1 6654 131 UPDATE ON PSEUDOEXFOLIATION SYNDROME PATHOGENESIS AND ASSOCIATIONS WITH INTRAOCULAR PRESSURE, GLAUCOMA AND SYSTEMIC DISEASES. PURPOSE OF REVIEW: PSEUDOEXFOLIATION (PEX) SYNDROME IS A COMMON AGE-RELATED DISORDER AFFECTING INTRAOCULAR AND EXTRAOCULAR TISSUES. THIS REVIEW FOCUSES ON RECENT PUBLICATIONS RELATED WITH THE PATHOGENESIS AND ASSOCIATIONS OF PEX SYNDROME WITH INTRAOCULAR PRESSURE (IOP), GLAUCOMA AND SYSTEMIC DISEASES. RECENT FINDINGS: IN PEX TISSUES, EXPRESSION OF LYSYL OXIDASE-LIKE 1 (LOXL1) WAS FOUND TO BE MARKEDLY DYSREGULATED. THIS MAY ADVERSELY AFFECT ELASTIN METABOLISM AND LEAD TO ELASTOTIC ALTERATION IN TISSUES SUCH AS LAMINA CRIBROSA. THERE IS INCREASING EVIDENCE THAT CELLULAR STRESS CONDITIONS AND LOW-GRADE CHRONIC INFLAMMATORY PROCESSES ARE INVOLVED IN THE PATHOGENESIS OF PEX. ALTHOUGH THERE IS AN INCREASED RISK FOR GLAUCOMA DEVELOPMENT IN PATIENTS WITH PEX AND OCULAR HYPERTENSION AS COMPARED WITH NON-PEX PATIENTS WITH OCULAR HYPERTENSION, LOXL1 SINGLE NUCLEOTIDE POLYMORPHISMS WERE NOT ASSOCIATED WITH INTRAOCULAR PRESSURE (IOP) DIFFERENCES. LACK OF ASSOCIATION OF PEX WITH ALL-CAUSE MORTALITY OR DEMENTIA HAS BEEN REPORTED RECENTLY. THE ASSOCIATION WITH VASCULAR DISEASES IS NOT CONSISTENT AMONG DIFFERENT STUDIES. SUMMARY: DESPITE THE HIGH PREVALENCE OF THE LOXL1 VARIANTS IN THE GENERAL POPULATION, A MUCH LOWER PROPORTION OF THE POPULATION DEVELOPS PEX, SUGGESTING THAT IN ADDITION TO LOXL1, OTHER GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO THE DEVELOPMENT OF PEX. ALSO, LOXL1 CANNOT HELP TO IDENTIFY THOSE WITH PEX AT INCREASED RISK FOR GLAUCOMA DEVELOPMENT. INCREASED RISK FOR GLAUCOMA DEVELOPMENT IN PEX PATIENTS WHO PRESENT WITH INCREASED IOP MAY BE RELATED TO OTHER FACTORS BEYOND IOP, CONTRIBUTING TO INCREASED VULNERABILITY OF THE OPTIC NERVE TO GLAUCOMA DEVELOPMENT IN THE PRESENCE OF PEX. 2015 2 1904 33 ENHANCED RETINAL GANGLION CELL SURVIVAL IN GLAUCOMA BY HYPOXIC POSTCONDITIONING AFTER DISEASE ONSET. THE NEUROPROTECTIVE EFFICACY OF ADAPTIVE EPIGENETICS, WHEREIN BENEFICIAL GENE EXPRESSION CHANGES ARE INDUCED BY NONHARMFUL "CONDITIONING" STIMULI, IS NOW WELL ESTABLISHED IN SEVERAL ACUTE, PRECLINICAL CENTRAL NERVOUS SYSTEM INJURY MODELS. RECENTLY, IN A MOUSE MODEL OF GLAUCOMA, WE DEMONSTRATED RETINAL GANGLION CELL (RGC) PROTECTION BY REPETITIVELY "PRECONDITIONING" WITH HYPOXIA PRIOR TO DISEASE ONSET, INDICATING AN EPIGENETIC APPROACH MAY ALSO YIELD BENEFITS IN CHRONIC NEURODEGENERATIVE DISEASE. HEREIN, WE DETERMINED WHETHER PRESENTING THE REPETITIVE HYPOXIC STIMULUS AFTER DISEASE INITIATION [REPETITIVE HYPOXIC "POSTCONDITIONING" (RH-POST)] COULD AFFORD SIMILAR FUNCTIONAL AND MORPHOLOGIC PROTECTION AGAINST GLAUCOMATOUS RGC INJURY. CHRONIC ELEVATIONS IN INTRAOCULAR PRESSURE (IOP) WERE INDUCED UNILATERALLY IN ADULT MALE C57BL/6 MICE BY EPISCLERAL VEIN LIGATION. MICE WERE RANDOMIZED TO AN RH-POST [1 H OF SYSTEMIC HYPOXIA (11% OXYGEN) EVERY OTHER DAY, STARTING 4 DAYS AFTER IOP ELEVATION] OR AN UNTREATED CONTROL GROUP. AFTER 3 WEEKS OF EXPERIMENTAL GLAUCOMA, THE 21-27% REDUCTION AND 5-25% PROLONGATION IN FLASH VISUAL-EVOKED POTENTIAL AMPLITUDES AND LATENCIES, RESPECTIVELY, AND THE 30% IMPAIRMENT IN VISUAL ACUITY WERE ROBUSTLY IMPROVED IN RH-POST-TREATED MICE, AS WAS THE 17% LOSS IN RGC SOMA NUMBER AND 20% REDUCTION IN AXON INTEGRITY. THESE PROTECTIVE EFFECTS WERE OBSERVED WITHOUT RH-POST AFFECTING IOP. THE PRESENT FINDINGS DEMONSTRATE THAT FUNCTIONAL AND MORPHOLOGIC PROTECTION OF RGCS CAN BE REALIZED BY STIMULATING EPIGENETIC RESPONSES DURING THE EARLY STAGES OF DISEASE, AND THUS CONSTITUTE A NEW CONCEPTUAL APPROACH TO GLAUCOMA THERAPEUTICS. 2015 3 123 33 A SYSTEMATIC REVIEW, META-ANALYSIS, AND NETWORK ANALYSIS OF DIAGNOSTIC MICRORNAS IN GLAUCOMA. GLAUCOMA IS A CHRONIC NEURODEGENERATIVE PROCESS OF THE OPTIC NERVE THAT IS THE LEADING CAUSE OF BLINDNESS WORLDWIDE, AND EARLY DIAGNOSIS OF THE DISEASE COULD GREATLY AFFECT PATIENTS' PROGNOSES. THE PATHOPHYSIOLOGY OF GLAUCOMA IS COMPLICATED BY A COMBINATION OF GENETIC AND EPIGENETIC FACTORS. DECIPHERING THE EARLY DIAGNOSTIC BIOMARKERS IN GLAUCOMA COULD ATTENUATE THE DISEASE'S GLOBAL BURDEN AND HELP US UNDERSTAND THE EXACT MECHANISMS INVOLVED IN GLAUCOMA. THE MICRORNAS ARE MEMBERS OF A LARGER FAMILY OF NON-CODING RNAS THAT PLAY AN ESSENTIAL ROLE IN THE EPIGENETIC BASIS OF GLAUCOMA. A SYSTEMATIC STUDY AND META-ANALYSIS OF DIAGNOSTIC MICRORNAS IN GLAUCOMA, JOINTLY WITH NETWORK ANALYSIS OF TARGET GENES, WERE CARRIED OUT ON PUBLISHED PAPERS ASSESSING DIFFERENTIALLY EXPRESSED MICRORNAS IN HUMAN SUBJECTS. IN TOTAL, 321 ARTICLES WERE FOUND, AND, AFTER SCREENING, SIX STUDIES WERE ELIGIBLE FOR FURTHER ANALYSIS. 52 DIFFERENTIALLY EXPRESSED MICRORNAS WERE FOUND, OF WHICH 28 AND 24 WERE UP-REGULATED AND DOWN-REGULATED, RESPECTIVELY. ONLY 12 MICRORNAS WERE QUALIFIED FOR META-ANALYSIS, WITH OVERALL SENSITIVITY AND SPECIFICITY OF 80% AND 74%, RESPECTIVELY. THEN, USING NETWORK ANALYSIS, IT BECAME APPARENT THAT THE VEGF-A, AKT1, CXCL12, AND HRAS GENES WERE THE MOST IMPORTANT TARGETS FOR THE MICRORNAS. PERTURBATIONS IN WNT SIGNALING, PROTEIN TRANSPORT, AND EXTRACELLULAR MATRIX ORGANIZATION PATHWAYS WERE DISCOVERED TO BE IMPORTANT IN THE ETIOLOGY OF GLAUCOMA USING THE COMMUNITY DETECTION APPROACH. THIS STUDY TRIES TO UNCOVER THE PROMISING MICRORNAS AND THEIR TARGET GENES THAT GOVERN THE EPIGENETICS OF GLAUCOMA. 2023 4 2770 30 EXTENDING INJURY- AND DISEASE-RESISTANT CNS PHENOTYPES BY REPETITIVE EPIGENETIC CONDITIONING. SIGNIFICANT REDUCTIONS IN THE EXTENT OF ACUTE INJURY IN THE CNS CAN BE ACHIEVED BY EXPOSURE TO DIFFERENT PRECONDITIONING STIMULI, BUT THE DURATION OF THE INDUCED PROTECTIVE PHENOTYPE IS TYPICALLY SHORT-LASTING, AND THUS IS DEEMED AS LIMITING ITS CLINICAL APPLICABILITY. EXTENDING THE PERIOD OVER WHICH SUCH ADAPTIVE EPIGENETIC CHANGES PERSIST - IN EFFECT, EXPANDING CONDITIONING'S "THERAPEUTIC WINDOW" - WOULD SIGNIFICANTLY BROADEN THE POTENTIAL APPLICATIONS OF SUCH A TREATMENT APPROACH IN PATIENTS. THE FREQUENCY OF THE CONDITIONING STIMULUS MAY HOLD THE KEY. WHILE TRANSIENT (1-3 DAYS) PROTECTION AGAINST CNS ISCHEMIC INJURY IS WELL ESTABLISHED PRECLINICALLY FOLLOWING A SINGLE PRECONDITIONING STIMULUS, REPETITIVELY PRESENTING PRECONDITIONING STIMULI EXTENDS THE DURATION OF ISCHEMIC TOLERANCE BY MANY WEEKS. MOREOVER, REPETITIVE INTERMITTENT POSTCONDITIONING ENHANCES POST-ISCHEMIC RECOVERY METRICS AND IMPROVES LONG-TERM SURVIVAL. INTERMITTENT CONDITIONING IS ALSO EFFICACIOUS FOR PREVENTING OR DELAYING INJURY IN PRECLINICAL MODELS OF CHRONIC NEURODEGENERATIVE DISEASE, AND FOR PROMOTING LONG-LASTING FUNCTIONAL IMPROVEMENTS IN A NUMBER OF OTHER PATHOLOGIES AS WELL. ALTHOUGH THE DETAILED MECHANISMS UNDERLYING THESE PROTRACTED KINDS OF NEUROPLASTICITY REMAIN LARGELY UNSTUDIED, ACCUMULATING EMPIRICAL EVIDENCE SUPPORTS THE CONTENTION THAT ALL OF THESE ADAPTIVE PHENOTYPES ARE EPIGENETICALLY MEDIATED. GOING FORWARD, ADDITIONAL PRECLINICAL DEMONSTRATIONS OF THE ABILITY TO INDUCE SUSTAINED BENEFICIAL PHENOTYPES THAT REDUCE THE BURDEN OF ACUTE AND CHRONIC NEURODEGENERATION, AND EXPERIMENTAL INTERROGATIONS OF THE REGULATORY CONSTRUCTS RESPONSIBLE FOR THESE EPIGENETIC RESPONSES, WILL ACCELERATE THE IDENTIFICATION OF NOT ONLY EFFICACIOUS BUT ALSO PRACTICAL, ADAPTIVE EPIGENETICS-BASED TREATMENTS FOR INDIVIDUALS WITH NEUROLOGICAL DISEASE. 2015 5 6023 28 THE BET PROTAC INHIBITOR DBET6 PROTECTS AGAINST RETINAL DEGENERATION AND INHIBITS THE CGAS-STING IN RESPONSE TO LIGHT DAMAGE. BACKGROUND: CHRONIC INFLAMMATION SIGNIFICANTLY CONTRIBUTES TO PHOTORECEPTOR DEATH IN BLINDING RETINAL DISEASES SUCH AS AGE-RELATED MACULAR DEGENERATION (AMD) AND RETINITIS PIGMENTOSA (RP). BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT ACT AS KEY PROINFLAMMATORY FACTORS. WE RECENTLY FOUND THE FIRST-GENERATION BET INHIBITOR JQ1 ALLEVIATED SODIUM IODATE-INDUCED RETINAL DEGENERATION BY SUPPRESSING CGAS-STING INNATE IMMUNITY. HERE, WE INVESTIGATED THE EFFECTS AND MECHANISM OF DBET6, A PROTEOLYSIS?TARGETING CHIMERA (PROTAC) SMALL MOLECULE THAT SELECTIVELY DEGRADES BET BY THE UBIQUITIN?PROTEASOME SYSTEM, IN LIGHT-INDUCED RETINAL DEGENERATION. METHODS: MICE WERE EXPOSED TO BRIGHT LIGHT TO INDUCE RETINAL DEGENERATION, AND THE ACTIVATION OF CGAS-STING WAS DETERMINED BY RNA-SEQUENCING AND MOLECULAR BIOLOGY. RETINAL FUNCTION, MORPHOLOGY, PHOTORECEPTOR VIABILITY AND RETINAL INFLAMMATION WERE EXAMINED IN THE PRESENCE AND ABSENCE OF DBET6 TREATMENT. RESULTS: INTRAPERITONEAL INJECTION OF DBET6 LED TO THE RAPID DEGRADATION OF BET PROTEIN IN THE RETINA WITHOUT DETECTABLE TOXICITY. DBET6 IMPROVED RETINAL RESPONSIVENESS AND VISUAL ACUITY AFTER LIGHT DAMAGE (LD). DBET6 ALSO REPRESSED LD-INDUCED RETINAL MACROPHAGES/MICROGLIA ACTIVATION, MULLER CELL GLIOSIS, PHOTORECEPTOR DEATH AND RETINAL DEGENERATION. ANALYSIS OF SINGLE-CELL RNA-SEQUENCING RESULTS REVEALED CGAS-STING COMPONENTS WERE EXPRESSED IN RETINAL MICROGLIA. LD LED TO DRAMATIC ACTIVATION OF THE CGAS-STING PATHWAY, WHEREAS DBET6 SUPPRESSED LD-INDUCED STING EXPRESSION IN REACTIVE MACROPHAGES/MICROGLIA AND THE RELATED INFLAMMATORY RESPONSE. CONCLUSIONS: THIS STUDY INDICATES TARGETED DEGRADATION OF BET BY DBET6 EXERTS NEUROPROTECTIVE EFFECTS BY INHIBITING CGAS-STING IN REACTIVE RETINAL MACROPHAGES/MICROGLIA, AND IS EXPECTED TO BECOME A NEW STRATEGY FOR TREATMENT OF RETINAL DEGENERATION. 2023 6 4275 32 MICROGLIA ACTIVATION IN THE MIDBRAIN OF THE HUMAN NEONATE: THE EFFECT OF PERINATAL HYPOXIC-ISCHEMIC INJURY. PERINATAL HYPOXIA-ISCHEMIA (PHI) IS A MAJOR RISK FACTOR FOR THE DEVELOPMENT OF NEUROPSYCHIATRIC DEFICITS LATER IN LIFE. WE PREVIOUSLY REPORTED THAT AFTER PROLONGED PHI, THE DOPAMINERGIC NEURONS OF THE HUMAN NEONATE SHOWED A DRAMATIC REDUCTION OF TYROSINE HYDROXYLASE (TH) IN THE SUBSTANTIA NIGRA, WITHOUT IMPORTANT SIGNS OF NEURONAL DEGENERATION DESPITE THE SIGNIFICANT REDUCTION IN THEIR CELL SIZE. SINCE MICROGLIA ACTIVATION COULD PRECEDE NEURONAL DEATH, WE NOW INVESTIGATED 2 MICROGLIA ACTIVATION MARKERS, IONIZED CALCIUM-BINDING ADAPTER MOLECULE 1 (IBA1), AND THE PHAGOCYTOSIS MARKER CD68. THE HIGHEST IBA1 IMMUNOREACTIVITY WAS FOUND IN NEONATES WITH NEUROPATHOLOGICAL LESIONS OF SEVERE/ABRUPT PHI, WHILE THE LOWEST IN SUBJECTS WITH MODERATE/PROLONGED OR OLDER PHI. SUBJECTS WITH VERY SEVERE/PROLONGED OR CHRONIC PHI SHOWED AN INCREASED IBA1 EXPRESSION AND VERY ACTIVATED MICROGLIAL MORPHOLOGY. HEAVY ATTACHMENT OF MICROGLIA ON TH NEURONS AND REMARKABLE EXPRESSION OF CD68 WERE ALSO OBSERVED INDICATING PHAGOCYTOSIS IN THIS GROUP. FEMALES APPEAR TO EXPRESS MORE IBA1 THAN MALES, SUGGESTING A GENDER DIFFERENCE IN MICROGLIA MATURATION AND IMMUNE REACTIVITY AFTER PHI INSULT. PHI-INDUCED MICROGLIAL "PRIMING" DURING THE SENSITIVE FOR BRAIN DEVELOPMENT PERINATAL/NEONATAL PERIOD, IN COMBINATION WITH GENETIC OR OTHER EPIGENETIC FACTORS, COULD PREDISPOSE THE SURVIVORS TO NEUROPSYCHIATRIC DISORDERS LATER IN LIFE, POSSIBLY THROUGH A SEXUALLY DIMORPHIC WAY. 2022 7 2473 26 EPIGENETIC TREATMENTS OF ADULT RATS PROMOTE RECOVERY FROM VISUAL ACUITY DEFICITS INDUCED BY LONG-TERM MONOCULAR DEPRIVATION. IN MAMMALS THE DEVELOPMENT OF THE VISUAL SYSTEM MAY BE ALTERED DURING A SENSITIVE PERIOD BY MODIFYING THE VISUAL INPUT TO ONE OR BOTH EYES. THESE PLASTIC PROCESSES ARE REDUCED AFTER THE END OF THE SENSITIVE PERIOD. IT HAS BEEN PROPOSED THAT REDUCED LEVELS OF PLASTICITY ARE AT THE BASIS OF THE LACK OF RECOVERY FROM EARLY VISUAL DEPRIVATION OBSERVED IN ADULT ANIMALS. A DEVELOPMENTAL DOWNREGULATION OF EXPERIENCE-DEPENDENT REGULATION OF HISTONE ACETYLATION HAS RECENTLY BEEN FOUND TO BE INVOLVED IN CLOSING THE SENSITIVE PERIOD. THEREFORE, WE TESTED WHETHER PHARMACOLOGICAL EPIGENETIC TREATMENTS INCREASING HISTONE ACETYLATION COULD BE USED TO REVERSE VISUAL ACUITY DEFICITS INDUCED BY LONG-TERM MONOCULAR DEPRIVATION INITIATED DURING THE SENSITIVE PERIOD. WE FOUND THAT CHRONIC INTRAPERITONEAL ADMINISTRATION OF VALPROIC ACID OR SODIUM BUTYRATE (TWO DIFFERENT HISTONE DEACETYLASES INHIBITORS) TO LONG-TERM MONOCULARLY DEPRIVED ADULT RATS COUPLED WITH REVERSE LID-SUTURING CAUSED A COMPLETE RECOVERY OF VISUAL ACUITY, TESTED ELECTROPHYSIOLOGICALLY AND BEHAVIORALLY. THUS, MANIPULATIONS OF THE EPIGENETIC MACHINERY CAN BE USED TO PROMOTE FUNCTIONAL RECOVERY FROM EARLY ALTERATIONS OF SENSORY INPUT IN THE ADULT CORTEX. 2010 8 3736 32 INNATE IMMUNE TOLERANCE IN MICROGLIA DOES NOT IMPACT ON CENTRAL NERVOUS SYSTEM PRION DISEASE. PRION DISEASES SUCH AS CREUTZFELDT-JAKOB DISEASE IN HUMANS, BOVINE SPONGIFORM ENCEPHALOPATHY IN CATTLE, AND SCRAPIE IN SHEEP, ARE INFECTIOUS AND CHRONIC NEURODEGENERATIVE DISEASES TO WHICH THERE ARE NO CURES. INFECTION WITH PRIONS IN THE CENTRAL NERVOUS SYSTEM (CNS) ULTIMATELY CAUSES EXTENSIVE NEURODEGENERATION, AND THIS IS ACCOMPANIED BY PROMINENT MICROGLIAL AND ASTROCYTIC ACTIVATION IN AFFECTED REGIONS. THE MICROGLIA ARE THE CNS MACROPHAGES AND HELP MAINTAIN NEURONAL HOMEOSTASIS, CLEAR DEAD OR DYING CELLS AND PROVIDE DEFENSE AGAINST PATHOGENS. THE MICROGLIA ALSO PROVIDE NEUROPROTECTION DURING CNS PRION DISEASE, BUT THEIR PRO-INFLAMMATORY ACTIVATION MAY EXACERBATE THE DEVELOPMENT OF THE NEUROPATHOLOGY. INNATE IMMUNE TOLERANCE INDUCED BY CONSECUTIVE SYSTEMIC BACTERIAL LIPOPOLYSACCHARIDE (LPS) TREATMENT CAN INDUCE LONG-TERM EPIGENETIC CHANGES IN THE MICROGLIA IN THE BRAIN THAT SEVERAL MONTHS LATER CAN DAMPEN THEIR RESPONSIVENESS TO SUBSEQUENT LPS TREATMENT AND IMPEDE THE DEVELOPMENT OF NEURITIC DAMAGE IN A TRANSGENIC MOUSE MODEL OF ALZHEIMER'S DISEASE-LIKE PATHOLOGY. WE THEREFORE REASONED THAT INNATE IMMUNE TOLERANCE IN MICROGLIA MIGHT SIMILARLY IMPEDE THE SUBSEQUENT DEVELOPMENT OF CNS PRION DISEASE. TO TEST THIS HYPOTHESIS GROUPS OF MICE WERE FIRST INFECTED WITH PRIONS BY INTRACEREBRAL INJECTION, AND 35 DAYS LATER GIVEN FOUR CONSECUTIVE SYSTEMIC INJECTIONS WITH LPS TO INDUCE INNATE IMMUNE TOLERANCE. OUR DATA SHOW THAT CONSECUTIVE SYSTEMIC LPS TREATMENT DID NOT AFFECT THE SUBSEQUENT DEVELOPMENT OF CNS PRION DISEASE. OUR DATA SUGGESTS INNATE IMMUNE TOLERANCE IN MICROGLIA DOES NOT INFLUENCE THE SUBSEQUENT ONSET OF PRION DISEASE-INDUCED NEUROPATHOLOGY IN MICE, DESPITE PREVIOUSLY PUBLISHED EVIDENCE OF THIS EFFECT IN AN ALZHEIMER'S DISEASE MOUSE MODEL. 2022 9 5280 27 PROMOTING SYMPATHOVAGAL BALANCE IN MULTIPLE SCLEROSIS; PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES. ACCUMULATED EVIDENCE SUGGESTS THAT CARDIOVASCULAR AUTONOMIC NERVOUS SYSTEM (ANS) DYSFUNCTION MAY BE THE UNDERLYING CAUSE OF MANY MS CLINICAL PRESENTATIONS, INCLUDING NEURODEGENERATION AND REDUCED RESPONSE TO IMMUNOMODULATORY THERAPIES, DEPRESSION, FATIGUE AND SLEEP DISORDERS, MIGRAINE, OSTEOPOROSIS, AND CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY, THE NEWER MS VASCULAR ETIOLOGY. WE HAVE RECENTLY DESCRIBED THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS WITH THE POTENTIAL INFLUENCING ANS ACTIVITY, AND THE INTERACTIONS AMONG THESE FACTORS. THIS REVIEW EXPANDS UPON PREVIOUS ONES, DESCRIBING THE PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES THAT COULD BE ADOPTED TO PREVENT AND MINIMIZE THE DETERIORATION IN ANS FUNCTION, PROMOTING A STATE OF SYMPATHOVAGAL BALANCE. HOWEVER, THESE STRATEGIES SHOULD NOT BE APPLIED AS "ONE SIZE FITS ALL", BUT SHOULD TAKE INTO ACCOUNT THE NATURE AND THE DEGREE OF ANS DYSFUNCTION. THESE STRATEGIES WOULD BE EFFECTIVE IN IMPROVING ANS FUNCTION NOT ONLY IN MS, BUT ALSO IN OTHER AUTOIMMUNE AND NEURODEGENERATIVE DISEASES, WHERE THE DYSFUNCTION OF THIS SYSTEM PLAYS A ROLE. 2016 10 1430 22 DIFFERENTIAL EXPRESSION OF SOX11 AND BDNF MRNA ISOFORMS IN THE INJURED AND REGENERATING NERVOUS SYSTEMS. IN BOTH THE CENTRAL NERVOUS SYSTEM (CNS) AND THE PERIPHERAL NERVOUS SYSTEM (PNS), AXONAL INJURY INDUCES CHANGES IN NEURONAL GENE EXPRESSION. IN THE PNS, A RELATIVELY WELL-CHARACTERIZED ALTERATION IN TRANSCRIPTIONAL ACTIVATION IS KNOWN TO PROMOTE AXONAL REGENERATION. THIS TRANSCRIPTIONAL CASCADE INCLUDES THE NEUROTROPHIN BDNF AND THE TRANSCRIPTION FACTOR SOX11. ALTHOUGH BOTH MOLECULES ACT TO FACILITATE SUCCESSFUL AXON REGENERATION IN THE PNS, THIS PROCESS DOES NOT OCCUR IN THE CNS. THE PRESENT STUDY EXAMINES THE DIFFERENTIAL EXPRESSION OF SOX11 AND BDNF MRNA ISOFORMS IN THE PNS AND CNS USING THREE EXPERIMENTAL PARADIGMS AT DIFFERENT TIME POINTS: (I) THE ACUTELY INJURED CNS (RETINA AFTER OPTIC NERVE CRUSH) AND PNS (DORSAL ROOT GANGLION AFTER SCIATIC NERVE CRUSH), (II) A CNS REGENERATION MODEL (RETINA AFTER OPTIC NERVE CRUSH AND INDUCED REGENERATION); AND (III) THE RETINA DURING A CHRONIC FORM OF CENTRAL NEURODEGENERATION (THE DBA/2J GLAUCOMA MODEL). WE FIND AN INITIAL INCREASE OF SOX11 IN BOTH PNS AND CNS AFTER INJURY; HOWEVER, THE EXPRESSION OF BDNF ISOFORMS IS HIGHER IN THE PNS RELATIVE TO THE CNS. SUSTAINED UPREGULATION OF SOX11 IS SEEN IN THE INJURED RETINA FOLLOWING REGENERATION TREATMENT, WHILE THE EXPRESSION OF TWO BDNF MRNA ISOFORMS IS SUPPRESSED. FURTHERMORE, TWO ISOFORMS OF SOX11 WITH DIFFERENT 3'UTR LENGTHS ARE PRESENT IN THE RETINA, AND THE LONG ISOFORM IS SPECIFICALLY UPREGULATED IN LATER STAGES OF GLAUCOMA. THESE RESULTS PROVIDE INSIGHT INTO THE MOLECULAR CASCADES ACTIVE DURING AXONAL INJURY AND REGENERATION IN MAMMALIAN NEURONS. 2017 11 6364 27 THE ROLE OF LONG NONCODING RNAS IN NEURODEGENERATIVE DISEASES. LONG NONCODING RNAS (LNCRNAS) ARE TRANSCRIPTS WITH LOW PROTEIN-CODING POTENTIAL BUT OCCUPY A LARGE PART OF TRANSCRIPTIONAL OUTPUT. THEIR ROLES INCLUDE REGULATING GENE EXPRESSION AT THE EPIGENETIC, TRANSCRIPTIONAL, AND POST-TRANSCRIPTIONAL LEVEL IN CELLULAR HOMEOSTASIS. HOWEVER, LNCRNA STUDIES ARE STILL IN THEIR INFANCY AND THE FUNCTIONS OF THE VAST MAJORITY OF LNCRNA TRANSCRIPTS REMAIN UNKNOWN. IT IS GENERALLY KNOWN THAT THE FUNCTION OF THE HUMAN NERVOUS SYSTEM LARGELY RELIES ON THE PRECISE REGULATION OF GENE EXPRESSION. VARIOUS STUDIES HAVE SHOWN THAT LNCRNAS HAVE A SIGNIFICANT IMPACT ON NORMAL NEURAL DEVELOPMENT AND ON THE DEVELOPMENT AND PROGRESSION OF NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE FOCUSED ON RECENT STUDIES ASSOCIATED WITH LNCRNAS IN NEURODEGENERATIVE DISEASES, INCLUDING ALZHEIMER'S DISEASE (AD), PARKINSON'S DISEASE (PD), HUNTINGTON'S DISEASE (HD), AMYOTROPHIC LATERAL SCLEROSIS (ALS), MULTIPLE SYSTEM ATROPHY (MSA), FRONTOTEMPORAL LOBAR DEGENERATION (FTLD), AND GLAUCOMA. GLAUCOMA, CAUSED BY UNEXPLAINED GANGLION CELL LESION AND APOPTOSIS, IS NOW LABELED AS A CHRONIC NEURODEGENERATIVE DISORDER [1], AND THEREFORE, WE DISCUSSED THE ASSOCIATION OF LNCRNAS WITH GLAUCOMA AS WELL. WE ILLUSTRATE THE ROLE OF SOME SPECIFIC LNCRNAS, WHICH MAY PROVIDE NEW INSIGHTS INTO OUR UNDERSTANDING OF THE ETIOLOGY AND PATHOPHYSIOLOGY OF THE NEURODEGENERATIVE DISEASES MENTIONED ABOVE. 2017 12 809 27 CHANGES IN CLASS I AND IIB HDACS BY DELTA-OPIOID IN CHRONIC RAT GLAUCOMA MODEL. PURPOSE: THIS STUDY DETERMINES IF DELTA-OPIOID RECEPTOR AGONIST (I.E. SNC-121)-INDUCED EPIGENETIC CHANGES VIA REGULATION OF HISTONE DEACETYLASES (HDACS) FOR RETINAL GANGLION CELL (RGC) NEUROPROTECTION IN GLAUCOMA MODEL. METHODS: INTRAOCULAR PRESSURE WAS RAISED IN RAT EYES BY INJECTING 2M HYPERTONIC SALINE INTO THE LIMBAL VEINS. SNC-121 (1 MG/KG; I.P.) WAS ADMINISTERED TO THE ANIMALS FOR 7 DAYS. RETINAS WERE COLLECTED AT DAYS 7 AND 42, POST-INJURY FOLLOWED BY MEASUREMENT OF HDAC ACTIVITIES, MRNA, AND PROTEIN EXPRESSION BY ENZYME ASSAY, QUANTITATIVE REAL-TIME PCR (QRT-PCR), WESTERN BLOTTING, AND IMMUNOHISTOCHEMISTRY. RESULTS: THE VISUAL ACUITY, CONTRAST SENSITIVITY, AND PATTERN ELECTRORETINOGRAMS (ERGS) WERE DECLINED IN OCULAR HYPERTENSIVE ANIMALS, WHICH WERE SIGNIFICANTLY IMPROVED BY SNC-121 TREATMENT. CLASS I AND IIB HDACS ACTIVITIES WERE SIGNIFICANTLY INCREASED AT DAYS 7 AND 42 IN OCULAR HYPERTENSIVE ANIMALS. THE MRNA AND PROTEIN EXPRESSION OF HDAC 1 WAS INCREASED BY 1.33 +/- 0.07-FOLD AND 20.2 +/- 2.7%, HDAC 2 BY 1.4 +/- 0.05-FOLD AND 17.0 +/- 2.4%, HDAC 3 BY 1.4 +/- 0.06-FOLD AND 17.4 +/- 3.4%, AND HDAC 6 BY 1.5 +/- 0.09-FOLD AND 15.1 +/- 3.3% AT DAY 7, POST-INJURY. BOTH THE MRNA AND PROTEIN EXPRESSION OF HDACS WERE POTENTIATED FURTHER AT DAY 42 IN OCULAR HYPERTENSIVE ANIMALS. HDAC ACTIVITIES, MRNA, AND PROTEIN EXPRESSION WERE BLOCKED BY SNC-121 TREATMENT AT DAYS 7 AND 42 IN OCULAR HYPERTENSIVE ANIMALS. CONCLUSIONS: DATA SUGGESTS THAT CLASS I AND IIB HDACS ARE ACTIVATED AND UPREGULATED DURING EARLY STAGES OF GLAUCOMA. EARLY INTERVENTION WITH DELTA-OPIOID RECEPTOR ACTIVATION RESULTED IN THE PROLONGED SUPPRESSION OF CLASS I AND IIB HDACS ACTIVITIES AND EXPRESSION, WHICH MAY, IN PART, PLAY A CRUCIAL ROLE IN RGC NEUROPROTECTION. 2020 13 232 22 ADAPTIVE PLASTICITY IN THE RETINA: PROTECTION AGAINST ACUTE INJURY AND NEURODEGENERATIVE DISEASE BY CONDITIONING STIMULI. ALTHOUGH BOTH PRECLINICAL AND CLINICAL CONDITIONING STUDIES IN HEART AND BRAIN LEAD THE FIELD OF CONDITIONING MEDICINE, INVESTIGATIONS OF RETINAL CONDITIONING STILL NUMBER MORE THAN 100. IN THIS BRIEF REVIEW, WE HIGHLIGHT FINDINGS TO DATE FROM ANIMAL AND CELL CULTURE MODELS OF CONDITIONING THAT PROVIDE DEMONSTRATED PROTECTION IN ACUTE AND CHRONIC RETINAL INJURY AND DISEASE MODELS. THE MULTITUDE OF STIMULI USED TO CONDITION THE RETINA, THE SIGNALING MEDIATORS AND PATHWAYS IDENTIFIED, AND THE INJURY- AND DISEASE-RESILIENT PHENOTYPES DOCUMENTED ARE DISCUSSED HEREIN, ALONG WITH OUR RECOMMENDATIONS FOR THE KINDS OF STUDIES NEEDED TO CONTINUE TO ADVANCE THIS PROMISING FIELD. IN OUR VIEW, THE ROBUST PROTECTION AFFORDED BY THESE ADAPTIVE EPIGENETIC RESPONSES TO CONDITIONING STRESS PROVIDES SIGNIFICANT INCENTIVES FOR BOTH FURTHERING OUR INVESTMENT IN BENCH RESEARCH AND UNDERWRITING CLINICAL TRIALS, SO THAT THE FULL POTENTIAL OF THIS THERAPY CAN BE REALIZED. 2018 14 1459 34 DISORDERED APP METABOLISM AND NEUROVASCULATURE IN TRAUMA AND AGING: COMBINED RISKS FOR CHRONIC NEURODEGENERATIVE DISORDERS. TRAUMATIC BRAIN INJURY (TBI), ADVANCED AGE, AND CEREBRAL VASCULAR DISEASE ARE FACTORS CONFERRING INCREASED RISK FOR LATE ONSET ALZHEIMER'S DISEASE (AD). THESE CONDITIONS ARE ALSO RELATED PATHOLOGICALLY THROUGH MULTIPLE INTERACTING MECHANISMS. THE HALLMARK PATHOLOGY OF AD CONSISTS OF PATHOLOGICAL AGGREGATES OF AMYLOID-BETA (ABETA) PEPTIDES AND TAU PROTEINS. THESE MOLECULES ARE ALSO INVOLVED IN NEUROPATHOLOGY OF SEVERAL OTHER CHRONIC NEURODEGENERATIVE DISEASES, AND ARE UNDER INTENSE INVESTIGATION IN THE AFTERMATH OF TBI AS POTENTIAL CONTRIBUTORS TO THE RISK FOR DEVELOPING AD AND CHRONIC TRAUMATIC ENCEPHALOPATHY (CTE). THE PATHOLOGY OF TBI IS COMPLEX AND DEPENDENT ON INJURY SEVERITY, AGE-AT-INJURY, AND LENGTH OF TIME BETWEEN INJURY AND NEUROPATHOLOGICAL EVALUATION. IN ADDITION, THE MECHANISMS INFLUENCING PATHOLOGY AND RECOVERY AFTER TBI LIKELY INVOLVE GENETIC/EPIGENETIC FACTORS AS WELL AS ADDITIONAL DISORDERS OR COMORBID STATES RELATED TO AGE AND CENTRAL AND PERIPHERAL VASCULAR HEALTH. IN THIS REGARD, DYSFUNCTION OF THE AGING NEUROVASCULAR SYSTEM COULD BE AN IMPORTANT LINK BETWEEN TBI AND CHRONIC NEURODEGENERATIVE DISEASES, EITHER AS A PRECIPITATING EVENT OR RELATED TO ACCUMULATION OF AD-LIKE PATHOLOGY WHICH IS AMPLIFIED IN THE CONTEXT OF AGING. THUS WITH ADVANCED AGE AND VASCULAR DYSFUNCTION, TBI CAN TRIGGER SELF-PROPAGATING CYCLES OF NEURONAL INJURY, PATHOLOGICAL PROTEIN AGGREGATION, AND SYNAPTIC LOSS RESULTING IN CHRONIC NEURODEGENERATIVE DISEASE. IN THIS REVIEW WE DISCUSS EVIDENCE SUPPORTING TBI AND AGING AS DUAL, INTERACTING RISK FACTORS FOR AD, AND THE ROLE OF ABETA AND CEREBRAL VASCULAR DYSFUNCTION IN THIS RELATIONSHIP. EVIDENCE IS DISCUSSED THAT ABETA IS INVOLVED IN CYTO- AND SYNAPTO-TOXICITY AFTER SEVERE TBI, AND THAT ITS CHRONIC EFFECTS ARE POTENTIATED BY AGING AND IMPAIRED CEREBRAL VASCULAR FUNCTION. FROM A THERAPEUTIC PERSPECTIVE, WE EMPHASIZE THAT IN THE FIELDS OF TBI- AND AGING-RELATED NEURODEGENERATION PROTECTIVE STRATEGIES SHOULD INCLUDE PRESERVATION OF NEUROVASCULAR FUNCTION. 2017 15 6648 37 UPDATE ON DIAGNOSIS, PATHOPHYSIOLOGY, AND MANAGEMENT OF DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD) IS A CHRONIC COMPLICATION OF DIABETES MELLITUS WHICH MAY EVENTUALLY LEAD TO END-STAGE KIDNEY DISEASE (ESKD). DESPITE IMPROVEMENTS IN GLYCAEMIC CONTROL AND BLOOD PRESSURE MANAGEMENT WITH RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) BLOCKADE, THE CURRENT THERAPY CANNOT COMPLETELY HALT DKD PROGRESSION TO ESKD IN SOME PATIENTS. DKD IS A HETEROGENEOUS DISEASE ENTITY IN TERMS OF ITS CLINICAL MANIFESTATIONS, HISTOPATHOLOGY AND THE RATE OF PROGRESSION, WHICH MAKES IT DIFFICULT TO DEVELOP EFFECTIVE THERAPEUTICS. IT WAS FORMERLY CONSIDERED THAT ALBUMINURIA PRECEDED KIDNEY FUNCTION DECLINE IN DKD, BUT RECENT EPIDEMIOLOGICAL STUDIES REVEALED THAT A DISTINCT GROUP OF PATIENTS PRESENTED KIDNEY DYSFUNCTION WITHOUT DEVELOPING ALBUMINURIA. OTHER COMORBIDITIES, SUCH AS HYPERTENSION, OBESITY AND GOUT, ALSO AFFECT THE CLINICAL COURSE OF DKD. THE PATHOPHYSIOLOGY OF DKD IS COMPLEX AND MULTIFACTORIAL, INVOLVING BOTH METABOLIC AND HAEMODYNAMIC FACTORS. THESE INDUCE ACTIVATION OF INTRACELLULAR SIGNALLING PATHWAYS, OXIDATIVE STRESS, HYPOXIA, DYSREGULATED AUTOPHAGY AND EPIGENETIC CHANGES, WHICH RESULT IN KIDNEY INFLAMMATION AND FIBROSIS. RECENTLY, TWO GROUPS OF ANTIDIABETIC DRUGS, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS AND GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS, WERE DEMONSTRATED TO PROVIDE RENOPROTECTION ON TOP OF THEIR GLUCOSE-LOWERING EFFECTS. SEVERAL OTHER THERAPEUTIC AGENTS ARE ALSO BEING DEVELOPED AND EVALUATED IN CLINICAL TRIALS. 2021 16 4109 35 MECHANISMS AND DRUG THERAPY OF PULMONARY HYPERTENSION AT HIGH ALTITUDE. PULMONARY VASOCONSTRICTION REPRESENTS A PHYSIOLOGICAL ADAPTIVE MECHANISM TO HIGH ALTITUDE. IF EXAGGERATED, HOWEVER, IT IS ASSOCIATED WITH IMPORTANT MORBIDITY AND MORTALITY. RECENT MECHANISTIC STUDIES USING SHORT-TERM ACUTE HIGH ALTITUDE EXPOSURE HAVE PROVIDED INSIGHT INTO THE IMPORTANCE OF DEFECTIVE VASCULAR ENDOTHELIAL AND RESPIRATORY EPITHELIAL NITRIC OXIDE (NO) SYNTHESIS, INCREASED ENDOTHELIN-1 BIOAVAILABILITY, AND OVERACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM IN CAUSING EXAGGERATED HYPOXIC PULMONARY HYPERTENSION IN HUMANS. BASED ON THESE STUDIES, DRUGS THAT INCREASE NO BIOAVAILABILITY, ATTENUATE ENDOTHELIN-1 INDUCED PULMONARY VASOCONSTRICTION, OR PREVENT EXAGGERATED SYMPATHETIC ACTIVATION HAVE BEEN SHOWN TO BE USEFUL FOR THE TREATMENT/PREVENTION OF EXAGGERATED PULMONARY HYPERTENSION DURING ACUTE SHORT-TERM HIGH ALTITUDE EXPOSURE. THE MECHANISMS UNDERPINNING CHRONIC PULMONARY HYPERTENSION IN HIGH ALTITUDE DWELLERS ARE LESS WELL UNDERSTOOD, BUT RECENT EVIDENCE SUGGESTS THAT THEY DIFFER IN SOME ASPECTS FROM THOSE INVOLVED IN SHORT-TERM ADAPTATION TO HIGH ALTITUDE. THESE DIFFERENCES HAVE CONSEQUENCES FOR THE CHOICE OF THE TREATMENT FOR CHRONIC PULMONARY HYPERTENSION AT HIGH ALTITUDE. FINALLY, RECENT DATA INDICATE THAT FETAL PROGRAMMING OF PULMONARY VASCULAR DYSFUNCTION IN OFFSPRING OF PREECLAMPSIA AND CHILDREN GENERATED BY ASSISTED REPRODUCTIVE TECHNOLOGIES REPRESENTS A NOVEL AND FREQUENT CAUSE OF PULMONARY HYPERTENSION AT HIGH ALTITUDE. IN ANIMAL MODELS OF FETAL PROGRAMMING OF HYPOXIC PULMONARY HYPERTENSION, EPIGENETIC MECHANISMS PLAY A ROLE, AND TARGETING OF THESE MECHANISMS WITH DRUGS LOWERS PULMONARY ARTERY PRESSURE. IF EPIGENETIC MECHANISMS ALSO ARE OPERATIONAL IN THE FETAL PROGRAMMING OF PULMONARY VASCULAR DYSFUNCTION IN HUMANS, SUCH DRUGS MAY BECOME NOVEL TOOLS FOR THE TREATMENT OF HYPOXIC PULMONARY HYPERTENSION. 2013 17 537 38 ASYMPTOMATIC HYPERURICEMIA: IS IT REALLY ASYMPTOMATIC? PURPOSE OF REVIEW: HYPERURICEMIA IS HIGHLY PREVALENT, AFFECTING APPROXIMATELY 38 MILLION INDIVIDUALS IN THE UNITED STATES. HOWEVER, THE SIGNIFICANCE OF ASYMPTOMATIC HYPERURICEMIA - HYPERURICEMIA IN THE ABSENCE OF GOUT - CONTINUES TO BE DEBATED. RECENT FINDINGS: ASYMPTOMATIC HYPERURICEMIA RESULTS IN MONOSODIUM URATE CRYSTAL DEPOSITION IN TISSUES, WHICH MAY PROMOTE CHRONIC INFLAMMATION. INTRACELLULARLY, HYPERURICEMIA INHIBITS THE MASTER REGULATOR ADENOSINE MONOPHOSPHATE (AMP)-ASSOCIATED PROTEIN KINASE AND MAY CONDITION INNATE IMMUNE RESPONSES THROUGH DURABLE EPIGENETIC MODIFICATIONS. AT THE POPULATION LEVEL, ASYMPTOMATIC HYPERURICEMIA IS ASSOCIATED WITH MULTIPLE COMORBIDITIES, INCLUDING HYPERTENSION, CHRONIC KIDNEY DISEASE, CORONARY ARTERY DISEASE, AND DIABETES; LIMITATIONS OF THESE STUDIES INCLUDE THAT MOST ARE RETROSPECTIVE AND SOME DO NOT RIGOROUSLY DISTINGUISH BETWEEN ASYMPTOMATIC HYPERURICEMIA AND GOUT. TREATMENT STUDIES SUGGEST THAT URATE LOWERING MAY REDUCE THE RISK OF INCIDENCE OR PROGRESSION OF SOME OF THESE COMORBIDITIES; UNFORTUNATELY, MANY OF THESE TREATMENT STUDIES ARE SMALL OR FLAWED, AND NOT ALL STUDY RESULTS ARE CONSISTENT. SUMMARY: ACCUMULATING EVIDENCE SUGGESTS THAT ASYMPTOMATIC HYPERURICEMIA CONTRIBUTES TO THE COMORBIDITIES WITH WHICH IT ASSOCIATES AND THAT PROPER ASYMPTOMATIC HYPERURICEMIA TREATMENT MAY REDUCE FUTURE RISK. ADDITIONAL PROSPECTIVE TRIALS ARE NEEDED TO DEFINITELY ESTABLISH CAUSALITY AND SUPPORT DECISION-MAKING AS TO WHETHER, AND WHICH PATIENTS WITH ASYMPTOMATIC HYPERURICEMIA WOULD WARRANT URATE-LOWERING TREATMENT. 2020 18 6375 41 THE ROLE OF NEURO-IMMUNE INTERACTION IN CHRONIC PAIN CONDITIONS; FUNCTIONAL SOMATIC SYNDROME, NEUROGENIC INFLAMMATION, AND PERIPHERAL NEUROPATHY. FUNCTIONAL SOMATIC SYNDROMES ARE INCREASINGLY DIAGNOSED IN CHRONICALLY ILL PATIENTS PRESENTING WITH AN ARRAY OF SYMPTOMS NOT ATTRIBUTED TO PHYSICAL AILMENTS. CONDITIONS SUCH AS CHRONIC FATIGUE SYNDROME, FIBROMYALGIA SYNDROME, OR IRRITABLE BOWEL SYNDROME ARE COMMON DISORDERS THAT BELONG IN THIS BROAD CATEGORY. SUCH SYNDROMES ARE CHARACTERISED BY THE PRESENCE OF ONE OR MULTIPLE CHRONIC SYMPTOMS INCLUDING WIDESPREAD MUSCULOSKELETAL PAIN, FATIGUE, SLEEP DISORDERS, AND ABDOMINAL PAIN, AMONGST OTHER ISSUES. SYMPTOMS ARE BELIEVED TO RELATE TO A COMPLEX INTERACTION OF BIOLOGICAL AND PSYCHOSOCIAL FACTORS, WHERE A DEFINITE AETIOLOGY HAS NOT BEEN ESTABLISHED. THEORIES SUGGEST CAUSATIVE PATHWAYS BETWEEN THE IMMUNE AND NERVOUS SYSTEMS OF AFFECTED INDIVIDUALS WITH SEVERAL RISK FACTORS IDENTIFIED IN PATIENTS PRESENTING WITH ONE OR MORE FUNCTIONAL SYNDROMES. RISK FACTORS INCLUDING STRESS AND CHILDHOOD TRAUMA ARE NOW RECOGNISED AS IMPORTANT CONTRIBUTORS TO CHRONIC PAIN CONDITIONS. EMOTIONAL, PHYSICAL, AND SEXUAL ABUSE DURING CHILDHOOD IS CONSIDERED A SEVERE STRESSOR HAVING A HIGH PREVALENCE IN FUNCTIONAL SOMATIC SYNDROME SUFFERS. SUCH TRAUMA PERMANENTLY ALTERS THE BIOLOGICAL STRESS RESPONSE OF THE SUFFERS LEADING TO NEUROEXCITATORY AND OTHER NERVE ISSUES ASSOCIATED WITH CHRONIC PAIN IN ADULTS. TRAUMATIC AND CHRONIC STRESS RESULTS IN EPIGENETIC CHANGES IN STRESS RESPONSE GENES, WHICH ULTIMATELY LEADS TO DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY AXIS, THE AUTONOMIC NERVOUS SYSTEM, AND THE IMMUNE SYSTEM MANIFESTING IN A BROAD ARRAY OF SYMPTOMS. IMPORTANTLY, THESE SYSTEMS ARE KNOWN TO BE DYSREGULATED IN PATIENTS SUFFERING FROM FUNCTIONAL SOMATIC SYNDROME. FUNCTIONAL SOMATIC SYNDROMES ARE ALSO HIGHLY PREVALENT CO-MORBIDITIES OF PSYCHIATRIC CONDITIONS, MOOD DISORDERS, AND ANXIETY. CONSEQUENTLY, THIS REVIEW AIMS TO PROVIDE INSIGHT INTO THE ROLE OF THE NERVOUS SYSTEM AND IMMUNE SYSTEM IN CHRONIC PAIN DISORDERS ASSOCIATED WITH THE MUSCULOSKELETAL SYSTEM, AND CENTRAL AND PERIPHERAL NERVOUS SYSTEMS. 2022 19 5690 32 SILENCING OF FEM1CR3 GENE EXPRESSION IN THE DBA/2J MOUSE PRECEDES RETINAL GANGLION CELL DEATH AND IS ASSOCIATED WITH HISTONE DEACETYLASE ACTIVITY. PURPOSE: DOWNREGULATION OF NORMAL GENE EXPRESSION IN DYING RETINAL GANGLION CELLS HAS BEEN DOCUMENTED IN BOTH ACUTE AND CHRONIC MODELS OF OPTIC NERVE DISEASE. THE AUTHORS EXAMINED THE MECHANISM AND TIMING OF THIS PHENOMENON IN DBA/2J MICE, USING GENETICALLY MODIFIED SUBSTRAINS OF THIS INBRED LINE. METHODS: DBA/2J MICE, DOUBLY CONGENIC FOR THE BAX MUTANT ALLELE AND THE GANGLION CELL REPORTER GENE FEM1C(ROSA3) (R3), WERE EVALUATED TO ELUCIDATE THE TIMING OF LOSS OF NORMAL GENE EXPRESSION DURING THE APOPTOTIC PROCESS. THE LOCALIZATION OF HISTONE DEACETYLASE 3 (HDAC3) AND NUCLEAR HISTONE H4 ACETYLATION WERE EXAMINED BY IMMUNOFLUORESCENCE IN DYING CELLS. THE ROLE OF HDACS IN GENE SILENCING DURING GLAUCOMA WAS INTERROGATED USING THE GLOBAL HDAC INHIBITOR TRICHOSTATIN A (TSA). RESULTS: SILENCING OF THE R3 ALLELE OCCURRED IN BAX(-/-) GANGLION CELLS, INDICATING THAT THIS PROCESS PRECEDED THE COMMITTED STEP OF THE INTRINSIC APOPTOTIC PATHWAY. WEEKLY TSA TREATMENT, BETWEEN THE AGES OF 6 AND 10 MONTHS, WAS ABLE TO ATTENUATE THE LOSS OF R3 EXPRESSION IN THE RETINA, BUT HAD NO EFFECT ON OPTIC NERVE DEGENERATION. DYING CELLS IN AGING DBA/2J MICE EXHIBITED NUCLEAR LOCALIZATION OF HDAC3 AND A DECREASE IN THE LEVEL OF H4 ACETYLATION. CONCLUSIONS: RETINAL GANGLION CELLS EXHIBIT A LOSS OF NORMAL GENE EXPRESSION AS AN EARLY (PRE-BAX INVOLVEMENT) PART OF THEIR APOPTOTIC PROGRAM DURING GLAUCOMATOUS DEGENERATION. THIS PROCESS CAN BE AMELIORATED, BUT NOT COMPLETELY BLOCKED, USING HDAC INHIBITORS. EPIGENETIC CHANGES TO ACTIVE CHROMATIN, SUCH AS DEACETYLATION, MAY BE MEDIATED BY HDAC3 IN DYING NEURONS. 2012 20 244 42 ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), ENVIRONMENT, EXPOSOME AND EPIGENETICS: A MOLECULAR PERSPECTIVE OF POSTNATAL NORMAL SPINAL GROWTH AND THE ETIOPATHOGENESIS OF AIS WITH CONSIDERATION OF A NETWORK APPROACH AND POSSIBLE IMPLICATIONS FOR MEDICAL THERAPY. GENETIC FACTORS ARE BELIEVED TO PLAY AN IMPORTANT ROLE IN THE ETIOLOGY OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS). DISCORDANT FINDINGS FOR MONOZYGOTIC (MZ) TWINS WITH AIS SHOW THAT ENVIRONMENTAL FACTORS INCLUDING DIFFERENT INTRAUTERINE ENVIRONMENTS ARE IMPORTANT IN ETIOLOGY, BUT WHAT THESE ENVIRONMENTAL FACTORS MAY BE IS UNKNOWN. RECENT EVIDENCE FOR COMMON CHRONIC NON-COMMUNICABLE DISEASES SUGGESTS EPIGENETIC DIFFERENCES MAY UNDERLIE MZ TWIN DISCORDANCE, AND BE THE LINK BETWEEN ENVIRONMENTAL FACTORS AND PHENOTYPIC DIFFERENCES. DNA METHYLATION IS ONE IMPORTANT EPIGENETIC MECHANISM OPERATING AT THE INTERFACE BETWEEN GENOME AND ENVIRONMENT TO REGULATE PHENOTYPIC PLASTICITY WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. THE WORD EXPOSOME REFERS TO THE TOTALITY OF ENVIRONMENTAL EXPOSURES FROM CONCEPTION ONWARDS, COMPRISING FACTORS IN EXTERNAL AND INTERNAL ENVIRONMENTS. THE WORD EXPOSOME IS USED HERE ALSO IN RELATION TO PHYSIOLOGIC AND ETIOPATHOGENETIC FACTORS THAT AFFECT NORMAL SPINAL GROWTH AND MAY INDUCE THE DEFORMITY OF AIS. IN NORMAL POSTNATAL SPINAL GROWTH WE PROPOSE A NEW TERM AND CONCEPT, PHYSIOLOGIC GROWTH-PLATE EXPOSOME FOR THE NORMAL PROCESSES PARTICULARLY OF THE INTERNAL ENVIRONMENTS THAT MAY HAVE EPIGENETIC EFFECTS ON GROWTH PLATES OF VERTEBRAE. IN AIS, WE PROPOSE A NEW TERM AND CONCEPT PATHOPHYSIOLOGIC SCOLIOGENIC EXPOSOME FOR THE ABNORMAL PROCESSES IN MOLECULAR PATHWAYS PARTICULARLY OF THE INTERNAL ENVIRONMENT CURRENTLY EXPRESSED AS ETIOPATHOGENETIC HYPOTHESES; THESE ARE SUGGESTED TO HAVE DEFORMING EFFECTS ON THE GROWTH PLATES OF VERTEBRAE AT CELL, TISSUE, STRUCTURE AND/OR ORGAN LEVELS THAT ARE CONSIDERED TO BE EPIGENETIC. NEW RESEARCH IS REQUIRED FOR CHROMATIN MODIFICATIONS INCLUDING DNA METHYLATION IN AIS SUBJECTS AND VERTEBRAL GROWTH PLATES EXCISED AT SURGERY. IN ADDITION, CONSIDERATION IS NEEDED FOR A POSSIBLE NETWORK APPROACH TO ETIOPATHOGENESIS BY CONSTRUCTING AIS DISEASOMES. THESE APPROACHES MAY LEAD THROUGH SCREENING, GENETIC, EPIGENETIC, BIOCHEMICAL, METABOLIC PHENOTYPES AND PHARMACOGENOMIC RESEARCH TO IDENTIFY SUSCEPTIBLE INDIVIDUALS AT RISK AND MODULATE ABNORMAL MOLECULAR PATHWAYS OF AIS. THE POTENTIAL OF EPIGENETIC-BASED MEDICAL THERAPY FOR AIS CANNOT BE ASSESSED AT PRESENT, AND MUST AWAIT NEW RESEARCH DERIVED FROM THE EVALUATION OF EPIGENETIC CONCEPTS OF SPINAL GROWTH IN HEALTH AND DEFORMITY. THE TENETS OUTLINED HERE FOR AIS ARE APPLICABLE TO OTHER MUSCULOSKELETAL GROWTH DISORDERS INCLUDING INFANTILE AND JUVENILE IDIOPATHIC SCOLIOSIS. 2011