1 4721 97 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 2 2004 33 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 3 6347 31 THE ROLE OF EPIGENETICS IN NEUROINFLAMMATORY-DRIVEN DISEASES. NEURODEGENERATIVE DISORDERS ARE CHARACTERIZED BY THE PROGRESSIVE LOSS OF CENTRAL AND/OR PERIPHERAL NERVOUS SYSTEM NEURONS. WITHIN THIS CONTEXT, NEUROINFLAMMATION COMES UP AS ONE OF THE MAIN FACTORS LINKED TO NEURODEGENERATION PROGRESSION. IN FACT, NEUROINFLAMMATION HAS BEEN RECOGNIZED AS AN OUTSTANDING FACTOR FOR ALZHEIMER'S DISEASE (AD), AMYOTROPHIC LATERAL SCLEROSIS (ALS), PARKINSON'S DISEASE (PD), AND MULTIPLE SCLEROSIS (MS). INTERESTINGLY, NEUROINFLAMMATORY DISEASES ARE CHARACTERIZED BY DRAMATIC CHANGES IN THE EPIGENETIC PROFILE, WHICH MIGHT PROVIDE NOVEL PROGNOSTIC AND THERAPEUTIC FACTORS TOWARDS NEUROINFLAMMATORY TREATMENT. DEEP CHANGES IN DNA AND HISTONE METHYLATION, ALONG WITH HISTONE ACETYLATION AND ALTERED NON-CODING RNA EXPRESSION, HAVE BEEN REPORTED AT THE ONSET OF INFLAMMATORY DISEASES. THE AIM OF THIS WORK IS TO REVIEW THE CURRENT KNOWLEDGE ON THIS FIELD. 2022 4 2988 19 GENETIC FACTORS AND SYSTEMIC SCLEROSIS. SYSTEMIC SCLEROSIS (SSC) IS A RARE CONNECTIVE TISSUE DISEASE OF UNKNOWN ETIOLOGY CHARACTERIZED BY CHRONIC INFLAMMATION AND FIBROSIS OF THE SKIN, VASCULAR ABNORMALITIES, AND VARIABLE INVOLVEMENT OF ORGANS INCLUDING KIDNEYS, GASTROINTESTINAL TRACT, HEART, AND LUNGS. SSC SHOWS A COMPLEX ETIOLOGY IN WHICH BOTH ENVIRONMENTAL AND GENETIC FACTORS SEEM TO INFLUENCE THE ONSET AND OUTCOME OF THE DISEASE. WE PROVIDE AN EXTENSIVE OVERVIEW OF THE GENETIC FACTORS AND EPIGENETIC MODIFICATIONS AND WHAT THEIR KNOWLEDGE HAS REVEALED IN TERMS OF ETIOPATHOGENESIS OF SSC. 2016 5 4590 32 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 6 4536 41 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 7 6907 35 [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 8 2546 42 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 9 4269 29 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 10 2224 20 EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF SYSTEMIC SCLEROSIS. SYSTEMIC SCLEROSIS IS A RARE CHRONIC AUTOIMMUNE DISEASE, WHICH MAINLY MANIFESTS AS IMMUNE DISORDERS, VASCULAR DAMAGE, AND PROGRESSIVE FIBROSIS. THE ETIOLOGY OF SSC IS COMPLEX AND INVOLVES MULTIPLE FACTORS. BOTH GENETIC AND ENVIRONMENTAL FACTORS ARE INVOLVED IN ITS PATHOGENESIS. AS ONE OF THE MOLECULAR MECHANISMS OF ENVIRONMENTAL FACTORS, EPIGENETIC REGULATION PLAYS AN IMPORTANT ROLE IN THE OCCURRENCE AND DEVELOPMENT OF SYSTEMIC SCLEROSIS, WHICH INVOLVES DNA METHYLATION, HISTONE MODIFICATION AND NON-CODING RNA REGULATION. THIS REVIEW SUMMARIZES RESEARCH ADVANCES IN EPIGENETICS, INCLUDING EXOSOMES, LNCRNA, AND MENTIONS POSSIBLE BIOMARKERS AND THERAPEUTIC TARGETS AMONG THEM. 2022 11 4439 33 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 12 5408 40 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 13 1611 44 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 14 6738 34 WHAT'S YOUR CUP OF TEA? THE ROLE OF HERBAL COMPOUNDS IN THE MANAGEMENT OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC, INFLAMMATORY, NEURODEGENERATIVE DISEASE THAT IS CHARACTERIZED BY A COMPLEX ETIOLOGY. EFFORTS TOWARDS THE MANAGEMENT OF MS HAVE LONG BEEN DIRECTED TOWARDS SYMPTOMATIC RELIEF, AS WELL AS THE USE OF IMMUNE-MODULATORY, DISEASE MODIFYING THERAPIES; HOWEVER, INCONSISTENT TREATMENT RESPONSES STILL PREVAIL, INCREASING THE RISK FOR DISEASE PROGRESSION. WHILE A GREAT DEAL OF RESEARCH ATTEMPTED TO UNRAVEL THE COMPLEXITY OF TREATMENT RESPONSES IN LIGHT OF EPIGENETIC VARIABILITY, PARALLEL EFFORTS IN THE DIRECTION OF ALTERNATIVE MEDICINE MAY BE AS PARAMOUNT. HERBAL COMPOUNDS HAVE LONG BEEN REGARDED AS SAFE AND VERSATILE OPTIONS FOR AIDING IN VARIOUS DISORDERS, INCLUDING NEURODEGENERATIVE CONDITIONS LIKE MS. NUMEROUS STUDIES HAVE TAKEN INTEREST IN A MYRIAD OF HERBAL PLANTS FOR THEIR POTENTIAL BENEFIT IN ALLEVIATING SOME OF THE MOST COMMON MS SYMPTOMS SUCH AS SPASTICITY AND FATIGUE, DELAYING THE PROGRESSION OF THE DISEASE, AS WELL AS INFLUENCING THE OVERALL QUALITY OF LIFE FOR MS PATIENTS. THIS REVIEW AIMS TO PROVIDE A COMPREHENSIVE OVERVIEW OF RECENT CLINICAL STUDIES EXAMINING THE EFFECTS OF VARIOUS HERBAL PLANTS ON DIFFERENT ASPECTS OF MS, IN AN ATTEMPT TO SHED LIGHT ON AN IMPORTANT TOOL FOR AIDING IN THE MANAGEMENT OF THIS COMPLEX AND MULTIFACTORIAL DISEASE. 2023 15 6021 30 THE BENEFICIAL AND DEBILITATING EFFECTS OF ENVIRONMENTAL AND MICROBIAL TOXINS, DRUGS, ORGANIC SOLVENTS AND HEAVY METALS ON THE ONSET AND PROGRESSION OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS), A CHRONIC INFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM IS COMMON AMONGST YOUNG ADULTS, LEADING TO MAJOR PERSONAL AND SOCIOECONOMIC BURDENS. HOWEVER, IT IS STILL CONSIDERED COMPLEX AND CHALLENGING TO UNDERSTAND AND TREAT, IN SPITE OF THE EFFORTS MADE TO EXPLAIN ITS ETIOPATHOLOGY. DESPITE THE DISCOVERY OF MANY GENETIC AND ENVIRONMENTAL FACTORS THAT MIGHT BE RELATED TO ITS ETIOLOGY, NO CLEAR ANSWER WAS FOUND ABOUT THE CAUSES OF THE ILLNESS AND NEITHER ABOUT THE DETAILED MECHANISM OF THESE ENVIRONMENTAL TRIGGERS THAT MAKE INDIVIDUALS SUSCEPTIBLE TO MS. IN THIS REVIEW, WE WILL ATTEMPT TO EXPLORE THE MAJOR CONTRIBUTORS TO MS AUTOIMMUNITY INCLUDING GENETIC, EPIGENETIC AND ECOLOGICAL FACTORS WITH A PARTICULAR FOCUS ON TOXINS, CHEMICALS OR DRUGS THAT MAY TRIGGER, MODIFY OR PREVENT MS DISEASE. 2019 16 6734 46 WHAT DO WE KNOW ABOUT THE ROLE OF LNCRNAS IN MULTIPLE SCLEROSIS? MULTIPLE SCLEROSIS IS A CHRONIC, INFLAMMATORY AND DEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM OF UNKNOWN AETIOLOGY ALTHOUGH WELL-DEFINED EVIDENCE SUPPORTS AN AUTOIMMUNE PATHOGENESIS. SO FAR, THE EXACT MECHANISMS LEADING TO AUTOIMMUNE DISEASES ARE STILL ONLY PARTIALLY UNDERSTOOD. WE KNOW THAT GENETIC, EPIGENETIC, MOLECULAR, AND CELLULAR FACTORS RESULTING IN PATHOGENIC INFLAMMATORY RESPONSES ARE CERTAINLY INVOLVED. LONG NON-CODING RNAS (LNCRNAS) ARE NON-PROTEIN CODING TRANSCRIPTS LONGER THAN 200 NUCLEOTIDES THAT PLAY AN IMPORTANT ROLE IN BOTH INNATE AND ACQUIRED IMMUNITY, SO THERE IS GREAT INTEREST IN LNCRNAS INVOLVED IN AUTOIMMUNE DISEASES. THE RESEARCH ON MULTIPLE SCLEROSIS HAS BEEN ENRICHED WITH MANY STUDIES ON THE MOLECULAR ROLE OF LNCRNAS IN THE PATHOGENESIS OF THE DISEASE AND THEIR POTENTIAL APPLICATION AS DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. IN PARTICULAR, MANY MULTIPLE SCLEROSIS FIELDS OF RESEARCH ARE BASED ON THE IDENTIFICATION OF LNCRNAS AS POSSIBLE BIOMARKERS ABLE TO PREDICT THE ONSET OF THE DISEASE, ITS ACTIVITY DEGREE, ITS PROGRESSION PHASE AND THE RESPONSE TO DISEASE-MODIFYING DRUGS. LAST BUT NOT LEAST, STUDIES ON LNCRNAS CAN PROVIDE A NEW MOLECULAR TARGET FOR NEW THERAPIES, MISSING, SO FAR, A CURE FOR MULTIPLE SCLEROSIS. WHILE OUR KNOWLEDGE ON THE ROLE OF LNCRNA IN MULTIPLE SCLEROSIS HAS RECENTLY IMPROVED, FURTHER STUDIES ARE REQUIRED TO BETTER UNDERSTAND THE SPECIFIC ROLE OF LNCRNAS IN THIS NEUROLOGICAL DISEASE. IN THIS REVIEW, WE PRESENT THE MOST RECENT STUDIES ON MOLECULAR CHARACTERIZATION OF LNCRNAS IN MULTIPLE SCLEROSIS DISORDER DISCUSSING THEIR CLINICAL RELEVANCE AS BIOMARKERS FOR DIAGNOSIS AND TREATMENTS. 2021 17 2662 33 EPSTEIN-BARR VIRUS AND MULTIPLE SCLEROSIS: A CONVOLUTED INTERACTION AND THE OPPORTUNITY TO UNRAVEL PREDICTIVE BIOMARKERS. SINCE THE EARLY 1980S, EPSTEIN-BARR VIRUS (EBV) INFECTION HAS BEEN DESCRIBED AS ONE OF THE MAIN RISK FACTORS FOR DEVELOPING MULTIPLE SCLEROSIS (MS), AND RECENTLY, NEW EPIDEMIOLOGICAL EVIDENCE HAS REINFORCED THIS PREMISE. EBV SEROCONVERSION PRECEDES ALMOST 99% OF THE NEW CASES OF MS AND LIKELY PREDATES THE FIRST CLINICAL SYMPTOMS. THE MOLECULAR MECHANISMS OF THIS ASSOCIATION ARE COMPLEX AND MAY INVOLVE DIFFERENT IMMUNOLOGICAL ROUTES, PERHAPS ALL RUNNING IN PARALLEL (I.E., MOLECULAR MIMICRY, THE BYSTANDER DAMAGE THEORY, ABNORMAL CYTOKINE NETWORKS, AND COINFECTION OF EBV WITH RETROVIRUSES, AMONG OTHERS). HOWEVER, DESPITE THE LARGE AMOUNT OF EVIDENCE AVAILABLE ON THESE TOPICS, THE ULTIMATE ROLE OF EBV IN THE PATHOGENESIS OF MS IS NOT FULLY UNDERSTOOD. FOR INSTANCE, IT IS UNCLEAR WHY AFTER EBV INFECTION SOME INDIVIDUALS DEVELOP MS WHILE OTHERS EVOLVE TO LYMPHOPROLIFERATIVE DISORDERS OR SYSTEMIC AUTOIMMUNE DISEASES. IN THIS REGARD, RECENT STUDIES SUGGEST THAT THE VIRUS MAY EXERT EPIGENETIC CONTROL OVER MS SUSCEPTIBILITY GENES BY MEANS OF SPECIFIC VIRULENCE FACTORS. SUCH GENETIC MANIPULATION HAS BEEN DESCRIBED IN VIRALLY-INFECTED MEMORY B CELLS FROM PATIENTS WITH MS AND ARE THOUGHT TO BE THE MAIN SOURCE OF AUTOREACTIVE IMMUNE RESPONSES. YET, THE ROLE OF EBV INFECTION IN THE NATURAL HISTORY OF MS AND IN THE INITIATION OF NEURODEGENERATION IS EVEN LESS CLEAR. IN THIS NARRATIVE REVIEW, WE WILL DISCUSS THE AVAILABLE EVIDENCE ON THESE TOPICS AND THE POSSIBILITY OF HARNESSING SUCH IMMUNOLOGICAL ALTERATIONS TO UNCOVER PREDICTIVE BIOMARKERS FOR THE ONSET OF MS AND PERHAPS FACILITATE PROGNOSTICATION OF THE CLINICAL COURSE. 2023 18 950 28 CHRONIC MILD STRESS EXACERBATES SEVERITY OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS IN ASSOCIATION WITH ALTERED NON-CODING RNA AND METABOLIC BIOMARKERS. THE CAUSAL FACTORS DETERMINING THE ONSET AND SEVERITY OF MULTIPLE SCLEROSIS (MS) ARE NOT WELL UNDERSTOOD. HERE, WE INVESTIGATED THE INFLUENCE OF CHRONIC STRESS ON CLINICAL SYMPTOMS, METABOLIC AND EPIGENETIC MANIFESTATIONS OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), A COMMON ANIMAL MODEL OF MS. LEWIS RATS WERE IMMUNIZED FOR MONOPHASIC EAE WITH MBP(69-88) AND WERE EXPOSED TO CHRONIC STRESS FOR 37DAYS STARTING 7DAYS PRIOR TO IMMUNIZATION. THE EXPOSURE TO STRESS ACCELERATED AND EXACERBATED THE CLINICAL SYMPTOMS OF EAE. BOTH STRESS AND EAE ALSO DISRUPTED METABOLIC STATUS AS INDICATED BY TRACE ELEMENTAL ANALYSIS IN BODY HAIR. STRESS PARTICULARLY EXACERBATED CHLORINE DEPOSITION IN EAE ANIMALS. MOREOVER, DEEP SEQUENCING REVEALED A CONSIDERABLE IMPACT OF STRESS ON MICRORNA EXPRESSION IN EAE. EAE BY ITSELF UPREGULATED MICRORNA EXPRESSION IN LUMBAR SPINAL CORD, INCLUDING MIR-21, MIR-142-3P, MIR-142-5P, MIR-146A, AND MIR-155. STRESS IN EAE FURTHER UP-REGULATED MIR-16, MIR-146A AND MIR-155 LEVELS. THE LATTER TWO MICRORNAS ARE RECOGNIZED BIOMARKERS OF HUMAN MS. THUS, STRESS MAY SYNERGISTICALLY EXACERBATE SEVERITY OF EAE BY ALTERING EPIGENETIC REGULATORY PATHWAYS. THE FINDINGS SUGGEST THAT STRESS MAY REPRESENT A SIGNIFICANT RISK FACTOR FOR SYMPTOMATIC DETERIORATION IN MS. STRESS-RELATED METABOLIC AND MICRORNA SIGNATURES SUPPORT THEIR VALUE AS BIOMARKERS FOR PREDICTING THE RISK AND SEVERITY OF MS. 2017 19 2192 26 EPIGENETIC METHODS AND TWIN STUDIES. GENOMIC PREDISPOSITION FAILS TO FULLY EXPLAIN THE ONSET OF COMPLEX DISEASES, WHICH IS WELL ILLUSTRATED BY THE LARGELY INCOMPLETE CONCORDANCE AMONG MONOZYGOTIC TWINS. EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, CHROMATIN REMODELING, AND NON-CODING RNA, ARE THE LINK BETWEEN ENVIRONMENTAL STIMULI AND DISEASE ONSET ON A PERMISSIVE GENETIC BACKGROUND IN AUTOIMMUNE AND CHRONIC INFLAMMATORY DISEASES. AUTOIMMUNE DISEASES NOW INCLUDE ALMOST 100 CONDITIONS AND ARE ESTIMATED TO CUMULATIVELY AFFECT UP TO 5% OF THE WORLD POPULATION WITH A HEALTHCARE EXPENDITURE SUPERIOR TO CANCER WORLDWIDE. MANY ADVANCES IN MEDICINE HAVE BEEN MADE TO TREAT THESE CONDITIONS BUT THERE ARE STILL GAPS, AND AN INNOVATIVE AND EFFICIENT THERAPY IS NEEDED. SYSTEMIC AUTOIMMUNE DISEASES INCLUDE RHEUMATOID ARTHRITIS, SYSTEMIC LUPUS ERYTHEMATOSUS, SYSTEMIC SCLEROSIS, SJOGREN SYNDROME, POLYMYOSITIS, AND DERMATOMYOSITIS. MONOZYGOTIC TWINS DISCORDANT FOR ANY DISEASE OFFER AN IDEAL STUDY DESIGN AS THEY ARE MATCHED FOR MANY FACTORS, INCLUDING GENETIC VARIATION AND THIS IS A REAL ADVANTAGE FOR EPIGENETICS STUDY. WE WILL HEREIN DISCUSS THE AVAILABLE DATA IN THE EPIGENETIC DIFFERENCES LEADING TO DISEASE DISCORDANCE IN MZ TWINS FOR SYSTEMIC LUPUS ERYTHEMATOSUS, RHEUMATOID ARTHRITIS, AND SYSTEMIC SCLEROSIS. 2020 20 2404 38 EPIGENETIC RESEARCH IN MULTIPLE SCLEROSIS: PROGRESS, CHALLENGES, AND OPPORTUNITIES. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY AND DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM. MS LIKELY RESULTS FROM A COMPLEX INTERPLAY BETWEEN PREDISPOSING CAUSAL GENE VARIANTS (THE STRONGEST INFLUENCE COMING FROM HLA CLASS II LOCUS) AND ENVIRONMENTAL RISK FACTORS SUCH AS SMOKING, INFECTIOUS MONONUCLEOSIS, AND LACK OF SUN EXPOSURE/VITAMIN D. HOWEVER, LITTLE IS KNOWN ABOUT THE MECHANISMS UNDERLYING MS DEVELOPMENT AND PROGRESSION. MOREOVER, THE CLINICAL HETEROGENEITY AND VARIABLE RESPONSE TO TREATMENT REPRESENT ADDITIONAL CHALLENGES TO A COMPREHENSIVE UNDERSTANDING AND EFFICIENT TREATMENT OF DISEASE. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION AND HISTONE POSTTRANSLATIONAL MODIFICATIONS, INTEGRATE INFLUENCES FROM THE GENES AND THE ENVIRONMENT TO REGULATE GENE EXPRESSION ACCORDINGLY. STUDYING EPIGENETIC MODIFICATIONS, WHICH ARE STABLE AND REVERSIBLE, MAY PROVIDE AN ALTERNATIVE APPROACH TO BETTER UNDERSTAND AND MANAGE DISEASE. WE HERE AIM TO REVIEW FINDINGS FROM EPIGENETIC STUDIES IN MS AND FURTHER DISCUSS THE CHALLENGES AND CLINICAL OPPORTUNITIES ARISING FROM EPIGENETIC RESEARCH, MANY OF WHICH APPLY TO OTHER DISEASES WITH SIMILAR COMPLEX ETIOLOGY. A GROWING BODY OF EVIDENCE SUPPORTS A ROLE OF EPIGENETIC PROCESSES IN THE MECHANISMS UNDERLYING IMMUNE PATHOGENESIS AND NERVOUS SYSTEM DYSFUNCTION IN MS. HOWEVER, DISPARITIES BETWEEN STUDIES SHED LIGHT ON THE NEED TO CONSIDER POSSIBLE CONFOUNDERS AND METHODOLOGICAL LIMITATIONS FOR A BETTER INTERPRETATION OF THE DATA. NEVERTHELESS, TRANSLATIONAL USE OF EPIGENETICS MIGHT OFFER NEW OPPORTUNITIES IN EPIGENETIC-BASED DIAGNOSTICS AND THERAPEUTIC TOOLS FOR A PERSONALIZED CARE OF MS PATIENTS. 2017