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 3846 23 IS ATHEROSCLEROSIS A NEUROGENIC PHENOMENON? IDENTIFIED RISK FACTORS FOR ATHEROSCLEROSIS INCLUDE DIET, AGE, GENDER, FAMILY HISTORY, STRESS, LIFESTYLE, SMOKING, DIABETES, DYSLIPIDEMIAS, HYPERTENSION, AND HIV. THE MECHANISTIC RATIONALE TO EXPLAIN THESE ASSOCIATIONS REMAINS POORLY UNDERSTOOD. WE BELIEVE THAT THESE SEEMINGLY UNRELATED ENTITIES MAY PROMOTE ATHEROSCLEROSIS THROUGH A COMMON PATHWAY BY INDUCING ADVENTITIAL AUTONOMIC DYSFUNCTION, SPECIFICALLY AS AN ADVENTITIAL STRESS DYSFUNCTION OF NEUROGENIC ORIGIN. ATHEROSCLEROSIS MAY REPRESENT A LOCAL VASCULAR MANIFESTATION OF THE GLOBAL AUTONOMIC DYSFUNCTION INDUCED BY AGE, SMOKING, HYPERTENSION, HIV, AND DIABETES. ATHEROSCLEROSIS MAY ALSO PARTICIPATE IN A FEED-FORWARD CYCLE AS AGING, DIABETES, DYSLIPIDEMIA, AND HYPERTENSION MAY ALSO REPRESENT INDEPENDENT DOWNSTREAM CONSEQUENCES OF GLOBAL SYMPATHETIC BIAS. CHRONIC PHYSIOLOGIC STRESS AND BEHAVIORAL STRESS CAN SHIFT THE AUTONOMIC BALANCE TOWARDS A STATE OF SYMPATHETIC PREDOMINANCE. THE HIGHLY COMMUNICABLE NATURE OF BEHAVIORAL STRESS MAY PARTIALLY IMPLICATE THE FAMILIAL ASSOCIATION OF ATHEROSCLEROSIS AS AN EPIGENETIC PHENOMENON, INDEPENDENT OF PUTATIVE GENETIC MECHANISMS. HOST STRESS, GLOBAL AUTONOMIC DYSFUNCTION, AND SYMPATHETIC BIAS MAY ALSO ARISE FROM CHRONIC MALADAPTIVE CONSUMPTION OF STRESSED FOODS, AS ORGANISMS DETECT AND ASSIMILATE THE STRESS PHENOTYPES OF THEIR DIETARY CONSTITUENTS THROUGH A PROCESS CALLED XENOHORMESIS. THE BENEFITS OF EXERCISE MAY OPERATE THROUGH REDUCTION OF CHRONIC PHYSIOLOGIC STRESS ASSOCIATED WITH GLOBAL SYMPATHETIC BIAS. THE NEUROGENIC ADVENTITIAL STRESS RESPONSE MAY EXPLAIN THE LOCAL TISSUE REMODELING SEEN IN ATHEROSCLEROSIS, INCLUDING ADVENTITIAL ADIPOSE DYSFUNCTION, INFLAMMATION, ADVENTITIAL ANGIOGENESIS, THROMBOSIS, AND ENDOTHELIAL DYSFUNCTION. WE BELIEVE THAT THE LOCATIONS OF ATHEROSCLEROTIC LESIONS CORRESPOND TO REGIONS OF NEUROGENIC ADVENTITIAL AUTONOMIC DYSFUNCTION, IN SIMILAR FASHION TO THE SEGMENTAL PATTERNS OF INVOLVEMENT FOUND IN INFLAMMATORY BOWEL DISEASE. THE DIFFUSE ATHEROSCLEROSIS EXHIBITED IN TRANSPLANTED HEARTS MAY REFLECT A DIFFUSE SYMPATHETIC BIAS OF THE DONOR HEART, SINCE TISSUES AND ORGANS EXHIBIT AN INTRINSIC SYMPATHETIC BIAS IN THE ABSENCE OF AN EXTRINSIC SOURCE OF AUTONOMIC HEGEMONY. ONCE WE REGARD ATHEROSCLEROSIS AS A NEUROGENIC PHENOMENON MANIFESTED IN ADVENTITIAL AUTONOMIC DYSFUNCTION, NOVEL DIAGNOSTIC AND THERAPEUTIC PARADIGMS BECOME EVIDENT. 2007 3 1386 30 DIABETES: AN UPDATE ON THE PANDEMIC AND POTENTIAL SOLUTIONS. DIABETES MELLITUS IS A CHRONIC METABOLIC DISEASE WITH DEADLY, DISABLING, AND COSTLY CONSEQUENCES FOR INDIVIDUALS, FAMILIES, COMMUNITIES, AND COUNTRIES. ALTHOUGH THEY ARE PHENOTYPICALLY DISTINCT, DIABETES SUBTYPES (TYPE 1, TYPE 2, GESTATIONAL, AND OTHER FORMS) ARE ALL DEFINED BY ELEVATED BLOOD GLUCOSE LEVELS. APPROXIMATELY 95 PERCENT OF DIABETES CASES WORLDWIDE ARE TYPE 2 DIABETES (PREVIOUSLY KNOWN AS ADULT-ONSET OR NON-INSULIN-DEPENDENT DIABETES), WHICH IS THE FOCUS OF THIS CHAPTER. TYPE 1 DIABETES (PREVIOUSLY KNOWN AS INSULIN-DEPENDENT DIABETES) MOST COMMONLY BEGINS IN CHILDHOOD AND ADOLESCENCE. GESTATIONAL DIABETES REFERS TO ELEVATED BLOOD GLUCOSE LEVELS DURING PREGNANCY AMONG WOMEN WITHOUT PREVIOUS DIABETES AND IS ASSOCIATED WITH FETAL, BIRTHING, AND EARLY CHILDHOOD COMPLICATIONS AS WELL AS HIGHER RISK OF THE MOTHER DEVELOPING POSTGESTATION DIABETES. THE GROWTH OF DIABETES AND ITS IMPACTS HAVE ACCELERATED WORLDWIDE SINCE THE END OF THE TWENTIETH CENTURY (NCD-RISC 2016), LIKELY CORRELATED WITH EXPANSION OF DIABETES RISK FACTORS, ESPECIALLY POPULATION AGING AND OBESITY. DIABETES IS A MULTIFACTORIAL CONDITION. BECAUSE GENETIC, EPIGENETIC, LIFESTYLE, ECONOMIC, AND PSYCHOSOCIAL FACTORS ALL CONTRIBUTE TO THE DEVELOPMENT OF DIABETES (MCCARTHY 2010; STUMVOLL, GOLDSTEIN, AND VAN HAEFTEN 2005), PREVENTING AND MANAGING THE CONDITION REQUIRE ACTION AT POLICY, PROGRAM, CLINICAL PRACTICE, AND INDIVIDUAL LEVELS (HILL AND OTHERS 2013). RELIABLE AND MEANINGFUL ESTIMATES OF BURDENS, RISK FACTORS, AND EFFECTIVENESS AND COST-EFFECTIVENESS OF INTERVENTIONS AS WELL AS EVALUATIONS OF EXISTING POLICIES, ARE LIMITED; DATA ARE ESPECIALLY SCARCE IN LOW- AND MIDDLE-INCOME COUNTRIES (LMICS). THIS CHAPTER FOCUSES ON WHAT CAN AND SHOULD BE DONE TO ADDRESS DIABETES. WE PRESENT THE AVAILABLE DATA REGARDING GLOBAL BURDENS AND TRENDS IN DIABETES; REVIEW AVAILABLE EVIDENCE AND ASSESS THE EFFECTIVENESS AND COST-EFFECTIVENESS OF INTERVENTIONS TO PREVENT, DETECT, AND CONTROL DIABETES; AND REPORT SUMMARY EXPERT OPINIONS REGARDING THE PRIORITY AND FEASIBILITY OF IMPLEMENTING THESE INTERVENTIONS. ASSIMILATING EVIDENCE FROM COUNTRIES AT DIFFERENT INCOME LEVELS, WE PROVIDE GLOBAL PERSPECTIVES ON THE DIABETES PANDEMIC, RECOMMEND PRIORITY INTERVENTIONS, AND IDENTIFY REMAINING DATA GAPS. 2017 4 1702 17 DYNAMIC SELF-GUIDING ANALYSIS OF ALZHEIMER'S DISEASE. WE APPLIED A SELF-GUIDING EVOLUTIONARY ALGORITHM TO INITIATE THE SYNTHESIS OF THE ALZHEIMER'S DISEASE-RELATED DATA AND LITERATURE. A PROTEIN INTERACTION NETWORK ASSOCIATED WITH AMYLOID-BETA PRECURSOR PROTEIN (APP) AND A SEED MODEL THAT TREATS ALZHEIMER'S DISEASE AS PROGRESSIVE DYSREGULATION OF APP-ASSOCIATED SIGNALING WERE USED AS DYNAMIC "GUIDES" AND STRUCTURAL "FILTERS" IN THE RECURSIVE SEARCH, ANALYSIS, AND ASSIMILATION OF DATA TO DRIVE THE EVOLUTION OF THE SEED MODEL IN SIZE, DETAIL, AND COMPLEXITY. ANALYSIS OF DATA AND LITERATURE ACROSS SUB-DISCIPLINES AND SYSTEM-SCALE DISCOVERY PLATFORMS SUGGESTS A KEY ROLE OF DYNAMIC CYTOSKELETAL CONNECTIVITY IN THE STABILITY, PLASTICITY, AND PERFORMANCE OF MULTICELLULAR NETWORKS AND ARCHITECTURES. CHRONIC IMPAIRMENT AND/OR DYSREGULATION OF CELL ADHESIONS/SYNAPSES, CYTOSKELETAL NETWORKS, AND/OR REVERSIBLE EPITHELIAL-TO-MESENCHYMAL-LIKE TRANSITIONS, WHICH ENABLE AND MEDIATE THE STABLE AND COHERENT YET DYNAMIC AND RECONFIGURABLE MULTICELLULAR ARCHITECTURES, MAY LEAD TO THE EMERGENCE AND PERSISTENCE OF THE DISORDERED, WOUND-LIKE POCKETS/MICROENVIRONMENTS OF CHRONICALLY DISCONNECTED CELLS. SUCH WOUND-LIKE MICROENVIRONMENTS SUPPORT AND ARE SUPPORTED BY PRO-INFLAMMATORY, PRO-SECRETION, DE-DIFFERENTIATED CELLULAR PHENOTYPES WITH ALTERED METABOLISM AND SIGNALING. THE CO-EVOLUTION OF WOUND-LIKE MICROENVIRONMENTS AND THEIR INHABITANTS MAY LEAD TO THE SELECTION AND STABILIZATION OF DEGENERATED CELLULAR PHENOTYPES, VIA ACQUISITION OF EPIGENETIC MODIFICATIONS AND MUTATIONS, WHICH EVENTUALLY RESULT IN DEGENERATIVE DISORDERS SUCH AS CANCER AND ALZHEIMER'S DISEASE. 2015 5 1113 21 COMMON PATHWAYS IN IDIOPATHIC PULMONARY FIBROSIS AND CANCER. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS MARKED BY A VERY DISAPPOINTING SURVIVAL RATE AND STILL REPRESENTS A CLINICAL DILEMMA. ACCORDING TO THE CURRENT PATHOGENIC HYPOTHESIS, CHRONIC DAMAGE OF THE ALVEOLAR EPITHELIUM IS FOLLOWED BY ABNORMAL TISSUE REPAIR AND IMPAIRMENT OF THE ALVEOLAR STRUCTURE. THIS PROCESS IS DRIVEN BY PATHOGENIC EVENTS VERY SIMILAR TO CANCER, INCLUDING EPIGENETIC AND GENETIC CHANGES, ALTERED RESPONSE TO REGULATORY SIGNALS, ABNORMAL EXPRESSION OF MICRORNAS AND ACTIVATION OF SPECIFIC SIGNALLING PATHWAYS. IPF ALSO RESEMBLES CANCER WITH REGARD TO ITS POOR RESPONSE TO MEDICAL TREATMENT AND PROGNOSIS, WHICH IS VERY OFTEN WORSE THAN MANY CANCERS. WE HAVE HYPOTHESISED THAT IPF MIGHT BE ASSIMILATED TO A NEOPROLIFERATIVE DISORDER OF THE LUNG. VIEWING IPF AS A CANCER-LIKE DISEASE MAY SATISFY THE NEED FOR A BETTER UNDERSTANDING OF THE PATHOGENESIS OF IPF BY EXPLOITING THE LARGE AMOUNT OF KNOWLEDGE THAT CANCER BIOLOGY EVOKES. THE RECOGNITION OF COMMON PATHOGENIC PATHWAYS BETWEEN THE TWO DISEASES MAY STIMULATE NEW CLINICAL TRIALS WITH CANCER DRUGS, DIFFERENT DRUG COMBINATIONS AND DIFFERENT LINES OF DRUGS, AS ALREADY EXPERIMENTED IN ONCOLOGY. MOREOVER, THE CONCEPT OF IPF AS A CANCER-LIKE DISORDER MAY IMPROVE THE ATTENTION GIVEN TO THIS DREADFUL DISEASE ON A PUBLIC, POLITICAL AND HEALTHCARE LEVEL. 2013 6 6471 34 TNF-ALPHA REGULATES DIABETIC MACROPHAGE FUNCTION THROUGH THE HISTONE ACETYLTRANSFERASE MOF. A CRITICAL COMPONENT OF WOUND HEALING IS THE TRANSITION FROM THE INFLAMMATORY PHASE TO THE PROLIFERATION PHASE TO INITIATE HEALING AND REMODELING OF THE WOUND. MACROPHAGES ARE CRITICAL FOR THE INITIATION AND RESOLUTION OF THE INFLAMMATORY PHASE DURING WOUND REPAIR. IN DIABETES, MACROPHAGES DISPLAY A SUSTAINED INFLAMMATORY PHENOTYPE IN LATE WOUND HEALING CHARACTERIZED BY ELEVATED PRODUCTION OF INFLAMMATORY CYTOKINES, SUCH AS TNF-ALPHA. PREVIOUS STUDIES HAVE SHOWN THAT AN ALTERED EPIGENETIC PROGRAM DIRECTS DIABETIC MACROPHAGES TOWARD A PROINFLAMMATORY PHENOTYPE, CONTRIBUTING TO A SUSTAINED INFLAMMATORY PHASE. MALES ABSENT ON THE FIRST (MOF) IS A HISTONE ACETYLTRANSFERASE (HAT) THAT HAS BEEN SHOWN BE A COACTIVATOR OF TNF-ALPHA SIGNALING AND PROMOTE NF-KAPPAB-MEDIATED GENE TRANSCRIPTION IN PROSTATE CANCER CELL LINES. BASED ON MOF'S ROLE IN TNF-ALPHA/NF-KAPPAB-MEDIATED GENE EXPRESSION, WE HYPOTHESIZED THAT MOF INFLUENCES MACROPHAGE-MEDIATED INFLAMMATION DURING WOUND REPAIR. WE USED MYELOID-SPECIFIC MOF-KNOCKOUT (LYZ2CRE MOFFL/FL) AND DIET-INDUCED OBESE (DIO) MICE TO DETERMINE THE FUNCTION OF MOF IN DIABETIC WOUND HEALING. MOF-DEFICIENT MICE EXHIBITED REDUCED INFLAMMATORY CYTOKINE GENE EXPRESSION. FURTHERMORE, WE FOUND THAT WOUND MACROPHAGES FROM DIO MICE HAD ELEVATED MOF LEVELS AND HIGHER LEVELS OF ACETYLATED HISTONE H4K16, MOF'S PRIMARY SUBSTRATE OF HAT ACTIVITY, ON THE PROMOTERS OF INFLAMMATORY GENES. WE FURTHER IDENTIFIED THAT MOF EXPRESSION COULD BE STIMULATED BY TNF-ALPHA AND THAT TREATMENT WITH ETANERCEPT, AN FDA-APPROVED TNF-ALPHA INHIBITOR, REDUCED MOF LEVELS AND IMPROVED WOUND HEALING IN DIO MICE. THIS REPORT IS THE FIRST TO OUR KNOWLEDGE TO DEFINE AN IMPORTANT ROLE FOR MOF IN REGULATING MACROPHAGE-MEDIATED INFLAMMATION IN WOUND REPAIR AND IDENTIFIES TNF-ALPHA INHIBITION AS A POTENTIAL THERAPY FOR THE TREATMENT OF CHRONIC INFLAMMATION IN DIABETIC WOUNDS. 2020 7 4615 26 NERVE INJURY DIMINISHES OPIOID ANALGESIA THROUGH LYSINE METHYLTRANSFERASE-MEDIATED TRANSCRIPTIONAL REPRESSION OF MU-OPIOID RECEPTORS IN PRIMARY SENSORY NEURONS. THE MU-OPIOID RECEPTOR (MOR, ENCODED BY OPRM1) AGONISTS ARE THE MAINSTAY ANALGESICS FOR TREATING MODERATE TO SEVERE PAIN. NERVE INJURY CAUSES DOWN-REGULATION OF MORS IN THE DORSAL ROOT GANGLION (DRG) AND DIMINISHES THE OPIOID EFFECT ON NEUROPATHIC PAIN. HOWEVER, THE EPIGENETIC MECHANISMS UNDERLYING THE DIMINISHED MOR EXPRESSION CAUSED BY NERVE INJURY ARE NOT CLEAR. G9A (ENCODED BY EHMT2), A HISTONE 3 AT LYSINE 9 METHYLTRANSFERASE, IS A KEY CHROMATIN REGULATOR RESPONSIBLE FOR GENE SILENCING. IN THIS STUDY, WE DETERMINED THE ROLE OF G9A IN DIMINISHED MOR EXPRESSION AND OPIOID ANALGESIC EFFECTS IN ANIMAL MODELS OF NEUROPATHIC PAIN. WE FOUND THAT NERVE INJURY IN RATS INDUCED A LONG-LASTING REDUCTION IN THE EXPRESSION LEVEL OF MORS IN THE DRG BUT NOT IN THE SPINAL CORD. NERVE INJURY CONSISTENTLY INCREASED THE ENRICHMENT OF THE G9A PRODUCT HISTONE 3 AT LYSINE 9 DIMETHYLATION IN THE PROMOTER OF OPRM1 IN THE DRG. G9A INHIBITION OR SIRNA KNOCKDOWN FULLY REVERSED MOR EXPRESSION IN THE INJURED DRG AND POTENTIATED THE MORPHINE EFFECT ON PAIN HYPERSENSITIVITY INDUCED BY NERVE INJURY. IN MICE LACKING EHMT2 IN DRG NEURONS, NERVE INJURY FAILED TO REDUCE THE EXPRESSION LEVEL OF MORS AND THE MORPHINE EFFECT. IN ADDITION, G9A INHIBITION OR EHMT2 KNOCKOUT IN DRG NEURONS NORMALIZED NERVE INJURY-INDUCED REDUCTION IN THE INHIBITORY EFFECT OF THE OPIOID ON SYNAPTIC GLUTAMATE RELEASE FROM PRIMARY AFFERENT NERVES. OUR FINDINGS INDICATE THAT G9A CONTRIBUTES CRITICALLY TO TRANSCRIPTIONAL REPRESSION OF MORS IN PRIMARY SENSORY NEURONS IN NEUROPATHIC PAIN. G9A INHIBITORS MAY BE USED TO ENHANCE THE OPIOID ANALGESIC EFFECT IN THE TREATMENT OF CHRONIC NEUROPATHIC PAIN. 2016 8 6732 19 WESTERN DIET AND THE IMMUNE SYSTEM: AN INFLAMMATORY CONNECTION. THE CONSUMPTION OF WESTERN-TYPE CALORICALLY RICH DIETS COMBINED WITH CHRONIC OVERNUTRITION AND A SEDENTARY LIFESTYLE IN WESTERN SOCIETIES EVOKES A STATE OF CHRONIC METABOLIC INFLAMMATION, TERMED METAFLAMMATION. METAFLAMMATION CONTRIBUTES TO THE DEVELOPMENT OF MANY PREVALENT NON-COMMUNICABLE DISEASES (NCDS), AND THESE LIFESTYLE-ASSOCIATED PATHOLOGIES REPRESENT A RISING PUBLIC HEALTH PROBLEM WITH GLOBAL EPIDEMIC DIMENSIONS. A BETTER UNDERSTANDING OF HOW MODERN LIFESTYLE AND WESTERN DIET (WD) ACTIVATE IMMUNE CELLS IS ESSENTIAL FOR THE DEVELOPMENT OF EFFICIENT PREVENTIVE AND THERAPEUTIC STRATEGIES FOR COMMON NCDS. HERE, WE REVIEW THE CURRENT MECHANISTIC UNDERSTANDING OF HOW THE WESTERN LIFESTYLE CAN INDUCE METAFLAMMATION, AND WE DISCUSS HOW THIS KNOWLEDGE CAN BE TRANSLATED TO PROTECT THE PUBLIC FROM THE HEALTH BURDEN ASSOCIATED WITH THEIR SELECTED LIFESTYLE. 2019 9 4807 17 OBESITY IN LOW- AND MIDDLE-INCOME COUNTRIES: BURDEN, DRIVERS, AND EMERGING CHALLENGES. WE HAVE REVIEWED THE DISTINCTIVE FEATURES OF EXCESS WEIGHT, ITS CAUSES, AND RELATED PREVENTION AND MANAGEMENT EFFORTS, AS WELL AS DATA GAPS AND RECOMMENDATIONS FOR FUTURE RESEARCH IN LOW- AND MIDDLE-INCOME COUNTRIES (LMICS). OBESITY IS RISING IN EVERY REGION OF THE WORLD, AND NO COUNTRY HAS BEEN SUCCESSFUL AT REVERSING THE EPIDEMIC ONCE IT HAS BEGUN. IN LMICS, OVERWEIGHT IS HIGHER IN WOMEN COMPARED WITH MEN, IN URBAN COMPARED WITH RURAL SETTINGS, AND IN OLDER COMPARED WITH YOUNGER INDIVIDUALS; HOWEVER, THE URBAN-RURAL OVERWEIGHT DIFFERENTIAL IS SHRINKING IN MANY COUNTRIES. OVERWEIGHT OCCURS ALONGSIDE PERSISTENT BURDENS OF UNDERWEIGHT IN LMICS, ESPECIALLY IN YOUNG WOMEN. CHANGES IN THE GLOBAL DIET AND PHYSICAL ACTIVITY ARE AMONG THE HYPOTHESIZED LEADING CONTRIBUTORS TO OBESITY. EMERGING RISK FACTORS INCLUDE ENVIRONMENTAL CONTAMINANTS, CHRONIC PSYCHOSOCIAL STRESS, NEUROENDOCRINE DYSREGULATION, AND GENETIC/EPIGENETIC MECHANISMS. DATA ON EFFECTIVE STRATEGIES TO PREVENT THE ONSET OF OBESITY IN LMICS OR ELSEWHERE ARE LIMITED. EXPANDING THE RESEARCH IN THIS AREA IS A KEY PRIORITY AND HAS IMPORTANT POSSIBILITIES FOR REVERSE INNOVATION THAT MAY ALSO INFORM INTERVENTIONS IN HIGH-INCOME COUNTRIES. 2017 10 2383 28 EPIGENETIC REGULATOR G9A PROVIDES GLUCOSE AS A SWEET KEY TO STRESS RESISTANCE. THE ABILITY TO ADAPT TO ACUTE AND CHRONIC STRESS IS IMPORTANT FOR ORGANISMS TO THRIVE IN EVOLUTIONARY NICHES AND FOR CELLS TO SURVIVE IN ADVERSE CONDITIONS. THE REGULATORY NETWORKS THAT CONTROL STRESS RESPONSES ARE EVOLUTIONARILY CONSERVED, AND MANY FACTORS THAT SELECTIVELY ACTIVATE STRESS RESPONSES HAVE BEEN IDENTIFIED. LESS WELL UNDERSTOOD ARE MECHANISMS THAT GUARD AGAINST UNNECESSARY INDUCTION OF CYTOPROTECTIVE FACTORS AND THAT CONNECT STRESS RESPONSES WITH CELLULAR METABOLISM TO CONTROL ENERGY EXPENDITURE DURING STRESS. THE WORK OF RIAHI AND COLLEAGUES REPRESENTS IMPORTANT PROGRESS IN THIS REGARD BECAUSE IT IDENTIFIES THE HISTONE METHYLTRANSFERASE G9A AS A MODULATOR OF OXIDATIVE STRESS RESPONSES. G9A DAMPENS THE EXPRESSION OF ANTIOXIDANT GENES, THUS PREVENTING INAPPROPRIATE ENERGY CONSUMPTION. MOREOVER, G9A PROMOTES THE WELL-PACED CATABOLISM OF STORAGE GLYCOGEN AND FAT DURING STRESS. THE IMPORTANCE OF ENERGY AVAILABILITY DURING STRESS IS FURTHER EVIDENCED BY EXOGENOUS GLUCOSE RESCUING THE VULNERABILITY OF THE G9A MUTANT TO OXIDATIVE STRESS. PRIOR WORK IN MULTIPLE MODEL SYSTEMS HAS IMPLICATED G9A IN SEVERAL OTHER ADAPTIVE RESPONSES. THEREFORE, ITS ROLE IN PACING ENERGY CONSUMPTION AND IN RESTRAINING EXCESSIVE STRESS RESPONSE GENE EXPRESSION UNDER STRESS MAY EXTEND TO OTHER ADAPTIVE RESPONSES ACROSS SPECIES. 2019 11 2883 22 G9A INHIBITS CREB-TRIGGERED EXPRESSION OF MU OPIOID RECEPTOR IN PRIMARY SENSORY NEURONS FOLLOWING PERIPHERAL NERVE INJURY. NEUROPATHIC PAIN, A DISTRESSING AND DEBILITATING DISORDER, IS STILL POORLY MANAGED IN CLINIC. OPIOIDS, LIKE MORPHINE, REMAIN THE MAINSTAY OF PRESCRIBED MEDICATIONS IN THE TREATMENT OF THIS DISORDER, BUT THEIR ANALGESIC EFFECTS ARE HIGHLY UNSATISFACTORY IN PART DUE TO NERVE INJURY-INDUCED REDUCTION OF OPIOID RECEPTORS IN THE FIRST-ORDER SENSORY NEURONS OF DORSAL ROOT GANGLIA. G9A IS A REPRESSOR OF GENE EXPRESSION. WE FOUND THAT NERVE INJURY-INDUCED INCREASES IN G9A AND ITS CATALYZED REPRESSIVE MARKER H3K9M2 ARE RESPONSIBLE FOR EPIGENETIC SILENCING OF OPRM1, OPRK1, AND OPRD1 GENES IN THE INJURED DORSAL ROOT GANGLIA. BLOCKING THESE INCREASES RESCUED DORSAL ROOT GANGLIA OPRM1, OPRK1, AND OPRD1 GENE EXPRESSION AND MORPHINE OR LOPERAMIDE ANALGESIA AND PREVENTED THE DEVELOPMENT OF MORPHINE OR LOPERAMIDE-INDUCED ANALGESIC TOLERANCE UNDER NEUROPATHIC PAIN CONDITIONS. CONVERSELY, MIMICKING THESE INCREASES REDUCED THE EXPRESSION OF THREE OPIOID RECEPTORS AND PROMOTED THE MU OPIOID RECEPTOR-GATED RELEASE OF PRIMARY AFFERENT NEUROTRANSMITTERS. MECHANISTICALLY, NERVE INJURY-INDUCED INCREASES IN THE BINDING ACTIVITY OF G9A AND H3K9ME2 TO THE OPRM1 GENE WERE ASSOCIATED WITH THE REDUCED BINDING OF CYCLIC AMP RESPONSE ELEMENT BINDING PROTEIN TO THE OPRM1 GENE. THESE FINDINGS SUGGEST THAT G9A PARTICIPATES IN THE NERVE INJURY-INDUCED REDUCTION OF THE OPRM1 GENE LIKELY THROUGH G9A-TRIGGERED BLOCKAGE IN THE ACCESS OF CYCLIC AMP RESPONSE ELEMENT BINDING PROTEIN TO THIS GENE. 2016 12 6380 28 THE ROLE OF OBESITY AND DIABETES IN DEMENTIA. CHRONIC CONDITIONS SUCH AS OBESITY, DIABETES, AND DEMENTIA ARE INCREASING IN THE UNITED STATES (US) POPULATION. KNOWLEDGE OF THESE CHRONIC CONDITIONS, PREVENTATIVE MEASURES, AND PROPER MANAGEMENT TACTICS IS IMPORTANT AND CRITICAL TO PREVENTING DISEASE. THE OVERLAP BETWEEN OBESITY, DIABETES, AND DEMENTIA IS BECOMING FURTHER ELUCIDATED. THESE CONDITIONS SHARE A SIMILAR ORIGIN THROUGH THE COMPONENTS OF INCREASING AGE, GENDER, GENETIC AND EPIGENETIC PREDISPOSITIONS, DEPRESSION, AND A HIGH-FAT WESTERN DIET (WD) THAT ALL CONTRIBUTE TO THE INFLAMMATORY STATE ASSOCIATED WITH THE DEVELOPMENT OF OBESITY, DIABETES, AND DEMENTIA. THIS INFLAMMATORY STATE LEADS TO THE DYSREGULATION OF FOOD INTAKE AND INSULIN RESISTANCE. OBESITY IS OFTEN THE CORNERSTONE THAT LEADS TO THE DEVELOPMENT OF DIABETES AND, SUBSEQUENTLY, IN THE CASE OF TYPE 2 DIABETES MELLITUS (T2DM), PROGRESSION TO "TYPE 3 DIABETES MELLITUS (T3DM)". OBESITY AND DEPRESSION ARE CLOSELY ASSOCIATED WITH DIABETES. HOWEVER, DEMENTIA CAN BE AVOIDED WITH LIFESTYLE MODIFICATIONS, BY SWITCHING TO A PLANT-BASED DIET (E.G., A MEDITERRANEAN DIET (MD)), AND INCREASING PHYSICAL ACTIVITY. DIET AND EXERCISE ARE NOT THE ONLY TREATMENT OPTIONS. THERE ARE SEVERAL SURGICAL AND PHARMACOLOGICAL INTERVENTIONS AVAILABLE FOR PREVENTION. CURRENT AND FUTURE RESEARCH WITHIN EACH OF THESE FIELDS IS WARRANTED AND OFFERS THE CHANCE FOR NEW TREATMENT OPTIONS AND A BETTER UNDERSTANDING OF THE PATHOGENESIS OF EACH CONDITION. 2022 13 6473 34 TO DO ONE AND TO GET MORE: PART II. DIABETES AND METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASES. TYPE 2 DIABETES MELLITUS (DM) IS CHARACTERIZED BY INABILITY OF FAULTY PANCREATIC BETA-CELLS TO SECRET A NORMAL AMOUNT OF INSULIN TO MAINTAIN NORMAL BODY CONSUMPTION, AND/OR PERIPHERAL TISSUE HAS A DECREASED SUSCEPTIBILITY TO INSULIN, RESULTING IN HYPERGLYCEMIA AND INSULIN RESISTANCE. SIMILAR TO OTHER CHRONIC SYSTEMIC INFLAMMATORY DISEASES, DM IS A RESULT FROM DYSREGULATED INTERACTIONS BETWEEN ETHNIC, GENETIC, EPIGENETIC, IMMUNOREGULATORY, HORMONAL, AND ENVIRONMENTAL FACTORS. THEREFORE, IT IS RATIONAL TO SUPPOSE THE CONCEPT AS "TO DO ONE AND TO GET MORE", WHILE USING ANTIDIABETIC AGENTS (ADA), A MAIN PHARMACOLOGIC AGENT FOR THE TREATMENT OF DM, CAN PROVIDE AN EXTRAGLYCEMIA EFFECT ON COMORBIDITIES OR CONCOMITTENT COMORBIDITIES TO DM. IN THIS REVIEW, BASED ON THE MUCH STRONG CORRELATION BETWEEN DM AND METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASES (MAFLD) SHOWN BY SIMILAR PATHOPHYSIOLOGICAL MECHANISMS AND A HIGH PREVALENCE OF DM IN MAFLD AND ITS VICE VERSA (A HIGH PREVALENCE OF MAFLD IN DM), IT IS POSSIBLE TO USE THE STRATEGY TO TARGET BOTH DISEASES SIMULTANEOUSLY. WE FOCUS ON A NEW CLASSIFICATION OF ADA, SUCH AS GLUCAGON-LIKE PEPTIDE-1 RECEPTOR (GLP1R) AGONIST AND SODIUM-GLUCOSE COTRANSPORTER-2 (SGLT-2) INHIBITORS TO SHOW THE POTENTIAL BENEFITS OF EXTRAGLYCEMIC EFFECT ON MAFLD. WE CONCLUDE THAT THE MANAGEMENT OF DM PATIENTS, ESPECIALLY FOR THOSE WHO NEED ADA AS ADJUVANT THERAPY SHOULD INCLUDE HEALTHY LIFESTYLE MODIFICATION TO OVERCOME THE METABOLIC SYNDROME, CONTRIBUTING TO THE URGENT NEED OF AN EFFECTIVE WEIGHT-REDUCTION STRATEGY. GLP1R AGONIST IS ONE OF EFFECTIVE BODY WEIGHT-LOWERING MEDICATIONS, WHICH MAY BE A BETTER CHOICE FOR DM COMPLICATED WITH MAFLD OR ITS-ASSOCIATED SEVERE FORM AS METABOLIC ASSOCIATED STEATOHEPATITIS (MASH), ALTHOUGH THE ROLE OF SGLT-2 INHIBITORS IS ALSO IMPRESSIVE. THE PRESCRIPTION OF THESE TWO CLASSES OF ADA MAY SATISFY THE CONCEPT "TO DO ONE AND TO GET MORE", BASED ON SUCCESSFUL SUGAR-LOWERING EFFECT FOR CONTROLLING DM AND EXTRAGLYCEMIA BENEFITS OF HEPATOPROTECTIVE ACTIVITY IN DM PATIENTS. 2022 14 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 15 4455 29 MOLECULAR MECHANISMS FOR THE VICIOUS CYCLE BETWEEN INSULIN RESISTANCE AND THE INFLAMMATORY RESPONSE IN OBESITY. THE COMPREHENSIVE ANABOLIC EFFECTS OF INSULIN THROUGHOUT THE BODY, IN ADDITION TO THE CONTROL OF GLYCEMIA, INCLUDE ENSURING LIPID HOMEOSTASIS AND ANTI-INFLAMMATORY MODULATION, ESPECIALLY IN ADIPOSE TISSUE (AT). THE PREVALENCE OF OBESITY, DEFINED AS A BODY MASS INDEX (BMI) >/= 30 KG/M(2), HAS BEEN INCREASING WORLDWIDE ON A PANDEMIC SCALE WITH ACCOMPANYING SYNDEMIC HEALTH PROBLEMS, INCLUDING GLUCOSE INTOLERANCE, INSULIN RESISTANCE (IR), AND DIABETES. IMPAIRED TISSUE SENSITIVITY TO INSULIN OR IR PARADOXICALLY LEADS TO DISEASES WITH AN INFLAMMATORY COMPONENT DESPITE HYPERINSULINEMIA. THEREFORE, AN EXCESS OF VISCERAL AT IN OBESITY INITIATES CHRONIC LOW-GRADE INFLAMMATORY CONDITIONS THAT INTERFERE WITH INSULIN SIGNALING VIA INSULIN RECEPTORS (INSRS). MOREOVER, IN RESPONSE TO IR, HYPERGLYCEMIA ITSELF STIMULATES A PRIMARILY DEFENSIVE INFLAMMATORY RESPONSE ASSOCIATED WITH THE SUBSEQUENT RELEASE OF NUMEROUS INFLAMMATORY CYTOKINES AND A REAL THREAT OF ORGAN FUNCTION DETERIORATION. IN THIS REVIEW, ALL COMPONENTS OF THIS VICIOUS CYCLE ARE CHARACTERIZED WITH PARTICULAR EMPHASIS ON THE INTERPLAY BETWEEN INSULIN SIGNALING AND BOTH THE INNATE AND ADAPTIVE IMMUNE RESPONSES RELATED TO OBESITY. INCREASED VISCERAL AT ACCUMULATION IN OBESITY SHOULD BE CONSIDERED THE MAIN ENVIRONMENTAL FACTOR RESPONSIBLE FOR THE DISRUPTION IN THE EPIGENETIC REGULATORY MECHANISMS IN THE IMMUNE SYSTEM, RESULTING IN AUTOIMMUNITY AND INFLAMMATION. 2023 16 6792 20 [DOHAD AND EPIGENETIC INFORMATION: SOCIETAL CHALLENGES]. THE CONCEPT OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) ALTERS OUR UNDERSTANDING OF WHAT CONSTITUTES "HEALTH" OR "DISEASE" INTENDED AS CHRONIC, NON-COMMUNICABLE DISEASES, WHICH DEVELOP OVER THE LIFE COURSE IN HIGH INCOME AND EMERGING COUNTRIES. IT IMPLIES A CHANGE IN PARADIGM FORMING A BASIS FOR PREVENTION POLICIES ACROSS THE GLOBE. IT ALSO IMPACTS PSYCHOLOGICAL, SOCIAL, ECONOMIC, ETHICAL AND LEGAL SCIENCES. IN LINE WITH THE UNANTICIPATED UNDERPINNING EPIGENETIC MECHANISMS ARE ALSO THE SOCIAL ISSUES (INCLUDING PUBLIC POLICIES) THAT COULD BE PRODUCED BY THE KNOWLEDGE RELATED TO DOHAD THAT OPENS A WIDE FIELD OF INQUIRY. THE INFORMATION UNVEILED BY EPIGENETICS COUPLED WITH INFORMATION ON LIFESTYLE INCLUDING DURING THE DEVELOPMENT PHASE, IS OF UNFORESEEN NATURE, RAISING ISSUES OF DIFFERENT NATURE. THEREFORE IT REQUIRES SPECIFIC ATTENTION AND RESEARCH, AND A SPECIFIC SUPPORT BY A PLURIDISCIPLINARY REFLECTION SINCE THE VERY BEGINNING OF ITS PRODUCTION, TO ANTICIPATE THE QUESTIONS THAT MIGHT BE RAISED IN THE FUTURE. 2016 17 37 39 A CHROMATIN REMODELING CHECKPOINT OF DIET-INDUCED MACROPHAGE ACTIVATION IN ADIPOSE TISSUE. THE INTERPLAY BETWEEN THE ENVIRONMENT AND THE IMMUNE CELLS IS LINKED TO METABOLIC HOMEOSTASIS UNDER PHYSIOLOGIC AND PATHOPHYSIOLOGIC CONDITIONS. DIABETES MELLITUS TYPE 2 (T2D) IS CONSIDERED AN IMMUNE-RELATED INFLAMMATORY DISORDER, IN WHICH THE ADIPOSE TISSUE MACROPHAGES (ATMS) ARE KEY PLAYERS ORCHESTRATING METABOLIC CHRONIC META-INFLAMMATION AND CONTRIBUTING TO THE PATHOGENESIS OF METABOLIC DISEASE. HOWEVER, THE MOLECULAR REGULATORS THAT INTEGRATE THE ENVIRONMENTAL SIGNALS TO CONTROL ATM ACTIVATION AND ADIPOSE INFLAMMATION DURING OBESITY AND T2D REMAIN UNCLEAR. EPIGENETIC MECHANISMS CONSTITUTE IMPORTANT PARAMETERS IN METABOLIC HOMEOSTASIS, OBESITY AND T2D VIA THE INTEGRATION OF THE ENVIRONMENTAL FACTORS TO THE TRANSCRIPTIONAL REGULATION OF GENE PROGRAMS. IN A VERY RECENT STUDY PUBLISHED IN DIABETES BY KONG ET AL., BAF60A HAS BEEN IDENTIFIED AS A KEY CHROMATIN REMODELING CHECKPOINT FACTOR THAT ASSOCIATES OBESITY-ASSOCIATED STRESS SIGNALS WITH META-INFLAMMATION AND SYSTEMIC HOMEOSTASIS. FURTHERMORE, THIS WORK UNCOVERS ATF3 AS AN IMPORTANT DOWNSTREAM EFFECTOR IN BAF60A-MEDIATED CHROMATIN REMODELING AND TRANSCRIPTIONAL REPROGRAMMING OF MACROPHAGE ACTIVATION IN ADIPOSE TISSUE. THE FINDINGS OF THIS RESEARCH MAY CONTRIBUTE TO THE DEVELOPMENT OF NEW THERAPEUTIC APPROACHES FOR OBESITY-INDUCED METABOLIC INFLAMMATION AND ASSOCIATED METABOLIC DISORDERS. 2022 18 5080 19 PHYTOPHARMACOLOGICAL STRATEGIES IN THE MANAGEMENT OF TYPE 2 DIABETES MELLITUS. TYPE 2 DIABETES MELLITUS (T2DM) IS A CHRONIC DISEASE WHICH CORRESPONDS TO 90% OF THE WORLDWIDE CASES OF DIABETES, MAINLY DUE TO EPIGENETIC FACTORS SUCH AS UNHEALTHY LIFESTYLES. FIRST LINE THERAPEUTIC APPROACHES ARE BASED ON LIFESTYLE CHANGES, MOST OF THE TIME COMPLEMENTED WITH MEDICATION MOSTLY ASSOCIATED WITH SEVERAL SIDE EFFECTS AND HIGH COSTS. AS A RESULT, THE SCIENTIFIC COMMUNITY IS CONSTANTLY WORKING FOR THE DISCOVERY AND DEVELOPMENT OF NATURAL THERAPEUTIC STRATEGIES THAT PROVIDE LOWER FINANCIAL IMPACT AND MINIMIZE SIDE EFFECTS. THIS REVIEW FOCUS ON THESE NATURE-BASED THERAPEUTIC STRATEGIES FOR PREVENTION AND CONTROL OF T2DM, WITH A SPECIAL EMPHASIS ON NATURAL COMPOUNDS THAT PRESENT PHARMACOLOGICAL ACTIVITY AS DIPEPTIDYL PEPTIDASE-4 (DPP4), ALPHA-AMYLASE, ALPHA-GLUCOSIDASE, LIPASE, AND PROTEIN TYROSINE PHOSPHATASE 1B (PTP1B) INHIBITORS. 2020 19 2179 24 EPIGENETIC MECHANISMS OF NEURAL PLASTICITY IN CHRONIC NEUROPATHIC PAIN. NEUROPATHIC PAIN IS A CHALLENGING CLINICAL PROBLEM AND REMAINS DIFFICULT TO TREAT. ALTERED GENE EXPRESSION IN PERIPHERAL SENSORY NERVES AND NEURONS DUE TO NERVE INJURY IS WELL DOCUMENTED AND CONTRIBUTES CRITICALLY TO THE SYNAPTIC PLASTICITY IN THE SPINAL CORD AND THE INITIATION AND MAINTENANCE OF CHRONIC PAIN. HOWEVER, OUR UNDERSTANDING OF THE EPIGENETIC MECHANISMS REGULATING THE TRANSCRIPTION OF PRO-NOCICEPTIVE (E.G., NMDA RECEPTORS AND ALPHA2DELTA-1) AND ANTINOCICEPTIVE (E.G., POTASSIUM CHANNELS AND OPIOID AND CANNABINOID RECEPTORS) GENES ARE STILL LIMITED. IN THIS REVIEW, WE SUMMARIZE RECENT STUDIES DETERMINING THE ROLES OF HISTONE MODIFICATIONS (INCLUDING METHYLATION, ACETYLATION, AND UBIQUITINATION), DNA METHYLATION, AND NONCODING RNAS IN NEUROPATHIC PAIN DEVELOPMENT. WE REVIEW THE EPIGENETIC WRITER, READER, AND ERASER PROTEINS THAT PARTICIPATE IN THE TRANSCRIPTIONAL CONTROL OF THE EXPRESSION OF KEY ION CHANNELS AND NEUROTRANSMITTER RECEPTORS IN THE DORSAL ROOT GANGLION AFTER TRAUMATIC NERVE INJURY, WHICH IS COMMONLY USED AS A PRECLINICAL MODEL OF NEUROPATHIC PAIN. A BETTER UNDERSTANDING OF EPIGENETIC REPROGRAMMING INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN COULD LEAD TO THE DEVELOPMENT OF NEW TREATMENTS FOR NEUROPATHIC PAIN. 2022 20 6606 28 TYPE 2 DIABETES ACROSS GENERATIONS: FROM PATHOPHYSIOLOGY TO PREVENTION AND MANAGEMENT. TYPE 2 DIABETES IS NOW A PANDEMIC AND SHOWS NO SIGNS OF ABATEMENT. IN THIS SEMINAR WE REVIEW THE PATHOPHYSIOLOGY OF THIS DISORDER, WITH PARTICULAR ATTENTION TO EPIDEMIOLOGY, GENETICS, EPIGENETICS, AND MOLECULAR CELL BIOLOGY. EVIDENCE IS EMERGING THAT A SUBSTANTIAL PART OF DIABETES SUSCEPTIBILITY IS ACQUIRED EARLY IN LIFE, PROBABLY OWING TO FETAL OR NEONATAL PROGRAMMING VIA EPIGENETIC PHENOMENA. MATERNAL AND EARLY CHILDHOOD HEALTH MIGHT, THEREFORE, BE CRUCIAL TO THE DEVELOPMENT OF EFFECTIVE PREVENTION STRATEGIES. DIABETES DEVELOPS BECAUSE OF INADEQUATE ISLET BETA-CELL AND ADIPOSE-TISSUE RESPONSES TO CHRONIC FUEL EXCESS, WHICH RESULTS IN SO-CALLED NUTRIENT SPILLOVER, INSULIN RESISTANCE, AND METABOLIC STRESS. THE LATTER DAMAGES MULTIPLE ORGANS. INSULIN RESISTANCE, WHILE FORCING BETA CELLS TO WORK HARDER, MIGHT ALSO HAVE AN IMPORTANT DEFENSIVE ROLE AGAINST NUTRIENT-RELATED TOXIC EFFECTS IN TISSUES SUCH AS THE HEART. REVERSAL OF OVERNUTRITION, HEALING OF THE BETA CELLS, AND LESSENING OF ADIPOSE TISSUE DEFECTS SHOULD BE TREATMENT PRIORITIES. 2011