1 3859 138 ISLET STRUCTURE AND FUNCTION IN THE GK RAT. TYPE 2 DIABETES MELLITUS (T2D) ARISES WHEN THE ENDOCRINE PANCREAS FAILS TO SECRETE SUFFICIENT INSULIN TO COPE WITH THE METABOLIC DEMAND BECAUSE OF BETA-CELL SECRETORY DYSFUNCTION AND/OR DECREASED BETA-CELL MASS. DEFINING THE NATURE OF THE PANCREATIC ISLET DEFECTS PRESENT IN T2D HAS BEEN DIFFICULT, IN PART BECAUSE HUMAN ISLETS ARE INACCESSIBLE FOR DIRECT STUDY. THIS REVIEW IS AIMED TO ILLUSTRATE TO WHAT EXTENT THE GOTO-KAKIZAKI RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2D, HAS PROVED TO BE A VALUABLE TOOL OFFERING SUFFICIENT COMMONALITIES TO STUDY THIS ASPECT. A COMPREHENSIVE COMPENDIUM OF THE MULTIPLE FUNCTIONAL GK ISLET ABNORMALITIES SO FAR IDENTIFIED IS PROPOSED IN THIS PERSPECTIVE. THE PATHOGENESIS OF DEFECTIVE BETA-CELL NUMBER AND FUNCTION IN THE GK MODEL IS ALSO DISCUSSED. IT IS PROPOSED THAT THE DEVELOPMENT OF T2D IN THE GK MODEL RESULTS FROM THE COMPLEX INTERACTION OF MULTIPLE EVENTS: (I) SEVERAL SUSCEPTIBILITY LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS (DISTINCT LOCI ENCODING IMPAIRMENT OF BETA-CELL METABOLISM AND INSULIN EXOCYTOSIS, BUT NO QUANTITATIVE TRAIT LOCUS FOR DECREASED BETA-CELL MASS); (II) GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE OFFSPRING PANCREAS (DECREASED BETA-CELL NEOGENESIS AND PROLIFERATION) TRANSMITTED OVER GENERATIONS; AND (III) LOSS OF BETA-CELL DIFFERENTIATION RELATED TO CHRONIC EXPOSURE TO HYPERGLYCAEMIA/HYPERLIPIDAEMIA, ISLET INFLAMMATION, ISLET OXIDATIVE STRESS, ISLET FIBROSIS AND PERTURBED ISLET VASCULATURE. 2010 2 5140 24 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 3 6164 115 THE GK RAT: A PROTOTYPE FOR THE STUDY OF NON-OVERWEIGHT TYPE 2 DIABETES. TYPE 2 DIABETES MELLITUS (T2D) ARISES WHEN THE ENDOCRINE PANCREAS FAILS TO SECRETE SUFFICIENT INSULIN TO COPE WITH THE METABOLIC DEMAND BECAUSE OF BETA-CELL SECRETORY DYSFUNCTION AND/OR DECREASED BETA-CELL MASS. DEFINING THE NATURE OF THE PANCREATIC ISLET DEFECTS PRESENT IN T2D HAS BEEN DIFFICULT, IN PART BECAUSE HUMAN ISLETS ARE INACCESSIBLE FOR DIRECT STUDY. THIS REVIEW IS AIMED TO ILLUSTRATE TO WHAT EXTENT THE GOTO KAKIZAKI RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2D, HAS PROVED TO BE A VALUABLE TOOL OFFERING SUFFICIENT COMMONALITIES TO STUDY THIS ASPECT. A COMPREHENSIVE COMPENDIUM OF THE MULTIPLE FUNCTIONAL GK ABNORMALITIES SO FAR IDENTIFIED IS PROPOSED IN THIS PERSPECTIVE, TOGETHER WITH THEIR TIME-COURSE AND INTERACTIONS. A SPECIAL FOCUS IS GIVEN TOWARD THE PATHOGENESIS OF DEFECTIVE BETA-CELL NUMBER AND FUNCTION IN THE GK MODEL. IT IS PROPOSED THAT THE DEVELOPMENT OF T2D IN THE GK MODEL RESULTS FROM THE COMPLEX INTERACTION OF MULTIPLE EVENTS: (1) SEVERAL SUSCEPTIBILITY LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS; (2) GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE OFFSPRING PANCREAS AND THE MAJOR INSULIN TARGET TISSUES; AND (3) ENVIRONMENTALLY INDUCED LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA/HYPERLIPIDEMIA, INFLAMMATION, AND OXIDATIVE STRESS. 2012 4 6163 84 THE GK RAT BETA-CELL: A PROTOTYPE FOR THE DISEASED HUMAN BETA-CELL IN TYPE 2 DIABETES? INCREASING EVIDENCE INDICATES THAT DECREASED FUNCTIONAL BETA-CELL MASS IS THE HALLMARK OF TYPE 2 DIABETES (T2D) MELLITUS. NOWADAYS, THE DEBATE FOCUSES ON THE POSSIBLE MECHANISMS RESPONSIBLE FOR ABNORMAL ISLET MICROENVIRONMENT, DECREASED BETA-CELL NUMBER, IMPAIRED BETA-CELL FUNCTION, AND THEIR MULTIFACTORIAL AETIOLOGIES. THIS REVIEW IS AIMED TO ILLUSTRATE TO WHAT EXTEND THE GOTO-KAKIZAKI RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2D, HAS PROVED BE A VALUABLE TOOL OFFERING SUFFICIENT COMMONALITIES TO STUDY THESE ASPECTS. WE PROPOSE THAT THE DEFECTIVE BETA-CELL MASS AND FUNCTION IN THE GK MODEL REFLECT THE COMPLEX INTERACTIONS OF MULTIPLE PATHOGENIC PLAYERS: (I) SEVERAL INDEPENDENT LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS (BUT NOT DECREASED BETA-CELL MASS); (II) GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE PANCREAS (DECREASED BETA-CELL NEOGENESIS AND/OR PROLIFERATION) WHICH IS TRANSMITTED TO THE NEXT GENERATION; AND (III) LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA/HYPERLIPIDEMIA, INFLAMMATORY MEDIATORS, OXIDATIVE STRESS AND TO PERTURBED ISLET MICROARCHITECTURE. 2009 5 1302 65 DEFECTIVE FUNCTIONAL BETA-CELL MASS AND TYPE 2 DIABETES IN THE GOTO-KAKIZAKI RAT MODEL. INCREASING EVIDENCE INDICATES THAT DECREASED FUNCTIONAL BETA-CELL MASS IS THE HALLMARK OF TYPE 2 DIABETES MELLITUS. THEREFORE, THE DEBATE FOCUSES ON THE POSSIBLE MECHANISMS RESPONSIBLE FOR ABNORMAL ISLET MICROENVIRONMENT, DECREASED BETA-CELL NUMBER, IMPAIRED BETA-CELL FUNCTION AND THEIR MULTIFACTORIAL ETIOLOGIES. THE INFORMATION AVAILABLE ON THE GOTO-KAKIZAKI/PAR RAT LINE, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS TYPE 2 DIABETES MELLITUS, ARE REVIEWED IN SUCH A PERSPECTIVE. WE PROPOSE THAT THE DEFECTIVE BETA-CELL MASS AND FUNCTION IN THE GOTO-KAKIZAKI/PAR MODEL REFLECT THE COMPLEX INTERACTIONS OF MULTIPLE PATHOGENIC PLAYERS, INCLUDING SEVERAL INDEPENDENT LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS (BUT NOT DECREASED BETA-CELL MASS), GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE PANCREAS (DECREASED BETA-CELL NEOGENESIS), WHICH IS TRANSMITTED TO THE NEXT GENERATION, AND LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA, INFLAMMATORY MEDIATORS, OXIDATIVE STRESS AND PERTURBED ISLET MICROARCHITECTURE. 2007 6 3512 25 IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS IS A DEVASTATING, AGE-RELATED LUNG DISEASE OF UNKNOWN CAUSE THAT HAS FEW TREATMENT OPTIONS. THIS DISEASE WAS ONCE THOUGHT TO BE A CHRONIC INFLAMMATORY PROCESS, BUT CURRENT EVIDENCE INDICATES THAT THE FIBROTIC RESPONSE IS DRIVEN BY ABNORMALLY ACTIVATED ALVEOLAR EPITHELIAL CELLS (AECS). THESE CELLS PRODUCE MEDIATORS THAT INDUCE THE FORMATION OF FIBROBLAST AND MYOFIBROBLAST FOCI THROUGH THE PROLIFERATION OF RESIDENT MESENCHYMAL CELLS, ATTRACTION OF CIRCULATING FIBROCYTES, AND STIMULATION OF THE EPITHELIAL TO MESENCHYMAL TRANSITION. THE FIBROBLAST AND MYOFIBROBLAST FOCI SECRETE EXCESSIVE AMOUNTS OF EXTRACELLULAR MATRIX, MAINLY COLLAGENS, RESULTING IN SCARRING AND DESTRUCTION OF THE LUNG ARCHITECTURE. THE MECHANISMS THAT LINK IDIOPATHIC PULMONARY FIBROSIS WITH AGEING AND ABERRANT EPITHELIAL ACTIVATION ARE UNKNOWN; EVIDENCE SUGGESTS THAT THE ABNORMAL RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND EPIGENETIC CHANGES HAVE A ROLE. IN THIS SEMINAR, WE REVIEW RECENT DATA ON THE CLINICAL COURSE, THERAPEUTIC OPTIONS, AND UNDERLYING MECHANISMS THOUGHT TO BE INVOLVED IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. 2011 7 3674 27 INFLAMMATION AND DYSREGULATED FIBROBLAST PROLIFERATION--NEW MECHANISMS? IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A DEVASTATING, AGE-RELATED LUNG DISEASE OF UNKNOWN CAUSE THAT HAS FEW TREATMENT OPTIONS. ONCE THOUGHT TO BE A CHRONIC INFLAMMATORY PROCESS, CURRENT EVIDENCE INDICATES THAT THE FIBROTIC RESPONSE MAY PRIMARILY BE DRIVEN BY ABNORMALLY ACTIVATED ALVEOLAR EPITHELIAL CELLS AND THE UNDERLYING MESENCHYME. THE MEDIATORS PRODUCED AND PRESENT IN THIS MICROENVIRONMENT INDUCE THE FORMATION OF FIBROBLAST FOCI THROUGH THE PROLIFERATION OF RESIDENT MESENCHYMAL CELLS, ATTRACTION OF CIRCULATING FIBROCYTES, AND STIMULATION OF EPITHELIAL TO MESENCHYMAL TRANSITION. THE FIBROBLAST AND MYOFIBROBLAST FOCI SECRETE EXCESSIVE AMOUNTS OF EXTRACELLULAR MATRIX, MAINLY COLLAGENS, RESULTING IN SCARRING AND DESTRUCTION OF THE LUNG ARCHITECTURE. THE DETAILED MECHANISMS THAT LINK IPF WITH AGEING AND ABERRANT EPITHELIAL ACTIVATION ARE UNKNOWN, BUT SOME EVIDENCE SUGGESTS THAT THE ABNORMAL RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND EPIGENETIC CHANGES MAY PLAY A ROLE. THIS REVIEW PROVIDES A BRIEF SYNOPSIS OF HIGHLIGHTS IN THE CURRENT UNDERSTANDING OF THE PATHOPHYSIOLOGY OF IPF, AS WELL AS NOVEL THERAPEUTICS BEING EXPLORED IN CLINICAL TRIALS FOR THE TREATMENT OF THIS DEVASTATING DISEASE. 2013 8 5250 64 PROGRAMMED DISORDERS OF BETA-CELL DEVELOPMENT AND FUNCTION AS ONE CAUSE FOR TYPE 2 DIABETES? THE GK RAT PARADIGM. NOW THAT THE REDUCTION IN BETA-MASS HAS BEEN CLEARLY ESTABLISHED IN HUMANS WITH TYPE 2 DIABETES MELLITUS (T2DM) 1-4, THE DEBATE FOCUSES ON THE POSSIBLE MECHANISMS RESPONSIBLE FOR DECREASED BETA-CELL NUMBER AND IMPAIRED BETA-CELL FUNCTION AND THEIR MULTIFACTORIAL ETIOLOGY. APPROPRIATE INBRED RODENT MODELS ARE ESSENTIAL TOOLS FOR IDENTIFICATION OF GENES AND ENVIRONMENTAL FACTORS THAT INCREASE THE RISK OF ABNORMAL BETA-CELL FUNCTION AND OF T2DM. THE INFORMATION AVAILABLE IN THE GOTO-KAKIZAKI (GK) RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2DM, ARE REVIEWED IN SUCH A PERSPECTIVE. WE PROPOSE THAT THE DEFECTIVE BETA-CELL MASS AND FUNCTION IN THE GK MODEL REFLECT THE COMPLEX INTERACTIONS OF THREE PATHOGENIC PLAYERS: (1) SEVERAL INDEPENDENT LOCI CONTAINING GENES CAUSING IMPAIRED INSULIN SECRETION; (2) GESTATIONAL METABOLIC IMPAIRMENT INDUCING A PROGRAMMING OF ENDOCRINE PANCREAS (DECREASED BETA-CELL NEOGENESIS) WHICH IS TRANSMITTED TO THE NEXT GENERATION; AND (3) SECONDARY (ACQUIRED) LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA (GLUCOTOXICITY). AN IMPORTANT MESSAGE IS THAT THE 'HERITABLE' DETERMINANTS OF T2DM ARE NOT SIMPLY DEPENDANT ON GENETIC FACTORS, BUT PROBABLY INVOLVE TRANSGENERATIONAL EPIGENETIC RESPONSES. 2005 9 5507 17 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 10 241 35 ADIPOCYTE, IMMUNE CELLS, AND MIRNA CROSSTALK: A NOVEL REGULATOR OF METABOLIC DYSFUNCTION AND OBESITY. OBESITY IS CHARACTERIZED AS A COMPLEX AND MULTIFACTORIAL EXCESS ACCRETION OF ADIPOSE TISSUE (AT) ACCOMPANIED WITH ALTERATIONS IN THE IMMUNE RESPONSE THAT AFFECTS VIRTUALLY ALL AGE AND SOCIOECONOMIC GROUPS AROUND THE GLOBE. THE ABNORMAL ACCUMULATION OF AT LEADS TO SEVERAL METABOLIC DISEASES, INCLUDING NONALCOHOLIC FATTY LIVER DISORDER (NAFLD), LOW-GRADE INFLAMMATION, TYPE 2 DIABETES MELLITUS (T2DM), CARDIOVASCULAR DISORDERS (CVDS), AND CANCER. AT IS AN ENDOCRINE ORGAN COMPOSED OF ADIPOCYTES AND IMMUNE CELLS, INCLUDING B-CELLS, T-CELLS AND MACROPHAGES. THESE IMMUNE CELLS SECRETE VARIOUS CYTOKINES AND CHEMOKINES AND CROSSTALK WITH ADIPOKINES TO MAINTAIN METABOLIC HOMEOSTASIS AND LOW-GRADE CHRONIC INFLAMMATION. A NOVEL FORM OF ADIPOKINES, MICRORNA (MIRS), IS EXPRESSED IN MANY DEVELOPING PERIPHERAL TISSUES, INCLUDING ATS, T-CELLS, AND MACROPHAGES, AND MODULATES THE IMMUNE RESPONSE. MIRS ARE ESSENTIAL FOR INSULIN RESISTANCE, MAINTAINING THE TUMOR MICROENVIRONMENT, AND OBESITY-ASSOCIATED INFLAMMATION (OAI). THE ABNORMAL REGULATION OF AT, T-CELLS, AND MACROPHAGE MIRS MAY CHANGE THE FUNCTION OF DIFFERENT ORGANS INCLUDING THE PANCREAS, HEART, LIVER, AND SKELETAL MUSCLE. SINCE OBESITY AND INFLAMMATION ARE CLOSELY ASSOCIATED, THE DYSREGULATED EXPRESSION OF MIRS IN INFLAMMATORY ADIPOCYTES, T-CELLS, AND MACROPHAGES SUGGEST THE IMPORTANCE OF MIRS IN OAI. THEREFORE, IN THIS REVIEW ARTICLE, WE HAVE ELABORATED THE ROLE OF MIRS AS EPIGENETIC REGULATORS AFFECTING ADIPOCYTE DIFFERENTIATION, IMMUNE RESPONSE, AT BROWNING, ADIPOGENESIS, LIPID METABOLISM, INSULIN RESISTANCE (IR), GLUCOSE HOMEOSTASIS, OBESITY, AND METABOLIC DISORDERS. FURTHER, WE WILL DISCUSS A SET OF ALTERED MIRS AS NOVEL BIOMARKERS FOR METABOLIC DISEASE PROGRESSION AND THERAPEUTIC TARGETS FOR OBESITY. 2021 11 1874 25 EMERGING ROLE OF NF-KAPPAB SIGNALING IN THE INDUCTION OF SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). THE MAJOR HALLMARK OF CELLULAR SENESCENCE IS AN IRREVERSIBLE CELL CYCLE ARREST AND THUS IT IS A POTENT TUMOR SUPPRESSOR MECHANISM. GENOTOXIC INSULTS, E.G. OXIDATIVE STRESS, ARE IMPORTANT INDUCERS OF THE SENESCENT PHENOTYPE WHICH IS CHARACTERIZED BY AN ACCUMULATION OF SENESCENCE-ASSOCIATED HETEROCHROMATIC FOCI (SAHF) AND DNA SEGMENTS WITH CHROMATIN ALTERATIONS REINFORCING SENESCENCE (DNA-SCARS). INTERESTINGLY, SENESCENT CELLS SECRETE PRO-INFLAMMATORY FACTORS AND THUS THE CONDITION HAS BEEN CALLED THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). EMERGING DATA HAS REVEALED THAT NF-KAPPAB SIGNALING IS THE MAJOR SIGNALING PATHWAY WHICH STIMULATES THE APPEARANCE OF SASP. IT IS KNOWN THAT DNA DAMAGE PROVOKES NF-KAPPAB SIGNALING VIA A VARIETY OF SIGNALING COMPLEXES CONTAINING NEMO PROTEIN, AN NF-KAPPAB ESSENTIAL MODIFIER, AS WELL AS VIA THE ACTIVATION OF SIGNALING PATHWAYS OF P38MAPK AND RIG-1, RETINOIC ACID INDUCIBLE GENE-1. GENOMIC INSTABILITY EVOKED BY CELLULAR STRESS TRIGGERS EPIGENETIC CHANGES, E.G. RELEASE OF HMGB1 PROTEINS WHICH ARE ALSO POTENT ENHANCERS OF INFLAMMATORY RESPONSES. MOREOVER, ENVIRONMENTAL STRESS AND CHRONIC INFLAMMATION CAN STIMULATE P38MAPK AND CERAMIDE SIGNALING AND INDUCE CELLULAR SENESCENCE WITH PRO-INFLAMMATORY RESPONSES. ON THE OTHER HAND, TWO CYCLIN-DEPENDENT KINASE INHIBITORS, P16INK4A AND P14ARF, ARE EFFECTIVE INHIBITORS OF NF-KAPPAB SIGNALING. WE WILL REVIEW IN DETAIL THE SIGNALING PATHWAYS WHICH ACTIVATE NF-KAPPAB SIGNALING AND TRIGGER SASP IN SENESCENT CELLS. 2012 12 6741 22 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 13 4380 29 MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS IN RHEUMATOID ARTHRITIS. CONTROL OF EXCESSIVE MITOCHONDRIAL OXIDATIVE STRESS COULD PROVIDE NEW TARGETS FOR BOTH PREVENTIVE AND THERAPEUTIC INTERVENTIONS IN THE TREATMENT OF CHRONIC INFLAMMATION OR ANY PATHOLOGY THAT DEVELOPS UNDER AN INFLAMMATORY SCENARIO, SUCH AS RHEUMATOID ARTHRITIS (RA). INCREASING EVIDENCE HAS DEMONSTRATED THE ROLE OF MITOCHONDRIAL ALTERATIONS IN AUTOIMMUNE DISEASES MAINLY DUE TO THE INTERPLAY BETWEEN METABOLISM AND INNATE IMMUNITY, BUT ALSO IN THE MODULATION OF INFLAMMATORY RESPONSE OF RESIDENT CELLS, SUCH AS SYNOVIOCYTES. THUS, MITOCHONDRIAL DYSFUNCTION DERIVED FROM SEVERAL DANGER SIGNALS COULD ACTIVATE TRICARBOXYLIC ACID (TCA) DISRUPTION, THEREBY FAVORING A VICIOUS CYCLE OF OXIDATIVE/MITOCHONDRIAL STRESS. MITOCHONDRIAL DYSFUNCTION CAN ACT THROUGH MODULATING INNATE IMMUNITY VIA REDOX-SENSITIVE INFLAMMATORY PATHWAYS OR DIRECT ACTIVATION OF THE INFLAMMASOME. BESIDES, MITOCHONDRIA ALSO HAVE A CENTRAL ROLE IN REGULATING CELL DEATH, WHICH IS DEEPLY ALTERED IN RA. ADDITIONALLY, MULTIPLE EVIDENCE SUGGESTS THAT PATHOLOGICAL PROCESSES IN RA CAN BE SHAPED BY EPIGENETIC MECHANISMS AND THAT IN TURN, MITOCHONDRIA ARE INVOLVED IN EPIGENETIC REGULATION. FINALLY, WE WILL DISCUSS ABOUT THE INVOLVEMENT OF SOME DIETARY COMPONENTS IN THE ONSET AND PROGRESSION OF RA. 2022 14 6182 34 THE IMPACT OF ADIPOSE TISSUE-DERIVED MIRNAS IN METABOLIC SYNDROME, OBESITY, AND CANCER. OBESITY IS A MULTIFACTORIAL AND COMPLEX CONDITION THAT IS CHARACTERIZED BY ABNORMAL AND EXCESSIVE WHITE ADIPOSE TISSUE ACCUMULATION, WHICH CAN LEAD TO THE DEVELOPMENT OF METABOLIC DISEASES, SUCH AS TYPE 2 DIABETES MELLITUS, NONALCOHOLIC FATTY LIVER DISEASE, CARDIOVASCULAR DISEASES, AND SEVERAL TYPES OF CANCER. OBESITY IS CHARACTERIZED BY EXCESSIVE ADIPOSE TISSUE ACCUMULATION AND ASSOCIATED WITH ALTERATIONS IN IMMUNITY, DISPLAYING A CHRONIC LOW-GRADE INFLAMMATION PROFILE. ADIPOSE TISSUE IS A DYNAMIC AND COMPLEX ENDOCRINE ORGAN COMPOSED NOT ONLY BY ADIPOCYTES, BUT SEVERAL IMMUNOLOGICAL CELLS, WHICH CAN SECRETE HORMONES, CYTOKINES AND MANY OTHER FACTORS CAPABLE OF REGULATING METABOLIC HOMEOSTASIS AND SEVERAL CRITICAL BIOLOGICAL PATHWAYS. REMARKABLY, ADIPOSE TISSUE IS A MAJOR SOURCE OF CIRCULATING MICRORNAS (MIRNAS), RECENTLY DESCRIBED AS A NOVEL FORM OF ADIPOKINES. SEVERAL ADIPOSE TISSUE-DERIVED MIRNAS ARE DEEPLY ASSOCIATED WITH ADIPOCYTES DIFFERENTIATION AND HAVE BEEN IDENTIFIED WITH AN ESSENTIAL ROLE IN OBESITY-ASSOCIATED INFLAMMATION, INSULIN RESISTANCE, AND TUMOR MICROENVIRONMENT. DURING OBESITY, ADIPOSE TISSUE CAN COMPLETELY CHANGE THE PROFILE OF THE SECRETED MIRNAS, INFLUENCING CIRCULATING MIRNAS AND IMPACTING THE DEVELOPMENT OF DIFFERENT PATHOLOGICAL CONDITIONS, SUCH AS OBESITY, METABOLIC SYNDROME, AND CANCER. IN THIS REVIEW, WE DISCUSS HOW MIRNAS CAN ACT AS EPIGENETIC REGULATORS AFFECTING ADIPOGENESIS, ADIPOCYTE DIFFERENTIATION, LIPID METABOLISM, BROWNING OF THE WHITE ADIPOSE TISSUE, GLUCOSE HOMEOSTASIS, AND INSULIN RESISTANCE, IMPACTING DEEPLY OBESITY AND METABOLIC DISEASES. MOREOVER, WE CHARACTERIZE HOW MIRNAS CAN OFTEN ACT AS ONCOGENIC AND TUMOR SUPPRESSOR MOLECULES, SIGNIFICANTLY MODULATING CANCER ESTABLISHMENT AND PROGRESSION. FURTHERMORE, WE HIGHLIGHT IN THIS MANUSCRIPT HOW ADIPOSE TISSUE-DERIVED MIRNAS CAN FUNCTION AS IMPORTANT NEW THERAPEUTIC TARGETS. 2020 15 2178 28 EPIGENETIC MECHANISMS OF MACROPHAGE ACTIVATION IN TYPE 2 DIABETES. THE ALARMING RISE OF OBESITY AND TYPE 2 DIABETES (T2D) HAS PUT A TREMENDOUS STRAIN ON GLOBAL HEALTHCARE SYSTEMS. OVER THE PAST DECADE EXTENSIVE RESEARCH HAS FOCUSED ON THE ROLE OF MACROPHAGES AS KEY MEDIATORS OF INFLAMMATION IN T2D. THE INFLAMMATORY ENVIRONMENT IN THE OBESE ADIPOSE TISSUE AND PANCREATIC BETA-CELL ISLETS CREATES AND PERPETUATES IMBALANCED INFLAMMATORY MACROPHAGE ACTIVATION. CONSEQUENCES OF THIS CHRONIC LOW-GRADE INFLAMMATION INCLUDE INSULIN RESISTANCE IN THE ADIPOSE TISSUE AND PANCREATIC BETA-CELL DYSFUNCTION. RECENTLY, THE EMERGING FIELD OF EPIGENETICS HAS PROVIDED NEW INSIGHTS INTO THE PATHOGENESIS OF T2D, WHILE ALSO AFFORDING POTENTIAL NEW OPPORTUNITIES FOR TREATMENT. IN MACROPHAGES, EPIGENETIC MECHANISMS ARE INCREASINGLY BEING RECOGNIZED AS CRUCIAL CONTROLLERS OF THEIR PHENOTYPE. HERE, WE FIRST DESCRIBE THE ROLE OF MACROPHAGES IN T2D. THEN WE ELABORATE ON EPIGENETIC MECHANISMS THAT REGULATE MACROPHAGE ACTIVATION, THEREBY FOCUSING ON T2D. NEXT, WE HIGHLIGHT HOW DIABETIC CONDITIONS SUCH AS HYPERLIPIDEMIA AND HYPERGLYCEMIA COULD INDUCE EPIGENETIC CHANGES THAT PROMOTE AN INFLAMMATORY MACROPHAGE PHENOTYPE. IN CONCLUSION WE DISCUSS POSSIBLE THERAPEUTIC INTERVENTIONS BY TARGETING MACROPHAGE EPIGENETICS AND SPECULATE ON FUTURE RESEARCH DIRECTIONS. 2017 16 798 31 CELLULAR SENESCENCE, SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE, AND CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS INCREASINGLY BEING ACCEPTED AS A TYPE OF RENAL AGEING. THE KIDNEY UNDERGOES AGE-RELATED ALTERATIONS IN BOTH STRUCTURE AND FUNCTION. TO DATE, A COMPREHENSIVE ANALYSIS OF CELLULAR SENESCENCE AND SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) IN CKD IS LACKING. HENCE, THIS REVIEW MAINLY DISCUSSES THE RELATIONSHIP BETWEEN THE TWO PHENOMENA TO SHOW THE STRIKING SIMILARITIES BETWEEN SASP AND CKD-ASSOCIATED SECRETORY PHENOTYPE (CASP). IT HAS BEEN REPORTED THAT REPLICATIVE SENESCENCE, STRESS-INDUCED PREMATURE AGEING, AND EPIGENETIC ABNORMALITIES PARTICIPATE IN THE OCCURRENCE AND DEVELOPMENT OF CKD. GENOMIC DAMAGE AND EXTERNAL ENVIRONMENTAL STIMULI CAUSE INCREASED LEVELS OF OXIDATIVE STRESS AND A CHRONIC INFLAMMATORY STATE AS A RESULT OF IRREVERSIBLE CELL CYCLE ARREST AND LOW DOSES OF SASP. SIMILAR TO SASP, CASP FACTORS ACTIVATE TISSUE REPAIR BY MULTIPLE MECHANISMS. ONCE TISSUE REPAIR FAILS, THE ACCUMULATED SASP OR CASP SPECIES AGGRAVATE DNA DAMAGE RESPONSE (DDR) AND CAUSE THE SENESCENT CELLS TO SECRETE MORE SASP FACTORS, ACCELERATING THE PROCESS OF CELLULAR AGEING AND EVENTUALLY LEADING TO VARIOUS AGEING-RELATED CHANGES. IT IS CONCLUDED THAT CELLULAR SENESCENCE AND SASP PARTICIPATE IN THE PATHOLOGICAL PROCESS OF CKD, AND CORRESPONDINGLY CKD ACCELERATED THE PROGRESSION OF CELL SENESCENCE AND THE SECRETION OF SASP. THESE RESULTS WILL FACILITATE THE INTEGRATION OF THESE MECHANISMS INTO THE CARE AND MANAGEMENT OF CKD AND OTHER AGE-RELATED DISEASES. 2017 17 4684 24 NEW POTENTIAL THERAPEUTIC APPROACHES TARGETING SYNOVIAL FIBROBLASTS IN RHEUMATOID ARTHRITIS. SYNOVIAL CELLS PLAY A KEY ROLE IN JOINT DESTRUCTION DURING CHRONIC INFLAMMATION. IN PARTICULAR, ACTIVATED SYNOVIAL FIBROBLASTS (SFS) UNDERGO INTRINSIC ALTERATIONS LEADING TO AN AGGRESSIVE PHENOTYPE MEDIATING CARTILAGE DESTRUCTION AND BONE EROSION IN RHEUMATOID ARTHRITIS (RA). RECENT RESEARCH HAS REVEALED A NUMBER OF TARGETS TO CONTROL ARTHRITOGENIC CHANGES IN SFS. THEREFORE, IDENTIFICATION OF SF PHENOTYPES, CONTROL OF EPIGENETIC CHANGES, MODULATION OF CELLULAR FUNCTIONS, OR REGULATION OF THE ACTIVITY OF CATION CHANNELS AND DIFFERENT SIGNALING PATHWAYS HAS BEEN INVESTIGATED. ALTHOUGH MANY OF THESE APPROACHES HAVE SHOWN EFFICACY IN VITRO AND IN ANIMAL MODELS OF RA, FURTHER RESEARCH IS NEEDED TO SELECT THE MOST RELEVANT TARGETS FOR DRUG DEVELOPMENT. THIS REVIEW IS FOCUSED ON THE ROLE OF SFS AS A POTENTIAL STRATEGY TO DISCOVER NOVEL THERAPEUTIC TARGETS IN RA AIMED AT PRESERVING JOINT ARCHITECTURE AND FUNCTION. 2021 18 4953 34 PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) INDUCED BY CIGARETTE SMOKE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMMON RESPIRATORY DISEASE THAT IS CHARACTERIZED BY FUNCTIONAL AND STRUCTURAL ALTERATIONS PRIMARILY CAUSED BY LONG-TERM INHALATION OF HARMFUL PARTICLES. CIGARETTE SMOKE (CS) INDUCES AIRWAY INFLAMMATION IN COPD, WHICH IS KNOWN TO PERSIST EVEN AFTER SMOKING CESSATION. THIS REVIEW DISCUSSES THE BASIC PATHOGENESIS OF COPD, WITH PARTICULAR FOCUS ON AN ENDOGENOUS PROTECTIVE MECHANISM AGAINST OXIDATIVE STRESS VIA NRF2, ALTERED IMMUNE RESPONSE OF THE AIRWAY INFLAMMATORY CELLS, EXAGGERATED CELLULAR SENESCENCE OF THE LUNG STRUCTURAL CELLS, AND CELL DEATH WITH EXPANDED INFLAMMATION. RECENTLY, CS-INDUCED MITOCHONDRIA AUTOPHAGY IS REPORTED TO INITIATE PROGRAMMED NECROSIS (NECROPTOSIS). NECROPTOSIS IS A NEW CONCEPT OF CELL DEATH WHICH IS DRIVEN BY A DEFINED MOLECULAR PATHWAY ALONG WITH EXAGGERATED INFLAMMATION. THIS NEW CELL DEATH MECHANISM IS OF IMPORTANCE DUE TO ITS ABILITY TO PRODUCE MORE INFLAMMATORY SUBSTANCES DURING THE PROCESS OF EPITHELIAL DEATH, CONTRIBUTING TO PERSISTENT AIRWAY INFLAMMATION THAT CANNOT BE EXPLAINED BY APOPTOSIS-DERIVED CELL DEATH. AUTOPHAGY IS AN AUTO-CELL COMPONENT DEGRADATION SYSTEM EXECUTED BY LYSOSOMES THAT CONTROLS PROTEIN AND ORGANELLE DEGRADATION FOR SUCCESSFUL HOMEOSTASIS. AS WELL AS IN THE PROCESS OF NECROPTOSIS, AUTOPHAGY IS ALSO OBSERVED DURING CELLULAR SENESCENCE. AGING OF THE LUNGS RESULTS IN THE ACQUISITION OF SENESCENCE-ASSOCIATED SECRETORY PHENOTYPES (SASP) THAT ARE KNOWN TO SECRETE INFLAMMATORY CYTOKINES, CHEMOKINES, GROWTH FACTORS, AND MATRIX METALLOPROTEINASES RESULTING IN CHRONIC LOW-GRADE INFLAMMATION. IN FUTURE RESEARCH, WE INTEND TO HIGHLIGHT THE GENETIC AND EPIGENETIC APPROACHES THAT CAN FACILITATE THE UNDERSTANDING OF DISEASE SUSCEPTIBILITY. THE GOAL OF PRECISION MEDICINE IS TO ESTABLISH MORE ACCURATE DIAGNOSIS AND TREATMENT METHODS BASED ON THE PATIENT-SPECIFIC PATHOGENIC CHARACTERISTICS. THIS REVIEW PROVIDES INSIGHTS INTO CS-INDUCED COPD PATHOGENESIS, WHICH CONTRIBUTES TO A VERY COMPLEX DISEASE. INVESTIGATING THE MECHANISM OF DEVELOPING COPD, ALONG WITH THE AVAILABILITY OF THE PARTICULAR INHIBITORS, WILL LEAD TO NEW THERAPEUTIC APPROACHES IN COPD TREATMENT. 2019 19 6452 20 THERAPIES TARGETING TRAINED IMMUNE CELLS IN INFLAMMATORY AND AUTOIMMUNE DISEASES. THE CONCEPT OF TRAINED IMMUNITY HAS RECENTLY EMERGED AS A MECHANISM CONTRIBUTING TO SEVERAL IMMUNE MEDIATED INFLAMMATORY CONDITIONS. TRAINED IMMUNITY IS DEFINED BY THE IMMUNOLOGICAL MEMORY DEVELOPED IN INNATE IMMUNE CELLS AFTER A PRIMARY NON-SPECIFIC STIMULUS THAT, IN TURN, PROMOTES A HEIGHTENED INFLAMMATORY RESPONSE UPON A SECONDARY CHALLENGE. THE MOST CHARACTERISTIC CHANGES ASSOCIATED TO THIS PROCESS INVOLVE THE REWIRING OF CELL METABOLISM AND EPIGENETIC REPROGRAMMING. UNDER PHYSIOLOGICAL CONDITIONS, THE ROLE OF TRAINED IMMUNE CELLS ENSURES A PROMPT RESPONSE. THIS ACTION IS LIMITED BY EFFECTIVE RESOLUTION OF INFLAMMATION AND TISSUE REPAIR IN ORDER TO RESTORE HOMEOSTASIS. HOWEVER, UNRESTRAINED ACTIVATION OF INNATE IMMUNE CELLS CONTRIBUTES TO THE DEVELOPMENT OF CHRONIC INFLAMMATION AND TISSUE DESTRUCTION THROUGH THE SECRETION OF INFLAMMATORY CYTOKINES, PROTEASES AND GROWTH FACTORS. THEREFORE, INTERVENTIONS AIMED AT REVERSING THE CHANGES INDUCED BY TRAINED IMMUNITY PROVIDE POTENTIAL THERAPEUTIC APPROACHES TO TREAT INFLAMMATORY AND AUTOIMMUNE DISEASES LIKE RHEUMATOID ARTHRITIS (RA). WE REVIEW CELLULAR APPROACHES THAT TARGET METABOLISM AND THE EPIGENETIC REPROGRAMMING OF DENDRITIC CELLS, MACROPHAGES, NATURAL KILLER CELLS, AND OTHER TRAINED CELLS IN THE CONTEXT OF AUTOIMMUNE INFLAMMATORY DISEASES. 2020 20 2221 24 EPIGENETIC MODIFICATIONS IN RHEUMATOID ARTHRITIS, A REVIEW. RHEUMATOID ARTHRITIS IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC JOINT INFLAMMATION AND PROGRESSIVE DESTRUCTION OF CARTILAGE AND BONE WHICH LEADS TO ULTIMATELY LOSS OF FUNCTION AND PAIN. ACTIVATED SYNOVIAL FIBROBLASTS ARE KEY EFFECTOR CELLS IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS. IN THE RECENT YEARS, EPIGENETIC CHANGES INCLUDING DNA METHYLATION, HISTONE ACETYLATION AND OTHER HISTONE MODIFICATIONS WERE IDENTIFIED THAT ARE ASSOCIATED WITH AN INTRINSIC ACTIVATION AND THE AGGRESSIVE PHENOTYPE OF THESE CELLS. SO FAR, NO THERAPIES TARGETING RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS EXIST. THIS REVIEW COMPRISES RECENT RESEARCH EFFORTS THAT PROPOSE EPIGENETIC MECHANISMS BEHIND THE ACTIVATION OF RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS AND OTHER CELL TYPES. 2013