1 6580 109 TREPONEMA DENTICOLA INCREASES MMP-2 EXPRESSION AND ACTIVATION IN THE PERIODONTIUM VIA REVERSIBLE DNA AND HISTONE MODIFICATIONS. HOST-DERIVED MATRIX METALLOPROTEINASES (MMPS) AND BACTERIAL PROTEASES MEDIATE DESTRUCTION OF EXTRACELLULAR MATRICES AND SUPPORTING ALVEOLAR BONE IN PERIODONTITIS. THE TREPONEMA DENTICOLA DENTILISIN PROTEASE INDUCES MMP-2 EXPRESSION AND ACTIVATION IN PERIODONTAL LIGAMENT (PDL) CELLS, AND DENTILISIN-MEDIATED ACTIVATION OF PRO-MMP-2 IS REQUIRED FOR CELLULAR FIBRONECTIN DEGRADATION. HERE, WE REPORT THAT T. DENTICOLA REGULATES MMP-2 EXPRESSION THROUGH EPIGENETIC MODIFICATIONS IN THE PERIODONTIUM. PDL CELLS WERE TREATED WITH EPIGENETIC ENZYME INHIBITORS BEFORE OR AFTER T. DENTICOLA CHALLENGE. FIBRONECTIN FRAGMENTATION, MMP-2 EXPRESSION, AND ACTIVATION WERE ASSESSED BY IMMUNOBLOT, ZYMOGRAPHY, AND QRT-PCR, RESPECTIVELY. CHROMATIN MODIFICATION ENZYME EXPRESSION IN T. DENTICOLA-CHALLENGED PDL CELLS AND PERIODONTAL TISSUES WERE EVALUATED USING GENE ARRAYS. SEVERAL CLASSES OF EPIGENETIC ENZYMES SHOWED SIGNIFICANT ALTERATIONS IN TRANSCRIPTION IN DISEASED TISSUE AND T. DENTICOLA-CHALLENGED PDL CELLS. T. DENTICOLA-MEDIATED MMP-2 EXPRESSION AND ACTIVATION WERE SIGNIFICANTLY REDUCED IN PDL CELLS TREATED WITH INHIBITORS OF AURORA KINASES AND HISTONE DEACETYLASES. IN CONTRAST, DNA METHYLTRANSFERASE INHIBITORS HAD LITTLE EFFECT, AND INHIBITORS OF HISTONE ACETYLTRANSFERASES, METHYLTRANSFERASES, AND DEMETHYLASES EXACERBATED T. DENTICOLA-MEDIATED MMP-2 EXPRESSION AND ACTIVATION. CHRONIC EPIGENETIC CHANGES IN PERIODONTAL TISSUES MEDIATED BY T. DENTICOLA OR OTHER ORAL MICROBES MAY CONTRIBUTE TO THE LIMITED SUCCESS OF CONVENTIONAL TREATMENT OF CHRONIC PERIODONTITIS AND MAY BE AMENABLE TO THERAPEUTIC REVERSAL. 2018 2 620 39 BIOCHEMISTRY AND MOLECULAR BIOLOGY OF GELATINASE B OR MATRIX METALLOPROTEINASE-9 (MMP-9): THE NEXT DECADE. RESEARCH ON MATRIX METALLOPROTEINASES (MMPS) AND IN PARTICULAR ON GELATINASE B, ALIAS MMP-9, HAS GROWN EXPONENTIALLY IN THE DECADE 2003-2012. STRUCTURAL DETAILS ABOUT FLEXIBILITY OF MMP-9 MONOMERS, TOGETHER WITH GLYCOSYLATION, OLIGOMERIZATION, HETEROGENEITY AND INSTABILITY OF THE WILDTYPE ENZYME EXPLAIN WHY CRYSTALLOGRAPHY EXPERIMENTS HAVE NOT YET BEEN SUCCESSFUL FOR THE INTACT ENZYME. MMP-9 MAY BE VIEWED AS A MULTIDOMAIN ENZYME IN WHICH THE HEMOPEXIN, THE O-GLYCOSYLATED AND THE CATALYTIC DOMAINS YIELD SUPPORT FOR ATTACHMENT, ARTICULATION AND CATALYSIS, RESPECTIVELY. THE STEPWISE PROTEOLYTIC ACTIVATION OF THE INACTIVE ZYMOGEN INTO A CATALYTICALLY ACTIVE FORM BECOMES GRADUALLY BETTER UNDERSTOOD. PRIMING OF ACTIVATION BY MMP-3 MAY BE EXECUTED BY MEPRINS THAT DESTABILIZE THE INTERACTION OF THE AMINOTERMINUS WITH THE THIRD FIBRONECTIN REPEAT. ALTERNATIVELY, AUTOCATALYTIC ACTIVATION MAY OCCUR IN THE PRESENCE OF MOLECULES THAT TIGHTLY BIND TO THE CATALYTIC SITE AND THAT PUSH THE CYSTEIN RESIDUE IN THE PRODOMAIN AWAY FROM THE CATALYTIC ZINC ION. THANKS TO THE DEVELOPMENT OF DEGRADOMICS TECHNOLOGIES, SUBSTRATE REPERTOIRES OF MMP-9 HAVE BEEN DEFINED, BUT IT REMAINS A CHALLENGE TO DETERMINE AND PROVE WHICH SUBSTRATES ARE BIOLOGICALLY RELEVANT. THE SUBSTRATE REPERTOIRE HAS BEEN ENLARGED FROM EXTRACELLULAR TO MEMBRANE-BOUND AND EFFICIENT INTRACELLULAR SUBSTRATES, SUCH AS CRYSTALLINS, TUBULINS AND ACTINS. BIOLOGICAL STUDIES OF MMP-9 HAVE TUNED THE FIELD FROM BEING PRIMARILY CANCER-ORIENTED TOWARDS VASCULAR AND INFLAMMATORY RESEARCH. IN TUMOR BIOLOGY, IT HAS BEEN INCREASINGLY APPRECIATED THAT MMP-9 FROM INFLAMMATORY CELLS, PARTICULARLY NEUTROPHILS, CO-DETERMINES PROGNOSIS AND OUTCOME. ASIDE FROM THE CATALYTIC FUNCTIONS EXECUTED BY AMINOTERMINAL DOMAINS OF MMP-9, THE CARBOXYTERMINAL HEMOPEXIN (PEX) DOMAIN OF GELATINASE B EXERTS NON-CATALYTIC ANTI-APOPTOTIC SIGNALING EFFECTS. THE RECOGNITION THAT GELATINASE B IS INDUCED BY MANY PRO-INFLAMMATORY CYTOKINES, WHEREAS ITS INHIBITORS ARE INCREASED BY ANTI-INFLAMMATORY CYTOKINES, HAS GENERATED INTEREST TO TARGET MMP-9 IN ACUTE LETHAL CONDITIONS, SUCH AS BACTERIAL MENINGITIS, SEPSIS AND ENDOTOXIN SHOCK, AND IN ACUTE EXACERBATIONS OF CHRONIC DISEASES. PREVIOUSLY DESCRIBED TRANSCRIPTIONAL REGULATION OF MMP-9 IS COMPLEMENTED BY EPIGENETIC CHECKPOINTS, INCLUDING HISTONE MODIFICATIONS AND MICRORNAS. BECAUSE ACTIVATION OF PROMMP-9 MAY BE EXECUTED BY OTHER MMPS, THE THERAPEUTIC DOGMA THAT MMP INHIBITORS NEED TO BE HIGHLY SELECTIVE MAY BE KEYED DOWN FOR THE TREATMENT OF LIFE-THREATENING CONDITIONS. WHEN INFLAMMATION AND MMP-9 FULFILL BENEFICIAL FUNCTIONS TO CLEAR DAMAGING PROTEIN COMPLEXES, SUCH AS IN SYSTEMIC AUTOIMMUNE DISEASES, THERAPEUTIC MMP INHIBITION HAS TO BE AVOIDED. IN MMP9 GENE KNOCKOUT MICE, SPECIFIC SPONTANEOUS PHENOTYPES EMERGED WITH EFFECTS ON THE SKELETAL, REPRODUCTIVE AND NERVOUS SYSTEMS. THESE FINDINGS NOT ONLY HAVE CLINICAL CORRELATES IN BONE GROWTH AND FERTILITY, BUT ALSO STIMULATE RESEARCH ON THE ROLES OF MMPS AND MMP-9 IN ENDOCRINOLOGY, IMMUNOLOGY AND THE NEUROSCIENCES. MMP9-DEFICIENT MICE ARE VALUABLE TOOLS TO DEFINE MMP-9 SUBSTRATES IN VIVO AND TO STUDY THE ROLE OF THIS ENZYME IN ANIMAL MODELS OF INFLAMMATORY, VASCULAR, NEOPLASTIC AND DEGENERATIVE DISEASES. FUTURE CHALLENGES INCLUDE SOLVING THE CRYSTAL STRUCTURE, DEFINITION OF THE FUNCTIONS OF COVALENT OLIGOMERS AND HETEROMERS IN BIOLOGY AND PATHOLOGY, LIFE-IMAGING OF MMP-9 ACTIVITY, SUBSTRATE DETERMINATION IN SITU AND THE STUDY OF INHIBITOR EFFECTS ON FERTILITY, CANCER AND INFLAMMATION AND IN NEUROBIOLOGY AND REGENERATIVE MEDICINE. SUCH STUDIES WILL BETTER DEFINE CONDITIONS IN WHICH INHIBITION OF MMP-9 IS BENEFICIAL OR HAS TO BE AVOIDED. 2013 3 5585 31 ROLE OF OXIDATIVE STRESS AND GENETIC POLYMORPHISM OF MATRIX METALLOPROTEINASE-2 AND TISSUE INHIBITOR OF METALLOPROTEINASE-2 IN COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), A COMPLAINT DESCRIBED BY PROGRESSIVE AND INADEQUATELY REVERSIBLE LIMITATION IN LUNGS WITH SYSTEMIC INFLAMMATION, IS LARGELY CURRENT IN INDIA. THERE'S NO REMEDY AVAILABLE SO FAR IT IS, THUS, IMPERATIVE TO UNDERSTAND THE UNDERPINNING PATHOGENESIS OF THE COMPLAINANT. A SET OF PROTEASES KNOWN AS MATRIX METALLOPROTEINASE (MMPS) ARE ESPECIALLY INVOLVED IN THE PROCESS OF ALVEOLAR DESTRUCTION AND MUCUS HYPERSECRETION. THERE ARE RESPONSIBLE FACTORS IN AN INHERITABLE POSITION TO CONTROL COPD LIKE MMPS AND TIMPS (TISSUE INHIBITOR OF METALLOPROTEINASES). MMPS DEGRADE EXTRACELLULAR MATRIX AND LEAD TO THE PATHOGENESIS OF COPD [1]. TIMPS PROTEINS THAT HELP TO INHIBIT THE MATRIX METALLOPROTEINASES. [2]. THIS REVIEW SUMMARIZES THE IMPLICIT PART OF CRUCIAL MMP-2 AND TIMP-2 IN COPD DISEASE. THOUGH THE CONCEPT SEEMS PROMISING, LIMITED KNOWLEDGE ABOUT THE EXACT FUNCTIONS OF A PARTICULAR MMP IN COPD AND THE COMPLICATIONS OF MMP IN SUBSTRATE AFFINITY MAKES THIS A GRUELING TASK. MMP2 AND TIMP2 BOTH ARE DIRECTLY OR INDIRECTLY REGULATED BY OXIDATIVE STRESS AND EPIGENETIC MECHANISM WHICH REGULATES THEIR EXPRESSIONS. COPD IS A SEDITIOUS RESPONSE TO FACTORS LIKE DUST, SMOKE, ETC., AND TRIGGERS EXTRA-PULMONARY GOODS WHICH CAUSE INFLAMMATION. [3]. THIS REVIEW EXPLAINS THE RELATIONSHIP BETWEEN MMP2 AND TIMP2 IN COPD PATIENTS WITH OXIDATIVE STRESS, ITS IMPACT ON COPD PATHOGENESIS, AND GENE EXPRESSION OF TIMP2 AND MMP2 WITH THEIR DOWNSTREAM EFFECTS. THIS ALSO GIVES SOME INSIGHTS INTO THERAPEUTIC INTERVENTIONS FOR TARGETING THESE ENZYMES. MMP2 AND TIMP2 BOTH PLAY A ROLE IN THE DEVELOPMENT OF COPD AND THEY NEED TO BE STUDIED WITH THE UTMOST FOCUS. 2023 4 2784 26 EZH2 PROMOTES EXTRACELLULAR MATRIX DEGRADATION VIA NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN PULPITIS. PULPITIS IS A COMPLICATED CHRONIC INFLAMMATORY PROCESS WHICH CAN BE IN A DYNAMIC BALANCE BETWEEN DAMAGE AND REPAIR. THE EXTRACELLULAR MATRIX PLAYS AN IMPORTANT REGULATORY ROLE IN WOUND HEALING AND TISSUE REPAIR. THE AIM OF THIS STUDY WAS TO EXPLORE THE ROLE OF THE EPIGENETIC MARK, ENHANCER OF ZESTE HOMOLOG 2 (EZH2) ON THE DEGRADATION OF EXTRACELLULAR MATRIX DURING PULPITIS. QUANTITATIVE POLYMERASE CHAIN REACTION WAS USED TO ASSESS THE EXPRESSION OF MATRIX METALLOPROTEINASES (MMPS) AND TYPE I COLLAGEN IN HUMAN DENTAL PULP CELLS (HDPCS) UPON EZH2 AND EI1 (EZH2 INHIBITOR) STIMULATION. THE MECHANISM OF EZH2 AFFECTING EXTRACELLULAR MATRIX WAS EXPLORED THROUGH QUANTITATIVE POLYMERASE CHAIN REACTION AND WESTERN BLOT. A RAT MODEL OF DENTAL PULP INFLAMMATION WAS ESTABLISHED, AND THE EXPRESSION OF TYPE I COLLAGEN IN DENTAL PULP UNDER EZH2 STIMULATION WAS DETECTED BY IMMUNOHISTOCHEMICAL STAINING. EZH2 UPREGULATED THE EXPRESSION OF MMP-1, MMP-3, MMP-8, AND MMP-10 AND DECREASED THE PRODUCTION OF TYPE I COLLAGEN IN HDPCS, WHILE EI1 HAD THE OPPOSITE EFFECT. EZH2 ACTIVATED THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN HDPCS, THE INHIBITION OF WHICH REVERSED THE INDUCTION OF MMPS AND THE SUPPRESSION OF TYPE I COLLAGEN. EZH2 CAN DOWNREGULATE THE TYPE I COLLAGEN LEVELS IN AN EXPERIMENTAL MODEL OF DENTAL PULPITIS IN RATS. EZH2 PROMOTES EXTRACELLULAR MATRIX DEGRADATION VIA NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN PULPITIS. EZH2 CAN DECREASE THE TYPE I COLLAGEN LEVELS IN VIVO AND IN VITRO. 2021 5 5078 27 PHYSIOLOGY AND PATHOPHYSIOLOGY OF MATRIX METALLOPROTEASES. MATRIX METALLOPROTEASES (MMPS) COMPRISE A FAMILY OF ENZYMES THAT CLEAVE PROTEIN SUBSTRATES BASED ON A CONSERVED MECHANISM INVOLVING ACTIVATION OF AN ACTIVE SITE-BOUND WATER MOLECULE BY A ZN(2+) ION. ALTHOUGH THE CATALYTIC DOMAIN OF MMPS IS STRUCTURALLY HIGHLY SIMILAR, THERE ARE MANY DIFFERENCES WITH RESPECT TO SUBSTRATE SPECIFICITY, CELLULAR AND TISSUE LOCALIZATION, MEMBRANE BINDING AND REGULATION THAT MAKE THIS A VERY VERSATILE FAMILY OF ENZYMES WITH A MULTITUDE OF PHYSIOLOGICAL FUNCTIONS, MANY OF WHICH ARE STILL NOT FULLY UNDERSTOOD. ESSENTIALLY, ALL MEMBERS OF THE MMP FAMILY HAVE BEEN LINKED TO DISEASE DEVELOPMENT, NOTABLY TO CANCER METASTASIS, CHRONIC INFLAMMATION AND THE ENSUING TISSUE DAMAGE AS WELL AS TO NEUROLOGICAL DISORDERS. THIS HAS STIMULATED A FLURRY OF STUDIES INTO MMP INHIBITORS AS THERAPEUTIC AGENTS, AS WELL AS INTO MEASURING MMP LEVELS AS DIAGNOSTIC OR PROGNOSTIC MARKERS. AS WITH MOST PROTEIN FAMILIES, DECIPHERING THE FUNCTION(S) OF MMPS IS DIFFICULT, AS THEY CAN MODIFY MANY PROTEINS. WHICH OF THESE REACTIONS ARE PHYSIOLOGICALLY OR PATHOPHYSIOLOGICALLY RELEVANT IS OFTEN NOT CLEAR, ALTHOUGH STUDIES ON KNOCKOUT ANIMALS, HUMAN GENETIC AND EPIGENETIC, AS WELL AS BIOCHEMICAL STUDIES USING NATURAL OR SYNTHETIC INHIBITORS HAVE PROVIDED INSIGHT TO A GREAT EXTENT. IN THIS REVIEW, WE WILL GIVE AN OVERVIEW OF 23 MEMBERS OF THE HUMAN MMP FAMILY AND DESCRIBE FUNCTIONS, LINKAGES TO DISEASE AND STRUCTURAL AND MECHANISTIC FEATURES. MMPS CAN BE GROUPED INTO SOLUBLE (INCLUDING MATRILYSINS) AND MEMBRANE-ANCHORED SPECIES. WE ADHERE TO THE 'MMP NOMENCLATURE' AND PROVIDE THE READER WITH REFERENCE TO THE MANY, OFTEN DIVERSE, NAMES FOR THIS ENZYME FAMILY IN THE INTRODUCTION. 2011 6 4880 20 OVERVIEW OF MMP-13 AS A PROMISING TARGET FOR THE TREATMENT OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON DEGENERATIVE DISEASE CHARACTERIZED BY THE DESTRUCTION OF ARTICULAR CARTILAGE AND CHRONIC INFLAMMATION OF SURROUNDING TISSUES. MATRIX METALLOPROTEINASE-13 (MMP-13) IS THE PRIMARY MMP INVOLVED IN CARTILAGE DEGRADATION THROUGH ITS PARTICULAR ABILITY TO CLEAVE TYPE II COLLAGEN. HENCE, IT IS AN ATTRACTIVE TARGET FOR THE TREATMENT OF OA. HOWEVER, THE DETAILED MOLECULAR MECHANISMS OF OA INITIATION AND PROGRESSION REMAIN ELUSIVE, AND, CURRENTLY, THERE ARE NO INTERVENTIONS AVAILABLE TO RESTORE DEGRADED CARTILAGE. THIS REVIEW FULLY ILLUSTRATES THE INVOLVEMENT OF MMP-13 IN THE INITIATION AND PROGRESSION OF OA THROUGH THE REGULATION OF MMP-13 ACTIVITY AT THE MOLECULAR AND EPIGENETIC LEVELS, AS WELL AS THE STRATEGIES THAT HAVE BEEN EMPLOYED AGAINST MMP-13. THE AIM OF THIS REVIEW IS TO IDENTIFY MMP-13 AS AN ATTRACTIVE TARGET FOR INHIBITOR DEVELOPMENT IN THE TREATMENT OF OA. 2021 7 3355 27 HISTONE EXTRACTION FROM HUMAN ARTICULAR CARTILAGE FOR THE STUDY OF EPIGENETIC REGULATION IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A CHRONIC DISEASE THAT AFFECTS ARTICULAR CARTILAGE, CAUSING ITS DEGENERATION. ALTHOUGH OA IS ONE OF THE MOST PREVALENT PATHOLOGIES GLOBALLY, THERE ARE NO DEFINITIVE TREATMENTS AVAILABLE. RECENTLY, RESEARCH HAS FOCUSED ON ELUCIDATING THE COMPLEX INTERPLAY THAT TAKES PLACE BETWEEN INFLAMMATORY PROCESSES AND EPIGENETIC REGULATION, SHOWING THAT HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS) CAN EXERT A PRONOUNCED EFFECT ON THE EXPRESSION OF OA-RELATED GENES. OA CHONDROCYTES ENHANCE THE PRODUCTION OF INTERLEUKIN 1BETA (IL-1BETA) AND INTERLEUKIN 8 (IL-8), WHICH ARE EPIGENETICALLY REGULATED. THESE CYTOKINES UPREGULATE THE SYNTHESIS OF MATRIX METALLOPROTEINASES (MMPS) AND AGGRECANASES, WHICH PROMOTE THE EXTRACELLULAR MATRIX (ECM) DESTRUCTION. THIS MOTIVATES THE STUDY OF HISTONE PTMS TO INVESTIGATE THE EPIGENETIC REGULATION OF PROINFLAMMATORY MOLECULES, BUT THE ABSENCE OF SPECIFIC PROTOCOLS TO EXTRACT HISTONES FROM HUMAN ARTICULAR CARTILAGE HAS COMPLICATED THIS TASK. THE LACK OF EFFECTIVE METHODS CAN BE EXPLAINED BY THE STRUCTURAL COMPLEXITY AND LOW CELLULARITY OF THIS TISSUE, WHICH ARE RESPONSIBLE FOR THE BIOMECHANICAL PROPERTIES THAT ALLOW THE MOVEMENT OF THE JOINT BUT ALSO COMPLICATE HISTONE ISOLATION. HERE, WE PROVIDE A HISTONE EXTRACTION PROCEDURE SPECIFICALLY ADAPTED FOR CRYOPRESERVED HUMAN ARTICULAR CARTILAGE THAT CAN BE USEFUL TO UNDERSTAND EPIGENETIC REGULATION IN OA AND ACCELERATE THE SEARCH FOR NOVEL STRATEGIES. 2022 8 3931 17 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 9 5145 25 POTENTIAL ROLE OF NUTRACEUTICALS VIA TARGETING A WNT/BETA-CATENIN AND NF-KAPPAB PATHWAY IN TREATMENT OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A DISEASE DUE TO THE AGING OF THE ARTICULAR CARTILAGE, A POST-MITOTIC TISSUE THAT STAYS FUNCTIONING UNTIL PRIMARY HOMEOSTATIC PROCESSES FAIL. BECAUSE OF PAIN AND DISABILITY, OA SIGNIFICANTLY INFLUENCES NATIONAL HEALTHCARE EXPENSES AND PATIENT QUALITY OF LIFE. IT IS A WHOLE-JOINT ILLNESS CHARACTERIZED BY INFLAMMATORY AND OXIDATIVE SIGNALING PATHWAYS AND SIGNIFICANT EPIGENETIC ALTERATIONS THAT CAUSE CARTILAGE EXTRACELLULAR MATRIX DEGRADATION. THE CANONICAL WNT PATHWAY (WNT/BETA-CATENIN PATHWAY) AND NUCLEAR FACTOR KAPPA B (NF-KAPPAB) SIGNALING PATHWAYS MAY FUNCTION IN JOINT TISSUES BY MODULATING THE ACTIVITY OF SYNOVIAL CELLS, OSTEOBLASTS, AND CHONDROCYTES. HOWEVER, FINDING INNOVATIVE WAYS TO TREAT OSTEOARTHRITIS AND GET THE JOINT BACK TO AVERAGE BALANCE IS STILL A STRUGGLE. NUTRACEUTICALS ARE DIETARY SUPPLEMENTS THAT PROMOTE JOINT HEALTH BY BALANCING ANABOLIC AND CATABOLIC SIGNALS. NEW THERAPEUTIC METHODS FOR OA TREATMENT HAVE BEEN DEVELOPED BASED ON MANY RESEARCH FINDINGS THAT SHOW NUTRACEUTICALS HAVE STRONG ANTI-INFLAMMATION, ANTIOXIDANT, ANTI-BONE RESORPTION, AND ANABOLIC PROPERTIES. FOR THE TREATMENT OF OSTEOARTHRITIS, WE EXPLORE THE POSSIBLE INVOLVEMENT OF NUTRACEUTICALS THAT TARGET THE WNT/BETA-CATENIN AND NF-KAPPAB PATHWAYS. PRACTICAL APPLICATIONS: IN KEEPING WITH THE AGING POPULATION, OSTEOARTHRITIS IS BECOMING MORE WIDESPREAD. IN THIS EXTENSIVE RESEARCH, WE STUDIED THE ROLE OF THE WNT/BETA-CATENIN AND NF-KAPPAB PATHWAY IN OA FORMATION AND PROGRESSION. NUTRACEUTICALS THAT TARGET THESE OA-RELATED SIGNALING PATHWAYS ARE A VIABLE THERAPY OPTION. WNT/BETA-CATENIN AND NF-KAPPAB SIGNALING PATHWAY ARE INHIBITED BY POLYPHENOLS, FLAVONOIDS, ALKALOIDS, AND VITAMINS FROM THE NUTRACEUTICAL CATEGORY, MAKING THEM POSSIBLE THERAPEUTIC DRUGS FOR OA THERAPY. 2022 10 5939 31 TARGETING MECHANOTRANSDUCTION AT THE TRANSCRIPTIONAL LEVEL: YAP AND BRD4 ARE NOVEL THERAPEUTIC TARGETS FOR THE REVERSAL OF LIVER FIBROSIS. LIVER FIBROSIS IS THE RESULT OF A DEREGULATED WOUND HEALING PROCESS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX. HEPATIC STELLATE CELLS (HSCS), WHICH ARE ACTIVATED IN RESPONSE TO LIVER INJURY, ARE THE MAJOR SOURCE OF EXTRACELLULAR MATRIX AND DRIVE THE WOUND HEALING PROCESS. HOWEVER, CHRONIC LIVER DAMAGE LEADS TO PERPETUAL HSC ACTIVATION, PROGRESSIVE FORMATION OF PATHOLOGICAL SCAR TISSUE AND ULTIMATELY, CIRRHOSIS AND ORGAN FAILURE. HSC ACTIVATION IS TRIGGERED LARGELY IN RESPONSE TO MECHANOSIGNALING FROM THE MICROENVIRONMENT, WHICH INDUCES A PROFIBROTIC NUCLEAR TRANSCRIPTION PROGRAM THAT PROMOTES HSC PROLIFERATION AND EXTRACELLULAR MATRIX SECRETION THEREBY SETTING UP A POSITIVE FEEDBACK LOOP LEADING TO MATRIX STIFFENING AND SELF-SUSTAINED, PATHOLOGICAL, HSC ACTIVATION. DESPITE THE SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF LIVER FIBROSIS, THE MOLECULAR MECHANISMS THROUGH WHICH THE EXTRACELLULAR MATRIX PROMOTES HSC ACTIVATION ARE NOT WELL UNDERSTOOD AND NO EFFECTIVE THERAPIES HAVE BEEN APPROVED TO DATE THAT CAN TARGET THIS EARLY, REVERSIBLE, STAGE IN LIVER FIBROSIS. SEVERAL NEW LINES OF INVESTIGATION NOW PROVIDE IMPORTANT INSIGHT INTO THIS AREA OF STUDY AND IDENTIFY TWO NUCLEAR TARGETS WHOSE INHIBITION HAS THE POTENTIAL OF REVERSING LIVER FIBROSIS BY INTERFERING WITH HSC ACTIVATION: YES-ASSOCIATED PROTEIN (YAP), A TRANSCRIPTIONAL CO-ACTIVATOR AND EFFECTOR OF THE MECHANOSENSITIVE HIPPO PATHWAY, AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC REGULATOR OF GENE EXPRESSION. YAP AND BRD4 ACTIVITY IS INDUCED IN RESPONSE TO MECHANICAL STIMULATION OF HSCS AND EACH PROTEIN INDEPENDENTLY CONTROLS WAVES OF EARLY GENE EXPRESSION NECESSARY FOR HSC ACTIVATION. SIGNIFICANTLY, INHIBITION OF EITHER PROTEIN CAN REVERT THE CHRONIC ACTIVATION OF HSCS AND IMPEDE PATHOLOGICAL PROGRESSION OF LIVER FIBROSIS IN CLINICALLY RELEVANT MODEL SYSTEMS. IN THIS REVIEW WE WILL DISCUSS THE ROLES OF THESE NUCLEAR CO-ACTIVATORS IN HSC ACTIVATION, THEIR MECHANISM OF ACTION IN THE FIBROTIC PROCESS IN THE LIVER AND OTHER ORGANS, AND THE POTENTIAL OF TARGETING THEIR ACTIVITY WITH SMALL MOLECULE DRUGS FOR FIBROSIS REVERSAL. 2016 11 4044 18 MACROPHAGES IN OXIDATIVE STRESS AND MODELS TO EVALUATE THE ANTIOXIDANT FUNCTION OF DIETARY NATURAL COMPOUNDS. ANTIOXIDANT TESTING OF NATURAL PRODUCTS HAS ATTRACTED INCREASING INTEREST IN RECENT YEARS, MAINLY DUE TO THE FACT THAT AN ANTIOXIDANT-RICH DIET MIGHT PROVIDE HEALTH BENEFITS. ACTIVATED MACROPHAGES ARE A MAJOR SOURCE OF REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES, AND PEROXYNITRITE GENERATED THROUGH THE SO-CALLED RESPIRATORY BURST. CONSTITUTIVELY RELEASED PROINFLAMMATORY CYTOKINE, ESPECIALLY TUMOR NECROSIS FACTOR-ALPHA, TRIGGERS NUCLEAR FACTOR-KAPPAB, AND ACTIVATOR PROTEIN-1 TRANSLOCATION LEADING TO THE OVER PRODUCTION OF REACTIVE OXYGEN SPECIES AND REACTIVE NITROGEN SPECIES IN MACROPHAGES. ACTIVATION OF TRANSCRIPTION FACTORS IN THE LONG-LIVED TISSUE-RESIDENT MACROPHAGES AND/OR MONOCYTE-DERIVED MACROPHAGES, TRIGGER EPIGENETIC MODIFICATIONS LEADING TO THE PATHOGENESIS OF CHRONIC DISEASES. NUTRACEUTICALS INCLUDING LIPID RAFT STRUCTURE DISRUPTION AGENT, CHOLESTEROL DEPLETION AGENT, FARNESYLTRANSFERASE INHIBITOR, NUCLEAR FACTOR-KAPPAB BLOCKER (ALPHA,BETA-UNSATURATED CARBONYL COMPOUNDS), GLUCOCORTICOID RECEPTOR AGONIST, AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AGONIST HAVE LONG BEEN USED TO INACTIVE MACROPHAGE. THE INHIBITION EFFECTS ON THE FORMATION OF NITRIC OXIDE, SUPEROXIDE, AND NITRITE PEROXIDE MAY BE RESPONSIBLE FOR THE ANTI-INFLAMMATORY FUNCTIONALITIES. ACTIVATED MACROPHAGE MODELS COULD BE USED TO IDENTIFY THE ACTIVE COMPONENTS FOR FUNCTIONAL DIETS DEVELOPMENT THROUGH A MULTIPLE TARGETS STRATEGY. 2017 12 6910 23 [TRANSFORMING GROWTH FACTOR-BETA AND RENAL FIBROSIS]. TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) IS A DRIVING FORCE OF RENAL FIBROSIS, WHICH MAY LEAD TO CHRONIC KIDNEY DISEASES AND EVEN END STAGE RENAL DISEASES. BY ACTIVATING CANONICAL AND NON-CANONICAL SIGNALING PATHWAYS, TGF-BETA PROMOTES THE SYNTHESIS OF EXTRACELLULAR MATRIX WHILE PREVENTING THEIR DEGRADATION. IN THE INJURED KIDNEY, TGF-BETA INDUCES APOPTOSIS, PROLIFERATION AND FIBROTIC RESPONSE OF RENAL CELLS INCLUDING EPITHELIAL CELLS, ENDOTHELIAL CELLS, PODOCYTES, FIBROBLASTS, PERICYTES AND MACROPHAGES, AND IT ALSO PROMOTES TRANSDIFFERENTIATION, ACTIVATION AND PROLIFERATION OF MYOFIBROBLASTS. ADDITIONALLY, TGF-BETA EXERTS PROFIBROTIC EFFECTS BY INTERPLAYING WITH OTHER SIGNALING PATHWAYS LIKE BMP-7, WNT/BETA-CATENIN AND MAP KINASE. SMAD3 IS THE CENTRAL PATHOLOGICAL GENE IN RENAL FIBROSIS, AND EPIGENETIC REGULATION OF TGF-BETA/SMAD3 IS A HOT TOPIC IN KIDNEY FIELD. ALTHOUGH DIRECT TARGETING TGF-BETA MAY CAUSE SIDE EFFECTS INCLUDING TUMORIGENESIS AND IMMUNE DISEASES, THE THERAPEUTIC STRATEGIES TARGETING THE BALANCE OF DOWNSTREAM SMAD3 AND SMAD7 MAY PREVENT OR DELAY THE PROGRESSION OF FIBROTIC KIDNEY DISEASE. 2018 13 699 30 BROMODOMAIN PROTEIN 4 IS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HEPATIC STELLATE CELL ACTIVATION. LIVER FIBROSIS IS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX IN LIVER. CHRONIC LIVER INJURY INDUCES THE ACTIVATION OF HEPATIC STELLATE CELL (HSCS), A KEY STEP IN LIVER FIBROGENESIS. THE ACTIVATED HSC IS THE PRIMARY SOURCE OF ECM AND CONTRIBUTES SIGNIFICANTLY TO LIVER FIBROSIS. TGFBETA1 IS THE MOST POTENT PRO-FIBROTIC CYTOKINE. BROMODOMAIN PROTEIN 4 (BRD4), AN EPIGENETIC READER OF HISTONE ACETYLATION MARKS, WAS CRUCIAL FOR PROFIBROTIC GENE EXPRESSION IN HSCS. THE PRESENT STUDY AIMED TO INVESTIGATE THE ROLES OF BRD4 IN TGFBETA1-DEPENDENT HSC ACTIVATION AND LIVER FIBROSIS, FOCUSING ON TGFBETA1-INDUCED ALTERATIONS OF THE LEVELS OF THE FIBROTIC-RELATED IMPORTANT PROTEINS IN HSCS BY EMPLOYING THE HETEROZYGOUS TGFBETA1 KNOCKOUT MICE AND BRD4 KNOCKDOWN IN VIVO AND IN VITRO. RESULTS REVEALED THAT BRD4 PROTEIN LEVEL WAS SIGNIFICANTLY UPREGULATED BY TGFBETA1 AND BRD4 KNOCKDOWN REDUCED TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. BRD4 WAS REQUIRED FOR THE INFLUENCES OF TGFBETA1 ON PDGFBETA RECEPTOR AND ON THE PATHWAYS OF SMAD3, STAT3, AND AKT. BRD4 ALSO MEDIATED TGFBETA1-INDUCED INCREASES IN HISTONE ACETYLTRANSFERASE P300, THE PIVOTAL PRO-INFLAMMATORY NFKB P65, AND TISSUE INHIBITOR OF METALLOPROTEINASE 1 WHEREAS BRD4 REDUCED CASPASE-3 PROTEIN LEVELS IN HSCS DURING LIVER INJURY, INDEPENDENT OF TGFBETA1. FURTHER EXPERIMENTS INDICATED THE INTERACTION BETWEEN TGFBETA1-INDUCED BRD4 AND NFKB P65 IN HSCS AND IN LIVER OF TAA-INDUCED LIVER INJURY. HUMAN CIRRHOTIC LIVERS WERE DEMONSTRATED A PARALLEL INCREASE IN THE PROTEIN LEVELS OF BRD4 AND NFKB P65 IN HSCS. THIS STUDY REVEALED THAT BRD4 WAS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. 2023 14 3688 24 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008 15 3800 26 INTERPLAY OF INFLAMMATORY MEDIATORS WITH EPIGENETICS AND CARTILAGE MODIFICATIONS IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA), A DEGENERATIVE DISEASE OF DIARTHRODIAL JOINTS, IS INFLUENCED BY MECHANICAL AND INFLAMMATORY FACTORS WITH AGING, OBESITY, CHRONIC INJURIES, AND SECONDARY DISEASES THOUGHT TO BE MAJOR FACTORS DRIVING THE PROCESS OF ARTICULAR CARTILAGE DEGENERATION. CHONDROCYTES, THE CELLULAR COMPONENT OF CARTILAGE, RESIDE IN AN AVASCULAR ENVIRONMENT AND NORMALLY HAVE LIMITED POTENTIAL TO REPLICATE. HOWEVER, EXTRINSIC FACTORS SUCH AS INJURY TO THE JOINT OR INTRINSIC ALTERATIONS TO THE CHONDROCYTES THEMSELVES CAN LEAD TO AN ALTERED PHENOTYPE AND DEVELOPMENT OF OA. SYNOVIAL INFLAMMATION IS ALSO A PIVOTAL ELEMENT OF THE OSTEOARTHRITIC, DEGENERATIVE PROCESS: INFLUX OF PRO-INFLAMMATORY CYTOKINES AND PRODUCTION OF MATRIX METALLOPROTEINASES ACCELERATE ADVANCED CELLULAR PROCESSES SUCH AS SYNOVITIS AND CARTILAGE DAMAGE. AS WELL AS A GENETIC INPUT, RECENT DATA HAVE HIGHLIGHTED EPIGENETIC FACTORS AS CONTRIBUTING TO DISEASE. STUDIES CONDUCTED OVER THE LAST DECADE HAVE FOCUSED ON THREE KEY ASPECTS IN OA; INFLAMMATION AND THE IMMUNE RESPONSE, GENOME-WIDE ASSOCIATION STUDIES THAT HAVE IDENTIFIED IMPORTANT GENES UNDERGOING EPIGENETIC MODIFICATIONS, AND FINALLY HOW CHONDROCYTES TRANSFORM IN THEIR FUNCTION DURING DEVELOPMENT AND DISEASE. DATA HIGHLIGHTED HERE HAVE IDENTIFIED CRITICAL INFLAMMATORY GENES INVOLVED IN OA AND HOW THESE FACTORS IMPACT CHONDROCYTE HYPERTROPHY IN THE DISEASE. THIS REVIEW ALSO ADDRESSES KEY INFLAMMATORY FACTORS IN SYNOVIAL INFLAMMATION, EPIGENETICS, AND CHONDROCYTE FATE, AND HOW AGENTS THAT INHIBIT EPIGENETIC MECHANISMS LIKE DNA METHYLATION AND HISTONE MODIFICATIONS COULD AID IN DEVELOPMENT OF LONG-TERM TREATMENT STRATEGIES FOR THE DISEASE. 2018 16 5052 31 PHARMACOLOGICAL TARGETING OF HEME OXYGENASE-1 IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON AGING-ASSOCIATED DISEASE THAT CLINICALLY MANIFESTS AS JOINT PAIN, MOBILITY LIMITATIONS, AND COMPROMISED QUALITY OF LIFE. TODAY, OA TREATMENT IS LIMITED TO PAIN MANAGEMENT AND JOINT ARTHROPLASTY AT THE LATER STAGES OF DISEASE PROGRESSION. OA PATHOGENESIS IS PREDOMINANTLY MEDIATED BY OXIDATIVE DAMAGE TO JOINT CARTILAGE EXTRACELLULAR MATRIX AND LOCAL CELLS SUCH AS CHONDROCYTES, OSTEOCLASTS, OSTEOBLASTS, AND SYNOVIAL FIBROBLASTS. UNDER NORMAL CONDITIONS, CELLS PREVENT THE ACCUMULATION OF REACTIVE OXYGEN SPECIES (ROS) UNDER OXIDATIVELY STRESSFUL CONDITIONS THROUGH THEIR ADAPTIVE CYTOPROTECTIVE MECHANISMS. HEME OXYGENASE-1 (HO-1) IS AN IRON-DEPENDENT CYTOPROTECTIVE ENZYME THAT FUNCTIONS AS THE INDUCIBLE FORM OF HO. HO-1 AND ITS METABOLITES CARBON MONOXIDE AND BILIVERDIN CONTRIBUTE TOWARDS THE MAINTENANCE OF REDOX HOMEOSTASIS. HO-1 EXPRESSION IS PRIMARILY REGULATED AT THE TRANSCRIPTIONAL LEVEL THROUGH TRANSCRIPTIONAL FACTOR NUCLEAR FACTOR ERYTHROID 2 (NF-E2)-RELATED FACTOR 2 (NRF2), SPECIFICITY PROTEIN 1 (SP1), TRANSCRIPTIONAL REPRESSOR BTB-AND-CNC HOMOLOGY 1 (BACH1), AND EPIGENETIC REGULATION. SEVERAL STUDIES REPORT THAT HO-1 EXPRESSION CAN BE REGULATED USING VARIOUS ANTIOXIDATIVE FACTORS AND CHEMICAL COMPOUNDS, SUGGESTING THERAPEUTIC IMPLICATIONS IN OA PATHOGENESIS AS WELL AS IN THE WIDER CONTEXT OF JOINT DISEASE. HERE, WE REVIEW THE PROTECTIVE ROLE OF HO-1 IN OA WITH A FOCUS ON THE REGULATORY MECHANISMS THAT MEDIATE HO-1 ACTIVITY. 2021 17 603 30 BETULINIC ACID INHIBITS ENDOMETRIOSIS THROUGH SUPPRESSION OF ESTROGEN RECEPTOR BETA SIGNALING PATHWAY. ENDOMETRIOSIS IS AN INFLAMMATORY GYNECOLOGICAL DISORDER CHARACTERIZED BY ENDOMETRIAL TISSUE GROWTH LOCATED OUTSIDE OF THE UTERINE CAVITY IN ADDITION TO CHRONIC PELVIC PAIN AND INFERTILITY. IN THIS STUDY, WE AIM TO DEVELOP A POTENTIAL THERAPEUTIC TREATMENT BASED ON THE PATHOGENESIS AND MECHANISM OF ENDOMETRIOSIS. OUR PRELIMINARY DATA SHOWED THAT THE EXPRESSION OF ESTROGEN RECEPTOR BETA (ERBETA) WAS SIGNIFICANTLY INCREASED, WHILE ERALPHA WAS SIGNIFICANTLY DECREASED, IN ENDOMETRIOTIC CELLS COMPARED TO NORMAL ENDOMETRIAL CELLS. FURTHER INVESTIGATION SHOWED THAT BETULINIC ACID (BA) TREATMENT SUPPRESSED ERBETA EXPRESSION THROUGH EPIGENETIC MODIFICATION ON THE ERBETA PROMOTER, WHILE HAD NO EFFECT ON ERALPHA EXPRESSION. IN ADDITION, BA TREATMENT SUPPRESSES ERBETA TARGET GENES, INCLUDING SUPEROXIDE DISMUTASE 2 (SOD2), NUCLEAR RESPIRATORY FACTOR-1 (NRF1), CYCLOOXYGENASE 2 (COX2), AND MATRIX METALLOPROTEINASE-1 (MMP1), SUBSEQUENTLY INCREASING OXIDATIVE STRESS, TRIGGERING MITOCHONDRIAL DYSFUNCTION, DECREASING ELEVATED PROINFLAMMATORY CYTOKINES, AND EVENTUALLY SUPPRESSING ENDOMETRIOTIC CELL PROLIFERATION, MIMICKING THE EFFECT OF ERBETA KNOCKDOWN. ON THE OTHER HAND, GAIN OF ERBETA BY LENTIVIRUS INFECTION IN NORMAL ENDOMETRIAL CELLS RESULTED IN INCREASED CELL PROLIFERATION AND PROINFLAMMATORY CYTOKINE RELEASE, WHILE BA TREATMENT DIMINISHED THIS EFFECT THROUGH ERBETA SUPPRESSION WITH SUBSEQUENT OXIDATIVE STRESS AND APOPTOSIS. OUR RESULTS INDICATE THAT ERBETA MAY BE A MAJOR DRIVING FORCE FOR THE DEVELOPMENT OF ENDOMETRIOSIS, WHILE BA INHIBITS ENDOMETRIOSIS THROUGH SPECIFIC SUPPRESSION OF THE ERBETA SIGNALING PATHWAY. THIS STUDY PROVIDES A NOVEL THERAPEUTIC STRATEGY FOR ENDOMETRIOSIS TREATMENT THROUGH BA-MEDIATED ERBETA SUPPRESSION. 2020 18 4679 28 NEW MOLECULAR TARGETS FOR THE TREATMENT OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A CHRONIC DEGENERATIVE JOINT DISORDER CHARACTERIZED BY DESTRUCTION OF THE ARTICULAR CARTILAGE, SUBCHONDRAL BONE ALTERATIONS AND SYNOVITIS. CURRENT TREATMENTS ARE FOCUSED ON SYMPTOMATIC RELIEF BUT THEY LACK EFFICACY TO CONTROL THE PROGRESSION OF THIS DISEASE WHICH IS A LEADING CAUSE OF DISABILITY. THEREFORE, THE DEVELOPMENT OF EFFECTIVE DISEASE-MODIFYING DRUGS IS URGENTLY NEEDED. DIFFERENT INITIATIVES ARE IN PROGRESS TO DEFINE THE MOLECULAR MECHANISMS INVOLVED IN THE INITIATION AND PROGRESSION OF OA. THESE STUDIES SUPPORT THE THERAPEUTIC POTENTIAL OF PATHWAYS RELEVANT IN JOINT METABOLISM SUCH AS WNT/BETA-CATENIN, DISCOIDIN DOMAIN RECEPTOR 2 OR PROTEINASE-ACTIVATED RECEPTOR 2. THE DYSREGULATION IN CARTILAGE CATABOLISM AND SUBCHONDRAL BONE REMODELING COULD BE IMPROVED BY SELECTIVE INHIBITORS OF MATRIX METALLOPROTEINASES, AGGRECANASES AND OTHER PROTEASES. ANOTHER APPROACH WOULD FAVOR THE ACTIVITY OF ANABOLIC PROCESSES BY USING GROWTH FACTORS OR REGULATORY MOLECULES. RECENT STUDIES HAVE ALSO REVEALED THE ROLE OF OXIDATIVE STRESS AND SYNOVITIS IN THE PROGRESSION OF THIS DISEASE, SUPPORTING THE DEVELOPMENT OF A NUMBER OF INHIBITORY STRATEGIES. NOVEL TARGETS IN OA ARE REPRESENTED BY GENES INVOLVED IN OA PATHOPHYSIOLOGY DISCOVERED USING GENE NETWORK, EPIGENETIC AND MICRORNA APPROACHES. FURTHER INSIGHTS INTO THE MOLECULAR MECHANISMS INVOLVED IN OA INITIATION AND PROGRESSION MAY LEAD TO THE DEVELOPMENT OF NEW THERAPIES ABLE TO CONTROL JOINT DESTRUCTION AND REPAIR. 2010 19 799 27 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 20 4097 20 MATRIX STIFFNESS REGULATES MACROPHAGE POLARIZATION IN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE AND THE PATHOLOGICAL BASIS OF MANY FATAL CARDIOVASCULAR DISEASES. MACROPHAGES, THE MAIN INFLAMMATORY CELLS IN ATHEROSCLEROTIC PLAQUE, HAVE A PARADOX ROLE IN DISEASE PROGRESSION. IN RESPONSE TO DIFFERENT MICROENVIRONMENTS, MACROPHAGES MAINLY HAVE TWO POLARIZED DIRECTIONS: PRO-INFLAMMATORY MACROPHAGES AND ANTI-INFLAMMATORY MACROPHAGES. MORE AND MORE EVIDENCE SHOWS THAT MACROPHAGE IS MECHANOSENSITIVE AND MATRIX STIFFNESS REGULATE MACROPHAGE PHENOTYPES IN ATHEROSCLEROSIS. HOWEVER, THE MOLECULAR MECHANISM OF MATRIX STIFFNESS REGULATING MACROPHAGE POLARIZATION STILL LACKS IN-DEPTH RESEARCH, WHICH HINDERS THE DEVELOPMENT OF NEW ANTI-ATHEROSCLEROTIC THERAPIES. IN THIS REVIEW, WE DISCUSS THE IMPORTANT ROLE OF MATRIX STIFFNESS IN REGULATING MACROPHAGE POLARIZATION THROUGH MECHANICAL SIGNAL TRANSDUCTION (HIPPO, PIEZO, CYTOSKELETON, AND INTEGRIN) AND EPIGENETIC MECHANISMS (MIRNA, DNA METHYLATION, AND HISTONE). WE HOPE TO PROVIDE A NEW PERSPECTIVE FOR ATHEROSCLEROSIS THERAPY BY TARGETING MATRIX STIFFNESS AND MACROPHAGE POLARIZATION. 2022