1 1125 155 COMPLEX INHIBITION OF AUTOPHAGY BY MITOCHONDRIAL ALDEHYDE DEHYDROGENASE SHORTENS LIFESPAN AND EXACERBATES CARDIAC AGING. AUTOPHAGY, A CONSERVATIVE DEGRADATION PROCESS FOR LONG-LIVED AND DAMAGED PROTEINS, PARTICIPATES IN A CASCADE OF BIOLOGICAL PROCESSES INCLUDING AGING. A NUMBER OF AUTOPHAGY REGULATORS HAVE BEEN IDENTIFIED. HERE WE DEMONSTRATED THAT MITOCHONDRIAL ALDEHYDE DEHYDROGENASE (ALDH2), AN ENZYME WITH THE MOST COMMON SINGLE POINT MUTATION IN HUMANS, GOVERNS CARDIAC AGING THROUGH REGULATION OF AUTOPHAGY. MYOCARDIAL MECHANICAL AND AUTOPHAGY PROPERTIES WERE EXAMINED IN YOUNG (4MONTHS) AND OLD (26-28MONTHS) WILD-TYPE (WT) AND GLOBAL ALDH2 TRANSGENIC MICE. ALDH2 OVEREXPRESSION SHORTENED LIFESPAN BY 7.7% WITHOUT AFFECTING AGING-ASSOCIATED CHANGES IN PLASMA METABOLIC PROFILES. MYOCARDIAL FUNCTION WAS COMPROMISED WITH AGING ASSOCIATED WITH CARDIAC HYPERTROPHY, THE EFFECTS WERE ACCENTUATED BY ALDH2. AGING OVERTLY SUPPRESSED AUTOPHAGY AND COMPROMISED AUTOPHAGY FLUX, THE EFFECTS WERE EXACERBATED BY ALDH2. AGING DAMPENED PHOSPHORYLATION OF JNK, BCL-2, IKKBETA, AMPK AND TSC2 WHILE PROMOTING PHOSPHORYLATION OF MTOR, THE EFFECTS OF WHICH WERE EXAGGERATED BY ALDH2. CO-IMMUNOPRECIPITATION REVEALED INCREASED DISSOCIATION BETWEEN BCL-2 AND BECLIN-1 (RESULT OF DECREASED BCL-2 PHOSPHORYLATION) IN AGING, THE EFFECT OF WHICH WAS EXACERBATED WITH ALDH2. CHRONIC TREATMENT OF THE AUTOPHAGY INDUCER RAPAMYCIN ALLEVIATED AGING-INDUCED CARDIAC DYSFUNCTION IN BOTH WT AND ALDH2 MICE. MOREOVER, ACTIVATION OF JNK AND INHIBITION OF EITHER BCL-2 OR IKKBETA OVERTLY ATTENUATED ALDH2 ACTIVATION-INDUCED ACCENTUATION OF CARDIOMYOCYTE AGING. EXAMINATION OF THE OTHERWISE ELDERLY INDIVIDUALS REVEALED A POSITIVE CORRELATION BETWEEN CARDIAC FUNCTION/GEOMETRY AND ALDH2 GENE MUTATION. TAKEN TOGETHER, OUR DATA REVEALED THAT ALDH2 ENZYME MAY SUPPRESS MYOCARDIAL AUTOPHAGY POSSIBLY THROUGH A COMPLEX JNK-BCL-2 AND IKKBETA-AMPK-DEPENDENT MECHANISM EN ROUTE TO ACCENTUATION OF MYOCARDIAL REMODELING AND CONTRACTILE DYSFUNCTION IN AGING. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED: GENETIC AND EPIGENETIC CONTROL OF HEART FAILURE - EDITED BY JUN REN & MEGAN YINGMEI ZHANG. 2017 2 4117 44 MECHANISMS OF AUTOPHAGIC RESPONSES TO ALTERED NUTRITIONAL STATUS. AUTOPHAGY IS A DYNAMIC PROCESS AND CRITICAL FOR CELLULAR REMODELING AND ORGANELLE QUALITY CONTROL. IN RESPONSE TO ALTERED NUTRITIONAL STATUS (E.G., FASTING AND FEEDING), AUTOPHAGIC ACTIVITY IS FINELY TUNED BY TRANSCRIPTIONAL, POSTTRANSLATIONAL, AND EPIGENETIC REGULATIONS VIA VARIOUS SIGNALING PATHWAYS, INCLUDING ENERGY SENSORS (E.G., MECHANISTIC TARGET OF RAPAMYCIN (MTOR)/ AMP-ACTIVATED PROTEIN KINASE - UNC-51 LIKE AUTOPHAGY ACTIVATING KINASE 1, MTORC1- WD REPEAT DOMAIN, PHOSPHOINOSITIDE INTERACTING 2, MTORC1- TRANSCRIPTION FACTOR EB, PERILIPIN 5- SIRTUIN 1, AND SIRTUIN 1-MEDIATED DEACETYLATION OF AUTOPHAGY PROTEINS), FASTING OR FEEDING INDUCED HORMONES (E.G., FIBROBLAST GROWTH FACTOR [FGF21]- PROTEIN KINASE A - JUMONJI DOMAIN-CONTAINING PROTEIN D3, FGF21- DOWNSTREAM REGULATORY ELEMENT ANTAGONIST MODULATOR - E3 LIGASE MIDLINE-1- TRANSCRIPTION FACTOR EB, FGF19-SHP- LYSINE-SPECIFIC DEMETHYLASE, INSULIN- INSULIN RECEPTOR SUBSTRATE - PROTEIN KINASE B - FORKHEAD BOX O, GLUCAGON- PROTEIN KINASE A - CAMP RESPONSE BINDING PROTEIN), AND LYSOSOMAL ENZYMES (E.G., CATHEPSIN B AND CATHEPSIN L). IN CONTRAST TO FASTING THAT INDUCES AUTOPHAGY AND HEALTH BENEFITS, NUTRIENT OVERSUPPLY (OVERFEEDING OR FEEDING ON HIGH ENERGY DIETS) DYSREGULATES AUTOPHAGY, WHICH HAS BEEN INCREASINGLY OBSERVED IN ANIMAL MODELS OF HUMAN CHRONIC DISEASES SUCH AS OBESITY, DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, AND CARDIOVASCULAR DISEASE. STUDIES HAVE REVEALED MULTIFACETED EFFECTS OF HIGH ENERGY DIETS ON AUTOPHAGY, BEING EITHER AN INHIBITOR OR ENHANCER OF AUTOPHAGY. THE CONUNDRUM MAY ARISE FROM THE VARIATIONS IN METHODS FOR AUTOPHAGY ANALYSIS, COMPONENTS OF HIGH ENERGY DIETS AND CONTROL DIETS FOR TREATMENTS, TREATMENT DURATIONS, AND THE AGES OF GENETIC BACKGROUNDS OF LABORATORY ANIMALS. IN THIS ARTICLE, WE REVIEWED THE EVIDENCE FROM BOTH HUMAN AND ANIMAL STUDIES, PRESENTING THE MOLECULAR MECHANISM OF AUTOPHAGIC RESPONSE TO ALTERED NUTRITIONAL STATUS AND DISCUSSING THE CONTRIBUTING FACTORS OF AND POSSIBLE SOLUTION TO THE CURRENT CONUNDRUM CONCERNING THE EXACT ROLE OF HIGH ENERGY DIETS IN AUTOPHAGIC REGULATION. 2022 3 719 42 CALORIE RESTRICTION-REGULATED MOLECULAR PATHWAYS AND ITS IMPACT ON VARIOUS AGE GROUPS: AN OVERVIEW. CALORIE RESTRICTION (CR) IF PLANNED PROPERLY WITH REGULAR EXERCISE AT DIFFERENT AGES CAN RESULT IN HEALTHY WEIGHT LOSS. CR CAN ALSO HAVE DIFFERENT BENEFICIAL EFFECTS ON IMPROVING LIFESPAN AND DECREASING THE AGE-ASSOCIATED DISEASES BY REGULATING PHYSIOLOGICAL, BIOCHEMICAL, AND MOLECULAR MARKERS. THE DIFFERENT PATHWAYS REGULATED BY CR INCLUDE:(1) AMP-ACTIVATED PROTEIN KINASE (AMPK), WHICH INVOLVES PGC-1ALPHA, SIRT1, AND SIRT3. AMPK ALSO EFFECTS MYOCYTE ENHANCER FACTOR 2 (MEF2), PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR DELTA, AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA, WHICH ARE INVOLVED IN MITOCHONDRIAL BIOGENESIS AND LIPID OXIDATION; (2) FORKHEAD BOX TRANSCRIPTION FACTOR'S SIGNALING IS RELATED TO THE DNA REPAIR, LIPID METABOLISM, PROTECTION OF PROTEIN STRUCTURE, AUTOPHAGY, AND RESISTANCE TO OXIDATIVE STRESS; (3) MAMMALIAN TARGET OF RAPAMYCIN (MTOR) SIGNALING, WHICH INVOLVES KEY FACTORS, SUCH AS S6 PROTEIN KINASE-1 (S6K1), MTOR COMPLEX-1 (MTORC1), AND 4E-BINDING PROTEIN (4E-BP). UNDER CR CONDITIONS, AMPK ACTIVATION AND MTOR INHIBITION HELPS IN THE ACTIVATION OF ULK1 COMPLEX ALONG WITH THE ACETYLTRANSFERASE MEC-17, WHICH IS NECESSARY FOR AUTOPHAGY; (4) INSULIN-LIKE GROWTH FACTOR-1 (IGF-1) PATHWAY DOWNREGULATION PROTECTS AGAINST CANCER AND SLOWS THE AGING PROCESS; (5) NUCLEAR FACTOR KAPPA B PATHWAY DOWNREGULATION DECREASES THE INFLAMMATION; AND (6) C-JUN N-TERMINAL KINASE AND P38 KINASE REGULATION AS A RESPONSE TO THE STRESS. THE ACUTE AND CHRONIC CR BOTH SHOWS ANTIDEPRESSION AND ANXIOLYTIC ACTION BY EFFECTING GHRELIN/GHS-R1A SIGNALING. CR ALSO REGULATES GSK3BETA KINASE AND PROTECTS AGAINST AGE-RELATED BRAIN ATROPHY. CR AT YOUNG AGE MAY SHOW MANY DELETERIOUS EFFECTS BY EFFECTING DIFFERENT MECHANISMS. PARENTAL CR BEFORE OR DURING CONCEPTION WILL ALSO AFFECT THE HEALTH AND DEVELOPMENT OF THE OFFSPRING BY CAUSING MANY EPIGENETIC MODIFICATIONS THAT SHOW TRANSGENERATIONAL TRANSMISSION. MATERNAL CR IS ASSOCIATED WITH INTRAUTERINE GROWTH RETARDATION EFFECTING THE OFFSPRING IN THEIR ADULTHOOD BY DEVELOPING DIFFERENT METABOLIC SYNDROMES. THE EPIGENETIC CHANGES WITH RESPONSE TO PATERNAL FOOD SUPPLY ALSO LINKED TO OFFSPRING HEALTH. CR AT MIDDLE AND OLD AGE PROVIDES A SIGNIFICANT PREVENTIVE IMPACT AGAINST THE DEVELOPMENT OF AGE-ASSOCIATED DISEASES. 2022 4 5868 27 SUPPRESSIVE EFFECTS OF METFORMIN ON T-HELPER 1-RELATED CHEMOKINES EXPRESSION IN THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1. PURPOSE OF THE STUDY: TYPE 1 AND TYPE 2 DIABETES MELLITUS (DM) ARE CHRONIC T-CELL-MEDIATED INFLAMMATORY DISEASES. METFORMIN IS A WIDELY USED DRUG FOR TYPE 2 DM THAT REDUCES THE NEED FOR INSULIN IN TYPE 1 DM. HOWEVER, WHETHER METFORMIN HAS AN ANTI-INFLAMMATORY EFFECT FOR TREATING DM IS UNKNOWN. WE INVESTIGATED THE ANTI-INFLAMMATORY MECHANISM OF METFORMIN IN THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1. MATERIALS AND METHODS: THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1 WAS PRETREATED WITH METFORMIN AND STIMULATED WITH LIPOPOLYSACCHARIDE (LPS). THE PRODUCTION OF T-HELPER (TH)-1-RELATED CHEMOKINES INCLUDING INTERFERON-GAMMA-INDUCED PROTEIN-10 (IP-10) AND MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1), TH2-RELATED CHEMOKINE MACROPHAGE-DERIVED CHEMOKINE, AND THE PROINFLAMMATORY CHEMOKINE TUMOR NECROSIS FACTOR-ALPHA WAS MEASURED USING ENZYME-LINKED IMMUNOSORBENT ASSAY. INTRACELLULAR SIGNALING PATHWAYS WERE INVESTIGATED USING WESTERN BLOT ANALYSIS AND CHROMATIN IMMUNOPRECIPITATION ASSAY. RESULTS: METFORMIN SUPPRESSED LPS-INDUCED IP-10 AND MCP-1 PRODUCTION AS WELL AS LPS-INDUCED PHOSPHORYLATION OF C-JUN N-TERMINAL KINASE (JNK), P38, EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK), AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB). MOREOVER, METFORMIN SUPPRESSED LPS-INDUCED ACETYLATION OF HISTONES H3 AND H4 AT THE IP-10 PROMOTER. CONCLUSIONS: METFORMIN SUPPRESSED THE PRODUCTION OF TH1-RELATED CHEMOKINES IP-10 AND MCP-1 IN THP-1 CELLS. SUPPRESSIVE EFFECTS OF METFORMIN ON IP-10 PRODUCTION MIGHT BE ATTRIBUTED AT LEAST PARTIALLY TO THE JNK, P38, ERK, AND NF-KAPPAB PATHWAYS AS WELL AS TO EPIGENETIC REGULATION THROUGH THE ACETYLATION OF HISTONES H3 AND H4. THESE RESULTS INDICATED THE THERAPEUTIC ANTI-INFLAMMATORY POTENTIAL OF METFORMIN. 2018 5 5695 37 SILENCING UHRF1 ENHANCES CELL AUTOPHAGY TO PREVENT ARTICULAR CHONDROCYTES FROM APOPTOSIS IN OSTEOARTHRITIS THROUGH PI3K/AKT/MTOR SIGNALING PATHWAY. OSTEOARTHRITIS (OA) IS A COMMON CHRONIC DEGENERATIVE JOINT DISEASE, AND CHONDROCYTE APOPTOSIS IS ONE OF MOST IMPORTANT PATHOLOGICAL CHANGES OF OA PATHOGENESIS. GROWING STUDIES HAVE SHOWN THAT UBIQUITIN-LIKE WITH PHD AND RING FINGER DOMAINS 1 (UHRF1) IS AN IMPORTANT EPIGENETIC REGULATORY FACTOR THAT REGULATES CELL PROLIFERATION AND APOPTOSIS OF VARIOUS TUMORS, BUT ITS ROLE IN OA REMAINS ILL-DEFINED. IN THE PRESENT STUDY, WE FOUND THAT UHRF1 EXPRESSION WAS INCREASED IN HUMAN OA CARTILAGE TISSUES, COMPARED WITH NORMAL CARTILAGE TISSUES. INTERLEUKIN-1BETA (IL-1BETA), A MAJOR INFLAMMATORY CYTOKINE THAT PROMOTES CARTILAGE DEGRADATION IN OA, WAS USED TO STIMULATE PRIMARY HUMAN CHONDROCYTES IN VITRO. THE EXPRESSION OF UHRF1 WAS ALSO ENHANCED IN IL-1BETA-INDUCED CHONDROCYTES. MOREOVER, DOWN-REGULATION OF UHRF1 INDUCED AN INCREASE ON CELL PROLIFERATION AND AUTOPHAGY, AND A DECREASE ON APOPTOSIS OF CHONDROCYTES AFTER IL-1BETA TREATMENT. FURTHER DATA INDICATED THAT SILENCING UHRF1 ATTENUATED THE UP-REGULATION OF IL-1BETA ON PHOSPHOINOSITIDE 3-KINASE (PI3K)/PROTEIN KINASE B (AKT)/MAMMALIAN TARGET OF RAPAMYCIN (MTOR) SIGNALING PATHWAY IN CHONDROCYTES. THEN, AN ACTIVATOR OF PI3K WEAKENED THE EFFECT OF UHRF1 SILENCING ON CELL PROLIFERATION, AUTOPHAGY, APOPTOSIS OF IL-1BETA-INDUCED CHONDROCYTES, AND THE CELL AUTOPHAGY SPECIAL INHIBITOR 3-METHYLADENINE (3-MA) ALSO SHOWED A SAME IMPACT ON UHRF1, HENCE SUGGESTING THAT KNOCKDOWN OF UHRF1 ENHANCES CELL AUTOPHAGY TO PROTECT CHONDROCYTES FROM APOPTOSIS IN OA THROUGH PI3K/AKT/MTOR SIGNALING PATHWAY. IN CONCLUSION, OUR STUDY SUGGESTS THAT UHRF1 MAY BE A POTENTIAL REGULATOR OF CHONDROCYTE APOPTOSIS IN THE PATHOGENESIS OF OA. 2020 6 5760 30 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION. 2016 7 5851 30 SUBEROYLANILIDE HYDROXAMIC ACID TRIGGERS AUTOPHAGY BY INFLUENCING THE MTOR PATHWAY IN THE SPINAL DORSAL HORN IN A RAT NEUROPATHIC PAIN MODEL. HISTONE ACETYLATION LEVELS CAN BE UPREGULATED BY TREATING CELLS WITH HISTONE DEACETYLASE INHIBITORS (HDACIS), WHICH CAN INDUCE AUTOPHAGY. AUTOPHAGY FLUX IN THE SPINAL CORD OF RATS FOLLOWING THE LEFT FIFTH LUMBER SPINAL NERVE LIGATION (SNL) IS INVOLVED IN THE PROGRESSION OF NEUROPATHIC PAIN. SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), ONE OF THE HDACIS CAN INTERFERE WITH THE EPIGENETIC PROCESS OF HISTONE ACETYLATION, WHICH HAS BEEN SHOWN TO EASE NEUROPATHIC PAIN. RECENT RESEARCH SUGGEST THAT SAHA CAN STIMULATE AUTOPHAGY VIA THE MAMMALIAN TARGET OF RAPAMYCIN (MTOR) PATHWAY IN SOME TYPES OF CANCER CELLS. HOWEVER, LITTLE IS KNOWN ABOUT THE ROLE OF SAHA AND AUTOPHAGY IN NEUROPATHIC PAIN AFTER NERVE INJURY. IN THE PRESENT STUDY, WE AIM TO INVESTIGATE AUTOPHAGY FLUX AND THE ROLE OF THE MTOR PATHWAY ON SPINAL CELLS AUTOPHAGY ACTIVATION IN NEUROPATHIC PAIN INDUCED BY SNL IN RATS THAT RECEIVED SAHA TREATMENT. AUTOPHAGY-RELATED PROTEINS AND MTOR OR ITS ACTIVE FORM WERE ASSESSED BY USING WESTERN BLOT, IMMUNOHISTOCHEMISTRY, DOUBLE IMMUNOFLUORESCENCE STAINING AND TRANSMISSION ELECTRON MICROSCOPY (TEM). WE FOUND THAT SAHA DECREASED THE PAW MECHANICAL WITHDRAWAL THRESHOLD (PMWT) OF THE LOWER COMPARED WITH SNL. AUTOPHAGY FLUX WAS MAINLY DISRUPTED IN THE ASTROCYTES AND NEURONAL CELLS OF THE SPINAL CORD DORSAL HORN ON POSTSURGICAL DAY 28 AND WAS REVERSED BY DAILY INTRATHECAL INJECTION OF SAHA (N = 100 NMOL/DAY OR N = 200 NMOL/DAY). SAHA ALSO DECREASED MTOR AND PHOSPHORYLATED MTOR (P-MTOR) EXPRESSION, ESPECIALLY P-MTOR EXPRESSION IN ASTROCYTES AND NEURONAL CELLS OF THE SPINAL DORSAL HORN. THESE RESULTS SUGGEST THAT SAHA ATTENUATES NEUROPATHIC PAIN AND CONTRIBUTES TO AUTOPHAGY FLUX IN ASTROCYTES AND NEURONAL CELLS OF THE SPINAL DORSAL HORN VIA THE MTOR SIGNALING PATHWAY. 2019 8 3701 24 INFLAMMATORY RESPONSE TO REGULATED CELL DEATH IN GOUT AND ITS FUNCTIONAL IMPLICATIONS. GOUT, A CHRONIC INFLAMMATORY ARTHRITIS DISEASE, IS CHARACTERIZED BY HYPERURICEMIA AND CAUSED BY INTERACTIONS BETWEEN GENETIC, EPIGENETIC, AND METABOLIC FACTORS. ACUTE GOUT SYMPTOMS ARE TRIGGERED BY THE INFLAMMATORY RESPONSE TO MONOSODIUM URATE CRYSTALS, WHICH IS MEDIATED BY THE INNATE IMMUNE SYSTEM AND IMMUNE CELLS (E.G., MACROPHAGES AND NEUTROPHILS), THE NACHT, LRR, AND PYD DOMAINS-CONTAINING PROTEIN 3 (NLRP3) INFLAMMASOME ACTIVATION, AND PRO-INFLAMMATORY CYTOKINE (E.G., IL-1BETA) RELEASE. RECENT STUDIES HAVE INDICATED THAT THE MULTIPLE PROGRAMMED CELL DEATH PATHWAYS INVOLVED IN THE INFLAMMATORY RESPONSE INCLUDE PYROPTOSIS, NETOSIS, NECROPTOSIS, AND APOPTOSIS, WHICH INITIATE INFLAMMATORY REACTIONS. IN THIS REVIEW, WE EXPLORE THE CORRELATION AND INTERACTIONS AMONG THESE FACTORS AND THEIR ROLES IN THE PATHOGENESIS OF GOUT TO PROVIDE FUTURE RESEARCH DIRECTIONS AND POSSIBILITIES FOR IDENTIFYING POTENTIAL NOVEL THERAPEUTIC TARGETS AND ENHANCING OUR UNDERSTANDING OF GOUT PATHOGENESIS. 2022 9 5479 33 RESVERATROL ATTENUATES CIGARETTE SMOKE EXTRACT INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY ACCELERATED LUNG AGING. SMOKING IS THE CRITICAL RISK FACTOR FOR COPD. CELLULAR SENESCENCE OF AIRWAY EPITHELIAL CELLS IS THE CYTOLOGICAL BASIS OF ACCELERATED LUNG AGING IN COPD, AND THE REGULATION OF MICRORNAS (MIRNAS) IS THE CENTRAL EPIGENETIC MECHANISM OF CELLULAR SENESCENCE. RESVERATROL (RES) IS A POLYPHENOL WITH ANTI-AGING PROPERTIES. THIS STUDY INVESTIGATED WHETHER RES ATTENUATES CIGARETTE SMOKE EXTRACT (CSE)-INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS (BEAS-2B) THROUGH THE MIR-34A/SIRT1/NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) PATHWAY. BEAS-2B CELLS WERE TREATED WITH RES, CSE AND TRANSFECTED WITH MIR-34A-5P MIMICS. CELLULAR SENESCENCE WAS EVALUATED BY SENESCENCE -RELATED BETA-GALACTOSIDASE (SA-BETA-GAL) STAINING AND EXPRESSION OF SENESCENCE-RELATED GENES (P16, P21, AND P53). THE EXPRESSIONS OF MIR-34A-5P, SIRT1, AND NF-KAPPAB P65 WERE EXAMINED USING QUANTITATIVE REAL TIME POLYMERASE CHAIN REACTION AND WESTERN BLOTTING. THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) WERE ASSESSED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. THE BINDING BETWEEN MIR-34A-5P AND SIRT1 WAS CONFIRMED BY DUAL-LUCIFERASE REPORTER ASSAY. THE RESULTS SHOWED THAT CSE DOSE-DEPENDENTLY DECREASED CELL VIABILITY AND ELEVATED CELLULAR SENESCENCE, CHARACTERIZED BY INCREASED SA-BETA-GAL STAINING AND SENESCENCE-RELATED GENE EXPRESSIONS (P16, P21, AND P53). FURTHER, CSE DOSE-DEPENDENTLY INCREASED THE EXPRESSION OF MIR-34A-5P AND SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN BEAS-2B CELLS. PRETREATMENT WITH RES INHIBITED CSE-INDUCED CELLULAR SENESCENCE AND SECRETION OF SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN A DOSE-DEPENDENT MANNER. MOREOVER, RES REVERSED THE CSE-INDUCED DOWN-REGULATION OF SIRT1 AND UP-REGULATION OF MIR-34A-5P AND NF-KAPPAB P65. SIRT1 IS A TARGET OF MIR-34A-5P. OVEREXPRESSION OF MIR-34A-5P VIA TRANSFECTION WITH MIR-34A-5P MIMIC IN BEAS-2B CELLS ATTENUATED THE INHIBITORY EFFECT OF RES ON CELLULAR SENESCENCE, ACCOMPANIED BY REVERSING THE EXPRESSION OF SIRT1 AND NF-KAPPAB P65. IN CONCLUSION, RES ATTENUATED CSE-INDUCED CELLULAR SENESCENCE IN BEAS-2B CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY, WHICH MAY PROVIDE A NEW APPROACH FOR COPD TREATMENT. 2022 10 5083 34 PICKING A BONE WITH WISP1 (CCN4): NEW STRATEGIES AGAINST DEGENERATIVE JOINT DISEASE. AS THE WORLD'S POPULATION CONTINUES TO AGE, IT IS ESTIMATED THAT DEGENERATIVE JOINT DISEASE DISORDERS SUCH AS OSTEOARTHRITIS WILL IMPACT AT LEAST 130 MILLION INDIVIDUALS THROUGHOUT THE GLOBE BY THE YEAR 2050. ADVANCED AGE, OBESITY, GENETICS, GENDER, BONE DENSITY, TRAUMA, AND A POOR LEVEL OF PHYSICAL ACTIVITY CAN LEAD TO THE ONSET AND PROGRESSION OF OSTEOARTHRITIS. HOWEVER, FACTORS THAT LEAD TO DEGENERATIVE JOINT DISEASE AND INVOLVE GENDER, GENETICS, EPIGENETIC MECHANISMS, AND ADVANCED AGE ARE NOT WITHIN THE CONTROL OF AN INDIVIDUAL. FURTHERMORE, CURRENT THERAPIES INCLUDING PAIN MANAGEMENT, IMPROVED NUTRITION, AND REGULAR PROGRAMS FOR EXERCISE DO NOT LEAD TO THE RESOLUTION OF OSTEOARTHRITIS. AS A RESULT, NEW AVENUES FOR TARGETING THE TREATMENT OF OSTEOARTHRITIS ARE DESPERATELY NEEDED. WNT1 INDUCIBLE SIGNALING PATHWAY PROTEIN 1 (WISP1), A MATRICELLULAR PROTEIN AND A DOWNSTREAM TARGET OF THE WINGLESS PATHWAY WNT1, IS ONE SUCH TARGET TO CONSIDER THAT GOVERNS CELLULAR PROTECTION, STEM CELL PROLIFERATION, AND TISSUE REGENERATION IN A NUMBER OF DISORDERS INCLUDING BONE DEGENERATION. HOWEVER, INCREASED WISP1 EXPRESSION ALSO HAS BEEN ASSOCIATED WITH THE PROGRESSION OF OSTEOARTHRITIS. WISP1 HAS AN INTRICATE RELATIONSHIP WITH A NUMBER OF PROLIFERATIVE AND PROTECTIVE PATHWAYS THAT INCLUDE PHOSPHOINOSITIDE 3-KINASE (PI 3-K), PROTEIN KINASE B (AKT), NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB), INTERLEUKIN -6 (IL-6), TRANSFORMING GROWTH FACTOR-BETA, MATRIX METALLOPROTEINASE, SMALL NON-CODING RIBONUCLEIC ACIDS (RNAS), SIRTUIN SILENT MATING TYPE INFORMATION REGULATION 2 HOMOLOG 1 (SACCHAROMYCES CEREVISIAE) (SIRT1), AND THE MECHANISTIC TARGET OF RAPAMYCIN (MTOR). TAKEN TOGETHER, THIS COMPLEX ASSOCIATION WISP1 HOLDS WITH THESE SIGNALING PATHWAYS NECESSITATES A FINE BIOLOGICAL REGULATION OF WISP1 ACTIVITY THAT CAN OFFSET THE PROGRESSION OF DEGENERATIVE JOINT DISEASE, BUT NOT LIMIT THE CELLULAR PROTECTIVE CAPABILITIES OF THE WISP1 PATHWAY. 2016 11 5489 30 REVERSING POST-INFECTIOUS EPIGENETIC-MEDIATED IMMUNE SUPPRESSION. THE IMMUNE RESPONSE MUST BALANCE THE PRO-INFLAMMATORY, CELL-MEDIATED CYTOTOXICITY WITH THE ANTI-INFLAMMATORY AND WOUND REPAIR RESPONSE. EPIGENETIC MECHANISMS MEDIATE THIS BALANCE AND LIMIT HOST IMMUNITY FROM INDUCING EXUBERANT COLLATERAL DAMAGE TO HOST TISSUE AFTER SEVERE AND CHRONIC INFECTIONS. HOWEVER, FOLLOWING TREATMENT FOR THESE INFECTIONS, INCLUDING SEPSIS, PNEUMONIA, HEPATITIS B, HEPATITIS C, HIV, TUBERCULOSIS (TB) OR SCHISTOSOMIASIS, DETRIMENTAL EPIGENETIC SCARS PERSIST, AND RESULT IN LONG-LASTING IMMUNE SUPPRESSION. THIS IS HYPOTHESIZED TO BE ONE OF THE CONTRIBUTING MECHANISMS EXPLAINING WHY SURVIVORS OF INFECTION HAVE INCREASED ALL-CAUSE MORTALITY AND INCREASED RATES OF UNRELATED SECONDARY INFECTIONS. THE MECHANISMS THAT INDUCE EPIGENETIC-MEDIATED IMMUNE SUPPRESSION HAVE BEEN DEMONSTRATED IN-VITRO AND IN ANIMAL MODELS. MODULATION OF THE AMP-ACTIVATED PROTEIN KINASE (AMPK)-MAMMALIAN TARGET OF RAPAMYCIN (MTOR), NUCLEAR FACTOR OF ACTIVATED T CELLS (NFAT) OR NUCLEAR RECEPTOR (NR4A) PATHWAYS IS ABLE TO BLOCK OR REVERSE THE DEVELOPMENT OF DETRIMENTAL EPIGENETIC SCARS. SIMILARLY, DRUGS THAT DIRECTLY MODIFY EPIGENETIC ENZYMES, SUCH AS THOSE THAT INHIBIT HISTONE DEACETYLASES (HDAC) INHIBITORS, DNA HYPOMETHYLATING AGENTS OR MODIFIERS OF THE NUCLEOSOME REMODELING AND DNA METHYLATION (NURD) COMPLEX OR POLYCOMB REPRESSIVE COMPLEX (PRC) HAVE DEMONSTRATED CAPACITY TO RESTORE HOST IMMUNITY IN THE SETTING OF CANCER-, LCMV- OR MURINE SEPSIS-INDUCED EPIGENETIC-MEDIATED IMMUNE SUPPRESSION. A THIRD CLINICALLY FEASIBLE STRATEGY FOR REVERSING DETRIMENTAL EPIGENETIC SCARS INCLUDES BIOENGINEERING APPROACHES TO EITHER DIRECTLY REVERSE THE DETRIMENTAL EPIGENETIC MARKS OR TO MODIFY THE EPIGENETIC ENZYMES OR TRANSCRIPTION FACTORS THAT INDUCE DETRIMENTAL EPIGENETIC SCARS. EACH OF THESE APPROACHES, ALONE OR IN COMBINATION, HAVE ABLATED OR REVERSED DETRIMENTAL EPIGENETIC MARKS IN IN-VITRO OR IN ANIMAL MODELS; TRANSLATIONAL STUDIES ARE NOW REQUIRED TO EVALUATE CLINICAL APPLICABILITY. 2021 12 4582 31 N-TERMINAL BET BROMODOMAIN INHIBITORS DISRUPT A BRD4-P65 INTERACTION AND REDUCE INDUCIBLE NITRIC OXIDE SYNTHASE TRANSCRIPTION IN PANCREATIC BETA-CELLS. CHRONIC INFLAMMATION OF PANCREATIC ISLETS IS A KEY DRIVER OF BETA-CELL DAMAGE THAT CAN LEAD TO AUTOREACTIVITY AND THE EVENTUAL ONSET OF AUTOIMMUNE DIABETES (T1D). IN THE ISLET, ELEVATED LEVELS OF PROINFLAMMATORY CYTOKINES INDUCE THE TRANSCRIPTION OF THE INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) GENE, NOS2, ULTIMATELY RESULTING IN INCREASED NITRIC OXIDE (NO). EXCESSIVE OR PROLONGED EXPOSURE TO NO CAUSES BETA-CELL DYSFUNCTION AND FAILURE ASSOCIATED WITH DEFECTS IN MITOCHONDRIAL RESPIRATION. RECENT STUDIES SHOWED THAT INHIBITION OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) FAMILY OF PROTEINS, A DRUGGABLE CLASS OF EPIGENETIC READER PROTEINS, PREVENTS THE ONSET AND PROGRESSION OF T1D IN THE NON-OBESE DIABETIC MOUSE MODEL. WE HYPOTHESIZED THAT BET PROTEINS CO-ACTIVATE TRANSCRIPTION OF CYTOKINE-INDUCED INFLAMMATORY GENE TARGETS IN BETA-CELLS AND THAT SELECTIVE, CHEMOTHERAPEUTIC INHIBITION OF BET BROMODOMAINS COULD REDUCE SUCH TRANSCRIPTION. HERE, WE INVESTIGATED THE ABILITY OF BET BROMODOMAIN SMALL MOLECULE INHIBITORS TO REDUCE THE BETA-CELL RESPONSE TO THE PROINFLAMMATORY CYTOKINE INTERLEUKIN 1 BETA (IL-1BETA). BET BROMODOMAIN INHIBITION ATTENUATED IL-1BETA-INDUCED TRANSCRIPTION OF THE INFLAMMATORY MEDIATOR NOS2 AND CONSEQUENT INOS PROTEIN AND NO PRODUCTION. REDUCED NOS2 TRANSCRIPTION IS CONSISTENT WITH INHIBITION OF NF-KAPPAB FACILITATED BY DISRUPTING THE INTERACTION OF A SINGLE BET FAMILY MEMBER, BRD4, WITH THE NF-KAPPAB SUBUNIT, P65. USING RECENTLY REPORTED SELECTIVE INHIBITORS OF THE FIRST AND SECOND BET BROMODOMAINS, INHIBITION OF ONLY THE FIRST BROMODOMAIN WAS NECESSARY TO REDUCE THE INTERACTION OF BRD4 WITH P65 IN BETA-CELLS. MOREOVER, INHIBITION OF THE FIRST BROMODOMAIN WAS SUFFICIENT TO MITIGATE IL-1BETA-DRIVEN DECREASES IN MITOCHONDRIAL OXYGEN CONSUMPTION RATES AND BETA-CELL VIABILITY. BY IDENTIFYING A ROLE FOR THE INTERACTION BETWEEN BRD4 AND P65 IN CONTROLLING THE RESPONSE OF BETA-CELLS TO PROINFLAMMATORY CYTOKINES, WE PROVIDE MECHANISTIC INFORMATION ON HOW BET BROMODOMAIN INHIBITION CAN DECREASE INFLAMMATION. THESE STUDIES ALSO SUPPORT THE POTENTIAL THERAPEUTIC APPLICATION OF MORE SELECTIVE BET BROMODOMAIN INHIBITORS IN ATTENUATING BETA-CELL INFLAMMATION. 2022 13 2969 43 GENETIC AND EPIGENETIC REGULATION OF THE INNATE IMMUNE RESPONSE TO GOUT. GOUT IS A DISEASE CAUSED BY URIC ACID (UA) ACCUMULATION IN THE JOINTS, CAUSING INFLAMMATION. TWO UA FORMS - MONOSODIUM URATE (MSU) AND SOLUBLE URIC ACID (SUA) HAVE BEEN SHOWN TO INTERACT PHYSICALLY WITH INFLAMMASOMES, ESPECIALLY WITH THE NOD-LIKE RECEPTOR (NLR) FAMILY PYRIN DOMAIN CONTAINING 3 (NLRP3), ALBEIT THE ROLE OF THE IMMUNE RESPONSE TO UA IS POORLY UNDERSTOOD, GIVEN THAT ASYMPTOMATIC HYPERURICEMIA DOES ALSO EXIST. MACROPHAGE PHAGOCYTOSIS OF UA ACTIVATE NLRP3, LEAD TO CYTOKINES RELEASE, AND ULTIMATELY, LEAD TO CHEMOATTRACT NEUTROPHILS AND LYMPHOCYTES TO THE GOUT FLARE JOINT SPOT. GENETIC VARIANTS OF INFLAMMASOME GENES AND OF GENES ENCODING THEIR MOLECULAR PARTNERS MAY INFLUENCE HYPERURICEMIA AND GOUT SUSCEPTIBILITY, WHILE ALSO INFLUENCING OTHER COMORBIDITIES SUCH AS METABOLIC SYNDROME AND CARDIOVASCULAR DISEASES. IN THIS REVIEW, WE SUMMARIZE THE INFLAMMATORY RESPONSES IN ACUTE AND CHRONIC GOUT, SPECIFICALLY FOCUSING ON INNATE IMMUNE CELL MECHANISMS AND GENETIC AND EPIGENETIC CHARACTERISTICS OF PARTICIPATING MOLECULES. UNPRECEDENTLY, A NOVEL UA BINDING PROTEIN - THE NEURONAL APOPTOSIS INHIBITOR PROTEIN (NAIP) - IS SUGGESTED AS RESPONSIBLE FOR THE ASYMPTOMATIC HYPERURICEMIA PARADOX.ABBREVIATION: BETA2-INTEGRINS: LEUKOCYTE-SPECIFIC ADHESION MOLECULES; ABCG2: ATP-BINDING CASSETE FAMILY/BREAST CANCER-RESISTANT PROTEIN; ACR: AMERICAN COLLEGE OF RHEUMATOLOGY; AIM2: ABSENT IN MELANOMA 2, TYPE OF PATTERN RECOGNITION RECEPTOR; ALPK1: ALPHA-PROTEIN KINASE 1; ANGPTL2: ANGIOPOIETIN-LIKE PROTEIN 2; ASC: APOPTOSIS-ASSOCIATED SPECK-LIKE PROTEIN; BIR: BACULOVIRUS INHIBITOR OF APOPTOSIS PROTEIN REPEAT; BIRC1: BACULOVIRUS IAP REPEAT-CONTAINING PROTEIN 1; BIRC2: BACULOVIRAL IAP REPEAT-CONTAINING PROTEIN 2; C5A: COMPLEMENT ANAPHYLATOXIN; CAMP: CYCLIC ADENOSINE MONOPHOSPHATE; CARD: CASPASE ACTIVATION AND RECRUITMENT DOMAINS; CARD8: CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 8; CASP1: CASPASE 1; CCL3: CHEMOKINE (C-C MOTIF) LIGAND 3; CD14: CLUSTER OF DIFFERENTIATION 14; CD44: CLUSTER OF DIFFERENTIATION 44; CG05102552: DNA-METHYLATION SITE, USUALLY CYTOSINE FOLLOWED BY GUANINE NUCLEOTIDES; CONTAINS ARBITRARY IDENTIFICATION CODE; CIDEC: CELL DEATH-INDUCING DNA FRAGMENTATION FACTOR-LIKE EFFECTOR FAMILY; CKD: CHRONIC KIDNEY DISEASE; CNV: COPY NUMBER VARIATION; CPT1A: CARNITINE PALMITOYL TRANSFERASE - TYPE 1A; CXCL1: CHEMOKINE (CXC MOTIF) LIGAND 1; DAMPS: DAMAGE ASSOCIATED MOLECULAR PATTERNS; DC: DENDRITIC CELLS; DNMT(1): MAINTENANCE DNA METHYLTRANSFERASE; EQTL: EXPRESSION QUANTITATIVE TRAIT LOCI; ERK1: EXTRACELLULAR SIGNAL-REGULATED KINASE 1; ERK2: EXTRACELLULAR SIGNAL-REGULATED KINASE 2; EULAR: EUROPEAN LEAGUE AGAINST RHEUMATISM; GMCSF: GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR; GWAS: GLOBAL WIDE ASSOCIATION STUDIES; H3K27ME3: TRI-METHYLATION AT THE 27TH LYSINE RESIDUE OF THE HISTONE H3 PROTEIN; H3K4ME1: MONO-METHYLATION AT THE 4TH LYSINE RESIDUE OF THE HISTONE H3 PROTEIN; H3K4ME3: TRI-METHYLATION AT THE 4TH LYSINE RESIDUE OF THE HISTONE H3 PROTEIN; HOTAIR: HUMAN GENE LOCATED BETWEEN HOXC11 AND HOXC12 ON CHROMOSOME 12; IKAPPABALPHA: CYTOPLASMATIC PROTEIN/NF-KAPPAB TRANSCRIPTION INHIBITOR; IAP: INHIBITORY APOPTOSIS PROTEIN; IFNGAMMA: INTERFERON GAMMA; IL-1BETA: INTERLEUKIN 1 BETA; IL-12: INTERLEUKIN 12; IL-17: INTERLEUKIN 17; IL18: INTERLEUKIN 18; IL1R1: INTERLEUKIN-1 RECEPTOR; IL-1RA: INTERLEUKIN-1 RECEPTOR ANTAGONIST; IL-22: INTERLEUKIN 22; IL-23: INTERLEUKIN 23; IL23R: INTERLEUKIN 23 RECEPTOR; IL-33: INTERLEUKIN 33; IL-6: INTERLEUKIN 6; IMP: INOSINE MONOPHOSPHATE; INSIG1: INSULIN-INDUCED GENE 1; JNK1: C-JUN N-TERMINAL KINASE 1; LNCRNA: LONG NON-CODING RIBONUCLEIC ACID; LRR: LEUCINE-RICH REPEATS; MIR: MATURE NON-CODING MICRORNAS MEASURING FROM 20 TO 24 NUCLEOTIDES, ANIMAL ORIGIN; MIR-1: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-145: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-146A: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE, "A" STANDS FOR MIR FAMILY; "A" FAMILY PRESENTS SIMILAR MIR SEQUENCE TO "B" FAMILY, BUT DIFFERENT PRECURSORS; MIR-20B: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; "B" STANDS FOR MIR FAMILY; "B" FAMILY PRESENTS SIMILAR MIR SEQUENCE TO "A" FAMILY, BUT DIFFERENT PRECURSORS; MIR-221: MIR - FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-221-5P: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; "5P" INDICATES DIFFERENT MATURE MIRNAS GENERATED FROM THE 5' ARM OF THE PRE-MIRNA HAIRPIN; MIR-223: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-223-3P: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; "3P" INDICATES DIFFERENT MATURE MIRNAS GENERATED FROM THE 3' ARM OF THE PRE-MIRNA HAIRPIN; MIR-22-3P: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE, "3P" INDICATES DIFFERENT MATURE MIRNAS GENERATED FROM THE 3' ARM OF THE PRE-MIRNA HAIRPIN; MLKL: MIXED LINEAGE KINASE DOMAIN-LIKE PSEUDO KINASE; MM2P: INDUCTOR OF M2-MACROPHAGE POLARIZATION; MSU: MONOSODIUM URATE; MTOR: MAMMALIAN TARGET OF RAPAMYCIN; MYD88: MYELOID DIFFERENTIATION PRIMARY RESPONSE 88; N-3-PUFAS: N-3-POLYUNSATURATED FATTY-ACIDS; NACHT: ACRONYM FOR NAIP (NEURONAL APOPTOSIS INHIBITOR PROTEIN), C2TA (MHC CLASS 2 TRANSCRIPTION ACTIVATOR), HET-E (INCOMPATIBILITY LOCUS PROTEIN FROM PODOSPORA ANSERINA) AND TP1 (TELOMERASE-ASSOCIATED PROTEIN); NAIP: NEURONAL APOPTOSIS INHIBITORY PROTEIN (HUMAN); NAIP1: NEURONAL APOPTOSIS INHIBITORY PROTEIN TYPE 1 (MURINE); NAIP5: NEURONAL APOPTOSIS INHIBITORY PROTEIN TYPE 5 (MURINE); NAIP6: NEURONAL APOPTOSIS INHIBITORY PROTEIN TYPE 6 (MURINE); NBD: NUCLEOTIDE-BINDING DOMAIN; NEK7: SMALLEST NIMA-RELATED KINASE; NET: NEUTROPHIL EXTRACELLULAR TRAPS; NF-KAPPAB: NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS; NFIL3: NUCLEAR-FACTOR, INTERLEUKIN 3 REGULATED PROTEIN; NIIMA: NETWORK OF IMMUNITY IN INFECTION, MALIGNANCY, AND AUTOIMMUNITY; NLR: NOD-LIKE RECEPTOR; NLRA: NOD-LIKE RECEPTOR NLRA CONTAINING ACIDIC DOMAIN; NLRB: NOD-LIKE RECEPTOR NLRA CONTAINING BIR DOMAIN; NLRC: NOD-LIKE RECEPTOR NLRA CONTAINING CARD DOMAIN; NLRC4: NOD-LIKE RECEPTOR FAMILY CARD DOMAIN CONTAINING 4; NLRP: NOD-LIKE RECEPTOR NLRA CONTAINING PYD DOMAIN; NLRP1: NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN, LEUCINE-RICH REPEAT, AND PYRIN DOMAIN CONTAINING 1; NLRP12: NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN, LEUCINE-RICH REPEAT, AND PYRIN DOMAIN CONTAINING 12; NLRP3: NOD-LIKE RECEPTOR FAMILY PYRIN DOMAIN CONTAINING 3; NOD2: NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN; NRBP1: NUCLEAR RECEPTOR-BINDING PROTEIN; NRF2: NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2; OR: ODDS RATIO; P2X: GROUP OF MEMBRANE ION CHANNELS ACTIVATED BY THE BINDING OF EXTRACELLULAR; P2X7: P2X PURINOCEPTOR 7 GENE; P38: MEMBER OF THE MITOGEN-ACTIVATED PROTEIN KINASE FAMILY; PAMPS: PATHOGEN ASSOCIATED MOLECULAR PATTERS; PBMC: PERIPHERAL BLOOD MONONUCLEAR CELLS; PGGT1B: GERANYLGERANYL TRANSFERASE TYPE-1 SUBUNIT BETA; PHGDH: PHOSPHOGLYCERATE DEHYDROGENASE; PI3-K: PHOSPHO-INOSITOL; PPARGAMMA: PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA; PPARGC1B: PEROXISOME PROLIFERATIVE ACTIVATED RECEPTOR, GAMMA, COACTIVATOR 1 BETA; PR3: PROTEINASE 3 ANTIGEN; PRO-CASP1: INACTIVE PRECURSOR OF CASPASE 1; PRO-IL1BETA: INACTIVE PRECURSOR OF INTERLEUKIN 1 BETA; PRR: PATTERN RECOGNITION RECEPTORS; PYD: PYRIN DOMAIN; RAPTOR: REGULATORY ASSOCIATED PROTEIN OF MTOR COMPLEX 1; RAS: RENIN-ANGIOTENSIN SYSTEM; REDD1: REGULATED IN DNA DAMAGE AND DEVELOPMENT 1; ROS: REACTIVE OXYGEN SPECIES; RS000*G: SINGLE NUCLEAR POLYMORPHISM, "*G" IS RELATED TO SNP WHERE REPLACED NUCLEOTIDE IS GUANINE, USUALLY PRECEDED BY AN ID NUMBER; SLC2A9: SOLUTE CARRIER FAMILY 2, MEMBER 9; SLC7A11: SOLUTE CARRIER FAMILY 7, MEMBER 11; SMA: SMOOTH MUSCULAR ATROPHY; SMAC: SECOND MITOCHONDRIAL-DERIVED ACTIVATOR OF CASPASES; SNP: SINGLE NUCLEAR POLYMORPHISM; SP3: SPECIFICITY PROTEIN 3; ST2: SERUM STIMULATION-2; STK11: SERINE/THREONINE KINASE 11; SUA: SOLUBLE URIC ACID; SYK: SPLEEN TYROSINE KINASE; TAK1: TRANSFORMING GROWTH FACTOR BETA ACTIVATED KINASE; TH1: TYPE 1 HELPER T CELLS; TH17: TYPE 17 HELPER T CELLS; TH2: TYPE 2 HELPER T CELLS; TH22: TYPE 22 HELPER T CELLS; TLR: TOOL-LIKE RECEPTOR; TLR2: TOLL-LIKE RECEPTOR 2; TLR4: TOLL-LIKE RECEPTOR 4; TNFALPHA: TUMOR NECROSIS FACTOR ALPHA; TNFR1: TUMOR NECROSIS FACTOR RECEPTOR 1; TNFR2: TUMOR NECROSIS FACTOR RECEPTOR 2; UA: URIC ACID; UBAP1: UBIQUITIN ASSOCIATED PROTEIN; ULT: URATE-LOWERING THERAPY; URAT1: URATE TRANSPORTER 1; VDAC1: VOLTAGE-DEPENDENT ANION-SELECTIVE CHANNEL 1. 2023 14 4044 24 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 15 141 27 ABERRANT DNA METHYLATION OF MTOR PATHWAY GENES PROMOTES INFLAMMATORY ACTIVATION OF IMMUNE CELLS IN DIABETIC KIDNEY DISEASE. DNA METHYLATION HAS BEEN IMPLICATED IN THE PATHOGENESIS OF DIABETIC KIDNEY DISEASE (DKD), BUT THE UNDERLYING MECHANISMS REMAIN UNCLEAR. IN THIS STUDY, WE TESTED THE HYPOTHESIS THAT ABERRANT DNA METHYLATION IN PERIPHERAL IMMUNE CELLS CONTRIBUTES TO DKD PROGRESSION. WE SHOWED THAT LEVELS OF DNA METHYLTRANSFERASE 1 (DNMT1), A KEY ENZYME FOR DNA METHYLATION, WERE INCREASED ALONG WITH INFLAMMATORY ACTIVITY OF PERIPHERAL BLOOD MONONUCLEAR CELLS IN DKD PATIENTS. INHIBITION OF DNMT1 WITH 5-AZA-2'-DEOXYCYTIDINE (5-AZA) MARKEDLY INCREASED THE PROPORTION OF CD4(+)CD25(+) REGULATORY T CELLS IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN CULTURE AND IN DIABETIC ANIMALS. ADOPTIVE TRANSFER OF IMMUNE CELLS FROM 5-AZA-TREATED ANIMALS SHOWED BENEFICIAL EFFECTS ON THE HOST IMMUNE SYSTEM, RESULTING IN A SIGNIFICANT IMPROVEMENT OF DKD. USING GENOME-WIDE DNA METHYLATION ASSAYS, WE IDENTIFIED THE DIFFERENTIALLY METHYLATED CYTOSINES IN THE PROMOTER REGIONS OF MAMMALIAN TARGET OF RAPAMYCIN (MTOR) REGULATORS IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF DIABETIC PATIENTS. FURTHER, MRNA ARRAYS CONFIRMED THE CONSISTENT INDUCTION OF GENES EXPRESSED IN THE MTOR PATHWAY. IMPORTANTLY, DOWN-REGULATION OF DNMT1 EXPRESSION VIA RNA INTERFERENCE RESULTED IN PROMINENT CYTOSINE DEMETHYLATION OF MTOR NEGATIVE REGULATORS AND SUBSEQUENT DECREASE OF MTOR ACTIVITY. LASTLY, MODULATION OF MTOR RESULTED IN CHANGES IN THE EFFECT OF 5-AZA ON DIABETIC IMMUNE CELLS. THUS, UP-REGULATION OF DNMT1 IN DIABETIC IMMUNE CELLS INDUCES ABERRANT CYTOSINE METHYLATION OF THE UPSTREAM REGULATORS OF MTOR, LEADING TO PATHOGENIC ACTIVATION OF THE MTOR PATHWAY AND CONSEQUENT INFLAMMATION IN DIABETIC KIDNEYS. HENCE, THIS STUDY HIGHLIGHTS THERAPEUTIC POTENTIAL OF TARGETING EPIGENETIC EVENTS IN IMMUNE SYSTEM FOR TREATING DKD. 2019 16 4304 29 MICRORNA-223 PROTECTS NEURONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. MULTIPLE SCLEROSIS IS A CHRONIC INFLAMMATORY, DEMYELINATING, AND NEURODEGENERATIVE DISEASE AFFECTING THE BRAIN, SPINAL CORD AND OPTIC NERVES. NEURONAL DAMAGE IS TRIGGERED BY VARIOUS HARMFUL FACTORS THAT ENGAGE DIVERSE SIGNALLING CASCADES IN NEURONS; THUS, THERAPEUTIC APPROACHES TO PROTECT NEURONS WILL NEED TO FOCUS ON AGENTS THAT CAN TARGET MULTIPLE BIOLOGICAL PROCESSES. WE HAVE THEREFORE FOCUSED OUR ATTENTION ON MICRORNAS: SMALL NON-CODING RNAS THAT PRIMARILY FUNCTION AS POST-TRANSCRIPTIONAL REGULATORS THAT TARGET MESSENGER RNAS AND REPRESS THEIR TRANSLATION INTO PROTEINS. A SINGLE MICRORNA CAN TARGET MANY FUNCTIONALLY RELATED MESSENGER RNAS MAKING MICRORNAS POWERFUL EPIGENETIC REGULATORS. DYSREGULATION OF MICRORNAS HAS BEEN DESCRIBED IN MANY NEURODEGENERATIVE DISEASES INCLUDING MULTIPLE SCLEROSIS. HERE, WE REPORT THAT TWO MICRORNAS, MIR-223-3P AND MIR-27A-3P, ARE UPREGULATED IN NEURONS IN THE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS MOUSE MODEL OF CNS INFLAMMATION AND IN GREY MATTER-CONTAINING MULTIPLE SCLEROSIS LESIONS. PRIOR WORK HAS SHOWN PERIPHERAL BLOOD MONONUCLEAR CELL CONDITIONED MEDIA CAUSES SUBLETHAL DEGENERATION OF NEURONS IN CULTURE. WE FIND OVEREXPRESSION OF MIR-27A-3P OR MIR-223-3P PROTECTS DISSOCIATED CORTICAL NEURONS FROM CONDITION MEDIA MEDIATED DEGENERATION. INTRODUCTION OF MIR-223-3P IN VIVO IN MOUSE RETINAL GANGLION CELLS PROTECTS THEIR AXONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. IN SILICO ANALYSIS REVEALED THAT MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING ARE ENRICHED AS MIR-27A-3P AND MIR-223-3P TARGETS. WE OBSERVE THAT ANTAGONISM OF NMDA AND AMPA TYPE GLUTAMATE RECEPTORS PROTECTS NEURONS FROM CONDITION MEDIA DEPENDENT DEGENERATION. OUR RESULTS SUGGEST THAT MIR-223-3P AND MIR-27A-3P ARE UPREGULATED IN RESPONSE TO INFLAMMATION TO MEDIATE A COMPENSATORY NEUROPROTECTIVE GENE EXPRESSION PROGRAM THAT DESENSITIZES NEURONS TO GLUTAMATE BY TARGETING MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING. 2019 17 6456 29 THYMOSIN BETA4 PREVENTS OXIDATIVE STRESS, INFLAMMATION, AND FIBROSIS IN ETHANOL- AND LPS-INDUCED LIVER INJURY IN MICE. THYMOSIN BETA 4 (TBETA4), AN ACTIN-SEQUESTERING PROTEIN, IS INVOLVED IN TISSUE DEVELOPMENT AND REGENERATION. IT PREVENTS INFLAMMATION AND FIBROSIS IN SEVERAL TISSUES. WE INVESTIGATED THE ROLE OF TBETA4 IN CHRONIC ETHANOL- AND ACUTE LIPOPOLYSACCHARIDE- (LPS-) INDUCED MOUSE LIVER INJURY. C57BL/6 MICE WERE FED 5% ETHANOL IN LIQUID DIET FOR 4 WEEKS PLUS BINGE ETHANOL (5 G/KG, GAVAGE) WITH OR WITHOUT LPS (2 MG/KG, INTRAPERITONEAL) FOR 6 HOURS. TBETA4 (1 MG/KG, INTRAPERITONEAL) WAS ADMINISTERED FOR 1 WEEK. WE DEMONSTRATED THAT TBETA4 PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN LIVER INJURY MARKERS AS WELL AS CHANGES IN LIVER PATHOLOGY. IT ALSO PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN OXIDATIVE STRESS BY DECREASING ROS AND LIPID PEROXIDATION AND INCREASING THE ANTIOXIDANTS, REDUCED GLUTATHIONE AND MANGANESE-DEPENDENT SUPEROXIDE DISMUTASE. IT ALSO PREVENTED THE ACTIVATION OF NUCLEAR FACTOR KAPPA B BY BLOCKING THE PHOSPHORYLATION OF THE INHIBITORY PROTEIN, IKAPPAB, THEREBY PREVENTED PROINFLAMMATORY CYTOKINE PRODUCTION. MOREOVER, TBETA4 PREVENTED FIBROGENESIS BY SUPPRESSING THE EPIGENETIC REPRESSOR, METHYL-CPG-BINDING PROTEIN 2, THAT COORDINATELY REVERSED THE EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AND DOWNREGULATED FIBROGENIC GENES, PLATELET-DERIVED GROWTH FACTOR-BETA RECEPTOR, ALPHA-SMOOTH MUSCLE ACTIN, COLLAGEN 1, AND FIBRONECTIN, RESULTING IN REDUCED FIBROSIS. OUR DATA SUGGEST THAT TBETA4 HAS ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTIFIBROTIC POTENTIAL DURING ALCOHOLIC LIVER INJURY. 2018 18 4211 28 METFORMIN FOR CARDIOVASCULAR PROTECTION, INFLAMMATORY BOWEL DISEASE, OSTEOPOROSIS, PERIODONTITIS, POLYCYSTIC OVARIAN SYNDROME, NEURODEGENERATION, CANCER, INFLAMMATION AND SENESCENCE: WHAT IS NEXT? DIABETES IS ACCOMPANIED BY SEVERAL COMPLICATIONS. HIGHER PREVALENCE OF CANCERS, CARDIOVASCULAR DISEASES, CHRONIC KIDNEY DISEASE (CKD), OBESITY, OSTEOPOROSIS, AND NEURODEGENERATIVE DISEASES HAS BEEN REPORTED AMONG PATIENTS WITH DIABETES. METFORMIN IS THE OLDEST ORAL ANTIDIABETIC DRUG AND CAN IMPROVE COEXISTING COMPLICATIONS OF DIABETES. CLINICAL TRIALS AND OBSERVATIONAL STUDIES UNCOVERED THAT METFORMIN CAN REMARKABLY PREVENT OR ALLEVIATE CARDIOVASCULAR DISEASES, OBESITY, POLYCYSTIC OVARIAN SYNDROME (PCOS), OSTEOPOROSIS, CANCER, PERIODONTITIS, NEURONAL DAMAGE AND NEURODEGENERATIVE DISEASES, INFLAMMATION, INFLAMMATORY BOWEL DISEASE (IBD), TUBERCULOSIS, AND COVID-19. IN ADDITION, METFORMIN HAS BEEN PROPOSED AS AN ANTIAGING AGENT. NUMEROUS MECHANISMS WERE SHOWN TO BE INVOLVED IN THE PROTECTIVE EFFECTS OF METFORMIN. METFORMIN ACTIVATES THE LKB1/AMPK PATHWAY TO INTERACT WITH SEVERAL INTRACELLULAR SIGNALING PATHWAYS AND MOLECULAR MECHANISMS. THE DRUG MODIFIES THE BIOLOGIC FUNCTION OF NF-KAPPAB, PI3K/AKT/MTOR, SIRT1/PGC-1ALPHA, NLRP3, ERK, P38 MAPK, WNT/BETA-CATENIN, NRF2, JNK, AND OTHER MAJOR MOLECULES IN THE INTRACELLULAR SIGNALING NETWORK. IT ALSO REGULATES THE EXPRESSION OF NONCODING RNAS. THEREBY, METFORMIN CAN REGULATE METABOLISM, GROWTH, PROLIFERATION, INFLAMMATION, TUMORIGENESIS, AND SENESCENCE. ADDITIONALLY, METFORMIN MODULATES IMMUNE RESPONSE, AUTOPHAGY, MITOPHAGY, ENDOPLASMIC RETICULUM (ER) STRESS, AND APOPTOSIS AND EXERTS EPIGENETIC EFFECTS. FURTHERMORE, METFORMIN PROTECTS AGAINST OXIDATIVE STRESS AND GENOMIC INSTABILITY, PRESERVES TELOMERE LENGTH, AND PREVENTS STEM CELL EXHAUSTION. IN THIS REVIEW, THE PROTECTIVE EFFECTS OF METFORMIN ON EACH DISEASE WILL BE DISCUSSED USING THE RESULTS OF RECENT META-ANALYSES, CLINICAL TRIALS, AND OBSERVATIONAL STUDIES. THEREAFTER, IT WILL BE METICULOUSLY EXPLAINED HOW METFORMIN REPROGRAMS INTRACELLULAR SIGNALING PATHWAYS AND ALTERS MOLECULAR AND CELLULAR INTERACTIONS TO MODIFY THE CLINICAL PRESENTATIONS OF SEVERAL DISEASES. 2021 19 1105 30 COMBINED INHIBITION OF HISTONE DEACETYLASES AND BET FAMILY PROTEINS AS EPIGENETIC THERAPY FOR NERVE INJURY-INDUCED NEUROPATHIC PAIN. CURRENT TREATMENTS FOR NEUROPATHIC PAIN HAVE OFTEN MODERATE EFFICACY AND PRESENT UNWANTED EFFECTS SHOWING THE NEED TO DEVELOP EFFECTIVE THERAPIES. ACCUMULATING EVIDENCE SUGGESTS THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN CHRONIC PAIN AND THE ANALGESIC ACTIVITY OF HISTONE DEACETYLASES (HDACS) INHIBITORS IS DOCUMENTED. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT INTERACT WITH ACETYLATED LYSINE RESIDUES ON HISTONES, BUT LITTLE IS KNOWN ABOUT THEIR IMPLICATION IN NEUROPATHIC PAIN. THUS, THE CURRENT STUDY WAS AIMED TO INVESTIGATE THE EFFECT OF THE COMBINATION OF HDAC AND BET INHIBITORS IN THE SPARED NERVE INJURY (SNI) MODEL IN MICE. INTRANASAL ADMINISTRATION OF I-BET762 (BET INHIBITOR) OR SAHA (HDAC INHIBITOR) ATTENUATED THERMAL AND MECHANICAL HYPERSENSITIVITY AND THIS ANTIALLODYNIC ACTIVITY WAS IMPROVED BY CO-ADMINISTRATION OF BOTH DRUGS. SPINAL CORD SECTIONS OF SNI MICE SHOWED AN INCREASED EXPRESSION OF HDAC1 AND BRD4 PROTEINS AND COMBINATION PRODUCED A STRONGER REDUCTION COMPARED TO EACH EPIGENETIC AGENT ALONE. SAHA AND I-BET762, ADMINISTERED ALONE OR IN COMBINATION, COUNTERACTED THE SNI-INDUCED MICROGLIA ACTIVATION BY INHIBITING THE EXPRESSION OF IBA1, CD11B, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS), THE ACTIVATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION-1 (STAT1) WITH COMPARABLE EFFICACY. CONVERSELY, THE EPIGENETIC INHIBITORS SHOWED A MODEST EFFECT ON SPINAL PROINFLAMMATORY CYTOKINES CONTENT THAT WAS SIGNIFICANTLY POTENTIATED BY THEIR COMBINATION. PRESENT RESULTS INDICATE A KEY ROLE OF ACETYLATED HISTONES AND THEIR RECRUITMENT BY BET PROTEINS ON MICROGLIA-MEDIATED SPINAL NEUROINFLAMMATION. TARGETING NEUROPATHIC PAIN WITH THE COMBINATION OF HDAC AND BET INHIBITORS MAY REPRESENT A PROMISING NEW THERAPEUTIC OPTION. 2021 20 4303 36 MICRORNA-223 INHIBITS TISSUE FACTOR EXPRESSION IN VASCULAR ENDOTHELIAL CELLS. OBJECTIVE: ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY PROCESS, IN WHICH VASCULAR ENDOTHELIAL CELLS (ECS) BECOME DYSFUNCTIONAL OWING TO THE EFFECTS OF CHEMICAL SUBSTANCES, SUCH AS INFLAMMATORY FACTOR AND GROWTH FACTORS. TISSUE FACTOR (TF) EXPRESSION IS INDUCED BY THE ABOVE CHEMICAL SUBSTANCES IN ACTIVATED ECS. TF INITIATES THROMBOSIS ON DISRUPTED ATHEROSCLEROTIC PLAQUES WHICH PLAYS AN ESSENTIAL ROLE DURING THE ONSET OF ACUTE CORONARY SYNDROMES (ACS). INCREASING EVIDENCES SUGGEST THE IMPORTANT ROLE OF MICRORNAS AS EPIGENETIC REGULATORS OF ATHEROSCLEROTIC DISEASE. THE AIM OF OUR STUDY IS TO IDENTIFY IF MICRORNA-223 (MIR-223) TARGETS TF IN ECS. METHODS AND RESULTS: BIOINFORMATIC ANALYSIS SHOWED THAT TF IS A TARGET CANDIDATE OF MIR-223. WESTERN BLOTTING ANALYSIS REVEALED THAT TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA) INCREASED TF EXPRESSION IN AORTA OF C57BL/6J MICE AND CULTURED ECS (EA.HY926 CELLS AND HUVEC) AFTER 4 H TREATMENT. IN TNF-ALPHA TREATED ECS, TF MRNA WAS ALSO INCREASED MEASURED BY REAL-TIME PCR. REAL-TIME PCR RESULTS SHOWED THAT MIR-223 LEVELS WERE DOWNREGULATED IN TNF-ALPHA-TREATED AORTA OF C57BL/6J MICE AND CULTURED ECS. TRANSFECTION OF ECS WITH MIR-223 MIMIC OR MIR-223 INHIBITOR MODIFIED TF EXPRESSION BOTH IN MRNA AND PROTEIN LEVELS. LUCIFERASE ASSAYS CONFIRMED THAT MIR-223 SUPPRESSED TF EXPRESSION BY BINDING TO THE SEQUENCE OF TF 3'-UNTRANSLATED REGIONS (3'UTR). TF PROCOAGULANT ACTIVITY WAS INHIBITED BY OVEREXPRESSING MIR-223 WITH OR WITHOUT TNF-ALPHA STIMULATION. CONCLUSIONS: MIR-223-MEDIATED SUPPRESSION OF TF EXPRESSION PROVIDES A NOVEL MOLECULAR MECHANISM FOR THE REGULATION OF COAGULATION CASCADE, AND SUGGESTS A CLUE AGAINST THROMBOGENESIS DURING THE PROCESS OF ATHEROSCLEROTIC PLAQUE RUPTURE. 2014