1 5764 155 SORAFENIB ATTENUATES FIBROTIC HEPATIC INJURY THROUGH MEDIATING LYSINE CROTONYLATION. BACKGROUND: LIVER FIBROSIS IS AN INDEPENDENT CONTRIBUTOR OF CHRONIC LIVER DISEASES, AND REGRESSING LIVER FIBROSIS IS CONSIDERED A POTENTIAL THERAPEUTIC TARGET FOR CHRONIC LIVER DISEASES. WE AIMED TO EXPLORE THE EFFECTS AND MECHANISM OF SORAFENIB IN LIVER FIBROSIS. METHODS: MALE SPRAGUE DAWLEY (SD) RATS WERE SUBJECTED TO SUBCUTANEOUS INJECTION OF CARBON TETRACHLORIDE (CCL(4)) FOR 8 WEEKS TO INDUCE LIVER FIBROSIS AND THEN TREATED WITH SORAFENIB. THE DEGREE OF LIVER FIBROSIS WAS ANALYZED BY HEMATOXYLIN-EOSIN (H&E) STAINING, MASSON STAINING, AND PICROSIRIUS RED (PSR) STAINING. SERUM BIOCHEMICAL INDEXES WERE DETECTED BY FULLY AUTOMATIC BIOCHEMICAL ANALYZER OR ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA). QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QRT-PCR) WAS PERFORMED TO DETECT THE EXPRESSION OF PRO-FIBROTIC GENES. IMMUNOHISTOCHEMICAL STAINING AND WESTERN BLOTTING WERE CARRIED OUT TO EVALUATE THE LEVELS OF LYSINE CROTONYLATION. RESULTS: LIVER INDEX WAS REDUCED WITH ORAL SORAFENIB IN CCL(4)-INDUCED RATS. SERUM LIVER FUNCTION (ALANINE AMINOTRANSFERASE (ALT), ASPARTATE AMINOTRANSFERASE (AST), AND TOTAL BILIRUBIN (TBIL)) AND FIBROSIS INDICATORS (TYPE III PROCOLLAGEN (PC-III), HYALURONIC ACID (HA), AND LAMININ (LN)) WERE ATTENUATED WITH SORAFENIB TREATMENT. SORAFENIB IMPROVED THE HEPATIC STRUCTURE AND FIBROTIC PROGRESSION. THE EXPRESSION OF FIBROSIS-RELATED GENES WAS REMARKELY REDUCED WITH SORAFENIB TREATMENT. MEANWHILE, SORAFENIB INHIBITED ALPHA-SMA AND COLLAGEN I CUMULATION INDUCED BY CCL(4) INJECTION. BESIDES, PROTEIN LYSINE CROTONYLATION ESPECIALLY THE CROTONYLATED H2BK12 (H2BK12CR) AND CROTONYLATED H3K18 (H3K18CR) WERE REVERSED BY SORAFENIB, WHICH WERE DECREASED IN RESPONSE TO CCL(4) TREATMENT. SPEARMAN CORRELATION ANALYSIS SHOWN LYSINE CROTONYLATION EXPRESSION WAS NEGATIVELY CORRELATED WITH SERUM FIBROTIC INDICATORS. CONVERSELY, CROTONYLATION-REGULATED ENZYMES, WHICH NEGATIVELY REGULATE PROTEIN CROTONYLATION, WERE INCREASED IN RESPONSE TO CCL(4) TREATMENT, WHILE SORAFENIB REDUCED THEIR EXPRESSION. CONCLUSION: SORAFENIB EXERTS SIGNIFICANT ANTI-FIBROTIC EFFECTS THROUGH MEDIATING CROTONYLATION-REGULATED ENZYMES AND PROTEIN CROTONYLATION IN FIBROTIC RATS. 2022 2 6741 15 WHERE TO STAND WITH STROMAL CELLS AND CHRONIC SYNOVITIS IN RHEUMATOID ARTHRITIS? THE SYNOVIUM EXERCISES ITS MAIN FUNCTION IN JOINT HOMEOSTASIS THROUGH THE SECRETION OF FACTORS (SUCH AS LUBRICIN AND HYALURONIC ACID) THAT ARE CRITICAL FOR THE JOINT LUBRICATION AND FUNCTION. THE MAIN SYNOVIUM CELL COMPONENTS ARE FIBROBLAST-LIKE SYNOVIOCYTES, MESENCHYMAL STROMAL/STEM CELLS AND MACROPHAGE-LIKE SYNOVIAL CELLS. IN THE SYNOVIUM, CELLS OF MESENCHYMAL ORIGIN MODULATE LOCAL INFLAMMATION AND FIBROSIS, AND INTERACT WITH DIFFERENT FIBROBLAST SUBTYPES AND WITH RESIDENT MACROPHAGES. IN PATHOLOGIC CONDITIONS, SUCH AS RHEUMATOID ARTHRITIS, FIBROBLAST-LIKE SYNOVIOCYTES PROLIFERATE ABNORMALLY, RECRUIT MESENCHYMAL STEM CELLS FROM SUBCHONDRAL BONE MARROW, AND INFLUENCE IMMUNE CELL ACTIVITY THROUGH EPIGENETIC AND METABOLIC ADAPTATIONS. THE RESULTING SYNOVIAL HYPERPLASIA LEADS TO SECONDARY CARTILAGE DESTRUCTION, JOINT SWELLING, AND PAIN. IN THE PRESENT REVIEW, WE SUMMARIZE RECENT FINDINGS ON THE MOLECULAR SIGNATURE AND THE ROLES OF STROMAL CELLS DURING SYNOVIAL PANNUS FORMATION AND RHEUMATOID ARTHRITIS PROGRESSION. 2019 3 3430 24 HYALURONAN AS TUNABLE DRUG DELIVERY SYSTEM. THE HYALURONAN (HA) POLYMER IS AN IMPORTANT MACROMOLECULE OF EXTRACELLULAR MATRIX WITH REMARKABLE STRUCTURE AND FUNCTIONS: IT IS A LINEAR AND UNBRANCHED POLYMER WITHOUT SULPHATE OR PHOSPHATE GROUPS AND HAS KEY ROLE IN SEVERAL BIOLOGICAL PROCESSES IN MAMMALS. IT IS UBIQUITOUS IN MAMMALIAN TISSUES WITH SEVERAL AND SPECIFIC FUNCTIONS, INFLUENCING CELL PROLIFERATION AND MIGRATION AS WELL AS ANGIOGENESIS AND INFLAMMATION. TO EXERT THESE IMPORTANT FUNCTIONS IN TISSUES HA MODIFIES THE CONCENTRATION AND SIZE. CONSIDERING THIS HA CONTENT IN TISSUES IS CAREFULLY CONTROLLED BY DIFFERENT MECHANISMS INCLUDING COVALENT MODIFICATION OF THE SYNTHETIC ENZYMES AND EPIGENETIC CONTROL OF THEIR GENE EXPRESSION. THE FUNCTION OF HA IS ALSO CRITICAL IN SEVERAL PATHOLOGIES INCLUDING CANCER, DIABETES AND CHRONIC INFLAMMATION. AMONG THESE BIOLOGICAL ROLES, THE STRUCTURAL PROPERTIES OF HA ALLOW TO USE THIS POLYMER IN REGENERATIVE MEDICINE INCLUDING COSMETICS AND DRUG DELIVERY. HA TAKES ADVANTAGE FROM ITS CAPACITY TO FORM GELS EVEN AT CONCENTRATION OF 1% PRODUCING SCAFFOLDS WITH VERY INTRIGUING MECHANICAL PROPERTIES. THESE HYDROGELS ARE USEFUL IN REGENERATIVE MEDICINE AS BIOCOMPATIBLE MATERIAL FOR ADVANCED THERAPEUTIC USES. IN THIS REVIEW WE HIGHLIGHT THE BIOLOGICAL ASPECTS OF HA ADDRESSING THE MECHANISMS CONTROLLING THE HA CONTENT IN TISSUES AND ITS ROLE AS DRUG DELIVERY SYSTEM. 2019 4 4096 23 MATRIX METALLOPROTEINASES, NEURAL EXTRACELLULAR MATRIX, AND CENTRAL NERVOUS SYSTEM PATHOLOGY. THE FUNCTIONALITY AND STABILITY OF THE CENTRAL NERVOUS SYSTEM (CNS) PABULUM, CALLED NEURAL EXTRACELLULAR MATRIX (NECM), IS PARAMOUNT FOR THE MAINTENANCE OF A HEALTHY NETWORK. THE LOOSENING OR THE DAMAGE OF THE SCAFFOLD DISRUPTS SYNAPTIC TRANSMISSION WITH THE CONSEQUENT IMBALANCE OF THE NEUROTRANSMITTERS, REACTIVE CELLS INVASION, ASTROCYTOSIS, NEW MATRIX DEPOSITION, DIGESTION OF THE PREVIOUS STRUCTURE AND ULTIMATELY, MALADAPTIVE PLASTICITY WITH THE LOSS OF NEURONAL VIABILITY. NECM IS CONSTANTLY AFFECTED BY CNS DISORDERS, PARTICULARLY IN CHRONIC MODIFYING SUCH AS NEURODEGENERATIVE DISEASE, OR IN ACUTE/SUBACUTE WITH CHRONIC SEQUELAE, LIKE CEREBROVASCULAR AND INFLAMMATORY PATHOLOGY. MATRIX METALLOPROTEINASES (MMPS) ARE THE MAIN INTERFERING AGENT OF NECM, GUIDING THE BALANCE OF DEGRADATION AND NEW DEPOSITION OF PROTEINS SUCH AS PROTEOGLYCANS AND GLYCOPROTEINS, OR GLYCOSAMINOGLYCANS, SUCH AS HYALURONIC ACID. ACTIVATION OF THESE ENZYMES IS MODULATED BY THEIR PHYSIOLOGIC INHIBITORS, THE TISSUE INHIBITORS OF MMPS OR VIA OTHER PROTEASES INHIBITORS, AS WELL AS GENETIC OR EPIGENETIC UP- OR DOWNREGULATION THROUGH MOLECULAR INTERACTION OR RECEPTOR ACTIVATION. THE APPROPRIATE UNDERSTANDING OF THE PATHWAYS UNDERLYING NECM MODIFICATIONS IN CNS PATHOLOGY IS PROBABLY ONE OF THE PIVOTAL FUTURE DIRECTIONS TO IDENTIFY THE HEALTHY BRAIN NETWORK AND SUBSEQUENTLY DESIGN NEW THERAPIES TO INTERFERE WITH THE PROGRESSION OF THE CNS DISEASE AND EVENTUALLY FIND APPROPRIATE THERAPIES. 2017 5 692 37 BRD4 PROMOTES HEPATIC STELLATE CELLS ACTIVATION AND HEPATIC FIBROSIS VIA MEDIATING P300/H3K27AC/PLK1 AXIS. HEPATIC FIBROSIS (HF) IS A REVERSIBLE WOUND-HEALING RESPONSE CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX (ECM) DEPOSITION AND SECONDARY TO PERSISTENT CHRONIC INJURY. BROMODOMAIN PROTEIN 4 (BRD4) COMMONLY FUNCTIONS AS A "READER" TO REGULATE EPIGENETIC MODIFICATIONS INVOLVED IN VARIOUS BIOLOGICAL AND PATHOLOGICAL EVENTS, BUT THE MECHANISM OF HF REMAINS UNCLEAR. IN THIS STUDY, WE ESTABLISHED A CCL(4)-INDUCED HF MODEL AND SPONTANEOUS RECOVERY MODEL IN MICE AND FOUND ABERRANT BRD4 EXPRESSION, WHICH WAS CONSISTENT WITH THE RESULTS IN HUMAN HEPATIC STELLATE CELLS (HSCS)- LX2 CELLS IN VITRO. SUBSEQUENTLY, WE FOUND THAT DISTRICTION AND INHIBITION OF BRD4 RESTRAINED TGFBETA-INDUCED TRANS-DIFFERENTIATION OF LX2 CELLS INTO ACTIVATED, PROLIFERATIVE MYOFIBROBLASTS AND ACCELERATED APOPTOSIS, AND BRD4 OVEREXPRESSION BLOCKED MDI-INDUCED LX2 CELLS INACTIVATION AND PROMOTED THE PROLIFERATION AND INHIBITED APOPTOSIS OF INACTIVATED CELLS. ADDITIONALLY, ADENO-ASSOCIATED VIRUS SEROTYPE 8-LOADED SHORT HAIRPIN RNA-MEDIATED BRD4 KNOCKDOWN IN MICE SIGNIFICANTLY ATTENUATED CCL(4)-INDUCED FIBROTIC RESPONSES INCLUDING HSCS ACTIVATION AND COLLAGEN DEPOSITION. MECHANISTICALLY, BRD4 DEFICIENCY INHIBITED PLK1 EXPRESSION IN ACTIVATED LX2 CELLS, AND CHIP AND CO-IP ASSAYS REVEALED THAT BRD4 REGULATION OF PLK1 WAS DEPENDENT ON P300-MEDIATED ACETYLATION MODIFICATION FOR H3K27 ON THE PLK1 PROMOTER. IN CONCLUSION, BRD4 DEFICIENCY IN THE LIVER ALLEVIATES CCL(4)-INDUCED HF IN MICE, AND BRD4 PARTICIPATES IN THE ACTIVATION AND REVERSAL OF HSCS THROUGH POSITIVELY REGULATING THE P300/H3K27AC/PLK1 AXIS, PROVIDING A POTENTIAL INSIGHT FOR HF THERAPY. 2023 6 1257 21 CURRENT TRENDS IN EPIGENETIC, CELLULAR AND MOLECULAR PATHWAYS IN MANAGEMENT OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS IS A SYSTEMIC CHRONIC POLYARTICULAR AUTOIMMUNE DISORDER OF JOINTS AND JOINT MEMBRANE MAINLY AFFECTING FEET AND HANDS. THE PATHOLOGICAL MANIFESTATION OF THE DISEASE INCLUDES INFILTRATION OF IMMUNE CELLS, HYPERPLASIA OF THE LINING OF SYNOVIUM, FORMATION OF PANNUS AND BONE AND CARTILAGE DESTRUCTION. IF LEFT UNTREATED, THE APPEARANCE OF SMALL FOCAL NECROSIS, ADHESION OF GRANULATION, AND FORMATION OF FIBROUS TISSUE ON THE SURFACE OF ARTICULAR CARTILAGE IS NOTED. THE DISEASE PRIMARILY AFFECTS NEARLY 1% OF THE POPULATION GLOBALLY, WOMEN BEING MORE AFFECTED THAN MEN WITH A RATIO 2:1 AND CAN INITIATE REGARDLESS OF ANY AGE. THE SYNOVIAL FIBROBLAST IN RHEUMATOID ARTHRITIS INDIVIDUALS EXHIBITS AN AGGRESSIVE PHENOTYPE WHICH UPREGULATES THE MANIFESTATION OF PROTOONCOGENES, ADHESIVE COMPOUNDS, INFLAMMATORY CYTOKINES AND MATRIX-DETERIORATING ENZYMES. APART FROM THE INFLAMMATORY EFFECTS OF CYTOKINES, CHEMOKINES ARE ALSO NOTED TO INDUCE SWELLING AND PAIN IN ARTHRITIC INDIVIDUALS BY RESIDING IN SYNOVIAL MEMBRANE AND FORMING PANNUS. THE CURRENT TREATMENT OF RHEUMATOID ARTHRITIS INCLUDES TREATMENT WITH NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, DISEASE-MODIFYING ANTIRHEUMATIC DRUGS, TREATMENT WITH BIOLOGICS SUCH AS INHIBITORS OF TNF-ALPHA, INTERLEUKINS, PLATELET ACTIVATING FACTOR, ETC. WHICH PROVIDES SIGNIFICANT RELIEF FROM SYMPTOMS AND AIDS IN MANAGEMENT OF THE DISEASE. THE CURRENT REVIEW HIGHLIGHTS THE PATHOGENESIS INVOLVED IN THE ONSET OF RHEUMATOID ARTHRITIS AND ALSO COVERS EPIGENETIC, CELLULAR AND MOLECULAR PARAMETERS ASSOCIATED WITH IT TO AID BETTER AND ADVANCED THERAPEUTIC APPROACHES FOR MANAGEMENT OF THE DEBILITATING DISEASE. 2023 7 3931 22 LIVER INJURY AND THE ACTIVATION OF THE HEPATIC MYOFIBROBLASTS. LIVER FIBROSIS IS A WOUND HEALING PROCESS, THE END RESULT OF CHRONIC LIVER INJURY ELICITED BY DIFFERENT NOXIOUS STIMULI. ACTIVATED HEPATIC STELLATE CELLS OR MYOFIBROBLASTS AND PORTAL MYOFIBROBLASTS ARE CONSIDERED AS THE MAIN PRODUCERS OF THE EXTRACELLULAR MATRIX IN THE LIVER. UPON LIVER INJURY THE QUIESCENT STELLATE CELLS TRANSDIFFERENTIATE INTO MYOFIBROBLASTS A PROCESS HIGHLIGHTED BY THE LOSS OF VITAMIN A STORES, UPREGULATION OF INTERSTITIAL TYPE COLLAGENS, SMOOTH MUSCLE ALPHA ACTIN, MATRIX METALLOPROTEINASES, PROTEOGLYCANS, AND THE INDUCTION OF CELL SURVIVAL PATHWAYS. ACTIVATION OF HEPATIC STELLATE CELLS IS A RESULT OF A COMPLEX INTERPLAY BETWEEN THE PARENCHYMAL CELLS, IMMUNE CELLS, EXTRACELLULAR MATRIX MECHANICS AND EXTRAHEPATIC MILIEU SUCH AS THE GUT MICROBIOME. IN THIS REVIEW WE WILL FOCUS ON THE PATHOMECHANISM OF STELLATE CELL ACTIVATION FOLLOWING CHRONIC LIVER INJURY; WITH THE AIM OF IDENTIFYING POSSIBLE TREATMENT TARGETS FOR ANTI-FIBROGENIC AGENTS. 2013 8 3537 26 IMMUNE DYSREGULATION IN KABUKI SYNDROME: A CASE REPORT OF EVANS SYNDROME AND HYPOGAMMAGLOBULINEMIA. KABUKI SYNDROME (KS) IS A RARE MULTISYSTEMIC DISEASE DUE TO MUTATIONS IN THE KMT2D OR KDM6A GENES, WHICH ACT AS EPIGENETIC MODULATORS OF DIFFERENT PROCESSES, INCLUDING IMMUNE RESPONSE. THE SYNDROME IS CHARACTERIZED BY ANOMALIES IN MULTIPLE ORGAN SYSTEMS, AND IT IS ASSOCIATED WITH AUTOIMMUNE AND INFLAMMATORY DISORDERS, AND AN UNDERLYING IMMUNOLOGICAL PHENOTYPE CHARACTERIZED BY IMMUNODEFICIENCY AND IMMUNE DYSREGULATION. UP TO 17% OF KS PATIENTS PRESENT WITH IMMUNE THROMBOCYTOPENIA CHARACTERIZED BY A SEVERE, CHRONIC OR RELAPSING COURSE, AND OFTEN ASSOCIATED TO OTHER HEMATOLOGICAL AUTOIMMUNE DISEASES INCLUDING AUTOIMMUNE HEMOLYTIC ANEMIA, EVENTUALLY RESULTING IN EVANS SYNDROME (ES). A 23-YEAR-OLD WOMAN, CLINICALLY DIAGNOSED WITH KS AND PRESENTING FROM THE AGE OF 3 YEARS WITH ES WAS REFERRED TO THE RARE DISEASES CENTRE OF OUR PEDIATRIC DEPARTMENT FOR CORTICOSTEROID-INDUCED HYPERGLYCEMIA. SEVERAL ES RELAPSES AND RECURRENT RESPIRATORY INFECTIONS IN THE PREVIOUS YEARS WERE REPORTED. SEVERE HYPOGAMMAGLOBULINEMIA, SPLENOMEGALY AND SIGNS OF CHRONIC LUNG INFLAMMATION WERE DIAGNOSED ONLY AT THE TIME OF OUR OBSERVATION. SUPPORTIVE TREATMENT WITH AMOXICILLIN-CLAVULANATE PROPHYLAXIS AND RECOMBINANT HUMAN HYALURONIDASE-FACILITATED SUBCUTANEOUS IMMUNOGLOBULIN REPLACEMENT WERE IMMEDIATELY STARTED. IN KS PATIENTS, THE FAILURE OF B-CELL DEVELOPMENT AND THE LACK OF AUTOREACTIVE IMMUNE CELLS SUPPRESSION CAN LEAD TO IMMUNODEFICIENCY AND AUTOIMMUNITY THAT MAY BE UNDIAGNOSED FOR A LONG TIME. OUR PATIENT'S CASE IS PARADIGMATIC SINCE SHE PRESENTED WITH PREVENTABLE MORBIDITY AND SEVERE LUNG DISEASE YEARS AFTER DISEASE ONSET. THIS CASE EMPHASIZES THE IMPORTANCE OF SUSPECTING IMMUNE DYSREGULATION IN KS. PATHOGENESIS AND IMMUNOLOGICAL COMPLICATIONS OF KS ARE DISCUSSED. MOREOVER, THE NEED TO PERFORM IMMUNOLOGIC EVALUATIONS IS HIGHLIGHTED BOTH AT THE TIME OF KS DIAGNOSIS AND DURING DISEASE FOLLOW-UP, IN ORDER TO ALLOW PROPER TREATMENT WHILE INTERCEPTING AVOIDABLE MORBIDITY IN THESE PATIENTS. 2023 9 4298 17 MICRORNA-146A GOVERNS FIBROBLAST ACTIVATION AND JOINT PATHOLOGY IN ARTHRITIS. SYNOVIAL FIBROBLASTS ARE KEY CELLS ORCHESTRATING THE INFLAMMATORY RESPONSE IN ARTHRITIS. HERE WE DEMONSTRATE THAT LOSS OF MIR-146A, A KEY EPIGENETIC REGULATOR OF THE INNATE IMMUNE RESPONSE, LEADS TO INCREASED JOINT DESTRUCTION IN A TNF-DRIVEN MODEL OF ARTHRITIS BY SPECIFICALLY REGULATING THE BEHAVIOR OF SYNOVIAL FIBROBLASTS. ABSENCE OF MIR-146A IN SYNOVIAL FIBROBLASTS DISPLAY A HIGHLY DEREGULATED GENE EXPRESSION PATTERN AND ENHANCED PROLIFERATION IN VITRO AND IN VIVO. DEFICIENCY OF MIR-146A INDUCES DEREGULATION OF TUMOR NECROSIS FACTOR (TNF) RECEPTOR ASSOCIATED FACTOR 6 (TRAF6) IN SYNOVIAL FIBROBLASTS, LEADING TO INCREASED PROLIFERATION. IN ADDITION, LOSS OF MIR-146A SHIFTS THE METABOLIC STATE OF FIBROBLASTS TOWARDS GLYCOLYSIS AND AUGMENTS THE ABILITY OF SYNOVIAL FIBROBLASTS TO SUPPORT THE GENERATION OF OSTEOCLASTS BY CONTROLLING THE BALANCE OF OSTEOCLASTOGENIC REGULATORY FACTORS RECEPTOR ACTIVATOR OF NF-KAPPAB LIGAND (RANKL) AND OSTEOPROTEGERIN (OPG). BONE MARROW TRANSPLANTATION EXPERIMENTS CONFIRMED THE IMPORTANCE OF MIR-146A IN THE RADIORESISTANT MESENCHYMAL COMPARTMENT FOR THE CONTROL OF ARTHRITIS SEVERITY, IN PARTICULAR FOR INFLAMMATORY JOINT DESTRUCTION. THIS STUDY THEREFORE IDENTIFIES MICRORNA-146A AS AN IMPORTANT LOCAL EPIGENETIC REGULATOR OF THE INFLAMMATORY RESPONSE IN ARTHRITIS. IT IS A CENTRAL ELEMENT OF AN ANTI-INFLAMMATORY FEEDBACK LOOP IN RESIDENT SYNOVIAL FIBROBLASTS, WHO ARE ORCHESTRATING THE INFLAMMATORY RESPONSE IN CHRONIC ARTHRITIS. MIR-146A RESTRICTS THEIR ACTIVATION, THEREBY PREVENTING EXCESSIVE TISSUE DAMAGE DURING ARTHRITIS. 2017 10 6009 21 THE ANTI-INFLAMMATORY MEDIATOR, VASOACTIVE INTESTINAL PEPTIDE, MODULATES THE DIFFERENTIATION AND FUNCTION OF TH SUBSETS IN RHEUMATOID ARTHRITIS. GENETIC BACKGROUND, EPIGENETIC MODIFICATIONS, AND ENVIRONMENTAL FACTORS TRIGGER AUTOIMMUNE RESPONSE IN RHEUMATOID ARTHRITIS (RA). SEVERAL PATHOGENIC INFECTIONS HAVE BEEN RELATED TO THE ONSET OF RA AND MAY CAUSE AN INADEQUATE IMMUNOLOGICAL TOLERANCE TOWARDS CRITICAL SELF-ANTIGENS LEADING TO CHRONIC JOINT INFLAMMATION AND AN IMBALANCE BETWEEN DIFFERENT T HELPER (TH) SUBSETS. VASOACTIVE INTESTINAL PEPTIDE (VIP) IS A MEDIATOR THAT MODULATES ALL THE STAGES COMPRISED BETWEEN THE ARRIVAL OF PATHOGENS AND TH CELL DIFFERENTIATION IN RA THROUGH ITS KNOWN ANTI-INFLAMMATORY AND IMMUNOMODULATORY ACTIONS. THIS "NEUROIMMUNOPEPTIDE" MODULATES THE PATHOGENIC ACTIVITY OF DIVERSE CELL SUBPOPULATIONS INVOLVED IN RA AS LYMPHOCYTES, FIBROBLAST-LIKE SYNOVIOCYTES (FLS), OR MACROPHAGES. IN ADDITION, VIP DECREASES THE EXPRESSION OF PATTERN RECOGNITION RECEPTOR (PRR) SUCH AS TOLL-LIKE RECEPTORS (TLRS) IN FLS FROM RA PATIENTS. THESE RECEPTORS ACT AS SENSORS OF PATHOGEN-ASSOCIATED MOLECULAR PATTERN (PAMP) AND DAMAGE-ASSOCIATED MOLECULAR PATTERN (DAMP) CONNECTING THE INNATE AND ADAPTIVE IMMUNE SYSTEM. MOREOVER, VIP MODULATES THE IMBALANCE BETWEEN TH SUBSETS IN RA, DECREASING PATHOGENIC TH1 AND TH17 SUBSETS AND FAVORING TH2 OR TREG PROFILE DURING THE DIFFERENTIATION/POLARIZATION OF NAIVE OR MEMORY TH CELLS. FINALLY, VIP REGULATES THE PLASTICITY BETWEEN THESES SUBSETS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF VIP EFFECTS ON THE AFOREMENTIONED FEATURES OF RA PATHOLOGY. 2018 11 5507 16 RHEUMATOID ARTHRITIS PROGRESSION MEDIATED BY ACTIVATED SYNOVIAL FIBROBLASTS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY SYNOVIAL HYPERPLASIA AND PROGRESSIVE JOINT DESTRUCTION. RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS (RASFS) ARE LEADING CELLS IN JOINT EROSION AND CONTRIBUTE ACTIVELY TO INFLAMMATION. RASFS SHOW AN ACTIVATED PHENOTYPE THAT IS INDEPENDENT OF THE INFLAMMATORY ENVIRONMENT AND REQUIRES THE COMBINATION OF SEVERAL FACTORS. ALTHOUGH NEW ASPECTS REGARDING RASF ACTIVATION VIA MATRIX DEGRADATION PRODUCTS, EPIGENETIC MODIFICATIONS, INFLAMMATORY FACTORS, TOLL-LIKE RECEPTOR (TLR) ACTIVATION AND OTHERS HAVE RECENTLY BEEN UNCOVERED, THE PRIMARY PATHOPHYSIOLOGICAL PROCESSES IN EARLY ARTHRITIS LEADING TO PERMANENT ACTIVATION ARE MOSTLY UNKNOWN. HERE, WE REVIEW NEW FINDINGS REGARDING RASF ACTIVATION AND THEIR ALTERED BEHAVIOR THAT CONTRIBUTE TO MATRIX DESTRUCTION AND INFLAMMATION AS WELL AS THEIR POTENTIAL TO SPREAD RA. 2010 12 4412 13 MOLECULAR AND CELLULAR BASIS OF RHEUMATOID JOINT DESTRUCTION. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE ASSOCIATED WITH JOINT DESTRUCTION. SYNOVIAL FIBROBLASTS ARE KEY PLAYERS IN THIS PATHOLOGICAL PROCESS. THEY FAVORISE A PRO-INFLAMMATORY ENVIRONMENT IN THE SYNOVIAL TISSUE, INTERACT WITH THE IMMUNE SYSTEM AND REGULATE THE DIFFERENTIATION OF MONOCYTES INTO OSTEOCLASTS. SYNOVIAL HYPERPLASIA IS ANOTHER CHARACTERISTIC OF RA, REFLECTING NOT ONLY AN IMBALANCE BETWEEN PROLIFERATION AND APOPTOSIS, BUT ALSO THE MIGRATION OF CELLS INTO THE SYNOVIAL TISSUE. GENE TRANSFER EXPERIMENTS HAVE BEEN USED AS IMPORTANT TOOLS FOR THE UNDERSTANDING OF MOLECULAR AND CELLULAR CHANGES THAT CHARACTERIZE THE ACTIVATED RA SYNOVIAL FIBROBLASTS. ACTIVATED SYNOVIAL FIBROBLASTS CAN INVADE CARTILAGE AND BONE. SYNOVIAL ACTIVATION IS DRIVEN BY CYTOKINES, SUCH AS TNFALPHA AND IL-1, AS WELL AS IL-15, 16, 17, 18, 22, 23, BUT ALSO BY CYTOKINE-INDEPENDENT MECHANISMS THAT INVOLVE THE INNATE IMMUNE SYSTEM (I.E. TLRS), A UNIQUE COMMUNICATION NETWORK OF MICROPARTICLES AND EPIGENETIC CHANGES (E.G. L1 RETROELEMENTS). 2006 13 6394 21 THE ROLE OF THE HOST-NEUTROPHIL BIOLOGY. NEUTROPHILIC POLYMORPHONUCLEAR LEUKOCYTES (NEUTROPHILS) ARE MYELOID CELLS PACKED WITH LYSOSOMAL GRANULES (HENCE ALSO CALLED GRANULOCYTES) THAT CONTAIN A FORMIDABLE ANTIMICROBIAL ARSENAL. THEY ARE TERMINALLY DIFFERENTIATED CELLS THAT PLAY A CRITICAL ROLE IN ACUTE AND CHRONIC INFLAMMATION, AS WELL AS IN THE RESOLUTION OF INFLAMMATION AND WOUND HEALING. NEUTROPHILS EXPRESS A DENSE ARRAY OF SURFACE RECEPTORS FOR MULTIPLE LIGANDS, RANGING FROM INTEGRINS TO SUPPORT THEIR EGRESS FROM BONE MARROW INTO THE CIRCULATION AND FROM THE CIRCULATION INTO TISSUES, TO CYTOKINE/CHEMOKINE RECEPTORS THAT DRIVE THEIR NAVIGATION TO THE SITE OF INFECTION OR TISSUE DAMAGE AND ALSO PRIME THEM FOR A SECOND STIMULUS, TO PATTERN RECOGNITION RECEPTORS AND IMMUNOGLOBULIN RECEPTORS TO FACILITATE THE DESTRUCTION AND REMOVAL OF INFECTIVE AGENTS OR DEBRIDEMENT OF DAMAGED TISSUES. WHEN AFFERENT NEUTROPHIL SIGNALS ARE PROPORTIONATE AND COORDINATED THEY WILL PHAGOCYTOSE OPSONIZED AND UNOPSONIZED BACTERIA, ACTIVATING THE NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE (RESPIRATORY BURST) TO GENERATE REACTIVE OXYGEN SPECIES, WHICH AUGMENT THE PROTEOLYTIC DESTRUCTION OF MICROBES SECURED WITHIN THE PHAGOSOME. A HIGHLY ORCHESTRATED PROCESS OF APOPTOSIS FOLLOWS, FORMING MEMBRANE-BOUND SUBSTRUCTURES THAT ARE REMOVED BY MACROPHAGES. NEUTROPHILS ARE CAPABLE OF VARIOUS OTHER FORMS OF PROGRAMMED CELL DEATH, SUCH AS NETOSIS AND PYROPTOTIC CELL DEATH, AS WELL AS NONPROGRAMMED CELL DEATH BY NECROSIS. IN RECENT YEARS, RESEARCH HAS REVEALED THAT NEUTROPHILS ARE CAPABLE OF FAR MORE SUBTLE CELL-CELL INTERACTIONS THAN PREVIOUSLY THOUGHT POSSIBLE. THIS INCLUDES SYNTHESIS OF VARIOUS INFLAMMATORY MEDIATORS AND ALSO MYELOID CELL TRAINING WITHIN BONE MARROW, WHERE EPIGENETIC AND METABOLIC SIGNALS ASSOCIATED WITH RETURNING NEUTROPHILS THAT UNDERGO REVERSE EGRESS FROM TISSUES INTO THE VASCULATURE AND BACK TO BONE MARROW PROGRAM A HYPERREACTIVE SUBSET OF NEUTROPHILS DURING MYELOPOIESIS THAT ARE CAPABLE OF HYPERSENSITIVE REACTIONS TO MICROBIAL AGGRESSORS. THESE CHARACTERISTICS ARE EVIDENT IN VARIOUS NEUTROPHIL SUBSETS/SUBPOPULATIONS, CREATING BROAD HETEROGENEITY IN THE BEHAVIOR AND BIOLOGICAL REPERTOIRE OF THESE SEEMINGLY SCHIZOPHRENIC IMMUNE CELLS. MOREOVER, NEUTROPHILS ARE CRITICAL EFFECTOR CELLS OF ADAPTIVE AND INNATE IMMUNITY, BINDING TO OPSONIZED BACTERIA AND DESTROYING THEM BY EXTRACELLULAR AND INTRACELLULAR METHODS. THE FORMER CREATES SUBSTANTIAL COLLATERAL HOST TISSUE DAMAGE, AS THEY ARE LESS SPECIFIC THAN T-CYTOTOXIC CELL-KILLING MECHANISMS, AND IN CONDITIONS SUCH AS PERI-IMPLANTITIS, WHERE PLASMA CELLS AND NEUTROPHILS DOMINATE THE IMMUNE INFILTRATE, BONE AND TISSUE DESTRUCTION ARE RAPID AND APPEAR RELENTLESS. FINALLY, THE ROLE OF NEUTROPHILS AS CONDUITS FOR PERIODONTAL-SYSTEMIC DISEASE CONNECTIONS AND FOR OXIDATIVE DAMAGE TO ACT AS A CAUSAL LINK BETWEEN THE TWO HAS ONLY RECENTLY BEEN REALIZED. IN THIS CHAPTER, WE ATTEMPT TO EXPAND ON THESE ISSUES, EMPHASIZING THE CONTRIBUTIONS OF EUROPEAN SCIENTISTS THROUGHOUT A DETAILED APPRAISAL OF THE BENEFITS AND SIDE EFFECTS OF NEUTROPHILIC INFLAMMATION AND IMMUNE FUNCTION. 2023 14 3245 20 HEPATIC STELLATE CELLS AS KEY TARGET IN LIVER FIBROSIS. PROGRESSIVE LIVER FIBROSIS, INDUCED BY CHRONIC VIRAL AND METABOLIC DISORDERS, LEADS TO MORE THAN ONE MILLION DEATHS ANNUALLY VIA DEVELOPMENT OF CIRRHOSIS, ALTHOUGH NO ANTIFIBROTIC THERAPY HAS BEEN APPROVED TO DATE. TRANSDIFFERENTIATION (OR "ACTIVATION") OF HEPATIC STELLATE CELLS IS THE MAJOR CELLULAR SOURCE OF MATRIX PROTEIN-SECRETING MYOFIBROBLASTS, THE MAJOR DRIVER OF LIVER FIBROGENESIS. PARACRINE SIGNALS FROM INJURED EPITHELIAL CELLS, FIBROTIC TISSUE MICROENVIRONMENT, IMMUNE AND SYSTEMIC METABOLIC DYSREGULATION, ENTERIC DYSBIOSIS, AND HEPATITIS VIRAL PRODUCTS CAN DIRECTLY OR INDIRECTLY INDUCE STELLATE CELL ACTIVATION. DYSREGULATED INTRACELLULAR SIGNALING, EPIGENETIC CHANGES, AND CELLULAR STRESS RESPONSE REPRESENT CANDIDATE TARGETS TO DEACTIVATE STELLATE CELLS BY INDUCING REVERSION TO INACTIVATED STATE, CELLULAR SENESCENCE, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS. CELL TYPE- AND TARGET-SPECIFIC PHARMACOLOGICAL INTERVENTION TO THERAPEUTICALLY INDUCE THE DEACTIVATION WILL ENABLE MORE EFFECTIVE AND LESS TOXIC PRECISION ANTIFIBROTIC THERAPIES. 2017 15 601 24 BETA-GLUCAN "TRAINED IMMUNITY" IMMUNOMODULATORY PROPERTIES POTENTIATE TISSUE WOUND MANAGEMENT AND ACCELERATE FITNESS RECOVER. INTRODUCTION: IT IS WELL ESTABLISHED THAT MODERATE PHYSICAL ACTIVITY CAN IMPROVE THE IMMUNE STATUS, RATHER EXCESS OR HIGH-INTENSITY PHYSICAL EXERCISE CAN CAUSE DAMAGE TO THE IMMUNE SYSTEM. IN ADDITION, MUSCLE INJURIES RESULTING FROM INCREASED FREQUENCY AND INTENSITY OF EXERCISES COMPROMISE INNATE IMMUNE ACTIVITY AND MAY DECREASE TISSUE REGENERATION. THUS, BETA-GLUCANS, A NATURAL COMPOUND, MAY REPRESENT AN IMPORTANT SUBSTANCE WITH STRONG IMMUNOMODULATORY PROPERTIES ACTING AS AN IMMUNOSTIMULANT THERAPY KNOWN AS "TRAINED IMMUNITY". THIS IMMUNE STIMULATING THERAPEUTIC IS AN IMMUNOLOGICAL MEMORY PHENOMENON LINKED TO THE INNATE IMMUNE SYSTEM, TRIGGERING CELLULAR CHANGES AT EPIGENETIC, TRANSCRIPTIONAL, AND FUNCTIONAL LEVELS, TO REGULATE THE IMMUNE SYSTEM AND RECOVER ITS HOMEOSTASIS WITH CLINICAL BENEFITS. CONCLUSION: THIS NARRATIVE REVIEW WORKS WITH THE CURRENT EVIDENCE REGARDING BETA-GLUCANS AS A POSSIBLE ALTERNATIVE THERAPY FOR WOUND HEALING AND ITS SAFETY AND EFFICACY IN THE TREATMENT OF MUSCLE INJURIES AND PHYSICAL RECOVERY INCLUDING OTHER CHRONIC CONDITIONS AND DISEASES. 2022 16 4181 14 MESENCHYMAL STEM CELLS IN IMMUNE-MEDIATED BONE MARROW FAILURE SYNDROMES. IMMUNE-MEDIATED BONE MARROW FAILURE SYNDROMES (BMFS) ARE CHARACTERIZED BY INEFFECTIVE MARROW HAEMOPOIESIS AND SUBSEQUENT PERIPHERAL CYTOPENIAS. INEFFECTIVE HAEMOPOIESIS IS THE RESULT OF A COMPLEX MARROW DEREGULATION INCLUDING GENETIC, EPIGENETIC, AND IMMUNE-MEDIATED ALTERATIONS IN HAEMOPOIETIC STEM/PROGENITOR CELLS, AS WELL AS ABNORMAL HAEMOPOIETIC-TO-STROMAL CELL INTERACTIONS, WITH ABNORMAL RELEASE OF HAEMOPOIETIC GROWTH FACTORS, CHEMOKINES, AND INHIBITORS. MESENCHYMAL STEM/STROMAL CELLS (MSCS) AND THEIR PROGENY (I.E., OSTEOBLASTS, ADIPOCYTES, AND RETICULAR CELLS) ARE CONSIDERED AS KEY CELLULAR COMPONENTS OF THE BONE MARROW HAEMOPOIETIC NICHE. MSCS MAY INTERFERE WITH HAEMOPOIETIC AS WELL AS IMMUNE REGULATION. EVIDENCE SUGGESTS THAT BONE MARROW MSCS MAY BE INVOLVED IN IMMUNE-MEDIATED BMFS UNDERLYING PATHOPHYSIOLOGY, HARBORING EITHER NATIVE ABNORMALITIES AND/OR SECONDARY DEFECTS, CAUSED BY EXPOSURE TO ACTIVATED MARROW COMPONENTS. THIS REVIEW SUMMARIZES PREVIOUS AS WELL AS MORE RECENT INFORMATION RELATED TO THE BIOLOGIC/FUNCTIONAL CHARACTERISTICS OF BONE MARROW MSCS IN MYELODYSPLASTIC SYNDROMES, ACQUIRED APLASTIC ANEMIA, AND CHRONIC IDIOPATHIC NEUTROPENIA. 2013 17 6218 18 THE JOINT SYNOVIUM: A CRITICAL DETERMINANT OF ARTICULAR CARTILAGE FATE IN INFLAMMATORY JOINT DISEASES. THE SYNOVIUM CONSTITUTES THE ENVELOPE OF ARTICULAR JOINTS AND IS A CRITICAL PROVIDER OF SYNOVIAL FLUID COMPONENTS AND ARTICULAR CARTILAGE NUTRIENTS. ITS INFLAMMATION IS A PREDOMINANT FEATURE AND CAUSE OF JOINT DEGENERATION IN DISEASES AS DIVERSE AS RHEUMATOID, PSORIATIC, JUVENILE AND IDIOPATHIC ARTHRITIS, AND LUPUS, GOUT AND LYME DISEASE. THESE INFLAMMATORY JOINT DISEASES (IJDS) ARE DUE TO A WIDE VARIETY OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS THAT TRIGGER, PROMOTE, AND PERPETUATE JOINT DESTABILIZATION. IN SPITE OF THIS VARIETY OF CAUSES, IJDS SHARE MAIN PATHOLOGICAL FEATURES, NAMELY INFLAMMATION OF THE JOINT SYNOVIUM (SYNOVITIS) AND PROGRESSIVE DEGENERATION OF ARTICULAR CARTILAGE. IN ADDITION TO BEING A DRIVING FORCE BEHIND THE DESTRUCTION OF ARTICULAR CARTILAGE IN IJD, SYNOVITIS IS ALSO INCREASINGLY BEING RECOGNIZED AS A SIGNIFICANT CONTRIBUTOR OF ARTICULAR CARTILAGE DEGENERATION IN OSTEOARTHRITIS, A DISEASE PRIMARILY DUE TO AGING- OR TRAUMA-RELATED WEAR AND TEAR OF CARTILAGE SURFACES. IN VIEW OF THIS IMPORTANT ROLE OF THE SYNOVIUM IN DETERMINING THE FATE OF ARTICULAR CARTILAGE, THIS REVIEW FOCUSES ON ITS UNDERLYING MECHANISMS IN THE PATHOLOGY OF IJD. WE ADDRESS THE ROLES OF SYNOVIAL FIBROBLASTS, MACROPHAGES AND ENDOTHELIAL CELLS IN THE MAINTENANCE OF JOINT HEALTH AND IN THE DESTRUCTION OF ARTICULAR CARTILAGE INTEGRITY DURING IJD. MOLECULAR MECHANISMS THAT HAVE BEEN RECENTLY SHOWN TO GOVERN THE PATHOLOGICAL ACTIVITIES OF THE RESIDENT SYNOVIAL CELLS ARE HIGHLIGHTED. FINALLY, ADVANTAGES AND DISADVANTAGES OF TARGETING THESE NEW MOLECULAR MECHANISMS FOR PREVENTING CARTILAGE DEGENERATION DUE TO CHRONIC INFLAMMATION ARE ALSO DISCUSSED. 2017 18 6621 16 UNDERSTANDING FIBROSIS IN SYSTEMIC SCLEROSIS: SHIFTING PARADIGMS, EMERGING OPPORTUNITIES. FIBROSIS IN MULTIPLE ORGANS IS A PROMINENT PATHOLOGICAL FINDING AND DISTINGUISHING HALLMARK OF SYSTEMIC SCLEROSIS (SSC). FINDINGS DURING THE PAST 5 YEARS HAVE CONTRIBUTED TO A MORE COMPLETE UNDERSTANDING OF THE COMPLEX CELLULAR AND MOLECULAR UNDERPINNING OF FIBROSIS IN SSC. FIBROBLASTS, THE PRINCIPAL EFFECTOR CELLS, ARE ACTIVATED IN THE PROFIBROTIC CELLULAR MILIEU BY CYTOKINES AND GROWTH FACTORS, DEVELOPMENTAL PATHWAYS, ENDOTHELIN 1 AND THROMBIN. INNATE IMMUNE SIGNALING VIA TOLL-LIKE RECEPTORS, MATRIX-GENERATED BIOMECHANICAL STRESS SIGNALING VIA INTEGRINS, HYPOXIA AND OXIDATIVE STRESS SEEM TO BE IMPLICATED IN PERPETUATING THE PROCESS. BEYOND CHRONIC FIBROBLAST ACTIVATION, FIBROSIS REPRESENTS A FAILURE TO TERMINATE TISSUE REPAIR, COUPLED WITH AN EXPANDED POPULATION OF MESENCHYMAL CELLS ORIGINATING FROM BONE MARROW AND TRANSDIFFERENTIATION OF EPITHELIAL CELLS, ENDOTHELIAL CELLS AND PERICYTES. IN ADDITION, STUDIES HAVE IDENTIFIED INTRINSIC ALTERATIONS IN SSC FIBROBLASTS RESULTING FROM EPIGENETIC CHANGES, AS WELL AS ALTERED MICRORNA EXPRESSION THAT MIGHT UNDERLIE THE CELL-AUTONOMOUS, PERSISTENT ACTIVATION PHENOTYPE OF THESE CELLS. PRECISE CHARACTERIZATION OF THE DEREGULATED EXTRACELLULAR AND INTRACELLULAR SIGNALING PATHWAYS, MEDIATORS AND CELLULAR DIFFERENTIATION PROGRAMS THAT CONTRIBUTE TO FIBROSIS IN SSC WILL FACILITATE THE DEVELOPMENT OF SELECTIVE, TARGETED THERAPEUTIC STRATEGIES. EFFECTIVE ANTIFIBROTIC THERAPY WILL ULTIMATELY INVOLVE NOVEL COMPOUNDS AND REPURPOSING OF DRUGS THAT ARE ALREADY APPROVED FOR OTHER INDICATIONS. 2011 19 3678 24 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 20 484 23 ARTICULAR CARTILAGE CHANGES IN MATURING ATHLETES: NEW TARGETS FOR JOINT REJUVENATION. CONTEXT: ARTICULAR CARTILAGE HAS A UNIQUE FUNCTIONAL ARCHITECTURE CAPABLE OF PROVIDING A LIFETIME OF PAIN-FREE JOINT MOTION. THIS TISSUE, HOWEVER, UNDERGOES SUBSTANTIAL AGE-RELATED PHYSIOLOGIC, MECHANICAL, BIOCHEMICAL, AND FUNCTIONAL CHANGES THAT REDUCE ITS ABILITY TO OVERCOME THE EFFECTS OF MECHANICAL STRESS AND INJURY. MANY FACTORS AFFECT JOINT FUNCTION IN THE MATURING ATHLETE-FROM CHONDROCYTE SURVIVAL AND METABOLISM TO STRUCTURAL COMPOSITION AND GENETIC/EPIGENETIC FACTORS GOVERNING CARTILAGE AND SYNOVIUM. AN EVALUATION OF AGE-RELATED CHANGES FOR JOINT HOMEOSTASIS AND RISK FOR OSTEOARTHRITIS IS IMPORTANT TO THE DEVELOPMENT OF NEW STRATEGIES TO REJUVENATE AGING JOINTS. OBJECTIVE: THIS REVIEW SUMMARIZES THE CURRENT LITERATURE ON THE BIOCHEMICAL, CELLULAR, AND PHYSIOLOGIC CHANGES OCCURRING IN AGING ARTICULAR CARTILAGE. DATA SOURCES: PUBMED (1969-2013) AND PUBLISHED BOOKS IN SPORTS HEALTH, CARTILAGE BIOLOGY, AND AGING. STUDY SELECTION: KEYWORDS INCLUDED AGING, ATHLETE, ARTICULAR CARTILAGE, EPIGENETICS, AND FUNCTIONAL PERFORMANCE WITH AGE. STUDY DESIGN: SYSTEMATIC REVIEW. LEVEL OF EVIDENCE: LEVEL 3. DATA EXTRACTION: TO BE INCLUDED, RESEARCH QUESTIONS ADDRESSED THE EFFECT OF AGE-RELATED CHANGES ON PERFORMANCE, ARTICULAR CARTILAGE BIOLOGY, MOLECULAR MECHANISM, AND MORPHOLOGY. RESULTS: THE MATURE ATHLETE FACES CHALLENGES IN MAINTAINING CARTILAGE HEALTH AND JOINT FUNCTION DUE TO AGE-RELATED CHANGES TO ARTICULAR CARTILAGE BIOLOGY, MORPHOLOGY, AND PHYSIOLOGY. THESE CHANGES INCLUDE CHONDROCYTE LOSS AND A DECLINE IN METABOLIC RESPONSE, ALTERATIONS TO MATRIX AND SYNOVIAL TISSUE COMPOSITION, AND DYSREGULATION OF REPARATIVE RESPONSES. CONCLUSION: ALTHOUGH PHYSICAL DECLINE HAS BEEN REGARDED AS A NORMAL PART OF AGING, MANY INDIVIDUALS MAINTAIN OVERALL FITNESS AND ENJOY TARGETED IMPROVEMENT TO THEIR ATHLETIC CAPACITY THROUGHOUT LIFE. HEALTHY ARTICULAR CARTILAGE AND JOINTS ARE NEEDED TO MAINTAIN ATHLETIC PERFORMANCE AND GENERAL ACTIVITIES. GENETIC AND POTENTIALLY REVERSIBLE EPIGENETIC FACTORS INFLUENCE CARTILAGE PHYSIOLOGY AND ITS RESPONSE TO MECHANICAL AND INJURIOUS STIMULI. IMPROVED UNDERSTANDINGS OF THE PHYSICAL AND MOLECULAR CHANGES TO ARTICULAR CARTILAGE WITH AGING ARE IMPORTANT TO DEVELOP SUCCESSFUL STRATEGIES FOR JOINT REJUVENATION. 2014