1 4304 146 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 2 3678 33 INFLAMMATION AND REGENERATION IN THE DENTIN-PULP COMPLEX: A DOUBLE-EDGED SWORD. DENTAL TISSUE INFECTION AND DISEASE RESULT IN ACUTE AND CHRONIC ACTIVATION OF THE INNATE IMMUNE RESPONSE, WHICH IS MEDIATED BY MOLECULAR AND CELLULAR SIGNALING. DIFFERENT CELL TYPES WITHIN THE DENTIN-PULP COMPLEX ARE ABLE TO DETECT INVADING BACTERIA AT ALL STAGES OF THE INFECTION. INDEED, AT RELATIVELY EARLY DISEASE STAGES, ODONTOBLASTS WILL RESPOND TO BACTERIAL COMPONENTS, AND AS THE DISEASE PROGRESSES, CORE PULPAL CELLS INCLUDING FIBROBLASTS, STEMS CELLS, ENDOTHELIAL CELLS, AND IMMUNE CELLS WILL BECOME INVOLVED. PATTERN RECOGNITION RECEPTORS, SUCH AS TOLL-LIKE RECEPTORS EXPRESSED ON THESE CELL TYPES, ARE RESPONSIBLE FOR DETECTING BACTERIAL COMPONENTS, AND THEIR LIGAND BINDING LEADS TO THE ACTIVATION OF THE NUCLEAR FACTOR-KAPPA B AND P38 MITOGEN-ACTIVATED PROTEIN (MAP) KINASE INTRACELLULAR SIGNALING CASCADES. SUBSEQUENT NUCLEAR TRANSLOCATION OF THE TRANSCRIPTION FACTOR SUBUNITS FROM THESE PATHWAYS WILL LEAD TO PROINFLAMMATORY MEDIATOR EXPRESSION, INCLUDING INCREASES IN CYTOKINES AND CHEMOKINES, WHICH TRIGGER HOST CELLULAR DEFENSE MECHANISMS. THE COMPLEX MOLECULAR SIGNALING WILL RESULT IN THE RECRUITMENT OF IMMUNE SYSTEM CELLS TARGETED AT COMBATING THE INVADING MICROBES; HOWEVER, THE TRAFFICKING AND ANTIBACTERIAL ACTIVITY OF THESE CELLS CAN LEAD TO COLLATERAL TISSUE DAMAGE. RECENT EVIDENCE SUGGESTS THAT IF INFLAMMATION IS RESOLVED RELATIVELY LOW LEVELS OF PROINFLAMMATORY MEDIATORS MAY PROMOTE TISSUE REPAIR, WHEREAS IF CHRONIC INFLAMMATION ENSUES REPAIR MECHANISMS BECOME INHIBITED. THUS, THE EFFECTS OF MEDIATORS ARE TEMPORAL CONTEXT DEPENDENT. ALTHOUGH CONTAINMENT AND REMOVAL OF THE INFECTION ARE KEYS TO ENABLE DENTAL TISSUE REPAIR, IT IS FEASIBLE THAT THE DEVELOPMENT OF ANTI-INFLAMMATORY AND IMMUNOMODULATORY APPROACHES, BASED ON MOLECULAR, EPIGENETIC, AND PHOTOBIOMODULATORY TECHNOLOGIES, MAY ALSO BE BENEFICIAL FOR FUTURE ENDODONTIC TREATMENTS. 2014 3 5580 37 ROLE OF NEUROTOXICANTS IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE: A MECHANISTIC INSIGHT. ALZHEIMER'S DISEASE (AD) IS THE MOST CONSPICUOUS CHRONIC NEURODEGENERATIVE SYNDROME, WHICH HAS BECOME A SIGNIFICANT CHALLENGE FOR THE GLOBAL HEALTHCARE SYSTEM. MULTIPLE STUDIES HAVE CORROBORATED A CLEAR ASSOCIATION OF NEUROTOXICANTS WITH AD PATHOGENICITY, SUCH AS AMYLOID BETA (ABETA) PROTEINS AND NEUROFIBRILLARY TANGLES (NFTS), SIGNALLING PATHWAY MODIFICATIONS, CELLULAR STRESS, COGNITIVE DYSFUNCTIONS, NEURONAL APOPTOSIS, NEUROINFLAMMATION, EPIGENETIC MODIFICATION, AND SO ON. THIS REVIEW, THEREFORE, AIMED TO ADDRESS SEVERAL ESSENTIAL MECHANISMS AND SIGNALLING CASCADES, INCLUDING WNT (WINGLESS AND INT.) SIGNALLING PATHWAY, AUTOPHAGY, MAMMALIAN TARGET OF RAPAMYCIN (MTOR), PROTEIN KINASE C (PKC) SIGNALLING CASCADES, CELLULAR REDOX STATUS, ENERGY METABOLISM, GLUTAMATERGIC NEUROTRANSMISSIONS, IMMUNE CELL STIMULATIONS (E.G. MICROGLIA, ASTROCYTES) AS WELL AS AN AMYLOID PRECURSOR PROTEIN (APP), PRESENILIN-1 (PSEN1), PRESENILIN-2 (PSEN2) AND OTHER AD-RELATED GENE EXPRESSIONS THAT HAVE BEEN PRETENTIOUS AND MODULATED BY THE VARIOUS NEUROTOXICANTS. THIS REVIEW CONCLUDED THAT NEUROTOXICANTS PLAY A MOMENTOUS ROLE IN DEVELOPING AD THROUGH MODULATING VARIOUS SIGNALLING CASCADES. NEVERTHELESS, COMPREHENSION OF THIS RISK AGENT-INDUCED NEUROTOXICITY IS FAR TOO LITTLE. MORE IN-DEPTH EPIDEMIOLOGICAL AND SYSTEMATIC INVESTIGATIONS ARE NEEDED TO UNDERSTAND THE POTENTIAL MECHANISMS BETTER TO ADDRESS THESE NEUROTOXICANTS AND IMPROVE APPROACHES TO THEIR RISK EXPOSURE THAT AID IN AD PATHOGENESIS.KEY MESSAGESINEVITABLE CASCADE MECHANISMS OF HOW ALZHEIMER'S DISEASE-RELATED (AD-RELATED) GENE EXPRESSIONS ARE MODULATED BY NEUROTOXICANTS HAVE BEEN DISCUSSED.INVOLVEMENT OF THE NEUROTOXICANTS-INDUCED PATHWAYS CAUSED AN EXTENDED RISK OF AD IS EXPLICITED.INTEGRATION OF CELL CULTURE, ANIMALS AND POPULATION-BASED ANALYSIS ON THE CLINICAL SEVERITY OF AD IS ADDRESSED. 2021 4 6887 30 [ROLE OF METAFLAMMATION AS A SYSTEMIC MANIFESTATION OF METABOLIC DISEASES]. VISCERAL OBESITY AS A COMPONENT OF THE METABOLIC SYNDROME IS CHARACTERIZED BY SYSTEMIC AND LOCAL INFLAMMATION, WHICH CAN BE QUANTIFIED IN ORGANS (METAFLAMMATION). THIS PROCESS CAN BE REGARDED AS A CHRONIC, STERILE, AND LOW-GRADE STATE OF INFLAMMATION WITHOUT INFECTION, TRAUMA, TUMOR OR AUTOIMMUNITY. IT IS CAUSED BY AN INFLAMMATION OF THE VISCERAL ADIPOSE TISSUE (ADIPOSE INFLAMMATION OR ADIPOFLAMMATION) DUE TO ADIPOCYTE HYPERTROPHY AND HYPERPLASIA WITH INCREASED INFILTRATION BY MONOCYTES AND MACROPHAGES. IMPORTANT IS THE PRESENCE OF PROINFLAMMATORY, SO-CALLED POLARIZED M1 MACROPHAGES THAT ARE INDUCED BY INTERFERON GAMMA (IFN-GAMMA) AND LIPOPOLYSACCHARIDES (LPS) WITH SECRETION OF INTERLEUKIN (IL)-6, TUMOR NECROSIS FACTOR (TNF) AND IL?1. IN CONTRAST, THE ANTI-INFLAMMATORY, SO-CALLED POLARIZED M2 MACROPHAGES INDUCED BY IL?4 AND IL-13 WITH SECRETION OF IL?8 AND IL-10 DECREASE. IN ADDITION, THE SECRETED ADIPOKINE PATTERN CHANGES FROM ANTI-INFLAMMATORY TO PROINFLAMMATORY. ADIPOCYTE NECROSIS, LOCAL HYPOXIA, DYSREGULATED AUTOPHAGY, ACTIVATION OF INFLAMMASOMES, MODULATION OF TOLL-LIKE RECEPTORS, AND EPIGENETIC FACTORS PLAY A COMPLEX ROLE. THIS MECHANISM RESULTS IN LOCAL INSULIN RESISTANCE AND SUBSEQUENTLY A SYSTEMIC INSULIN RESISTANCE OF PERIPHERAL ORGANS AS WELL AS A SPILLOVER OF LOCAL MEDIATORS OF INFLAMMATION INTO THE SYSTEMIC CIRCULATION (MEASURED AS OBESITY C?REACTIVE PROTEIN, CRP). THE ACTIVATION OF INFLAMMATORY SIGNAL TRANSDUCTION CASCADES LEADS TO INHIBITORY PHOSPHORYLATION OF THE INSULIN SIGNALING PATHWAY AND A WEAKENING OF THE EFFECT OF INSULIN. IN PARALLEL, ECTOPIC LIPID ACCUMULATION OCCURS IN THE LIVER, MUSCULATURE, PANCREAS, PERICARDIUM AND LUNGS. DIACYLGLYCEROL (DAG) ACTIVATES SPECIFIC ISOFORMS OF PROTEIN KINASE C (EPSILON IN THE LIVER AND TAU IN THE MUSCULATURE), WHICH IN TURN LEAD TO INHIBITION OF THE INSULIN SIGNALING PATHWAY. INSULIN RESISTANCE IN OBESITY AND TYPE 2 DIABETES MELLITUS IS AN INFLAMMATORY DISEASE. THE AIM OF FUTURE TRANSLATIONAL APPROACHES IS AN ANTI-INFLAMMATORY, MOLECULARLY INDIVIDUALIZED (PRECISION MEDICINE) TREATMENT IN ADIPOSE TISSUE (TARGETED THERAPY) AND IN ORGANS OF INSULIN RESISTANCE. 2023 5 799 25 CELLULAR SIGNALING AND POTENTIAL NEW TREATMENT TARGETS IN DIABETIC RETINOPATHY. DYSFUNCTION AND DEATH OF MICROVASCULAR CELLS AND IMBALANCE BETWEEN THE PRODUCTION AND THE DEGRADATION OF EXTRACELLULAR MATRIX (ECM) PROTEINS ARE A CHARACTERISTIC FEATURE OF DIABETIC RETINOPATHY (DR). GLUCOSE-INDUCED BIOCHEMICAL ALTERATIONS IN THE VASCULAR ENDOTHELIAL CELLS MAY ACTIVATE A CASCADE OF SIGNALING PATHWAYS LEADING TO INCREASED PRODUCTION OF ECM PROTEINS AND CELLULAR DYSFUNCTION/DEATH. CHRONIC DIABETES LEADS TO THE ACTIVATION OF A NUMBER OF SIGNALING PROTEINS INCLUDING PROTEIN KINASE C, PROTEIN KINASE B, AND MITOGEN-ACTIVATED PROTEIN KINASES. THESE SIGNALING CASCADES ARE ACTIVATED IN RESPONSE TO HYPERGLYCEMIA-INDUCED OXIDATIVE STRESS, POLYOL PATHWAY, AND ADVANCED GLYCATION END PRODUCT FORMATION AMONG OTHERS. THE ABERRANT SIGNALING PATHWAYS ULTIMATELY LEAD TO ACTIVATION OF TRANSCRIPTION FACTORS SUCH AS NUCLEAR FACTOR-KAPPAB AND ACTIVATING PROTEIN-1. THE ACTIVITY OF THESE TRANSCRIPTION FACTORS IS ALSO REGULATED BY EPIGENETIC MECHANISMS THROUGH TRANSCRIPTIONAL COACTIVATOR P300. THESE COMPLEX SIGNALING PATHWAYS MAY BE INVOLVED IN GLUCOSE-INDUCED ALTERATIONS OF ENDOTHELIAL CELL PHENOTYPE LEADING TO THE PRODUCTION OF INCREASED ECM PROTEINS AND VASOACTIVE EFFECTOR MOLECULES CAUSING FUNCTIONAL AND STRUCTURAL CHANGES IN THE MICROVASCULATURE. UNDERSTANDING OF SUCH MECHANISTIC PATHWAYS WILL HELP TO DEVELOP FUTURE ADJUVANT THERAPIES FOR DIABETIC RETINOPATHY. 2007 6 6758 25 WNT SIGNALING IN STEM CELL BIOLOGY AND REGENERATIVE MEDICINE. WNT FAMILY MEMBERS ARE SECRETED-TYPE GLYCOPROTEINS TO ORCHESTRATE EMBRYOGENESIS, TO MAINTAIN HOMEOSTASIS, AND TO INDUCE PATHOLOGICAL CONDITIONS. FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, LRP5, LRP6, AND ROR2 ARE TRANSMEMBRANE RECEPTORS TRANSDUCING WNT SIGNALS BASED ON LIGAND-DEPENDENT PREFERENTIALITY FOR CAVEOLIN- OR CLATHRIN-MEDIATED ENDOCYTOSIS. WNT SIGNALS ARE TRANSDUCED TO CANONICAL PATHWAY FOR CELL FATE DETERMINATION, AND TO NON-CANONICAL PATHWAYS FOR REGULATION OF PLANAR CELL POLARITY, CELL ADHESION, AND MOTILITY. MYC, CCND1, AXIN2, FGF20, WISP1, JAG1, DKK1 AND GLUCAGON ARE TARGET GENES OF CANONICAL WNT SIGNALING CASCADE, WHILE CD44, VIMENTIN AND STX5 ARE TARGET GENES OF NON-CANONICAL WNT SIGNALING CASCADES. HOWEVER, TARGET GENES OF WNT SIGNALING CASCADES ARE DETERMINED IN A CONTEXT-DEPENDENT MANNER DUE TO EXPRESSION PROFILE OF TRANSCRIPTION FACTORS AND EPIGENETIC STATUS. WNT SIGNALING CASCADES NETWORK WITH NOTCH, FGF, BMP AND HEDGEHOG SIGNALING CASCADES TO REGULATE THE BALANCE OF STEM CELLS AND PROGENITOR CELLS. HERE WNT SIGNALING IN EMBRYONIC STEM CELLS, NEURAL STEM CELLS, MESENCHYMAL STEM CELLS, HEMATOPOIETIC STEM CELLS, AND INTESTINAL STEM CELLS WILL BE REVIEWED. WNT3, WNT5A AND WNT10B ARE EXPRESSED IN UNDIFFERENTIATED HUMAN EMBRYONIC STEM CELLS, WHILE WNT6, WNT8B AND WNT10B IN ENDODERM PRECURSOR CELLS. WNT6 IS EXPRESSED IN INTESTINAL CRYPT REGION FOR STEM OR PROGENITOR CELLS. TNF/ALPHA-WNT10B SIGNALING IS A NEGATIVE FEEDBACK LOOP TO MAINTAIN HOMEOSTASIS OF ADIPOSE TISSUE AND GASTROINTESTINAL MUCOSA WITH CHRONIC INFLAMMATION. RECOMBINANT WNT PROTEIN OR WNT MIMETIC (CIRCULAR PEPTIDE, SMALL MOLECULE COMPOUND, OR RNA APTAMER) IN COMBINATION WITH NOTCH MIMETIC, FGF PROTEIN, AND BMP PROTEIN OPENS A NEW WINDOW TO TISSUE ENGINEERING FOR REGENERATIVE MEDICINE. 2008 7 4149 29 MECHANISTIC INSIGHT INTO THE EFFECTS OF CURCUMIN ON NEUROINFLAMMATION-DRIVEN CHRONIC PAIN. CHRONIC PAIN IS A PERSISTENT AND UNREMITTING CONDITION THAT HAS IMMENSE EFFECTS ON PATIENTS' QUALITY OF LIFE. STUDIES HAVE SHOWN THAT NEUROINFLAMMATION IS ASSOCIATED WITH THE INDUCTION AND PROGRESSION OF CHRONIC PAIN. THE ACTIVATION OF MICROGLIA AND ASTROCYTES IS THE MAJOR HALLMARK OF SPINAL NEUROINFLAMMATION LEADING TO NEURONAL EXCITABILITY IN THE PROJECTION NEURONS. EXCESSIVE ACTIVATION OF MICROGLIA AND ASTROCYTES IS ONE OF THE MAJOR CONTRIBUTING FACTORS TO THE EXACERBATION OF PAIN. HOWEVER, THE CURRENT CHRONIC PAIN TREATMENTS, MAINLY BY TARGETING THE NEURONAL CELLS, REMAIN INEFFECTIVE AND UNABLE TO MEET THE PATIENTS' NEEDS. CURCUMIN, A NATURAL PLANT PRODUCT FOUND IN THE CURCUMA GENUS, IMPROVES CHRONIC PAIN BY DIMINISHING THE RELEASE OF INFLAMMATORY MEDIATORS FROM THE SPINAL GLIA. THIS REVIEW DETAILS THE ROLE OF CURCUMIN IN MICROGLIA AND ASTROCYTES BOTH IN VITRO AND IN VIVO AND HOW IT IMPROVES PAIN. WE ALSO DESCRIBE THE MECHANISM OF CURCUMIN BY HIGHLIGHTING THE MAJOR GLIA-MEDIATED CASCADES IN PAIN. MOREOVER, THE ROLE OF CURCUMIN ON INFLAMMASOME AND EPIGENETIC REGULATION IS DISCUSSED. FURTHERMORE, WE DISCUSS THE STRATEGIES USED TO IMPROVE THE EFFICACY OF CURCUMIN. THIS REVIEW ILLUSTRATES THAT CURCUMIN MODULATING MICROGLIA AND ASTROCYTES COULD ASSURE THE TREATMENT OF CHRONIC PAIN BY SUPPRESSING SPINAL NEUROINFLAMMATION. 2021 8 5140 26 POTENTIAL REGULATORS OF THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE DURING SENESCENCE AND AGING. SENESCENT CELLS EXPRESS AND SECRETE A VARIETY OF EXTRACELLULAR MODULATORS THAT INCLUDE CYTOKINES, CHEMOKINES, PROTEASES, GROWTH FACTORS, AND SOME ENZYMES ASSOCIATED WITH EXTRACELLULAR MATRIX REMODELING, DEFINED AS THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). SASP REINFORCES SENESCENT CELL CYCLE ARREST, STIMULATES AND RECRUITS IMMUNE CELLS FOR IMMUNE-MEDIATED CLEARANCE OF POTENTIALLY TUMORIGENIC CELLS, LIMITS OR INDUCES FIBROSIS, AND PROMOTES WOUND HEALING AND TISSUE REGENERATION. ON THE OTHER HAND, SASP MEDIATES CHRONIC INFLAMMATION LEADING TO THE DESTRUCTION OF TISSUE STRUCTURE AND FUNCTION AND STIMULATING THE GROWTH AND SURVIVAL OF TUMOR CELLS. SASP IS HIGHLY HETEROGENEOUS AND THE ROLE OF SASP DEPENDS ON THE CONTEXT. THE REGULATION OF SASP OCCURS AT MULTIPLE LEVELS INCLUDING CHROMATIN REMODELING, TRANSCRIPTION, MRNA TRANSLATION, INTRACELLULAR TRAFFICKING, AND SECRETION. SEVERAL SASP MODULATORS HAVE ALREADY BEEN IDENTIFIED SETTING THE STAGE FOR FUTURE RESEARCH ON THEIR CLINICAL APPLICATIONS. IN THIS REVIEW, WE SUMMARIZE IN DETAIL THE POTENTIAL SIGNALING PATHWAYS THAT TRIGGER AND REGULATE SASP PRODUCTION DURING AGING AND SENESCENCE. 2022 9 911 27 CHRONIC EXPOSURE TO TNF REPROGRAMS CELL SIGNALING PATHWAYS IN FIBROBLAST-LIKE SYNOVIOCYTES BY ESTABLISHING LONG-TERM INFLAMMATORY MEMORY. FIBROBLAST-LIKE SYNOVIOCYTES (FLS) PLAY A CRITICAL ROLE IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS (RA). CHRONIC INFLAMMATION INDUCES TRANSCRIPTOMIC AND EPIGENETIC MODIFICATIONS THAT IMPARTS A PERSISTENT CATABOLIC PHENOTYPE TO THE FLS, DESPITE THEIR DISSOCIATION FROM THE INFLAMMATORY ENVIRONMENT. WE ANALYZED HIGH THROUGHPUT GENE EXPRESSION AND CHROMATIN ACCESSIBILITY DATA FROM HUMAN AND MOUSE FLS FROM OUR AND OTHER STUDIES AVAILABLE ON PUBLIC REPOSITORIES, WITH THE GOAL OF IDENTIFYING THE PERSISTENTLY REPROGRAMMED SIGNALING PATHWAYS DRIVEN BY CHRONIC INFLAMMATION. WE FOUND THAT THE GENE EXPRESSION CHANGES INDUCED BY SHORT-TERM TUMOR NECROSIS FACTOR-ALPHA (TNF) TREATMENT WERE LARGELY SUSTAINED IN THE FLS EXPOSED TO CHRONIC INFLAMMATION. THESE CHANGES THAT INCLUDED BOTH ACTIVATION AND REPRESSION OF GENE EXPRESSION, WERE ACCOMPANIED BY THE REMODELING OF CHROMATIN ACCESSIBILITY. THE SUSTAINED ACTIVATED GENES (SAGS) INCLUDED ESTABLISHED PRO-INFLAMMATORY SIGNALING COMPONENTS KNOWN TO ACT AT MULTIPLE LEVELS OF NF-KAPPAB, STAT AND AP-1 SIGNALING CASCADES. INTERESTINGLY, THE SUSTAINED REPRESSED GENES (SRGS) INCLUDED CRITICAL MEDIATORS AND TARGETS OF THE BMP SIGNALING PATHWAY. WE THUS IDENTIFIED SUSTAINED REPRESSION OF BMP SIGNALING AS A UNIQUE CONSTITUENT OF THE LONG-TERM INFLAMMATORY MEMORY INDUCED BY CHRONIC INFLAMMATION. WE POSTULATE THAT SIMULTANEOUS TARGETING OF THESE ACTIVATED AND REPRESSED SIGNALING PATHWAYS MAY BE NECESSARY TO COMBAT RA PERSISTENCE. 2020 10 6532 29 TRANSCRIPTIONAL REGULATION OF INFLAMMASOMES. INFLAMMASOMES ARE MULTIMOLECULAR COMPLEXES WITH POTENT INFLAMMATORY ACTIVITY. AS SUCH, THEIR ACTIVITY IS TIGHTLY REGULATED AT THE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL LEVELS. IN THIS REVIEW, WE PRESENT THE TRANSCRIPTIONAL REGULATION OF INFLAMMASOME GENES FROM SENSORS (E.G., NLRP3) TO SUBSTRATES (E.G., IL-1BETA). LINEAGE-DETERMINING TRANSCRIPTION FACTORS SHAPE INFLAMMASOME RESPONSES IN DIFFERENT CELL TYPES WITH PROFOUND CONSEQUENCES ON THE RESPONSIVENESS TO INFLAMMASOME-ACTIVATING STIMULI. PRO-INFLAMMATORY SIGNALS (STERILE OR MICROBIAL) HAVE A KEY TRANSCRIPTIONAL IMPACT ON INFLAMMASOME GENES, WHICH IS LARGELY MEDIATED BY NF-KAPPAB AND THAT TRANSLATES INTO HIGHER ANTIMICROBIAL IMMUNE RESPONSES. FURTHERMORE, DIVERSE INTRINSIC (E.G., CIRCADIAN CLOCK, METABOLITES) OR EXTRINSIC (E.G., XENOBIOTICS) SIGNALS ARE INTEGRATED BY SIGNAL-DEPENDENT TRANSCRIPTION FACTORS AND CHROMATIN STRUCTURE CHANGES TO MODULATE TRANSCRIPTIONALLY INFLAMMASOME RESPONSES. FINALLY, ANTI-INFLAMMATORY SIGNALS (E.G., IL-10) COUNTERBALANCE INFLAMMASOME GENES INDUCTION TO LIMIT DELETERIOUS INFLAMMATION. TRANSCRIPTIONAL REGULATIONS THUS APPEAR AS THE FIRST LINE OF INFLAMMASOME REGULATION TO RAISE THE DEFENSE LEVEL IN FRONT OF STRESS AND INFECTIONS BUT ALSO TO LIMIT EXCESSIVE OR CHRONIC INFLAMMATION. 2020 11 4333 39 MICRORNAS: KEY PLAYERS IN MICROGLIA AND ASTROCYTE MEDIATED INFLAMMATION IN CNS PATHOLOGIES. THE SIGNIFICANCE OF MICROGLIA AND ASTROCYTES IN NEURAL DEVELOPMENT, IN MAINTAINING SYNAPTIC CONNECTIONS AND HOMEOSTASIS IN THE HEALTHY BRAIN IS WELL ESTABLISHED. MICROGLIA ARE DYNAMIC IMMUNE CELLS OF THE BRAIN THAT ELICIT AN IMMUNE RESPONSE DURING BRAIN DAMAGE AND ALSO PARTICIPATE IN TISSUE REPAIR AND REGENERATION, WHILE ASTROCYTES CONTRIBUTE TO THE LOCAL INFLAMMATORY RESPONSE BY PRODUCING PROINFLAMMATORY CYTOKINES AND RESOLVING NEURONAL DAMAGE THROUGH PRODUCTION OF ANTI-INFLAMMATORY CYTOKINES AND NEUROTROPHIC FACTORS. RECENT EFFORTS HAVE FOCUSED ON ELUCIDATING THE EPIGENETIC MECHANISMS WHICH REGULATE GLIAL CELL BEHAVIOR IN NORMAL AND PATHOLOGIC STATES. AN IMPORTANT CLASS OF EPIGENETIC REGULATORS IS MICRORNAS (MIRNAS) WHICH ARE SMALL NON-CODING RNA MOLECULES THAT REGULATE GENE EXPRESSION POSTTRANSCRIPTIONALLY. CERTAIN DYSREGULATED MIRNAS CONTRIBUTE TO CHRONIC MICROGLIAL INFLAMMATION IN THE BRAIN, THEREBY LEADING TO PROGRESSION OF NEUROLOGICAL DISEASES LIKE ALZHEIMER'S DISEASE, TRAUMATIC INJURY, AMYOTROPHIC LATERAL SCLEROSIS AND STROKE. FURTHER, SEVERAL MIRNAS ARE DIFFERENTIALLY EXPRESSED IN ASTROCYTES AFTER ISCHEMIA AND SPINAL CORD INJURY. DESPITE KNOWLEDGE ABOUT MIRNAS IN NEUROINFLAMMATION, LITTLE IS KNOWN ABOUT EFFECTIVE DELIVERY ROUTES AND PHARMACOKINETIC DATA FOR MIRNA BASED THERAPEUTICS. THIS REVIEW SUMMARIZES THE CURRENT RESEARCH ON THE ROLE OF MIRNAS IN PROMOTING AND INHIBITING INFLAMMATORY RESPONSE OF MICROGLIA AND ASTROCYTES IN A DISEASE-SPECIFIC MANNER. IN ADDITION, MIRNA DELIVERY AS A THERAPEUTIC STRATEGY TO TREAT NEUROINFLAMMATION IS DISCUSSED. 2016 12 5429 23 REGULATION OF TYPE I INTERFERON RESPONSES. TYPE I INTERFERONS (IFNS) ACTIVATE INTRACELLULAR ANTIMICROBIAL PROGRAMMES AND INFLUENCE THE DEVELOPMENT OF INNATE AND ADAPTIVE IMMUNE RESPONSES. CANONICAL TYPE I IFN SIGNALLING ACTIVATES THE JANUS KINASE (JAK)-SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) PATHWAY, LEADING TO TRANSCRIPTION OF IFN-STIMULATED GENES (ISGS). HOST, PATHOGEN AND ENVIRONMENTAL FACTORS REGULATE THE RESPONSES OF CELLS TO THIS SIGNALLING PATHWAY AND THUS CALIBRATE HOST DEFENCES WHILE LIMITING TISSUE DAMAGE AND PREVENTING AUTOIMMUNITY. HERE, WE SUMMARIZE THE SIGNALLING AND EPIGENETIC MECHANISMS THAT REGULATE TYPE I IFN-INDUCED STAT ACTIVATION AND ISG TRANSCRIPTION AND TRANSLATION. THESE REGULATORY MECHANISMS DETERMINE THE BIOLOGICAL OUTCOMES OF TYPE I IFN RESPONSES AND WHETHER PATHOGENS ARE CLEARED EFFECTIVELY OR CHRONIC INFECTION OR AUTOIMMUNE DISEASE ENSUES. 2014 13 842 31 CHEMOKINES IN CHRONIC PAIN: CELLULAR AND MOLECULAR MECHANISMS AND THERAPEUTIC POTENTIAL. CHRONIC PAIN RESULTING FROM NERVE INJURY, TISSUE INFLAMMATION, AND TUMOR INVASION OR TREATMENT, IS A MAJOR HEALTH PROBLEM IMPACTING THE QUALITY OF LIFE AND PRODUCING A SIGNIFICANT ECONOMIC AND SOCIAL BURDEN. HOWEVER, THE CURRENT ANALGESIC DRUGS INCLUDING NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND OPIOIDS ARE INADEQUATE TO RELIEVE CHRONIC PAIN DUE TO THE LACK OF EFFICACY OR SEVERE SIDE-EFFECTS. CHEMOKINES ARE A FAMILY OF SMALL SECRETED PROTEINS THAT BIND TO G PROTEIN-COUPLED RECEPTORS TO TRIGGER INTRACELLULAR SIGNALING PATHWAYS AND DIRECT CELL MIGRATION, PROLIFERATION, SURVIVAL, AND INFLAMMATION UNDER HOMEOSTATIC AND PATHOLOGICAL CONDITIONS. ACCUMULATING EVIDENCE SUPPORTS THE IMPORTANT ROLE OF CHEMOKINES AND CHEMOKINE RECEPTORS IN THE PERIPHERAL AND CENTRAL NERVOUS SYSTEM IN MEDIATING CHRONIC PAIN VIA ENHANCING NEUROINFLAMMATION. IN THIS REVIEW, WE FOCUS ON RECENT PROGRESS IN UNDERSTANDING THE COMPREHENSIVE ROLES OF CHEMOKINES AND CHEMOKINE RECEPTORS IN THE GENERATION AND MAINTENANCE OF DIFFERENT TYPES OF CHRONIC PAIN, INCLUDING NEUROPATHIC PAIN, INFLAMMATORY PAIN, CANCER PAIN, AND VISCERAL PAIN. THE CURRENT REVIEW ALSO SUMMARIZES THE UPSTREAM SIGNALING OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION ON THE EXPRESSION OF CHEMOKINES AND CHEMOKINE RECEPTORS AS WELL AS THE DOWNSTREAM SIGNALING OF CHEMOKINE RECEPTORS UNDERLYING CHRONIC PAIN. AS CHRONIC ITCH AND CHRONIC PAIN SHARE SOME COMMON MECHANISMS, WE ALSO DISCUSS THE EMERGING ROLES OF CHEMOKINES AND CHEMOKINE RECEPTORS IN CHRONIC ITCH. TARGETING SPECIFIC CHEMOKINES OR CHEMOKINE RECEPTORS BY SIRNAS, BLOCKING ANTIBODIES, OR SMALL-MOLECULE ANTAGONISTS MAY OFFER NEW THERAPEUTIC POTENTIAL FOR THE MANAGEMENT OF CHRONIC PAIN. 2020 14 6110 25 THE EPIGENETIC ALTERATION OF SYNOVIAL CELL GENE EXPRESSION IN RHEUMATOID ARTHRITIS AND THE ROLES OF NUCLEAR FACTOR KAPPAB AND NOTCH SIGNALING PATHWAYS. RHEUMATOID ARTHRITIS (RA) IS A COMPLEX PROCESS OF CHRONIC AND PROGRESSIVE INFLAMMATION ASSOCIATED WITH ACTIVATION OF NUMEROUS SIGNALING MOLECULES AND TRANSCRIPTION FACTORS AND HYPERPROLIFERATION OF SYNOVIOCYTES OF THE AFFECTED JOINTS, ALTHOUGH THE GREATER PART OF ITS PATHOPHYSIOLOGICAL PROCESS IS EXPLAINED BY ACTIVATION OF NUCLEAR FACTOR KAPPAB (NF-KAPPAB). FOR EXAMPLE, THE SELF-PERPETUATING NATURE OF THE RHEUMATOID INFLAMMATION IS ASCRIBABLE TO OVEREXPRESSION OF THE PROINFLAMMATORY CYTOKINES TUMOR NECROSIS FACTOR ALPHA AND INTERLEUKIN-1BETA, KNOWN TO ELICIT THE ACTIVATION CASCADE FOR NF-KAPPAB AND ACTIVATOR PROTEIN-1 THAT ARE RESPONSIBLE FOR TRANSCRIPTIONAL INDUCTION OF THESE CYTOKINES AMONG OTHER TARGET GENES, WHICH CONFORM A POSITIVE FEEDBACK LOOP FOR CONTINUATION AND EXPANSION OF THE INFLAMMATORY RESPONSES. IN ADDITION, COMPARATIVE GENE EXPRESSION PROFILE ANALYSES HAVE REVEALED ACTIVATION OF A NUMBER OF GENES THAT EXPLAIN THE "TRANSFORMED-LIKE" PHENOTYPE OF SYNOVIOCYTES. AMONG THE GENES EXPRESSED IN RHEUMATOID SYNOVIOCYTES UPON INFLAMMATORY STIMULI, INDUCTION OF GENE EXPRESSION OF NOTCH PROTEINS AND ITS LIGAND HAVE BEEN FOUND. POSSIBLE ROLES OF NOTCH SIGNALING IN RA SYNOVIOCYTES ARE DISCUSSED. 2005 15 4368 47 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 16 3469 34 HYPOXIA-INDUCIBLE HISTONE LYSINE DEMETHYLASES: IMPACT ON THE AGING PROCESS AND AGE-RELATED DISEASES. HYPOXIA IS AN ENVIRONMENTAL STRESS AT HIGH ALTITUDE AND UNDERGROUND CONDITIONS BUT IT IS ALSO PRESENT IN MANY CHRONIC AGE-RELATED DISEASES, WHERE BLOOD FLOW INTO TISSUES IS IMPAIRED. THE OXYGEN-SENSING SYSTEM STIMULATES GENE EXPRESSION PROTECTING TISSUES AGAINST HYPOXIC INSULTS. HYPOXIA STABILIZES THE EXPRESSION OF HYPOXIA-INDUCIBLE TRANSCRIPTION FACTOR-1ALPHA (HIF-1ALPHA), WHICH CONTROLS THE EXPRESSION OF HUNDREDS OF SURVIVAL GENES RELATED TO E.G. ENHANCED ENERGY METABOLISM AND AUTOPHAGY. MOREOVER, MANY STRESS-RELATED SIGNALING MECHANISMS, SUCH AS OXIDATIVE STRESS AND ENERGY METABOLIC DISTURBANCES, AS WELL AS THE SIGNALING CASCADES VIA CERAMIDE, MTOR, NF-KAPPAB, AND TGF-BETA PATHWAYS, CAN ALSO INDUCE THE EXPRESSION OF HIF-1ALPHA PROTEIN TO FACILITATE CELL SURVIVAL IN NORMOXIA. HYPOXIA IS LINKED TO PROMINENT EPIGENETIC CHANGES IN CHROMATIN LANDSCAPE. SCREENING STUDIES HAVE INDICATED THAT THE STABILIZATION OF HIF-1ALPHA INCREASES THE EXPRESSION OF DISTINCT HISTONE LYSINE DEMETHYLASES (KDM). HIF-1ALPHA STIMULATES THE EXPRESSION OF KDM3A, KDM4B, KDM4C, AND KDM6B, WHICH ENHANCE GENE TRANSCRIPTION BY DEMETHYLATING H3K9 AND H3K27 SITES (REPRESSIVE EPIGENETIC MARKS). IN ADDITION, HIF-1ALPHA INDUCES THE EXPRESSION OF KDM2B AND KDM5B, WHICH REPRESS TRANSCRIPTION BY DEMETHYLATING H3K4ME2,3 SITES (ACTIVATING MARKS). HYPOXIA-INDUCIBLE KDMS SUPPORT LOCALLY THE GENE TRANSCRIPTION INDUCED BY HIF-1ALPHA, ALTHOUGH THEY CAN ALSO CONTROL GENOME-WIDE CHROMATIN LANDSCAPE, ESPECIALLY KDMS WHICH DEMETHYLATE H3K9 AND H3K27 SITES. THESE EPIGENETIC MARKS HAVE IMPORTANT ROLE IN THE CONTROL OF HETEROCHROMATIN SEGMENTS AND 3D FOLDING OF CHROMOSOMES, AS WELL AS THE GENETIC LOCI REGULATING CELL TYPE COMMITMENT, PROLIFERATION, AND CELLULAR SENESCENCE, E.G. THE INK4 BOX. A CHRONIC STIMULATION OF HIF-1ALPHA CAN PROVOKE TISSUE FIBROSIS AND CELLULAR SENESCENCE, WHICH BOTH ARE INCREASINGLY PRESENT WITH AGING AND AGE-RELATED DISEASES. WE WILL REVIEW THE REGULATION OF HIF-1ALPHA-DEPENDENT INDUCTION OF KDMS AND CLARIFY THEIR ROLE IN PATHOLOGICAL PROCESSES EMPHASIZING THAT LONG-TERM STRESS-RELATED INSULTS CAN IMPAIR THE MAINTENANCE OF CHROMATIN LANDSCAPE AND PROVOKE CELLULAR SENESCENCE AND TISSUE FIBROSIS ASSOCIATED WITH AGING AND AGE-RELATED DISEASES. 2016 17 4969 34 PATHOLOGICAL NEUROINFLAMMATORY CONVERSION OF REACTIVE ASTROCYTES IS INDUCED BY MICROGLIA AND INVOLVES CHROMATIN REMODELING. FOLLOWING BRAIN INJURY OR IN NEURODEGENERATIVE DISEASES, ASTROCYTES BECOME REACTIVE AND MAY SUFFER PATHOLOGICAL REMODELING, FEATURES OF WHICH ARE THE LOSS OF THEIR HOMEOSTATIC FUNCTIONS AND A PRO-INFLAMMATORY GAIN OF FUNCTION THAT FACILITATES NEURODEGENERATION. PHARMACOLOGICAL INTERVENTION TO MODULATE THIS ASTROGLIAL RESPONSE AND NEUROINFLAMMATION IS AN INTERESTING NEW THERAPEUTIC RESEARCH STRATEGY, BUT IT STILL REQUIRES A DEEPER UNDERSTANDING OF THE UNDERLYING CELLULAR AND MOLECULAR MECHANISMS OF THE PHENOMENON. BASED ON THE KNOWN MICROGLIAL-ASTROGLIAL INTERACTION, THE PROMINENT ROLE OF THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY IN MEDIATING ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION, AND ITS ABILITY TO RECRUIT CHROMATIN-REMODELING ENZYMES, WE FIRST EXPLORED THE MICROGLIAL ROLE IN THE INITIATION OF ASTROGLIAL PRO-INFLAMMATORY CONVERSION AND THEN MONITORED THE PROGRESSION OF EPIGENETIC CHANGES IN THE ASTROCYTIC CHROMATIN. DIFFERENT CONFIGURATIONS OF PRIMARY GLIAL CULTURE WERE USED TO MODULATE MICROGLIA-ASTROCYTE CROSSTALK WHILE INDUCING PRO-INFLAMMATORY GAIN OF FUNCTION BY LIPOPOLYSACCHARIDE (LPS) EXPOSURE. IN VIVO, BRAIN ISCHEMIA BY CORTICAL DEVASCULARIZATION (PIAL DISRUPTION) WAS PERFORMED TO VERIFY THE PRESENCE OF EPIGENETIC MARKS IN REACTIVE ASTROCYTES. OUR RESULTS SHOWED THAT 1) MICROGLIA IS REQUIRED TO INITIATE THE PATHOLOGICAL CONVERSION OF ASTROCYTES BY TRIGGERING THE NF-KAPPAB SIGNALING PATHWAY; 2) THIS INTERACTION IS MEDIATED BY SOLUBLE FACTORS AND INDUCES STABLE ASTROGLIAL PHENOTYPIC CHANGES; 3) THE PATHOLOGICAL CONVERSION PROMOTES CHROMATIN REMODELING WITH STABLE INCREASE IN H3K9K14AC, TEMPORARY INCREASE IN H3K27AC, AND TEMPORARY REDUCTION IN HETEROCHROMATIN MARK H3K9ME3; AND 4) IN VIVO REACTIVE ASTROCYTES SHOW INCREASED H3K27AC MARK IN THE NEUROINFLAMMATORY MILIEU FROM THE ISCHEMIC PENUMBRA. OUR FINDINGS INDICATE THAT ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION IS ASSOCIATED WITH PROFOUND CHANGES IN THE CONFIGURATION OF ASTROCYTIC CHROMATIN, WHICH IN TURN ARE INITIATED BY MICROGLIA-DERIVED CUES. THESE RESULTS OPEN A NEW AVENUE IN THE STUDY OF POTENTIAL PHARMACOLOGICAL INTERVENTIONS THAT MODIFY THE INITIATION AND STABILIZATION OF ASTROGLIAL PATHOLOGICAL REMODELING, WHICH WOULD BE USEFUL IN ACUTE AND CHRONIC CNS INJURY. EPIGENETIC CHANGES REPRESENT A PLAUSIBLE PHARMACOLOGICAL TARGET TO INTERFERE WITH THE STABILIZATION OF THE PATHOLOGICAL ASTROGLIAL PHENOTYPE. 2021 18 3694 34 INFLAMMATORY COMPONENTS OF THE THYROID CANCER MICROENVIRONMENT: AN AVENUE FOR IDENTIFICATION OF NOVEL BIOMARKERS. THE INCIDENCE OF THYROID CANCER IN THE UNITED STATES IS ON THE RISE WITH AN APPRECIABLY HIGH DISEASE RECURRENCE RATE OF 20-30%. ANAPLASTIC THYROID CANCER (ATC), ALTHOUGH RARE IN OCCURRENCE, IS AN AGGRESSIVE FORM OF CANCER WITH LIMITED TREATMENT OPTIONS AND BLEAK CURE RATES. THIS CHAPTER USES DISCUSSIONS OF IN VITRO MODELS THAT ARE REPRESENTATIVE OF PAPILLARY, ANAPLASTIC, AND FOLLICULAR THYROID CANCER TO EVALUATE THE CROSSTALK BETWEEN SPECIFIC CELLS OF THE TUMOR MICROENVIRONMENT (TME), WHICH SERVES AS A HIGHLY HETEROGENEOUS REALM OF SIGNALING CASCADES AND METABOLISM THAT ARE ASSOCIATED WITH TUMORIGENESIS. THE CELLULAR CONSTITUENTS OF THE TME CARRY OUT VARYING CHARACTERISTIC IMMUNOMODULATORY FUNCTIONS THAT ARE DISCUSSED THROUGHOUT THIS CHAPTER. THE AFOREMENTIONED CELL TYPES INCLUDE CANCER-ASSOCIATED FIBROBLASTS (CAFS), ENDOTHELIAL CELLS (ECS), AND CANCER STEM CELLS (CSCS), AS WELL AS SPECIFIC IMMUNE CELLS, INCLUDING NATURAL KILLER (NK) CELLS, DENDRITIC CELLS (DCS), MAST CELLS, T REGULATORY (TREG) CELLS, CD8+ T CELLS, AND TUMOR-ASSOCIATED MACROPHAGES (TAMS). TAM-MEDIATED INFLAMMATION IS ASSOCIATED WITH A POOR PROGNOSIS OF THYROID CANCER, AND THE MOLECULAR BASIS OF THE CELLULAR CROSSTALK BETWEEN MACROPHAGES AND THYROID CANCER CELLS WITH RESPECT TO INDUCING A METASTATIC PHENOTYPE IS NOT YET KNOWN. THE DYNAMIC NATURE OF THE PHYSIOLOGICAL TRANSITION TO PATHOLOGICAL METASTATIC PHENOTYPES WHEN ESTABLISHING THE TME ENCOMPASSES A WIDE RANGE OF CHARACTERISTICS THAT ARE FURTHER EXPLORED WITHIN THIS CHAPTER, INCLUDING THE ROLES OF SOMATIC MUTATIONS AND EPIGENETIC ALTERATIONS THAT DRIVE THE GENETIC HETEROGENEITY OF CANCER CELLS, ALLOWING FOR SELECTIVE ADVANTAGES THAT AID IN THEIR PROLIFERATION. INDUCTION OF THESE PROLIFERATING CELLS IS TYPICALLY ACCOMPLISHED THROUGH INFLAMMATORY INDUCTION, WHEREBY CHRONIC INFLAMMATION SETS UP A CONSTANT PHYSIOLOGICAL STATE OF INFLAMMATORY CELL RECRUITMENT. THE SECRETIONS OF THESE INFLAMMATORY CELLS CAN ALTER THE GENETIC MAKEUP OF PROLIFERATING CELLS, WHICH CAN IN TURN, PROMOTE TUMOR GROWTH.THIS CHAPTER ALSO PRESENTS AN IN-DEPTH ANALYSIS OF MOLECULAR INTERACTIONS WITHIN THE TME, INCLUDING SECRETORY CYTOKINES AND EXOSOMES. SINCE THE EXOSOMAL CARGO OF A CELL IS A REFLECTION AND FINGERPRINT OF THE ORIGINATING PARENTAL CELLS, THE PROFILING OF EXOSOMAL MIRNA DERIVED FROM THYROID CANCER CELLS AND MACROPHAGES IN THE TME MAY SERVE AS AN IMPORTANT STEP IN BIOMARKER DISCOVERY. IDENTIFICATION OF A DISTINCT SET OF TUMOR SUPPRESSIVE MIRNAS DOWNREGULATED IN ATC-SECRETED EXOSOMES INDICATES THEIR ROLE IN THE REGULATION OF TUMOR SUPPRESSIVE GENES THAT MAY INCREASE THE METASTATIC PROPENSITY OF ATC. ADDITIONALLY, THE HIGH EXPRESSION OF PRO-INFLAMMATORY CYTOKINES IN STUDIES LOOKING AT THYROID CANCER AND ACTIVATED MACROPHAGE CONDITIONED MEDIA SUGGESTS THE EXISTENCE OF AN INFLAMMATORY TME IN THYROID CANCER. NEW FINDINGS ARE SUGGESTIVE OF THE PRESENCE OF A METASTATIC NICHE IN ATC TISSUES THAT IS INFLUENCED BY THYROID TUMOR MICROENVIRONMENT SECRETOME-INDUCED EPITHELIAL TO MESENCHYMAL TRANSITION (EMT), MEDIATED BY A RECIPROCAL INTERACTION BETWEEN THE PRO-INFLAMMATORY M1 MACROPHAGES AND THE THYROID CANCER CELLS. THUS, TARGETING THE METASTATIC THYROID CARCINOMA MICROENVIRONMENT COULD OFFER POTENTIAL THERAPEUTIC BENEFITS AND SHOULD BE EXPLORED FURTHER IN PRECLINICAL AND TRANSLATIONAL MODELS OF HUMAN METASTATIC THYROID CANCER. 2021 19 1349 24 DETERMINANTS OF INNATE IMMUNITY IN VISCERAL LEISHMANIASIS AND THEIR IMPLICATION IN VACCINE DEVELOPMENT. LEISHMANIASIS IS ENDEMIC TO THE TROPICAL AND SUBTROPICAL REGIONS OF THE WORLD AND IS TRANSMITTED BY THE BITE OF AN INFECTED SAND FLY. THE MULTIFACETED INTERACTIONS BETWEEN LEISHMANIA, THE HOST INNATE IMMUNE CELLS, AND THE ADAPTIVE IMMUNITY DETERMINE THE SEVERITY OF PATHOGENESIS AND DISEASE DEVELOPMENT. LEISHMANIA PARASITES ESTABLISH A CHRONIC INFECTION BY SUBVERSION AND ATTENUATION OF THE MICROBICIDAL FUNCTIONS OF PHAGOCYTIC INNATE IMMUNE CELLS SUCH AS NEUTROPHILS, MACROPHAGES AND DENDRITIC CELLS (DCS). OTHER INNATE CELLS SUCH AS INFLAMMATORY MONOCYTES, MAST CELLS AND NK CELLS, ALSO CONTRIBUTE TO RESISTANCE AND/OR SUSCEPTIBILITY TO LEISHMANIA INFECTION. IN ADDITION TO THE CYTOKINE/CHEMOKINE SIGNALS FROM THE INNATE IMMUNE CELLS, RECENT STUDIES IDENTIFIED THE SUBTLE SHIFTS IN THE METABOLIC PATHWAYS OF THE INNATE CELLS THAT ACTIVATE DISTINCT IMMUNE SIGNAL CASCADES. THE NEXUS BETWEEN METABOLIC PATHWAYS, EPIGENETIC REPROGRAMMING AND THE IMMUNE SIGNALING CASCADES THAT DRIVE THE DIVERGENT INNATE IMMUNE RESPONSES, REMAINS TO BE FULLY UNDERSTOOD IN LEISHMANIA PATHOGENESIS. FURTHER, DEVELOPMENT OF SAFE AND EFFICACIOUS VACCINES AGAINST LEISHMANIASIS REQUIRES A BROADER UNDERSTANDING OF THE EARLY INTERACTIONS BETWEEN THE PARASITES AND INNATE IMMUNE CELLS. IN THIS REVIEW WE FOCUS ON THE CURRENT UNDERSTANDING OF THE SPECIFIC ROLE OF INNATE IMMUNE CELLS, THE METABOLOMIC AND EPIGENETIC REPROGRAMMING AND IMMUNE REGULATION THAT OCCURS DURING VISCERAL LEISHMANIASIS, AND THE STRATEGIES USED BY THE PARASITE TO EVADE AND MODULATE HOST IMMUNITY. WE HIGHLIGHT HOW SUCH PATHWAYS COULD BE EXPLOITED IN THE DEVELOPMENT OF SAFE AND EFFICACIOUS LEISHMANIA VACCINES. 2021 20 4332 38 MICRORNAS: IMPORTANT MODULATORS OF OXLDL-MEDIATED SIGNALING IN ATHEROSCLEROSIS. OXIDIZED LOW-DENSITY LIPOPROTEIN (OXLDL) IS KNOWN TO BE A MAJOR RISK FACTOR FOR THE INITIATION AND DEVELOPMENT OF ATHEROSCLEROSIS. IT CAN ELICIT AN ARRAY OF ATHEROGENIC RESPONSES IN MULTIPLE TYPES OF CELLS RESIDING IN THE ARTERIAL WALL, SUCH AS ENDOTHELIAL CELLS (ECS), MACROPHAGES, DENDRITIC CELLS (DCS), AND VASCULAR SMOOTH MUSCLE CELLS (VSMCS). ALTHOUGH THEY HAVE BEEN STUDIED FOR MANY YEARS, THE DETAILED MECHANISMS MODULATING OXLDL-INDUCED INFLAMMATION HAVE NOT BEEN FULLY ELUCIDATED. EPIGENETIC MECHANISMS CONSIST OF DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS), AND MICRORNA (MIRNA) ALTERATIONS. RECENTLY, EPIGENETIC FACTORS, ESPECIALLY MIRNAS, HAVE EMERGED AS NOVEL COMPONENTS OF THE GENE EXPRESSION REGULATING OXLDL-TRIGGERED SIGNAL TRANSDUCTION. IN ADDITION TO THEIR REGULATORY ROLES IN SIGNALING MOLECULES, INCREASING EVIDENCE SUGGESTS THAT THE DIFFERENT GENETIC STABILITY AND CROSS-TALK REGULATION AMONG THESE EPIGENETIC FACTORS MAY BE PARTICULARLY IMPORTANT TO THE SUSTAINED INFLAMMATION INITIATED BY TEMPORAL OXLDL STIMULATION. THEREFORE, IN THIS REVIEW, WE PRIMARILY FOCUSED ON THE FUNCTIONAL ROLE OF MIRNAS, AS WELL AS OTHER EPIGENETIC FACTORS, ON MODULATING OXLDL-INDUCED SIGNAL TRANSDUCTION IN DIFFERENT VASCULAR CELLS, WITH A SPECIAL EMPHASIS ON THE CROSSTALK INTERACTIONS BETWEEN MIRNAS AND OTHER EPIGENETIC PLAYERS THAT HELP TRANSLATE TRANSIENT ENVIRONMENT INSULTS INTO CHRONIC INFLAMMATION. MOREOVER, WE EXTENSIVELY DISCUSSED THE POTENTIAL APPLICABILITY OF MIRNAS AS DISEASE BIOMARKERS AND THERAPEUTIC TARGETS IN DIAGNOSING AND TREATING ATHEROSCLEROSIS. 2013