, WE REVIEW THE BASIS OF THE MOST IMPORTANT HORMONAL FACTORS INVOLVED IN THE DEVELOPMENT AND PROGRESSION OF MAFLD THAT ACT BOTH INDEPENDENTLY AND IN AN INTERRELATED MANNER. 2022 4 3816 37 INTRAUTERINE PROGRAMMING OF CARTILAGINOUS 11BETA-HSD2 INDUCED BY CORTICOSTERONE AND CAFFEINE MEDIATED SUSCEPTIBILITY TO ADULT OSTEOARTHRITIS. OUR PREVIOUS STUDY REPORTED THAT PRENATAL CAFFEINE EXPOSURE (PCE) COULD INDUCE CHONDRODYSPLASIA AND INCREASE THE SUSCEPTIBILITY TO OSTEOARTHRITIS IN OFFSPRING RATS. HOWEVER, THE POTENTIAL MECHANISMS AND INITIATING FACTORS REMAIN UNKNOWN. THIS STUDY AIMS TO INVESTIGATE WHETHER 11BETA-HSD2, A GLUCOCORTICOID-METABOLIZING ENZYME, IS INVOLVED IN THE SUSCEPTIBILITY OF OSTEOARTHRITIS INDUCED BY PCE AND TO FURTHER EXPLORE ITS POTENTIAL MECHANISMS AND INITIATING FACTORS. FIRSTLY, WE FOUND THAT PCE REDUCED CARTILAGE MATRIX SYNTHESIS (AGGRECAN/COL2A1 EXPRESSION) IN MALE ADULT OFFSPRING RATS AND EXHIBITED AN OSTEOARTHRITIS PHENOTYPE FOLLOWING CHRONIC STRESS, WHICH WAS ASSOCIATED WITH PERSISTENTLY REDUCED H3K9AC AND H3K27AC LEVELS AT THE PROMOTER OF 11BETA-HSD2 AS WELL AS ITS EXPRESSION IN THE CARTILAGE FROM FETUS TO ADULTHOOD. THE EXPRESSION OF 11BETA-HSD2, AGGRECAN AND COL2A1 WERE ALL DECREASED BY CORTICOSTERONE IN THE FETAL CHONDROCYTES, WHILE OVEREXPRESSION OF 11BETA-HSD2 COULD PARTIALLY ALLEVIATE THE DECREASE OF MATRIX SYNTHESIS INDUCED BY CORTICOSTERONE IN VITRO. FURTHERMORE, THE GLUCOCORTICOID RECEPTOR (GR) ACTIVATED BY GLUCOCORTICOIDS DIRECTLY BONDED TO THE PROMOTER REGION OF 11BETA-HSD2 TO INHIBIT ITS EXPRESSION. MEANWHILE, THE ACTIVATED GR REDUCED THE H3K9AC AND H3K27AC LEVELS OF 11BETA-HSD2 BY RECRUITING HDAC4 AND PROMOTING GR-HDAC4 PROTEIN INTERACTION TO INHIBIT THE 11BETA-HSD2 EXPRESSION. MOREOVER, CAFFEINE COULD REDUCE THE EXPRESSION OF 11BETA-HSD2 BY INHIBITING THE CAMP/PKA SIGNALING PATHWAY BUT WITHOUT REDUCING THE H3K9AC AND H3K27AC LEVELS OF 11BETA-HSD2, THEREBY SYNERGISTICALLY ENHANCING THE CORTICOSTERONE EFFECT. IN CONCLUSION, THE PERSISTENTLY REDUCED H3K9AC AND H3K27AC LEVELS OF 11BETA-HSD2 FROM FETUS TO ADULTHOOD MEDIATED THE INHIBITION OF CARTILAGE MATRIX SYNTHESIS AND THE INCREASED SUSCEPTIBILITY TO OSTEOARTHRITIS. THIS EPIGENETIC PROGRAMMING CHANGE IN UTERO WAS INDUCED BY GLUCOCORTICOIDS WITH SYNERGISTIC EFFECT OF CAFFEINE. 2022 5 2241 32 EPIGENETIC MODULATION IN PERIODONTITIS: INTERACTION OF ADIPONECTIN AND JMJD3-IRF4 AXIS IN MACROPHAGES. EMERGING EVIDENCE SUGGESTS AN IMPORTANT ROLE FOR EPIGENETIC MECHANISMS IN MODULATING SIGNALS DURING MACROPHAGE POLARIZATION AND INFLAMMATION. JMJD3, A JMJC FAMILY HISTONE DEMETHYLASE NECESSARY FOR M2 POLARIZATION IS ALSO REQUIRED FOR EFFECTIVE INDUCTION OF MULTIPLE M1 GENES BY LIPOPOLYSACCHARIDE (LPS). HOWEVER, THE EFFECTS OF JMJD3 TO INFLAMMATION IN THE CONTEXT OF OBESITY REMAINS UNKNOWN. TO ADDRESS THIS DEFICIENCY, WE FIRSTLY EXAMINED THE EXPRESSION OF JMJD3 IN MACROPHAGE ISOLATED FROM BONE MARROW AND ADIPOSE TISSUE OF DIET INDUCED OBESITY (DIO) MICE. THE RESULTS INDICATED THAT JMJD3 WAS DOWN-REGULATED IN OBESITY. ADIPONECTIN (APN), A FACTOR SECRETED BY ADIPOSE TISSUE WHICH IS DOWN-REGULATED IN OBESITY, FUNCTIONS TO SWITCH MACROPHAGE POLARIZATION FROM M1 TO M2, THEREBY ATTENUATING CHRONIC INFLAMMATION. INTRIGUINGLY, OUR RESULTS INDICATED THAT APN CONTRIBUTED TO JMJD3 UP-REGULATION, REDUCED MACROPHAGE INFILTRATION IN OBESE ADIPOSE TISSUE, AND ABOLISHED THE UP-REGULATION OF JMJD3 IN PERITONEAL MACROPHAGES ISOLATED FROM DIO MICE WHEN CHALLENGED WITH PORPHYROMONAS GINGIVALIS LPS (PG.LPS). TO ELUCIDATE THE INTERACTION OF APN AND JMJD3 INVOLVED IN MACROPHAGE TRANSFORMATION IN THE CONTEXT OF INFLAMMATION, WE DESIGNED THE LOSS AND GAIN-FUNCTION EXPERIMENTS OF APN IN VIVO WITH APN(-/-) MICE WITH EXPERIMENTAL PERIODONTITIS AND IN VITRO WITH MACROPHAGE ISOLATED FROM APN(-/-) MICE. FOR THE FIRST TIME, WE FOUND THAT APN CAN HELP TO REDUCE PERIODONTITIS-RELATED BONE LOSS, MODULATE JMJD3 AND IRF4 EXPRESSION, AND MACROPHAGE INFILTRATION. THEREFORE, IT CAN BE INFERRED THAT APN MAY CONTRIBUTE TO ANTI-INFLAMMATION MACROPHAGE POLARIZATION BY REGULATING JMJD3 EXPRESSION, WHICH PROVIDES A BASIS FOR MACROPHAGE-CENTERED EPIGENETIC THERAPEUTIC STRATEGIES. 2016 6 4450 28 MOLECULAR MECHANISMS AND CELLULAR CONTRIBUTION FROM LUNG FIBROSIS TO LUNG CANCER DEVELOPMENT. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE, FIBROSING INTERSTITIAL LUNG DISEASE (ILD) OF UNKNOWN AETIOLOGY, WITH A MEDIAN SURVIVAL OF 2-4 YEARS FROM THE TIME OF DIAGNOSIS. ALTHOUGH IPF HAS UNKNOWN AETIOLOGY BY DEFINITION, THERE HAVE BEEN IDENTIFIED SEVERAL RISKS FACTORS INCREASING THE PROBABILITY OF THE ONSET AND PROGRESSION OF THE DISEASE IN IPF PATIENTS SUCH AS CIGARETTE SMOKING AND ENVIRONMENTAL RISK FACTORS ASSOCIATED WITH DOMESTIC AND OCCUPATIONAL EXPOSURE. AMONG THEM, CIGARETTE SMOKING TOGETHER WITH CONCOMITANT EMPHYSEMA MIGHT PREDISPOSE IPF PATIENTS TO LUNG CANCER (LC), MOSTLY TO NON-SMALL CELL LUNG CANCER (NSCLC), INCREASING THE RISK OF LUNG CANCER DEVELOPMENT. TO THIS PURPOSE, IPF AND LC SHARE SEVERAL CELLULAR AND MOLECULAR PROCESSES DRIVING THE PROGRESSION OF BOTH PATHOLOGIES SUCH AS FIBROBLAST TRANSITION PROLIFERATION AND ACTIVATION, ENDOPLASMIC RETICULUM STRESS, OXIDATIVE STRESS, AND MANY GENETIC AND EPIGENETIC MARKERS THAT PREDISPOSE IPF PATIENTS TO LC DEVELOPMENT. NINTEDANIB, A TYROSINE-KINASE INHIBITOR, WAS FIRSTLY DEVELOPED AS AN ANTICANCER DRUG AND THEN RECOGNIZED AS AN ANTI-FIBROTIC AGENT BASED ON THE COMMON TARGET MOLECULAR PATHWAY. IN THIS REVIEW OUR AIM IS TO DESCRIBE THE UPDATED STUDIES ON COMMON CELLULAR AND MOLECULAR MECHANISMS BETWEEN IPF AND LUNG CANCER, KNOWLEDGE OF WHICH MIGHT HELP TO FIND NOVEL THERAPEUTIC TARGETS FOR THIS DISEASE COMBINATION. 2021 7 6153 23 THE FUNCTION OF THE METALS IN REGULATING EPIGENETICS DURING PARKINSON'S DISEASE. PARKINSON'S MEANS PARKINSON'S DISEASE, A CHRONIC DEGENERATIVE DISEASE OF CENTRAL NERVOUS SYSTEM. THE MAIN AREA WHICH IS AFFECTED BY THIS DISEASE IS MOTOR SYSTEM. SINCE IT FIRSTLY FOUNDED BY JAMES PARKINSON IN HIS 1817 PUBLICATION, NOWADAYS, PEOPLE STILL HAVE LOTS OF QUESTIONS ABOUT THIS DISEASE. THIS REVIEW MAINLY SUMMARIZES THE EPIGENETICS OF PARKINSON'S. DNA METHYLATION IS ONE OF THE EPIGENETIC MECHANISMS OF PARKINSON'S. DURING THE DEVELOPMENT OF DISEASE, GLOBAL HYPOMETHYLATION, AND HYPERMETHYLATION HAPPEN IN DIFFERENT AREAS OF PATIENTS. ANOTHER EPIGENETIC MECHANISM IS HISTONE MODIFICATION. PEOPLE BELIEVE THAT SOME METALS CAN INDUCE PARKINSON'S DISEASE BY MODULATING EPIGENETIC MECHANISMS. THIS REVIEW SUMMARIZES THE RELATIONSHIPS BETWEEN DIFFERENT METALS AND PARKINSON'S DISEASE. HOWEVER, THE SPECIFIC ROLES OF MOST METALS IN EPIGENETICS ARE STILL UNKNOWN, WHICH NEED FURTHER RESEARCH. 2020 8 1129 31 COMPREHENSIVE ANALYSIS OF MRNA-LNCRNA CO-EXPRESSION PROFILES IN MOUSE BRAIN DURING INFECTION WITH TOXOPLASMA GONDII. TOXOPLASMA GONDII IS AN OBLIGATE INTRACELLULAR PROTOZOAN PARASITE WHICH SERIOUSLY THREATENS THE HEALTH OF DOMESTIC ANIMALS AND HUMANS. LONG NON-CODING RNAS (LNCRNAS) ARE NON-PROTEIN-CODING TRANSCRIPTS GREATER THAN 200 NUCLEOTIDES, WHICH ARE WIDELY INVOLVED IN TRANSCRIPTIONAL AND EPIGENETIC REGULATIONS. HOWEVER, LITTLE IS KNOWN ABOUT THE ROLES OF HOST LNCRNAS IN THE RESPONSE TO T. GONDII INFECTIONS. IN THIS STUDY, USING ILLUMINA SEQUENCING TECHNOLOGY, WE ANALYZED THE EXPRESSION PROFILES OF MRNAS AND LNCRNAS IN BALB/C MOUSE BRAIN FOLLOWING INFECTION BY T. GONDII PRU STRAIN (TYPE II GENOTYPE) CYSTS. THE IDENTIFIED DIFFERENTIALLY EXPRESSED (DE) RNAS WERE SUBJECTED TO BIOINFORMATICS ANALYSIS. A TOTAL OF 2,090 ANNOTATED LNCRNAS ALONG WITH 3,577 NOVEL LNCRNAS WERE IDENTIFIED. IN THE ACUTELY INFECTED MOUSE BRAIN, A TOTAL OF 330 MRNAS AND 19 LNCRNAS WERE DYS-REGULATED, WHEREAS 136 DE MRNAS AND 9 DE LNCRNAS WERE IDENTIFIED IN CHRONICALLY INFECTED MOUSE BRAIN. GO ANALYSIS REVEALED THAT THESE DE MRNAS IDENTIFIED AT ACUTE INFECTION STAGE WERE INVOLVED IN IMMUNE RESPONSE, WHEREAS DE MRNAS FOUND AT CHRONIC INFECTION STAGE WERE MOSTLY ENRICHED IN RESPONSE TO PROTOZOAN. KEGG ANALYSIS SHOWED THAT DE MRNAS WERE SIGNIFICANTLY ENRICHED IN DISEASE RELATED PATHWAYS. IN ADDITION, THE PUTATIVE MRNA-LNCRNA CO-EXPRESSION NETWORK WAS CONSTRUCTED, AND SEVERAL HUB REGULATORY RNAS WERE IDENTIFIED BASED ON THE TRANSCRIPTOME DATA. THIS STUDY FIRSTLY CHARACTERIZED THE CO-EXPRESSION PROFILE OF MRNAS AND LNCRNAS IN MOUSE BRAIN INFECTED WITH T. GONDII AND PROVIDED A FRAMEWORK FOR FURTHER STUDIES OF THE ROLES OF LNCRNAS IN HOST NEUROPATHOLOGY DURING TOXOPLASMOSIS PROGRESSION. 2023 9 2219 38 EPIGENETIC MODIFICATIONS IN HEPATIC STELLATE CELLS CONTRIBUTE TO LIVER FIBROSIS. LIVER FIBROSIS REPRESENTS THE FINAL COMMON PATHWAY OF VIRTUALLY ALL TYPES OF CHRONIC LIVER DISEASES, AND IT HAS BEEN A MAJOR PUBLIC HEALTH CONCERN. MANY GENES HAVE BEEN DEMONSTRATED TO BE INVOLVED IN THE PATHOGENESIS OF LIVER FIBROSIS, WHILE THE MECHANISMS UNDERLYING GENE REGULATION STILL NEEDS FURTHER RESEARCH. ON THE OTHER HAND, HEPATIC STELLATE CELLS (HSCS) ARE QUIESCENT CELLS IN THE PERISINUSOIDAL SPACE IN LIVER. HSCS FACILITATE HEPATOCYTES INTERACTIONS VIA RELEASING SOLUBLE INFLAMMATORY FACTORS AND PRODUCING EXTRACELLULAR MATRIX. HSCS CAN BE ACTIVATED IN RESPONSE TO LIVER INJURY, AND THEY DIFFERENTIATE TO MYOFIBROBLASTS, WHICH GREATLY CONTRIBUTE TO THE FIBROGENESIS PROCESS. VARIOUS EPIGENETIC PROCEDURES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND FORMATION OF PARTICULAR CHROMATIN STRUCTURE, PLAY CRUCIAL ROLES IN THE GENE TRANSCRIPTIONAL EXPRESSION IN HSCS, REGULATING VARIOUS VITAL PROCESSES. FOR INSTANCE, EPIGENETIC MODULATION ON THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPAR-GAMMA) GENE PROMOTER ACCOUNTS FOR HSC DIFFERENTIATION THROUGH INTERACTING PATHWAYS. ABERRANT EXPRESSION OF A SERIES OF HISTONES AND CHEMOKINES IN ACTIVATED HSCS CAN AGGRAVATE INFLAMMATION AND OXIDATIVE STRESS, WHICH IN TURN PROMOTES DIFFERENTIATION OF HSCS TO MYOFIBROBLASTS AND ENHANCES THE WHOLE FIBROGENESIS PROCESS. DEGRADATION OF EXTRACELLULAR MATRIX IS ALSO REGULATED THROUGH EPIGENETIC MODULATION ON MATRIX ASSOCIATED ENZYMES. MOREOVER, FIBROSIS-RELATED EPIGENETIC MODIFICATIONS IN THE PARENTAL GENERATION MAY BE INHERITED TO THEIR OFFSPRING. IN THIS REVIEW, WE FIRSTLY SUMMARIZE THE VITAL EPIGENETIC MODIFICATIONS OF FIBROSIS-RELATED GENES IN HSCS, AND HIGHLIGHT SPECIFIC NUCLEIC ACID SEQUENCES AND STRUCTURES IN GENE PROMOTERS AS IMPORTANT ACTION SITES, WHICH MAY PROVIDE INDICATORS FOR LIVER FIBROSIS DIAGNOSIS IN THE FUTURE. 2013 10 1932 29 ENVIRONMENTAL EXPOSURES: AN UNDERRECOGNIZED CONTRIBUTION TO NONCOMMUNICABLE DISEASES. PREVIOUS ATTEMPTS TO DETERMINE THE DEGREE TO WHICH EXPOSURE TO ENVIRONMENTAL FACTORS CONTRIBUTE TO NONCOMMUNICABLE DISEASES (NCDS) HAVE BEEN VERY CONSERVATIVE AND HAVE SIGNIFICANTLY UNDERESTIMATED THE ACTUAL CONTRIBUTION OF THE ENVIRONMENT FOR AT LEAST TWO REASONS. FIRSTLY, MOST PREVIOUS REPORTS HAVE EXCLUDED THE CONTRIBUTION OF LIFESTYLE BEHAVIORAL RISK FACTORS, BUT THESE USUALLY INVOLVE SIGNIFICANT EXPOSURE TO ENVIRONMENTAL CHEMICALS THAT INCREASE RISK OF DISEASE. SECONDLY, EARLY LIFE EXPOSURE TO CHEMICAL CONTAMINANTS IS NOW CLEARLY ASSOCIATED WITH AN ELEVATED RISK OF SEVERAL DISEASES LATER IN LIFE, BUT THESE CONNECTIONS ARE OFTEN DIFFICULT TO DISCERN. THIS IS ESPECIALLY TRUE FOR ASTHMA AND NEURODEVELOPMENTAL CONDITIONS, BUT THERE IS ALSO A MAJOR CONTRIBUTION TO THE DEVELOPMENT OF OBESITY AND CHRONIC DISEASES. MOST CANCERS ARE CAUSED BY ENVIRONMENTAL EXPOSURES IN GENETICALLY SUSCEPTIBLE INDIVIDUALS. IN ADDITION, NEW INFORMATION SHOWS SIGNIFICANT ASSOCIATIONS BETWEEN CARDIOVASCULAR DISEASES AND DIABETES AND EXPOSURE TO ENVIRONMENTAL CHEMICALS PRESENT IN AIR, FOOD, AND WATER. THESE RELATIONSHIPS LIKELY REFLECT THE COMBINATION OF EPIGENETIC EFFECTS AND GENE INDUCTION. ENVIRONMENTAL FACTORS CONTRIBUTE SIGNIFICANTLY MORE TO NCDS THAN PREVIOUS REPORTS HAVE SUGGESTED. PREVENTION NEEDS TO SHIFT FOCUS FROM INDIVIDUAL RESPONSIBILITY TO SOCIETAL RESPONSIBILITY AND AN UNDERSTANDING THAT EFFECTIVE PREVENTION OF NCDS ULTIMATELY RELIES ON IMPROVED ENVIRONMENTAL MANAGEMENT TO REDUCE EXPOSURE TO MODIFIABLE RISKS. 2013 11 1183 25 CONVERGING RELATIONSHIPS OF OBESITY AND HYPERURICEMIA WITH SPECIAL REFERENCE TO METABOLIC DISORDERS AND PLAUSIBLE THERAPEUTIC IMPLICATIONS. BACKGROUND: OBESITY AND HYPERURICEMIA MUTUALLY INFLUENCE METABOLIC SYNDROME. THIS STUDY DISCUSSES THE METABOLIC RELATIONSHIPS BETWEEN OBESITY AND HYPERURICEMIA IN TERMS OF PATHOPHYSIOLOGY, COMPLICATIONS, AND TREATMENTS. METHODS: WE SEARCHED FOR PRECLINICAL OR CLINICAL STUDIES ON THE PATHOPHYSIOLOGY, COMPLICATIONS, AND THERAPY OF OBESITY AND HYPERURICEMIA ON THE PUBMED DATABASE. RESULTS: IN THIS SYSTEMIC REVIEW, WE SUMMARIZED OUR SEARCHING RESULTS ON TOPICS OF PATHOPHYSIOLOGY, COMPLICATIONS AND THERAPEUTIC STRATEGY. IN PATHOPHYSIOLOGY, WE FIRSTLY INTRODUCE GENETIC VARIATIONS FOR OBESITY, HYPERURICEMIA AND THEIR RELATIONSHIPS BY GENETIC STUDIES. SECONDLY, WE TALK ABOUT THE EPIGENETIC INFLUENCES ON OBESITY AND HYPERURICEMIA. THIRDLY, WE DESCRIBE THE CENTRAL METABOLIC REGULATION AND THE ROLE OF HYPERURICEMIA. THEN, WE REFER TO THE CHARACTER OF ADIPOSE TISSUE INFLAMMATION AND OXIDATIVE STRESS IN THE OBESITY AND HYPERURICEMIA. IN THE LAST PART OF THIS TOPIC, WE REVIEWED THE CRITICAL LINKS OF GUT MICROBIOTA IN THE OBESITY AND HYPERURICEMIA. IN THE FOLLOWING PART, WE REVIEW THE PATHOPHYSIOLOGY OF MAJOR COMPLICATIONS IN OBESITY AND HYPERURICEMIA INCLUDING INSULIN RESISTANCE AND TYPE 2 DIABETES MELLITUS, CHRONIC KIDNEY DISEASE, CARDIOVASCULAR DISEASES, AND CANCERS. FINALLY, WE RECAPITULATE THE THERAPEUTIC STRATEGIES ESPECIALLY THE NOVEL PHARMACEUTIC INTERVENTIONS FOR OBESITY AND HYPERURICEMIA, WHICH CONCURRENTLY SHOW THE MUTUAL METABOLIC INFLUENCES BETWEEN TWO DISEASES. CONCLUSION: THE DATA REVIEWED HERE DELINEATE THE METABOLIC RELATIONSHIPS BETWEEN OBESITY AND HYPERURICEMIA, AND PROVIDE A COMPREHENSIVE OVERVIEW OF THE THERAPEUTIC TARGETS FOR THE MANAGEMENT OF METABOLIC SYNDROMES. 2020 12 3311 34 HIGHLIGHTING THE TRAJECTORY FROM INTRAUTERINE GROWTH RESTRICTION TO FUTURE OBESITY. DURING THE LAST DECADES SEVERAL LINES OF EVIDENCE REPORTED THE ASSOCIATION OF AN ADVERSE INTRAUTERINE ENVIRONMENT, LEADING TO INTRAUTERINE RESTRICTION, WITH FUTURE DISEASE, SUCH AS OBESITY AND METABOLIC SYNDROME, BOTH LEADING TO INCREASED CARDIOVASCULAR AND CANCER RISK. THE UNDERLYING EXPLANATION FOR THIS ASSOCIATION HAS FIRSTLY BEEN EXPRESSED BY THE BARKER'S HYPOTHESIS, THE "THRIFTY PHENOTYPE HYPOTHESIS". ACCORDING TO THIS HYPOTHESIS, A FETUS FACING AN ADVERSE INTRAUTERINE ENVIRONMENT ADAPTS TO THIS ENVIRONMENT THROUGH A REPROGRAMMING OF ITS ENDOCRINE-METABOLIC STATUS, DURING THE CRUCIAL WINDOW OF DEVELOPMENTAL PLASTICITY TO SAVE ENERGY FOR SURVIVAL, PROVIDING LESS ENERGY AND NUTRIENTS TO THE ORGANS THAT ARE NOT ESSENTIAL FOR SURVIVAL. THIS THEORY EVOLVED TO THE CONCEPT OF THE DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASE (DOHAD). THUS, IN THE SETTING OF AN ADVERSE, F. EX. PROTEIN RESTRICTED INTRAUTERINE ENVIRONMENT, WHILE THE ENERGY IS MAINLY DIRECTED TO THE BRAIN, THE PERIPHERAL ORGANS, F.EX. THE MUSCLES AND THE LIVER UNDERGO AN ADAPTATION THAT IS EXPRESSED THROUGH INSULIN RESISTANCE. THE ADAPTATION AT THE HEPATIC LEVEL PREDISPOSES TO FUTURE DYSLIPIDEMIA, THE MODIFICATIONS AT THE VASCULAR LEVEL TO ENDOTHELIAL DAMAGE AND FUTURE HYPERTENSION AND, OVERALL, THROUGH THE INSULIN RESISTANCE TO THE DEVELOPMENT OF METABOLIC SYNDROME. ALL THESE ADAPTATIONS ARE SUGGESTED TO TAKE PLACE THROUGH EPIGENETIC MODIFICATIONS OF THE EXPRESSION OF GENES WITHOUT CHANGE OF THEIR AMINO-ACID SEQUENCE. THE EPIGENETIC MODIFICATIONS LEADING TO FUTURE OBESITY AND CARDIOVASCULAR RISK ARE THOUGHT TO INDUCE APPETITE DYSREGULATION, PROMOTING FOOD INTAKE AND ADIPOGENESIS, FACILITATING OBESITY DEVELOPMENT. THE EPIGENETIC MODIFICATIONS MAY EVEN PERSIST INTO THE NEXT GENERATION EVEN THOUGH THE SUBSEQUENT GENERATION HAS NOT BEEN EXPOSED TO AN ADVERSE INTRAUTERINE ENVIRONMENT, A NOTION DEFINED AS THE "TRANSGENERATIONAL TRANSFER OF ENVIRONMENTAL INFORMATION". AS A CONSEQUENCE, IF THE INCREASED PUBLIC HEALTH BURDEN AND COSTS OF NON-COMMUNICABLE CHRONIC DISEASES SUCH AS OBESITY, HYPERTENSION, METABOLIC SYNDROME AND TYPE 2 DIABETES HAVE TO BE MINIMIZED, SPECIAL ATTENTION SHOULD BE LAID TO THE HEALTHY LIFESTYLE HABITS OF WOMEN OF REPRODUCTIVE AGE, INCLUDING HEALTHY DIET AND PHYSICAL ACTIVITY TO BE ESTABLISHED LONG BEFORE ANY PREGNANCY TAKES PLACE IN ORDER TO PROVIDE THE BEST CONDITIONS FOR BOTH SOMATIC AND MENTAL HEALTH OF FUTURE GENERATIONS. 2022 13 4880 29 OVERVIEW OF MMP-13 AS A PROMISING TARGET FOR THE TREATMENT OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON DEGENERATIVE DISEASE CHARACTERIZED BY THE DESTRUCTION OF ARTICULAR CARTILAGE AND CHRONIC INFLAMMATION OF SURROUNDING TISSUES. MATRIX METALLOPROTEINASE-13 (MMP-13) IS THE PRIMARY MMP INVOLVED IN CARTILAGE DEGRADATION THROUGH ITS PARTICULAR ABILITY TO CLEAVE TYPE II COLLAGEN. HENCE, IT IS AN ATTRACTIVE TARGET FOR THE TREATMENT OF OA. HOWEVER, THE DETAILED MOLECULAR MECHANISMS OF OA INITIATION AND PROGRESSION REMAIN ELUSIVE, AND, CURRENTLY, THERE ARE NO INTERVENTIONS AVAILABLE TO RESTORE DEGRADED CARTILAGE. THIS REVIEW FULLY ILLUSTRATES THE INVOLVEMENT OF MMP-13 IN THE INITIATION AND PROGRESSION OF OA THROUGH THE REGULATION OF MMP-13 ACTIVITY AT THE MOLECULAR AND EPIGENETIC LEVELS, AS WELL AS THE STRATEGIES THAT HAVE BEEN EMPLOYED AGAINST MMP-13. THE AIM OF THIS REVIEW IS TO IDENTIFY MMP-13 AS AN ATTRACTIVE TARGET FOR INHIBITOR DEVELOPMENT IN THE TREATMENT OF OA. 2021 14 3800 30 INTERPLAY OF INFLAMMATORY MEDIATORS WITH EPIGENETICS AND CARTILAGE MODIFICATIONS IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA), A DEGENERATIVE DISEASE OF DIARTHRODIAL JOINTS, IS INFLUENCED BY MECHANICAL AND INFLAMMATORY FACTORS WITH AGING, OBESITY, CHRONIC INJURIES, AND SECONDARY DISEASES THOUGHT TO BE MAJOR FACTORS DRIVING THE PROCESS OF ARTICULAR CARTILAGE DEGENERATION. CHONDROCYTES, THE CELLULAR COMPONENT OF CARTILAGE, RESIDE IN AN AVASCULAR ENVIRONMENT AND NORMALLY HAVE LIMITED POTENTIAL TO REPLICATE. HOWEVER, EXTRINSIC FACTORS SUCH AS INJURY TO THE JOINT OR INTRINSIC ALTERATIONS TO THE CHONDROCYTES THEMSELVES CAN LEAD TO AN ALTERED PHENOTYPE AND DEVELOPMENT OF OA. SYNOVIAL INFLAMMATION IS ALSO A PIVOTAL ELEMENT OF THE OSTEOARTHRITIC, DEGENERATIVE PROCESS: INFLUX OF PRO-INFLAMMATORY CYTOKINES AND PRODUCTION OF MATRIX METALLOPROTEINASES ACCELERATE ADVANCED CELLULAR PROCESSES SUCH AS SYNOVITIS AND CARTILAGE DAMAGE. AS WELL AS A GENETIC INPUT, RECENT DATA HAVE HIGHLIGHTED EPIGENETIC FACTORS AS CONTRIBUTING TO DISEASE. STUDIES CONDUCTED OVER THE LAST DECADE HAVE FOCUSED ON THREE KEY ASPECTS IN OA; INFLAMMATION AND THE IMMUNE RESPONSE, GENOME-WIDE ASSOCIATION STUDIES THAT HAVE IDENTIFIED IMPORTANT GENES UNDERGOING EPIGENETIC MODIFICATIONS, AND FINALLY HOW CHONDROCYTES TRANSFORM IN THEIR FUNCTION DURING DEVELOPMENT AND DISEASE. DATA HIGHLIGHTED HERE HAVE IDENTIFIED CRITICAL INFLAMMATORY GENES INVOLVED IN OA AND HOW THESE FACTORS IMPACT CHONDROCYTE HYPERTROPHY IN THE DISEASE. THIS REVIEW ALSO ADDRESSES KEY INFLAMMATORY FACTORS IN SYNOVIAL INFLAMMATION, EPIGENETICS, AND CHONDROCYTE FATE, AND HOW AGENTS THAT INHIBIT EPIGENETIC MECHANISMS LIKE DNA METHYLATION AND HISTONE MODIFICATIONS COULD AID IN DEVELOPMENT OF LONG-TERM TREATMENT STRATEGIES FOR THE DISEASE. 2018 15 5821 30 STRESS IN OBESITY AND ASSOCIATED METABOLIC AND CARDIOVASCULAR DISORDERS. OBESITY HAS SIGNIFICANT IMPLICATIONS FOR HEALTHCARE, SINCE IT IS A MAJOR RISK FACTOR FOR BOTH TYPE 2 DIABETES AND THE METABOLIC SYNDROME. THIS SYNDROME IS A COMMON AND COMPLEX DISORDER COMBINING OBESITY, DYSLIPIDEMIA, HYPERTENSION, AND INSULIN RESISTANCE. IT IS ASSOCIATED WITH HIGH ATHEROSCLEROTIC CARDIOVASCULAR RISK, WHICH CAN ONLY PARTIALLY BE EXPLAINED BY ITS COMPONENTS. THEREFORE, TO EXPLAIN HOW OBESITY CONTRIBUTES TO THE DEVELOPMENT OF METABOLIC AND CARDIOVASCULAR DISORDERS, MORE AND BETTER INSIGHT IS REQUIRED INTO THE EFFECTS OF PERSONAL AND ENVIRONMENTAL STRESS ON DISEASE PROCESSES. IN THIS PAPER, WE SHOW THAT OBESITY IS A CHRONIC INFLAMMATORY DISEASE, WHICH HAS MANY MOLECULAR MECHANISMS IN COMMON WITH ATHEROSCLEROSIS. FURTHERMORE, WE FOCUS ON THE ROLE OF OXIDATIVE STRESS ASSOCIATED WITH OBESITY IN THE DEVELOPMENT OF THE METABOLIC SYNDROME. WE DISCUSS HOW SEVERAL STRESS CONDITIONS ARE RELATED TO INFLAMMATION AND OXIDATIVE STRESS IN ASSOCIATION WITH OBESITY AND ITS COMPLICATIONS. WE ALSO EMPHASIZE THE RELATION BETWEEN STRESS CONDITIONS AND THE DEREGULATION OF EPIGENETIC CONTROL MECHANISMS BY MEANS OF MICRORNAS AND SHOW HOW THIS IMPAIRMENT FURTHER CONTRIBUTES TO THE DEVELOPMENT OF OBESITY, CLOSING THE VICIOUS CIRCLE. FINALLY, WE DISCUSS THE LIMITATIONS OF CURRENT ANTI-INFLAMMATION AND ANTIOXIDANT THERAPY TO TREAT OBESITY. 2012 16 4152 28 MECHANISTIC INSIGHTS INTO THE PLEIOTROPIC EFFECTS OF BUTYRATE AS A POTENTIAL THERAPEUTIC AGENT ON NAFLD MANAGEMENT: A SYSTEMATIC REVIEW. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST COMMON CHRONIC DISEASES WORLDWIDE. AS A MULTIFACETED DISEASE, NAFLD'S PATHOGENESIS IS NOT ENTIRELY UNDERSTOOD, BUT RECENT EVIDENCE REVEALS THAT GUT MICROBIOTA PLAYS A SIGNIFICANT ROLE IN ITS PROGRESSION. BUTYRATE, A GUT MICROBIOTA METABOLITE, HAS BEEN REPORTED TO HAVE HEPATO-PROTECTIVE EFFECTS IN NAFLD ANIMAL MODELS. THE PURPOSE OF THIS SYSTEMATIC REVIEW IS TO DETERMINE HOW BUTYRATE AFFECTS THE RISK FACTORS FOR NAFLD. SEARCHES WERE CONDUCTED USING RELEVANT KEYWORDS IN ELECTRONIC DATABASES UP TO MARCH 2022. ACCORDING TO THE EVIDENCE PRESENTED IN THIS STUDY, BUTYRATE CONTRIBUTES TO A WIDE VARIETY OF BIOLOGICAL PROCESSES IN THE GUT-LIVER AXIS. ITS BENEFICIAL PROPERTIES INCLUDE IMPROVING INTESTINAL HOMEOSTASIS AND LIVER HEALTH AS WELL AS ANTI-INFLAMMATORY, METABOLISM REGULATORY AND ANTI-OXIDATIVE EFFECTS. THESE EFFECTS MAY BE ATTRIBUTED TO BUTYRATE'S ABILITY TO REGULATE GENE EXPRESSION AS AN EPIGENETIC MODULATOR AND TRIGGER CELLULAR RESPONSES AS A SIGNALLING MOLECULE. HOWEVER, THE EXACT UNDERLYING MECHANISMS REMAIN UNCLEAR. HUMAN TRIALS HAVE NOT BEEN PERFORMED ON THE EFFECT OF BUTYRATE ON NAFLD, SO THERE ARE CONCERNS ABOUT WHETHER THE RESULTS OF ANIMAL STUDIES CAN BE TRANSLATED TO HUMANS. THIS REVIEW SUMMARISES THE CURRENT KNOWLEDGE ABOUT THE PROPERTIES OF BUTYRATE, PARTICULARLY ITS POTENTIAL EFFECTS AND MECHANISMS ON LIVER HEALTH AND NAFLD MANAGEMENT. 2022 17 2930 28 GENES AND DIET IN THE PREVENTION OF CHRONIC DISEASES IN FUTURE GENERATIONS. NUTRITION IS A MODIFIABLE KEY FACTOR THAT IS ABLE TO INTERACT WITH BOTH THE GENOME AND EPIGENOME TO INFLUENCE HUMAN HEALTH AND FERTILITY. IN PARTICULAR, SPECIFIC GENETIC VARIANTS CAN INFLUENCE THE RESPONSE TO DIETARY COMPONENTS AND NUTRIENT REQUIREMENTS, AND CONVERSELY, THE DIET ITSELF IS ABLE TO MODULATE GENE EXPRESSION. IN THIS CONTEXT AND THE ERA OF PRECISION MEDICINE, NUTRIGENETIC AND NUTRIGENOMIC STUDIES OFFER SIGNIFICANT OPPORTUNITIES TO IMPROVE THE PREVENTION OF METABOLIC DISTURBANCES, SUCH AS TYPE 2 DIABETES, GESTATIONAL DIABETES, HYPERTENSION, AND CARDIOVASCULAR DISEASES, EVEN WITH TRANSGENERATIONAL EFFECTS. THE PRESENT REVIEW TAKES INTO ACCOUNT THE INTERACTIONS BETWEEN DIET, GENES AND HUMAN HEALTH, AND PROVIDES AN OVERVIEW OF THE ROLE OF NUTRIGENETICS, NUTRIGENOMICS AND EPIGENETICS IN THE PREVENTION OF NON-COMMUNICABLE DISEASES. MOREOVER, WE FOCUS OUR ATTENTION ON THE MECHANISM OF INTERGENERATIONAL OR TRANSGENERATIONAL TRANSMISSION OF THE SUSCEPTIBILITY TO METABOLIC DISTURBANCES, AND UNDERLINE THAT THE REVERSIBILITY OF EPIGENETIC MODIFICATIONS THROUGH DIETARY INTERVENTION COULD COUNTERACT PERTURBATIONS INDUCED BY LIFESTYLE AND ENVIRONMENTAL FACTORS. 2020 18 4801 23 OBESITY AND INSULIN RESISTANCE: ASSOCIATIONS WITH CHRONIC INFLAMMATION, GENETIC AND EPIGENETIC FACTORS. BACKGROUND: OBESITY IS KNOWN TO BE A MULTIFACTORIAL DISEASE. IN ITS PATHOGENESIS, DIFFERENT FACTORS SUCH AS CHRONIC INFLAMMATION, OXIDATIVE STRESS, INSULIN RESISTANCE, GENETIC FACTORS, ENVIRONMENTAL EFFECTS, VEGETATIVE DISTURBANCE, AND UNBALANCED NUTRITION PLAY A SIGNIFICANT ROLE. METHODOLOGY: THIS STUDY DESCRIBES THE ASSOCIATION OF OBESITY AND INSULIN RESISTANCE WITH CHRONIC INFLAMMATION, GENETIC, AND EPIGENETIC FACTORS. PREVIOUS LITERATURE HAS BEEN REVIEWED TO EXPLAIN THE RELATION OF OBESITY WITH THOSE FACTORS INVOLVED IN CHRONIC LOW-GRADE INFLAMMATION AND INSULIN. RESULTS: OBESITY IS ASSOCIATED WITH A DECREASE IN GHRELIN SECRETION, ELEVATED PLASMA LEPTIN LEVELS, OXIDATIVE STRESS, INCREASED MACROPHAGE PHAGOCYTIC ACTIVITY, AND THE INDUCTION OF PROINFLAMMATORY SYNTHESIS OF CYTOKINES AND INTERFERON-GAMMA. OBESITY IS LINKED TO DECREASED LEVELS OF CYTOCHROME P450 (CYP) ENZYMES AND IMPAIRED DETOXIFICATION PROCESSES. DEFICIENCY OF VITAMINS AND MINERALS CAN ALSO PLAY A SIGNIFICANT ROLE IN THE DEVELOPMENT OF OXIDATIVE STRESS AND CHRONIC INFLAMMATION IN OBESITY. THERE IS EVIDENCE OF ASSOCIATIONS BETWEEN A GENETIC PREDISPOSITION TO OBESITY IN CHILDREN WITH ELEVATED LEVELS OF CERTAIN MIRNAS. CONCLUSION: THE PURPOSE OF THE PRESENT REVIEW IS AN ANALYSIS OF THE MULTIPLE FACTORS ASSOCIATED WITH OBESITY. 2021 19 996 25 CHRONIC STRESS, EPIGENETICS, AND ADIPOSE TISSUE METABOLISM IN THE OBESE STATE. IN OBESITY, ENDOCRINE AND METABOLIC PERTURBATIONS, INCLUDING THOSE INDUCED BY CHRONIC ACTIVATION OF THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS, ARE ASSOCIATED WITH THE ACCUMULATION OF ADIPOSE TISSUE AND INFLAMMATION. SUCH CHANGES ARE ATTRIBUTABLE TO A COMBINATION OF GENETIC AND EPIGENETIC FACTORS THAT ARE INFLUENCED BY THE ENVIRONMENT AND EXACERBATED BY CHRONIC ACTIVATION OF THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS. STRESS EXPOSURE AT DIFFERENT LIFE STAGES CAN ALTER ADIPOSE TISSUE METABOLISM DIRECTLY THROUGH EPIGENETIC MODIFICATION OR INDIRECTLY THROUGH THE MANIPULATION OF HYPOTHALAMIC APPETITE REGULATION, AND THEREBY CONTRIBUTE TO ENDOCRINE CHANGES THAT FURTHER DISRUPT WHOLE-BODY ENERGY BALANCE. THIS REVIEW SYNTHESIZES CURRENT KNOWLEDGE, WITH AN EMPHASIS ON HUMAN CLINICAL TRIALS, TO DESCRIBE METABOLIC CHANGES IN ADIPOSE TISSUE AND ASSOCIATED ENDOCRINE, GENETIC AND EPIGENETIC CHANGES IN THE OBESE STATE. IN PARTICULAR, WE DISCUSS EPIGENETIC CHANGES INDUCED BY STRESS EXPOSURE AND THEIR CONTRIBUTION TO APPETITE AND ADIPOCYTE DYSFUNCTION, WHICH COLLECTIVELY PROMOTE THE PATHOGENESIS OF OBESITY. SUCH KNOWLEDGE IS CRITICAL FOR PROVIDING FUTURE DIRECTIONS OF METABOLISM RESEARCH AND TARGETS FOR TREATING METABOLIC DISORDERS. 2020 20 4891 26 OXIDATIVE STRESS AND INFLAMMATORY MARKERS IN PREDIABETES AND DIABETES. PREDIABETES IS A STATE OF ELEVATED PLASMA GLUCOSE IN WHICH THE THRESHOLD FOR DIABETES HAS NOT YET BEEN REACHED AND CAN PREDISPOSE TO THE DEVELOPMENT OF TYPE 2 DIABETES AND CARDIOVASCULAR DISEASES. INSULIN RESISTANCE AND IMPAIRED BETA-CELL FUNCTION ARE OFTEN ALREADY PRESENT IN PREDIABETES. HYPERGLYCEMIA CAN UPREGULATE MARKERS OF CHRONIC INFLAMMATION AND CONTRIBUTE TO INCREASED REACTIVE OXYGEN SPECIES (ROS) GENERATION, WHICH ULTIMATELY CAUSE VASCULAR DYSFUNCTION. CONVERSELY, INCREASED OXIDATIVE STRESS AND INFLAMMATION CAN LEAD TO INSULIN RESISTANCE AND IMPAIRED INSULIN SECRETION. PROPER TREATMENT OF HYPERGLYCEMIA AND INHIBITION OF ROS OVERPRODUCTION IS CRUCIAL FOR DELAYING ONSET OF DIABETES AND FOR PREVENTION OF CARDIOVASCULAR COMPLICATIONS. THUS, IT IS IMPERATIVE TO DETERMINE THE MECHANISMS INVOLVED IN THE PROGRESSION FROM PREDIABETES TO DIABETES INCLUDING A CLARIFICATION OF HOW OLD AND NEW MEDICATIONS AFFECT OXIDATIVE AND IMMUNE MECHANISMS OF DIABETES. IN THIS REVIEW, WE DISCUSS THE RELATIONSHIP BETWEEN OXIDATIVE STRESS AND HYPERGLYCEMIA ALONG WITH LINKS BETWEEN INFLAMMATION AND PREDIABETES. ADDITIONALLY, THE EFFECTS OF HYPERGLYCEMIC MEMORY, MICROVESICLES, MICRO-RNA, AND EPIGENETIC REGULATION ON INFLAMMATION, OXIDATIVE STATE, AND GLYCEMIC CONTROL ARE HIGHLIGHTED. ADIPOSE TISSUE AND THEIR INFLUENCE ON CHRONIC INFLAMMATION ARE ALSO BRIEFLY REVIEWED. FINALLY, THE ROLE OF IMMUNE-TARGETED THERAPIES AND ANTI-DIABETIC MEDICATION ON GLYCEMIC CONTROL AND OXIDATIVE STRESS ARE DISCUSSED. 2019