1 5408 129 REGULATION AND SIGNALING OF THE GPR17 RECEPTOR IN OLIGODENDROGLIAL CELLS. REMYELINATION, NAMELY, THE FORMATION OF NEW MYELIN SHEATHS AROUND DENUDED AXONS, COUNTERACTS AXONAL DEGENERATION AND RESTORES NEURONAL FUNCTION. CONSIDERABLE ADVANCES HAVE BEEN MADE IN UNDERSTANDING THIS REGENERATIVE PROCESS THAT OFTEN FAILS IN DISEASES LIKE MULTIPLE SCLEROSIS, LEAVING AXONS DEMYELINATED AND VULNERABLE TO DAMAGE, THUS CONTRIBUTING TO DISEASE PROGRESSION. THE IDENTIFICATION OF THE MEMBRANE RECEPTOR GPR17 ON A SUBSET OF OLIGODENDROCYTE PRECURSOR CELLS (OPCS), WHICH MEDIATE REMYELINATION IN THE ADULT CENTRAL NERVOUS SYSTEM (CNS), HAS LED TO A HUGE AMOUNT OF EVIDENCE THAT VALIDATED THIS RECEPTOR AS A NEW ATTRACTIVE TARGET FOR REMYELINATING THERAPIES. HERE, WE SUMMARIZE THE ROLE OF GPR17 IN OPC FUNCTION, MYELINATION AND REMYELINATION, DESCRIBING ITS ATYPICAL PHARMACOLOGY, ITS DOWNSTREAM SIGNALING, AND THE GENETIC AND EPIGENETIC FACTORS MODULATING ITS ACTIVITY. WE ALSO HIGHLIGHT CRUCIAL INSIGHTS INTO GPR17 PATHOPHYSIOLOGY COMING FROM THE DEMONSTRATION THAT OLIGODENDROCYTE INJURY, ASSOCIATED WITH INFLAMMATION IN CHRONIC NEURODEGENERATIVE CONDITIONS, IS INVARIABLY CHARACTERIZED BY ABNORMAL AND PERSISTENT GPR17 UPREGULATION, WHICH, IN TURN, IS ACCOMPANIED BY A BLOCK OF OPCS AT IMMATURE PREMYELINATING STAGES. FINALLY, WE DISCUSS THE CURRENT LITERATURE IN LIGHT OF THE POTENTIAL EXPLOITMENT OF GPR17 AS A THERAPEUTIC TARGET TO PROMOTE REMYELINATION. 2020 2 2882 47 G-PROTEIN-COUPLED RECEPTOR GPR17 REGULATES OLIGODENDROCYTE DIFFERENTIATION IN RESPONSE TO LYSOLECITHIN-INDUCED DEMYELINATION. OLIGODENDROCYTES ARE THE MYELIN-PRODUCING CELLS OF THE CENTRAL NERVOUS SYSTEM (CNS). A VARIETY OF BRAIN DISORDERS FROM "CLASSICAL" DEMYELINATING DISEASES, SUCH AS MULTIPLE SCLEROSIS, STROKE, SCHIZOPHRENIA, DEPRESSION, DOWN SYNDROME AND AUTISM, ARE SHOWN MYELINATION DEFECTS. OLIGODENDROCYTE MYELINATION IS REGULATED BY A COMPLEX INTERPLAY OF INTRINSIC, EPIGENETIC AND EXTRINSIC FACTORS. GPR17 (G PROTEIN-COUPLED RECEPTOR 17) IS A G PROTEIN-COUPLED RECEPTOR, AND HAS BEEN IDENTIFIED TO BE A REGULATOR FOR OLIGODENDROCYTE DEVELOPMENT. HERE, WE DEMONSTRATE THAT THE ABSENCE OF GPR17 ENHANCES REMYELINATION IN VIVO WITH A TOXIN-INDUCED MODEL WHEREBY FOCAL DEMYELINATED LESIONS ARE GENERATED IN SPINAL CORD WHITE MATTER OF ADULT MICE BY LOCALIZED INJECTION OF LPC(L-A-LYSOPHOSPHATIDYLCHOLINE). THE INCREASED EXPRESSION OF THE ACTIVATED FORM OF ERK1/2 (PHOSPHO-ERK1/2) IN LESION AREAS SUGGESTED THE POTENTIAL ROLE OF ERK1/2 ACTIVITY ON THE GPR17-DEPENDENT MODULATION OF MYELINATION. THE ABSENCE OF GPR17 ENHANCES REMYELINATION IS CORRELATE WITH THE ACTIVATED ERK1/2 (PHOSPHO-ERK1/2).BEING A MEMBRANE RECEPTOR, GPR17 REPRESENTS AN IDEAL DRUGGABLE TARGET TO BE EXPLOITED FOR INNOVATIVE REGENERATIVE APPROACHES TO ACUTE AND CHRONIC CNS DISEASES. 2018 3 2856 35 FROM METHYLATION TO MYELINATION: EPIGENOMIC AND TRANSCRIPTOMIC PROFILING OF CHRONIC INACTIVE DEMYELINATED MULTIPLE SCLEROSIS LESIONS. IN THE PROGRESSIVE PHASE OF MULTIPLE SCLEROSIS (MS), THE HAMPERED DIFFERENTIATION CAPACITY OF OLIGODENDROCYTE PRECURSOR CELLS (OPCS) EVENTUALLY RESULTS IN REMYELINATION FAILURE. WE HAVE PREVIOUSLY SHOWN THAT DNA METHYLATION OF ID2/ID4 IS HIGHLY INVOLVED IN OPC DIFFERENTIATION AND REMYELINATION. IN THIS STUDY, WE TOOK AN UNBIASED APPROACH BY DETERMINING GENOME-WIDE DNA METHYLATION PATTERNS WITHIN CHRONICALLY DEMYELINATED MS LESIONS AND INVESTIGATED HOW CERTAIN EPIGENETIC SIGNATURES RELATE TO OPC DIFFERENTIATION CAPACITY. WE COMPARED GENOME-WIDE DNA METHYLATION AND TRANSCRIPTIONAL PROFILES BETWEEN CHRONICALLY DEMYELINATED MS LESIONS AND MATCHED NORMAL-APPEARING WHITE MATTER (NAWM), MAKING USE OF POST-MORTEM BRAIN TISSUE (N = 9/GROUP). DNA METHYLATION DIFFERENCES THAT INVERSELY CORRELATED WITH MRNA EXPRESSION OF THEIR CORRESPONDING GENES WERE VALIDATED FOR THEIR CELL-TYPE SPECIFICITY IN LASER-CAPTURED OPCS USING PYROSEQUENCING. THE CRISPR-DCAS9-DNMT3A/TET1 SYSTEM WAS USED TO EPIGENETICALLY EDIT HUMAN-IPSC-DERIVED OLIGODENDROCYTES TO ASSESS THE EFFECT ON CELLULAR DIFFERENTIATION. OUR DATA SHOW HYPERMETHYLATION OF CPGS WITHIN GENES THAT CLUSTER IN GENE ONTOLOGIES RELATED TO MYELINATION AND AXON ENSHEATHMENT. CELL TYPE-SPECIFIC VALIDATION INDICATES A REGION-DEPENDENT HYPERMETHYLATION OF MBP, ENCODING FOR MYELIN BASIC PROTEIN, IN OPCS OBTAINED FROM WHITE MATTER LESIONS COMPARED TO NAWM-DERIVED OPCS. BY ALTERING THE DNA METHYLATION STATE OF SPECIFIC CPGS WITHIN THE PROMOTOR REGION OF MBP, USING EPIGENETIC EDITING, WE SHOW THAT CELLULAR DIFFERENTIATION AND MYELINATION CAN BE BIDIRECTIONALLY MANIPULATED USING THE CRISPR-DCAS9-DNMT3A/TET1 SYSTEM IN VITRO. OUR DATA INDICATE THAT OPCS WITHIN CHRONICALLY DEMYELINATED MS LESIONS ACQUIRE AN INHIBITORY PHENOTYPE, WHICH TRANSLATES INTO HYPERMETHYLATION OF CRUCIAL MYELINATION-RELATED GENES. ALTERING THE EPIGENETIC STATUS OF MBP CAN RESTORE THE DIFFERENTIATION CAPACITY OF OPCS AND POSSIBLY BOOST (RE)MYELINATION. 2023 4 4721 40 NONCODING RNAS IN MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS), A CHRONIC INFLAMMATORY DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM, IS CHARACTERIZED BY AXONAL DEGENERATION AND GLIOSIS. ALTHOUGH THE CAUSES OF MS REMAIN UNKNOWN, GENE DYSREGULATION IN THE CENTRAL NERVOUS SYSTEM HAS BEEN ASSOCIATED WITH THE DISEASE PATHOGENESIS. AS SUCH, THE VARIOUS REGULATORS OF GENE EXPRESSION MAY BE CONTRIBUTING FACTORS. THE NONCODING (NC) RNAS HAVE PIQUED THE INTEREST OF MS RESEARCHERS DUE TO THEIR KNOWN FUNCTIONS IN HUMAN PHYSIOLOGY AND VARIOUS PATHOLOGICAL PROCESSES, DESPITE BEING GENERALLY CHARACTERIZED AS TRANSCRIPTS WITHOUT APPARENT PROTEIN-CODING CAPACITY. ACCUMULATING EVIDENCE HAS INDICATED THAT NCRNAS PARTICIPATE IN THE REGULATION OF MS BY ACTING AS EPIGENETIC FACTORS, ESPECIALLY THE LONG (L) NCRNAS AND THE MICRO (MI) RNAS, AND THEY ARE NOW RECOGNIZED AS KEY REGULATORY MOLECULES IN MS. IN THIS REVIEW, WE SUMMARIZE THE MOST CURRENT STUDIES ON THE CONTRIBUTION OF NCRNAS IN MS PATHOGENIC PROCESSES AND DISCUSS THEIR POTENTIAL APPLICATIONS IN THE DIAGNOSIS AND TREATMENT OF MS. 2018 5 5426 41 REGULATION OF SIRTUIN EXPRESSION IN AUTOIMMUNE NEUROINFLAMMATION: INDUCTION OF SIRT1 IN OLIGODENDROCYTE PROGENITOR CELLS. IN MULTIPLE SCLEROSIS (MS) REGENERATION OF OLIGODENDROCYTES FOLLOWING INFLAMMATORY DEMYELINATION IS LIMITED BY THE COMPROMISED ABILITY OF PROGENITORS TO REPOPULATE LESIONED AREAS AND TRANSITION TO FUNCTIONALLY COMPETENT OLIGODENDROCYTES. REGARDING UNDERLYING MECHANISMS, THE INVOLVEMENT OF EPIGENETIC PROCESSES HAS BEEN SUGGESTED, E.G. THE CONTRIBUTION OF HISTONE DEACETYLASES (HDAC) KNOWN TO REGULATE OLIGODENDROCYTE PROGENITOR CELL (OPC) DIFFERENTIATION. HOWEVER, THEIR PRECISE EXPRESSION PATTERNS, PARTICULAR OF REDOX-SENSITIVE NAD(+) HDACS, REMAINS LARGELY UNKNOWN. IN THIS STUDY, WE DETERMINED THE EXPRESSION AND ACTIVITY OF SIRTUINS, MEMBERS OF THE HDAC CLASS III FAMILY WITH A SPECIFIC FOCUS ON SIRT1, PREVIOUSLY ASSOCIATED WITH NEURODEGENERATIVE, INFLAMMATORY AND DEMYELINATING DISORDERS OF THE CENTRAL NERVOUS SYSTEM (CNS). BY INVESTIGATING MOUSE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), A MODEL FOR MS, WE FOUND THAT TRANSCRIPTION OF SIRT1, SIRT2 AND SIRT6 WAS SIGNIFICANTLY INCREASED IN THE CNS DURING CHRONIC DISEASE STAGES. WE CONFIRMED THIS FINDING FOR SIRT1 PROTEIN EXPRESSION AND WERE ABLE TO LOCALIZE UPREGULATED SIRT1 IN NUCLEI OF NG2(+) OR PDGFRALPHA(+) OPCS IN DEMYELINATED BRAIN LESIONS. IN CULTURED MOUSE A2B5(+) OPCS BLOCKADE OF SIRT1 ACTIVITY BY THE SMALL MOLECULE COMPOUND EX527 ENHANCED MITOTIC ACTIVITY BUT DID NOT AFFECT THE CAPACITY TO DIFFERENTIATE. A SIMILAR PATTERN WAS DETECTABLE IN OPCS DERIVED FROM SIRT1-DEFICIENT ANIMALS. TAKEN TOGETHER, OUR DATA SUGGEST THAT SIRT1 INHIBITION MAY HELP TO EXPAND THE ENDOGENOUS POOL OF OPCS WITHOUT AFFECTING THEIR DIFFERENTIATION. 2019 6 4590 28 NANOPORE SEQUENCING IDENTIFIES DIFFERENTIALLY METHYLATED GENES IN THE CENTRAL NERVOUS SYSTEM IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNE-MEDIATED DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS) THAT MIGHT BE TRIGGERED BY ABERRANT EPIGENETIC CHANGES IN THE GENOME. DNA METHYLATION IS THE MOST STUDIED EPIGENETIC MECHANISM THAT PARTICIPATES IN MS PATHOGENESIS. HOWEVER, THE OVERALL METHYLATION LEVEL IN THE CNS OF MS PATIENTS REMAINS ELUSIVE. WE USED DIRECT LONG-READ NANOPORE DNA SEQUENCING AND CHARACTERIZED THE DIFFERENTIALLY METHYLATED GENES IN THE BRAIN FROM MICE WITH EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), AN ANIMAL MODEL OF MS. WE IDENTIFIED 163 HYPOMETHYLATED PROMOTERS AND 327 HYPERMETHYLATED PROMOTERS. THESE GENOMIC ALTERATIONS WERE LINKED TO VARIOUS BIOLOGICAL PROCESSES INCLUDING METABOLISM, IMMUNE RESPONSES, NEURAL ACTIVITIES, AND MITOCHONDRIAL DYNAMICS, ALL OF WHICH ARE VITAL FOR EAE DEVELOPMENT. OUR RESULTS INDICATE A GREAT POTENTIAL OF NANOPORE SEQUENCING IN IDENTIFYING GENOMIC DNA METHYLATION IN EAE AND PROVIDE IMPORTANT GUIDANCE FOR FUTURE STUDIES INVESTIGATING THE MS/EAE PATHOLOGY. 2023 7 1611 42 DNA METHYLATION: A NEW PLAYER IN MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A NEUROLOGICAL AND CHRONIC INFLAMMATORY DISEASE THAT IS MEDIATED BY DEMYELINATION AND AXONAL DEGENERATION IN THE CENTRAL NERVOUS SYSTEM (CNS). STUDIES HAVE SHOWN THAT IMMUNE SYSTEM COMPONENTS SUCH AS CD4+, CD8+, CD44+ T CELLS, B LYMPHATIC CELLS, AND INFLAMMATORY CYTOKINES PLAY A CRITICAL ROLE IN INFLAMMATORY PROCESSES AND MYELIN DAMAGE ASSOCIATED WITH MS. NEVERTHELESS, THE PATHOGENESIS OF MS REMAINS POORLY DEFINED. DNA METHYLATION, A SIGNIFICANT EPIGENETIC MODIFICATION, IS REPORTED TO BE EXTENSIVELY INVOLVED IN MS PATHOGENESIS THROUGH THE REGULATION OF GENE EXPRESSION. THIS REVIEW FOCUSES ON DNA METHYLATION INVOLVED IN MS PATHOGENESIS. EVIDENCE SHOWED THE HYPERMETHYLATION OF HUMAN LEUKOCYTE ANTIGEN-DRB1 (HLA-DRB1) IN CD4+ T CELLS, THE GENOME-WIDE DNA METHYLATION IN CD8+ T CELLS, THE HYPERMETHYLATION OF INTERLEUKIN-4 (IL-4)/FORKHEAD WINGED HELIX TRANSCRIPTION FACTOR 3 (FOXP3), AND THE DEMETHYLATION OF INTERFERON-GAMMA (IFN-GAMMA)/IL-17A IN CD44+ ENCEPHALITOGENIC T CELLS. STUDIES ALSO SHOWED THE HYPERMETHYLATION OF SH2-CONTAINING PROTEIN TYROSINE PHOSPHATASE-1 (SHP-1) IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND METHYLATED CHANGES OF GENES REGULATING OLIGODENDROCYTE AND NEURONAL FUNCTION IN NORMAL-APPEARING WHITE MATTER. CLARIFYING THE MECHANISM OF ABERRANT METHYLATION ON MS MAY EXPLAIN PART OF THE PATHOLOGY AND WILL LEAD TO THE DEVELOPMENT OF A NEW THERAPEUTIC TARGET FOR THE TREATMENT OF MS IN THE FUTURE. 2017 8 6531 41 TRANSCRIPTIONAL REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) BY METHYL CPG BINDING PROTEIN 2 (MECP2): A NOVEL MECHANISM FOR RE-MYELINATION AND/OR MYELIN REPAIR INVOLVED IN THE TREATMENT OF MULTIPLE SCLEROSIS (MS). MULTIPLE SCLEROSIS (MS) IS A CHRONIC PROGRESSIVE, NEUROLOGICAL DISEASE CHARACTERIZED BY THE TARGETED IMMUNE SYSTEM-MEDIATED DESTRUCTION OF CENTRAL NERVOUS SYSTEM (CNS) MYELIN. AUTOREACTIVE CD4+ T HELPER CELLS HAVE A KEY ROLE IN ORCHESTRATING MS-INDUCED MYELIN DAMAGE. ONCE ACTIVATED, CIRCULATING TH1-CELLS SECRETE A VARIETY OF INFLAMMATORY CYTOKINES THAT FOSTER THE BREAKDOWN OF BLOOD-BRAIN BARRIER (BBB) EVENTUALLY INFILTRATING INTO THE CNS. INSIDE THE CNS, THEY BECOME REACTIVATED UPON EXPOSURE TO THE MYELIN STRUCTURAL PROTEINS AND CONTINUE TO PRODUCE INFLAMMATORY CYTOKINES SUCH AS TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) THAT LEADS TO DIRECT ACTIVATION OF ANTIBODIES AND MACROPHAGES THAT ARE INVOLVED IN THE PHAGOCYTOSIS OF MYELIN. PROLIFERATING OLIGODENDROCYTE PRECURSORS (OPS) MIGRATING TO THE LESION SITES ARE CAPABLE OF ACUTE REMYELINATION BUT UNABLE TO COMPLETELY REPAIR OR RESTORE THE IMMUNE SYSTEM-MEDIATED MYELIN DAMAGE. THIS RESULTS IN VARIOUS PERMANENT CLINICAL NEUROLOGICAL DISABILITIES SUCH AS COGNITIVE DYSFUNCTION, FATIGUE, BOWEL/BLADDER ABNORMALITIES, AND NEUROPATHIC PAIN. AT PRESENT, THERE IS NO CURE FOR MS. RECENT REMYELINATION AND/OR MYELIN REPAIR STRATEGIES HAVE FOCUSED ON THE ROLE OF THE NEUROTROPHIN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND ITS UPSTREAM TRANSCRIPTIONAL REPRESSOR METHYL CPG BINDING PROTEIN (MECP2). RESEARCH IN THE FIELD OF EPIGENETIC THERAPEUTICS INVOLVING HISTONE DEACETYLASE (HDAC) INHIBITORS AND LYSINE ACETYL TRANSFERASE (KAT) INHIBITORS IS BEING EXPLORED TO REPRESS THE DETRIMENTAL EFFECTS OF MECP2. THIS REVIEW WILL ADDRESS THE ROLE OF MECP2 AND BDNF IN REMYELINATION AND/OR MYELIN REPAIR AND THE POTENTIAL OF HDAC AND KAT INHIBITORS AS NOVEL THERAPEUTIC INTERVENTIONS FOR MS. 2016 9 2004 32 EPIGENETIC ASPECTS OF MULTIPLE SCLEROSIS AND FUTURE THERAPEUTIC OPTIONS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY AND NEURODEGENERATIVE DISEASE ACCOMPANIED BY DEMYELINATION OF NEURONS IN THE CENTRAL NERVOUS SYSTEM THAT MOSTLY AFFECTS YOUNG ADULTS, ESPECIALLY WOMEN. THIS DISEASE HAS TWO PHASES INCLUDING RELAPSING-REMITTING FORM (RR-MS) BY EPISODES OF RELAPSE AND PERIODS OF CLINICAL REMISSION AND SECONDARY-PROGRESSIVE FORM (SP-MS), WHICH CAUSES MORE DISABILITY. THE INHERITANCE PATTERN OF MS IS NOT EXACTLY IDENTIFIED AND THERE IS AN AGREEMENT THAT IT HAS A COMPLEX PATTERN WITH AN INTERPLAY AMONG ENVIRONMENTAL, GENETIC AND EPIGENETIC ALTERNATIONS. EPIGENETIC MECHANISMS THAT ARE IDENTIFIED FOR MS PATHOGENESIS ARE DNA METHYLATION, HISTONE MODIFICATION AND SOME MICRORNAS' ALTERNATIONS. SEVERAL CELLULAR PROCESSES INCLUDING APOPTOSIS, DIFFERENTIATION AND EVOLUTION CAN BE MODIFIED ALONG WITH EPIGENETIC CHANGES. SOME ALTERNATIONS ARE ASSOCIATED WITH EPIGENETIC MECHANISMS IN MS PATIENTS AND THESE CHANGES CAN BECOME KEY POINTS FOR MS THERAPY. THEREFORE, THE AIM OF THIS REVIEW WAS TO DISCUSS EPIGENETIC MECHANISMS THAT ARE ASSOCIATED WITH MS PATHOGENESIS AND FUTURE THERAPEUTIC APPROACHES. 2021 10 6907 26 [THE ROLE OF THE CIRCULAR RNAS IN MULTIPLE SCLEROSIS AND OTHER NEUROIMMUNE DISORDERS]. IN RECENT YEARS NON-CODING RNAS HAVE RECEIVED INCREASING ATTENTION AS AN IMPORTANT EPIGENETIC MECHANISM, WITH PARTICULAR ROLE OF MICRO RNAS. AS THE REGULATION OF MIRNA EXPRESSION IS HIGHLY DYNAMIC AND COMPLEX, GROWING EVIDENCE SUGGESTS THE EXISTENCE OF ANOTHER HIGHER LEVEL OF REGULATORY MECHANISM INVOLVED IN MIRNA ACTIVITY - CIRCULAR RNAS (CIRCRNAS). CIRCRNAS REPRESENT NOVEL, UNIQUE CLASS OF ENDOGENOUS NCRNAS CONTROLLING THE EXPRESSION AND FUNCTION OF MIRNA. THEY ARE CALLED NATURAL MIRNA "SPONGES". ACCUMULATING EVIDENCE REVEALS CIRCRNAS ROLE IN PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES INCLUDING CNS AND IMMUNE REGULATION. PREVIOUS STUDIES IMPLICATED MIRNAS IN REGULATION OF AUTOIMMUNE DEMYELINATION IN MS. MULTIPLE SCLEROSIS IS A CHRONIC NEUROLOGICAL INFLAMMATORY DEMYELINATING DISORDER OF THE CENTRAL NERVOUS SYSTEM. WHILE THE ETIOLOGY OF MS IS STILL NOT FULLY UNDERSTOOD, ACCUMULATING EVIDENCE SUGGESTS THAT IT IS A MULTIFACTORIAL ENTITY WITH SIGNIFICANT INVOLVEMENT OF AUTOIMMUNE PROCESSES. 2022 11 4304 44 MICRORNA-223 PROTECTS NEURONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. MULTIPLE SCLEROSIS IS A CHRONIC INFLAMMATORY, DEMYELINATING, AND NEURODEGENERATIVE DISEASE AFFECTING THE BRAIN, SPINAL CORD AND OPTIC NERVES. NEURONAL DAMAGE IS TRIGGERED BY VARIOUS HARMFUL FACTORS THAT ENGAGE DIVERSE SIGNALLING CASCADES IN NEURONS; THUS, THERAPEUTIC APPROACHES TO PROTECT NEURONS WILL NEED TO FOCUS ON AGENTS THAT CAN TARGET MULTIPLE BIOLOGICAL PROCESSES. WE HAVE THEREFORE FOCUSED OUR ATTENTION ON MICRORNAS: SMALL NON-CODING RNAS THAT PRIMARILY FUNCTION AS POST-TRANSCRIPTIONAL REGULATORS THAT TARGET MESSENGER RNAS AND REPRESS THEIR TRANSLATION INTO PROTEINS. A SINGLE MICRORNA CAN TARGET MANY FUNCTIONALLY RELATED MESSENGER RNAS MAKING MICRORNAS POWERFUL EPIGENETIC REGULATORS. DYSREGULATION OF MICRORNAS HAS BEEN DESCRIBED IN MANY NEURODEGENERATIVE DISEASES INCLUDING MULTIPLE SCLEROSIS. HERE, WE REPORT THAT TWO MICRORNAS, MIR-223-3P AND MIR-27A-3P, ARE UPREGULATED IN NEURONS IN THE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS MOUSE MODEL OF CNS INFLAMMATION AND IN GREY MATTER-CONTAINING MULTIPLE SCLEROSIS LESIONS. PRIOR WORK HAS SHOWN PERIPHERAL BLOOD MONONUCLEAR CELL CONDITIONED MEDIA CAUSES SUBLETHAL DEGENERATION OF NEURONS IN CULTURE. WE FIND OVEREXPRESSION OF MIR-27A-3P OR MIR-223-3P PROTECTS DISSOCIATED CORTICAL NEURONS FROM CONDITION MEDIA MEDIATED DEGENERATION. INTRODUCTION OF MIR-223-3P IN VIVO IN MOUSE RETINAL GANGLION CELLS PROTECTS THEIR AXONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. IN SILICO ANALYSIS REVEALED THAT MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING ARE ENRICHED AS MIR-27A-3P AND MIR-223-3P TARGETS. WE OBSERVE THAT ANTAGONISM OF NMDA AND AMPA TYPE GLUTAMATE RECEPTORS PROTECTS NEURONS FROM CONDITION MEDIA DEPENDENT DEGENERATION. OUR RESULTS SUGGEST THAT MIR-223-3P AND MIR-27A-3P ARE UPREGULATED IN RESPONSE TO INFLAMMATION TO MEDIATE A COMPENSATORY NEUROPROTECTIVE GENE EXPRESSION PROGRAM THAT DESENSITIZES NEURONS TO GLUTAMATE BY TARGETING MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING. 2019 12 80 44 A NEW ROLE FOR THE P2Y-LIKE GPR17 RECEPTOR IN THE MODULATION OF MULTIPOTENCY OF OLIGODENDROCYTE PRECURSOR CELLS IN VITRO. OLIGODENDROCYTE PRECURSOR CELLS (OPCS, ALSO CALLED NG2 CELLS) ARE SCATTERED THROUGHOUT BRAIN PARENCHYMA, WHERE THEY FUNCTION AS A RESERVOIR TO REPLACE LOST OR DAMAGED OLIGODENDROCYTES, THE MYELIN-FORMING CELLS. THE HYPOTHESIS THAT, UNDER SOME CIRCUMSTANCES, OPCS CAN ACTUALLY BEHAVE AS MULTIPOTENT CELLS, THUS GENERATING ASTROCYTES AND NEURONS AS WELL, HAS ARISEN FROM SOME IN VITRO AND IN VIVO EVIDENCE, BUT THE MOLECULAR PATHWAYS CONTROLLING THIS ALTERNATIVE FATE OF OPCS ARE NOT FULLY UNDERSTOOD. THEIR IDENTIFICATION WOULD OPEN NEW OPPORTUNITIES FOR NEURONAL REPLACE STRATEGIES, BY FOSTERING THE INTRINSIC ABILITY OF THE BRAIN TO REGENERATE. HERE, WE SHOW THAT THE ANTI-EPILEPTIC EPIGENETIC MODULATOR VALPROIC ACID (VPA) CAN PROMOTE THE GENERATION OF NEW NEURONS FROM NG2(+) OPCS UNDER NEUROGENIC PROTOCOLS IN VITRO, THROUGH THEIR INITIAL DE-DIFFERENTIATION TO A STEM CELL-LIKE PHENOTYPE THAT THEN EVOLVES TO "HYBRID" CELL POPULATION, SHOWING OPC MORPHOLOGY BUT EXPRESSING THE NEURONAL MARKER BETAIII-TUBULIN AND THE GPR17 RECEPTOR, A KEY DETERMINANT IN DRIVING OPC TRANSITION TOWARDS MYELINATING OLIGODENDROCYTES. UNDER THESE CONDITIONS, THE PHARMACOLOGICAL BLOCKADE OF THE P2Y-LIKE RECEPTOR GPR17 BY CANGRELOR, A DRUG RECENTLY APPROVED FOR HUMAN USE, PARTIALLY MIMICS THE EFFECTS MEDIATED BY VPA THUS ACCELERATING CELLS' NEUROGENIC CONVERSION. THESE DATA SHOW A CO-LOCALIZATION BETWEEN NEURONAL MARKERS AND GPR17 IN VITRO, AND SUGGEST THAT, BESIDES ITS INVOLVEMENT IN OLIGODENDROGENESIS, GPR17 CAN DRIVE THE FATE OF NEURAL PRECURSOR CELLS BY INSTRUCTING PRECURSORS TOWARDS THE NEURONAL LINEAGE. BEING A MEMBRANE RECEPTOR, GPR17 REPRESENTS AN IDEAL "DRUGGABLE" TARGET TO BE EXPLOITED FOR INNOVATIVE REGENERATIVE APPROACHES TO ACUTE AND CHRONIC BRAIN DISEASES. 2016 13 2546 44 EPIGENETICS IN MULTIPLE SCLEROSIS: MOLECULAR MECHANISMS AND DIETARY INTERVENTION. INTRODUCTION: MULTIPLE SCLEROSIS (MS) IS A CHRONIC, INFLAMMATORY, NEURODEGENERATIVE DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS). UNFORTUNATELY, MS CAUSES IMPORTANT DISABILITY IN YOUNG ADULTS AND ITS PREVALENCE IS INCREASING. WHILE THE ETIOLOGY OF MS ETIOLOGY IS NOT COMPLETELY UNDERSTOOD, IT SEEMS TO BE A MULTIFACTORIAL ENTITY THAT IS INFLUENCED BY BOTH GENETIC AND EPIGENETIC MODIFICATIONS. EPIGENETIC MECHANISMS ADD OR REMOVE DIFFERENT CHEMICAL GROUPS FOR THE ACTIVATION OR INHIBITION OF GENE EXPRESSION TO BLOCK THE PRODUCTION OF PROINFLAMMATORY PROTEINS. IT IS TRULY IMPORTANT TO IDENTIFY THE FACTORS THAT CAN TRIGGER EPIGENETIC CHANGES IN MS TO COMPLEMENT THE THERAPEUTIC APPROACH, PREVENT DISABILITY AND IMPROVE PATIENTS QUALITY OF LIFE. HERE, WE HAVE CONDUCTED A REVIEW OF EXTERNAL FACTORS THAT INFLUENCE IN MS AND THEIR EPIGENETIC MECHANISMS. FOR EXAMPLE, HYPOMETHYLATION CAN PROMOTE CHANGES IN THE MYELIN AND SUBSEQUENT AUTOIMMUNE REACTIONS. THERAPEUTIC TOOLS CAN BE USED, INCLUDING THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A, WHICH AMELIORATES DEMYELINATING DISEASES IN RODENTS. HOWEVER, DRUGS ARE NOT ONLY THE THERAPEUTIC OPTION: RECENT STUDIES HAVE ALSO EVALUATED THE THERAPEUTIC POTENTIAL OF SEVERAL BIOACTIVE DIETARY COMPONENTS IN NEURODEGENERATION AND AXONAL DYSFUNCTION. NUMEROUS FOOD-DERIVED MOLECULES EXERT IMPORTANT METABOLIC ACTIONS. THESE MOLECULES INCLUDE PLANT POLYPHENOLS SUCH AS CATECHINS AND ISOFLAVONES, OMEGA-3 AND OMEGA-6 POLYUNSATURATED FATTY ACIDS, SHORT-CHAIN FATTY ACIDS, SULFUR-CONTAINING COMPOUNDS SUCH AS DALLY SULFIDE AND OTHER COMPOUNDS. ANTIOXIDANT AND ANTI-INFLAMMATORY COMPONENTS IN THE DIET INVOLVE TRANSCRIPTION FACTORS AS WELL. HOWEVER, MANY EXTERNAL FACTORS HAVE SHOWN TO INFLUENCE MS, ALTHOUGH NO SPECIFIC EPIGENETIC MECHANISMS ARE KNOWN. CONCLUSION: IN THIS REVIEW, WE GATHER BOTH ESTABLISHED AND NEW EVIDENCES ABOUT THE GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS INFLUENCING MS AND THE DIETARY COMPONENTS THAT COULD MODULATE MS RELAPSE AND PROGRESSION. 2018 14 4368 44 MIRNA-DEPENDENT CD4(+) T CELL DIFFERENTIATION IN THE PATHOGENESIS OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS CHARACTERIZED BY MULTIFOCAL LESIONS, CHRONIC INFLAMMATORY CONDITION, AND DEGENERATIVE PROCESSES WITHIN THE CENTRAL NERVOUS SYSTEM (CNS) LEADING TO DEMYELINATION. THE MOST IMPORTANT CELLS INVOLVED IN ITS PATHOGENESIS ARE THOSE WHICH ARE CD4(+), PARTICULARLY PROINFLAMMATORY TH1/TH17 AND REGULATORY TREG. SIGNAL CASCADES ASSOCIATED WITH CD4(+) DIFFERENTIATION ARE REGULATED BY MICRORNAS (MIRNAS): SHORT, SINGLE-STRANDED RNAS, RESPONSIBLE FOR NEGATIVE REGULATION OF GENE EXPRESSION AT THE POSTTRANSCRIPTIONAL LEVEL. SEVERAL MIRNAS HAVE BEEN CONSISTENTLY REPORTED AS SHOWING DYSREGULATED EXPRESSION IN MS, AND THEIR EXPRESSION PATTERNS MAY BE ELEVATED OR DECREASED, DEPENDING ON THE FUNCTION OF SPECIFIC MIRNA IN THE IMMUNE SYSTEM. STUDIES IN MS PATIENTS INDICATE THAT, AMONG OTHERS, MIR-141, MIR-200A, MIR-155, MIR-223, AND MIR-326 ARE UPREGULATED, WHILE MIR-15B, MIR-20B, MIR-26A, AND MIR-30A ARE DOWNREGULATED. DYSREGULATION OF THESE MIRNAS MAY CONTRIBUTE TO THE IMBALANCE BETWEEN PRO- AND ANTI-INFLAMMATORY PROCESSES, SINCE THEIR TARGETS ARE ASSOCIATED WITH THE REGULATION OF TH1/TH17 AND TREG CELL DIFFERENTIATION. HIGHLY EXPRESSED MIRNAS CAN IN TURN SUPPRESS TRANSLATION OF KEY TH1/TH17 DIFFERENTIATION INHIBITORS. MIRNA DYSREGULATION MAY RESULT FROM THE IMPACT OF VARIOUS FACTORS AT EACH STAGE OF THEIR BIOGENESIS. IMMATURE MIRNA UNDERGOES MULTISTAGE TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL MODIFICATIONS; THEREFORE, ANY PROTEIN INVOLVED IN THE PROCESSING OF MIRNAS CAN POTENTIALLY LEAD TO DISTURBANCES IN THEIR EXPRESSION. EPIGENETIC MODIFICATIONS THAT HAVE A DIRECT IMPACT ON MIRNA GENE TRANSCRIPTION MAY ALSO PLAY AN IMPORTANT ROLE. 2021 15 6117 36 THE EPIGENETIC DRUG TRICHOSTATIN A AMELIORATES EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS VIA T CELL TOLERANCE INDUCTION AND IMPAIRED INFLUX OF T CELLS INTO THE SPINAL CORD. MULTIPLE SCLEROSIS IS A T CELL MEDIATED CHRONIC DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM. ALTHOUGH CURRENTLY AVAILABLE THERAPIES REDUCE RELAPSES, THEY DO NOT FACILITATE TOLERIZATION OF MYELIN ANTIGEN-SPECIFIC T LYMPHOCYTES TO ENSURE PROLONGED PROTECTION AGAINST MULTIPLE SCLEROSIS. HERE, WE SHOW THAT TREATMENT OF NOD MICE WITH THE HISTONE DEACETYLASE INHIBITOR, TRICHOSTATIN A AFFORDS ROBUST PROTECTION AGAINST MYELIN PEPTIDE INDUCED EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, A MOUSE MODEL OF MULTIPLE SCLEROSIS. PROTECTION WAS ACCOMPANIED BY HISTONE HYPERACETYLATION, AND REDUCED INFLAMMATION AND AXONAL DAMAGE IN THE SPINAL CORD. DRUG TREATMENT DIMINISHED THE GENERATION OF CD4(+) MEMORY T CELLS AND INDUCED TOLERANCE IN CD4(+) T CELLS RECOGNIZING THE IMMUNIZING MYELIN PEPTIDE. DURING THE EARLY IMMUNIZATION PERIOD, CD4(+) T CELLS PRODUCING GM-CSF+IFN-GAMMA, GM-CSF+IL-17A, AS WELL AS THOSE EXPRESSING BOTH IL-17A+IFN-GAMMA (DOUBLE-PRODUCERS) WERE DETECTED IN THE SECONDARY LYMPHOID ORGANS FOLLOWED BY THE APPEARANCE OF CELLS PRODUCING IFN-GAMMA AND GM-CSF. ON THE OTHER HAND, IFN-GAMMA PRODUCING TH1 CELLS APPEAR FIRST IN THE SPINAL CORD FOLLOWED BY CELLS PRODUCING IL-17A AND GM-CSF. TREATMENT WITH TRICHOSTATIN A SUBSTANTIALLY REDUCED THE FREQUENCIES OF ALL T CELLS SECRETING VARIOUS LYMPHOKINES BOTH IN THE PERIPHERY AND IN THE SPINAL CORD. THESE DATA INDICATE THAT EPIGENETIC MODIFICATIONS INDUCED BY HISTONE HYPERACETYLATION FACILITATES T CELL TOLERANCE INDUCTION IN THE PERIPHERY LEADING TO REDUCED MIGRATION OF T CELLS TO THE SPINAL CORD AND MITIGATION OF NEURONAL DAMAGE AND IMPROVED CLINICAL OUTCOME. THESE RESULTS SUGGEST THAT EPIGENETIC MODULATION OF THE GENOME MAY SIMILARLY OFFER BENEFITS TO MULTIPLE SCLEROSIS PATIENTS VIA ABROGATING THE FUNCTION OF ENCEPHALITOGENIC T LYMPHOCYTES WITHOUT EXERTING SEVERE SIDE EFFECTS ASSOCIATED WITH CURRENTLY USED DISEASE-MODIFYING THERAPIES. 2017 16 4536 42 MULTIPLE SCLEROSIS - RISK FACTORS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNOLOGICAL CONDITION OF THE CENTRAL NERVOUS SYSTEM (CNS) AFFECTING MAINLY YOUNG ADULT INDIVIDUALS. THE PREVALENCE RANGES APPROXIMATELY BETWEEN 50 AND 300 PER 100000 INDIVIDUALS. IT IS CHARACTERIZED BY AN INFLAMMATORY PROCESS, DEMYELINATION AND AXONAL LOSS. IMMUNOLOGICAL MECHANISMS RESULTING IN THE DAMAGE TO THE MYELIN SHEATH EFFECTING THEN IN IMPAIRED NERVE IMPULSE CONDUCTION HAVE THE KEY ROLE IN MS PATHOGENESIS. THE ROLE OF INFLAMMATORY FACTORS HAS ALSO BEEN PROVED. HOWEVER, IT HAS NOT BEEN EXPLICITLY SHOWN WHETHER SUCH AN INFLAMMATORY PROCESS IS THE TRIGGERING FACTOR OR SECONDARY TO A YET UNKNOWN INFECTIOUS FACTOR OR A DEGENERATIVE PROCESS OF THE CNS. THEREFORE, RECOGNITION OF THE EPIGENETIC RISK FACTORS, SUCH AS: GEOGRAPHICAL LATITUDE, VITAMIN D LEVEL, HYGIENE HYPOTHESIS, EPSTEIN-BARR VIRUS (EBV) INFECTION AND OTHERS MAY CONTRIBUTE TO BETTER UNDERSTANDING OF THE MECHANISM UNDERLYING MULTIPLE SCLEROSIS. ADDITIONALLY, THEY MAY PROVIDE GUIDELINES FOR MORE EFFICIENT THERAPIES AND BETTER PREVENTION OF THE DISEASE. AIM OF THIS REVIEW IS TO PRESENT MOST CURRENT DATA ON MULTIPLE SCLEROSIS RISK FACTORS, CONSIDERING THOSE LESS KNOWN. 2020 17 4439 38 MOLECULAR GENETIC AND EPIGENETIC BASIS OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC IMMUNE-MEDIATED DISEASE OF SPINAL CORD AND BRAIN. THE INITIAL EVENT IN MS OCCURS WHEN ACTIVATED CD4(+) T CELLS IN PERIPHERY EXACERBATES IMMUNE RESPONSES BY STIMULATING IMMUNE CELLS SUCH AS B CELLS, CD8(+) CELLS, MAST CELLS, GRANULOCYTES AND MONOCYTES. THESE PROINFLAMMATORY CELLS PASS BLOOD BRAIN BARRIER BY SECRETING PROINFLAMMATORY CYTOKINES INCLUDING TNF-ALPHA AND INF-(GAMMA) WHICH ACTIVATE ADHESION FACTORS. APCS (ANTIGEN-PRESENTING CELLS) REACTIVATE CD4(+) T CELLS AFTER INFILTRATING THE CNS AND CD4(+) T CELLS PRODUCE CYTOKINES AND CHEMOKINES. THESE PROINFLAMMATORY CYTOKINES AGGRAVATE INFLAMMATION BY INDUCING MYELIN PHAGOCYTOSIS THROUGH MICROGLIA AND ASTROCYTES ACTIVATION. MS IS BELIEVED TO HAVE A MULTIFACTORIAL ORIGIN THAT INCLUDES A COMBINATION OF MULTIPLE GENETIC, ENVIRONMENTAL AND STOCHASTIC FACTORS. ALTHOUGH THE EXACT COMPONENT OF MS RISKS THAT CAN BE EXPLAINED BY THESE FACTORS IS DIFFICULT TO DETERMINE, ESTIMATES BASED ON GENETIC AND EPIDEMIOLOGICAL STUDIES SUGGEST THAT UP TO 60-70 % OF THE TOTAL RISK OF MS MAY BE CONTRIBUTE TO GENETIC FACTORS. IN CONTINUE, FIRSTLY WE PROVIDE AN OVERVIEW OF THE CURRENT UNDERSTANDING OF EPIGENETIC MECHANISMS, AND SO PRESENT EVIDENCE OF HOW THE EPIGENETIC MODIFICATIONS CONTRIBUTE TO INCREASED SUSCEPTIBILITY OF MS. WE ALSO EXPLAIN HOW SPECIFIED EPIGENETIC MODIFICATIONS MAY INFLUENCE THE PATHOPHYSIOLOGY AND KEY ASPECTS OF DISEASE IN MS (DEMYELINATION, REMYELINATION, INFLAMMATION, AND NEURODEGENERATION). FINALLY, WE TEND TO DISCUSS HOW ENVIRONMENTAL FACTORS AND EPIGENETIC MECHANISMS MAY INTERACT TO HAVE AN EFFECT ON MS RISK AND CLINICAL OUTCOME AND RECOMMEND NEW THERAPEUTIC INTERVENTIONS THAT MIGHT MODULATE PATIENTS' EPIGENETIC PROFILES. 2017 18 4350 38 MIR-181A-5P IS A POTENTIAL CANDIDATE EPIGENETIC BIOMARKER IN MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS) CHARACTERIZED BY DEMYELINATION AND AXONAL DEGENERATION. ABNORMAL EXPRESSION OF MICRORNAS (MIRNAS) PLAYS AN IMPORTANT ROLE IN MS PATHOLOGY. IN THIS COHORT STUDY, DIFFERENTIAL EXPRESSION OF THE FOUR MIRNAS (HSA-MIR-155-5P, HSA-MIR-9-5P, HSA-MIR-181A-5P, AND HSA-MIR-125B-5P) WAS INVESTIGATED IN 69 INDIVIDUALS, INCLUDING 39 MS PATIENTS (RELAPSING-REMITTING MS (RRMS), N = 27; SECONDARY PROGRESSIVE MS (SPMS), N = 12) AND 30 HEALTHY CONTROLS. IN SILICO ANALYSES REVEALED POSSIBLE GENES AND PATHWAYS SPECIFIC TO MIRNAS. PERIPHERAL BLOOD MIRNA EXPRESSIONS WERE DETECTED BY QUANTITATIVE REAL-TIME PCR (QPCR). HSA-MIR-181A-5P WAS DOWNREGULATED AND ASSOCIATED WITH INCREASED MS RISK (P = 0.012). THE OTHER THREE MIRNAS WERE UPREGULATED AND NOT ASSOCIATED WITH MS (P < 0.05). THE AREA UNDER THE CURVE (AUC) IS 0.779. IN SILICO ANALYSES SHOWED THAT HSA-MIR-181A-5P MAY PARTICIPATE IN MS PATHOLOGY BY TARGETING MAP2K1, CREB1, ATXN1, AND ATXN3 GENES IN INFLAMMATION AND NEURODEGENERATION PATHWAYS. THE CIRCULATORY HSA-MIR-181A-5P CAN REGULATE TARGET GENES, REVERSING THE MECHANISMS INVOLVED IN MS PATHOLOGIES SUCH AS PROTEIN UPTAKE AND PROCESSING, CELL PROLIFERATION AND SURVIVAL, INFLAMMATION, AND NEURODEGENERATION. THUS, THIS MIRNA COULD BE USED AS AN EPIGENOMIC-GUIDED DIAGNOSTIC TOOL AND FOR THERAPEUTIC PURPOSE. 2022 19 1994 33 EPIGENETIC AND GENE EXPRESSION ALTERATIONS OF FOXP3 IN THE T CELLS OF EAE MOUSE MODEL OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNE DISEASE WITH DEMYELINATION AND NEURODEGENERATION OF THE CENTRAL NERVOUS SYSTEM. IT HAS BEEN SHOWN THAT THE REGULATORY T (TREG) CELLS ARE RESPONSIBLE FOR MAINTAINING TOLERANCE TO SELF-ANTIGENS AND CAN SUPPRESS THE AUTOIMMUNE PROCESS IN SEVERAL ANIMAL MODELS SUCH AS EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), A MOUSE MODEL OF MS. RECENT BASIC STUDIES HAVE DEMONSTRATED THAT FORKHEAD BOX P (FOXP3) AND BTB DOMAIN AND CNC HOMOLOG 2 (BACH2) ARE THE MASTER TRANSCRIPTION FACTORS OF THESE CELLS PLAYING A PIVOTAL ROLE IN THE POLARIZATION OF NAIVE T CELLS INTO TREG CELLS. IN THE CURRENT STUDY, THE EXPRESSION OF FOXP3 AND BACH2 GENES AND FOXP3 PROMOTER METHYLATION WERE EVALUATED IN T CELLS OF THE EAE-INDUCED MICE. THE RESULTS OF THIS STUDY SHOWED A PROMINENT AND SIGNIFICANT HYPERMETHYLATION OF THE FOXP3 GENE PROMOTER IN THE EAE-INDUCED MICE COMPARED TO THE SHAM AND CONTROL GROUPS. THE EXPRESSION OF FOXP3 AND BACH2 GENES WAS SIGNIFICANTLY DECREASED IN THE EAE GROUP IN COMPARISON WITH THE SHAM AND CONTROL GROUPS. THIS STUDY SUGGESTS THAT THE EPIGENETIC MODIFICATION OF FOXP3 GENE IS INVOLVED IN THE PATHOGENESIS OF EAE AND THIS COULD BE IMPORTANT IN THERAPY IN AN APPROPRIATE AND LOGICAL STATEMENT. 2017 20 4269 30 MICROBIAL DYSBIOSIS AND LACK OF SCFA PRODUCTION IN A SPANISH COHORT OF PATIENTS WITH MULTIPLE SCLEROSIS. BACKGROUND: MULTIPLE SCLEROSIS (MS) IS A CHRONIC, DEMYELINATING, AND IMMUNE-MEDIATED DISEASE OF THE CENTRAL NERVOUS SYSTEM CAUSED BY A COMBINATION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. THE INCIDENCE OF MS HAS INCREASED IN THE PAST SEVERAL DECADES, SUGGESTING CHANGES IN THE ENVIRONMENTAL RISK FACTORS. MUCH EFFORT HAS BEEN MADE IN THE DESCRIPTION OF THE GUT MICROBIOTA IN MS; HOWEVER, LITTLE IS KNOWN ABOUT THE DYSBIOSIS ON ITS FUNCTION. THE MICROBIOTA PRODUCES THOUSANDS OF BIOLOGICALLY ACTIVE SUBSTANCES AMONG WHICH ARE NOTABLE THE SHORT-CHAIN FATTY ACID (SCFA) EXCRETION. OBJECTIVES: ANALYZE THE INTERACTION BETWEEN MICROBIOTA, SCFAS, DIET, AND MS. METHODS: 16S, NUTRITIONAL QUESTIONNAIRES, AND SCFAS QUANTIFICATION HAVE BEEN RECOVERED FROM MS PATIENTS AND CONTROLS. RESULTS: OUR RESULTS REVEALED AN INCREMENT IN THE PHYLUM PROTEOBACTERIA, ESPECIALLY THE FAMILY ENTEROBACTERIACEAE, A LACK IN TOTAL SCFA EXCRETION, AND AN ALTERED PROFILE OF SCFAS IN A SPANISH COHORT OF MS PATIENTS. THESE ALTERATIONS ARE MORE EVIDENT IN PATIENTS WITH HIGHER DISABILITY. CONCLUSIONS: THE ABUNDANCE OF PROTEOBACTERIA AND ACETATE AND THE LOW EXCRETION OF TOTAL SCFAS, ESPECIALLY BUTYRATE, ARE COMMON CHARACTERISTICS OF MS PATIENTS, AND BESIDES, BOTH ARE ASSOCIATED WITH A WORSE PROGNOSIS OF THE DISEASE. 2022