1 4368 139 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 2 6907 39 [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 3 4372 51 MIRNAS, OXIDATIVE STRESS, AND CANCER: A COMPREHENSIVE AND UPDATED REVIEW. OXIDATIVE STRESS REFERS TO ELEVATED LEVELS OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS). ROS HOMEOSTASIS FUNCTIONS AS A SIGNALING PATHWAY FOR NORMAL CELL SURVIVAL AND APPROPRIATE CELL SIGNALING. CHRONIC INFLAMMATION INDUCED BY IMBALANCED LEVELS OF ROS CONTRIBUTES TO MANY DISEASES AND DIFFERENT TYPES OF CANCER. ROS CAN ALTER THE EXPRESSION OF ONCOGENES AND TUMOR SUPPRESSOR GENES THROUGH EPIGENETIC MODIFICATIONS, TRANSCRIPTION FACTORS, AND NON-CODING RNAS. MICRORNAS (MIRNAS) ARE SMALL NON-CODING RNAS THAT PLAY A KEY ROLE IN MOST BIOLOGICAL PATHWAYS. EACH MIRNA REGULATES HUNDREDS OF TARGET GENES BY INHIBITING PROTEIN TRANSLATION AND/OR PROMOTING MESSENGER RNA DEGRADATION. IN NORMAL CONDITIONS, MIRNAS PLAY A PHYSIOLOGICAL ROLE IN CELL PROLIFERATION, DIFFERENTIATION, AND APOPTOSIS. HOWEVER, DIFFERENT FACTORS THAT CAN DYSREGULATE CELL SIGNALING AND CELLULAR HOMEOSTASIS CAN ALSO AFFECT MIRNA EXPRESSION. THE ALTERATION OF MIRNA EXPRESSION CAN WORK AGAINST DISTURBING FACTORS OR MEDIATE THEIR EFFECTS. OXIDATIVE STRESS IS ONE OF THESE FACTORS. CONSIDERING THE COMPLEX INTERPLAY BETWEEN ROS LEVEL AND MIRNA REGULATION AND BOTH OF THESE WITH CANCER DEVELOPMENT, WE REVIEW THE ROLE OF MIRNAS IN CANCER, FOCUSING ON THEIR FUNCTION IN OXIDATIVE STRESS. 2020 4 4285 47 MICRORNA EPIGENETIC SIGNATURES IN HUMAN DISEASE. MICRORNAS (MIRNAS) ARE SHORT NON-CODING RNAS THAT ACT AS IMPORTANT REGULATORS OF GENE EXPRESSION AS PART OF THE EPIGENETIC MACHINERY. IN ADDITION TO POSTTRANSCRIPTIONAL GENE SILENCING BY MIRNAS, THE EPIGENETIC MECHANISMS ALSO INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS AND THEIR CROSSTALK. EPIGENETIC MODIFICATIONS WERE REPORTED TO PLAY AN IMPORTANT ROLE IN MANY DISEASE ONSETS AND PROGRESSIONS AND CAN BE USED TO EXPLAIN SEVERAL FEATURES OF COMPLEX DISEASES, SUCH AS LATE ONSET AND FLUCTUATION OF SYMPTOMS. HOWEVER, MIRNAS NOT ONLY FUNCTION AS A PART OF EPIGENETIC MACHINERY, BUT ARE ALSO EPIGENETICALLY MODIFIED BY DNA METHYLATION AND HISTONE MODIFICATION LIKE ANY OTHER PROTEIN-CODING GENE. THERE IS A STRONG CONNECTION BETWEEN EPIGENOME AND MIRNOME, AND ANY DYSREGULATION OF THIS COMPLEX SYSTEM CAN RESULT IN VARIOUS PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. IN ADDITION, MIRNAS PLAY AN IMPORTANT ROLE IN TOXICOGENOMICS AND MAY EXPLAIN THE RELATIONSHIP BETWEEN TOXICANT EXPOSURE AND TUMORIGENESIS. THE PRESENT REVIEW PROVIDES INFORMATION ON 63 MIRNA GENES SHOWN TO BE EPIGENETICALLY REGULATED IN ASSOCIATION WITH 21 DISEASES, INCLUDING 11 CANCER TYPES: CARDIAC FIBROSIS, CARDIOVASCULAR DISEASE, PREECLAMPSIA, HIRSCHSPRUNG'S DISEASE, RHEUMATOID ARTHRITIS, SYSTEMIC SCLEROSIS, SYSTEMIC LUPUS ERYTHEMATOSUS, TEMPORAL LOBE EPILEPSY, AUTISM, PULMONARY FIBROSIS, MELANOMA, ACUTE MYELOID LEUKEMIA, CHRONIC LYMPHOCYTIC LEUKEMIA, COLORECTAL, GASTRIC, CERVICAL, OVARIAN, PROSTATE, LUNG, BREAST, AND BLADDER CANCER. THE REVIEW REVEALED THAT HSA-MIR-34A, HSA-MIR-34B, AND HSA-MIR-34C ARE THE MOST FREQUENTLY REPORTED EPIGENETICALLY DYSREGULATED MIRNAS. THERE IS A NEED TO FURTHER STUDY MOLECULAR MECHANISMS OF VARIOUS DISEASES TO BETTER UNDERSTAND THE CROSSTALK BETWEEN EPIGENETICS AND GENE EXPRESSION AND TO DEVELOP NEW THERAPEUTIC OPTIONS AND BIOMARKERS. 2016 5 5406 33 REGULATING THE REGULATORS: MICRORNA AND ASTHMA. ONE OBSTACLE TO DEVELOPING AN EFFECTIVE THERAPEUTIC STRATEGY TO TREAT OR PREVENT ASTHMA IS THAT THE FUNDAMENTAL CAUSES OF ASTHMA ARE NOT TOTALLY UNDERSTOOD. ASTHMA IS THOUGHT TO BE A CHRONIC TH2 IMMUNE-MEDIATED INFLAMMATORY DISEASE. EPIGENETIC CHANGES ARE RECOGNIZED TO PLAY A ROLE IN THE INITIATION AND MAINTENANCE OF A TH2 RESPONSE. MICRORNAS (MIRNAS) ARE KEY EPIGENETIC REGULATORS OF GENE EXPRESSION, AND THEIR EXPRESSION IS HIGHLY REGULATED, THEREFORE, DEREGULATION OF MIRNAS MAY PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF ASTHMA. PROFILING CIRCULATING MIRNA MIGHT PROVIDE THE HIGHEST SPECIFICITY AND SENSITIVITY TO DIAGNOSE ASTHMA; SIMILARLY, CORRECTING POTENTIAL DEFECTS IN THE MIRNA REGULATION NETWORK MAY LEAD TO NEW THERAPEUTIC MODALITIES TO TREAT THIS DISEASE. 2011 6 4348 55 MIR-146A DYSREGULATES ENERGY METABOLISM DURING NEUROINFLAMMATION. ALZHEIMER'S DISEASE (AD) AND OTHER NEURODEGENERATIVE DISEASES ARE CHARACTERIZED BY CHRONIC NEUROINFLAMMATION AND A REDUCTION IN BRAIN ENERGY METABOLISM. AN IMPORTANT ROLE HAS EMERGED FOR SMALL, NON-CODING RNA MOLECULES KNOWN AS MICRORNAS (MIRNAS) IN THE PATHOPHYSIOLOGY OF MANY NEURODEGENERATIVE DISORDERS. AS EPIGENETIC REGULATORS, MIRNAS POSSESS THE CAPACITY TO REGULATE AND FINE TUNE PROTEIN PRODUCTION BY INHIBITING TRANSLATION. SEVERAL MIRNAS, WHICH INCLUDE MIR-146A, ARE ELEVATED IN THE BRAIN, CSF, AND PLASMA OF AD PATIENTS. MIR-146A PARTICIPATES IN PATHWAYS THAT REGULATE IMMUNE ACTIVATION AND HAS SEVERAL MRNA TARGETS WHICH ENCODE FOR PROTEINS INVOLVED IN CELLULAR ENERGY METABOLISM. AN ADDITIONAL ROLE FOR EXTRACELLULAR VESICLES (EVS) HAS ALSO EMERGED IN THE PROGRESSION AD, AS EVS CAN TRANSFER FUNCTIONALLY ACTIVE PROTEINS AND RNAS FROM DISEASED TO HEALTHY CELLS. IN THE CURRENT STUDY, WE EXPOSED VARIOUS CELL TYPES PRESENT WITHIN THE CNS TO IMMUNOMODULATORY MOLECULES AND OBSERVED SIGNIFICANT UPREGULATION OF MIR-146A EXPRESSION, BOTH WITHIN CELLS AND WITHIN THEIR SECRETED EVS. FURTHER, WE ASSESSED THE EFFECTS OF MIR-146A OVEREXPRESSION ON BIOENERGETIC FUNCTION IN PRIMARY RAT GLIAL CELLS AND FOUND SIGNIFICANT REDUCTIONS IN OXIDATIVE PHOSPHORYLATION AND GLYCOLYSIS. LASTLY, WE CORRELATED MIR-146A EXPRESSION LEVELS WITHIN VARIOUS REGIONS OF THE AD BRAIN TO DISEASE STAGING AND FOUND SIGNIFICANT, POSITIVE CORRELATIONS. THESE NOVEL RESULTS DEMONSTRATE THAT THE MODULATION OF MIR-146A IN RESPONSE TO NEUROINFLAMMATORY STIMULI MAY MEDIATE THE LOSS OF MITOCHONDRIAL INTEGRITY AND FUNCTION IN CELLS, THEREBY CONTRIBUTING TO THE PROGRESSION OF BETA-AMYLOID AND TAU PATHOLOGY IN THE AD BRAIN. MULTIPLE INFLAMMATORY STIMULI CAN UPREGULATE MIRNA-146A EXPRESSION WITHIN NEURONS, MIXED GLIAL CELLS, AND BRAIN ENDOTHELIAL CELLS, WHICH IS EITHER RETAINED WITHIN THESE CELLS OR RELEASED FROM THEM AS EXTRACELLULAR VESICLE CARGO. THE UPREGULATION OF MIR-146A DISRUPTS CELLULAR BIOENERGETICS IN MIXED GLIAL CELLS. THIS MECHANISM MAY PLAY A CRITICAL ROLE IN THE NEUROINFLAMMATORY RESPONSE OBSERVED DURING ALZHEIMER'S DISEASE. 2022 7 3772 35 INTERACTION BETWEEN MICRORNA AND DNA METHYLATION IN ATHEROSCLEROSIS. ATHEROSCLEROSIS (AS) IS A CHRONIC INFLAMMATORY DISEASE ACCOMPANIED BY COMPLEX PATHOLOGICAL CHANGES, SUCH AS ENDOTHELIAL DYSFUNCTION, FOAM CELL FORMATION, AND VASCULAR SMOOTH MUSCLE CELL PROLIFERATION. MANY APPROACHES, INCLUDING REGULATING AS-RELATED GENE EXPRESSION IN THE TRANSCRIPTIONAL OR POST-TRANSCRIPTIONAL LEVEL, CONTRIBUTE TO ALLEVIATING AS DEVELOPMENT. THE DNA METHYLATION IS A CRUCIAL EPIGENETIC MODIFICATION IN REGULATING CELL FUNCTION BY SILENCING THE RELATIVE GENE EXPRESSION. THE MICRORNA (MIRNA) IS A TYPE OF NONCODING RNA THAT PLAYS AN IMPORTANT ROLE IN GENE POST-TRANSCRIPTIONAL REGULATION AND DISEASE DEVELOPMENT. THE DNA METHYLATION AND THE MIRNA ARE IMPORTANT EPIGENETIC FACTORS IN AS. HOWEVER, RECENT STUDIES HAVE FOUND A MUTUAL REGULATION BETWEEN THESE TWO FACTORS IN AS DEVELOPMENT. IN THIS STUDY, RECENT INSIGHTS INTO THE ROLES OF MIRNA AND DNA METHYLATION AND THEIR INTERACTION IN THE AS PROGRESSION ARE REVIEWED. 2021 8 6396 47 THE ROLE OF THE MIR-148/-152 FAMILY IN PHYSIOLOGY AND DISEASE. MICRORNAS (MIRNAS) ARE ENDOGENOUSLY ENCODED APPROXIMATELY 22 NT SMALL NON-CODING RNAS. THEY FUNCTION AS KEY PLAYERS OF MANY CELLULAR PROCESSES BY BASE PAIRING WITH TARGET MRNAS AND THEREBY IMPAIRING GENE EXPRESSION AT THE POST-TRANSCRIPTIONAL LEVEL. RECENT FINDINGS DEMONSTRATE A CRITICAL ROLE OF MANY MIRNAS IN IMMUNE CELL DIFFERENTIATION AND IMMUNE RESPONSES, WHICH IS ALSO ASSOCIATED WITH THE DEVELOPMENT AND PROGRESSION OF MANY TUMOR AND NON-TUMOR DISEASES. HERE WE REVIEW THE MULTIFACETED MIRNA-148/-152 FAMILY MEMBERS CONSISTING OF MIR-148A, MIR-148B AND MIR-152. NEXT TO REGULATION MECHANISMS THAT CONTROL THE EXPRESSION OF THIS MIRNA FAMILY, WE WILL FOCUS ON (I) THE ROLE OF MIR-148A IN REGULATING B AND T LYMPHOCYTE FUNCTION AND ITS ROLE IN ASSOCIATED DISEASES AND (II) THE IMPORTANCE OF MIR-148/-152 FAMILY MEMBERS FOR CANCER INITIATION, TUMOR GROWTH AND METASTASIS FORMATION. IN ADDITION, THIS REVIEW AIMS TO HIGHLIGHT SOME SELECTED TARGETS OF THE MIRNA-148/-152 FAMILY MEMBERS, WHICH ARE INVOLVED IN THE BIOLOGY OF CANCER AND MAINTENANCE OF EPIGENETIC PATTERNS. IN CONCLUSION, MEMBERS OF THE MIR-148/-152 FAMILY MIGHT REPRESENT PROGNOSTIC MARKERS AND/OR POTENTIAL THERAPEUTIC TARGETS FOR TREATMENT OF AUTOIMMUNE DISORDERS, CHRONIC INFLAMMATORY DISEASES AND MULTIPLE TYPES OF CANCER. 2017 9 2036 38 EPIGENETIC CHANGES OF THE IMMUNE SYSTEM WITH ROLE IN TUMOR DEVELOPMENT. TUMOR DEVELOPMENT IS CLOSELY RELATED TO CHRONIC INFLAMMATION AND TO EVASION OF IMMUNE DEFENSE MECHANISMS BY NEOPLASTIC CELLS. THE MEDIATORS OF THE INFLAMMATORY PROCESS AS WELL AS PROTEINS INVOLVED IN IMMUNE RESPONSE OR IMMUNE RESPONSE EVASION CAN BE SUBJECT TO VARIOUS EPIGENETIC CHANGES SUCH AS METHYLATION, ACETYLATION, OR PHOSPHORYLATION. SOME OF THESE, SUCH AS CYTOKINE SUPPRESSORS, ARE UNDERGOING REPRESSION THROUGH EPIGENETIC CHANGES, AND OTHERS SUCH AS CYTOKINES OR CHEMOKINES ARE UNDERGOING ACTIVATION THROUGH EPIGENETIC CHANGES, BOTH MODIFICATIONS HAVING AS A RESULT TUMOR PROGRESSION. THE ACTIVATING CHANGES CAN AFFECT THE RECEPTOR MOLECULES INVOLVED IN IMMUNE RESPONSE AND THESE PROMOTE INFLAMMATION AND SUBSEQUENTLY TUMOR DEVELOPMENT WHILE THE INACTIVATING CHANGES SEEM TO BE RELATED TO THE TUMOR REGRESSION PROCESS. THE PROTEINS INVOLVED IN ANTIGEN PRESENTATION, AND, THEREFORE IN IMMUNE RESPONSE ESCAPE, SUCH AS CLASSICAL HLA PROTEINS AND RELATED APM (ANTIGEN PRESENTATION MACHINERY) WITH THEIR EPIGENETIC CHANGES CONTRIBUTE TO THE TUMOR DEVELOPMENT PROCESS, EITHER TO TUMOR PROGRESSION OR REGRESSION, DEPENDING ON THE IMMUNE EFFECTOR CELLS THAT ARE IN PLAY. 2018 10 4289 35 MICRORNA IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS THE MOST PREVALENT DEGENERATIVE JOINT DISEASE AND IS ACCOMPANIED BY PAIN AND JOINT DYSFUNCTION. ITS CLINICAL TREATMENT TENDS TO BE UNSATISFACTORY. NOVEL TARGETS IN OA INCLUDE GENES THAT ARE INVOLVED IN OA PATHOPHYSIOLOGY AND HAVE BEEN DISCOVERED USING GENE NETWORK, EPIGENETIC AND MICRORNA (MIRNA) APPROACHES. MIRNA HAS BEEN IMPLICATED IN IMPORTANT CELLULAR PROCESSES SUCH AS LIPID METABOLISM, APOPTOSIS, DIFFERENTIATION AND ORGAN DEVELOPMENT. THE IMPORTANCE OF MIRNA REGULATION IN CELLULAR FUNCTION IS BECOMING INCREASINGLY CLEAR AS NEW MIRNA TARGETS ARE REVEALED. THE PRESENT REVIEW SUMMARIZES THE CURRENT EVIDENCE OF THE IMPORTANT ROLE PLAYED BY MIRNA IN DETERMINING THE COMPLEX GENE EXPRESSION PATTERNS OF OA CHONDROCYTES AND THEIR ROLE IN THE REGULATION OF TRANSCRIPTION, AND POSSIBLE DEMETHYLATION MECHANISMS THAT MIGHT BE APPLICABLE IN OA. IN SUMMARY, MIRNA MAY HAVE IMPORTANT DIAGNOSTIC AND THERAPEUTIC POTENTIAL, AND MIGHT PROVIDE A NOVEL MEANS OF TREATING OA. 2011 11 6800 49 [EPIGENETIC DISTURBANCES IN SYSTEMIC LUPUS ERYTHEMATOSUS]. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE THAT RESULTS IN UNCONTROLLED IMMUNE SYSTEM ACTIVATION AND OVERPRODUCTION OF AUTOANTIBODIES. THE PATHOGENESIS OF THE DISEASE IS COMPLEX AND NOT FULLY UNDERSTOOD, NEVERTHELESS, GENETIC AND ENVIRONMENTAL FACTORS PLAY AN IMPORTANT ROLE. SO FAR, ABOUT 30 GENES HAVE BEEN IDENTIFIED TO BE INVOLVED IN THE SLE PATHOMECHANISM. HOWEVER, NOT ALL GENETICALLY PREDISPOSED INDIVIDUALS DEVELOP THE DISEASE. THIS PHENOMENON CAN BE ASSOCIATED WITH EPIGENETIC CHANGES THAT OCCUR UNDER THE INFLUENCE OF ENVIRONMENTAL FACTORS. THEY CAN AFFECT GENE EXPRESSION AND ARE POTENTIALLY HEREDITARY, BUT DO NOT LEAD TO CHANGES IN THE NUCLEOTIDE SEQUENCE. EPIGENETIC DYSFUNCTIONS, IDENTIFIED IN THE COURSE OF THE DISEASE, LEAD TO CHANGES IN THE EXPRESSION OF GENES THAT PLAY A KEY ROLE IN MAINTAINING THE BODY'S IMMUNE TOLERANCE. MAJOR MECHANISMS OF EPIGENETIC VARIABILITY ARE: DNA METHYLATION, HISTONE PROTEIN MODIFICATION, NON-CODING RNA EXPRESSION, AS WELL AS GENE IMPRINTING. THE MAJOR EPIGENETIC DYSFUNCTIONS AFFECTING THE PATHOGENESIS OF THE DISEASE ARE GLOBAL HYPOMETHYLATION ON CD4+ T CELLS RESULTING FROM ERK SIGNALING PATHWAY REGULATION, HISTONE HYPOACETYLATION, HISTONE H3 LYSINE METHYLATION, AND REACTIVATION OF INACTIVE CHROMOSOME X. IN LUPUS PATIENTS, VARIOUS EPIGENETIC MECHANISMS INTERACT WITH EACH OTHER, ENHANCING THE EXPRESSION OR SILENCING OF GENES RESPONSIBLE FOR THE PRODUCTION OF PRO-INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINES AND ACTIVATION OF AUTOREACTIVE B-LYMPHOCYTES. 2018 12 6309 25 THE REGULATION OF MIRNAS IN INFLAMMATION-RELATED CARCINOGENESIS. CHRONIC INFLAMMATION PLAYS IMPORTANT ROLES IN THE INITIATION AND DEVELOPMENT OF VARIOUS CANCERS, PARTICULARLY GASTROINTESTINAL CANCER. CANCER IS CHARACTERIZED BY STEPWISE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS OF GENES. AS A HIGH RISK FACTOR FOR CANCER, CHRONIC INFLAMMATORY RESPONSE PRODUCES GREAT AMOUNT OF MEDIATORS, INCLUDING CYTOKINES, REACTIVE OXYGEN AND NITROGEN SPECIES, PROTEINASES, WHICH CAN INDUCE GENETIC AND EPIGENETIC CHANGES OF CANCER-ASSOCIATED GENES AND PATHWAYS. FURTHERMORE, INFLAMMATION ALSO MODULATES THE EXPRESSION OF MIRNAS THAT NOT ONLY REGULATE THE EXPRESSION OF TUMOR-RELATED PROTEINS BUT ALSO ENHANCE THE TUMOR-PROMOTING INFLAMMATORY PROCESS. IN THE CURRENT REVIEW, WE SUMMARIZE THE MECHANISMS BY WHICH INFLAMMATORY MEDIATORS AND SIGNALING REGULATE THE BIOSYNTHESIS OF MIRNAS, AS WELL AS THE INVOLVEMENT OF MIRNAS IN THE FEEDBACK LOOPS PROMOTING INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2015 13 3949 47 LNCRNAS IN T LYMPHOCYTES: RNA REGULATION AT THE HEART OF THE IMMUNE RESPONSE. GENOME-WIDE ANALYSES IN THE LAST DECADE HAVE UNCOVERED THE PRESENCE OF A LARGE NUMBER OF LONG NON-PROTEIN-CODING TRANSCRIPTS THAT SHOW HIGHLY TISSUE- AND STATE-SPECIFIC EXPRESSION PATTERNS. HIGH-THROUGHPUT SEQUENCING ANALYSES IN DIVERSE SUBSETS OF IMMUNE CELLS HAVE REVEALED A COMPLEX AND DYNAMIC EXPRESSION PATTERN FOR THESE LONG NONCODING RNAS (LNCRNAS) THAT CORRELATE WITH THE FUNCTIONAL STATES OF IMMUNE CELLS. ALTHOUGH THE VAST MAJORITY OF LNCRNAS EXPRESSED IN IMMUNE CELLS REMAIN UNSTUDIED, FUNCTIONAL STUDIES PERFORMED ON A SMALL SUBSET HAVE INDICATED THAT THEIR STATE-SPECIFIC EXPRESSIONS PATTERN FREQUENTLY HAS A REGULATORY IMPACT ON THE FUNCTION OF IMMUNE CELLS. IN VIVO AND IN VITRO STUDIES HAVE POINTED TO THE INVOLVEMENT OF LNCRNAS IN A WIDE VARIETY OF CELLULAR PROCESSES, INCLUDING BOTH THE INNATE AND ADAPTIVE IMMUNE RESPONSE THROUGH MECHANISMS RANGING FROM EPIGENETIC AND TRANSCRIPTIONAL REGULATION TO SEQUESTRATION OF FUNCTIONAL MOLECULES IN SUBCELLULAR COMPARTMENTS. THIS REVIEW WILL FOCUS MAINLY ON THE ROLE OF LNCRNAS IN CD4(+) AND CD8(+) T CELLS, WHICH PLAY PIVOTAL ROLES IN ADAPTIVE IMMUNITY. RECENT STUDIES HAVE POINTED TO KEY PHYSIOLOGICAL FUNCTIONS FOR LNCRNAS DURING SEVERAL DEVELOPMENTAL AND FUNCTIONAL STAGES OF THE LIFE CYCLE OF LYMPHOCYTES. ALTHOUGH LNCRNAS PLAY IMPORTANT PHYSIOLOGICAL ROLES IN LYMPHOCYTIC RESPONSE TO ANTIGENIC STIMULATION, DIFFERENTIATION INTO EFFECTOR CELLS, AND SECRETION OF CYTOKINES, THEIR DYSREGULATED EXPRESSION CAN PROMOTE OR SUSTAIN PATHOLOGICAL STATES SUCH AS AUTOIMMUNITY, CHRONIC INFLAMMATION, CANCER, AND VIREMIA. THIS, TOGETHER WITH THEIR HIGHLY CELL TYPE-SPECIFIC EXPRESSION PATTERNS, MAKES LNCRNAS IDEAL THERAPEUTIC TARGETS AND UNDERSCORES THE NEED FOR ADDITIONAL STUDIES INTO THE ROLE OF THESE UNDERSTUDIED TRANSCRIPTS IN ADAPTIVE IMMUNE RESPONSE. 2021 14 4439 39 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 15 4330 49 MICRORNAS: AN EPIGENETIC TOOL TO STUDY CELIAC DISEASE. THIS ARTICLE SUMMARIZES RECENT FINDINGS ON THE ROLE OF MICRORNAS (MIRNAS) IN BIOLOGICAL PROCESSES ASSOCIATED WITH THE REGULATION OF CHRONIC INFLAMMATION AND AUTOIMMUNITY. MIRNAS ARE SMALL NON-CODING RNA MOLECULES THAT HAVE BEEN RECENTLY EMERGED AS A NEW CLASS OF MODULATORS OF GENE EXPRESSION AT THE POST-TRANSCRIPTIONAL LEVEL. MIRNAS BIND TO COMPLEMENTARY SEQUENCES OF SPECIFIC TARGETS OF MESSENGERS RNA, WHICH CAN INTERFERE WITH PROTEIN SYNTHESIS. WE REVIEWED STUDIES THAT EVALUATED THE EXPRESSION PATTERNS OF MIRNAS IN DIFFERENT AUTOIMMUNE DISEASES, ESPECIALLY IN CELIAC DISEASE (CD). CD IS A CHRONIC ENTEROPATHY TRIGGERED BY GLUTEN PROTEINS, CHARACTERIZED BY ALTERED IMMUNE RESPONSES IN GENETICALLY SUSCEPTIBLE INDIVIDUALS THAT RESULTS IN DAMAGE TO THE BOWEL MUCOSA. CD HAS A HIGH PREVALENCE AND AN EFFECTIVE TREATMENT BY A SPECIFIC DIET ("GLUTEN FREE DIET"). GENETIC FACTORS CONFER SUSCEPTIBILITY BUT DO NOT EXPLAIN THE WHOLE DISEASE, SUGGESTING THAT ENVIRONMENTAL FACTORS DO PLAY A RELEVANT ROLE IN THE DEVELOPMENT OF THE CONDITION.THE EVALUATION OF THE POTENTIAL ROLE OF MIRNA IS OF PARTICULAR INTEREST IN CD GIVEN THAT THESE EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF AUTOIMMUNE AND INFLAMMATORY DISEASES HAVE BEEN RECENTLY DESCRIBED. IMPROVING OUR UNDERSTANDING OF MIRNAS IN CD WILL CONTRIBUTE TO CLARIFY THE ROLE OF ALTERED EPIGENETIC REGULATION IN THE DEVELOPMENT AND COURSE OF THIS DISEASE. 2014 16 6533 47 TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES ASSOCIATED WITH SEVERE ASTHMA. THE 10% OF PATIENTS WITH THE MOST SEVERE ASTHMA ARE RESPONSIBLE FOR A LARGE PART OF HEALTHCARE EXPENDITURE AND MORBIDITY. UNDERSTANDING THE PROCESSES INVOLVED IS KEY IF NEW THERAPEUTIC APPROACHES ARE TO BE DEVELOPED. EVIDENCE IS ACCUMULATING THAT CHRONIC DISEASES SUCH AS ASTHMA ARE ASSOCIATED WITH TEMPORAL AND SPATIAL ALTERATIONS IN THE PATTERN OF INFLAMMATORY GENE EXPRESSION WITHIN THE AIRWAYS. EXPRESSION OF THESE GENES CAN BE REGULATED BY TRANSCRIPTIONAL, POSTTRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS. IT IS WELL ESTABLISHED THAT BINDING OF ACTIVATED TRANSCRIPTION FACTORS TO SPECIFIC INDUCIBLE GENE PROMOTER SITES IS TIGHTLY CONTROLLED BY CHROMATIN STATE AS A RESULT OF HISTONE MODIFICATIONS, PARTICULARLY THE BALANCE BETWEEN HISTONE ACETYLATION AND DEACETYLATION [1]. THE INTERACTION BETWEEN TRANSCRIPTION FACTORS AND THE PROMOTER IS KEY TO THE DIVERSIFICATION OF GENE EXPRESSION IN A TIME DEPENDENT MANNER LEADING TO ALTERED GENE EXPRESSION PROFILES. ALTERATIONS OF THE ACCESSIBILITY OF TRANSCRIPTION FACTORS TO THE DNA CAN HAVE RESIDING EFFECTS UPON GENE TRANSCRIPTION. THIS REVIEW WILL FOCUS ON THE REGULATION OF SEVERAL GROUPS OF KEY GENES WHICH ARE INVOLVED IN CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA DRAWING MAINLY FROM OUR EXPERIENCE OF STUDYING THESE PROCESSES IN AIRWAY SMOOTH MUSCLE CELLS. AN OVERVIEW IS SHOWN IN FIGURE 1. 2011 17 2909 43 GENE EXPRESSION PROFILING IN FIBROMYALGIA INDICATES AN AUTOIMMUNE ORIGIN OF THE DISEASE AND OPENS NEW AVENUES FOR TARGETED THERAPY. FIBROMYALGIA IS A CHRONIC DISORDER CHARACTERIZED BY WIDESPREAD PAIN AND BY SEVERAL NON-PAIN SYMPTOMS. AUTOIMMUNITY, SMALL FIBER NEUROPATHY AND NEUROINFLAMMATION HAVE BEEN SUGGESTED TO BE INVOLVED IN THE PATHOGENESIS OF THE DISEASE. WE HAVE INVESTIGATED THE GENE EXPRESSION PROFILE IN PERIPHERAL BLOOD MONONUCLEAR CELLS OBTAINED FROM TEN PATIENTS AND TEN HEALTHY SUBJECTS. OF THE 545,500 TRANSCRIPTS ANALYZED, 1673 RESULTED MODULATED IN FIBROMYALGIC PATIENTS. THE MAJORITY OF THESE GENES ARE INVOLVED IN BIOLOGICAL PROCESSES AND PATHWAYS LINKED TO THE CLINICAL MANIFESTATIONS OF THE DISEASE. MOREOVER, GENES INVOLVED IN IMMUNOLOGICAL PATHWAYS CONNECTED TO INTERLEUKIN-17 AND TO TYPE I INTERFERON SIGNATURES WERE ALSO MODULATED, SUGGESTING THAT AUTOIMMUNITY PLAYS A ROLE IN THE DISEASE. WE THEN AIMED AT IDENTIFYING DIFFERENTIALLY EXPRESSED LONG NON-CODING RNAS (LNCRNAS) FUNCTIONALLY CONNECTED TO MODULATED GENES BOTH DIRECTLY AND VIA MICRORNA TARGETING. ONLY TWO LNCRNAS OF THE 298 FOUND MODULATED IN PATIENTS, WERE ABLE TO TARGET THE MOST HIGHLY CONNECTED GENES IN THE FIBROMYALGIA INTERACTOME, SUGGESTING THEIR INVOLVEMENT IN CRUCIAL GENE REGULATION. OUR GENE EXPRESSION DATA WERE CONFIRMED BY REAL TIME PCR, BY AUTOANTIBODY TESTING, DETECTION OF SOLUBLE MEDIATORS AND TH-17 POLARIZATION IN A VALIDATION COHORT OF 50 PATIENTS. OUR RESULTS INDICATE THAT GENETIC AND EPIGENETIC MECHANISMS AS WELL AS AUTOIMMUNITY PLAY A PIVOTAL ROLE IN THE PATHOGENESIS OF FIBROMYALGIA. 2020 18 6340 36 THE ROLE OF EPIGENETIC FACTORS IN PSORIASIS. PSORIASIS IS A CHRONIC, SYSTEMIC, IMMUNE-MEDIATED DISEASE WITH AN INCIDENCE OF APPROXIMATELY 2%. THE PATHOGENESIS OF THE DISEASE IS COMPLEX AND NOT YET FULLY UNDERSTOOD. GENETIC FACTORS PLAY A SIGNIFICANT ROLE IN THE PATHOGENESIS OF THE DISEASE. IN PREDISPOSED INDIVIDUALS, MULTIPLE TRIGGER FACTORS MAY CONTRIBUTE TO DISEASE ONSET AND EXACERBATIONS OF SYMPTOMS. ENVIRONMENTAL FACTORS (STRESS, INFECTIONS, CERTAIN MEDICATIONS, NICOTINISM, ALCOHOL, OBESITY) PLAY A SIGNIFICANT ROLE IN THE PATHOGENESIS OF PSORIASIS. IN ADDITION, EPIGENETIC MECHANISMS ARE CONSIDERED RESULT IN MODULATION OF INDIVIDUAL GENE EXPRESSION AND AN INCREASED LIKELIHOOD OF THE DISEASE. STUDIES HIGHLIGHT THE SIGNIFICANT ROLE OF EPIGENETIC FACTORS IN THE ETIOLOGY AND PATHOGENESIS OF PSORIASIS. EPIGENETIC MECHANISMS IN PSORIASIS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS. EPIGENETIC MECHANISMS INDUCE GENE EXPRESSION CHANGES UNDER THE INFLUENCE OF CHEMICAL MODIFICATIONS OF DNA AND HISTONES, WHICH ALTER CHROMATIN STRUCTURE AND ACTIVATE TRANSCRIPTION FACTORS OF SELECTED GENES, THUS LEADING TO TRANSLATION OF NEW MRNA WITHOUT AFFECTING THE DNA SEQUENCE. EPIGENETIC FACTORS CAN REGULATE GENE EXPRESSION AT THE TRANSCRIPTIONAL (VIA HISTONE MODIFICATION, DNA METHYLATION) AND POSTTRANSCRIPTIONAL LEVELS (VIA MICRORNAS AND LONG NON-CODING RNAS). THIS STUDY AIMS TO PRESENT AND DISCUSS THE DIFFERENT EPIGENETIC MECHANISMS IN PSORIASIS BASED ON A REVIEW OF THE AVAILABLE LITERATURE. 2021 19 5573 35 ROLE OF MICRORNA IN SEVERE ASTHMA. THE VARIOUS ROLES OF MICRORNAS (MIRNAS) IN THE EPIGENETIC REGULATION OF HUMAN DISEASE ARE GAINING IMPORTANCE AS AREAS OF RESEARCH, AND A BETTER UNDERSTANDING OF THESE ROLES MAY IDENTIFY TARGETS FOR DEVELOPMENT OF NOVEL THERAPIES FOR SEVERE ASTHMA. MIRNAS, A CLASS OF SMALL NON-CODING RNAS THAT SERVE AS POST-TRANSCRIPTIONAL GENE REPRESSORS, ARE RECOGNIZED AS CRITICAL COMPONENTS IN REGULATING TISSUE HOMEOSTASIS. ALTERATION IN MIRNA EXPRESSION DISRUPTS HOMEOSTASIS AND IS AN UNDERLYING MECHANISM FOR DEVELOPMENT OF CHRONIC RESPIRATORY DISEASES, INCLUDING ASTHMA. DIFFERENTIAL PROFILES OF MIRNA EXPRESSION ARE INVOLVED IN INFLAMMATION AND REMODELING PATHOGENICITY VIA ACTIVATING AIRWAY STRUCTURAL CELLS AND IMMUNE CELLS AND INDUCING CYTOKINE RELEASES. MIRNA ACTION LEADS TO ASTHMA PROGRESSION FROM MILD TO SEVERE STAGES. HERE, CURRENT KNOWLEDGE OF THE HETEROGENEOUS ROLES OF MIRNAS IN SEVERE ASTHMA, INCLUDING BIOLOGICAL MECHANISMS UNDERLYING TH2 AND MACROPHAGE POLARIZATION, TYPE 2 INNATE LYMPHOID CELL (ILC2) BIOLOGY REGULATION, STEROID-RESISTANT ASTHMA PHENOTYPE, AIRWAY SMOOTH MUSCLE (ASM) DYSFUNCTION, AND IMPAIRED ANTI-VIRAL INNATE IMMUNE, ARE REVIEWED. 2019 20 6136 53 THE EPIGENETICS OF MULTIPLE SCLEROSIS AND OTHER RELATED DISORDERS. MULTIPLE SCLEROSIS (MS) IS A DEMYELINATING DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE CENTRAL NERVOUS SYSTEM (CNS) GRAY AND WHITE MATTER. ALTHOUGH THE CAUSE OF MS IS UNKNOWN, IT IS WIDELY APPRECIATED THAT INNATE AND ADAPTIVE IMMUNE PROCESSES CONTRIBUTE TO ITS PATHOGENESIS. THESE INCLUDE MICROGLIA/MACROPHAGE ACTIVATION, PRO-INFLAMMATORY T-CELL (TH1) RESPONSES AND HUMORAL RESPONSES. ADDITIONALLY, THERE IS EVIDENCE INDICATING THAT MS HAS A NEURODEGENERATIVE COMPONENT SINCE NEURONAL AND AXONAL LOSS OCCURS EVEN IN THE ABSENCE OF OVERT INFLAMMATION. THESE ASPECTS ALSO FORM THE RATIONALE FOR CLINICAL MANAGEMENT OF THE DISEASE. HOWEVER, THE CURRENTLY AVAILABLE THERAPIES TO CONTROL THE DISEASE ARE ONLY PARTIALLY EFFECTIVE AT BEST INDICATING THAT MORE EFFECTIVE THERAPEUTIC SOLUTIONS ARE URGENTLY NEEDED. IT IS APPRECIATED THAT IN THE IMMUNE-DRIVEN AND NEURODEGENERATIVE PROCESSES MS-SPECIFIC DEREGULATION OF GENE EXPRESSIONS AND RESULTING PROTEIN DYSFUNCTION ARE THOUGHT TO PLAY A CENTRAL ROLE. THESE DEVIATIONS IN GENE EXPRESSION PATTERNS CONTRIBUTE TO THE INFLAMMATORY RESPONSE IN THE CNS, AND TO NEURONAL OR AXONAL LOSS. EPIGENETIC MECHANISMS CONTROL TRANSCRIPTION OF MOST, IF NOT ALL GENES, IN NUCLEATED CELLS INCLUDING CELLS OF THE CNS AND IN HAEMATOPOIETIC CELLS. MS-SPECIFIC ALTERATIONS IN EPIGENETIC REGULATION OF GENE EXPRESSION MAY THEREFORE LIE AT THE HEART OF THE DEREGULATION OF GENE EXPRESSION IN MS. AS SUCH, EPIGENETIC MECHANISMS MOST LIKELY PLAY AN IMPORTANT ROLE IN DISEASE PATHOGENESIS. IN THIS REVIEW WE DISCUSS A ROLE FOR MS-SPECIFIC DEREGULATION OF EPIGENETIC FEATURES THAT CONTROL GENE EXPRESSION IN THE CNS AND IN THE PERIPHERY. FURTHERMORE, WE DISCUSS THE APPLICATION OF SMALL MOLECULE INHIBITORS THAT TARGET THE EPIGENETIC MACHINERY TO AMELIORATE DISEASE IN EXPERIMENTAL ANIMAL MODELS, INDICATING THAT SUCH APPROACHES MAY BE APPLICABLE TO MS PATIENTS. 2014