1   664 98 BLOOD REFLUX-INDUCED EPIGENETIC FACTORS HDACS AND DNMTS ARE ASSOCIATED WITH THE DEVELOPMENT OF HUMAN CHRONIC VENOUS DISEASE. BLOOD REFLUX AND METABOLIC REGULATION PLAY IMPORTANT ROLES IN CHRONIC VENOUS DISEASE (CVD) DEVELOPMENT. HISTONE DEACETYLASES (HDACS) AND DNA METHYLTRANSFERASES (DNMTS) SERVE AS REPRESSORS THAT INHIBIT METABOLIC SIGNALING, WHICH IS INDUCED BY PROATHEROGENIC FLOW TO PROMOTE AORTIC ENDOTHELIAL CELL (EC) DYSFUNCTION AND ATHEROSCLEROSIS. THE AIM OF THIS STUDY WAS TO ELUCIDATE THE RELATIONSHIP BETWEEN BLOOD REFLUX AND EPIGENETIC FACTORS HDACS AND DNMTS IN CVD. HUMAN VARICOSE VEINS WITH DIFFERENT LEVELS OF BLOOD REFLUX VERSUS NORMAL VEINS WITH NORMAL VENOUS FLOW WERE EXAMINED. THE RESULTS SHOW THAT HDAC-1, -2, -3, -5, AND -7 ARE OVEREXPRESSED IN THE ENDOTHELIUM OF VARICOSE VEINS WITH BLOOD REFLUX. BLOOD REFLUX-INDUCED HDACS ARE ENHANCED IN THE VARICOSE VEINS WITH A LONGER DURATION TIME OF BLOOD REFLUX. IN CONTRAST, THESE HDACS ARE RARELY EXPRESSED IN THE ENDOTHELIUM OF THE NORMAL VEIN WITH NORMAL VENOUS FLOW. SIMILAR RESULTS ARE OBTAINED FOR DNMT1 AND DNMT3A. OUR FINDINGS SUGGEST THAT THE EPIGENETIC FACTORS, HDACS AND DNMTS, ARE INDUCED IN VENOUS ECS IN RESPONSE TO BLOOD REFLUX BUT ARE INHIBITED IN RESPONSE TO NORMAL VENOUS FLOW. BLOOD REFLUX-INDUCED HDACS AND DNMTS COULD INHIBIT METABOLIC REGULATION AND PROMOTE VENOUS EC DYSFUNCTION, WHICH IS HIGHLY CORRELATED WITH CVD PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
2   809 31 CHANGES IN CLASS I AND IIB HDACS BY DELTA-OPIOID IN CHRONIC RAT GLAUCOMA MODEL. PURPOSE: THIS STUDY DETERMINES IF DELTA-OPIOID RECEPTOR AGONIST (I.E. SNC-121)-INDUCED EPIGENETIC CHANGES VIA REGULATION OF HISTONE DEACETYLASES (HDACS) FOR RETINAL GANGLION CELL (RGC) NEUROPROTECTION IN GLAUCOMA MODEL. METHODS: INTRAOCULAR PRESSURE WAS RAISED IN RAT EYES BY INJECTING 2M HYPERTONIC SALINE INTO THE LIMBAL VEINS. SNC-121 (1 MG/KG; I.P.) WAS ADMINISTERED TO THE ANIMALS FOR 7 DAYS. RETINAS WERE COLLECTED AT DAYS 7 AND 42, POST-INJURY FOLLOWED BY MEASUREMENT OF HDAC ACTIVITIES, MRNA, AND PROTEIN EXPRESSION BY ENZYME ASSAY, QUANTITATIVE REAL-TIME PCR (QRT-PCR), WESTERN BLOTTING, AND IMMUNOHISTOCHEMISTRY. RESULTS: THE VISUAL ACUITY, CONTRAST SENSITIVITY, AND PATTERN ELECTRORETINOGRAMS (ERGS) WERE DECLINED IN OCULAR HYPERTENSIVE ANIMALS, WHICH WERE SIGNIFICANTLY IMPROVED BY SNC-121 TREATMENT. CLASS I AND IIB HDACS ACTIVITIES WERE SIGNIFICANTLY INCREASED AT DAYS 7 AND 42 IN OCULAR HYPERTENSIVE ANIMALS. THE MRNA AND PROTEIN EXPRESSION OF HDAC 1 WAS INCREASED BY 1.33 +/- 0.07-FOLD AND 20.2 +/- 2.7%, HDAC 2 BY 1.4 +/- 0.05-FOLD AND 17.0 +/- 2.4%, HDAC 3 BY 1.4 +/- 0.06-FOLD AND 17.4 +/- 3.4%, AND HDAC 6 BY 1.5 +/- 0.09-FOLD AND 15.1 +/- 3.3% AT DAY 7, POST-INJURY. BOTH THE MRNA AND PROTEIN EXPRESSION OF HDACS WERE POTENTIATED FURTHER AT DAY 42 IN OCULAR HYPERTENSIVE ANIMALS. HDAC ACTIVITIES, MRNA, AND PROTEIN EXPRESSION WERE BLOCKED BY SNC-121 TREATMENT AT DAYS 7 AND 42 IN OCULAR HYPERTENSIVE ANIMALS. CONCLUSIONS: DATA SUGGESTS THAT CLASS I AND IIB HDACS ARE ACTIVATED AND UPREGULATED DURING EARLY STAGES OF GLAUCOMA. EARLY INTERVENTION WITH DELTA-OPIOID RECEPTOR ACTIVATION RESULTED IN THE PROLONGED SUPPRESSION OF CLASS I AND IIB HDACS ACTIVITIES AND EXPRESSION, WHICH MAY, IN PART, PLAY A CRUCIAL ROLE IN RGC NEUROPROTECTION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
3  4843 27 ONE YEAR IN REVIEW 2019: BEHCET'S SYNDROME. SEVERAL EPIDEMIOLOGIC STUDIES REPORT ON THE PREVALENCE OF BEHCET'S SYNDROME (BS) AND DEMOGRAPHIC AND CLINICAL FINDINGS IN PATIENTS FROM DIFFERENT COUNTRIES AND ETHNICITIES. ALTHOUGH THESE STUDIES POINT OUT GEOGRAPHIC DIFFERENCES IN DISEASE COURSE, METHODOLOGIC DIFFERENCES MAKE IT DIFFICULT TO COMPARE THE RESULTS OF THESE STUDIES. RECENT DATA SUGGEST THAT NEUTROPHIL EXTRACELLULAR TRAP LEVELS ARE ELEVATED IN PATIENTS WITH BS, AND THAT IT MAY BE A POTENTIAL THERAPEUTIC TARGET FOR THE REDUCTION OR PREVENTION OF BS-ASSOCIATED THROMBOTIC RISK. DETAILS ON THE MODE OF FUNCTIONING OF ERAP HAVE BEEN DELINEATED AND FURTHER EPIGENETIC DATA REPORTED. WALL THICKNESS OF LOWER EXTREMITY VEINS IS INCREASED AMONG BS PATIENTS WITHOUT ANY APPARENT CLINICAL INVOLVEMENT. MAGNETIC RESONANCE (MR) VENOGRAPHY AND DOPPLER ULTRASONOGRAPHY (USG) WERE COMPARABLE IN THE DIAGNOSIS OF CHRONIC DEEP VEIN THROMBOSIS, WHILE MR VENOGRAPHY IS MORE EFFECTIVE IN DETECTING COLLATERAL FORMATIONS. RESULTS WERE ALSO COLLECTED ON SOME DIETARY AND NON-DIETARY FACTORS IN TRIGGERING ORAL ULCERS, WHILE SMOKING SEEMS TO HAVE A PROTECTIVE ROLE. WITH REGARDS TO THE THERAPY, IT HAS BEEN DEMONSTRATED THAT ENDOVASCULAR INTERVENTIONS CARRY THE RISK OF INDUCING PATHERGY PHENOMENON. APREMILAST HAS BEEN CONVINCINGLY SHOWN TO BE USEFUL FOR ORAL ULCERS OF BS AND CLASSICAL IMMUNOSUPPRESSIVES ARE EFFECTIVE AS FIRST LINE THERAPY IN MORE THAN HALF OF PATIENTS WITH UVEITIS. WHILE INFLIXIMAB AND ADALIMUMAB SEEM TO BE EQUALLY EFFECTIVE IN THE TREATMENT OF REFRACTORY UVEITIS OF BS, THE COMBINATION OF ADALIMUMAB AND IMMUNOSUPPRESSIVES APPEARS TO BE SUPERIOR TO IMMUNOSUPPRESSIVES ALONE FOR VENOUS THROMBOSIS OF THE EXTREMITIES. IN ADDITION, TOCILIZUMAB MIGHT BE AN ALTERNATIVE TO ANTI-TNF AGENTS FOR PATIENTS WITH ARTERIAL INVOLVEMENT REFRACTORY TO IMMUNOSUPPRESSIVES. ON THE OTHER HAND, THE PLACE OF IL-17 INHIBITION IN THE TREATMENT OF BS STILL REMAINS QUESTIONABLE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4  6619 28 UNDERSTANDING CHRONIC VENOUS DISEASE: A CRITICAL OVERVIEW OF ITS PATHOPHYSIOLOGY AND MEDICAL MANAGEMENT. CHRONIC VENOUS DISEASE (CVD) IS A MULTIFACTORIAL CONDITION AFFECTING AN IMPORTANT PERCENTAGE OF THE GLOBAL POPULATION. IT RANGES FROM MILD CLINICAL SIGNS, SUCH AS TELANGIECTASIAS OR RETICULAR VEINS, TO SEVERE MANIFESTATIONS, SUCH AS VENOUS ULCERATIONS. HOWEVER, VARICOSE VEINS (VVS) ARE THE MOST COMMON MANIFESTATION OF CVD. THE EXPLICIT MECHANISMS OF THE DISEASE ARE NOT WELL-UNDERSTOOD. IT SEEMS THAT GENETICS AND A PLETHORA OF ENVIRONMENTAL AGENTS PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT AND PROGRESSION OF CVD. THE EXPOSURE TO THESE FACTORS LEADS TO ALTERED HEMODYNAMICS OF THE VENOUS SYSTEM, DESCRIBED AS AMBULATORY VENOUS HYPERTENSION, THEREFORE PROMOTING MICROCIRCULATORY CHANGES, INFLAMMATORY RESPONSES, HYPOXIA, VENOUS WALL REMODELING, AND EPIGENETIC VARIATIONS, EVEN WITH IMPORTANT SYSTEMIC IMPLICATIONS. THUS, A PROPER CLINICAL MANAGEMENT OF PATIENTS WITH CVD IS ESSENTIAL TO PREVENT POTENTIAL HARMS OF THE DISEASE, WHICH ALSO ENTAILS A SIGNIFICANT LOSS OF THE QUALITY OF LIFE IN THESE INDIVIDUALS. HENCE, THE AIM OF THE PRESENT REVIEW IS TO COLLECT THE CURRENT KNOWLEDGE OF CVD, INCLUDING ITS EPIDEMIOLOGY, ETIOLOGY, AND RISK FACTORS, BUT EMPHASIZING THE PATHOPHYSIOLOGY AND MEDICAL CARE OF THESE PATIENTS, INCLUDING CLINICAL MANIFESTATIONS, DIAGNOSIS, AND TREATMENTS. FURTHERMORE, FUTURE DIRECTIONS WILL ALSO BE COVERED IN THIS WORK IN ORDER TO PROVIDE POTENTIAL FIELDS TO EXPLORE IN THE CONTEXT OF CVD.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5  6220 26 THE KIDNEY IS THE MAJOR SITE OF S-ADENOSYLHOMOCYSTEINE DISPOSAL IN HUMANS. S-ADENOSYLHOMOCYSTEINE (SAH), THE METABOLIC PRECURSOR OF HOMOCYSTEINE IN THE BODY, IS A POTENT INHIBITOR OF METHYLATION REACTIONS. SEVERAL METHYLATION REACTIONS PLAY A MAJOR ROLE IN EPIGENETIC REGULATION OF PROTEIN EXPRESSION, ATHEROSCLEROSIS, AND CANCER DEVELOPMENT. HERE WE STUDIED THE MECHANISMS RESPONSIBLE FOR THE MAINTENANCE OF CIRCULATING SAH LEVELS BY MEASUREMENT OF THE ARTERIO-VENOUS DIFFERENCES ACROSS THE KIDNEY, SPLANCHNIC ORGANS, AND THE LUNG IN HUMANS. THE LUNGS DID NOT REMOVE OR ADD ANY CIRCULATING SAH, WHEREAS THE LIVER RELEASED IT INTO THE HEPATIC VEINS. THE KIDNEY EXTRACTED 40% OF SAH AND THE SAH ARTERIO-VENOUS DIFFERENCE ACROSS THE KIDNEY WAS DIRECTLY AND SIGNIFICANTLY RELATED TO ITS ARTERIAL LEVELS. THUS, THE KIDNEY PLAYS A MAJOR ROLE IN MAINTAINING SAH LEVELS AND MAY, INDIRECTLY, CONTROL TISSUE TRANSMETHYLATION REACTIONS. OUR FINDINGS OF A PIVOTAL ROLE FOR THE HUMAN KIDNEY IN SULFUR AMINO ACID METABOLISM MAY ALSO ACCOUNT FOR THE INCREASED PLASMA LEVELS OF SAH IN PATIENTS WITH CHRONIC KIDNEY DISEASES.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6  4167 22 MEDICINE AND PHLEBOLYMPHOLOGY: TIME TO CHANGE? BIOMEDICAL SCIENCE IS UNDERGOING A REAPPRAISAL OF ITS SCIENTIFIC ADVANCEMENT PROCESS AND OF THE RELATED HEALTHCARE MANAGEMENT. PROGRESS IN MEDICINE SHOULD COMBINE IMPROVEMENTS OF KNOWLEDGE, EFFICACY, AND SAFETY OF DIAGNOSTIC/THERAPEUTIC PROCEDURES, WITH ADEQUATE COST-EFFECTIVENESS PROFILES. THIS NARRATIVE REVIEW IS AIMED AT ASSESSING IN MEDICINE, MORE SPECIFICALLY IN PHLEBOLOGY AND LYMPHOLOGY: (A) SCIENTIFIC LITERATURE POSSIBLE BIASES, (B) THE LEVEL OF EVIDENCE, COMPREHENSIVENESS, AND COST-EFFECTIVENESS OF THE MAIN THERAPEUTIC OPTIONS, AND (C) THE POSSIBLE CONTRIBUTION OF INTEGRATIVE AND TRANSLATIONAL MEDICINE. CURRENT MEDICAL RESEARCH MAY HAVE COGNITIVE BIASES, OR INDUSTRY-TIED INFLUENCES, WHICH IMPACTS CLINICAL PRACTICE. SOME REDUCTIONISM, WITH AN INCREASING USE OF DRUGS AND TECHNOLOGY, OFTEN NEGLECTING THE UNDERSTANDING AND CARE OF THE ROOT CAUSATIVE PATHWAYS OF THE DISEASES, IS AFFECTING BIOMEDICAL SCIENCE AS WELL. AGING BRINGS A RELEVANT BURDEN OF CHRONIC DEGENERATIVE DISEASES AND DISABILITIES, WITH RELEVANT SOCIO-ECONOMIC REPERCUSSIONS; THUS, A MAJOR ATTENTION TO COST-EFFECTIVENESS AND APPROPRIATENESS OF HEALTHCARE IS WARRANTED. IN THIS SCENARIO, COSTLY AND INNOVATIVE BUT RELATIVELY VALIDATED THERAPIES MAY TEND TO BE ADOPTED IN VENOUS AND LYMPHATIC DISEASES, SUCH AS VARICOSE VEINS, LEG VENOUS ULCER, POST-THROMBOTIC SYNDROME, PELVIC CONGESTION SYNDROME, AND LYMPHEDEMA. CONVERSELY, A MORE COMPREHENSIVE APPROACH TO THE BASIC PATHOPHYSIOLOGY OF CHRONIC VENOUS AND LYMPHATIC INSUFFICIENCY AND THE INCLUSION OF PHARMACOECONOMICS ANALYSES WOULD BENEFIT OVERALL PATIENTS' MANAGEMENT. ERRONEOUS LIFESTYLE AND NUTRITION, TOGETHER WITH CHRONIC STRESS-INDUCED SYNDROMES, SIGNIFICANTLY INFLUENCE CHRONIC DEGENERATIVE PHLEBO-LYMPHATIC DISEASES. THE MAIN ACTIVE EPIGENETIC SOCIO-BIOLOGIC FACTORS ARE OBESITY, DYSFUNCTIONS OF MUSCULO-RESPIRATORY-VASCULAR PUMPS, PRO-INFLAMMATORY NUTRITION, HYPERACTIVATION OF STRESS AXIS, AND SEDENTARISM. AN OVERALL CRITICAL VIEW OF THE SCIENTIFIC EVIDENCE AND INNOVATIONS IN PHEBOLYMPHOLOGY COULD BE OF HELP TO IMPROVE EFFICACY, SAFETY, AND SUSTAINABILITY OF CURRENT PRACTICE. TRANSLATIONAL AND INTEGRATIVE MEDICINE MAY CONTRIBUTE TO A PATIENT-CENTERED APPROACH. CONVERSELY, REDUCTIONISM, EMINENCE/REIMBURSEMENT-BASED DECISIONAL PROCESSES, PATIENTS' LACK OF EDUCATION, INDUSTRY-INFLUENCED SCIENCE, AND PHYSICIAN'S IMPROVABLE AWARENESS, MAY COMPROMISE EFFICACY, SAFETY, APPROPRIATENESS, AND COST-EFFECTIVENESS OF FUTURE DIAGNOSTIC AND THERAPEUTIC PATTERNS OF PHLEBOLOGY AND LYMPHOLOGY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7  1904 28 ENHANCED RETINAL GANGLION CELL SURVIVAL IN GLAUCOMA BY HYPOXIC POSTCONDITIONING AFTER DISEASE ONSET. THE NEUROPROTECTIVE EFFICACY OF ADAPTIVE EPIGENETICS, WHEREIN BENEFICIAL GENE EXPRESSION CHANGES ARE INDUCED BY NONHARMFUL "CONDITIONING" STIMULI, IS NOW WELL ESTABLISHED IN SEVERAL ACUTE, PRECLINICAL CENTRAL NERVOUS SYSTEM INJURY MODELS. RECENTLY, IN A MOUSE MODEL OF GLAUCOMA, WE DEMONSTRATED RETINAL GANGLION CELL (RGC) PROTECTION BY REPETITIVELY "PRECONDITIONING" WITH HYPOXIA PRIOR TO DISEASE ONSET, INDICATING AN EPIGENETIC APPROACH MAY ALSO YIELD BENEFITS IN CHRONIC NEURODEGENERATIVE DISEASE. HEREIN, WE DETERMINED WHETHER PRESENTING THE REPETITIVE HYPOXIC STIMULUS AFTER DISEASE INITIATION [REPETITIVE HYPOXIC "POSTCONDITIONING" (RH-POST)] COULD AFFORD SIMILAR FUNCTIONAL AND MORPHOLOGIC PROTECTION AGAINST GLAUCOMATOUS RGC INJURY. CHRONIC ELEVATIONS IN INTRAOCULAR PRESSURE (IOP) WERE INDUCED UNILATERALLY IN ADULT MALE C57BL/6 MICE BY EPISCLERAL VEIN LIGATION. MICE WERE RANDOMIZED TO AN RH-POST [1 H OF SYSTEMIC HYPOXIA (11% OXYGEN) EVERY OTHER DAY, STARTING 4 DAYS AFTER IOP ELEVATION] OR AN UNTREATED CONTROL GROUP. AFTER 3 WEEKS OF EXPERIMENTAL GLAUCOMA, THE 21-27% REDUCTION AND 5-25% PROLONGATION IN FLASH VISUAL-EVOKED POTENTIAL AMPLITUDES AND LATENCIES, RESPECTIVELY, AND THE 30% IMPAIRMENT IN VISUAL ACUITY WERE ROBUSTLY IMPROVED IN RH-POST-TREATED MICE, AS WAS THE 17% LOSS IN RGC SOMA NUMBER AND 20% REDUCTION IN AXON INTEGRITY. THESE PROTECTIVE EFFECTS WERE OBSERVED WITHOUT RH-POST AFFECTING IOP. THE PRESENT FINDINGS DEMONSTRATE THAT FUNCTIONAL AND MORPHOLOGIC PROTECTION OF RGCS CAN BE REALIZED BY STIMULATING EPIGENETIC RESPONSES DURING THE EARLY STAGES OF DISEASE, AND THUS CONSTITUTE A NEW CONCEPTUAL APPROACH TO GLAUCOMA THERAPEUTICS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8  2759 29 EXPRESSION OF IL-17 AND ITS GENE PROMOTER METHYLATION STATUS ARE ASSOCIATED WITH THE PROGRESSION OF CHRONIC HEPATITIS B VIRUS INFECTION. TO EXPLORE INTERLEUKIN-17 (IL-17) AND ITS EPIGENETIC REGULATION DURING THE PROGRESSION OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION.A TOTAL OF 162 PATIENTS WITH CHRONIC HBV INFECTION, INCLUDING 75 WITH CHRONIC HEPATITIS B (CHB), 54 WITH HEPATITIS B-ASSOCIATED LIVER CIRRHOSIS AND 33 WITH HEPATITIS B-ASSOCIATED HEPATOCELLULAR CARCINOMA (HBV-HCC), WERE ENROLLED IN THIS STUDY. THIRTY HEALTHY ADULTS OF THE SAME ETHNICITY WERE ENROLLED IN THE CONTROL GROUP. WHOLE VENOUS BLOOD WAS OBTAINED FROM THE PATIENTS AND NORMAL CONTROLS (N = 30). CLINICAL AND LABORATORY PARAMETERS WERE ASSESSED, AND WE PERFORMED ENZYME-LINKED IMMUNOSORBENT ASSAY AND QUANTITATIVE REAL-TIME PCR TO MEASURE THE SERUM LEVELS AND RELATIVE MRNA EXPRESSION OF IL-17, RESPECTIVELY. IL-17 PROMOTER METHYLATION IN PERIPHERAL BLOOD MONONUCLEAR CELLS WAS ASSESSED BY METHYLATION-SPECIFIC PCR. WE ANALYZED THE SERUM AND MRNA LEVELS OF IL-17 AND IL-17 PROMOTER METHYLATION IN THE 4 GROUPS AS WELL AS THE EFFECT OF METHYLATION ON SERUM IL-17 LEVELS. CORRELATIONS BETWEEN THE IL-17 PROMOTER METHYLATION STATUS AND CLINICAL PARAMETERS WERE ANALYZED BY SPEARMAN CORRELATION ANALYSIS.COMPARED TO THE NORMAL CONTROL GROUP, THE PATIENT GROUPS EXHIBITED SIGNIFICANTLY HIGHER SERUM AND RELATIVE MRNA LEVELS OF IL-17. THE METHYLATION DISTRIBUTION AMONG THE PATIENTS WAS SIGNIFICANTLY LOWER THAN THAT AMONG THE NORMAL CONTROLS (P < .05), WITH THE HBV-HCC GROUP SHOWING THE LOWEST IL-17 GENE METHYLATION FREQUENCY. THE AVERAGE IL-17 PROMOTER CG METHYLATION LEVEL WAS NEGATIVELY CORRELATED WITH IL-17 MRNA EXPRESSION (R = -0.39, P = .03), AND NEGATIVE CORRELATIONS BETWEEN IL-17 PROMOTER METHYLATION AND PROTHROMBIN TIME ACTIVITY (R = -0.585, P = .035), ALANINE AMINOTRANSFERASE (R = -0.522, P < .01), ASPARTATE AMINOTRANSFERASE (R = -0.315, P < .05), AND THE MODEL FOR END-STAGE LIVER DISEASE SCORE (R = -0.461, P < .05) WERE OBSERVED. IL-17 SERUM LEVELS IN THE METHYLATED-PROMOTER GROUPS WERE SIGNIFICANTLY LOWER THAN THOSE IN THE UNMETHYLATED-PROMOTER GROUPS.IL-17 EXPRESSION AND PROMOTER METHYLATION WERE ASSOCIATED WITH CHRONIC HBV INFECTION PROGRESSION, ESPECIALLY IN THE HBV-HCC GROUP. THE IL-17 PROMOTER STATUS MAY HELP CLINICIANS INITIATE THE CORRECT TREATMENT STRATEGY AT THE CHB STAGE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9  6039 31 THE CHEMOKINE RECEPTOR CXCR2 SUPPORTS NOCICEPTIVE SENSITIZATION AFTER TRAUMATIC BRAIN INJURY. CHRONIC PAIN AFTER TRAUMATIC BRAIN INJURY (TBI) IS VERY COMMON, BUT THE MECHANISMS LINKING TBI TO PAIN AND THE PAIN-RELATED INTERACTIONS OF TBI WITH PERIPHERAL INJURIES ARE POORLY UNDERSTOOD. CHEMOKINE RECEPTORS PLAY AN IMPORTANT ROLE IN BOTH PAIN AND BRAIN INJURY. IN THE CURRENT WORK, WE PURSUED THE HYPOTHESIS THAT THE EPIGENETICALLY REGULATED CXC CHEMOKINE RECEPTOR 2 (CXCR2) IS A CRUCIAL MODULATOR OF NOCICEPTIVE SENSITIZATION INDUCED BY TBI. FOR THESE STUDIES, WE USED THE RAT LATERAL FLUID PERCUSSION MODEL OF TBI. HISTONE ACTYLTRANSFERASE ACTIVITY WAS BLOCKED USING ANACARDIC ACID BEGINNING IMMEDIATELY FOLLOWING INJURY, OR DELAYED FOR SEVEN DAYS PRIOR TO ADMINISTRATION. THE SELECTIVE CXCR2 ANTAGONIST SCH527123 ADMINISTERED SYSTEMICALLY OR INTRATHECALLY WAS USED TO PROBE THE ROLE OF CHEMOKINE SIGNALING ON MECHANICAL HINDPAW SENSITIZATION AFTER TBI. THE EXPRESSION OF THE CXCR2 RECEPTOR WAS ACCOMPLISHED USING REAL-TIME PCR, IMMUNOHISTOCHEMISTRY, AND WESTERN BLOTTING, WHILE EPIGENETIC REGULATION WAS ASSESSED USING CHROMATIN IMMUNOPRECIPITATION ASSAY. THE SPINAL LEVELS OF SEVERAL PAIN-RELATED MEDIATORS INCLUDING CXCL1, AN ENDOGENOUS LIGAND FOR CXCR2, AS WELL AS BRAIN-DERIVED NEUROTROPHIC FACTOR AND PRODYNORPHIN WERE MEASURED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. WE OBSERVED THAT ANACARDIC ACID POTENTLY BLOCKED AND REVERSED MECHANICAL HINDPAW SENSITIZATION AFTER TBI. THE SAME DRUG WAS ABLE TO PREVENT THE UPREGULATION OF CXCR2 AFTER TBI, BUT DID NOT AFFECT THE SPINAL EXPRESSION OF OTHER PAIN MEDIATORS. ON THE OTHER HAND, BOTH SYSTEMICALLY AND INTRATHECALLY ADMINISTERED SCH527123 REVERSED HINDPAW ALLODYNIA AFTER TBI. MOST OF THE SPINAL CXCR2 APPEARED TO BE EXPRESSED BY SPINAL CORD NEURONS. CHROMATIN IMMUNOPRECIPITATION EXPERIMENTS DEMONSTRATED TBI-ENHANCED ASSOCIATION OF THE CXCR2 PROMOTER WITH ACETYLATED-H3K9 HISTONE PROTEIN THAT WAS ALSO REVERSIBLE USING ANACARDIC ACID. TAKEN TOGETHER, OUR FINDINGS SUGGESTED THAT TBI CAUSES THE UPREGULATION OF SPINAL CXCR2 THROUGH AN EPIGENETIC MECHANISM ULTIMATELY SUPPORTING NOCICEPTIVE SENSITIZATION. THE USE OF CXCR2 ANTAGONISTS MAY, THEREFORE, BE USEFUL IN PAIN RESULTING FROM TBI.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10  3832 27 INVOLVEMENT OF SPINAL SIRT1 IN DEVELOPMENT OF CHRONIC CONSTRICTION INJURY INDUCED NEUROPATHIC PAIN IN RATS. IT IS KNOWN THAT THE EPIGENETIC PROCESS OF HISTONE ACETYLATION IS INVOLVED IN THE NEUROPATHIC PAIN. THE AIM OF THIS STUDY WAS TO DETERMINE WHETHER SIRTUIN TYPE 1 (SIRT1), AN NAD(+) DEPENDENT DEACETYLASE, AFFECTED ALLODYNIA AND HYPERALGESIA IN NEUROPATHIC PAIN. THE NEUROPATHIC PAIN MODEL WAS ESTABLISHED BY LIGATURE OF THE RIGHT SCIATIC NERVE TO INDUCE CHRONIC CONSTRICTION INJURY (CCI) IN RATS. HISTONE ACETYLTRANSFERASE (HAT) ACTIVITY WAS INCREASED AND, AND HISTONE DEACETYLASE (HDAC) ACTIVITY WAS DECLINED IN TISSUE OF THE SPINAL DORSA HORN IN CCI RATES BY MEANS OF ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA). THE PERSISTENT HYPERALGESIA AND ALLODYNIA CAUSED BY CCI WERE ASSOCIATED WITH DOWNREGULATION OF SIRT1 AND UPREGULATION OF ACETYLATED-H3 (AC-H3) IN TISSUE OF THE SPINAL CORD BY WESTERN BLOT ASSAY, WHICH WAS REVERSED AFTER INTRATHECAL INJECTION OF SIRT1 AGONIST SRT1720. SRT1720 TREATMENT ACHIEVED ANALGESIC THROUGH INHIBITING THE ACETYLATION OF NUCLEAR FACTOR KAPPA B (NF-KAPPAB) AND BLOCKING THE RELEASES OF THE INFLAMMATORY FACTORS INCLUDING TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) AND INTERLEUKIN (IL)-6 BY MEANS OF WESTERN BLOT AND REAL-TIME QUANTITATIVE PCR (RT-PCR), RESPECTIVELY. TAKEN TOGETHER, THESE DATA SUGGEST THAT SIRT1 IN THE SPINAL CORD PLAYS AN IMPORTANT ROLE IN THE NEUROPATHIC PAIN IN THE RAT MODEL.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11  1061 31 CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS IS CHARACTERIZED BY AN UPREGULATION OF PERIPHERAL T-REGULATORY CELL POLARIZED TOWARDS T-BET AND TIGIT. BACKGROUND: NON-INFECTIOUS UVEITIS CAN CAUSE CHRONIC RELAPSING AND REMITTING OCULAR INFLAMMATION, WHICH MAY REQUIRE HIGH DOSE SYSTEMIC IMMUNOSUPPRESSION TO PREVENT SEVERE SIGHT LOSS. IT HAS BEEN CLASSICALLY DESCRIBED AS AN AUTOIMMUNE DISEASE, MEDIATED BY PRO-INFLAMMATORY TH1 AND TH17 T-CELL SUBSETS. STUDIES SUGGEST THAT NATURAL IMMUNOSUPPRESSIVE CD4(+)CD25(+)FOXP3(+) T-REGULATORY CELLS (TREGS) ARE INVOLVED IN RESOLUTION OF INFLAMMATION AND MAY BE INVOLVED IN THE MAINTENANCE OF CLINICAL REMISSION. OBJECTIVE: TO INVESTIGATE WHETHER THERE IS A PERIPHERAL BLOOD IMMUNOREGULATORY PHENOTYPE ASSOCIATED WITH CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS BY COMPARING PERIPHERAL BLOOD LEVELS OF TREG, TH1, AND TH17, AND ASSOCIATED DNA METHYLATION AND CYTOKINE LEVELS IN PATIENTS WITH ACTIVE UVEITIC DISEASE, CONTROL SUBJECTS AND PATIENTS (WITH PREVIOUSLY ACTIVE DISEASE) IN CLINICAL REMISSION INDUCED BY IMMUNOSUPPRESSIVE DRUGS. METHODS: ISOLATED PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM PERIPHERAL BLOOD SAMPLES FROM PROSPECTIVELY RECRUITED SUBJECTS WERE ANALYZED BY FLOW CYTOMETRY FOR CD3, CD4, FOXP3, TIGIT, T-BET, AND RELATED ORPHAN RECEPTOR GAMMAT. EPIGENETIC DNA METHYLATION LEVELS OF FOXP3 TREG-SPECIFIC DEMETHYLATED REGION (TSDR), FOXP3 PROMOTER, TBX21, RORC2, AND TIGIT LOCI WERE DETERMINED IN CRYOPRESERVED PBMC USING A NEXT-GENERATION SEQUENCING APPROACH. RELATED CYTOKINES WERE MEASURED IN BLOOD SERA. FUNCTIONAL SUPPRESSIVE CAPACITY OF TREG WAS ASSESSED USING T-CELL PROLIFERATION ASSAYS. RESULTS: FIFTY PATIENTS WITH UVEITIS (INTERMEDIATE, POSTERIOR, AND PANUVEITIS) AND 10 CONTROL SUBJECTS WERE RECRUITED. THE FREQUENCY OF CD4(+)CD25(+)FOXP3(+) TREG, TIGIT(+) TREG, AND T-BET(+) TREG AND THE RATIO OF TREG TO TH1 WERE SIGNIFICANTLY HIGHER IN REMISSION PATIENTS COMPARED WITH PATIENTS WITH ACTIVE UVEITIC DISEASE; AND TIGIT(+) TREGS WERE A SIGNIFICANT PREDICTOR OF CLINICAL REMISSION. TREG FROM PATIENTS IN CLINICAL REMISSION DEMONSTRATED A HIGH LEVEL OF IN VITRO SUPPRESSIVE FUNCTION COMPARED WITH TREG FROM CONTROL SUBJECTS AND FROM PATIENTS WITH UNTREATED ACTIVE DISEASE. PBMC FROM PATIENTS IN CLINICAL REMISSION HAD SIGNIFICANTLY LOWER METHYLATION LEVELS AT THE FOXP3 TSDR, FOXP3 PROMOTER, AND TIGIT LOCI AND HIGHER LEVELS AT RORC LOCI THAN THOSE WITH ACTIVE DISEASE. CLINICAL REMISSION WAS ALSO ASSOCIATED WITH SIGNIFICANTLY HIGHER SERUM LEVELS OF TRANSFORMING GROWTH FACTOR BETA AND IL-10, WHICH POSITIVELY CORRELATED WITH TREG LEVELS, AND LOWER SERUM LEVELS OF IFNGAMMA, IL-17A, AND IL-22 COMPARED WITH PATIENTS WITH ACTIVE DISEASE. CONCLUSION: CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS HAS AN IMMUNOREGULATORY PHENOTYPE CHARACTERIZED BY UPREGULATION OF PERIPHERAL TREG, POLARIZED TOWARD T-BET AND TIGIT. THESE FINDINGS MAY ASSIST WITH INDIVIDUALIZED THERAPY OF UVEITIS, BY INFORMING WHETHER DRUG THERAPY HAS INDUCED PHENOTYPICALLY STABLE TREG ASSOCIATED WITH LONG-TERM CLINICAL REMISSION.	2018	

12  1238 24 CURCUMIN BLOCKS CHRONIC MORPHINE ANALGESIC TOLERANCE AND BRAIN-DERIVED NEUROTROPHIC FACTOR UPREGULATION. THIS STUDY WAS CARRIED OUT BASED ON THE ASSUMPTION THAT BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MAY COUNTERBALANCE THE ACTION OF MORPHINE IN THE BRAIN. MORPHINE ANALGESIC TOLERANCE AFTER DAILY ADMINISTRATIONS FOR SIX DAYS WAS BLOCKED BY INTRACEREBROVENTRICULAR INJECTION OF ANTI-BDNF IGG ON DAY 5, BUT NOT BY ADMINISTRATIONS ON DAYS 1-4. CHRONIC MORPHINE TREATMENT SIGNIFICANTLY INCREASED THE EXPRESSION OF EXON I AND IV BDNF TRANSCRIPTS, INDICATING DIFFERENTIAL REGULATION OF BDNF GENE EXPRESSION. DAILY ADMINISTRATION OF THE CREB-BINDING PROTEIN INHIBITOR CURCUMIN ABOLISHED THE UPREGULATION OF BDNF TRANSCRIPTION AND MORPHINE ANALGESIC TOLERANCE. THESE RESULTS SUGGEST THAT CURCUMIN MIGHT BE A PROMISING ADJUVANT TO REDUCE MORPHINE ANALGESIC TOLERANCE, AND THAT EPIGENETIC CONTROL COULD BE A NEW STRATEGY USEFUL FOR THE CONTROL OF THIS PROBLEM.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  6646 32 UP-REGULATION OF HDACS, A HARBINGER OF URAEMIC ENDOTHELIAL DYSFUNCTION, IS PREVENTED BY DEFIBROTIDE. ENDOTHELIAL DYSFUNCTION IS AN EARLIER CONTRIBUTOR TO THE DEVELOPMENT OF ATHEROSCLEROSIS IN CHRONIC KIDNEY DISEASE (CKD), IN WHICH THE ROLE OF EPIGENETIC TRIGGERS CANNOT BE RULED OUT. ENDOTHELIAL PROTECTIVE STRATEGIES, SUCH AS DEFIBROTIDE (DF), MAY BE USEFUL IN THIS SCENARIO. WE EVALUATED CHANGES INDUCED BY CKD ON ENDOTHELIAL CELL PROTEOME AND EXPLORED THE EFFECT OF DF AND THE MECHANISMS INVOLVED. HUMAN UMBILICAL CORD VEIN ENDOTHELIAL CELLS WERE EXPOSED TO SERA FROM HEALTHY DONORS (N = 20) AND PATIENTS WITH END-STAGE RENAL DISEASE ON HAEMODIALYSIS (N = 20). DIFFERENTIAL PROTEIN EXPRESSION WAS INVESTIGATED BY USING A PROTEOMIC APPROACH, WESTERN BLOT AND IMMUNOFLUORESCENCE. HDAC1 AND HDAC2 OVEREXPRESSION WAS DETECTED. INCREASED HDAC1 EXPRESSION OCCURRED AT BOTH CYTOPLASM AND NUCLEUS. THESE EFFECTS WERE DOSE-DEPENDENTLY INHIBITED BY DF. BOTH THE HDACS INHIBITOR TRICHOSTATIN A AND DF PREVENTED THE UP-REGULATION OF THE ENDOTHELIAL DYSFUNCTION MARKERS INDUCED BY THE URAEMIC MILIEU: INTERCELLULAR ADHESION MOLECULE-1, SURFACE TOLL-LIKE RECEPTOR-4, VON WILLEBRAND FACTOR AND REACTIVE OXYGEN SPECIES. MOREOVER, DF DOWN-REGULATED HDACS EXPRESSION THROUGH THE PI3/AKT SIGNALLING PATHWAY. HDACS APPEAR AS KEY MODULATORS OF THE CKD-INDUCED ENDOTHELIAL DYSFUNCTION AS SPECIFIC BLOCKADE BY TRICHOSTATIN A OR BY DF PREVENTS ENDOTHELIAL DYSFUNCTION RESPONSES TO THE CKD INSULT. MOREOVER, DF EXERTS ITS ENDOTHELIAL PROTECTIVE EFFECT BY INHIBITING HDAC UP-REGULATION LIKELY THROUGH PI3K/AKT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  6654 25 UPDATE ON PSEUDOEXFOLIATION SYNDROME PATHOGENESIS AND ASSOCIATIONS WITH INTRAOCULAR PRESSURE, GLAUCOMA AND SYSTEMIC DISEASES. PURPOSE OF REVIEW: PSEUDOEXFOLIATION (PEX) SYNDROME IS A COMMON AGE-RELATED DISORDER AFFECTING INTRAOCULAR AND EXTRAOCULAR TISSUES. THIS REVIEW FOCUSES ON RECENT PUBLICATIONS RELATED WITH THE PATHOGENESIS AND ASSOCIATIONS OF PEX SYNDROME WITH INTRAOCULAR PRESSURE (IOP), GLAUCOMA AND SYSTEMIC DISEASES. RECENT FINDINGS: IN PEX TISSUES, EXPRESSION OF LYSYL OXIDASE-LIKE 1 (LOXL1) WAS FOUND TO BE MARKEDLY DYSREGULATED. THIS MAY ADVERSELY AFFECT ELASTIN METABOLISM AND LEAD TO ELASTOTIC ALTERATION IN TISSUES SUCH AS LAMINA CRIBROSA. THERE IS INCREASING EVIDENCE THAT CELLULAR STRESS CONDITIONS AND LOW-GRADE CHRONIC INFLAMMATORY PROCESSES ARE INVOLVED IN THE PATHOGENESIS OF PEX. ALTHOUGH THERE IS AN INCREASED RISK FOR GLAUCOMA DEVELOPMENT IN PATIENTS WITH PEX AND OCULAR HYPERTENSION AS COMPARED WITH NON-PEX PATIENTS WITH OCULAR HYPERTENSION, LOXL1 SINGLE NUCLEOTIDE POLYMORPHISMS WERE NOT ASSOCIATED WITH INTRAOCULAR PRESSURE (IOP) DIFFERENCES. LACK OF ASSOCIATION OF PEX WITH ALL-CAUSE MORTALITY OR DEMENTIA HAS BEEN REPORTED RECENTLY. THE ASSOCIATION WITH VASCULAR DISEASES IS NOT CONSISTENT AMONG DIFFERENT STUDIES. SUMMARY: DESPITE THE HIGH PREVALENCE OF THE LOXL1 VARIANTS IN THE GENERAL POPULATION, A MUCH LOWER PROPORTION OF THE POPULATION DEVELOPS PEX, SUGGESTING THAT IN ADDITION TO LOXL1, OTHER GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO THE DEVELOPMENT OF PEX. ALSO, LOXL1 CANNOT HELP TO IDENTIFY THOSE WITH PEX AT INCREASED RISK FOR GLAUCOMA DEVELOPMENT. INCREASED RISK FOR GLAUCOMA DEVELOPMENT IN PEX PATIENTS WHO PRESENT WITH INCREASED IOP MAY BE RELATED TO OTHER FACTORS BEYOND IOP, CONTRIBUTING TO INCREASED VULNERABILITY OF THE OPTIC NERVE TO GLAUCOMA DEVELOPMENT IN THE PRESENCE OF PEX.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15  5305 41 PROTEOMICS ANALYSIS OF HUMAN OBESITY REVEALS THE EPIGENETIC FACTOR HDAC4 AS A POTENTIAL TARGET FOR OBESITY. SEDENTARY LIFESTYLE AND EXCESSIVE ENERGY INTAKE ARE PROMINENT CONTRIBUTORS TO OBESITY; A MAJOR RISK FACTORS FOR THE DEVELOPMENT OF INSULIN RESISTANCE, TYPE 2 DIABETES AND CARDIOVASCULAR DISEASES. ELUCIDATING THE MOLECULAR MECHANISMS UNDERLYING THESE CHRONIC CONDITIONS IS OF RELEVANT IMPORTANCE AS IT MIGHT LEAD TO THE IDENTIFICATION OF NOVEL ANTI-OBESITY TARGETS. THE PURPOSE OF THE CURRENT STUDY IS TO INVESTIGATE DIFFERENTIALLY EXPRESSED PROTEINS BETWEEN LEAN AND OBESE SUBJECTS THROUGH A SHOT-GUN QUANTITATIVE PROTEOMICS APPROACH USING PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) EXTRACTS AS WELL AS POTENTIAL MODULATION OF THOSE PROTEINS BY PHYSICAL EXERCISE. USING THIS APPROACH, A TOTAL OF 47 PROTEINS SHOWED AT LEAST 1.5 FOLD CHANGE BETWEEN LEAN AND OBESE SUBJECTS. IN OBESE, THE PROTEOMIC PROFILING BEFORE AND AFTER 3 MONTHS OF PHYSICAL EXERCISE SHOWED DIFFERENTIAL EXPRESSION OF 38 PROTEINS. THROMBOSPONDIN 1 (TSP1) WAS AMONG THE PROTEINS THAT WERE UPREGULATED IN OBESE SUBJECTS AND THEN DECREASED BY PHYSICAL EXERCISE. CONVERSELY, THE HISTONE DEACETYLASE 4 (HDAC4) WAS DOWNREGULATED IN OBESE SUBJECTS AND THEN INDUCED BY PHYSICAL EXERCISE. THE PROTEOMIC DATA WAS FURTHER VALIDATED BY QRT-PCR, WESTERN BLOT AND IMMUNOHISTOCHEMISTRY IN BOTH PBMCS AND ADIPOSE TISSUE. WE ALSO SHOWED THAT HDAC4 LEVELS CORRELATED POSITIVELY WITH MAXIMUM OXYGEN CONSUMPTION (VO2 MAX) BUT NEGATIVELY WITH BODY MASS INDEX, PERCENT BODY FAT, AND THE INFLAMMATORY CHEMOKINE RANTES. IN FUNCTIONAL ASSAYS, OUR DATA INDICATED THAT ECTOPIC EXPRESSION OF HDAC4 SIGNIFICANTLY IMPAIRED TNF-ALPHA-DEPENDENT ACTIVATION OF NF-KAPPAB, ESTABLISHING THUS A LINK BETWEEN HDAC4 AND REGULATION OF THE IMMUNE SYSTEM. TOGETHER, THE EXPRESSION PATTERN OF HDAC4 IN OBESE SUBJECTS BEFORE AND AFTER PHYSICAL EXERCISE, ITS CORRELATION WITH VARIOUS PHYSICAL, CLINICAL AND METABOLIC PARAMETERS ALONG WITH ITS INHIBITORY EFFECT ON NF-KAPPAB ARE SUGGESTIVE OF A PROTECTIVE ROLE OF HDAC4 AGAINST OBESITY. HDAC4 COULD THEREFORE REPRESENT A POTENTIAL THERAPEUTIC TARGET FOR THE CONTROL AND MANAGEMENT OF OBESITY AND PRESUMABLY INSULIN RESISTANCE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16   487 30 ASPIRIN PROTECTS HUMAN CORONARY ARTERY ENDOTHELIAL CELLS AGAINST ATHEROGENIC ELECTRONEGATIVE LDL VIA AN EPIGENETIC MECHANISM: A NOVEL CYTOPROTECTIVE ROLE OF ASPIRIN IN ACUTE MYOCARDIAL INFARCTION. AIMS: L5 IS THE MOST NEGATIVELY CHARGED SUBFRACTION OF HUMAN LOW-DENSITY LIPOPROTEIN (LDL) AND IS THE ONLY SUBFRACTION OF LDL CAPABLE OF INDUCING APOPTOSIS IN CULTURED VASCULAR ENDOTHELIAL CELLS (ECS) BY INHIBITING FIBROBLAST GROWTH FACTOR-2 (FGF2) TRANSCRIPTION. WE EXAMINED WHETHER PLASMA L5 LEVELS ARE ELEVATED IN PATIENTS WITH ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION (STEMI) AND WHETHER ASPIRIN PROVIDES EPIGENETIC PROTECTION OF HUMAN CORONARY ARTERY ECS (HCAECS) EXPOSED TO L5. METHODS AND RESULTS: PLASMA L5 LEVELS WERE COMPARED BETWEEN PATIENTS WITH STEMI (N = 10) AND CONTROL SUBJECTS WITH CHEST PAIN SYNDROME BUT A NORMAL CORONARY ARTERIOGRAM (N = 5). L5 WAS ISOLATED FROM THE PLASMA OF STEMI PATIENTS AND CONTROL SUBJECTS, AND APOPTOSIS, FGF2 EXPRESSION, AND FGF2 PROMOTER METHYLATION WERE EXAMINED IN HCAECS TREATED WITH L5 AND ASPIRIN. PLASMA L5 LEVELS WERE SIGNIFICANTLY HIGHER IN STEMI PATIENTS THAN IN CONTROL SUBJECTS (P < 0.001). TREATMENT OF HCAECS WITH L5 RESULTED IN REDUCED SURVIVAL AND FGF2 EXPRESSION AND INCREASED CPG METHYLATION OF THE FGF2 PROMOTER. CO-TREATMENT OF HCAECS WITH L5 AND A PHYSIOLOGICALLY RELEVANT, LOW CONCENTRATION OF ASPIRIN (0.2 MM) ATTENUATED THE ADVERSE EFFECTS OF L5 ON HCAEC SURVIVAL, FGF2 EXPRESSION, AND FGF2 PROMOTER METHYLATION. IN CONTRAST, HIGH CONCENTRATIONS OF ASPIRIN (>/=1.0 MM) ACCENTUATED THE EFFECTS OF L5. CONCLUSIONS: OUR RESULTS SHOW THAT L5 LEVELS ARE SIGNIFICANTLY INCREASED IN STEMI PATIENTS. FURTHERMORE, L5 IMPAIRS HCAEC FUNCTION THROUGH CPG METHYLATION OF THE FGF2 PROMOTER, WHICH IS SUPPRESSED IN THE PRESENCE OF LOW-CONCENTRATION ASPIRIN. OUR RESULTS PROVIDE EVIDENCE OF A NOVEL MECHANISM OF ASPIRIN IN THE PREVENTION OF MI.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
17  5402 28 REDUCTION OF SIRT1-MEDIATED EPIGENETIC UPREGULATION OF NAV1.7 CONTRIBUTES TO OXALIPLATIN-INDUCED NEUROPATHIC PAIN. BACKGROUND: CLINICALLY, NEUROPATHIC PAIN IS A SEVERE SIDE EFFECT OF OXALIPLATIN CHEMOTHERAPY, WHICH USUALLY LEADS TO DOSE REDUCTION OR CESSATION OF TREATMENT. DUE TO THE UNAWARENESS OF DETAILED MECHANISMS OF OXALIPLATIN-INDUCED NEUROPATHIC PAIN, IT IS DIFFICULT TO DEVELOP AN EFFECTIVE THERAPY AND LIMITS ITS CLINICAL USE. OBJECTIVES: THE AIM OF THE PRESENT STUDY WAS TO IDENTIFY THE ROLE OF SIRTUIN 1 (SIRT1) REDUCTION IN EPIGENETIC REGULATION OF THE EXPRESSION OF VOLTAGE-GATED SODIUM CHANNELS 1.7 (NAV1.7) IN THE DORSAL ROOT GANGLION (DRG) DURING OXALIPLATIN-INDUCED NEUROPATHIC PAIN. STUDY DESIGN: CONTROLLED ANIMAL STUDY. SETTING: UNIVERSITY LABORATORY. METHODS: THE VON FREY TEST WAS PERFORMED TO EVALUATE PAIN BEHAVIOR IN RATS. REAL-TIME QUANTITATIVE POLYMERASE CHAIN REACTION, WESTERN BLOTTING, ELECTROPHYSIOLOGICAL RECORDING, CHROMATIN IMMUNOPRECIPITATION, AND SMALL INTERFERING RNA (SIRNA) WERE USED TO ILLUSTRATE THE MECHANISMS. RESULTS: IN THE PRESENT STUDY, WE FOUND THAT BOTH THE ACTIVITY AND EXPRESSION OF SIRT1 WERE SIGNIFICANTLY DECREASED IN RAT DRG FOLLOWING OXALIPLATIN TREATMENT. THE ACTIVATOR OF SIRT1, RESVERATROL, NOT ONLY INCREASED THE ACTIVITY AND EXPRESSION OF SIRT1, BUT ALSO ATTENUATED THE MECHANICAL ALLODYNIA FOLLOWING OXALIPLATIN TREATMENT. IN ADDITION, LOCAL KNOCKDOWN OF SIRT1 BY INTRATHECAL INJECTION OF SIRT1 SIRNA CAUSED MECHANICAL ALLODYNIA IN NAIVE RATS. BESIDES, OXALIPLATIN TREATMENT ENHANCED THE ACTION POTENTIAL FIRING FREQUENCY OF DRG NEURONS AND THE EXPRESSION OF NAV1.7 IN DRG AND ACTIVATION OF SIRT1 BY RESVERATROL REVERSED THIS EFFECT. FURTHERMORE, BLOCKING NAV1.7 BY PROTX II (A SELECTIVE NAV1.7 CHANNEL BLOCKER) REVERSED OXALIPLATIN-INDUCED MECHANICAL ALLODYNIA. IN ADDITION, HISTONE H3 HYPERACETYLATION AT THE NAV1.7 PROMOTER IN DRG OF RATS FOLLOWING OXALIPLATIN TREATMENT WAS SIGNIFICANTLY SUPPRESSED BY ACTIVATION OF SIRT1 WITH RESVERATROL. MOREOVER, BOTH THE EXPRESSION OF NAV1.7 AND HISTONE H3 ACETYLATION AT THE NAV1.7 PROMOTER WERE UPREGULATED IN THE DRG BY LOCAL KNOCKDOWN OF SIRT1 WITH SIRT1 SIRNA IN NAIVE RATS. LIMITATIONS: MORE UNDERLYING MECHANISM(S) OF SIRT1 REDUCTION AFTER OXALIPLATIN TREATMENT NEEDS TO BE EXPLORED IN FUTURE RESEARCH. CONCLUSIONS: THESE FINDINGS SUGGEST THAT REDUCTION OF SIRT1-MEDIATED EPIGENETIC UPREGULATION OF NAV1.7 IN THE DRG CONTRIBUTES TO THE DEVELOPMENT OF OXALIPLATIN-INDUCED NEUROPATHIC PAIN IN RATS. THE INTRATHECAL DRUG DELIVERY TREATMENT OF ACTIVATING SIRT1 MIGHT BE A NOVEL THERAPEUTIC OPTION FOR OXALIPLATIN-INDUCED NEUROPATHIC PAIN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  1236 25 CURCUMIN AMELIORATES NEPHROSCLEROSIS VIA SUPPRESSION OF HISTONE ACETYLATION INDEPENDENT OF HYPERTENSION. BACKGROUND: ALTHOUGH HISTONE ACETYLATION, AN EPIGENETIC MODIFICATION, HAS BEEN REPORTED TO BE RELATED TO THE PROGRESSION OF VARIOUS DISEASES, ITS INVOLVEMENT IN NEPHROSCLEROSIS IS UNCLEAR. METHODS: DAHL SALT-SENSITIVE RATS WERE USED AS A MODEL OF NEPHROSCLEROSIS IN THIS STUDY. THE RATS WERE DIVIDED INTO THREE GROUPS: (I) NORMAL-SALT DIET GROUP, (II) HIGH-SALT DIET GROUP (HS), AND (III) HS ADMINISTERED DAILY WITH CURCUMIN, A HISTONE ACETYLTRANSFERASE INHIBITOR (HS+C). AT 6 WEEKS AFTER THE TREATMENT, THE KIDNEYS WERE DISSECTED. MORPHOLOGIC CHANGES WERE ASSESSED BY MASSON'S TRICHROME STAINING. THE NUMBER OF MACROPHAGES, FIBROBLASTS AND THE CELLS EXPRESSING ACETYLATED HISTONE H3 AT LYS 9 (H3K9) WERE ASSESSED BY IMMUNOHISTOCHEMISTRY. RESULTS: ALTHOUGH BOTH HS AND HS+C RATS REVEALED A MARKED INCREASE IN SYSTOLIC BLOOD PRESSURE, SERUM CREATININE WAS INCREASED ONLY IN HS RATS AT 6 WEEKS. IN THE HS RATS, NEPHROSCLEROSIS WAS INDUCED, ACCOMPANYING A SIGNIFICANT ACCUMULATION OF MACROPHAGES AND FIBROBLASTS. THE INFLAMMATION AND FIBROSIS WAS MARKEDLY SUPPRESSED IN THE HS+C GROUP. THE LEVEL OF HISTONE ACETYLATION AT LYS 9 WAS ENHANCED IN THE HS RATS, WHEREAS CURCUMIN ADMINISTRATION SUPPRESSED THE HISTONE ACETYLATION. MOREOVER, IN THE HS RATS, INTERLEUKIN-6 GENE EXPRESSION WAS ASSOCIATED WITH ACETYLATED H3K9, AS REVEALED BY CHROMATIN IMMUNOPRECIPITATION ASSAY. CONCLUSIONS: OUR RESULTS SUGGESTED THAT CURCUMIN AMELIORATES NEPHROSCLEROSIS VIA SUPPRESSION OF HISTONE ACETYLATION, INDEPENDENTLY OF HYPERTENSION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19  4359 35 MIR-422A SUPPRESSES SMAD4 PROTEIN EXPRESSION AND PROMOTES RESISTANCE TO MUSCLE LOSS. BACKGROUND: LOSS OF MUSCLE MASS AND STRENGTH ARE IMPORTANT SEQUELAE OF CHRONIC DISEASE, BUT THE RESPONSE OF INDIVIDUALS IS REMARKABLY VARIABLE, SUGGESTING IMPORTANT GENETIC AND EPIGENETIC MODULATORS OF MUSCLE HOMEOSTASIS. SUCH FACTORS ARE LIKELY TO MODIFY THE ACTIVITY OF PATHWAYS THAT REGULATE WASTING, BUT TO DATE, FEW SUCH FACTORS HAVE BEEN IDENTIFIED. METHODS: THE EFFECT OF MIR-422A ON SMAD4 EXPRESSION AND TRANSFORMING GROWTH FACTOR (TGF)-BETA SIGNALLING WERE DETERMINED BY WESTERN BLOTTING AND LUCIFERASE ASSAY. MIRNA EXPRESSION WAS DETERMINED BY QPCR IN PLASMA AND MUSCLE BIOPSY SAMPLES FROM A CROSS-SECTIONAL STUDY OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND A LONGITUDINAL STUDY OF PATIENTS UNDERGOING AORTIC SURGERY, WHO WERE SUBSEQUENTLY ADMITTED TO THE INTENSIVE CARE UNIT (ICU). RESULTS: MIR-422A WAS IDENTIFIED, BY A SCREEN, AS A MICRORNA THAT WAS PRESENT IN THE PLASMA OF PATIENTS WITH COPD AND NEGATIVELY ASSOCIATED WITH MUSCLE STRENGTH AS WELL AS BEING READILY DETECTABLE IN THE MUSCLE OF PATIENTS. IN VITRO, MIR-422A SUPPRESSED SMAD4 EXPRESSION AND INHIBITED TGF-BETA AND BONE MORPHOGENETIC PROTEIN-DEPENDENT LUCIFERASE ACTIVITY IN MUSCLE CELLS. IN MALE PATIENTS WITH COPD AND THOSE UNDERGOING AORTIC SURGERY AND ON THE ICU, A MODEL OF ICU-ASSOCIATED MUSCLE WEAKNESS, QUADRICEPS EXPRESSION OF MIR-422A WAS POSITIVELY ASSOCIATED WITH MUSCLE STRENGTH (MAXIMAL VOLUNTARY CONTRACTION R = 0.59, P < 0.001 AND R = 0.51, P = 0.004, FOR COPD AND AORTIC SURGERY, RESPECTIVELY). FURTHERMORE, PRE-SURGERY LEVELS OF MIR-422A WERE INVERSELY ASSOCIATED WITH THE AMOUNT OF MUSCLE THAT WOULD BE LOST IN THE FIRST POST-OPERATIVE WEEK (R = -0.57, P < 0.001). CONCLUSIONS: THESE DATA SUGGEST THAT DIFFERENCES IN MIR-422A EXPRESSION CONTRIBUTE TO THE SUSCEPTIBILITY TO MUSCLE WASTING ASSOCIATED WITH CHRONIC AND ACUTE DISEASE AND THAT AT LEAST PART OF THIS ACTIVITY MAY BE MEDIATED BY REDUCED TGF-BETA SIGNALLING IN SKELETAL MUSCLE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20  1781 22 EFFECT OF 1 YEAR B AND D VITAMIN SUPPLEMENTATION ON LINE-1 REPETITIVE ELEMENT METHYLATION IN OLDER SUBJECTS. BACKGROUND: DISTURBED DNA METHYLATION IS CAUSALLY RELATED TO CHRONIC DISEASES LIKE CANCER AND ATHEROSCLEROSIS. B VITAMINS ARE COFACTORS REQUIRED FOR METHYL GROUP SYNTHESIS AND MAY THEREFORE AFFECT DNA METHYLATION. VITAMIN D HAS EPIGENETIC EFFECTS. WE TESTED IF B AND D VITAMIN SUPPLEMENTATION HAS AN EFFECT ON GENOMIC LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) METHYLATION AND THE METABOLITES S-ADENOSYLMETHIONINE (SAM) AND S-ADENOSYLHOMOCYSTEINE (SAH). METHODS: FIFTY SUBJECTS (MEDIAN AGE 68.0 YEARS) WERE SUPPLEMENTED WITH A DAILY ORAL DOSE OF B VITAMINS (500 MICROG FOLIC ACID, 500 MICROG VITAMIN B12 AND 50 MG VITAMIN B6), 1200 IU VITAMIN D AND 456 MG CALCIUM. FASTING BLOOD SAMPLES WERE COLLECTED BEFORE AND AFTER 1 YEAR OF SUPPLEMENTATION. LINE-1 METHYLATION WAS DETERMINED IN GENOMIC DNA FROM BLOOD CELLS AS A SURROGATE FOR WHOLE GENOME METHYLATION. IN ADDITION, SAM, SAH AND TOTAL HOMOCYSTEINE (THCY) WERE MEASURED IN PLASMA SAMPLES. RESULTS: PLASMA HOMOCYSTEINE DECREASED SIGNIFICANTLY AFTER SUPPLEMENTATION (12.8 VS. 9.1 MICROMOL/L; P<0.05), WHEREAS SAM, SAH, THE SAM/SAH RATIO AND LINE-1 METHYLATION DID NOT CHANGE SIGNIFICANTLY. LINE-1 METHYLATION WAS NOT SIGNIFICANTLY CORRELATED WITH SAH, HOMOCYSTEINE OR B VITAMINS. CONCLUSIONS: LONG-TERM VITAMIN B SUPPLEMENTATION HAD NO EFFECT ON LINE-1 METHYLATION IN BLOOD CELLS NOR ON PLASMA LEVELS OF SAM AND SAH. VITAMIN B AND D SUPPLEMENTATION SEEMS TO HAVE NO EFFECT ON DNA METHYLATION, ESPECIALLY IN CASES WHERE NO SEVERE DEFICIENCY EXISTS.	2013