1  3839 149 IPSC-DERIVED NEURAL PRECURSOR CELLS: POTENTIAL FOR CELL TRANSPLANTATION THERAPY IN SPINAL CORD INJURY. A NUMBER OF STUDIES HAVE DEMONSTRATED THAT TRANSPLANTATION OF NEURAL PRECURSOR CELLS (NPCS) PROMOTES FUNCTIONAL RECOVERY AFTER SPINAL CORD INJURY (SCI). HOWEVER, THE NPCS HAD BEEN MOSTLY HARVESTED FROM EMBRYONIC STEM CELLS OR FETAL TISSUE, RAISING THE ETHICAL CONCERN. YAMANAKA AND HIS COLLEAGUES ESTABLISHED INDUCED PLURIPOTENT STEM CELLS (IPSCS) WHICH COULD BE GENERATED FROM SOMATIC CELLS, AND THIS INNOVATIVE DEVELOPMENT HAS MADE RAPID PROGRESSION IN THE FIELD OF SCI REGENERATION. WE AND OTHER GROUPS SUCCEEDED IN PRODUCING NPCS FROM IPSCS, AND DEMONSTRATED BENEFICIAL EFFECTS AFTER TRANSPLANTATION FOR ANIMAL MODELS OF SCI. IN PARTICULAR, EFFICACY OF HUMAN IPSC-NPCS IN NON-HUMAN PRIMATE SCI MODELS FOSTERED MOMENTUM OF CLINICAL APPLICATION FOR SCI PATIENTS. AT THE SAME TIME, HOWEVER, ARTIFICIAL INDUCTION METHODS IN IPSC TECHNOLOGY CREATED ALTERNATIVE ISSUES INCLUDING GENETIC AND EPIGENETIC ABNORMALITIES, AND TUMORIGENICITY AFTER TRANSPLANTATION. TO OVERCOME THESE PROBLEMS, IT IS CRITICALLY IMPORTANT TO SELECT ORIGINS OF SOMATIC CELLS, USE INTEGRATION-FREE SYSTEM DURING TRANSFECTION OF REPROGRAMMING FACTORS, AND THOROUGHLY INVESTIGATE THE CHARACTERISTICS OF IPSC-NPCS WITH RESPECT TO QUALITY MANAGEMENT. MOREOVER, SINCE MOST OF THE PREVIOUS STUDIES HAVE FOCUSED ON SUBACUTE PHASE OF SCI, ESTABLISHMENT OF EFFECTIVE NPC TRANSPLANTATION SHOULD BE EVALUATED FOR CHRONIC PHASE HEREAFTER. OUR GROUP IS CURRENTLY PREPARING CLINICAL-GRADE HUMAN IPSC-NPCS, AND WILL MOVE FORWARD TOWARD CLINICAL STUDY FOR SUBACUTE SCI PATIENTS SOON IN THE NEAR FUTURE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
2   328  22 ALPHA-KETOGLUTARIC ACID AMELIORATES INTERVERTEBRAL DISC DEGENERATION BY BLOCKING THE IL-6/JAK2/STAT3 PATHWAY. INTERVERTEBRAL DISC DEGENERATION (IVDD) IS THE MAJOR CAUSE OF LOW BACK PAIN. ALPHA-KETOGLUTARIC ACID (ALPHA-KG), AN IMPORTANT INTERMEDIATE IN ENERGY METABOLISM, HAS VARIOUS FUNCTIONS, INCLUDING EPIGENETIC REGULATION, MAINTENANCE OF REDOX HOMEOSTASIS, AND ANTI-AGING, BUT WHETHER IT CAN AMELIORATE IVDD HAS NOT BEEN REPORTED. HERE, WE EXAMINED THE IMPACTS OF LONG-TERM ADMINISTRATION OF A-KG ON AGING-ASSOCIATED IVDD IN ADULT RATS. IN VIVO AND IN VITRO EXPERIMENTS SHOWED THAT ALPHA-KG SUPPLEMENTATION EFFECTIVELY AMELIORATED IVDD IN RATS AND THE SENESCENCE OF NUCLEUS PULPOSUS CELLS (NPCS). ALPHA-KG SUPPLEMENTATION SIGNIFICANTLY ATTENUATED SENESCENCE, APOPTOSIS AND MMP-13 PROTEIN EXPRESSION, AND IT INCREASED THE SYNTHESIS OF AGGRECAN AND COLLAGEN II IN IL-1BETA-TREATED NPCS. IN ADDITION, ALPHA-KG SUPPLEMENTATION REDUCED THE LEVELS OF IL-6, PHOSPHORYLATED JAK2 AND STAT3, AND THE NUCLEAR TRANSLOCATION OF P-STAT3 IN IL-1BETA-INDUCED DEGENERATING NPCS. THE EFFECTS OF ALPHA-KG WERE ENHANCED BY AG490 IN NPCS. THE UNDERLYING MECHANISM MAY INVOLVE THE INHIBITION OF JAK2/STAT3 PHOSPHORYLATION AND THE REDUCTION OF IL-6 EXPRESSION. OUR FINDINGS MAY HELP IN THE DEVELOPMENT OF NEW THERAPEUTIC STRATEGIES FOR IVDD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3  4033  29 M6A HYPOMETHYLATION OF DNMT3B REGULATED BY ALKBH5 PROMOTES INTERVERTEBRAL DISC DEGENERATION VIA E4F1 DEFICIENCY. BACKGROUND: THE INTERVERTEBRAL DISC (IVD) DEGENERATION IS THE LEADING CAUSE OF LOW BACK PAIN, WHICH ACCOUNTS FOR A MAIN CAUSE OF DISABILITY. N6-METHYLADENOSINE (M6A) IS THE MOST ABUNDANT INTERNAL MODIFICATION IN EUKARYOTIC MESSENGER RNAS AND IS INVOLVED IN VARIOUS DISEASES AND CELLULAR PROCESSES BY MODULATING MRNA FATE. HOWEVER, THE CRITICAL ROLE OF M6A REGULATION IN IVD DEGENERATION REMAINS UNCLEAR. NUCLEUS PULPOSUS CELL (NPC) SENESCENCE IS CRITICAL FOR THE PROGRESSION OF IVD DEGENERATION. HERE, WE UNCOVERED THE ROLE AND EXPLORED THE REGULATORY MECHANISM OF M6A IN NPC SENESCENCE DURING IVD DEGENERATION. METHODS: IDENTIFICATION OF NPC SENESCENCE DURING IVD DEGENERATION WAS BASED ON THE ANALYSIS OF TISSUE SAMPLES AND THE CELLULAR MODEL. ALKBH5 UPREGULATION INDUCING CELLULAR SENESCENCE WAS CONFIRMED BY FUNCTIONAL EXPERIMENTS IN VIVO AND IN VITRO. CHIP-QPCR AND DNA-PULLDOWN WERE USED TO REVEAL INCREASED ALKBH5 WAS REGULATED BY KDM4A-MEDIATED H3K9ME3. FURTHERMORE, ME-RIP-SEQ WAS PERFORMED TO IDENTIFY M6A HYPOMETHYLATION OF DNMT3B TRANSCRIPTS IN SENESCENT NPCS. STABILITY ANALYSIS SHOWED THAT DNMT3B EXPRESSION WAS ENHANCED FOR LESS YTHDF2 RECOGNITION AND INCREASED DNMT3B PROMOTED NPC SENESCENCE AND IVD DEGENERATION VIA E4F1 METHYLATION BY IN VIVO AND IN VITRO ANALYSES. RESULTS: EXPRESSION OF ALKBH5 IS ENHANCED DURING IVD DEGENERATION AND NPC SENESCENCE, DUE TO DECREASED KDM4A-MEDIATED H3K9ME3 MODIFICATION. FUNCTIONALLY, ALKBH5 CAUSES NPC SENESCENCE BY DEMETHYLATING DNMT3B TRANSCRIPTS AND IN TURN PROMOTING ITS EXPRESSION VIA LESS YTHDF2 RECOGNITION AND FOLLOWING DEGRADATION DUE TO TRANSCRIPT HYPOMETHYLATION IN VITRO AND IN VIVO. INCREASED DNMT3B PROMOTES THE DEVELOPMENT OF IVD DEGENERATION AND NPC SENESCENCE, MECHANISTICALLY BY METHYLATING CPG ISLANDS OF E4F1 AT THE PROMOTER REGION AND THUS RESTRAINING ITS TRANSCRIPTION AND EXPRESSION. CONCLUSIONS: COLLECTIVELY, OUR FINDINGS REVEAL AN EPIGENETIC INTERPLAY MECHANISM IN NPC SENESCENCE AND IVD DEGENERATION, PRESENTING A CRITICAL PRO-SENESCENCE ROLE OF ALKBH5 AND M6A HYPOMETHYLATION, HIGHLIGHTING THE THERAPEUTIC POTENTIAL OF TARGETING THE M6A/DNMT3B/E4F1 AXIS FOR TREATING IVD DEGENERATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4   454  83 APPLICATIONS OF INDUCED PLURIPOTENT STEM CELL TECHNOLOGIES IN SPINAL CORD INJURY. NUMEROUS BASIC RESEARCH STUDIES HAVE SUGGESTED THE POTENTIAL EFFICACY OF NEURAL PRECURSOR CELL (NPC) TRANSPLANTATION IN SPINAL CORD INJURY (SCI). HOWEVER, IN MOST SUCH STUDIES, THE ORIGIN OF THE CELLS USED WAS MAINLY FETAL TISSUE OR EMBRYONIC STEM CELLS, BOTH OF WHICH CARRY POTENTIAL ETHICAL CONCERNS WITH RESPECT TO CLINICAL USE. THE DEVELOPMENT OF INDUCED PLURIPOTENT STEM CELLS (IPSCS) OPENED A NEW PATH TOWARD REGENERATIVE MEDICINE FOR SCI. IPSCS CAN BE GENERATED FROM SOMATIC CELLS BY INDUCTION OF TRANSCRIPTION FACTORS, AND INDUCED TO DIFFERENTIATE INTO NPCS WITH CHARACTERISTICS OF CELLS OF THE CENTRAL NERVOUS SYSTEM. THE BENEFICIAL EFFECT OF IPSC-DERIVED NPC TRANSPLANTATION HAS BEEN REPORTED FROM OUR GROUP AND OTHERS WORKING IN RODENT AND NON-HUMAN PRIMATE MODELS. THESE PROMISING RESULTS FACILITATE THE APPLICATION OF IPSCS FOR CLINICAL APPLICATIONS IN SCI PATIENTS. HOWEVER, IPSCS ALSO HAVE ISSUES, SUCH AS GENETIC/EPIGENETIC ABNORMALITIES AND TUMORIGENESIS BECAUSE OF THE ARTIFICIAL INDUCTION METHOD, THAT MUST BE ADDRESSED PRIOR TO CLINICAL USE. THE SELECTION OF SOMATIC CELLS, GENERATION OF INTEGRATION-FREE IPSCS, AND CHARACTERIZATION OF DIFFERENTIATED NPCS WITH THOROUGH QUALITY MANAGEMENT ARE ALL NEEDED TO ADDRESS THESE POTENTIAL RISKS. TO ENHANCE THE EFFICACY OF THE TRANSPLANTED IPSC-NPCS, ESPECIALLY AT CHRONIC PHASE OF SCI, ADMINISTRATION OF A CHONDROITINASE OR SEMAPHORIN3A INHIBITOR REPRESENTS A POTENTIALLY IMPORTANT MEANS OF PROMOTING AXONAL REGENERATION THROUGH THE LESION SITE. THE COMBINED USE OF REHABILITATION WITH SUCH CELL THERAPY APPROACHES IS ALSO IMPORTANT, AS REPETITIVE TRAINING ENHANCES NEURITE OUTGROWTH OF TRANSPLANTED CELLS AND STRENGTHENS NEURAL CIRCUITS AT CENTRAL PATTERN GENERATORS. OUR GROUP HAS ALREADY EVALUATED CLINICAL GRADE IPSC-DERIVED NPCS, AND WE LOOK FORWARD TO INITIATING CLINICAL TESTING AS THE NEXT STEP TOWARD DETERMINING WHETHER THIS APPROACH IS SAFE AND EFFECTIVE FOR CLINICAL USE. THIS ARTICLE IS PART OF THE MINI REVIEW SERIES "60TH ANNIVERSARY OF THE JAPANESE SOCIETY FOR NEUROCHEMISTRY".	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5  5253  31 PROGRAMMING CHANGES OF HIPPOCAMPAL MIR-134-5P/SOX2 SIGNAL MEDIATE THE SUSCEPTIBILITY TO DEPRESSION IN PRENATAL DEXAMETHASONE-EXPOSED FEMALE OFFSPRING. DEPRESSION IS A NEUROPSYCHIATRIC DISORDER AND HAS INTRAUTERINE DEVELOPMENTAL ORIGINS. THIS STUDY AIMED TO CONFIRM THE DEPRESSION SUSCEPTIBILITY IN OFFSPRING RATS INDUCED BY PRENATAL DEXAMETHASONE EXPOSURE (PDE) AND TO FURTHER EXPLORE THE INTRAUTERINE PROGRAMMING MECHANISM. WISTAR RATS WERE INJECTED WITH DEXAMETHASONE (0.2 MG/KG.D) SUBCUTANEOUSLY DURING THE GESTATIONAL DAYS 9-20 AND PART OF THE OFFSPRING WAS GIVEN CHRONIC STRESS AT POSTNATAL WEEKS 10-12. BEHAVIORAL RESULTS SHOWED THAT THE ADULT PDE FEMALE OFFSPRING WAS SUSCEPTIBLE TO DEPRESSION, ACCOMPANIED BY INCREASED HIPPOCAMPAL MIR-134-5P EXPRESSION AND DECREASED SEX-DETERMINING REGION Y-BOX 2 (SOX2) EXPRESSION, AS WELL AS DISORDERS OF NEURAL PROGENITOR CELLS PROLIFERATION AND HIPPOCAMPAL NEUROGENESIS. THE PDE FEMALE FETAL RATS PRESENTED CONSISTENT CHANGES WITH THE ADULT OFFSPRING, ACCOMPANIED BY THE UPREGULATION OF GLUCOCORTICOID RECEPTOR (GR) EXPRESSION AND DECREASED SIRTUIN 1 (SIRT1) EXPRESSION. WE FURTHER FOUND THAT THE H3K9AC LEVEL OF THE MIR-134-5P PROMOTER WAS SIGNIFICANTLY INCREASED IN THE PDE FETAL HIPPOCAMPUS, AS WELL AS IN ADULT OFFSPRING BEFORE AND AFTER CHRONIC STRESS. IN VITRO, THE CHANGES OF GR/SIRT1/MIR-134-5P/SOX2 SIGNAL BY DEXAMETHASONE WERE CONSISTENT WITH IN VIVO EXPERIMENTS, WHICH COULD BE REVERSED BY GR RECEPTOR ANTAGONIST, SIRT1 AGONIST, AND MIR-134-5P INHIBITOR. THIS STUDY CONFIRMED THAT PDE LED TO AN INCREASED EXPRESSION LEVEL AS WELL AS H3K9AC LEVEL OF MIR-134-5P BY ACTIVATING THE GR/SIRT1 PATHWAY IN THE FETAL HIPPOCAMPUS AND THEN INHIBITED THE SOX2 EXPRESSION. THE PROGRAMMING EFFECT MEDIATED BY THE ABNORMAL EPIGENETIC MODIFICATION COULD LAST FROM INTRAUTERINE TO ADULTHOOD, WHICH CONSTITUTES THE INTRAUTERINE PROGRAMMING MECHANISM LEADING TO HIPPOCAMPAL NEUROGENESIS DISORDERS AND DEPRESSION SUSCEPTIBILITY IN FEMALE OFFSPRING. INTRAUTERINE PROGRAMMING MECHANISM FOR THE INCREASED DEPRESSIVE SUSCEPTIBILITY IN ADULT FEMALE OFFSPRING BY PRENATAL DEXAMETHASONE EXPOSURE (PDE). GR, GLUCOCORTICOID RECEPTOR; SIRT1, SIRTUIN 1; SOX2, SEX-DETERMINING REGION Y-BOX 2; NPCS, NEUROPROGENITOR CELLS; H3K9AC, HISTONE 3 LYSINE 9 ACETYLATION; GRE, GLUCOCORTICOID RESPONSE ELEMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6  2284  11 EPIGENETIC REGULATION IN INTERVERTEBRAL DISC DEGENERATION. INTERVERTEBRAL DISC (IVD) DEGENERATION IS THE LEADING CAUSE OF LOW BACK PAIN, WHICH HAS A STRIKING IMPACT ON NUMEROUS PATIENTS. THEREFORE, COMPREHENSIVELY ILLUMINATING THE REGULATORY MECHANISMS OF IVD DEGENERATION IS OF GREAT SIGNIFICANCE. HERE, WE DISCUSS THE LATEST ADVANCES IN UNDERSTANDING THE MAIN EPIGENETIC MECHANISMS REGULATING IVD DEGENERATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7  5191  22 PRENATAL DEXAMETHASONE EXPOSURE PROGRAMS THE DECREASED TESTOSTERONE SYNTHESIS IN OFFSPRING RATS BY LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS. PRENATAL DEXAMETHASONE EXPOSURE (PDE) CAN DECREASE MATERNAL ENDOGENOUS GLUCOCORTICOID LEVEL AND INDUCE TESTICULAR DYSPLASIA IN MALE OFFSPRING RATS. IN THIS STUDY WE INVESTIGATED LOW LEVEL ENDOGENOUS GLUCOCORTICOID-MEDIATED TESTICULAR DYSPLASIA IN PDE OFFSPRING AND ELUCIDATED THE INTRAUTERINE EPIGENETIC PROGRAMMING MECHANISMS. PREGNANT RATS WERE INJECTED WITH DEXAMETHASONE (0.2 MG.KG(-1).D(-1), SC) ON GESTATIONAL DAY (GD) 9-20. THE OFFSPRING RAT BLOOD AND TESTIS WERE COLLECTED AFTER EUTHANASIA ON GD20, POSTNATAL WEEK (PW) 12 OR PW28. WE SHOWED THAT PDE INDUCED ABNORMAL MORPHOLOGY OF TESTIS AND SIGNIFICANTLY DECREASED THE EXPRESSION OF TESTOSTERONE SYNTHESIS-RELATED GENES AS WELL AS TESTOSTERONE PRODUCTION BEFORE AND AFTER BIRTH. MEANWHILE, SERUM CORTICOSTERONE, THE EXPRESSION AND HISTONE 3 LYSINE 14 ACETYLATION (H3K14AC) OF TESTICULAR INSULIN-LIKE GROWTH FACTOR 1 (IGF1) WERE SIGNIFICANTLY DECREASED. AFTER THE PREGNANT RATS WERE SUBJECTED TO CHRONIC STRESS FOR 2 WEEKS (PW10-12), SERUM CORTICOSTERONE LEVEL WAS INCREASED IN THE ADULT PDE OFFSPRING, AND THE ABOVE-MENTIONED OTHER INDICATORS WERE ALSO IMPROVED. CULTURED LEYDIG CELLS (TM3) WERE TREATED WITH CORTICOSTERONE (62.5-500 NM) IN VITRO. WE SHOWED THAT CORTICOSTERONE CONCENTRATION-DEPENDENTLY INHIBITED GLUCOCORTICOID RECEPTOR ALPHA (GRALPHA) AND MIR-124-3P EXPRESSION, INCREASED HISTONE DEACETYLASE 5 (HDAC5) EXPRESSION, AND DECREASED IGF1 H3K14AC LEVEL AND THE EXPRESSION OF IGF1/STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR), SUGGESTING THAT CORTICOSTERONE AT LOWER THAN PHYSIOLOGICAL LEVEL (<500 NM) INHIBITED TESTOSTERONE SYNTHESIS BY REDUCING H3K14AC AND THE EXPRESSION LEVEL OF IGF1 THROUGH GRALPHA/MIR-124-3P/HDAC5 PATHWAY. IN CONCLUSION, PDE CAN CAUSE PERSISTENT INHIBITION OF TESTOSTERONE SYNTHESIS BEFORE AND AFTER BIRTH IN THE OFFSPRING RATS BY LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8  4579  21 N(6)-METHYLADENOSINE METHYLASE METTL3 CONTRIBUTES TO NEUROPATHIC PAIN BY EPIGENETIC SILENCING OF MU OPIOID RECEPTOR. WE AIMED AT EXPLORING THE ROLE AND MECHANISM OF METTL3-MEDIATED M(6)A MODIFICATION IN NEUROPATHIC PAIN. MALE SPRAGUE-DAWLEY RATS WERE RANDOMLY DIVIDED INTO FOUR GROUPS: SHAM OPERATION GROUP (SHAM GROUP), CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE MODEL GROUP (NPP GROUP), INTRATHECAL INJECTION OF VIRUS DOWN-REGULATED METTL3 + CCI MODEL GROUP (M3 + NPP GROUP) AND INTRATHECAL INJECTION OF NEGATIVE CONTROL VIRUS + CCI MODEL GROUP (SCR + NPP GROUP). THE M3 + NPP GROUP AND THE SCR + NPP GROUP WERE INTRATHECALLY INJECTED WITH VIRUS NINETEEN DAYS BEFORE OPERATION. THE PAW WITHDRAWAL MECHANICAL THRESHOLDS AND PAW WITHDRAWAL LATENCY WERE RESPECTIVELY RECORDED ONE DAY BEFORE OPERATION, THREE DAYS, FIVE DAYS AND SEVEN DAYS AFTER OPERATION. THE RATS WERE SACRIFICED ON THE SEVENTH DAY AFTER OPERATION, AND THEIR SPINAL CORD TISSUES WERE TAKEN. THE FROZEN SECTIONS OF RATS WERE PERFORMED TO OBSERVE THE EXPRESSION OF GREEN FLUORESCENT PROTEIN OF THE VIRUS. THE METHYLATION LEVEL OF RNA, THE PROTEIN EXPRESSION OF M(6)A-RELATED ENZYME (METTL3) AND MU OPIOID RECEPTOR (MOR) IN SPINAL CORD TISSUES OF THE FOUR GROUPS WERE MEASURED. DOWNREGULATION OF METTL3 HAD NO EFFECT ON THE OVERALL METHYLATION LEVEL OF THE SPINAL CORD, BUT IT COULD REGULATE THE METHYLATION LEVEL OF THE OPRM1 GENE RNA ENCODING MOR, PARTIALLY RESTORE THE EXPRESSION OF MOR, AND RELIEVE PAIN IN RATS. IN THE PROCESS OF NPP, METTL3 MAY INHIBIT THE EXPRESSION OF MOR BY REGULATING THE METHYLATION LEVEL OF OPRM1 GENE RNA ENCODING MOR, AND ULTIMATELY PROMOTE THE OCCURRENCE AND DEVELOPMENT OF NPP.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9  3036  27 GENISTEIN AMELIORATES RENAL FIBROSIS THROUGH REGULATION SNAIL VIA M6A RNA DEMETHYLASE ALKBH5. RENAL TUBULE-INTERSTITIAL FIBROSIS IS RELATED TO CHRONIC KIDNEY DISEASE PROGRESSION AND A TYPICAL FEATURE OF THE AGING KIDNEY. EPIGENETIC MODIFICATIONS OF FIBROSIS-PRONE GENES REGULATE THE DEVELOPMENT OF RENAL FIBROSIS. AS A KIND OF "EPIGENETIC DIET", SOY ISOFLAVONE GENISTEIN WAS REPORTED TO HAVE RENAL PROTECTIVE ACTION AND EPIGENETIC-MODULATING EFFECTS. HOWEVER, ITS RENAL PROTECTION ROLE AND UNDERLYING MECHANISMS ARE YET TO BE FULLY CLARIFIED. HEREIN, WE SHOWED THAT GENISTEIN EXHIBITS A DEMONSTRABLE ANTI-FIBROTIC EFFECT ON KIDNEY IN VIVO UUO (UNILATERAL URETERAL OCCLUSION) MODEL AND RENAL EPITHELIAL CELLS IN VITRO MODEL. THE MECHANISM IS STRONGLY ASSOCIATED WITH EPITHELIAL-TO-MESENCHYMAL TRANSITION AND M6A RNA DEMETHYLASE ALKBH5. MOUSE FIBROTIC KIDNEYS INDUCED BY UUO EXHIBITED ADVERSE EXPRESSION OF RENAL FIBROSIS-RELATED PROTEINS AND SIGNIFICANT INCREASES IN THE TOTAL M6A LEVEL. AS AN ERASER, ALKBH5 SHOWED SEVERER SUPPRESSION IN THE RENAL FIBROSIS PROCESS. HOWEVER, GENISTEIN PRETREATMENT RESTORED ALKBH5 LOSS REMARKABLY AND REDUCED RENAL FIBROSIS, ABNORMAL PROTEIN, AND INFLAMMATORY MARKERS. THE EXAMINATION OF POSSIBLE MECHANISMS REVEALED THAT GENISTEIN PROMOTED ALKBH5 AND MAYBE INDUCED THE LEVEL OF MRNA M6A METHYLATION IN SOME EPITHELIAL-TO-MESENCHYMAL TRANSITION-RELATED TRANSCRIPTION FACTORS. WE FOUND SNAIL WAS THE CRITICAL REGULATOR AND CRITICAL FOR THE PROTECTIVE ROLE OF GENISTEIN. TO VERIFY THE RELATIONSHIP BETWEEN ALKBH5 AND SNAIL, WE GENERATED KNOCKDOWN AND OVEREXPRESSION OF ALKBH5 CELLS IN VITRO. ALKBH5 KNOCKDOWN ENHANCED THE MESENCHYMAL PHENOTYPE MARKER ALPHA-SMOOTH MUSCLE ACTIN AND SNAIL EXPRESSION. IN AGREEMENT, OVEREXPRESSION ALKBH5 INCREASED EPITHELIAL ADHESION MOLECULE E-CADHERIN AND REDUCED SNAIL EXPRESSION. IN CONCLUSION, GENISTEIN INCREASED RENAL ALKBH5 EXPRESSION IN UUO-INDUCED RENAL FIBROSIS AND REDUCED RNA M6A LEVELS AND AMELIORATES RENAL DAMAGES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10  2197  23 EPIGENETIC MODIFICATION OF BDNF MEDIATES NEUROPATHIC PAIN VIA MIR-30A-3P/EP300 AXIS IN CCI RATS. RECENT INVESTIGATION OF MICRORNAS ON CHRONIC PAIN HAS DEVELOPED A BREAKTHROUGH IN NEUROPATHIC PAIN MANAGEMENT. IN THE PRESENT STUDY, DECREASED EXPRESSION OF MIR-30A-3P WAS REPORTED USING QRT-PCR ANALYSIS AND LOSS OF MIR-30A-3P PROMOTED NEUROPATHIC PAIN PROGRESSION IN SCIATIC NERVE CHRONIC CONSTRICTIVE INJURY RATS THROUGH DETERMINING THE PAIN THRESHOLD. WE PREDICTED MIR-30A-3P COULD TARGET E-CADHERIN TRANSCRIPTIONAL ACTIVATOR (EP300) VIA BIOINFORMATICS ANALYSIS. MEANWHILE, WE FOUND THAT BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IS INVOLVED IN NEUROPATHIC PAIN. HERE, WE EXHIBITED THAT EP300 EPIGENETICALLY UP-REGULATED BDNF VIA ENHANCING ACETYLATED HISTONE H3 AND H4 ON THE PROMOTER. FOR ANOTHER, MIR-30A-3P WAS ABLE TO MODIFY THE LEVEL OF BDNF AND ACETYLATED HISTONE H3 AND H4. LOSS OF MIR-30A-3P ENHANCED EP300 AND BDNF COLOCALIZATION IN CCI RATS. SUBSEQUENTLY, IT WAS SHOWN THAT INCREASED EP300 INDUCED NEUROPATHIC PAIN BY AN ENHANCEMENT OF NEURONAL BDNF LEVEL IN VIVO. TO SUM UP, IT WAS REVEALED THAT EPIGENETIC MODIFICATION OF BDNF PROMOTED NEUROPATHIC PAIN VIA EP300 INDUCED BY MIR-30A-3P IN CCI RATS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
11  4260  22 METTL3-MEDIATED M6A MODIFICATION OF SIRT1 MRNA INHIBITS PROGRESSION OF ENDOMETRIOSIS BY CELLULAR SENESCENCE ENHANCING. BACKGROUND: ENDOMETRIOSIS (EMS), THE ECTOPIC PLANTING OF FUNCTIONAL ENDOMETRIUM OUTSIDE OF THE UTERUS, IS A LEADING CAUSE OF INFERTILITY AND PELVIC PAIN. AS A FUNDAMENTAL MRNA MODIFICATION, N6-METHYLADENOSINE (M6A) PARTICIPATES IN VARIOUS PATHOLOGICAL PROCESSES. HOWEVER, THE ROLE OF M6A RNA MODIFICATION IN ENDOMETRIOSIS REMAINS UNCLEAR. THE PRESENT STUDY EXPLORES METTL3-MEDIATED M6A MODIFICATION AND THE MECHANISMS INVOLVED IN ENDOMETRIOSIS. METHODS: THE DOMINANT M6A REGULATORS IN EMS WERE ANALYSED USING RT?PCR. CANDIDATE TARGETS AND POSSIBLE MECHANISMS OF METTL3 WERE ASSESSED BY M6A-MRNA EPITRANSCRIPTOMIC MICROARRAY AND RNA SEQUENCING. A PRIMARY ESCS MODEL WAS EMPLOYED TO VERIFY THE EFFECT OF METTL3 ON M6A MODIFICATION OF SIRT1 MRNA, AND THE MECHANISM WAS ELUCIDATED BY RT?PCR, WESTERN BLOTTING, MERIP, AND RIP ASSAYS. CCK-8 VIABILITY ASSAYS, TRANSWELL INVASION ASSAYS, EDU PROLIFERATION ASSAYS, WOUND HEALING MIGRATION ASSAYS, AND SENESCENCE-ASSOCIATED BETA-GALACTOSIDASE STAINING WERE PERFORMED TO ILLUMINATE THE POTENTIAL BIOLOGICAL MECHANISM OF METTL3 AND SIRT1 IN ESCS IN VITRO. AN IN VIVO PGRCRE/ + METTL3 -/- FEMALE HOMOZYGOUS MOUSE MODEL AND A NUDE MOUSE XENOGRAFT MODEL WERE EMPLOYED TO FURTHER INVESTIGATE THE PHYSIOLOGIC CONSEQUENCES OF METTL3-MEDIATED M6A ALTERATION ON EMS. RESULTS: OUR DATA SHOW THAT DECREASED METTL3 EXPRESSION SIGNIFICANTLY DOWNREGULATES M6A RNA METHYLATION LEVELS IN ESCS. SILENCING M6A MODIFICATIONS MEDIATED BY METTL3 ACCELERATES ESCS VIABILITY, PROLIFERATION, MIGRATION, AND INVASION IN VITRO. THE M6A READER PROTEIN YTHDF2 BINDS TO M6A MODIFICATIONS TO INDUCE THE DEGRADATION OF SIRT1 MRNA. SIRT1/FOXO3A SIGNALLING PATHWAY ACTIVATION IS SUBSEQUENTLY INHIBITED, PROMOTING THE CELLULAR SENESCENCE OF ESCS AND INHIBITING THE ECTOPIC IMPLANTATION OF ESCS IN VITRO AND IN VIVO. CONCLUSIONS: OUR FINDINGS DEMONSTRATE THAT METTL3-MEDIATED M6A METHYLATION EPIGENETICALLY REGULATES THE ECTOPIC IMPLANTATION OF ESCS, RESULTING IN THE PROGRESSION OF ENDOMETRIOSIS. OUR STUDY ESTABLISHES METTL3-YTHDF2-SIRT1/FOXO3A AS A CRITICAL AXIS AND POTENTIAL MECHANISM IN ENDOMETRIOSIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
12  4259  36 METTL3 SUPPRESSES NEUROPATHIC PAIN VIA MODULATING N6-METHYLADENOSINE-DEPENDENT PRIMARY MIR-150 PROCESSING. METHYLTRANSFERASE-LIKE 3 (METTL3)-MODULATED N6-METHYLADENOSINE (M6A) WAS RECENTLY IDENTIFIED AS AN IMPORTANT EPIGENETIC REGULATION TYPE DURING RNA PROCESSING AND CONTRIBUTES TO MULTIPLE PATHOLOGICAL PROCESSES. NEUROPATHIC PAIN (NP) IS INDUCED BY A LESION OF THE SOMATOSENSORY NERVOUS SYSTEM, AND THE DETAILED PATHWAYS BY WHICH METTL3/M6A REGULATED TO MODULATE GENE DYSREGULATION AND ENABLE NP HAVE REMAINED UNCLEAR. THEREFORE, THIS STUDY INVESTIGATED THE FUNCTION OF METTL3-MEDIATED M6A METHYLATION ON MIRNA MATURATION, AND INVESTIGATED HOW THIS REGULATION CONTRIBUTES TO NP PROGRESSION. A RAT MODEL CHARACTERIZED WITH TYPICAL NP WAS ESTABLISHED BY A SPARED NERVE-INJURY (SNI) METHOD. BY ANALYZING THE EXPRESSION LEVELS OF METTL3 AND M6A METHYLATION, WE FOUND THAT METTL3, ALONG WITH M6A METHYLATION, WAS DRAMATICALLY DOWNREGULATED IN NP RATS IN CONTRAST TO THE SHAM ONES. FUNCTIONALLY, ENHANCED METTL3 PROMOTED THE M6A METHYLATION IN TOTAL RNAS AND INHIBITED NP PROGRESSION, WHEREAS SILENCING METTL3 SUPPRESSED M6A METHYLATION AND INCREASED NP SEVERITY. MECHANISTICALLY, METTL3 ACCELERATED MIR-150 MATURATION VIA MEDIATING M6A METHYLATION OF PRIMIR-150 AT LOCUS 498, COOPERATING WITH THE "M6A READER" YTHDF2. MEANWHILE, MIR-150 COULD DIRECTLY TARGET BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA, AND THE METTL3/MIR-150/BDNF REGULATORY PATHWAY WAS FINALLY ESTABLISHED. CLINICALLY, WE PROVED THAT SERUM METTL3 MRNA WAS ALSO DOWNREGULATED IN SHINGLES PATIENTS WITH NP, SUGGESTING ITS DIAGNOSTIC POTENTIAL. IN CONCLUSION, WE DEMONSTRATED AN ESSENTIAL FUNCTION OF METTL3-REGULATED N6-METHYLADENOSINE DURING NP PROGRESSION VIA MODULATING PRIMIR-150 MATURATION. SERUM METTL3 COULD EFFECTIVELY DIFFERENTIATE NP PATIENTS FROM HEALTHY PEOPLE, AND IS USEFUL FOR DYNAMIC MONITORING OF DISEASES AFTER TREATMENT. THEREFORE, THE METTL3/MIR-150/BDNF PATHWAY MAY BE A PROMISING THERAPEUTIC TARGET FOR NP PATIENTS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13  5480  30 RESVERATROL REVERSES MORPHINE-INDUCED NEUROINFLAMMATION IN MORPHINE-TOLERANT RATS BY REVERSAL HDAC1 EXPRESSION. BACKGROUND/PURPOSE: WE PREVIOUSLY SHOWED THAT SUBSEQUENT INTRATHECAL (I.T.) INJECTION OF RESVERATROL (30 MUG) SIGNIFICANTLY REVERSES MORPHINE-EVOKED NEUROINFLAMMATION IN MORPHINE-TOLERANT RATS. THE PRESENT STUDY EXAMINED THE UNDERLYING MECHANISM. METHODS: MALE WISTAR RATS WERE IMPLANTED WITH TWO I.T. CATHETERS, ONE OF WHICH WAS CONNECTED TO A MINIOSMOTIC PUMP AND USED FOR MORPHINE (15 MUG/H) OR SALINE INFUSION FOR 120 HOURS. TO EXAMINE THE EFFECTS ON SPINAL CORD EXPRESSION OF HISTONE DEACETYLASE 1 (HDAC1), THE INFLAMMATORY CYTOKINE TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), AND TNF RECEPTOR (TNFR) 1 AND TNFR2 DURING TOLERANCE INDUCTION, A TAIL-FLICK TEST WAS PERFORMED PRIOR TO INFUSION AND AFTER 24 HOURS, 48 HOURS, 72 HOURS, 96 HOURS, AND 120 HOURS OF INFUSION. RESULTS: RESVERATROL TREATMENT PRIOR TO MORPHINE CHALLENGE RESTORED THE ANTINOCICEPTIVE EFFECT OF MORPHINE IN MORPHINE-TOLERANT RATS AND REVERSED THE MORPHINE INFUSION-INDUCED INCREASE IN HDAC1, TNF-ALPHA, AND TNFR1 EXPRESSION. MOREOVER, CHRONIC MORPHINE INFUSION INCREASED TNFR1-SPECIFIC EXPRESSION IN NEURON IN MORPHINE-TOLERANT RAT SPINAL CORDS, AND THIS EFFECT WAS ALMOST COMPLETELY INHIBITED BY RESVERATROL TREATMENT PRIOR TO MORPHINE CHALLENGE. CONCLUSION: RESVERATROL RESTORES THE ANTINOCICEPTIVE EFFECT OF MORPHINE BY REVERSING MORPHINE INFUSION-INDUCED SPINAL CORD NEUROINFLAMMATION AND INCREASE IN TNFR1 EXPRESSION. THE REVERSAL OF THE MORPHINE-INDUCED INCREASE IN TNFR1 EXPRESSION BY RESVERATROL IS PARTIALLY DUE TO REVERSAL OF THE MORPHINE INFUSION-INDUCED INCREASE IN HDAC1 EXPRESSION. RESVERATROL PRETREATMENT CAN BE USED AS AN ADJUVANT IN CLINICAL PAIN MANAGEMENT FOR PATIENTS WHO NEED LONG-TERM MORPHINE TREATMENT OR WITH NEUROPATHIC PAIN.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14  2364  31 EPIGENETIC REGULATION OF SPINAL CORD GENE EXPRESSION CONTROLS OPIOID-INDUCED HYPERALGESIA. BACKGROUND: THE LONG TERM USE OF OPIOIDS FOR THE TREATMENT OF PAIN LEADS TO A GROUP OF MALADAPTATIONS WHICH INCLUDES OPIOID-INDUCED HYPERALGESIA (OIH). OIH TYPICALLY RESOLVES WITHIN FEW DAYS AFTER CESSATION OF MORPHINE TREATMENT IN MICE BUT IS PROLONGED FOR WEEKS IF HISTONE DEACETYLASE (HDAC) ACTIVITY IS INHIBITED DURING OPIOID TREATMENT. THE PRESENT WORK SEEKS TO IDENTIFY GENE TARGETS SUPPORTING THE EPIGENETIC EFFECTS RESPONSIBLE FOR OIH PROLONGATION. RESULTS: MICE WERE TREATED WITH MORPHINE ACCORDING TO AN ASCENDING DOSE PROTOCOL. SOME MICE ALSO RECEIVED THE SELECTIVE HDAC INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) ADDITIONALLY. CHRONIC MORPHINE TREATMENT WITH SIMULTANEOUS HDAC INHIBITION ENHANCED OIH, AND SEVERAL SPINAL CORD GENES WERE UP-REGULATED. THE EXPRESSION OF BDNF (BRAIN-DERIVED NEUROTROPHIC FACTOR) AND PDYN (PRODYNORPHIN) WERE MOST CLOSELY RELATED TO THE OBSERVED BEHAVIORAL CHANGES. CHIP (CHROMATIN IMMUOPRECIPATION) ASSAYS DEMONSTRATED THAT PROMOTER REGIONS OF PDYN AND BDNF WERE STRONGLY ASSOCIATED WITH ACEH3K9 (ACETYLATED HISTONE H3 LYSINE9) AFTER MORPHINE AND SAHA TREATMENT. FURTHERMORE, MORPHINE TREATMENT CAUSED AN INCREASE IN SPINAL BDNF AND DYNORPHIN LEVELS, AND THESE LEVELS WERE FURTHER INCREASED IN SAHA TREATED MICE. THE SELECTIVE TRKB (TROPOMYOSIN-RECEPTOR-KINASE) ANTAGONIST ANA-12 REDUCED OIH WHEN GIVEN ONE OR SEVEN DAYS AFTER CESSATION OF MORPHINE. TREATMENT WITH THE SELECTIVE KAPPA OPIOID RECEPTOR ANTAGONIST NOR-BNI ALSO REDUCED ESTABLISHED OIH. THE CO-ADMINISTRATION OF EITHER RECEPTOR ANTAGONIST AGENT DAILY WITH MORPHINE RESULTED IN ATTENUATION OF HYPERALGESIA PRESENT ONE DAY AFTER CESSATION OF TREATMENT. ADDITIONALLY, REPEATED MORPHINE EXPOSURE INDUCED A RISE IN BDNF EXPRESSION THAT WAS ASSOCIATED WITH AN INCREASED NUMBER OF BDNF+ CELLS IN THE SPINAL CORD DORSAL HORN, SHOWING STRONG CO-LOCALIZATION WITH ACEH3K9 IN NEURONAL CELLS. LASTLY, SPINAL APPLICATION OF LOW DOSE BDNF OR DYNORPHIN A AFTER RESOLUTION OF OIH PRODUCED MECHANICAL HYPERSENSITIVITY, WITH NO EFFECT IN CONTROLS. CONCLUSIONS: THE PRESENT STUDY IDENTIFIED TWO GENES WHOSE EXPRESSION IS REGULATED BY EPIGENETIC MECHANISMS DURING MORPHINE EXPOSURE. TREATMENTS AIMED AT PREVENTING THE ACETYLATION OF HISTONES OR BLOCKING BDNF AND DYNORPHIN SIGNALING MAY REDUCE OIH AND IMPROVE LONG-TERM PAIN USING OPIOIDS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15  3812  34 INTRAUTERINE ENDOGENOUS HIGH GLUCOCORTICOIDS PROGRAM OVARIAN DYSFUNCTION IN FEMALE OFFSPRING SECONDARY TO PRENATAL CAFFEINE EXPOSURE. OVARIAN DYSFUNCTION HAS AN INTRAUTERINE ORIGIN, AND PRENATAL CAFFEINE EXPOSURE (PCE) COULD LEAD TO ABNORMAL FOLLICLE COUNTS IN OFFSPRING AFTER BIRTH. HOWEVER, THE EFFECT OF PCE ON OFFSPRING OVARIAN FUNCTION AND ITS MECHANISM OF INTRAUTERINE PROGRAMMING HAVE NOT BEEN REPORTED THUS FAR. IN THIS STUDY, PREGNANT WISTAR RATS WERE INTRAGASTRICALLY ADMINISTERED CAFFEINE (30 AND 120 MG/KG.D) AT GESTATIONAL DAYS 9-20 (GD9-20). CERTAIN TESTS WERE PERFORMED ON THE BLOOD, OVARIES AND HYPOTHALAMUS OF FEMALE OFFSPRING AT DIFFERENT TIME POINTS. PCE FEMALE OFFSPRING HAD OVARIAN DYSFUNCTION IN ADULTHOOD COMPARED WITH THE CONTROL. FURTHER RESULTS SHOWED THAT IN UTERO OVARIAN MORPHOLOGICAL DEVELOPMENT AND ESTRADIOL SYNTHESIS WERE INHIBITED BUT RAPIDLY INCREASED DURING PUBERTY IN THE PCE GROUP. THE HISTONE 3 LYSINE 27 ACETYLATION (H3K27AC) LEVEL OF THE INSULIN-LIKE GROWTH FACTOR 1 (IGF1) PROMOTER REGION AND ITS EXPRESSION WERE DECREASED IN THE OVARY, WHICH WAS DUE TO EXPOSURE TO HIGH LEVELS OF FETAL BLOOD CORTICOSTERONE, AND THE H3K27AC LEVEL OF IGF1 AND ITS EXPRESSION SHIFTED TO INCREASE AFTER BIRTH WITH A DECREASE IN SERUM CORTICOSTERONE LEVELS. CHRONIC STRESS LED TO INCREASED SERUM CORTICOSTERONE LEVELS IN ADULT OFFSPRING, WHEREAS OVARIAN MORPHOLOGICAL DEVELOPMENT, THE H3K27AC LEVEL OF IGF1 AND ITS EXPRESSION, AND ESTRADIOL SYNTHESIS WERE SIGNIFICANTLY INHIBITED. MOREOVER, THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-OVARIAN (HPO) AXIS WAS INCREASED IN THE EARLY POSTNATAL PERIOD OF PCE OFFSPRING, AND CHRONIC STRESS REVERSED THESE CHANGES. IN THE KGN CELL LINE, IT WAS FOUND THAT CORTISOL COULD PROMOTE THE TRANSLOCATION OF THE GLUCOCORTICOID RECEPTOR (GR) INTO THE NUCLEUS AND UPREGULATE HISTONE DEACETYLASE 10 (HDAC10) TO INHIBIT THE H3K27AC LEVEL OF IGF1 AND ITS EXPRESSION AND ESTRADIOL SYNTHESIS. IN SUMMARY, PCE IS ASSOCIATED WITH OVARIAN DYSFUNCTION IN FEMALE ADULT OFFSPRING, AND THE POTENTIAL MECHANISM IS RELATED TO INTRAUTERINE HIGH GLUCOCORTICOID EXPOSURE BY ACTIVATING THE GR AND RECRUITING HDAC10 TO AFFECT OVARIAN GLUCOCORTICOID-IGF1 AXIS PROGRAMMING AND TO INHIBIT ESTRADIOL SYNTHESIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  3201  33 HDAC2 IN PRIMARY SENSORY NEURONS CONSTITUTIVELY RESTRAINS CHRONIC PAIN BY REPRESSING ALPHA2DELTA-1 EXPRESSION AND ASSOCIATED NMDA RECEPTOR ACTIVITY. ALPHA2DELTA-1 (ENCODED BY THE CACNA2D1 GENE) IS A NEWLY DISCOVERED NMDA RECEPTOR-INTERACTING PROTEIN AND IS THE THERAPEUTIC TARGET OF GABAPENTINOIDS (E.G., GABAPENTIN AND PREGABALIN) FREQUENTLY USED FOR TREATING PATIENTS WITH NEUROPATHIC PAIN. NERVE INJURY CAUSES SUSTAINED ALPHA2DELTA-1 UPREGULATION IN THE DORSAL ROOT GANGLION (DRG), WHICH PROMOTES NMDA RECEPTOR SYNAPTIC TRAFFICKING AND ACTIVATION IN THE SPINAL DORSAL HORN, A HALLMARK OF CHRONIC NEUROPATHIC PAIN. HOWEVER, LITTLE IS KNOWN ABOUT HOW NERVE INJURY INITIATES AND MAINTAINS THE HIGH EXPRESSION LEVEL OF ALPHA2DELTA-1 TO SUSTAIN CHRONIC PAIN. HERE, WE SHOW THAT NERVE INJURY CAUSED HISTONE HYPERACETYLATION AND DIMINISHED ENRICHMENT OF HISTONE DEACETYLASE-2 (HDAC2), BUT NOT HDAC3, AT THE CACNA2D1 PROMOTER IN THE DRG. STRIKINGLY, HDAC2 KNOCKDOWN OR CONDITIONAL KNOCKOUT IN DRG NEURONS IN MALE AND FEMALE MICE CONSISTENTLY INDUCED LONG-LASTING MECHANICAL PAIN HYPERSENSITIVITY, WHICH WAS READILY REVERSED BY BLOCKING NMDA RECEPTORS, INHIBITING ALPHA2DELTA-1 WITH GABAPENTIN OR DISRUPTING THE ALPHA2DELTA-1-NMDA RECEPTOR INTERACTION AT THE SPINAL CORD LEVEL. HDAC2 DELETION IN DRG NEURONS INCREASED HISTONE ACETYLATION LEVELS AT THE CACNA2D1 PROMOTER, UPREGULATED ALPHA2DELTA-1 IN THE DRG, AND POTENTIATED ALPHA2DELTA-1-DEPENDENT NMDA RECEPTOR ACTIVITY AT PRIMARY AFFERENT CENTRAL TERMINALS IN THE SPINAL DORSAL HORN. CORRESPONDINGLY, HDAC2 KNOCKDOWN-INDUCED PAIN HYPERSENSITIVITY WAS BLUNTED IN CACNA2D1 KNOCKOUT MICE. THUS, OUR FINDINGS REVEAL THAT HDAC2 FUNCTIONS AS A PIVOTAL TRANSCRIPTIONAL REPRESSOR OF NEUROPATHIC PAIN VIA CONSTITUTIVELY SUPPRESSING ALPHA2DELTA-1 EXPRESSION AND ENSUING PRESYNAPTIC NMDA RECEPTOR ACTIVITY IN THE SPINAL CORD. HDAC2 ENRICHMENT LEVELS AT THE CACNA2D1 PROMOTER IN DRG NEURONS CONSTITUTE A UNIQUE EPIGENETIC MECHANISM THAT GOVERNS ACUTE-TO-CHRONIC PAIN TRANSITION.SIGNIFICANCE STATEMENT EXCESS ALPHA2DELTA-1 PROTEINS PRODUCED AFTER NERVE INJURY DIRECTLY INTERACT WITH GLUTAMATE NMDA RECEPTORS TO POTENTIATE SYNAPTIC NMDA RECEPTOR ACTIVITY IN THE SPINAL CORD, A PROMINENT MECHANISM OF NERVE PAIN. BECAUSE ALPHA2DELTA-1 UPREGULATION AFTER NERVE INJURY IS LONG LASTING, GABAPENTINOIDS RELIEVE PAIN SYMPTOMS ONLY TEMPORARILY. OUR STUDY DEMONSTRATES FOR THE FIRST TIME THE UNEXPECTED ROLE OF INTRINSIC HDAC2 ACTIVITY AT THE ALPHA2DELTA-1 GENE PROMOTER IN LIMITING ALPHA2DELTA-1 GENE TRANSCRIPTION, NMDA RECEPTOR-DEPENDENT SYNAPTIC PLASTICITY, AND CHRONIC PAIN DEVELOPMENT AFTER NERVE INJURY. THESE FINDINGS CHALLENGE THE PREVAILING VIEW ABOUT THE ROLE OF GENERAL HDAC ACTIVITY IN PROMOTING CHRONIC PAIN. RESTORING THE REPRESSIVE HDAC2 FUNCTION AND/OR REDUCING HISTONE ACETYLATION AT THE ALPHA2DELTA-1 GENE PROMOTER IN PRIMARY SENSORY NEURONS COULD LEAD TO LONG-LASTING RELIEF OF NERVE PAIN.	2022	

17  2300  25 EPIGENETIC REGULATION OF BDNF EXPRESSION IN THE PRIMARY SENSORY NEURONS AFTER PERIPHERAL NERVE INJURY: IMPLICATIONS IN THE DEVELOPMENT OF NEUROPATHIC PAIN. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IS KNOWN TO BE UP-REGULATED IN THE DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY, AND TO CONTRIBUTE TO NEUROPATHIC PAIN. HERE, WE FOUND THAT THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA AT DAY 7 POST-INJURY WERE INHIBITED ONLY WHEN ANTI-BDNF ANTIBODY WAS INTRATHECALLY ADMINISTRATED AT DAY 2 POST-INJURY. CONSISTENT WITH BEHAVIORAL RESULTS, WESTERN BLOT ANALYSIS SHOWED THAT THE EXPRESSION LEVELS OF BDNF PROTEIN IN THE SPINAL DORSAL HORN WERE MARKEDLY INDUCED DURING EARLY STAGE POST-INJURY. MOREOVER, THE MAXIMAL INCREASE IN BDNF MRNA EXPRESSION IN THE DRG WAS OBSERVED AT DAY 1 POST-INJURY, AND SIGNIFICANTLY ELEVATED LEVELS WERE SUSTAINED FOR AT LEAST 14 DAYS. FOUR OF FIVE BDNF MRNA TRANSCRIPTS WERE UP-REGULATED AFTER NERVE INJURY, AND THE MOST INDUCIBLE TRANSCRIPT WAS EXON I. USING A CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY, WE FOUND THAT NERVE INJURY PROMOTES HISTONE H3 AND H4 ACETYLATION, TRANSCRIPTIONALLY ACTIVE MODIFICATIONS, AT BDNF PROMOTER I AT DAY 1 POST-INJURY, AND THE LEVELS OF HISTONE ACETYLATION REMAIN ELEVATED FOR AT LEAST 7 DAYS. TAKEN TOGETHER, OUR FINDINGS SUGGEST THAT AN INITIAL INCREASE IN BDNF EXON I EXPRESSION CONTROLLED BY EPIGENETIC MECHANISMS MIGHT HAVE A CRUCIAL ROLE IN THE DEVELOPMENT OF NEUROPATHIC PAIN.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
18  1320  22 DEMETHYLATION REGULATION OF BDNF GENE EXPRESSION IN DORSAL ROOT GANGLION NEURONS IS IMPLICATED IN OPIOID-INDUCED PAIN HYPERSENSITIVITY IN RATS. REPEATED ADMINISTRATION OF MORPHINE MAY RESULT IN OPIOID-INDUCED HYPERSENSITIVITY (OIH), WHICH INVOLVES ALTERED EXPRESSION OF NUMEROUS GENES, INCLUDING BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IN DORSAL ROOT GANGLION (DRG) NEURONS. YET, IT REMAINS UNCLEAR HOW BDNF EXPRESSION IS INCREASED IN DRG NEURONS AFTER REPEATED MORPHINE TREATMENT. DNA METHYLATION IS AN IMPORTANT MECHANISM OF EPIGENETIC CONTROL OF GENE EXPRESSION. IN THE CURRENT STUDY, WE HYPOTHESIZED THAT THE DEMETHYLATION REGULATION OF CERTAIN BDNF GENE PROMOTERS IN DRG NEURONS MAY CONTRIBUTE TO THE DEVELOPMENT OF OIH. REAL-TIME RT-PCR WAS USED TO ASSESS CHANGES IN THE MRNA TRANSCRIPTION LEVELS OF MAJOR BDNF EXONS INCLUDING EXON I, II, IV, VI, AS WELL AS TOTAL BDNF MRNA IN DRGS FROM RATS AFTER REPEATED MORPHINE ADMINISTRATION. THE LEVELS OF EXON IV AND TOTAL BDNF MRNA WERE SIGNIFICANTLY UPREGULATED BY REPEATED MORPHINE ADMINISTRATION, AS COMPARED TO THAT IN SALINE CONTROL GROUP. FURTHER, ELISA ARRAY AND IMMUNOCYTOCHEMISTRY STUDY REVEALED A ROBUST UPREGULATION OF BDNF PROTEIN EXPRESSION IN DRG NEURONS AFTER REPEATED MORPHINE EXPOSURE. CORRESPONDINGLY, THE METHYLATION LEVELS OF BDNF EXON IV PROMOTER SHOWED A SIGNIFICANT DOWNREGULATION BY MORPHINE TREATMENT. IMPORTANTLY, INTRATHECAL ADMINISTRATION OF A BDNF ANTIBODY, BUT NOT CONTROL IGG, SIGNIFICANTLY INHIBITED MECHANICAL HYPERSENSITIVITY THAT DEVELOPED IN RATS AFTER REPEATED MORPHINE TREATMENT. CONVERSELY, INTRATHECAL ADMINISTRATION OF AN INHIBITOR OF DNA METHYLATION, 5-AZA-2'-DEOXYCYTIDINE (5-AZA-DC) MARKEDLY UPREGULATED THE BDNF PROTEIN EXPRESSION IN DRG NEURONS AND ENHANCED THE MECHANICAL ALLODYNIA AFTER REPEATED MORPHINE EXPOSURE. TOGETHER, OUR FINDINGS SUGGEST THAT DEMETHYLATION REGULATION OF BDNF GENE PROMOTER MAY BE IMPLICATED IN THE DEVELOPMENT OF OIH THROUGH EPIGENETIC CONTROL OF BDNF EXPRESSION IN DRG NEURONS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19  6058  31 THE DEFICIENCY OF N6-METHYLADENOSINE DEMETHYLASE ALKBH5 ENHANCES THE NEURODEGENERATIVE DAMAGE INDUCED BY COBALT. COBALT EXPOSURE, EVEN AT LOW CONCENTRATIONS, INDUCES NEURODEGENERATIVE DAMAGE, SUCH AS ALZHEIMER'S DISEASE (AD). THE SPECIFIC UNDERLYING MECHANISMS REMAIN UNCLEAR. OUR PREVIOUS STUDY DEMONSTRATED THAT M(6)A METHYLATION ALTERATION IS INVOLVED IN COBALT-INDUCED NEURODEGENERATIVE DAMAGE, SUCH AS IN AD. HOWEVER, THE ROLE OF M(6)A RNA METHYLATION AND ITS UNDERLYING MECHANISMS ARE POORLY UNDERSTOOD. IN THIS STUDY, BOTH EPIDEMIOLOGICAL AND LABORATORY STUDIES SHOWED THAT COBALT EXPOSURE COULD DOWNREGULATE THE EXPRESSION OF THE M(6)A DEMETHYLASE ALKBH5, SUGGESTING A KEY ROLE FOR ALKBH5. MOREOVER, METHYLATED RNA IMMUNOPRECIPITATION AND SEQUENCING (MERIP-SEQ) ANALYSIS REVEALED THAT ALKBH5 DEFICIENCY IS ASSOCIATED WITH NEURODEGENERATIVE DISEASES. KEGG PATHWAY AND GENE ONTOLOGY ANALYSES FURTHER REVEALED THAT THE DIFFERENTIALLY M(6)A-MODIFIED GENES RESULTING FROM ALKBH5 DOWNREGULATION AND COBALT EXPOSURE WERE AGGREGATED IN THE PATHWAYS OF PROLIFERATION, APOPTOSIS, AND AUTOPHAGY. SUBSEQUENTLY, ALKBH5 DEFICIENCY WAS SHOWN TO EXACERBATE CELL VIABILITY DECLINE, MOTIVATE CELL APOPTOSIS AND ATTENUATE CELL AUTOPHAGY INDUCED BY COBALT WITH EXPERIMENTAL TECHNIQUES OF GENE OVEREXPRESSION/INHIBITION. IN ADDITION, MORPHOLOGICAL CHANGES IN NEURONS AND THE EXPRESSION OF AD-RELATED PROTEINS, SUCH AS APP, P-TAU, AND TAU, IN THE CEREBRAL HIPPOCAMPUS OF WILD-TYPE AND ALKBH5 KNOCKOUT MICE AFTER CHRONIC COBALT EXPOSURE WERE ALSO INVESTIGATED. BOTH IN VITRO AND IN VIVO RESULTS SHOWED THAT LOWER EXPRESSION OF ALKBH5 AGGRAVATED COBALT-INDUCED NEURODEGENERATIVE DAMAGE. THESE RESULTS SUGGEST THAT ALKBH5, AS AN EPIGENETIC REGULATOR, COULD BE A POTENTIAL TARGET FOR ALLEVIATING COBALT-INDUCED NEURODEGENERATIVE DAMAGE. IN ADDITION, WE PROPOSE A NOVEL STRATEGY FOR THE PREVENTION AND TREATMENT OF ENVIRONMENTAL TOXICANT-RELATED NEURODEGENERATION FROM AN EPIGENETIC PERSPECTIVE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
20  4095  26 MATERNALLY DERIVED LOW GLUCOCORTICOID MEDIATES ADRENAL DEVELOPMENTAL PROGRAMMING ALTERATION IN OFFSPRING INDUCED BY DEXAMETHASONE. ADVERSE ENVIRONMENTS DURING PREGNANCY CAN INCREASE SUSCEPTIBILITY TO CHRONIC DISEASES IN ADULT OFFSPRING. THE OCCURRENCE AND DEVELOPMENT OF FETAL-ORIGINATED DISEASES WERE ASSOCIATED WITH ADRENAL DEVELOPMENTAL PROGRAMMING AND HOMEOSTASIS ALTERATION IN OFFSPRING. DEXAMETHASONE IS WIDELY USED FOR PRETERM DELIVERY-RELATED PREGNANCY DISEASES, BUT THE INTRAUTERINE PROGRAMMING ALTERATION AND ITS OCCURRENCE MECHANISM OF PRENATAL DEXAMETHASONE EXPOSURE (PDE) ON ADRENAL DEVELOPMENT IN OFFSPRING HAVE NOT BEEN CLARIFIED. IN THIS STUDY, PRENATAL DEXAMETHASONE THERAPY COULD INHIBIT NEONATAL DEVELOPMENT AND CAUSE A LOW EXPOSURE OF MATERNALLY DERIVED GLUCOCORTICOID IN CLINIC. THEN, WE ESTABLISHED A RAT MODEL OF PDE AND OBSERVED A SIMILAR PHENOMENON. FURTHER, THE ADRENAL STEROIDOGENIC FUNCTION WAS CONTINUOUSLY INHIBITED IN THE PDE MALE OFFSPRING RATS, ACCOMPANIED BY THE DECREASED H3K27AC LEVEL OF ADRENAL INSULIN-LIKE GROWTH FACTOR 1 (IGF1) AND ITS EXPRESSION. MOREOVER, CHRONIC STRESS IN PDE ADULT OFFSPRING RATS COULD REVERSE THE CHANGES OF THE ABOVE INDICATORS THROUGH THE HIGH LEVEL OF GLUCOCORTICOID. IN COMBINATION WITH IN VIVO, IN VITRO AND A SERIES OF INTERFERENCE EXPERIMENTS, WE CONFIRMED THAT THE LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS INHIBITED THE ADRENAL IGF1 EXPRESSION AND STEROIDOGENIC FUNCTION THROUGH THE GRALPHA/MIR-370-3P/SIRT3 PATHWAY. IN SUMMARY, PDE COULD CONTINUOUSLY INHIBIT THE ADRENAL STEROIDOGENIC FUNCTION IN THE MALE OFFSPRING, WHICH IS ASSOCIATED WITH THE MATERNALLY DERIVED LOW GLUCOCORTICOID-MEDIATED THE ADRENAL DEVELOPMENTAL PROGRAMMING ALTERATION IN OFFSPRING. THIS STUDY PROVIDES A THEORETICAL AND EXPERIMENTAL BASIS FOR EXPLAINING THE ADRENAL DEVELOPMENT ORIGIN OF PDE-INDUCED ADULT CHRONIC DISEASES.	2021