1 2001 110 EPIGENETIC AND NON-EPIGENETIC REGULATION OF KLOTHO IN KIDNEY DISEASE. KLOTHO IS A NOVEL RENOPROTECTIVE ANTI-AGING PROTEIN AVAILABLE IN MEMBRANE-BOUND OR SOLUBLE FORM. KLOTHO IS EXPRESSED IN BRAIN, PANCREAS, AND OTHER SOLID ORGANS BUT SHOWS HIGHEST EXPRESSION LEVELS IN THE KIDNEY. KLOTHO SUSTAINS NORMAL KIDNEY PHYSIOLOGY BUT KLOTHO REGULATION ALSO CONTRIBUTES TO THE PROGRESSION OF KIDNEY DISEASE. SYSTEMIC AND INTRARENAL LEVELS OF KLOTHO FALL DRASTICALLY DURING ACUTE KIDNEY INJURY, KIDNEY FIBROSIS, DIABETIC NEPHROPATHY, AND OTHER FORMS OF CHRONIC KIDNEY DISEASE, ETC. MOREOVER, EXOGENOUS SUPPLEMENTATION OR OVEREXPRESSION OF ENDOGENOUS KLOTHO ATTENUATES KIDNEY DISEASE. THE REGULATION OF ENDOGENOUS KLOTHO EXPRESSION INVOLVES EPIGENETIC AS WELL AS NON-EPIGENETIC MECHANISMS. THE EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION, POST-TRANSLATIONAL HISTONE MODIFICATIONS, MIRNAS REGULATE THE CHANGE IN KLOTHO EXPRESSION IN KIDNEY DISEASE. NON-EPIGENETIC MECHANISMS SUCH AS ER STRESS, WNT SIGNALING, ACTIVATION OF THE RENIN ANGIOTENSIN SYSTEM (RAS), EXCESSIVE REACTIVE OXYGEN SPECIES AND CYTOKINE GENERATION, ALBUMIN OVERLOAD, AND PPAR-GAMMA SIGNALING ALSO CONTRIBUTE TO KLOTHO REGULATION. EVOLVING EVIDENCE HIGHLIGHT THE CAPACITY OF NATURAL PRODUCTS TO REGULATE KLOTHO EXPRESSION IN KIDNEY DISEASE. ALL THESE PRECLINICAL DATA SUGGEST THAT KLOTHO COULD BE A NOVEL BIOMARKER AS WELL AS THERAPEUTIC TARGET. HERE WE REVIEW THE DIFFERENT MECHANISMS OF KLOTHO REGULATION IN THE CONTEXT OF KLOTHO AS A BIOMARKER AND POTENTIAL THERAPEUTIC AGENT. 2021 2 4971 26 PATHOPHYSIOLOGIC MECHANISMS IN DIABETIC KIDNEY DISEASE: A FOCUS ON CURRENT AND FUTURE THERAPEUTIC TARGETS. DIABETIC KIDNEY DISEASE (DKD) IS THE PRIMARY CAUSE OF CHRONIC KIDNEY DISEASE AROUND THE GLOBE AND IS ONE OF THE MAIN COMPLICATIONS IN PATIENTS WITH TYPE 1 AND 2 DIABETES. THE STANDARD TREATMENT FOR DKD IS DRUGS CONTROLLING HYPERGLYCEMIA AND HIGH BLOOD PRESSURE. RENIN ANGIOTENSIN ALDOSTERONE SYSTEM BLOCKADE AND SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITION HAVE YIELDED PROMISING RESULTS IN DKD, BUT MANY DIABETIC PATIENTS ON SUCH TREATMENTS NEVERTHELESS CONTINUE TO DEVELOP DKD, LEADING TO KIDNEY FAILURE AND CARDIOVASCULAR COMORBIDITIES. NEW THERAPEUTIC OPTIONS ARE URGENTLY REQUIRED. WE REVIEW HERE THE PROMISING THERAPEUTIC AVENUES BASED ON INSIGHTS INTO THE MECHANISMS OF DKD THAT HAVE RECENTLY EMERGED, INCLUDING MINERALOCORTICOID RECEPTOR ANTAGONISTS, SGLT2 INHIBITORS, GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST, ENDOTHELIN RECEPTOR A INHIBITION, ANTI-INFLAMMATORY AGENTS, AUTOPHAGY ACTIVATORS AND EPIGENETIC REMODELLING. THE INVOLVEMENT OF SEVERAL MOLECULAR MECHANISMS IN DKD PATHOGENESIS, TOGETHER WITH THE GENETIC AND EPIGENETIC VARIABILITY OF THIS CONDITION, MAKES IT DIFFICULT TO TARGET THIS HETEROGENEOUS PATIENT POPULATION WITH A SINGLE DRUG. PERSONALIZED MEDICINE, TAKING INTO ACCOUNT THE GENETIC AND MECHANISTIC VARIABILITY, MAY THEREFORE IMPROVE RENAL AND CARDIOVASCULAR PROTECTION IN DIABETIC PATIENTS WITH DKD. 2020 3 885 24 CHRONIC CONSTRICTION INJURY-INDUCED CHANGES IN CIRCULAR RNA EXPRESSION PROFILING OF THE DORSAL ROOT GANGLION IN A RAT MODEL OF NEUROPATHIC PAIN. BACKGROUND: THE PATHOGENESIS OF NEUROPATHIC PAIN (NP) HAS NOT BEEN FULLY ELUCIDATED. GENE CHANGES IN DORSAL ROOT GANGLIA (DRG) MAY CONTRIBUTE TO THE DEVELOPMENT OF NP. CIRCULAR RNAS (CIRCRNAS) ARE A CLASS OF ENDOGENOUS NONCODING RNAS THAT FORM COVALENTLY CLOSED LOOP STRUCTURES AND ARE CRUCIAL FOR GENETIC AND EPIGENETIC REGULATION. HOWEVER, LITTLE IS KNOWN ABOUT CIRCRNA CHANGES IN DRG NEURONS AFTER PERIPHERAL NERVE INJURY. METHODS: A SCIATIC NERVE CHRONIC CONSTRICTION INJURY (CCI) MODEL WAS ESTABLISHED TO INDUCE NEUROPATHIC PAIN. WE PERFORMED GENOME-WIDE CIRCRNA ANALYSIS OF FOUR PAIRED DORSAL ROOT GANGLION (DRG) SAMPLES (L4-L5) FROM CCI AND NEGATIVE CONTROL (NC) RATS USING NEXT-GENERATION SEQUENCING TECHNOLOGY. THE DIFFERENTIALLY EXPRESSED CIRCRNAS (DECIRCRNAS) WERE IDENTIFIED BY DIFFERENTIAL EXPRESSION ANALYSIS, AND THE EXPRESSION PROFILE OF CIRCRNAS WAS VALIDATED BY QUANTITATIVE PCR. GENE ONTOLOGY AND KYOTO ENCYCLOPEDIA OF GENES AND GENOMES ANALYSES WERE PERFORMED TO PREDICT THE FUNCTION OF DECIRCRNAS. RESULTS: A TOTAL OF 374 DECIRCRNAS WERE IDENTIFIED BETWEEN CCI AND NC RATS USING CIRCRNA HIGH-THROUGHPUT SEQUENCING. AMONG THEM, 290 WERE UPREGULATED AND 84 WERE DOWNREGULATED IN THE CCI GROUP. THE EXPRESSION LEVELS OF NINE DECIRCRNAS WERE VALIDATED BY QPCR. FUNCTIONAL ANNOTATION ANALYSIS SHOWED THAT THE DECIRCRNAS WERE MAINLY ENRICHED IN PATHWAYS AND FUNCTIONS, INCLUDING 'DOPAMINERGIC SYNAPSE,' 'RENIN SECRETION,' 'MITOGEN-ACTIVATED PROTEIN KINASE SIGNALING PATHWAY,' AND 'NEUROGENESIS.' COMPETING ENDOGENOUS RNA ANALYSIS SHOWED THAT THE TOP 50 CIRCRNAS EXHIBITED INTERACTIONS WITH FOUR PAIN-RELATED MICRORNAS (MIRNAS). CIRC:CHR2:33950934-33955969 WAS THE LARGEST NODE IN THE CIRCRNA-MIRNA INTERACTION NETWORK. CONCLUSIONS: PERIPHERAL NERVE INJURY-INDUCED NEUROPATHIC PAIN LED TO CHANGES IN THE COMPREHENSIVE EXPRESSION PROFILE OF CIRCRNAS IN THE DRG OF RATS. DECIRCRNAS MAY ADVANCE OUR UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING NEUROPATHIC PAIN. 2022 4 6575 25 TREATMENT OF DIABETIC KIDNEY DISEASE: CURRENT AND FUTURE. DIABETIC KIDNEY DISEASE (DKD) IS THE MAJOR CAUSE OF END-STAGE KIDNEY DISEASE. HOWEVER, ONLY RENIN-ANGIOTENSIN SYSTEM INHIBITOR WITH MULTIDISCIPLINARY TREATMENTS IS EFFECTIVE FOR DKD. IN 2019, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR SHOWED EFFICACY AGAINST DKD IN CANAGLIFLOZIN AND RENAL EVENTS IN DIABETES WITH ESTABLISHED NEPHROPATHY CLINICAL EVALUATION (CREDENCE) TRIAL, ADDING A NEW TREATMENT OPTION. HOWEVER, THE PROGRESSION OF DKD HAS NOT BEEN COMPLETELY CONTROLLED. THE PATIENTS WITH TRANSIENT EXPOSURE TO HYPERGLYCEMIA DEVELOP DIABETIC COMPLICATIONS, INCLUDING DKD, EVEN AFTER NORMALIZATION OF THEIR BLOOD GLUCOSE. TEMPORARY HYPERGLYCEMIA CAUSES ADVANCED GLYCATION END PRODUCT (AGE) ACCUMULATIONS AND EPIGENETIC CHANGES AS METABOLIC MEMORY. THE DRUGS THAT IMPROVE METABOLIC MEMORY ARE AWAITED, AND AGE INHIBITORS AND HISTONE MODIFICATION INHIBITORS ARE THE FOCUS OF CLINICAL AND BASIC RESEARCH. IN ADDITION, INCRETIN-RELATED DRUGS SHOWED A RENOPROTECTIVE ABILITY IN MANY CLINICAL TRIALS, AND THESE TRIALS WITH RENAL OUTCOME AS THEIR PRIMARY ENDPOINT ARE CURRENTLY ONGOING. HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITORS RECENTLY APPROVED FOR RENAL ANEMIA MAY BE RENOPROTECTIVE SINCE THEY IMPROVE TUBULOINTERSTITIAL HYPOXIA. FURTHERMORE, NF-E2-RELATED FACTOR 2 ACTIVATORS IMPROVED THE GLOMERULAR FILTRATION RATE OF DKD PATIENTS IN BARDOXOLONE METHYL TREATMENT: RENAL FUNCTION IN CHRONIC KIDNEY DISEASE/TYPE 2 DIABETES (BEAM) TRIAL AND PHASE II STUDY OF BARDOXOLONE METHYL IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES (TSUBAKI) TRIAL. THUS, FOLLOWING SGLT2 INHIBITOR, NUMEROUS NOVEL DRUGS COULD BE UTILIZED IN TREATING DKD. FUTURE STUDIES ARE EXPECTED TO PROVIDE NEW INSIGHTS. 2021 5 6648 26 UPDATE ON DIAGNOSIS, PATHOPHYSIOLOGY, AND MANAGEMENT OF DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD) IS A CHRONIC COMPLICATION OF DIABETES MELLITUS WHICH MAY EVENTUALLY LEAD TO END-STAGE KIDNEY DISEASE (ESKD). DESPITE IMPROVEMENTS IN GLYCAEMIC CONTROL AND BLOOD PRESSURE MANAGEMENT WITH RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) BLOCKADE, THE CURRENT THERAPY CANNOT COMPLETELY HALT DKD PROGRESSION TO ESKD IN SOME PATIENTS. DKD IS A HETEROGENEOUS DISEASE ENTITY IN TERMS OF ITS CLINICAL MANIFESTATIONS, HISTOPATHOLOGY AND THE RATE OF PROGRESSION, WHICH MAKES IT DIFFICULT TO DEVELOP EFFECTIVE THERAPEUTICS. IT WAS FORMERLY CONSIDERED THAT ALBUMINURIA PRECEDED KIDNEY FUNCTION DECLINE IN DKD, BUT RECENT EPIDEMIOLOGICAL STUDIES REVEALED THAT A DISTINCT GROUP OF PATIENTS PRESENTED KIDNEY DYSFUNCTION WITHOUT DEVELOPING ALBUMINURIA. OTHER COMORBIDITIES, SUCH AS HYPERTENSION, OBESITY AND GOUT, ALSO AFFECT THE CLINICAL COURSE OF DKD. THE PATHOPHYSIOLOGY OF DKD IS COMPLEX AND MULTIFACTORIAL, INVOLVING BOTH METABOLIC AND HAEMODYNAMIC FACTORS. THESE INDUCE ACTIVATION OF INTRACELLULAR SIGNALLING PATHWAYS, OXIDATIVE STRESS, HYPOXIA, DYSREGULATED AUTOPHAGY AND EPIGENETIC CHANGES, WHICH RESULT IN KIDNEY INFLAMMATION AND FIBROSIS. RECENTLY, TWO GROUPS OF ANTIDIABETIC DRUGS, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS AND GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS, WERE DEMONSTRATED TO PROVIDE RENOPROTECTION ON TOP OF THEIR GLUCOSE-LOWERING EFFECTS. SEVERAL OTHER THERAPEUTIC AGENTS ARE ALSO BEING DEVELOPED AND EVALUATED IN CLINICAL TRIALS. 2021 6 5363 22 RECENT ADVANCES IN DIABETIC KIDNEY DISEASES: FROM KIDNEY INJURY TO KIDNEY FIBROSIS. DIABETIC KIDNEY DISEASE (DKD) IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE. THE NATURAL HISTORY OF DKD INCLUDES GLOMERULAR HYPERFILTRATION, PROGRESSIVE ALBUMINURIA, DECLINING ESTIMATED GLOMERULAR FILTRATION RATE, AND, ULTIMATELY, KIDNEY FAILURE. IT IS KNOWN THAT DKD IS ASSOCIATED WITH METABOLIC CHANGES CAUSED BY HYPERGLYCEMIA, RESULTING IN GLOMERULAR HYPERTROPHY, GLOMERULOSCLEROSIS, AND TUBULOINTERSTITIAL INFLAMMATION AND FIBROSIS. HYPERGLYCEMIA IS ALSO KNOWN TO CAUSE PROGRAMMED EPIGENETIC MODIFICATION. HOWEVER, THE DETAILED MECHANISMS INVOLVED IN THE ONSET AND PROGRESSION OF DKD REMAIN ELUSIVE. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES REGARDING THE PATHOGENIC MECHANISMS INVOLVED IN DKD. 2021 7 6192 28 THE IMPACT OF NUTRITIONAL INSULTS DURING FETAL LIFE ON BLOOD PRESSURE. NUMEROUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES PROVIDE COMPELLING EVIDENCE THAT NUTRITIONAL INSULTS THAT IMPACT FETAL GROWTH PROGRAM A MARKED INCREASE IN BLOOD PRESSURE IN LATER LIFE. SEX AND AGE ALSO INFLUENCE THE DEVELOPMENTAL PROGRAMMING OF HYPERTENSION; YET THE EXACT MECHANISMS THAT PERMANENTLY CHANGE THE STRUCTURE, PHYSIOLOGY, AND ENDOCRINE HEALTH OF AN INDIVIDUAL ACROSS THEIR LIFESPAN FOLLOWING EXPOSURE TO A NUTRITIONAL INSULT ARE NOT ENTIRELY CLEAR. FETAL EXPOSURE TO MATERNAL GLUCOCORTICOIDS IS POSTULATED AS AN INITIATING EVENT. IN ADDITION, INAPPROPRIATE SUPPRESSION OR ACTIVATION OF THE RENIN ANGIOTENSIN SYSTEM (RAS) AND/OR ACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM (SNS) LEADING TO MARKED INCREASES IN OXIDATIVE STRESS AND ENDOTHELIN PRODUCTION ARE IMPLICATED IN THE ETIOLOGY OF HYPERTENSION THAT HAS ITS ORIGINS IN FETAL LIFE. THE RISK OF HYPERTENSION AND CHRONIC DISEASE IN ONE GENERATION IS TRANSMITTED TO THE NEXT IN THE ABSENCE OF AN ADDITIONAL PRENATAL INSULT IMPLICATING EPIGENETIC PROCESSES. YET, FURTHER STUDIES ARE NEEDED TO FULLY ELUCIDATE THE MECHANISMS THAT CONTRIBUTE TO HYPERTENSION PROGRAMMED IN RESPONSE TO NUTRITIONAL INSULTS DURING EARLY LIFE IN ORDER TO IMPROVE THE CARDIOVASCULAR HEALTH OF AN INDIVIDUAL ACROSS THEIR LIFESPAN. 2015 8 4137 25 MECHANISMS OF METABOLIC MEMORY AND RENAL HYPOXIA AS A THERAPEUTIC TARGET IN DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD) IS A WORLDWIDE PUBLIC HEALTH PROBLEM. THE DEFINITION OF DKD IS UNDER DISCUSSION. ALTHOUGH THE TERM DKD WAS ORIGINALLY DEFINED AS 'KIDNEY DISEASE SPECIFIC TO DIABETES,' DKD FREQUENTLY MEANS CHRONIC KIDNEY DISEASE WITH DIABETES MELLITUS AND INCLUDES NOT ONLY CLASSICAL DIABETIC NEPHROPATHY, BUT ALSO KIDNEY DYSFUNCTION AS A RESULT OF NEPHROSCLEROSIS AND OTHER CAUSES. METABOLIC MEMORY PLAYS A CRUCIAL ROLE IN THE PROGRESSION OF VARIOUS COMPLICATIONS OF DIABETES, INCLUDING DKD. THE MECHANISMS OF METABOLIC MEMORY IN DKD ARE SUPPOSED TO INCLUDE ADVANCED GLYCATION END-PRODUCTS, DEOXYRIBONUCLEIC ACID METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RIBONUCLEIC ACID INCLUDING MICRO RIBONUCLEIC ACID. REGARDLESS OF THE PRESENCE OF DIABETES MELLITUS, THE FINAL COMMON PATHWAY IN CHRONIC KIDNEY DISEASE IS CHRONIC KIDNEY HYPOXIA, WHICH INFLUENCES EPIGENETIC PROCESSES, INCLUDING DEOXYRIBONUCLEIC ACID METHYLATION, HISTONE MODIFICATION, AND CONFORMATIONAL CHANGES IN MICRO RIBONUCLEIC ACID AND CHROMATIN. THEREFORE, HYPOXIA AND OXIDATIVE STRESS ARE APPROPRIATE TARGETS OF THERAPIES AGAINST DKD. PROLYL HYDROXYLASE DOMAIN INHIBITOR ENHANCES THE DEFENSIVE MECHANISMS AGAINST HYPOXIA. BARDOXOLONE METHYL PROTECTS AGAINST OXIDATIVE STRESS, AND CAN EVEN REVERSE IMPAIRED RENAL FUNCTION; A PHASE 2 TRIAL WITH CONSIDERABLE ATTENTION TO HEART COMPLICATIONS IS CURRENTLY ONGOING IN JAPAN. 2017 9 5574 24 ROLE OF MICRORNA-143 IN NERVE INJURY-INDUCED UPREGULATION OF DNMT3A EXPRESSION IN PRIMARY SENSORY NEURONS. PERIPHERAL NERVE INJURY INCREASED THE EXPRESSION OF THE DNA METHYLTRANSFERASE 3A (DNMT3A) MRNA AND ITS ENCODING DNMT3A PROTEIN IN INJURED DORSAL ROOT GANGLIA (DRG). THIS INCREASE IS CONSIDERED AS AN ENDOGENOUS INSTIGATOR IN NEUROPATHIC PAIN GENESIS THROUGH EPIGENETIC SILENCING OF PAIN-ASSOCIATED GENES (SUCH AS OPRM1) IN INJURED DRG. HOWEVER, HOW DRG DNMT3A IS INCREASED FOLLOWING PERIPHERAL NERVE INJURY IS STILL ELUSIVE. WE REPORTED HERE THAT PERIPHERAL NERVE INJURY CAUSED BY THE FIFTH SPINAL NERVE LIGATION (SNL) DOWNREGULATED MICRORNA (MIR)-143 EXPRESSION IN INJURED DRG. THIS DOWNREGULATION WAS REQUIRED FOR SNL-INDUCED DRG DNMT3A INCREASE AS RESCUING MIR-143 DOWNREGULATION THROUGH MICROINJECTION OF MIR-143 MIMICS INTO INJURED DRG BLOCKED THE SNL-INDUCED INCREASE IN DNMT3A AND RESTORED THE SNL-INDUCED DECREASES IN OPRM1 MRNA AND ITS ENCODING MU OPIOID RECEPTOR (MOR) IN INJURED DRG, IMPAIRED SPINAL CORD CENTRAL SENSITIZATION AND NEUROPATHIC PAIN, AND IMPROVED MORPHINE ANALGESIC EFFECTS FOLLOWING SNL. MIMICKING SNL-INDUCED DRG MIR-143 DOWNREGULATION THROUGH DRG MICROINJECTION OF MIR143 INHIBITORS IN NAIVE RATS INCREASED THE EXPRESSION OF DNMT3A AND REDUCED THE EXPRESSION OF OPRM1 MRNA AND MOR IN INJECTED DRG AND PRODUCED NEUROPATHIC PAIN-LIKE SYMPTOMS. THESE FINDINGS SUGGEST THAT MIR-143 IS A NEGATIVE REGULATOR IN DNMT3A EXPRESSION IN THE DRG UNDER NEUROPATHIC PAIN CONDITIONS AND MAY BE A POTENTIAL TARGET FOR THERAPEUTIC MANAGEMENT OF NEUROPATHIC PAIN. 2017 10 3913 23 LIFESTYLE MODIFICATIONS AND NUTRITIONAL AND THERAPEUTIC INTERVENTIONS IN DELAYING THE PROGRESSION OF CHRONIC KIDNEY DISEASE: A REVIEW. CHRONIC KIDNEY DISEASE (CKD) IS A DEBILITATING PROGRESSIVE ILLNESS THAT AFFECTS MORE THAN 10% OF THE WORLD'S POPULATION. IN THIS LITERATURE REVIEW, WE DISCUSSED THE ROLES OF NUTRITIONAL INTERVENTIONS, LIFESTYLE MODIFICATIONS, HYPERTENSION (HTN) AND DIABETES MELLITUS (DM) CONTROL, AND MEDICATIONS IN DELAYING THE PROGRESSION OF CKD. WALKING, WEIGHT LOSS, LOW-PROTEIN DIET (LPD), ADHERENCE TO THE ALTERNATE MEDITERRANEAN (AMED) DIET, AND ALTERNATIVE HEALTHY EATING INDEX (AHEI)-2010 SLOW THE PROGRESSION OF CKD. HOWEVER, SMOKING AND BINGE ALCOHOL DRINKING INCREASE THE RISK OF CKD PROGRESSION. IN ADDITION, HYPERGLYCEMIA, ALTERED LIPID METABOLISM, LOW-GRADE INFLAMMATION, OVER-ACTIVATION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS), AND OVERHYDRATION (OH) INCREASE DIABETIC CKD PROGRESSION. THE KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES (KDIGO) GUIDELINES RECOMMEND BLOOD PRESSURE (BP) CONTROL OF <140/90 MMHG IN PATIENTS WITHOUT ALBUMINURIA AND <130/80 MMHG IN PATIENTS WITH ALBUMINURIA TO PREVENT CKD PROGRESSION. MEDICAL THERAPIES AIM TO TARGET EPIGENETIC ALTERATIONS, FIBROSIS, AND INFLAMMATION. CURRENTLY, RAAS BLOCKADE, SODIUM-GLUCOSE COTRANSPORTER-2 (SGLT2) INHIBITORS, PENTOXIFYLLINE, AND FINERENONE ARE APPROVED FOR MANAGING CKD. IN ADDITION, ACCORDING TO THE COMPLETED STUDY OF DIABETIC NEPHROPATHY WITH ATRASENTAN (SONAR), ATRASENTAN, AN ENDOTHELIN RECEPTOR ANTAGONIST (ERA), DECREASED THE RISK OF RENAL EVENTS IN DIABETIC CKD PATIENTS. HOWEVER, ONGOING TRIALS ARE STUDYING THE ROLE OF OTHER AGENTS IN SLOWING THE PROGRESSION OF CKD. 2023 11 5951 23 TARGETING THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM TO PREVENT HYPERTENSION AND KIDNEY DISEASE OF DEVELOPMENTAL ORIGINS. THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) IS IMPLICATED IN HYPERTENSION AND KIDNEY DISEASE. THE DEVELOPING KIDNEY CAN BE PROGRAMMED BY VARIOUS EARLY-LIFE INSULTS BY SO-CALLED RENAL PROGRAMMING, RESULTING IN HYPERTENSION AND KIDNEY DISEASE IN ADULTHOOD. THIS THEORY IS KNOWN AS DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD). CONVERSELY, EARLY RAAS-BASED INTERVENTIONS COULD REVERSE PROGRAM PROCESSES TO PREVENT A DISEASE FROM OCCURRING BY SO-CALLED REPROGRAMMING. IN THE CURRENT REVIEW, WE MAINLY SUMMARIZE (1) THE CURRENT KNOWLEDGE ON THE RAAS IMPLICATED IN RENAL PROGRAMMING; (2) CURRENT EVIDENCE SUPPORTING THE CONNECTIONS BETWEEN THE ABERRANT RAAS AND OTHER MECHANISMS BEHIND RENAL PROGRAMMING, SUCH AS OXIDATIVE STRESS, NITRIC OXIDE DEFICIENCY, EPIGENETIC REGULATION, AND GUT MICROBIOTA DYSBIOSIS; AND (3) AN OVERVIEW OF HOW RAAS-BASED REPROGRAMMING INTERVENTIONS MAY PREVENT HYPERTENSION AND KIDNEY DISEASE OF DEVELOPMENTAL ORIGINS. TO ACCELERATE THE TRANSITION OF RAAS-BASED INTERVENTIONS FOR PREVENTION OF HYPERTENSION AND KIDNEY DISEASE, AN EXTENDED COMPREHENSION OF THE RAAS IMPLICATED IN RENAL PROGRAMMING IS NEEDED, AS WELL AS A GREATER FOCUS ON FURTHER CLINICAL TRANSLATION. 2021 12 4615 21 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 13 1654 26 DORSAL ROOT GANGLIA COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1 CONTRIBUTES TO PERIPHERAL NERVE INJURY-INDUCED PAIN HYPERSENSITIVITIES. NEUROPATHIC PAIN IS ASSOCIATED WITH GENE EXPRESSION CHANGES WITHIN THE DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY, WHICH INVOLVES EPIGENETIC MECHANISMS. COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1 (CARM1), AN EPIGENETIC ACTIVATOR, REGULATES GENE TRANSCRIPTIONAL ACTIVITY BY PROTEIN POSTTRANSLATIONAL MODIFICATIONS. HOWEVER, WHETHER CARM1 PLAYS AN ESSENTIAL ROLE IN THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN IS UNKNOWN. WE REPORT HERE THAT PERIPHERAL NERVE INJURY INDUCED THE UPREGULATION OF THE MRNA AND PROTEIN EXPRESSION OF CARM1 IN THE INJURED DRG, AND BLOCKING ITS EXPRESSION THROUGH SMALL INTERFERING RNA (SIRNA) IN THE INJURED DRG ATTENUATED THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN. FURTHERMORE, PHARMACOLOGICAL INHIBITION OF CARM1 MITIGATED PERIPHERAL NERVE INJURY-INDUCED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA. GIVEN THAT CARM1 INHIBITION OR KNOCKDOWN ATTENUATED THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN AFTER PERIPHERAL NERVE INJURY, OUR FINDINGS SUGGEST THAT CARM1 MAY SERVE AS A PROMISING THERAPEUTIC TARGET FOR NEUROPATHIC PAIN TREATMENT IN CLINICAL APPLICATIONS. 2018 14 4433 27 MOLECULAR COMPLEXITIES UNDERLYING THE VASCULAR COMPLICATIONS OF DIABETES MELLITUS - A COMPREHENSIVE REVIEW. DIABETES IS A CHRONIC DISEASE, CHARACTERIZED BY HYPERGLYCEMIA, WHICH REFERS TO THE ELEVATED LEVELS OF GLUCOSE IN THE BLOOD, DUE TO THE INABILITY OF THE BODY TO PRODUCE OR USE INSULIN EFFECTIVELY. CHRONIC HYPERGLYCEMIA LEVELS LEAD TO MACROVASCULAR AND MICROVASCULAR COMPLICATIONS. THE MACROVASCULAR COMPLICATIONS CONSIST OF PERIPHERAL ARTERY DISEASE (PAD), CARDIOVASCULAR DISEASES (CVD) AND CEREBROVASCULAR DISEASES, WHILE THE MICROVASCULAR COMPLICATIONS COMPRISE OF DIABETIC MICROANGIOPATHY, DIABETIC NEPHROPATHY, DIABETIC RETINOPATHY AND DIABETIC NEUROPATHY. VASCULAR ENDOTHELIAL DYSFUNCTION PLAYS A CRUCIAL ROLE IN MEDIATING BOTH MACROVASCULAR AND MICROVASCULAR COMPLICATIONS UNDER HYPERGLYCEMIC CONDITIONS. IN DIABETIC MICROVASCULATURE, THE INTRACELLULAR HYPERGLYCEMIA CAUSES DAMAGE TO THE VASCULAR ENDOTHELIUM THROUGH - (I) ACTIVATION OF FOUR BIOCHEMICAL PATHWAYS, NAMELY THE POLYOL PATHWAY, PROTEIN KINASE C (PKC) PATHWAY, ADVANCED GLYCATION END PRODUCTS (AGE) PATHWAY AND HEXOSAMINE PATHWAY, ALL OF WHICH COMMUTES GLUCOSE AND ITS INTERMEDIATES LEADING TO OVERPRODUCTION OF REACTIVE OXYGEN SPECIES, (II) DYSREGULATION OF GROWTH FACTORS AND CYTOKINES, (III) EPIGENETIC CHANGES WHICH CONCERN THE CHANGES IN DNA AS A RESPONSE TO INTRACELLULAR CHANGES, AND (IV) ABNORMALITIES IN NON-CODING RNAS, SPECIFICALLY MICRORNAS. THIS REVIEW WILL FOCUS ON GAINING AN UNDERSTANDING OF THE MOLECULAR COMPLEXITIES UNDERLYING THE VASCULAR COMPLICATIONS IN DIABETES MELLITUS, TO INCREASE OUR UNDERSTANDING TOWARDS THE DEVELOPMENT OF NEW MECHANISTIC THERAPEUTIC STRATEGIES TO PREVENT OR TREAT DIABETES-INDUCED VASCULAR COMPLICATIONS. 2020 15 2199 21 EPIGENETIC MODIFICATION OF DRG NEURONAL GENE EXPRESSION SUBSEQUENT TO NERVE INJURY: ETIOLOGICAL CONTRIBUTION TO COMPLEX REGIONAL PAIN SYNDROMES (PART II). CUMULATING EVIDENCE INDICATED THAT NERVE INJURY-ASSOCIATED CELLULAR AND MOLECULAR CHANGES PLAY AN ESSENTIAL ROLE IN CONTRIBUTING TO THE DEVELOPMENT OF PATHOLOGICAL PAIN, AND MORE RECENT FINDINGS IMPLICATED THE CRITICAL ROLE OF EPIGENETIC MECHANISMS IN PAIN-RELATED SENSITIZATION IN THE DRG SUBSEQUENT TO NERVE INJURY. IN THIS PART OF THE DYAD REVIEW (PART II), WE REVIEWED AND PAID SPECIAL ATTENTION ON THE ETIOLOGICAL CONTRIBUTION OF DGR GENE EXPRESSION MODULATED BY EPIGENETIC MECHANISMS OF CRPS. AS ESSENTIAL EFFECTORS TO DIFFERENT MOLECULAR ACTIVATION, WE FIRST DISCUSSED THE ACTIVATION OF VARIOUS SIGNALING PATHWAYS THAT SUBSEQUENTLY FROM NERVE INJURY, AND IN FURTHER ILLUSTRATED THE FUNDAMENTAL AND FUNCTIONAL UNDERPINNINGS OF NERVE INJURY-INDUCED PAIN, IN WHICH WE ARGUED FOR THE POTENTIAL EPIGENETIC MECHANISMS IN RESPONSE TO SENSITIZING STIMULI OR INJURY. THEREFORE, UNDERSTANDING THE SPECIFIC MEDIATING FACTORS THAT INFLUENCE INDIVIDUAL EPIGENETIC DIFFERENCES CONTRIBUTING TO PAIN SENSITIVITY AND RESPONSIVENESS TO ANALGESICS POSSESSES CRUCIAL CLINICAL IMPLICATIONS. 2014 16 6665 34 UPSTREAM AND DOWNSTREAM REGULATORS OF KLOTHO EXPRESSION IN CHRONIC KIDNEY DISEASE. KLOTHO IS A CRITICAL PROTEIN THAT PROTECTS THE KIDNEY. KLOTHO IS SEVERELY DOWNREGULATED IN CHRONIC KIDNEY DISEASE (CKD), AND ITS DEFICIENCY IS IMPLICATED IN THE PATHOGENESIS AND PROGRESSION OF CKD. CONVERSELY, AN INCREASE IN KLOTHO LEVELS RESULTS IN IMPROVED KIDNEY FUNCTION AND DELAYS CKD PROGRESSION, SUPPORTING THE NOTION THAT MODULATING KLOTHO LEVELS COULD REPRESENT A POSSIBLE THERAPEUTIC STRATEGY FOR CKD TREATMENT. NEVERTHELESS, THE REGULATORY MECHANISMS RESPONSIBLE FOR THE LOSS OF KLOTHO REMAIN ELUSIVE. PREVIOUS STUDIES HAVE DEMONSTRATED THAT OXIDATIVE STRESS, INFLAMMATION, AND EPIGENETIC MODIFICATIONS CAN MODULATE KLOTHO LEVELS. THESE MECHANISMS RESULT IN A DECREASE IN KLOTHO MRNA TRANSCRIPT LEVELS AND REDUCED TRANSLATION, THUS CAN BE GROUPED TOGETHER AS UPSTREAM REGULATORY MECHANISMS. HOWEVER, THERAPEUTIC STRATEGIES THAT AIM TO RESCUE KLOTHO LEVELS BY TARGETING THESE UPSTREAM MECHANISMS DO NOT ALWAYS RESULT IN INCREASED KLOTHO, INDICATING THE INVOLVEMENT OF OTHER REGULATORY MECHANISMS. EMERGING EVIDENCE HAS SHOWN THAT ENDOPLASMIC RETICULUM (ER) STRESS, THE UNFOLDED PROTEIN RESPONSE, AND ER-ASSOCIATED DEGRADATION ALSO AFFECT THE MODIFICATION, TRANSLOCATION, AND DEGRADATION OF KLOTHO, AND THUS ARE PROPOSED TO BE DOWNSTREAM REGULATORY MECHANISMS. HERE, WE DISCUSS THE CURRENT UNDERSTANDING OF UPSTREAM AND DOWNSTREAM REGULATORY MECHANISMS OF KLOTHO AND EXAMINE POTENTIAL THERAPEUTIC STRATEGIES TO UPREGULATE KLOTHO EXPRESSION FOR CKD TREATMENT. 2023 17 6441 19 THERAPEUTIC APPROACHES FOR NONALCOHOLIC FATTY LIVER DISEASE: ESTABLISHED TARGETS AND DRUGS. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), AS A MULTISYSTEMIC DISEASE, IS THE MOST PREVALENT CHRONIC LIVER DISEASE CHARACTERIZED BY EXTREMELY COMPLEX PATHOGENIC MECHANISMS AND MULTIFACTORIAL ETIOLOGY, WHICH OFTEN DEVELOPS AS A CONSEQUENCE OF OBESITY, METABOLIC SYNDROME. PATHOPHYSIOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF NAFLD INCLUDE DIET, OBESITY, INSULIN RESISTANCE (IR), GENETIC AND EPIGENETIC DETERMINANTS, INTESTINAL DYSBIOSIS, OXIDATIVE/NITROSATIVE STRESS, AUTOPHAGY DYSREGULATION, HEPATIC INFLAMMATION, GUT-LIVER AXIS, GUT MICROBES, IMPAIRED MITOCHONDRIAL METABOLISM AND REGULATION OF HEPATIC LIPID METABOLISM. SOME OF THE NEW DRUGS FOR THE TREATMENT OF NAFLD ARE INTRODUCED HERE. ALL OF THEM ACHIEVE THERAPEUTIC OBJECTIVES BY INTERFERING WITH CERTAIN PATHOPHYSIOLOGICAL PATHWAYS OF NAFLD, INCLUDING FIBROBLAST GROWTH FACTORS (FGF) ANALOGUES, PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARS) AGONISTS, GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS, G PROTEIN-COUPLED RECEPTORS (GPCRS), SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS (SGLT-2I), FARNESOID X RECEPTOR (FXR), FATTY ACID SYNTHASE INHIBITOR (FASNI), ANTIOXIDANTS, ETC. THIS REVIEW DESCRIBES SOME PATHOPHYSIOLOGICAL MECHANISMS OF NAFLD AND ESTABLISHED TARGETS AND DRUGS. 2023 18 4644 14 NEUROPATHIC PAIN TREATMENT: STILL A CHALLENGE. NEUROPATHIC PAIN (NP) IS THE RESULT OF A SERIES OF CONDITIONS CAUSED BY DISEASES OR LESIONS TO THE SOMATOSENSORY SYSTEM. DUE TO THE BETTER UNDERSTANDING OF NP PATHOPHYSIOLOGY PREVIOUSLY UNEXPLORED THERAPIES HAVE BEEN USED WITH ENCOURAGING RESULTS. IN THIS GROUP, ACETYL-L-CARNITINE, ALPHA-LIPOIC-ACID, CANNABINOIDS, CLONIDINE, EMA401, BOTULINUM TOXIN TYPE A AND NEW VOLTAGE-GATED SODIUM CHANNEL BLOCKERS, CAN BE INCLUDED. BESIDES, CHANGING PARADIGMS MAY OCCUR WITH THE ADVENT OF OPTOGENETICS AND A BETTER UNDERSTANDING OF EPIGENETIC REGULATION. WE REVIEWED THE PUBLISHED LITERATURE ON THE PHARMACOLOGICAL TREATMENT OF NP. DESPITE THE INTERESTING RESULTS, RANDOMIZED CONTROLLED TRIALS ARE DEMANDED THE MAJORITY OF THE THERAPIES PREVIOUSLY MENTIONED. IN SPITE OF SEVERAL STUDIES FOR THE RELIEF OF NP, PAIN CONTROL CONTINUES BEING A CHALLENGE. 2016 19 5354 24 RE1-SILENCING TRANSCRIPTION FACTOR CONTROLS THE ACUTE-TO-CHRONIC NEUROPATHIC PAIN TRANSITION AND CHRM2 RECEPTOR GENE EXPRESSION IN PRIMARY SENSORY NEURONS. NEUROPATHIC PAIN IS ASSOCIATED WITH PERSISTENT CHANGES IN GENE EXPRESSION IN PRIMARY SENSORY NEURONS, BUT THE UNDERLYING EPIGENETIC MECHANISMS THAT CAUSE THESE CHANGES REMAIN UNCLEAR. THE MUSCARINIC CHOLINERGIC RECEPTORS (MACHRS), PARTICULARLY THE M2 SUBTYPE (ENCODED BY THE CHOLINERGIC RECEPTOR MUSCARINIC 2 (CHRM2) GENE), ARE CRITICALLY INVOLVED IN THE REGULATION OF SPINAL NOCICEPTIVE TRANSMISSION. HOWEVER, LITTLE IS KNOWN ABOUT HOW CHRM2 EXPRESSION IS TRANSCRIPTIONALLY REGULATED. HERE WE SHOW THAT NERVE INJURY PERSISTENTLY INCREASED THE EXPRESSION OF RE1-SILENCING TRANSCRIPTION FACTOR (REST, ALSO KNOWN AS NEURON-RESTRICTIVE SILENCING FACTOR [NRSF]), A GENE-SILENCING TRANSCRIPTION FACTOR, IN THE DORSAL ROOT GANGLION (DRG). REMARKABLY, NERVE INJURY-INDUCED CHRONIC BUT NOT ACUTE PAIN HYPERSENSITIVITY WAS ATTENUATED IN MICE WITH REST KNOCKOUT IN DRG NEURONS. ALSO, SIRNA-MEDIATED REST KNOCKDOWN REVERSED NERVE INJURY-INDUCED CHRONIC PAIN HYPERSENSITIVITY IN RATS. NERVE INJURY PERSISTENTLY REDUCED CHRM2 EXPRESSION IN THE DRG AND DIMINISHED THE ANALGESIC EFFECT OF MUSCARINE. THE RE1 BINDING SITE ON THE CHRM2 PROMOTER IS REQUIRED FOR REST-MEDIATED CHRM2 REPRESSION, AND NERVE INJURY INCREASED THE ENRICHMENT OF REST IN THE CHRM2 PROMOTER IN THE DRG. FURTHERMORE, REST KNOCKDOWN OR GENETIC ABLATION IN DRG NEURONS NORMALIZED CHRM2 EXPRESSION AND AUGMENTED MUSCARINE'S ANALGESIC EFFECT ON NEUROPATHIC PAIN AND FULLY REVERSED THE NERVE INJURY-INDUCED REDUCTION IN THE INHIBITORY EFFECT OF MUSCARINE ON GLUTAMATERGIC INPUT TO SPINAL DORSAL HORN NEURONS. OUR FINDINGS INDICATE THAT NERVE INJURY-INDUCED REST UP-REGULATION IN DRG NEURONS PLAYS AN IMPORTANT ROLE IN THE ACUTE-TO-CHRONIC PAIN TRANSITION AND IS ESSENTIAL FOR THE TRANSCRIPTIONAL REPRESSION OF CHRM2 IN NEUROPATHIC PAIN. 2018 20 4618 27 NERVE INJURY-INDUCED EPIGENETIC SILENCING OF OPIOID RECEPTORS CONTROLLED BY DNMT3A IN PRIMARY AFFERENT NEURONS. OPIOIDS ARE THE GOLD STANDARD FOR PHARMACOLOGICAL TREATMENT OF NEUROPATHIC PAIN, BUT THEIR ANALGESIC EFFECTS ARE UNSATISFACTORY IN PART DUE TO NERVE INJURY-INDUCED DOWNREGULATION OF OPIOID RECEPTORS IN DORSAL ROOT GANGLIA (DRG) NEURONS. HOW NERVE INJURY DRIVES SUCH DOWNREGULATION REMAINS ELUSIVE. DNA METHYLTRANSFERASE (DNMT)-TRIGGERED DNA METHYLATION REPRESSES GENE EXPRESSION. WE SHOW HERE THAT BLOCKING THE NERVE INJURY-INDUCED INCREASE IN DRG DNMT3A (A DE NOVO DNMT) RESCUED THE EXPRESSION OF OPRM1 AND OPRK1 MRNAS AND THEIR RESPECTIVE ENCODING MU-OPIOID RECEPTOR (MOR) AND KAPPA-OPIOID RECEPTOR (KOR) PROTEINS IN THE INJURED DRG. BLOCKING THIS INCREASE ALSO PREVENTED THE NERVE INJURY-INDUCED INCREASE IN DNA METHYLATION IN THE PROMOTER AND 5'-UNTRANSLATED REGION OF THE OPRM1 GENE IN THE INJURED DRG, RESTORED MORPHINE OR LOPERAMIDE (A PERIPHERAL ACTING MOR PREFERRING AGONIST) ANALGESIC EFFECTS, AND ATTENUATED THE DEVELOPMENT OF THEIR ANALGESIC TOLERANCE UNDER NEUROPATHIC PAIN CONDITIONS. MIMICKING THIS INCREASE REDUCED THE EXPRESSION OF OPRM1 AND OPRK1 MRNAS AND THEIR CODING MOR AND KOR IN DRG AND AUGMENTED MOR-GATED NEUROTRANSMITTER RELEASE FROM THE PRIMARY AFFERENTS. MECHANISTICALLY, DNMT3A REGULATION OF OPRM1 GENE EXPRESSION REQUIRED THE METHYL-CPG-BINDING PROTEIN 1, MBD1, AS MBD1 KNOCKOUT RESULTED IN THE DECREASED BINDING OF DNMT3A TO THE OPRM1 GENE PROMOTER AND BLOCKED THE DNMT3A-TRIGGERED REPRESSION OF OPRM1 GENE EXPRESSION IN DRG NEURONS. THESE DATA SUGGEST THAT DNMT3A IS REQUIRED FOR NERVE INJURY-INDUCED AND MBD1-MEDIATED EPIGENETIC SILENCING OF THE MOR AND KOR IN THE INJURED DRG. DNMT3A INHIBITION MAY SERVE AS A PROMISING ADJUVANT THERAPY FOR OPIOID USE IN NEUROPATHIC PAIN MANAGEMENT. 2017