1 5392 144 REDOXISOME AND DIABETIC RETINOPATHY: PATHOPHYSIOLOGY AND THERAPEUTIC INTERVENTIONS. DIABETIC RETINOPATHY (DR) IS A CHRONIC MICROVASCULAR COMPLICATION OF DIABETES MELLITUS (DM). IT IS A WORLDWIDE GROWING EPIDEMIC DISEASE CONSIDERED TO BE THE LEADING CAUSE OF VISION-LOSS AND BLINDNESS IN PEOPLE WITH DM. REDOX REACTIONS OCCURRING AT THE EXTRA- AND INTRACELLULAR LEVELS ARE ESSENTIAL FOR THE MAINTENANCE OF CELLULAR HOMEOSTASIS. DYSREGULATION OF REDOX HOMEOSTASIS ARE IMPLICATED IN THE ONSET AND DEVELOPMENT OF DR. THIOREDOXIN1 (TRX1) AND THIOREDOXIN2 (TRX2) ARE CYTOPLASMIC AND MITOCHONDRIALLY LOCALIZED ANTIOXIDANT PROTEINS UBIQUITOUSLY EXPRESSED IN VARIOUS CELLS AND CONTROL CELLULAR REACTIVE OXYGEN SPECIES (ROS) BY REDUCING THE DISULFIDES INTO THIOL GROUPS. THIOREDOXIN-INTERACTING PROTEIN (TXNIP) BINDS TO TRX SYSTEM AND INHIBITS THE ACTIVE REDUCED FORM OF TRX THROUGH DISULFIDE EXCHANGE REACTION. RECENT STUDIES INDICATE THE ASSOCIATION OF TRX/TXNIP WITH REDOX SIGNAL TRANSDUCTION PATHWAYS INCLUDING ACTIVATION OF NOD-LIKE RECEPTOR PYRIN DOMAIN CONTAINING PROTEIN-3 (NLRP3) INFLAMMASOME, APOPTOSIS, AUTOPHAGY/MITOPHAGY, EPIGENETIC MODIFICATIONS IN A REDOX-DEPENDENT MANNER. THUS, IT IS IMPORTANT TO GAIN A MORE IN-DEPTH UNDERSTANDING ABOUT THE CELLULAR AND MOLECULAR MECHANISMS THAT LINKS REDOXISOME AND ER/MITOCHONDRIAL DYSFUNCTION TO DRIVE THE PROGRESSION OF DR. THE PURPOSE OF THIS REVIEW IS TO PROVIDE A MECHANISTIC UNDERSTANDING OF THE COMPLEX MOLECULAR MECHANISMS AND PATHOPHYSIOLOGICAL ROLES ASSOCIATED WITH REDOXISOME, THE TRX/TXNIP REDOX SIGNALING COMPLEX UNDER OXIDATIVE STRESS IN THE DEVELOPMENT OF DR. ALSO, THE MOLECULAR TARGETS OF FDA APPROVED DRUGS AND CLINICAL TRIALS IN ADDITION TO EFFECTIVE ANTIOXIDANT STRATEGIES FOR THE TREATMENT OF DIABETIC RETINOPATHY ARE REVIEWED. 2022 2 3152 44 GLUCOSE VARIABILITY: HOW DOES IT WORK? A GROWING BODY OF EVIDENCE POINTS TO THE ROLE OF GLUCOSE VARIABILITY (GV) IN THE DEVELOPMENT OF THE MICROVASCULAR AND MACROVASCULAR COMPLICATIONS OF DIABETES. IN THIS REVIEW, WE SUMMARIZE DATA ON GV-INDUCED BIOCHEMICAL, CELLULAR AND MOLECULAR EVENTS INVOLVED IN THE PATHOGENESIS OF DIABETIC COMPLICATIONS. CURRENT DATA INDICATE THAT THE DETERIORATING EFFECT OF GV ON TARGET ORGANS CAN BE REALIZED THROUGH OXIDATIVE STRESS, GLYCATION, CHRONIC LOW-GRADE INFLAMMATION, ENDOTHELIAL DYSFUNCTION, PLATELET ACTIVATION, IMPAIRED ANGIOGENESIS AND RENAL FIBROSIS. THE EFFECTS OF GV ON OXIDATIVE STRESS, INFLAMMATION, ENDOTHELIAL DYSFUNCTION AND HYPERCOAGULABILITY COULD BE AGGRAVATED BY HYPOGLYCEMIA, ASSOCIATED WITH HIGH GV. OSCILLATING HYPERGLYCEMIA CONTRIBUTES TO BETA CELL DYSFUNCTION, WHICH LEADS TO A FURTHER INCREASE IN GV AND COMPLETES THE VICIOUS CIRCLE. IN CELLS, THE GV-INDUCED CYTOTOXIC EFFECT INCLUDES MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS AND DISTURBANCES IN AUTOPHAGIC FLUX, WHICH ARE ACCOMPANIED BY REDUCED VIABILITY, ACTIVATION OF APOPTOSIS AND ABNORMALITIES IN CELL PROLIFERATION. THESE EFFECTS ARE REALIZED THROUGH THE UP- AND DOWN-REGULATION OF A LARGE NUMBER OF GENES AND THE ACTIVITY OF SIGNALING PATHWAYS SUCH AS PI3K/AKT, NF-KAPPAB, MAPK (ERK), JNK AND TGF-BETA/SMAD. EPIGENETIC MODIFICATIONS MEDIATE THE POSTPONED EFFECTS OF GLUCOSE FLUCTUATIONS. THE MULTIPLE DETERIORATIVE EFFECTS OF GV PROVIDE FURTHER SUPPORT FOR CONSIDERING IT AS A THERAPEUTIC TARGET IN DIABETES. 2021 3 1898 31 ENDOTHELINS IN CARDIOVASCULAR BIOLOGY AND THERAPEUTICS. CARDIOVASCULAR DISEASE IS A MAJOR CONTRIBUTOR TO GLOBAL MORBIDITY AND MORTALITY AND IS THE COMMON END POINT OF MANY CHRONIC DISEASES. THE ENDOTHELINS COMPRISE THREE STRUCTURALLY SIMILAR PEPTIDES OF 21 AMINO ACIDS IN LENGTH. ENDOTHELIN 1 (ET-1) AND ET-2 ACTIVATE TWO G PROTEIN-COUPLED RECEPTORS - ENDOTHELIN RECEPTOR TYPE A (ET(A)) AND ENDOTHELIN RECEPTOR TYPE B (ET(B)) - WITH EQUAL AFFINITY, WHEREAS ET-3 HAS A LOWER AFFINITY FOR ET(A). ET-1 IS THE MOST POTENT VASOCONSTRICTOR IN THE HUMAN CARDIOVASCULAR SYSTEM AND HAS REMARKABLY LONG-LASTING ACTIONS. ET-1 CONTRIBUTES TO VASOCONSTRICTION, VASCULAR AND CARDIAC HYPERTROPHY, INFLAMMATION, AND TO THE DEVELOPMENT AND PROGRESSION OF CARDIOVASCULAR DISEASE. ENDOTHELIN RECEPTOR ANTAGONISTS HAVE REVOLUTIONIZED THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION. CLINICAL TRIALS CONTINUE TO EXPLORE NEW APPLICATIONS OF ENDOTHELIN RECEPTOR ANTAGONISTS, PARTICULARLY IN TREATMENT-RESISTANT HYPERTENSION, CHRONIC KIDNEY DISEASE AND PATIENTS RECEIVING ANTIANGIOGENIC THERAPIES. TRANSLATIONAL STUDIES HAVE IDENTIFIED IMPORTANT ROLES FOR THE ENDOTHELIN ISOFORMS AND NEW THERAPEUTIC TARGETS DURING DEVELOPMENT, IN FLUID-ELECTROLYTE HOMEOSTASIS, AND IN CARDIOVASCULAR AND NEURONAL FUNCTION. NOVEL PHARMACOLOGICAL STRATEGIES ARE EMERGING IN THE FORM OF SMALL-MOLECULE EPIGENETIC MODULATORS, BIOLOGICS (SUCH AS MONOCLONAL ANTIBODIES FOR ET(B)) AND POSSIBLY SIGNALLING PATHWAY-BIASED AGONISTS AND ANTAGONISTS. 2019 4 2597 36 EPIGENETICS OF SUBCELLULAR STRUCTURE FUNCTIONING IN THE ORIGIN OF RISK OR RESILIENCE TO COMORBIDITY OF NEUROPSYCHIATRIC AND CARDIOMETABOLIC DISORDERS. MECHANISMS CONTROLLING MITOCHONDRIAL FUNCTION, PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM (ER) AND NUCLEAR PROCESSES SUCH AS TELOMERE LENGTH AND DNA REPAIR MAY BE SUBJECT TO EPIGENETIC CUES THAT RELATE THE GENOMIC EXPRESSION AND ENVIRONMENTAL EXPOSURES IN EARLY STAGES OF LIFE. THEY MAY ALSO BE INVOLVED IN THE COMORBID APPEARANCE OF CARDIOMETABOLIC (CMD) AND NEUROPSYCHIATRIC DISORDERS (NPD) DURING ADULTHOOD. MITOCHONDRIAL FUNCTION AND PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM ARE ASSOCIATED WITH OXIDATIVE STRESS AND ELEVATED INTRACELLULAR CALCIUM LEVELS AND MAY ALSO UNDERLIE THE VULNERABILITY FOR COMORBID CMD AND NPD. MITOCHONDRIA PROVIDE KEY METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+), ATP, ALPHA-KETOGLUTARATE AND ACETYL COENZYME A THAT ARE REQUIRED FOR MANY TRANSCRIPTIONAL AND EPIGENETIC PROCESSES. THEY ARE ALSO A SOURCE OF FREE RADICALS. ON THE OTHER HAND, EPIGENETIC MARKERS IN NUCLEAR DNA DETERMINE MITOCHONDRIAL BIOGENESIS. THE ER IS THE SUBCELLULAR ORGANELLE IN WHICH SECRETORY PROTEINS ARE FOLDED. MANY ENVIRONMENTAL FACTORS STOP THE ABILITY OF CELLS TO PROPERLY FOLD PROTEINS AND MODIFY POST-TRANSLATIONALLY SECRETORY AND TRANSMEMBRANE PROTEINS LEADING TO ENDOPLASMIC RETICULUM STRESS AND OXIDATIVE STRESS. ER FUNCTIONING MAY BE EPIGENETICALLY DETERMINED. CHRONIC ER STRESS IS EMERGING AS A KEY CONTRIBUTOR TO A GROWING LIST OF HUMAN DISEASES, INCLUDING CMD AND NPD. TELOMERE LOSS CAUSES CHROMOSOMAL FUSION, ACTIVATION OF THE CONTROL OF DNA DAMAGE-RESPONSES, UNSTABLE GENOME AND ALTERED STEM CELL FUNCTION, WHICH MAY UNDERLIE THE COMORBIDITY OF CMD AND NPD. THE LENGTH OF TELOMERES IS RELATED TO OXIDATIVE STRESS AND MAY BE EPIGENETICALLY PROGRAMMED. PATHWAYS INVOLVED IN DNA REPAIR MAY BE EPIGENETICALLY PROGRAMMED AND MAY CONTRIBUTE TO DISEASES. IN THIS PAPER, WE DESCRIBE SUBCELLULAR MECHANISMS THAT ARE DETERMINED BY EPIGENETIC MARKERS AND THEIR POSSIBLE RELATION TO THE DEVELOPMENT OF INCREASED SUSCEPTIBILITY TO DEVELOP CMD AND NPD. 2018 5 4414 27 MOLECULAR AND CELLULAR MECHANISMS OF PROPOLIS AND ITS POLYPHENOLIC COMPOUNDS AGAINST CANCER. IN RECENT YEARS, INTEREST IN NATURAL PRODUCTS SUCH AS ALTERNATIVE SOURCES OF PHARMACEUTICALS FOR NUMEROUS CHRONIC DISEASES, INCLUDING TUMORS, HAS BEEN RENEWED. PROPOLIS, A NATURAL PRODUCT COLLECTED BY HONEYBEES, AND POLYPHENOLIC/FLAVONOID PROPOLIS-RELATED COMPONENTS MODULATE ALL STEPS OF THE CANCER PROGRESSION PROCESS. ANTICANCER ACTIVITY OF PROPOLIS AND ITS COMPOUNDS RELIES ON VARIOUS MECHANISMS: CELL-CYCLE ARREST AND ATTENUATION OF CANCER CELLS PROLIFERATION, REDUCTION IN THE NUMBER OF CANCER STEM CELLS, INDUCTION OF APOPTOSIS, MODULATION OF ONCOGENE SIGNALING PATHWAYS, INHIBITION OF MATRIX METALLOPROTEINASES, PREVENTION OF METASTASIS, ANTI-ANGIOGENESIS, ANTI-INFLAMMATORY EFFECTS ACCOMPANIED BY THE MODULATION OF THE TUMOR MICROENVIRONMENT (BY MODIFYING MACROPHAGE ACTIVATION AND POLARIZATION), EPIGENETIC REGULATION, ANTIVIRAL AND BACTERICIDAL ACTIVITIES, MODULATION OF GUT MICROBIOTA, AND ATTENUATION OF CHEMOTHERAPY-INDUCED DELETERIOUS SIDE EFFECTS. INGREDIENTS FROM PROPOLIS ALSO "SENSITIZE" CANCER CELLS TO CHEMOTHERAPEUTIC AGENTS, LIKELY BY BLOCKING THE ACTIVATION OF THE TRANSCRIPTION FACTOR NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB). IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE RELATED TO THE THE EFFECTS OF FLAVONOIDS AND OTHER POLYPHENOLIC COMPOUNDS FROM PROPOLIS ON TUMOR GROWTH AND METASTASIZING ABILITY, AND DISCUSS POSSIBLE MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE MODULATION OF INFLAMMATORY PATHWAYS AND CELLULAR PROCESSES THAT AFFECT SURVIVAL, PROLIFERATION, INVASION, ANGIOGENESIS, AND METASTASIS OF THE TUMOR. 2022 6 6022 33 THE BENEFICIAL EFFECTS OF ZN ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES. ZINC IS ONE OF THE ESSENTIAL TRACE ELEMENTS AND PARTICIPATES IN NUMEROUS PHYSIOLOGICAL PROCESSES. ABNORMALITIES IN ZINC HOMEOSTASIS OFTEN RESULT IN THE PATHOGENESIS OF VARIOUS CHRONIC METABOLIC DISORDERS, SUCH AS DIABETES AND ITS COMPLICATIONS. ZINC HAS INSULIN-MIMETIC AND ANTI-DIABETIC EFFECTS AND DEFICIENCY HAS BEEN SHOWN TO AGGRAVATE DIABETES-INDUCED OXIDATIVE STRESS AND TISSUE INJURY IN DIABETIC RODENT MODELS AND HUMAN SUBJECTS WITH DIABETES. AKT SIGNALING PATHWAY PLAYS A CENTRAL ROLE IN INSULIN-STIMULATED GLUCOSE METABOLISM AND CELL SURVIVAL. ANTI-DIABETIC EFFECTS OF ZINC ARE LARGELY DEPENDENT ON THE ACTIVATION OF AKT SIGNALING. ZN IS ALSO AN INDUCER OF METALLOTHIONEIN THAT PLAYS IMPORTANT ROLE IN ANTI-OXIDATIVE STRESS AND DAMAGE. HOWEVER, THE EXACT MOLECULAR MECHANISMS UNDERLYING ZINC-INDUCED ACTIVATION OF AKT SIGNALING PATHWAY REMAINS TO BE ELUCIDATED. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN DECIPHERING THE POSSIBLE MECHANISMS OF ZINC ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES CONDITIONS. INSIGHTS INTO THE EFFECTS OF ZINC ON EPIGENETIC REGULATION AND AUTOPHAGY IN DIABETIC NEPHROPATHY ARE ALSO DISCUSSED IN THE LATTER PART OF THIS REVIEW. 2018 7 4507 26 MRTF: BASIC BIOLOGY AND ROLE IN KIDNEY DISEASE. A LESSER KNOWN BUT CRUCIALLY IMPORTANT DOWNSTREAM EFFECT OF RHO FAMILY GTPASES IS THE REGULATION OF GENE EXPRESSION. THIS MAJOR ROLE IS MEDIATED VIA THE CYTOSKELETON, THE ORGANIZATION OF WHICH DICTATES THE NUCLEOCYTOPLASMIC SHUTTLING OF A SET OF TRANSCRIPTION FACTORS. CENTRAL AMONG THESE IS MYOCARDIN-RELATED TRANSCRIPTION FACTOR (MRTF), WHICH UPON ACTIN POLYMERIZATION TRANSLOCATES TO THE NUCLEUS AND BINDS TO ITS COGNATE PARTNER, SERUM RESPONSE FACTOR (SRF). THE MRTF/SRF COMPLEX THEN DRIVES A LARGE COHORT OF GENES INVOLVED IN CYTOSKELETON REMODELING, CONTRACTILITY, EXTRACELLULAR MATRIX ORGANIZATION AND MANY OTHER PROCESSES. ACCORDINGLY, MRTF, ACTIVATED BY A VARIETY OF MECHANICAL AND CHEMICAL STIMULI, AFFECTS A PLETHORA OF FUNCTIONS WITH PHYSIOLOGICAL AND PATHOLOGICAL RELEVANCE. THESE INCLUDE CELL MOTILITY, DEVELOPMENT, METABOLISM AND THUS METASTASIS FORMATION, INFLAMMATORY RESPONSES AND-PREDOMINANTLY-ORGAN FIBROSIS. THE AIM OF THIS REVIEW IS TWOFOLD: TO PROVIDE AN UP-TO-DATE SUMMARY ABOUT THE BASIC BIOLOGY AND REGULATION OF THIS VERSATILE TRANSCRIPTIONAL COACTIVATOR; AND TO HIGHLIGHT ITS PRINCIPAL INVOLVEMENT IN THE PATHOBIOLOGY OF KIDNEY DISEASE. ACTING THROUGH BOTH DIRECT TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS, MRTF PLAYS A KEY (YET NOT FULLY APPRECIATED) ROLE IN THE INDUCTION OF A PROFIBROTIC EPITHELIAL PHENOTYPE (PEP) AS WELL AS IN FIBROBLAST-MYOFIBROBLAST TRANSITION, PRIME PATHOMECHANISMS IN CHRONIC KIDNEY DISEASE AND RENAL FIBROSIS. 2021 8 3933 28 LIVER SINUSOIDAL ENDOTHELIAL CELLS ARE IMPLICATED IN MULTIPLE FIBROTIC MECHANISMS. CHRONIC LIVER DISEASES ARE ATTRIBUTED TO LIVER INJURY. DEVELOPMENT OF FIBROSIS FROM CHRONIC LIVER DISEASES IS A DYNAMIC PROCESS THAT INVOLVES MULTIPLE MOLECULAR AND CELLULAR PROCESSES. AS THE FIRST TO BE IMPACTED BY INJURY, LIVER SINUSOIDAL ENDOTHELIAL CELLS (LSECS) ARE INVOLVED IN THE PATHOGENESIS OF LIVER DISEASES CAUSED BY A VARIETY OF ETIOLOGIES. MOREOVER, CAPILLARIZATION OF LSECS HAS BEEN RECOGNIZED AS AN IMPORTANT EVENT IN THE DEVELOPMENT OF CHRONIC LIVER DISEASES AND FIBROSIS. STUDIES HAVE REPORTED THAT VARIOUS CYTOKINES (SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR, TRANSFORMING GROWTH FACTOR-BETA), AND PATHWAYS (SUCH AS HEDGEHOG, AND NOTCH), AS WELL AS EPIGENETIC AND METABOLIC FACTORS ARE INVOLVED IN THE DEVELOPMENT OF LSEC-MEDIATED LIVER FIBROSIS. THIS REVIEW DESCRIBES THE COMPLEXITY AND PLASTICITY OF LSECS IN FIBROTIC LIVER DISEASES FROM SEVERAL PERSPECTIVES, INCLUDING THE CROSS-TALK BETWEEN LSECS AND OTHER INTRA-HEPATIC CELLS. MOREOVER, IT SUMMARIZES THE MECHANISMS OF SEVERAL KINDS OF LSECS-TARGETING ANTI-FIBROSIS CHEMICALS, AND PROVIDES A THEORETICAL BASIS FOR FUTURE STUDIES. 2021 9 2373 36 EPIGENETIC REGULATION OF THE N-TERMINAL TRUNCATED ISOFORM OF MATRIX METALLOPROTEINASE-2 (NTT-MMP-2) AND ITS PRESENCE IN RENAL AND CARDIAC DISEASES. SEVERAL CLINICAL AND EXPERIMENTAL STUDIES HAVE DOCUMENTED A COMPELLING AND CRITICAL ROLE FOR THE FULL-LENGTH MATRIX METALLOPROTEINASE-2 (FL-MMP-2) IN ISCHEMIC RENAL INJURY, PROGRESSIVE RENAL FIBROSIS, AND DIABETIC NEPHROPATHY. A NOVEL N-TERMINAL TRUNCATED ISOFORM OF MMP-2 (NTT-MMP-2) WAS RECENTLY DISCOVERED, WHICH IS INDUCED BY HYPOXIA AND OXIDATIVE STRESS BY THE ACTIVATION OF A LATENT PROMOTER LOCATED IN THE FIRST INTRON OF THE MMP2 GENE. THIS NTT-MMP-2 ISOFORM IS ENZYMATICALLY ACTIVE BUT REMAINS INTRACELLULAR IN OR NEAR THE MITOCHONDRIA. IN THIS PERSPECTIVE ARTICLE, WE FIRST PRESENT THE FINDINGS ABOUT THE DISCOVERY OF THE NTT-MMP-2 ISOFORM, AND ITS FUNCTIONAL AND STRUCTURAL DIFFERENCES AS COMPARED WITH THE FL-MMP-2 ISOFORM. BASED ON PUBLICLY AVAILABLE EPIGENOMICS DATA FROM THE ENCYCLOPEDIA OF DNA ELEMENTS (ENCODE) PROJECT, WE PROVIDE INSIGHTS INTO THE EPIGENETIC REGULATION OF THE LATENT PROMOTER LOCATED IN THE FIRST INTRON OF THE MMP2 GENE, WHICH SUPPORT THE ACTIVATION OF THE NTT-MMP-2 ISOFORM. WE THEN FOCUS ON ITS FUNCTIONAL ASSESSMENT BY COVERING THE ALTERATIONS FOUND IN THE KIDNEY OF TRANSGENIC MICE EXPRESSING THE NTT-MMP-2 ISOFORM. NEXT, WE HIGHLIGHT RECENT FINDINGS REGARDING THE PRESENCE OF THE NTT-MMP-2 ISOFORM IN RENAL DYSFUNCTION, IN KIDNEY AND CARDIAC DISEASES, INCLUDING DAMAGE OBSERVED IN AGING, ACUTE ISCHEMIA-REPERFUSION INJURY (IRI), CHRONIC KIDNEY DISEASE, DIABETIC NEPHROPATHY, AND HUMAN RENAL TRANSPLANTS WITH DELAYED GRAFT FUNCTION. FINALLY, WE BRIEFLY DISCUSS HOW OUR INSIGHTS MAY GUIDE FURTHER EXPERIMENTAL AND CLINICAL STUDIES THAT ARE NEEDED TO ELUCIDATE THE UNDERLYING MECHANISMS AND THE ROLE OF THE NTT-MMP-2 ISOFORM IN RENAL DYSFUNCTION, WHICH MAY HELP TO ESTABLISH IT AS A POTENTIAL THERAPEUTIC TARGET IN KIDNEY DISEASES. 2021 10 4763 30 NRF2-RELATED EPIGENETIC MODIFICATIONS IN CARDIAC AND VASCULAR COMPLICATIONS OF DIABETES MELLITUS. DIABETES MELLITUS (DM) IS A HIGHLY PREVALENT CHRONIC DISEASE THAT IS ACCOMPANIED WITH SERIOUS COMPLICATIONS, ESPECIALLY CARDIAC AND VASCULAR COMPLICATIONS. THUS, THERE IS AN URGENT NEED TO IDENTIFY NEW STRATEGIES TO TREAT DIABETIC CARDIAC AND VASCULAR COMPLICATIONS. NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) HAS BEEN VERIFIED AS A CRUCIAL TARGET FOR THE PREVENTION AND TREATMENT OF DIABETIC COMPLICATIONS. THE FUNCTION OF NRF2 IN THE TREATMENT OF DIABETIC COMPLICATIONS HAS BEEN WIDELY REPORTED, BUT THE ROLE OF NRF2-RELATED EPIGENETIC MODIFICATIONS REMAINS UNCLEAR. THE PURPOSE OF THIS REVIEW IS TO SUMMARIZE THE RECENT ADVANCES IN TARGETING NRF2-RELATED EPIGENETIC MODIFICATIONS IN THE TREATMENT OF CARDIAC AND VASCULAR COMPLICATIONS ASSOCIATED WITH DM. WE ALSO DISCUSS AGONISTS THAT COULD POTENTIALLY REGULATE NRF2-ASSOCIATED EPIGENETIC MECHANISMS. THIS REVIEW PROVIDES A BETTER UNDERSTANDING OF STRATEGIES TO TARGET NRF2 TO PROTECT AGAINST DM-RELATED CARDIAC AND VASCULAR COMPLICATIONS. 2021 11 5571 33 ROLE OF MICRORNA 1207-5P AND ITS HOST GENE, THE LONG NON-CODING RNA PVT1, AS MEDIATORS OF EXTRACELLULAR MATRIX ACCUMULATION IN THE KIDNEY: IMPLICATIONS FOR DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY IS THE MOST COMMON CAUSE OF CHRONIC KIDNEY FAILURE AND END-STAGE RENAL DISEASE IN THE WESTERN WORLD. ONE OF THE MAJOR CHARACTERISTICS OF THIS DISEASE IS THE EXCESSIVE ACCUMULATION OF EXTRACELLULAR MATRIX (ECM) IN THE KIDNEY GLOMERULI. WHILE BOTH ENVIRONMENTAL AND GENETIC DETERMINANTS ARE RECOGNIZED FOR THEIR ROLE IN THE DEVELOPMENT OF DIABETIC NEPHROPATHY, EPIGENETIC FACTORS, SUCH AS DNA METHYLATION, LONG NON-CODING RNAS, AND MICRORNAS, HAVE ALSO RECENTLY BEEN FOUND TO UNDERLIE SOME OF THE BIOLOGICAL MECHANISMS, INCLUDING ECM ACCUMULATION, LEADING TO THE DISEASE. WE PREVIOUSLY FOUND THAT A LONG NON-CODING RNA, THE PLASMACYTOMA VARIANT TRANSLOCATION 1 (PVT1), INCREASES PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) AND TRANSFORMING GROWTH FACTOR BETA 1 (TGF-BETA1) IN MESANGIAL CELLS, THE TWO MAIN CONTRIBUTORS TO ECM ACCUMULATION IN THE GLOMERULI UNDER HYPERGLYCEMIC CONDITIONS, AS WELL AS FIBRONECTIN 1 (FN1), A MAJOR ECM COMPONENT. HERE, WE REPORT THAT MIR-1207-5P, A PVT1-DERIVED MICRORNA, IS ABUNDANTLY EXPRESSED IN KIDNEY CELLS, AND IS UPREGULATED BY GLUCOSE AND TGF-BETA1. WE ALSO FOUND THAT LIKE PVT1, MIR-1207-5P INCREASES EXPRESSION OF TGF-BETA1, PAI-1, AND FN1 BUT IN A MANNER THAT IS INDEPENDENT OF ITS HOST GENE. IN ADDITION, REGULATION OF MIR-1207-5P EXPRESSION BY GLUCOSE AND TGFBETA1 IS INDEPENDENT OF PVT1. THESE RESULTS PROVIDE EVIDENCE SUPPORTING IMPORTANT ROLES FOR MIR-1207-5P AND ITS HOST GENE IN THE COMPLEX PATHOGENESIS OF DIABETIC NEPHROPATHY. 2013 12 4968 36 PATHOLOGICAL MECHANISMS AND THERAPEUTIC OUTLOOKS FOR ARTHROFIBROSIS. ARTHROFIBROSIS IS A FIBROTIC JOINT DISORDER THAT BEGINS WITH AN INFLAMMATORY REACTION TO INSULTS SUCH AS INJURY, SURGERY AND INFECTION. EXCESSIVE EXTRACELLULAR MATRIX AND ADHESIONS CONTRACT POUCHES, BURSAE AND TENDONS, CAUSE PAIN AND PREVENT A NORMAL RANGE OF JOINT MOTION, WITH DEVASTATING CONSEQUENCES FOR PATIENT QUALITY OF LIFE. ARTHROFIBROSIS AFFECTS PEOPLE OF ALL AGES, WITH PUBLISHED RATES VARYING. THE RISK FACTORS AND BEST MANAGEMENT STRATEGIES ARE LARGELY UNKNOWN DUE TO A POOR UNDERSTANDING OF THE PATHOLOGY AND LACK OF DIAGNOSTIC BIOMARKERS. HOWEVER, CURRENT RESEARCH INTO THE PATHOGENESIS OF FIBROSIS IN ORGANS NOW INFORMS THE UNDERSTANDING OF ARTHROFIBROSIS. THE PROCESS BEGINS WHEN STRESS SIGNALS STIMULATE IMMUNE CELLS. THE RESULTING CASCADE OF CYTOKINES AND MEDIATORS DRIVES FIBROBLASTS TO DIFFERENTIATE INTO MYOFIBROBLASTS, WHICH SECRETE FIBRILLAR COLLAGENS AND TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA). POSITIVE FEEDBACK NETWORKS THEN DYSREGULATE PROCESSES THAT NORMALLY TERMINATE HEALING PROCESSES. WE PROPOSE TWO SUBTYPES OF ARTHROFIBROSIS OCCUR: ACTIVE ARTHROFIBROSIS AND RESIDUAL ARTHROFIBROSIS. IN THE LATTER THE FIBROGENIC PROCESSES HAVE RESOLVED BUT THE JOINT REMAINS STIFF. THE BEST THERAPEUTIC APPROACH FOR EACH SUBTYPE MAY DIFFER SIGNIFICANTLY. TREATMENT TYPICALLY INVOLVES SURGERY, HOWEVER, A PHARMACOLOGICAL APPROACH TO CORRECT DYSREGULATED CELL SIGNALLING COULD BE MORE EFFECTIVE. RECENT RESEARCH SHOWS THAT MYOFIBROBLASTS ARE CAPABLE OF REVERSING DIFFERENTIATION, AND UNDERSTANDING THE MECHANISMS OF PATHOGENESIS AND RESOLUTION WILL BE ESSENTIAL FOR THE DEVELOPMENT OF CELL-BASED TREATMENTS. THERAPIES WITH SIGNIFICANT PROMISE ARE CURRENTLY AVAILABLE, WITH MORE IN DEVELOPMENT, INCLUDING THOSE THAT INHIBIT TGF-BETA SIGNALLING AND EPIGENETIC MODIFICATIONS. THIS REVIEW FOCUSES ON PATHOGENESIS OF STERILE ARTHROFIBROSIS AND THERAPEUTIC TREATMENTS. 2019 13 4558 33 MUTATIONS IN THE NF-KAPPAB SIGNALING PATHWAY: IMPLICATIONS FOR HUMAN DISEASE. THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) SIGNALING PATHWAY IS A MULTI-COMPONENT PATHWAY THAT REGULATES THE EXPRESSION OF HUNDREDS OF GENES THAT ARE INVOLVED IN DIVERSE AND KEY CELLULAR AND ORGANISMAL PROCESSES, INCLUDING CELL PROLIFERATION, CELL SURVIVAL, THE CELLULAR STRESS RESPONSE, INNATE IMMUNITY AND INFLAMMATION. NOT SURPRISINGLY, MIS-REGULATION OF THE NF-KAPPAB PATHWAY, EITHER BY MUTATION OR EPIGENETIC MECHANISMS, IS INVOLVED IN MANY HUMAN AND ANIMAL DISEASES, ESPECIALLY ONES ASSOCIATED WITH CHRONIC INFLAMMATION, IMMUNODEFICIENCY OR CANCER. THIS REVIEW DESCRIBES HUMAN DISEASES IN WHICH MUTATIONS IN THE COMPONENTS OF THE CORE NF-KAPPAB SIGNALING PATHWAY HAVE BEEN IMPLICATED AND DISCUSSES THE MOLECULAR MECHANISMS BY WHICH THESE ALTERATIONS IN NF-KAPPAB SIGNALING ARE LIKELY TO CONTRIBUTE TO THE DISEASE PATHOLOGY. THESE MUTATIONS CAN BE GERMLINE OR SOMATIC AND INCLUDE GENE AMPLIFICATION (E.G., REL), POINT MUTATIONS AND DELETIONS (REL, NFKB2, IKBA, CYLD, NEMO) AND CHROMOSOMAL TRANSLOCATIONS (BCL-3). IN ADDITION, HUMAN GENETIC DISEASES ARE BRIEFLY DESCRIBED WHEREIN MUTATIONS AFFECT PROTEIN MODIFIERS OR TRANSDUCERS OF NF-KAPPAB SIGNALING OR DISRUPT NF-KAPPAB-BINDING SITES IN PROMOTERS/ENHANCERS. 2006 14 2446 22 EPIGENETIC STRATEGIES SYNERGIZE WITH PD-L1/PD-1 TARGETED CANCER IMMUNOTHERAPIES TO ENHANCE ANTITUMOR RESPONSES. IMMUNOTHERAPY STRATEGIES TARGETING THE PROGRAMMED CELL DEATH LIGAND 1 (PD-L1)/PROGRAMMED CELL DEATH 1 (PD-1) PATHWAY IN CLINICAL TREATMENTS HAVE ACHIEVED REMARKABLE SUCCESS IN TREATING MULTIPLE TYPES OF CANCER. HOWEVER, OWING TO THE HETEROGENEITY OF TUMORS AND INDIVIDUAL IMMUNE SYSTEMS, PD-L1/PD-1 BLOCKADE STILL SHOWS SLOW RESPONSE RATES IN CONTROLLING MALIGNANCIES IN MANY PATIENTS. ACCUMULATING EVIDENCE HAS SHOWN THAT AN EFFECTIVE RESPONSE TO ANTI-PD-L1/ANTI-PD-1 THERAPY REQUIRES ESTABLISHING AN INTEGRATED IMMUNE CYCLE. DAMAGE IN ANY STEP OF THE IMMUNE CYCLE IS ONE OF THE MOST IMPORTANT CAUSES OF IMMUNOTHERAPY FAILURE. IMPAIRMENTS IN THE IMMUNE CYCLE CAN BE RESTORED BY EPIGENETIC MODIFICATION, INCLUDING REPROGRAMMING THE ENVIRONMENT OF TUMOR-ASSOCIATED IMMUNITY, ELICITING AN IMMUNE RESPONSE BY INCREASING THE PRESENTATION OF TUMOR ANTIGENS, AND BY REGULATING T CELL TRAFFICKING AND REACTIVATION. THUS, A RATIONAL COMBINATION OF PD-L1/PD-1 BLOCKADE AND EPIGENETIC AGENTS MAY OFFER GREAT POTENTIAL TO RETRAIN THE IMMUNE SYSTEM AND TO IMPROVE CLINICAL OUTCOMES OF CHECKPOINT BLOCKADE THERAPY. 2020 15 2965 55 GENETIC AND EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF DIABETIC RETINOPATHY: A MOLECULAR LINK TO REGULATE GENE EXPRESSION. INTENSIFICATION IN THE FREQUENCY OF DIABETES AND THE ASSOCIATED VASCULAR COMPLICATIONS HAS BEEN A ROOT CAUSE OF BLINDNESS AND VISUAL IMPAIRMENT WORLDWIDE. ONE SUCH VASCULAR COMPLICATION WHICH HAS BEEN THE PROMINENT CAUSE OF BLINDNESS; RETINAL VASCULATURE, NEURONAL AND GLIAL ABNORMALITIES IS DIABETIC RETINOPATHY (DR), A CHRONIC COMPLICATED OUTCOME OF TYPE 1 AND TYPE 2 DIABETES. IT HAS ALSO BECOME CLEAR THAT "GENETIC" VARIATIONS IN POPULATION ALONE CAN'T EXPLAIN THE DEVELOPMENT AND PROGRESSION OF DIABETES AND ITS COMPLICATIONS INCLUDING DR. DR EXPERIENCES ENGAGEMENT OF FOREMOST MEDIATORS OF DIABETES SUCH AS HYPERGLYCEMIA, OXIDANT STRESS, AND INFLAMMATORY FACTORS THAT LEAD TO THE DYSREGULATION OF "EPIGENETIC" MECHANISMS INVOLVING HISTONE ACETYLATION AND HISTONE AND DNA METHYLATION, CHROMATIN REMODELING AND EXPRESSION OF A COMPLEX SET OF STRESS-REGULATED AND DISEASE-ASSOCIATED GENES. IN ADDITION, BOTH ELEVATED GLUCOSE CONCENTRATION AND INSULIN RESISTANCE LEAVE A ROBUST EFFECT ON EPIGENETIC REPROGRAMMING OF THE ENDOTHELIAL CELLS TOO, SINCE ENDOTHELIUM ASSOCIATED WITH THE EYE AIDS IN MAINTAINING THE VASCULAR HOMEOSTASIS. FURTHERMORE, SEVERAL STUDIES CONDUCTED ON THE DISEASE SUGGEST THAT THE MODIFICATIONS OF THE EPIGENOME MIGHT BE THE FUNDAMENTAL MECHANISM(S) FOR THE PROPOSED METABOLIC MEMORY' RESULTING INTO PROLONGED GENE EXPRESSION FOR INFLAMMATION AND CELLULAR DYSFUNCTION EVEN AFTER ATTAINING THE GLYCEMIC CONTROL IN DIABETICS. HENCEFORTH, THE PRESENT REVIEW FOCUSES ON THE ASPECTS OF GENETIC AND EPIGENETIC ALTERATIONS IN GENES SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR AND ALDOSE REDUCTASE CONSIDERED BEING ASSOCIATED WITH DR. IN ADDITION, WE DISCUSS BRIEFLY THE ROLE OF THE THIOREDOXIN-INTERACTING PROTEIN TXNIP, WHICH IS STRONGLY INDUCED BY HIGH GLUCOSE AND DIABETES, IN CELLULAR OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION POTENTIALLY LEADING TO CHROMATIN REMODELING AND OCULAR COMPLICATIONS OF DIABETES. THE IDENTIFICATION OF DISEASE-ASSOCIATED GENES AND THEIR EPIGENETIC REGULATIONS WILL LEAD TO POTENTIAL NEW DRUGS AND GENE THERAPIES AS WELL AS PERSONALIZED MEDICINE TO PREVENT OR SLOW DOWN THE PROGRESSION OF DR. 2016 16 3762 38 INTEGRATING THE TUMOR-SUPPRESSIVE ACTIVITY OF MASPIN WITH P53 IN RETUNING THE EPITHELIAL HOMEOSTASIS: A WORKING HYPOTHESIS AND APPLICABLE PROSPECTS. EPITHELIAL MALIGNANT TRANSFORMATION AND TUMOROUS DEVELOPMENT WERE BELIEVED TO BE CLOSELY ASSOCIATED WITH THE LOSS OF ITS MICROENVIRONMENT INTEGRITY AND HOMEOSTASIS. THE TUMOR-SUPPRESSIVE MOLECULES MASPIN AND P53 WERE DEMONSTRATED TO PLAY A CRUCIAL ROLE IN BODY EPITHELIAL AND IMMUNE HOMEOSTASIS. DOWNREGULATION OF MASPIN AND MUTATION OF P53 WERE FREQUENTLY ASSOCIATED WITH MALIGNANT TRANSFORMATION AND POOR PROGNOSIS IN VARIOUS HUMAN CANCERS. IN THIS REVIEW, WE FOCUSED ON SUMMARIZING THE PROGRESS OF THE MOLECULAR NETWORK OF MASPIN IN STUDYING EPITHELIAL TUMOROUS DEVELOPMENT AND ITS RESPONSE TO CLINIC TREATMENT AND TRY TO CLARIFY THE UNDERLYING ANTITUMOR MECHANISM. NOTABLY, MASPIN EXPRESSION WAS REPORTED TO BE TRANSCRIPTIONALLY ACTIVATED BY P53, AND THE TRANSCRIPTIONAL ACTIVITY OF P53 WAS DEMONSTRATED TO BE ENHANCED BY ITS ACETYLATION THROUGH INHIBITION OF HDAC1. AS AN ENDOGENOUS INHIBITOR OF HDAC1, MASPIN POSSIBLY POTENTIATES THE TRANSCRIPTIONAL ACTIVITY OF P53 BY ACETYLATING THE P53 PROTEIN. HEREBY, IT COULD FORM A "SELF-PROPELLING" ANTITUMOR MECHANISM. THUS, WE SUMMARIZED THAT, UPON STIMULATION OF CELLULAR STRESS AND BY INTEGRATING WITH P53, THE AROUSED MASPIN PLAYED THE EPIGENETIC SURVEILLANT ROLE TO PREVENT THE EPITHELIAL DIGRESSIONAL PROCESS AND RETUNE THE EPITHELIAL HOMEOSTASIS, WHICH IS INVOLVED IN ACTIVATING HOST IMMUNE SURVEILLANCE, REGULATING THE INFLAMMATORY FACTORS, AND FINE-TUNING ITS ASSOCIATED CELL SIGNALING PATHWAYS. CONSEQUENTIALLY, IN A NORMAL PHYSIOLOGICAL CONDITION, ACTIVATION OF THE ABOVE "SELF-PROPELLING" ANTITUMOR MECHANISM OF MASPIN AND P53 COULD REDUCE CELLULAR STRESS (E.G., CHRONIC INFECTION/INFLAMMATION, OXIDATIVE STRESS, TRANSFORMATION) EFFECTIVELY AND ACHIEVE CANCER PREVENTION. MEANWHILE, DESIGNING A STRATEGY OF MIMICKING MASPIN'S EPIGENETIC REGULATION ACTIVITY WITH INTEGRATING P53 TUMOR-SUPPRESSIVE ACTIVITY COULD ENHANCE THE CHEMOTHERAPY EFFICACY THEORETICALLY IN A PATHOLOGICAL CONDITION OF CANCER. 2022 17 6584 30 TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 : OUR NEW PARTNER IN HUMAN ONCOLOGY? INFLAMMATION IS RECOGNIZED AS ONE OF THE HALLMARKS OF CANCER. INDEED, STRONG EVIDENCE INDICATES THAT CHRONIC INFLAMMATION PLAYS A MAJOR ROLE IN ONCOGENESIS, PROMOTING GENOME INSTABILITY, EPIGENETIC ALTERATIONS, PROLIFERATION AND DISSEMINATION OF CANCER CELLS. MONONUCLEAR PHAGOCYTES (MPS) HAVE BEEN IDENTIFIED AS KEY CONTRIBUTORS OF THE INFLAMMATORY INFILTRATE IN SEVERAL SOLID HUMAN NEOPLASIA, PROMOTING ANGIOGENESIS AND CANCER PROGRESSION. ONE OF THE MOST DESCRIBED AMPLIFIERS OF MPS PRO-INFLAMMATORY INNATE IMMUNE RESPONSE IS THE TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 (TREM-1). GROWING EVIDENCE SUGGESTS TREM-1 INVOLVEMENT IN ONCOGENESIS THROUGH CANCER RELATED INFLAMMATION AND THE SURROUNDING TUMOR MICROENVIRONMENT. IN HUMAN ONCOLOGY, HIGH LEVELS OF TREM-1 AND/OR ITS SOLUBLE FORM HAVE BEEN ASSOCIATED WITH POORER SURVIVAL DATA IN SEVERAL SOLID MALIGNANCIES, ESPECIALLY IN HEPATOCELLULAR CARCINOMA AND LUNG CANCER. TREM-1 SHOULD BE CONSIDERED AS A POTENTIAL BIOMARKER IN HUMAN ONCOLOGY AND COULD BE USED AS A NEW THERAPEUTIC TARGET OF INTEREST IN HUMAN ONCOLOGY (TREM-1 INHIBITORS, TREM-1 AGONISTS). MORE CLINICAL STUDIES ARE URGENTLY NEEDED TO CONFIRM TREM-1 (AND TREM FAMILY) ROLES IN THE PROGNOSIS AND THE TREATMENT OF HUMAN SOLID CANCERS. 2022 18 4031 33 LYSINE DEACETYLASE (KDAC) REGULATORY PATHWAYS: AN ALTERNATIVE APPROACH TO SELECTIVE MODULATION. PROTEIN LYSINE DEACETYLASES (KDACS), INCLUDING THE CLASSIC ZN(2+) -DEPENDENT HISTONE DEACETYLASES (HDACS) AND THE NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+) )-REQUIRING SIRTUINS, ARE ENZYMES THAT PLAY CRITICAL ROLES IN NUMEROUS BIOLOGICAL PROCESSES, PARTICULARLY THE EPIGENETIC REGULATION OF GLOBAL GENE EXPRESSION PROGRAMS IN RESPONSE TO INTERNAL AND EXTERNAL CUES. DYSREGULATION OF KDACS IS CHARACTERISTIC OF SEVERAL HUMAN DISEASES, INCLUDING CHRONIC METABOLIC, NEURODEGENERATIVE, AND CARDIOVASCULAR DISEASES AND MANY CANCERS. THIS HAS LED TO THE DEVELOPMENT OF KDAC MODULATORS, TWO OF WHICH (HDAC INHIBITORS VORINOSTAT AND ROMIDEPSIN) HAVE BEEN APPROVED FOR THE TREATMENT OF CUTANEOUS T CELL LYMPHOMA. BY THEIR NATURE, EXISTING KDAC MODULATORS ARE RELATIVELY NONSPECIFIC, LEADING TO PAN-KDAC CHANGES AND UNDESIRED SIDE EFFECTS. GIVEN THAT KDACS ARE REGULATED AT MANY LEVELS, INCLUDING TRANSCRIPTIONAL, POST-TRANSLATIONAL, SUBCELLULAR LOCALIZATION, AND THROUGH THEIR COMPLEXATION WITH OTHER PROTEINS, IT SHOULD BE POSSIBLE TO AFFECT SPECIFIC KDAC ACTIVITY THROUGH MANIPULATION OF ENDOGENOUS SIGNALING PATHWAYS. IN THIS MINIREVIEW, WE DISCUSS OUR PRESENT KNOWLEDGE OF THE CELLULAR CONTROLS OF KDAC ACTIVITY AND EXAMPLES OF THEIR PHARMACOLOGIC REGULATION. 2014 19 2533 31 EPIGENETICS IN AUTOIMMUNE CONNECTIVE TISSUE DISEASES. BACKGROUND. AUTOIMMUNE CONNECTIVE TISSUE DISEASES (ACTDS) ENCOMPASS A HETEROGENEOUS GROUP OF CHRONIC IMMUNE-MEDIATED INFLAMMATORY DISORDERS, PRIMARILY AFFECTING CONNECTIVE TISSUES AND CLINICALLY CHARACTERIZED BY VARIABLE MULTISYSTEM MANIFESTATIONS, FREQUENTLY OVERLAPPING. ENVIRONMENTAL FACTORS ARE THOUGHT TO PROMOTE ACTD DEVELOPMENT IN GENETIC PREDISPOSING/ENDOCRINE PERMISSIVE BACKGROUND THROUGH THE INDUCTION OF EPIGENETIC MODIFICATIONS, CONSISTING OF STABLE, HERITABLE, BUT POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION, OCCURRING WITHOUT ALTERATIONS OF THE DNA SEQUENCE. ACTUALLY, EPIGENETIC MECHANISMS (SUCH AS HISTONE MODIFICATIONS, DNA METHYLATION, NUCLEOSOME POSITIONING, AND RNA INTERFERENCE) LINK GENOTYPE UPSTREAM AND PHENOTYPE DOWNSTREAM, AND, IF PERSISTENTLY ABERRANT, MAY CAUSE A VARIETY OF HUMAN DISEASES, INCLUDING ACTDS. WE AIMED TO REVIEW THE RECENT ADVANCES IN THE KNOWLEDGE OF THE ACTD EPIGENETIC ALTERATIONS. METHODS: A DETAILED SEARCH OF THE AVAILABLE LITERATURE WAS PERFORMED IN THE PUBMED (U.S. NATIONAL LIBRARY OF MEDICINE) DATABASE. RESULTS: GROWING EVIDENCE UNDERLINES THE RELEVANT ROLE OF EPIGENETIC DEFECTS IN THE ACTD PATHOGENESIS, AND SPECIFIC EPIGENETIC PATTERNS CAN REPRESENT DISEASE BIOMARKERS. IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA), EPIGENETIC VARIATIONS INTERACT DETERMINING THE TYPICAL "AGGRESSIVE" PHENOTYPE DISPLAYED BY RA SYNOVIAL FIBROBLASTS. EPIGENETIC MODIFICATIONS ARE INVOLVED IN THE PROFIBROTIC PROCESS THAT CHARACTERIZES SYSTEMIC SCLEROSIS. IN SYSTEMIC LUPUS ERYTHEMATOSUS AND SJOGREN'S SYNDROME, COMPLEX EPIGENETIC CHANGES ALTERING GENE EXPRESSION HAVE BEEN DEMONSTRATED. CONCLUSIONS: COMPREHENSIVE STUDIES WILL CONTRIBUTE TO FURTHER DEFINE THE ABERRANT EPIGENETIC MECHANISMS INVOLVED IN THE ACTDS ETIOPATHOGENESIS. MOREOVER, BEING EPIGENETIC CHANGES POTENTIALLY REVERSIBLE, THE IDENTIFICATION OF ACTDS EPIGENETIC BIOMARKERS WILL ALLOW THE DEVELOPMENT OF THERAPEUTIC STRATEGIES ADDRESSED TO TARGET DYSREGULATED GENES AND CORRECT ABERRANT EPIGENOMIC ALTERATIONS. 2014 20 1569 24 DNA METHYLATION OF TXNIP INDEPENDENTLY ASSOCIATED WITH INFLAMMATION AND DIABETES MELLITUS IN TWINS. THIOREDOXIN-INTERACTING PROTEIN (TXNIP) PLAYS A KEY ROLE IN DIABETES DEVELOPMENT AND PROGNOSIS THROUGH ITS ROLE IN PANCREATIC BETA-CELL DYSFUNCTION AND DEATH AS WELL AS IN UPREGULATING THE INFLAMMATORY RESPONSE IN HYPERGLYCEMIA. DNA METHYLATION (DNAM) OF TXNIP (TXNIP-CG19693031) IS ASSOCIATED WITH THE PREVALENCE AND INCIDENCE OF TYPE 2 DIABETES (T2D); HOWEVER, ITS ROLE IN INFLAMMATION AND ITS RELATIONSHIP WITH T2D REMAIN UNCLEAR. WE AIMED TO INVESTIGATE THE EPIGENETIC ASSOCIATIONS OF TXNIP-CG19693031 WITH A PANEL OF INFLAMMATORY BIOMARKERS AND TO EXAMINE WHETHER THESE INFLAMMATORY BIOMARKERS MODIFY THE ASSOCIATION BETWEEN TXNIP-CG19693031 METHYLATION AND DIABETES IN 218 MIDDLE-AGED MALE TWINS FROM THE EMORY TWIN STUDY. WE CONFIRMED THE ASSOCIATION OF TXNIP-CG19693031 DNAM WITH T2D, AS WELL AS WITH HBA1C, INSULIN AND FASTING GLUCOSE. WE FOUND THAT HYPOMETHYLATION AT TXNIP-CG19693031 IS STRONGLY ASSOCIATED WITH BOTH TYPE 2 DIABETES AND HIGHER LEVELS OF INFLAMMATORY BIOMARKERS (VCAM-1, ICAM-1, MMP-2, SRAGE AND P-SELECTIN); HOWEVER, THE RELATIONSHIP BETWEEN TXNIP-CG19693031 AND T2D IS INDEPENDENT OF THE LEVELS OF THESE INFLAMMATORY BIOMARKERS. OUR RESULTS SUGGEST THAT DNA METHYLATION OF TXNIP IS LINKED WITH MULTIPLE BIOLOGICAL PROCESSES, THROUGH WHICH THE TXNIP MAY HAVE BROAD INFLUENCE ON CHRONIC DISEASE RISK. 2021