1 603 126 BETULINIC ACID INHIBITS ENDOMETRIOSIS THROUGH SUPPRESSION OF ESTROGEN RECEPTOR BETA SIGNALING PATHWAY. ENDOMETRIOSIS IS AN INFLAMMATORY GYNECOLOGICAL DISORDER CHARACTERIZED BY ENDOMETRIAL TISSUE GROWTH LOCATED OUTSIDE OF THE UTERINE CAVITY IN ADDITION TO CHRONIC PELVIC PAIN AND INFERTILITY. IN THIS STUDY, WE AIM TO DEVELOP A POTENTIAL THERAPEUTIC TREATMENT BASED ON THE PATHOGENESIS AND MECHANISM OF ENDOMETRIOSIS. OUR PRELIMINARY DATA SHOWED THAT THE EXPRESSION OF ESTROGEN RECEPTOR BETA (ERBETA) WAS SIGNIFICANTLY INCREASED, WHILE ERALPHA WAS SIGNIFICANTLY DECREASED, IN ENDOMETRIOTIC CELLS COMPARED TO NORMAL ENDOMETRIAL CELLS. FURTHER INVESTIGATION SHOWED THAT BETULINIC ACID (BA) TREATMENT SUPPRESSED ERBETA EXPRESSION THROUGH EPIGENETIC MODIFICATION ON THE ERBETA PROMOTER, WHILE HAD NO EFFECT ON ERALPHA EXPRESSION. IN ADDITION, BA TREATMENT SUPPRESSES ERBETA TARGET GENES, INCLUDING SUPEROXIDE DISMUTASE 2 (SOD2), NUCLEAR RESPIRATORY FACTOR-1 (NRF1), CYCLOOXYGENASE 2 (COX2), AND MATRIX METALLOPROTEINASE-1 (MMP1), SUBSEQUENTLY INCREASING OXIDATIVE STRESS, TRIGGERING MITOCHONDRIAL DYSFUNCTION, DECREASING ELEVATED PROINFLAMMATORY CYTOKINES, AND EVENTUALLY SUPPRESSING ENDOMETRIOTIC CELL PROLIFERATION, MIMICKING THE EFFECT OF ERBETA KNOCKDOWN. ON THE OTHER HAND, GAIN OF ERBETA BY LENTIVIRUS INFECTION IN NORMAL ENDOMETRIAL CELLS RESULTED IN INCREASED CELL PROLIFERATION AND PROINFLAMMATORY CYTOKINE RELEASE, WHILE BA TREATMENT DIMINISHED THIS EFFECT THROUGH ERBETA SUPPRESSION WITH SUBSEQUENT OXIDATIVE STRESS AND APOPTOSIS. OUR RESULTS INDICATE THAT ERBETA MAY BE A MAJOR DRIVING FORCE FOR THE DEVELOPMENT OF ENDOMETRIOSIS, WHILE BA INHIBITS ENDOMETRIOSIS THROUGH SPECIFIC SUPPRESSION OF THE ERBETA SIGNALING PATHWAY. THIS STUDY PROVIDES A NOVEL THERAPEUTIC STRATEGY FOR ENDOMETRIOSIS TREATMENT THROUGH BA-MEDIATED ERBETA SUPPRESSION. 2020 2 919 31 CHRONIC HYPOXIA DURING GESTATION CAUSES EPIGENETIC REPRESSION OF THE ESTROGEN RECEPTOR-ALPHA GENE IN OVINE UTERINE ARTERIES VIA HEIGHTENED PROMOTER METHYLATION. ESTROGEN RECEPTOR-ALPHA (ERALPHA) PLAYS A KEY ROLE IN THE ADAPTATION OF INCREASED UTERINE BLOOD FLOW IN PREGNANCY. CHRONIC HYPOXIA IS A COMMON STRESS TO MATERNAL CARDIOVASCULAR HOMEOSTASIS AND CAUSES INCREASED RISK OF PREECLAMPSIA. STUDIES IN PREGNANT SHEEP DEMONSTRATED THAT HYPOXIA DURING GESTATION DOWNREGULATED ERALPHA GENE EXPRESSION IN UTERINE ARTERIES. THE PRESENT STUDY TESTED THE HYPOTHESIS THAT HYPOXIA CAUSES EPIGENETIC REPRESSION OF THE ERALPHA GENE IN UTERINE ARTERIES VIA HEIGHTENED PROMOTER METHYLATION. OVINE ERALPHA PROMOTER OF 2035 BP SPANNING FROM -2000 TO +35 OF THE TRANSCRIPTION START SITE WAS CLONED. NO ESTROGEN OR HYPOXIA-INDUCIBLE FACTOR RESPONSE ELEMENTS WERE FOUND AT THE PROMOTER. TWO TRANSCRIPTION FACTOR BINDING SITES, USF(-15) AND SP1(-520), CONTAINING CPG DINUCLEOTIDES WERE IDENTIFIED, WHICH HAD SIGNIFICANT EFFECTS ON THE PROMOTER ACTIVITY. THE USF ELEMENT BINDS TRANSCRIPTION FACTORS USF1 AND USF2, AND THE SP1 ELEMENT BINDS SP1, AS WELL AS ERALPHA THROUGH SP1. DELETION OF THE SP1 SITE ABROGATED 17BETA-ESTRADIOL-INDUCED INCREASE IN THE PROMOTER ACTIVITY. IN NORMOXIC CONTROL SHEEP, CPG METHYLATION AT THE SP1 BUT NOT THE USF SITE WAS SIGNIFICANTLY DECREASED IN UTERINE ARTERIES OF PREGNANT AS COMPARED WITH NONPREGNANT ANIMALS. IN PREGNANT SHEEP EXPOSED TO LONG-TERM HIGH-ALTITUDE HYPOXIA, CPG METHYLATION AT BOTH SP1 AND USF SITES IN UTERINE ARTERIES WAS SIGNIFICANTLY INCREASED. METHYLATION INHIBITED TRANSCRIPTION FACTOR BINDING AND THE PROMOTER ACTIVITY. THE RESULTS PROVIDE EVIDENCE OF HYPOXIA CAUSING HEIGHTENED PROMOTER METHYLATION AND RESULTANT ERALPHA GENE REPRESSION IN UTERINE ARTERIES AND SUGGEST NEW INSIGHTS OF MOLECULAR MECHANISMS LINKING GESTATIONAL HYPOXIA TO ABERRANT UTEROPLACENTAL CIRCULATION AND INCREASED RISK OF PREECLAMPSIA. 2012 3 2482 34 EPIGENETIC UPREGULATION OF METABOTROPIC GLUTAMATE RECEPTOR 2 IN THE SPINAL CORD ATTENUATES OESTROGEN-INDUCED VISCERAL HYPERSENSITIVITY. OBJECTIVE: EPIGENETIC MECHANISMS ARE POTENTIAL TARGETS TO RELIEVE SOMATIC PAIN. HOWEVER, LITTLE IS KNOWN WHETHER EPIGENETIC REGULATION INTERFERES WITH VISCERAL PAIN. PREVIOUS STUDIES SHOW THAT OESTROGEN FACILITATES VISCERAL PAIN. THIS STUDY AIMED TO DETERMINE WHETHER HISTONE HYPERACETYLATION IN THE SPINAL CORD COULD ATTENUATE OESTROGEN-FACILITATED VISCERAL PAIN. DESIGN: THE EFFECT OF THE HISTONE DEACETYLASE INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) ON THE MAGNITUDE OF THE VISCEROMOTOR RESPONSE (VMR) TO COLORECTAL DISTENTION WAS EXAMINED IN OVARIECTOMISED RATS WITH/WITHOUT OESTROGEN REPLACEMENT. AN ADDITIONAL INTERACTION WITH THE METABOTROPIC GLUTAMATE RECEPTOR 2/3 (MGLUR2/3) ANTAGONIST LY341495 WAS TESTED. THE LEVELS OF ACETYLATED HISTONE AND MGLUR2 MRNA AND PROTEIN WERE ANALYSED. THE BINDING OF ACETYLATED H3 AND OESTROGEN RECEPTOR ALPHA (ERALPHA) TO THE GRM2 PROMOTER WAS MEASURED BY CHROMATIN IMMUNOPRECIPITATION COUPLED WITH QPCR. RESULTS: IN OVARIECTOMISED RATS, 17BETA-ESTRADIOL (E2), BUT NOT SAFFLOWER OIL, INCREASED THE MAGNITUDE OF THE VMR TO COLORECTAL DISTENTION. SAHA ATTENUATED THE E2-FACILITATED VMR, BUT HAD NO EFFECT IN SAFFLOWER OIL-TREATED RATS. SUBSEQUENT SPINAL ADMINISTRATION OF LY341495 REVERSED THE ANTINOCICEPTIVE EFFECT OF SAHA IN E2 RATS. IN ADDITION, SAHA INCREASED MGLUR2 MRNA AND PROTEIN IN THE SPINAL DORSAL HORN FOLLOWING E2, BUT NOT VEHICLE, TREATMENT. IN CONTRAST, NEITHER E2 NOR SAHA ALONE ALTERED MGLUR2 MRNA. SAHA INCREASED BINDING OF H3K9AC AND ERALPHA TO THE SAME REGIONS OF THE GRM2 PROMOTER IN E2-SAHA-TREATED ANIMALS. CONCLUSIONS: HISTONE HYPERACETYLATION IN THE SPINAL CORD ATTENUATES THE PRONOCICEPTIVE EFFECTS OF OESTROGEN ON VISCERAL SENSITIVITY, SUGGESTING THAT EPIGENETIC REGULATION MAY BE A POTENTIAL APPROACH TO RELIEVE VISCERAL PAIN. 2015 4 2667 35 ESTROGEN AND SEROTONIN ENHANCE STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN FEMALE RATS BY UP-REGULATING BRAIN-DERIVED NEUROTROPHIC FACTOR IN SPINAL CORD. BACKGROUND: WE PREVIOUSLY REPORTED THAT FEMALE OFFSPRING OF DAMS SUBJECTED TO CHRONIC PRENATAL STRESS (CPS) DEVELOP ENHANCED VISCERAL HYPERSENSITIVITY (VHS) FOLLOWING EXPOSURE TO CHRONIC STRESS IN ADULT LIFE THAT IS MEDIATED BY UP-REGULATION OF SPINAL CORD BDNF. THE AIMS OF THIS STUDY WERE TO EXAMINE THE ROLES OF ESTROGEN RECEPTOR ALPHA (ERALPHA) AND AN INCREASE IN SPINAL SEROTONIN SIGNALING IN PROMOTING THIS ENHANCED VHS IN FEMALE RATS AND UP-REGULATION OF SPINAL CORD BDNF TRANSCRIPTION. METHODS: PREGNANT DAMS WERE EXPOSED TO CHRONIC STRESS FROM E11 UNTIL DELIVERY. AT 8 WEEKS, A CHRONIC ADULT STRESS (CAS) PROTOCOL WAS APPLIED FOR NINE DAYS. KEY RESULTS: OVARIECTOMY BEFORE CAS OR TREATMENT WITH LETROZOLE BEFORE AND DURING CAS SIGNIFICANTLY PREVENTED THE DEVELOPMENT OF ENHANCED VHS IN FEMALE CPS+CAS RATS. INTRATHECAL APPLICATION OF ERALPHA SIRNA SIGNIFICANTLY REDUCED VHS, DECREASED LUMBAR-SACRAL SPINAL CORD EXPRESSION OF BOTH ERALPHA AND BDNF, AND REVERSED PRO-TRANSCRIPTIONAL EPIGENETIC MODIFICATIONS AT BDNF PROMOTER LX. CEREBROSPINAL FLUID SEROTONIN LEVELS AND 5HT3A RECEPTOR EXPRESSION IN THE LS SPINAL CORD WERE BOTH SIGNIFICANTLY INCREASED IN FEMALE CPS+CAS RATS. DURING CAS, INTRATHECAL INFUSION OF ALOSETRON SIGNIFICANTLY DECREASED VHS, REDUCED BDNF AND ERALPHA EXPRESSION IN THE LS SPINAL CORD, AND ATTENUATED RNA POL II AND ERALPHA BINDING TO THE BNDF CORE PROMOTER IX. CONCLUSIONS & INFERENCES: SEROTONIN-MEDIATED ACTIVATION OF 5HT3A RECEPTORS IN THE SPINAL CORD DRIVES THE DEVELOPMENT OF ENHANCED FEMALE-SPECIFIC VHS IN OUR TWO HIT CPS+CAS THROUGH UP-REGULATION OF SPINAL CORD ERALPHA. 2021 5 1899 34 ENERGY BALANCE MODULATION IMPACTS EPIGENETIC REPROGRAMMING, ERALPHA AND ERBETA EXPRESSION, AND MAMMARY TUMOR DEVELOPMENT IN MMTV-NEU TRANSGENIC MICE. THE ASSOCIATION BETWEEN OBESITY AND BREAST CANCER RISK AND PROGNOSIS IS WELL ESTABLISHED IN ESTROGEN RECEPTOR (ER)-POSITIVE DISEASE BUT LESS CLEAR IN HER2-POSITIVE DISEASE. HERE, WE REPORT PRECLINICAL EVIDENCE SUGGESTING WEIGHT MAINTENANCE THROUGH CALORIE RESTRICTION (CR) MAY LIMIT RISK OF HER2-POSITIVE BREAST CANCER. IN FEMALE MMTV-HER2/NEU TRANSGENIC MICE, WE FOUND THAT ERALPHA AND ERBETA EXPRESSION, MAMMARY TUMORIGENESIS, AND SURVIVAL ARE ENERGY BALANCE DEPENDENT IN ASSOCIATION WITH EPIGENETIC REPROGRAMMING. MICE WERE RANDOMIZED TO RECEIVE A CR, OVERWEIGHT-INDUCING, OR DIET-INDUCED OBESITY REGIMEN (N = 27/GROUP). SUBSETS OF MICE (N = 4/GROUP/TIME POINT) WERE EUTHANIZED AFTER 1, 3, AND 5 MONTHS TO CHARACTERIZE DIET-DEPENDENT METABOLIC, TRANSCRIPTIONAL, AND EPIGENETIC PERTURBATIONS. REMAINING MICE WERE FOLLOWED UP TO 22 MONTHS. RELATIVE TO THE OVERWEIGHT AND DIET-INDUCED OBESITY REGIMENS, CR DECREASED BODY WEIGHT, ADIPOSITY, AND SERUM METABOLIC HORMONES AS EXPECTED AND ALSO ELICITED AN INCREASE IN MAMMARY ERALPHA AND ERBETA EXPRESSION. INCREASED DNA METHYLATION ACCOMPANIED THIS PATTERN, PARTICULARLY AT CPG DINUCLEOTIDES LOCATED WITHIN BINDING OR FLANKING REGIONS FOR THE TRANSCRIPTIONAL REGULATOR CCCTC-BINDING FACTOR OF ESR1 AND ESR2, CONSISTENT WITH SUSTAINED TRANSCRIPTIONAL ACTIVATION OF ERALPHA AND ERBETA. MAMMARY EXPRESSION OF THE DNA METHYLATION ENZYME DNMT1 WAS STABLE IN CR MICE BUT INCREASED OVER TIME IN OVERWEIGHT AND DIET-INDUCED OBESITY MICE, SUGGESTING CR OBVIATES EPIGENETIC ALTERATIONS CONCURRENT WITH CHRONIC EXCESS ENERGY INTAKE. IN THE SURVIVAL STUDY, CR ELICITED A SIGNIFICANT SUPPRESSION IN SPONTANEOUS MAMMARY TUMORIGENESIS. OVERALL, OUR FINDINGS SUGGEST A MECHANISTIC RATIONALE TO PREVENT OR REVERSE EXCESS BODY WEIGHT AS A STRATEGY TO REDUCE HER2-POSITIVE BREAST CANCER RISK. CANCER RES; 77(9); 2500-11. (C)2017 AACR. 2017 6 3667 35 INFILTRATING MACROPHAGES INDUCE ERALPHA EXPRESSION THROUGH AN IL17A-MEDIATED EPIGENETIC MECHANISM TO SENSITIZE ENDOMETRIAL CANCER CELLS TO ESTROGEN. PERSISTENT UNOPPOSED ESTROGEN STIMULATION IS A CENTRAL ONCOGENIC MECHANISM DRIVING THE FORMATION OF TYPE I ENDOMETRIAL CANCER. RECENT EPIDEMIOLOGIC AND CLINICAL STUDIES OF ENDOMETRIAL CANCER HAVE ALSO REVEALED A ROLE FOR INSULIN RESISTANCE, CLINICALLY MANIFESTED BY CHRONIC INFLAMMATION. HOWEVER, THE ROLE OF INFLAMMATION IN ESTROGEN-DRIVEN ENDOMETRIAL CANCER IS NOT WELL CHARACTERIZED. IN THIS STUDY, WE INVESTIGATED THE ASSOCIATION BETWEEN INFILTRATING MACROPHAGES AND ESTROGEN SENSITIVITY IN ENDOMETRIAL CANCER. EVALUATING TISSUE SAMPLES AND SERUM FROM PATIENTS WITH PRECANCEROUS LESIONS OR ENDOMETRIAL CANCER, WE FOUND THAT TISSUE MACROPHAGE INFILTRATION, BUT NOT SERUM ESTRADIOL LEVELS, CORRELATED POSITIVELY WITH ENDOMETRIAL CANCER DEVELOPMENT. FURTHERMORE, IL4/IL13-INDUCED CD68(+)CD163(+) MACROPHAGES ENHANCED THE PROLIFERATIVE EFFECTS OF ESTRADIOL IN ENDOMETRIAL CANCER CELLS BY UPREGULATING ESTROGEN RECEPTOR ALPHA (ERALPHA), BUT NOT ERBETA. MECHANISTIC INVESTIGATIONS REVEALED THAT CD68(+)CD163(+) MACROPHAGES SECRETED CYTOKINES, SUCH AS IL17A, THAT UPREGULATED ERALPHA EXPRESSION THROUGH TET1-MEDIATED EPIGENETIC MODULATION OF THE ERALPHA GENE. OVERALL, OUR FINDINGS SHOW HOW CYTOKINES PRODUCED BY INFILTRATING MACROPHAGES IN THE ENDOMETRIAL MICROENVIRONMENT CAN INDUCE EPIGENETIC UPREGULATION OF ERALPHA EXPRESSION, WHICH IN TURN SENSITIZES ENDOMETRIAL CELLS TO ESTROGEN STIMULATION. THE CONCEPT THAT INFLAMMATION-INDUCED ESTROGEN SENSITIVITY IN THE ENDOMETRIUM ACTS AS A DRIVER OF TYPE I ENDOMETRIAL CANCER HAS IMPLICATIONS FOR INFILTRATING MACROPHAGES AS A PROGNOSTIC BIOMARKER OF PROGRESSION IN THIS DISEASE SETTING. 2016 7 5239 44 PROGESTERONE ALLEVIATES ENDOMETRIOSIS VIA INHIBITION OF UTERINE CELL PROLIFERATION, INFLAMMATION AND ANGIOGENESIS IN AN IMMUNOCOMPETENT MOUSE MODEL. ENDOMETRIOSIS, DEFINED AS GROWTH OF THE ENDOMETRIAL CELLS OUTSIDE THE UTERUS, IS AN INFLAMMATORY DISORDER THAT IS ASSOCIATED WITH CHRONIC PELVIC PAIN AND INFERTILITY IN WOMEN OF CHILDBEARING AGE. ALTHOUGH THE ESTROGEN-DEPENDENCE OF ENDOMETRIOSIS IS WELL KNOWN, THE ROLE OF PROGESTERONE IN DEVELOPMENT OF THIS DISEASE REMAINS POORLY UNDERSTOOD. IN THIS STUDY, WE DEVELOPED A DISEASE MODEL IN WHICH ENDOMETRIOSIS WAS INDUCED IN THE PERITONEAL CAVITIES OF IMMUNOCOMPETENT FEMALE MICE, AND MAINTAINED WITH EXOGENOUS ESTROGEN. THE ENDOMETRIOSIS-LIKE LESIONS THAT WERE IDENTIFIED AT A VARIETY OF ECTOPIC LOCATIONS EXHIBITED ABUNDANT BLOOD SUPPLY AND EXTENSIVE ADHESIONS. HISTOLOGICAL EXAMINATION REVEALED THAT THESE LESIONS HAD A WELL-ORGANIZED ENDOMETRIAL ARCHITECTURE AND FIBROTIC RESPONSE, RESEMBLING THOSE RECOVERED FROM CLINICAL PATIENTS. IN ADDITION, AN EXTENSIVE PROLIFERATION, INFLAMMATORY RESPONSE, AND LOSS OF ESTROGEN RECEPTOR ALPHA (ERALPHA) AND PROGESTERONE RECEPTOR (PR) EXPRESSION WERE ALSO OBSERVED IN THESE LESIONS. INTERESTINGLY, ADMINISTRATION OF PROGESTERONE BEFORE, BUT NOT AFTER, LESION INDUCTION SUPPRESSED LESION EXPANSION AND MAINTAINED ERALPHA AND PR EXPRESSIONS. THESE PROGESTERONE-PRETREATED LESIONS EXHIBITED ATTENUATION IN KI67, CD31, AND PRO-INFLAMMATORY CYTOKINE EXPRESSION AS WELL AS MACROPHAGE INFILTRATION, INDICATING THAT PROGESTERONE AMELIORATES ENDOMETRIOSIS PROGRESSION BY INHIBITING CELL PROLIFERATION, INFLAMMATION AND NEOVASCULARIZATION. OUR STUDIES FURTHER SHOWED THAT SUPPRESSION OF GLOBAL DNA METHYLATION BY APPLICATION OF DNA METHYLTRANSFERASE INHIBITOR TO FEMALE MICE BEARING ECTOPIC LESIONS RESTRAINED LESION EXPANSION AND RESTORED ERALPHA AND PR EXPRESSION IN EUTOPIC ENDOMETRIUM AND ECTOPIC LESIONS. THESE RESULTS INDICATE THAT EPIGENETIC REGULATION OF TARGET GENE EXPRESSION VIA DNA METHYLATION CONTRIBUTES, AT LEAST IN PART, TO PROGESTERONE RESISTANCE IN ENDOMETRIOSIS. 2016 8 2480 28 EPIGENETIC UPREGULATION OF LARGE-CONDUCTANCE CA2+-ACTIVATED K+ CHANNEL EXPRESSION IN UTERINE VASCULAR ADAPTATION TO PREGNANCY. OUR PREVIOUS STUDY DEMONSTRATED THAT PREGNANCY INCREASED LARGE-CONDUCTANCE CA(2+)-ACTIVATED POTASSIUM CHANNEL BETA1 SUBUNIT (BKBETA1) EXPRESSION AND LARGE-CONDUCTANCE CA(2+)-ACTIVATED POTASSIUM CHANNEL ACTIVITY IN UTERINE ARTERIES, WHICH WERE ABROGATED BY CHRONIC HYPOXIA. THE PRESENT STUDY TESTED THE HYPOTHESIS THAT PROMOTER METHYLATION/DEMETHYLATION IS A KEY MECHANISM IN EPIGENETIC REPROGRAMMING OF BKBETA1 EXPRESSION PATTERNS IN UTERINE ARTERIES. OVINE BKBETA1 PROMOTER OF 2315 BP SPANNING FROM -2211 TO +104 OF THE TRANSCRIPTION START SITE WAS CLONED, AND AN SP1-380 BINDING SITE THAT CONTAINS CPG DINUCLEOTIDE IN ITS CORE BINDING SEQUENCES WAS IDENTIFIED. SITE-DIRECTED DELETION OF THE SP1 SITE SIGNIFICANTLY DECREASED THE BKBETA1 PROMOTER ACTIVITY. ESTROGEN RECEPTOR-ALPHA BOUND TO THE SP1 SITE THROUGH TETHERING TO SP1 AND UPREGULATED THE EXPRESSION OF BKBETA1. THE SP1 BINDING SITE AT BKBETA1 PROMOTER WAS HIGHLY METHYLATED IN UTERINE ARTERIES OF NONPREGNANT SHEEP, AND METHYLATION INHIBITED TRANSCRIPTION FACTOR BINDING AND BKBETA1 PROMOTER ACTIVITY. PREGNANCY CAUSED A SIGNIFICANT DECREASE IN CPG METHYLATION AT THE SP1 BINDING SITE AND INCREASED SP1 BINDING TO THE BKBETA1 PROMOTER AND BKBETA1 MRNA ABUNDANCE. CHRONIC HYPOXIA DURING GESTATION ABROGATED THIS PREGNANCY-INDUCED DEMETHYLATION AND UPREGULATION OF BKBETA1 EXPRESSION. THE RESULTS PROVIDE EVIDENCE OF A NOVEL MECHANISM OF PROMOTER DEMETHYLATION IN PREGNANCY-INDUCED REPROGRAMMING OF LARGE-CONDUCTANCE CA(2+)-ACTIVATED POTASSIUM CHANNEL EXPRESSION AND FUNCTION IN UTERINE ARTERIES AND SUGGEST NEW INSIGHTS OF EPIGENETIC MECHANISMS LINKING GESTATIONAL HYPOXIA TO ABERRANT UTEROPLACENTAL CIRCULATION AND INCREASED RISK OF PREECLAMPSIA. 2014 9 978 43 CHRONIC OXIDATIVE STRESS CAUSES ESTROGEN-INDEPENDENT AGGRESSIVE PHENOTYPE, AND EPIGENETIC INACTIVATION OF ESTROGEN RECEPTOR ALPHA IN MCF-7 BREAST CANCER CELLS. THE ROLE OF CHRONIC OXIDATIVE STRESS IN THE DEVELOPMENT AND AGGRESSIVE GROWTH OF ESTROGEN RECEPTOR (ER)-POSITIVE BREAST CANCER IS WELL KNOWN; HOWEVER, THE MECHANISTIC UNDERSTANDING IS NOT CLEAR. ESTROGEN-INDEPENDENT GROWTH IS ONE OF THE FEATURES OF AGGRESSIVE SUBTYPE OF BREAST CANCER. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE EFFECT OF OXIDATIVE STRESS ON ESTROGEN SENSITIVITY AND EXPRESSION OF NUCLEAR ESTROGEN RECEPTORS IN ER-POSITIVE BREAST CANCER CELLS. MCF-7 CELLS CHRONICALLY EXPOSED TO HYDROGEN PEROXIDE WERE USED AS A CELL MODEL IN THIS STUDY, AND THEIR GROWTH IN RESPONSE TO 17-BETA ESTRADIOL WAS EVALUATED BY CELL VIABILITY, CELL CYCLE, AND CELL MIGRATION ANALYSIS. RESULTS WERE FURTHER CONFIRMED AT MOLECULAR LEVEL BY ANALYSIS OF GENE EXPRESSIONS AT TRANSCRIPT AND PROTEIN LEVELS. HISTONE H3 MODIFICATIONS, EXPRESSION OF EPIGENETIC REGULATORY GENES, AND THE EFFECT OF DNA DEMETHYLATION WERE ALSO ANALYZED. LOSS OF GROWTH IN RESPONSE TO ESTROGEN WITH A DECREASE IN ERALPHA EXPRESSION WAS OBSERVED IN MCF-7 CELLS ADAPTED TO CHRONIC OXIDATIVE STRESS. INCREASES IN MTTFA AND NRF1 IN THESE CELLS FURTHER SUGGESTED THE ROLE OF MITOCHONDRIA-DEPENDENT REDOX-SENSITIVE GROWTH SIGNALING AS AN ALTERNATIVE PATHWAY TO ESTROGEN-DEPENDENT GROWTH. CHANGES IN EXPRESSION OF EPIGENETIC REGULATORY GENES, LEVELS OF HISTONE H3 MODIFICATIONS AS WELL AS SIGNIFICANT RESTORATIONS OF BOTH ERALPHA EXPRESSION AND ESTROGEN RESPONSE BY 5-AZA-2'-DEOXYCYTIDINE FURTHER CONFIRMED THE EPIGENETIC BASIS FOR ESTROGEN-INDEPENDENT GROWTH IN THESE CELLS. IN CONCLUSION, RESULTS OF THIS STUDY SUGGEST THAT CHRONIC OXIDATIVE STRESS CAN CONVERT ESTROGEN-DEPENDENT NONAGGRESSIVE BREAST CANCER CELLS INTO ESTROGEN-INDEPENDENT AGGRESSIVE FORM POTENTIALLY BY EPIGENETIC MECHANISM. 2015 10 2668 35 ESTROGEN RECEPTORS AND ENDOMETRIOSIS. ENDOMETRIOSIS IS A FREQUENT AND CHRONIC INFLAMMATORY DISEASE WITH IMPACTS ON REPRODUCTION, HEALTH AND QUALITY OF LIFE. THIS DISORDER IS HIGHLY ESTROGEN-DEPENDENT AND THE PURPOSE OF HORMONAL TREATMENTS IS TO DECREASE THE ENDOGENOUS OVARIAN PRODUCTION OF ESTROGENS. HIGH ESTROGEN PRODUCTION IS A CONSISTENTLY OBSERVED ENDOCRINE FEATURE OF ENDOMETRIOSIS. MRNA AND PROTEIN LEVELS OF ESTROGEN RECEPTORS (ER) ARE DIFFERENT BETWEEN A NORMAL HEALTHY ENDOMETRIUM AND ECTOPIC/EUTOPIC ENDOMETRIAL LESIONS: ENDOMETRIOTIC STROMAL CELLS EXPRESS EXTRAORDINARILY HIGHER ERBETA AND SIGNIFICANTLY LOWER ERALPHA LEVELS COMPARED WITH ENDOMETRIAL STROMAL CELLS. ABERRANT EPIGENETIC REGULATION SUCH AS DNA METHYLATION IN ENDOMETRIOTIC CELLS IS ASSOCIATED WITH THE PATHOGENESIS AND DEVELOPMENT OF ENDOMETRIOSIS. ALTHOUGH THERE IS A LARGE BODY OF DATA REGARDING ERS IN ENDOMETRIOSIS, OUR UNDERSTANDING OF THE ROLES OF ERALPHA AND ERBETA IN THE PATHOGENESIS OF ENDOMETRIOSIS REMAINS INCOMPLETE. THE GOAL OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE LINKS BETWEEN ENDOMETRIOSIS, ERS AND THE RECENT ADVANCES OF TREATMENT STRATEGIES BASED ON ERS MODULATION. WE WILL ALSO ATTEMPT TO SUMMARIZE THE CURRENT UNDERSTANDING OF THE MOLECULAR AND CELLULAR MECHANISMS OF ACTION OF ERS AND HOW THIS COULD PAVE THE WAY TO NEW THERAPEUTIC STRATEGIES. 2020 11 2745 35 EXPRESS: HISTONE HYPERACETYLATION MODULATES SPINAL TYPE II METABOTROPIC GLUTAMATE RECEPTOR ALLEVIATING STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN FEMALE RATS. STRESS IS OFTEN A TRIGGER TO EXACERBATE CHRONIC PAIN INCLUDING VISCERAL HYPERSENSITIVITY ASSOCIATED WITH IRRITABLE BOWEL SYNDROME, A FEMALE PREDOMINANT FUNCTIONAL BOWEL DISORDER. EPIGENETIC MECHANISMS THAT MEDIATE STRESS RESPONSES ARE A POTENTIAL TARGET TO INTERFERE WITH VISCERAL PAIN. THE PURPOSE OF THIS STUDY WAS TO EXAMINE THE EFFECT OF A HISTONE DEACETYLASE INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID, ON VISCERAL HYPERSENSITIVITY INDUCED BY A SUBCHRONIC STRESSOR IN FEMALE RATS AND TO INVESTIGATE THE INVOLVEMENT OF SPINAL GLUTAMATE RECEPTORS. THREE DAILY SESSIONS OF FORCED SWIM INDUCED VISCERAL HYPERSENSITIVITY. INTRATHECAL SUBEROYLANILIDE HYDROXAMIC ACID PREVENTED OR REVERSED THE STRESS-INDUCED VISCERAL HYPERSENSITIVITY, INCREASED SPINAL HISTONE 3 ACETYLATION AND INCREASED MGLUR2 AND MGLUR3 EXPRESSION. CHROMATIN IMMUNOPRECIPITATION (CHIP) ANALYSIS REVEALED ENRICHMENT OF H3K9AC AND H3K18AC AT SEVERAL PROMOTER GRM2 AND GRM3 REGIONS. THE MGLUR2/3 ANTAGONIST LY341495 REVERSED THE INHIBITORY EFFECT OF SUBEROYLANILIDE HYDROXAMIC ACID ON THE STRESS-INDUCED VISCERAL HYPERSENSITIVITY. IN SURPRISING CONTRAST, STRESS AND/OR SUBEROYLANILIDE HYDROXAMIC ACID HAD NO EFFECT ON SPINAL NMDA RECEPTOR EXPRESSION OR FUNCTION. THESE DATA REVEAL HISTONE MODIFICATION MODULATES MGLUR2/3 EXPRESSION IN THE SPINAL CORD TO ATTENUATE STRESSINDUCED VISCERAL HYPERSENSITIVITY. HDAC INHIBITORS MAY PROVIDE A POTENTIAL APPROACH TO RELIEVE VISCERAL HYPERSENSITIVITY ASSOCIATED WITH IRRITABLE BOWEL SYNDROME. 2016 12 5657 31 SEX-DEPENDENT PRONOCICEPTIVE ROLE OF SPINAL ALPHA(5) -GABA(A) RECEPTOR AND ITS EPIGENETIC REGULATION IN NEUROPATHIC RODENTS. EXTRASYNAPTIC ALPHA(5) -SUBUNIT CONTAINING GABA(A) (ALPHA(5) -GABA(A) ) RECEPTORS PARTICIPATE IN CHRONIC PAIN. PREVIOUSLY, WE REPORTED A SEX DIFFERENCE IN THE ACTION OF ALPHA(5) -GABA(A) RECEPTORS IN DYSFUNCTIONAL PAIN. HOWEVER, THE UNDERLYING MECHANISMS REMAIN UNKNOWN. THE AIM OF THIS STUDY WAS TO EXAMINE THIS SEXUAL DIMORPHISM IN NEUROPATHIC RODENTS AND THE MECHANISMS INVOLVED. FEMALE AND MALE WISTAR RATS OR ICR MICE WERE SUBJECTED TO NERVE INJURY FOLLOWED BY ALPHA(5) -GABA(A) RECEPTOR INVERSE AGONIST INTRATHECAL ADMINISTRATION, L-655,708. THE DRUG PRODUCED AN ANTIALLODYNIC EFFECT IN NERVE-INJURED FEMALE RATS AND MICE, AND A LOWER EFFECT IN MALES. WE HYPOTHESIZED THAT CHANGES IN ALPHA(5) -GABA(A) RECEPTOR, PROBABLY INFLUENCED BY HORMONAL AND EPIGENETIC STATUS, MIGHT UNDERLIE THIS SEX DIFFERENCE. THUS, WE PERFORMED QPCR AND WESTERN BLOT. NERVE INJURY INCREASED ALPHA(5) -GABA(A) MRNA AND PROTEIN IN FEMALE DORSAL ROOT GANGLIA (DRG) AND DECREASED THEM IN DRG AND SPINAL CORD OF MALES. TO INVESTIGATE THE HORMONAL INFLUENCE OVER ALPHA(5) -GABA(A) RECEPTOR ACTIONS, WE PERFORMED NERVE INJURY TO OVARIECTOMIZED RATS AND RECONSTITUTED THEM WITH 17BETA-ESTRADIOL (E2). OVARIECTOMY ABROGATED L-655,708 ANTIALLODYNIC EFFECT AND E2 RESTORED IT. OVARIECTOMY DECREASED ALPHA(5) -GABA(A) RECEPTOR AND ESTROGEN RECEPTOR ALPHA PROTEIN IN DRG OF NEUROPATHIC FEMALE RATS, WHILE E2 ENHANCED THEM. SINCE DNA METHYLATION MIGHT CONTRIBUTE TO ALPHA(5) -GABA(A) RECEPTOR DOWN-REGULATION IN MALES, WE EXAMINED CPG ISLAND DNA METHYLATION OF ALPHA(5) -GABA(A) RECEPTOR CODING GENE THROUGH PYROSEQUENCING. NERVE INJURY INCREASED METHYLATION IN MALE, BUT NOT FEMALE RATS. PHARMACOLOGICAL INHIBITION OF DNA METHYLTRANSFERASES INCREASED ALPHA(5) -GABA(A) RECEPTOR AND ENABLED L-655,708 ANTINOCICEPTIVE EFFECT IN MALE RATS. THESE RESULTS SUGGEST THAT ALPHA(5) -GABA(A) RECEPTOR IS A SUITABLE TARGET TO TREAT CHRONIC PAIN IN FEMALES. 2021 13 3999 32 LOSS OF HDAC3 RESULTS IN NONRECEPTIVE ENDOMETRIUM AND FEMALE INFERTILITY. ENDOMETRIOSIS IS A DISEASE IN WHICH TISSUE THAT NORMALLY GROWS INSIDE THE UTERUS GROWS OUTSIDE THE UTERUS AND CAUSES CHRONIC PELVIC PAIN AND INFERTILITY. HOWEVER, THE EXACT MECHANISMS OF THE PATHOGENESIS OF ENDOMETRIOSIS-ASSOCIATED INFERTILITY ARE UNKNOWN. EPIGENETIC DYSREGULATION HAS RECENTLY BEEN IMPLICATED IN INFERTILITY. HERE, WE REPORT A REDUCTION OF HISTONE DEACETYLASE 3 (HDAC3) PROTEIN AMOUNTS IN EUTOPIC ENDOMETRIUM OF INFERTILE WOMEN WITH ENDOMETRIOSIS COMPARED TO A CONTROL GROUP. TO INVESTIGATE THE EFFECT OF HDAC3 LOSS IN THE UTERUS, WE GENERATED MICE WITH CONDITIONAL ABLATION OF HDAC3 IN PROGESTERONE RECEPTOR (PGR)-POSITIVE CELLS (PGR(CRE/+)HDAC3(F/F) ; HDAC3(D/D) ). LOSS OF HDAC3 IN THE UTERUS OF MICE RESULTS IN INFERTILITY DUE TO IMPLANTATION FAILURE AND DECIDUALIZATION DEFECT. EXPRESSION MICROARRAY AND CHIP-SEQ ANALYSES IDENTIFIED COL1A1 AND COL1A2 AS DIRECT TARGETS OF HDAC3 IN BOTH MICE AND HUMANS. REDUCTION OF HDAC3 ABROGATED DECIDUALIZATION IN A PRIMARY CULTURE OF HUMAN ENDOMETRIAL STROMAL CELLS (HESCS) SIMILAR TO THAT OBSERVED IN INFERTILE PATIENTS WITH ENDOMETRIOSIS. WHEREAS ATTENUATION OF HDAC3 RESULTED IN P300 RECRUITMENT TO COL1A1 AND COL1A2 GENES IN THE UTERUS OF MICE AS WELL AS HESCS, INHIBITION OF P300 PERMITTED HESCS TO UNDERGO DECIDUALIZATION. COLLECTIVELY, WE FOUND ATTENUATION OF HDAC3 AND OVEREXPRESSION OF COLLAGEN TYPE I IN THE EUTOPIC ENDOMETRIUM OF INFERTILE PATIENTS WITH ENDOMETRIOSIS. HDAC3 LOSS CAUSED A DEFECT OF DECIDUALIZATION THROUGH THE ABERRANT TRANSCRIPTIONAL ACTIVATION OF COL1A1 AND COL1A2 GENES IN MICE AND COL1A1 AND COL1A2 GENES IN HUMANS. OUR RESULTS SUGGEST THAT HDAC3 IS CRITICAL FOR ENDOMETRIAL RECEPTIVITY AND DECIDUALIZATION. 2019 14 6612 25 ULTRA-LOW-DOSE NALOXONE ENHANCES THE ANTINOCICEPTIVE EFFECT OF MORPHINE IN PTX-TREATED RATS: REGULATION ON GLOBAL HISTONE METHYLATION. OBJECTIVE: EPIGENETIC REPROGRAMMING MAY HAVE A POSSIBLE ROLE IN NEUROPATHIC PAIN DEVELOPMENT; THE PRESENT STUDY EXAMINED THE GLOBAL PATTERNS OF LYSINE HISTONE MODIFICATION. IN THIS SERIAL STUDY WE ANALYZED THE LEVELS OF HISTONE 3 LYSINE 4 MONOMETHYLATION, HISTONE 3 LYSINE 4 DIMETHYLATION, AND HISTONE 3 LYSINE 9 TRIMETHYLATION IN PERTUSSIS TOXIN (PTX)-INDUCED THERMAL HYPERALGESIC RAT SPINAL CORDS. METHODS: MALE WISTAR RATS IMPLANTED WITH AN INTRATHECAL CATHETER RECEIVED A SINGLE INTRATHECAL PTX (1 MUG IN 5 MUL SALINE) INJECTION. FOUR DAYS LATER, THEY WERE RANDOMLY ASSIGNED TO RECEIVE EITHER A SINGLE INJECTION OF SALINE, OR ULTRA-LOW-DOSE NALOXONE (15 NG IN 5 MUL SALINE), FOLLOWED BY MORPHINE (10 MUG IN 5 MUL SALINE) INJECTION 30 MINUTES LATER. RESULTS: THE RESULTS SHOWED THAT PTX INJECTION INDUCED THERMAL HYPERALGESIA AND SIGNIFICANT INCREASE OF GLOBAL HISTONE METHYLATION IN THE SPINAL CORDS. INTRATHECAL MORPHINE ALONE DID NOT AFFECT THE THERMAL HYPERALGESIA AND GLOBAL HISTONE METHYLATION. IN CONTRAST, INTRATHECAL ADMINISTRATION OF ULTRA-LOW-DOSE NALOXONE PLUS MORPHINE SIGNIFICANTLY ATTENUATED THE PTX-INDUCED THERMAL HYPERALGESIA AND DOWN-REGULATED THE GLOBAL HISTONE METHYLATION. CONCLUSION: THE RESULTS SUGGEST THAT ULTRA-LOW-DOSE NALOXONE MIGHT BE CLINICAL VALUABLE FOR NEUROPATHIC PAIN MANAGEMENT VIA REGULATING GLOBAL HISTONE MODIFICATION. 2012 15 1320 32 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 16 1854 34 ELEVATED SEMINAL PLASMA ESTRADIOL AND EPIGENETIC INACTIVATION OF ESR1 AND ESR2 IS ASSOCIATED WITH CP/CPPS. CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME (CP/CPPS) IS ASSOCIATED WITH URINARY TRACT SYMPTOMS AND HORMONAL IMBALANCES AMONGST OTHERS. THE HETEROGENEOUS CLINICAL PRESENTATION, UNEXPLORED MOLECULAR BACKGROUND AND LACK OF PROSTATE BIOPSIES COMPLICATE THERAPY. HERE, USING LIQUID BIOPSIES, WE PERFORMED A COMPREHENSIVE TRANSLATIONAL STUDY ON MEN DIAGNOSED WITH CP/CPPS TYPE III (N= 50; MEDIAN AGE 39.8, RANGE 23-65) AND AGE-MATCHED CONTROLS (N= 61; MEDIAN AGE 36.8, RANGE 20-69), CONSIDERING BIOCHEMICAL PARAMETERS OF BLOOD AND EJACULATES, AND EPIGENETIC REGULATION OF THE ESTROGEN RECEPTOR GENES (ESR1 AND ESR2) IN LEUKOCYTES ISOLATED FROM BLOOD (SYSTEMIC REGULATION) AND IN SOMATIC CELLS ISOLATED FROM EJACULATES (LOCAL REGULATION). WE FOUND ELEVATED 17BETA-ESTRADIOL (E(2)) LEVELS IN SEMINAL PLASMA, BUT NOT IN BLOOD PLASMA, THAT WAS SIGNIFICANTLY ASSOCIATED WITH CP/CPPS AND IMPAIRED URINARY TRACT SYMPTOMS. IN EJACULATED SOMATIC CELLS OF CP/CPPS PATIENTS WE FOUND THAT ESR1 AND ESR2 WERE BOTH SIGNIFICANTLY HIGHER METHYLATED IN CPG-PROMOTERS AND EXPRESSIONALLY DOWN-REGULATED IN COMPARISON TO CONTROLS. MAST CELLS ARE REPORTED TO CONTRIBUTE TO CP/CPPS AND ARE ESTROGEN RESPONSIVE. CONSISTENT WITH THIS, WE FOUND THAT E(2) -TREATMENT OF HUMAN MAST CELL LINES (HMC-1 AND LAD2) RESULTED IN ALTERED CYTOKINE AND CHEMOKINE EXPRESSION. INTERESTINGLY, IN HMC-1 CELLS, POSSESSING EPIGENETICALLY INACTIVATED ESR1 AND ESR2, E(2) -TREATMENT LED TO A REDUCED TRANSCRIPTION OF A NUMBER OF INFLAMMATORY GENES. OVERALL, THESE DATA SUGGEST THAT ELEVATED LOCAL E(2) LEVELS ASSOCIATE WITH AN EPIGENETIC DOWN-REGULATION OF THE ESTROGEN RECEPTORS AND HAVE A PROMINENT ROLE IN CP/CPPS. INVESTIGATING E(2) LEVELS IN SEMEN COULD THEREFORE SERVE AS A PROMISING BIOMARKER TO SELECT PATIENTS FOR ESTROGEN TARGETED THERAPY. 2018 17 3459 29 HYPOMETHYLATION OF NERVE GROWTH FACTOR (NGF) PROMOTES BINDING OF C/EBPALPHA AND CONTRIBUTES TO INFLAMMATORY HYPERALGESIA IN RATS. BACKGROUND: CHRONIC PAIN USUALLY ACCOMPANIED BY TISSUE DAMAGE AND INFLAMMATION. HOWEVER, THE PATHOGENESIS OF CHRONIC PAIN REMAINS UNCLEAR. METHODS: WE INVESTIGATED THE ROLE OF NERVE GROWTH FACTOR (NGF) IN CHRONIC INFLAMMATORY PAIN INDUCED BY COMPLETE FREUND'S ADJUVANT (CFA), EXPLORED THE METHYLATION STATUS OF CPG ISLANDS IN THE PROMOTER REGION OF THE NGF GENE, AND CLARIFIED THE FUNCTION AND MECHANISM OF C/EBPALPHA-NGF SIGNALING PATHWAY FROM EPIGENETIC PERSPECTIVE IN THE CHRONIC INFLAMMATORY PAIN MODEL. RESULTS: CFA INDUCED SIGNIFICANT HYPERALGESIA AND CONTINUOUS UPREGULATION OF NGF MRNA AND PROTEIN LEVELS IN THE L4-6 DORSAL ROOT GANGLIONS (DRGS) IN RATS. HYPOMETHYLATION OF CPG ISLANDS OCCURRED IN THE NGF GENE PROMOTER REGION AFTER CFA TREATMENT. AT THE SAME TIME, THE MIR-29B EXPRESSION LEVEL WAS SIGNIFICANTLY INCREASED, WHILE THE DNA METHYLTRANSFERASE 3B (DNMT3B) LEVEL REDUCED SIGNIFICANTLY. MOREOVER, CFA TREATMENT PROMOTED BINDING OF C/EBPALPHA TO THE NGF GENE PROMOTER REGION AND C/EBPALPHA SIRNA TREATMENT OBVIOUSLY DECREASED EXPRESSION OF NGF LEVELS AND ALSO ALLEVIATE INFLAMMATORY HYPERALGESIA SIGNIFICANTLY IN RATS. CONCLUSION: COLLECTIVELY, THE RESULTS INDICATED THAT CFA LEADS TO THE UPREGULATION OF MIR-29B LEVEL, WHICH REPRESSES THE EXPRESSION OF DNMT3B, ENHANCES THE DEMETHYLATION OF THE NGF GENE PROMOTER REGION, AND PROMOTES THE BINDING OF C/EBPALPHA WITH THE NGF GENE PROMOTER, THUS RESULTS IN THE UPREGULATION OF NGF GENE EXPRESSION AND MAINTENANCE OF CHRONIC INFLAMMATORY PAIN. 2020 18 3741 32 INSIGHT INTO THE POTENTIAL MECHANISMS OF ENDOCRINE DISRUPTION BY DIETARY PHYTOESTROGENS IN THE CONTEXT OF THE ETIOPATHOGENESIS OF ENDOMETRIOSIS. PHYTOESTROGENS (PES) ARE ESTROGEN-LIKE NONSTEROIDAL COMPOUNDS DERIVED FROM PLANTS (E.G., NUTS, SEEDS, FRUITS, AND VEGETABLES) AND FUNGI THAT ARE STRUCTURALLY SIMILAR TO 17BETA-ESTRADIOL. PES BIND TO ALL TYPES OF ESTROGEN RECEPTORS, INCLUDING ERALPHA AND ERBETA RECEPTORS, NUCLEAR RECEPTORS, AND A MEMBRANE-BOUND ESTROGEN RECEPTOR KNOWN AS THE G PROTEIN-COUPLED ESTROGEN RECEPTOR (GPER). AS ENDOCRINE-DISRUPTING CHEMICALS (EDCS) WITH PRO- OR ANTIESTROGENIC PROPERTIES, PES CAN POTENTIALLY DISRUPT THE HORMONAL REGULATION OF HOMEOSTASIS, RESULTING IN DEVELOPMENTAL AND REPRODUCTIVE ABNORMALITIES. HOWEVER, A LACK OF PES IN THE DIET DOES NOT RESULT IN THE DEVELOPMENT OF DEFICIENCY SYMPTOMS. TO PROPERLY ASSESS THE BENEFITS AND RISKS ASSOCIATED WITH THE USE OF A PE-RICH DIET, IT IS NECESSARY TO DISTINGUISH BETWEEN ENDOCRINE DISRUPTION (ENDOCRINE-MEDIATED ADVERSE EFFECTS) AND NONSPECIFIC EFFECTS ON THE ENDOCRINE SYSTEM. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT DISEASE OF UNKNOWN ETIOPATHOGENESIS, IN WHICH TISSUE SIMILAR TO THE LINING OF THE UTERUS (THE ENDOMETRIUM) GROWS OUTSIDE OF THE UTERUS WITH SUBSEQUENT COMPLICATIONS BEING MANIFESTED AS A RESULT OF LOCAL INFLAMMATORY REACTIONS. ENDOMETRIOSIS AFFECTS 10-15% OF WOMEN OF REPRODUCTIVE AGE AND IS ASSOCIATED WITH CHRONIC PELVIC PAIN, DYSMENORRHEA, DYSPAREUNIA, AND INFERTILITY. IN THIS REVIEW, THE ENDOCRINE-DISRUPTIVE ACTIONS OF PES ARE REVIEWED IN THE CONTEXT OF ENDOMETRIOSIS TO DETERMINE WHETHER A PE-RICH DIET HAS A POSITIVE OR NEGATIVE EFFECT ON THE RISK AND COURSE OF ENDOMETRIOSIS. 2023 19 3832 27 INVOLVEMENT OF SPINAL SIRT1 IN DEVELOPMENT OF CHRONIC CONSTRICTION INJURY INDUCED NEUROPATHIC PAIN IN RATS. IT IS KNOWN THAT THE EPIGENETIC PROCESS OF HISTONE ACETYLATION IS INVOLVED IN THE NEUROPATHIC PAIN. THE AIM OF THIS STUDY WAS TO DETERMINE WHETHER SIRTUIN TYPE 1 (SIRT1), AN NAD(+) DEPENDENT DEACETYLASE, AFFECTED ALLODYNIA AND HYPERALGESIA IN NEUROPATHIC PAIN. THE NEUROPATHIC PAIN MODEL WAS ESTABLISHED BY LIGATURE OF THE RIGHT SCIATIC NERVE TO INDUCE CHRONIC CONSTRICTION INJURY (CCI) IN RATS. HISTONE ACETYLTRANSFERASE (HAT) ACTIVITY WAS INCREASED AND, AND HISTONE DEACETYLASE (HDAC) ACTIVITY WAS DECLINED IN TISSUE OF THE SPINAL DORSA HORN IN CCI RATES BY MEANS OF ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA). THE PERSISTENT HYPERALGESIA AND ALLODYNIA CAUSED BY CCI WERE ASSOCIATED WITH DOWNREGULATION OF SIRT1 AND UPREGULATION OF ACETYLATED-H3 (AC-H3) IN TISSUE OF THE SPINAL CORD BY WESTERN BLOT ASSAY, WHICH WAS REVERSED AFTER INTRATHECAL INJECTION OF SIRT1 AGONIST SRT1720. SRT1720 TREATMENT ACHIEVED ANALGESIC THROUGH INHIBITING THE ACETYLATION OF NUCLEAR FACTOR KAPPA B (NF-KAPPAB) AND BLOCKING THE RELEASES OF THE INFLAMMATORY FACTORS INCLUDING TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) AND INTERLEUKIN (IL)-6 BY MEANS OF WESTERN BLOT AND REAL-TIME QUANTITATIVE PCR (RT-PCR), RESPECTIVELY. TAKEN TOGETHER, THESE DATA SUGGEST THAT SIRT1 IN THE SPINAL CORD PLAYS AN IMPORTANT ROLE IN THE NEUROPATHIC PAIN IN THE RAT MODEL. 2018 20 1809 28 EFFECTS OF ANTIPSYCHOTIC DRUGS ON THE EPIGENETIC MODIFICATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR GENE EXPRESSION IN THE HIPPOCAMPI OF CHRONIC RESTRAINT STRESS RATS. RECENT STUDIES HAVE SHOWN THAT ANTIPSYCHOTIC DRUGS HAVE EPIGENETIC EFFECTS. HOWEVER, THE EFFECTS OF ANTIPSYCHOTIC DRUGS ON HISTONE MODIFICATION REMAIN UNCLEAR. THEREFORE, WE INVESTIGATED THE EFFECTS OF ANTIPSYCHOTIC DRUGS ON THE EPIGENETIC MODIFICATION OF THE BDNF GENE IN THE RAT HIPPOCAMPUS. RATS WERE SUBJECTED TO CHRONIC RESTRAINT STRESS (6 H/D FOR 21 D) AND THEN WERE ADMINISTERED WITH EITHER OLANZAPINE (2 MG/KG) OR HALOPERIDOL (1 MG/KG). THE LEVELS OF HISTONE H3 ACETYLATION AND MECP2 BINDING AT BDNF PROMOTER IV WERE ASSESSED WITH CHROMATIN IMMUNOPRECIPITATION ASSAYS. THE MRNA LEVELS OF TOTAL BDNF WITH EXON IV, HDAC5, DNMT1, AND DNMT3A WERE ASSESSED WITH A QUANTITATIVE RT-PCR PROCEDURE. CHRONIC RESTRAINT STRESS RESULTED IN THE DOWNREGULATION OF TOTAL AND EXON IV BDNF MRNA LEVELS AND A DECREASE IN HISTONE H3 ACETYLATION AND AN INCREASE IN MECP2 BINDING AT BDNF PROMOTER IV. FURTHERMORE, THERE WERE ROBUST INCREASES IN THE EXPRESSION OF HDAC5 AND DNMTS. OLANZAPINE ADMINISTRATION LARGELY PREVENTED THESE CHANGES. THE ADMINISTRATION OF HALOPERIDOL HAD NO EFFECT. THESE FINDINGS SUGGEST THAT THE ANTIPSYCHOTIC DRUG OLANZAPINE INDUCED HISTONE MODIFICATION OF BDNF GENE EXPRESSION IN THE HIPPOCAMPUS AND THAT THESE EPIGENETIC ALTERATIONS MAY REPRESENT ONE OF THE MECHANISMS UNDERLYING THE ACTIONS OF ANTIPSYCHOTIC DRUGS. 2018