1  1997 115 EPIGENETIC AND INFLAMMATORY EVENTS IN EXPERIMENTAL PERIODONTITIS FOLLOWING SYSTEMIC MICROBIAL CHALLENGE. AIM: THE PURPOSE OF THIS STUDY WAS TO DETERMINE INFLAMMATORY AND EPIGENETIC FEATURES FOLLOWING INDUCTION OF ORAL AND GUT DYSBIOSIS IN EXPERIMENTAL PERIODONTITIS IN ORDER TO EXAMINE THE INTERPLAY BETWEEN ORAL AND SYSTEMIC INFECTION. MATERIALS AND METHODS: PERIODONTITIS WAS INDUCED IN 6- TO 8-WEEK-OLD C57BL/6 MICE BY (A) LIGATURE PLACEMENT (LIG GROUP) (ORAL CHALLENGE); (B) P. GINGIVALIS GAVAGE (PG GROUP) (SYSTEMIC CHALLENGE); AND (C) THE COMBINATION OF THE TWO MODELS ORAL AND SYSTEMIC CHALLENGE (PG + LIG). THE DURATION OF THE EXPERIMENT WAS 60 DAYS, AND THE ANIMALS WERE THEN SACRIFICED FOR ANALYSES. ALVEOLAR BONE LOSS WAS ASSESSED, AND A MULTIPLEX IMMUNOASSAY WAS PERFORMED. MAXILLAE AND GUT TISSUES WERE IMMUNOSTAINED FOR DNMT3B (DE NOVO METHYLATION MARKER), B AND T LYMPHOCYTE ATTENUATOR (BTLA) AND IL-18R1 (INFLAMMATION MARKERS). RESULTS: PG AND PG + LIG GROUPS EXHIBITED HIGHER BONE LOSS WHEN COMPARED TO SHAM. BAFF, VEGF, RANKL, RANTES AND IP-10 WERE SIGNIFICANTLY HIGHER WITH PG GAVAGE. LIKEWISE, DNMT3B WAS OVEREXPRESSED IN BOTH GUT AND MAXILLA AFTER THE PG ADMINISTRATION. THE SAME PATTERN WAS OBSERVED FOR BTLA AND IL-18R1 IN GUT TISSUES. CONCLUSIONS: THE SYSTEMIC MICROBIAL CHALLENGE EITHER ALONE OR IN COMBINATION WITH LOCAL CHALLENGE LEADS TO DISTINCT PATTERNS OF INFLAMMATORY AND EPIGENETIC FEATURES WHEN COMPARED TO SIMPLY LOCALLY INDUCED EXPERIMENTAL PERIODONTITIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2   703  23 BTLA EXPRESSION IN CLL: EPIGENETIC REGULATION AND IMPACT ON CLL B CELL PROLIFERATION AND ABILITY TO IL-4 PRODUCTION. IN OUR PREVIOUS STUDY, WHILE CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CASES SHOWED HIGHER LEVELS OF B AND T LYMPHOCYTE ATTENUATOR (BTLA) MRNA COMPARED TO CONTROLS, LOWER BTLA PROTEIN EXPRESSION WAS OBSERVED IN CASES COMPARED TO CONTROLS. HENCE WE HYPOTHESIZE THAT MICRO RNA (MIR) 155-5P REGULATES BTLA EXPRESSION IN CLL. IN LINE WITH EARLIER DATA, EXPRESSION OF BTLA MRNA AND MIR-155-5P IS ELEVATED IN CLL (P = 0.034 AND P = 0.0006, RESPECTIVELY) AS WELL AS IN MEC-1 CELL LINE (P = 0.009 AND 0.016, RESPECTIVELY). INHIBITION OF MIR-155-5P PARTIALLY RESTORED BTLA PROTEIN EXPRESSION IN CLL PATIENTS (P = 0.01) AND IN MEC-1 CELL LINES (P = 0.058). ADDITIONALLY, WE AIMED TO EVALUATE THE SIGNIFICANCE OF BTLA DEFICIENCY IN CLL CELLS ON PROLIFERATION AND IL-4 PRODUCTION OF B CELLS. WE FOUND THAT SECRETION OF IL-4 IS NOT DEPENDENT ON BTLA EXPRESSION, SINCE FRACTIONS OF BTLA POSITIVE AND BTLA NEGATIVE B CELLS EXPRESSING INTRACELLULAR IL-4 WERE SIMILAR IN CLL PATIENTS AND CONTROLS. WE DEMONSTRATED THAT IN CONTROLS THE FRACTION OF PROLIFERATING CELLS IS LOWER IN BTLA POSITIVE THAN IN BTLA NEGATIVE B CELLS (P = 0.059), WHICH WAS NOT OBSERVED IN CLL. HOWEVER, THE FREQUENCY OF BTLA POSITIVE KI67+ B CELLS IN CLL WAS HIGHER COMPARED TO CORRESPONDING CELLS FROM CONTROLS (P = 0.055) WHILE THERE WERE NO DIFFERENCES BETWEEN THE EXAMINED GROUPS REGARDING FREQUENCY OF BTLA NEGATIVE KI67+ B CELLS. OUR STUDIES SUGGEST THAT MIR-155-5P IS INVOLVED IN BTLA DEFICIENCY, AFFECTING PROLIFERATION OF CLL B CELLS, WHICH MAY BE ONE OF THE MECHANISMS RESPONSIBLE FOR CLL PATHOGENESIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
3  3832  20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4  6918  25 [WNT3A SIGNALING PATHWAY PLAYS A ROLE IN NEUROPATHIC PAIN THROUGH EPIGENETIC MODIFICATION OF JMJD6]. TO EXPLORE WHETHER WNT3A EXERTS A ROLE IN NEUROPATHIC PAIN THROUGH JUMONJI C DOMAIN 6 (JMJD6)-ASSOCIATED EPIGENETIC MODIFICATION. METHODS: SD RATS WERE DIVIDED INTO 4 GROUPS: A SHAM GROUP, A CHRONIC CONSTRICTION INJURY (CCI) GROUP, A CCI+NEGATIVE LENTIVIRAL EXPRESSION VECTOR (LV-NC) GROUP AND A CCI+LENTIVIRAL OVEREXPRESSION VECTOR (LV-JMJD6) GROUP. THE SCIATIC NERVE CCI MODEL OF SD RAT AND JMJD6 LENTIVIRAL EXPRESSION VECTOR WERE CONSTRUCTED. ON THE THIRD DAY AFTER CCI, THE INTRATHECAL CATHETER WAS PREPARED, AND 20 MUL OF NORMAL SALINE AND LENTIVIRUS-CONTAINING REAGENT (VIRUS TITER 1X108 TU/ML) WERE ADMINISTERED. THE RATS' PAW WITHDRAWAL MECHANICAL THRESHOLD (PWMT) AND PAW WITHDRAWAL THERMAL LATENCY (PWTL) WERE MONITORED, AND WESTERN BLOTTING WAS USED TO DETECT THE EXPRESSION OF WNT3A AND NR2B PROTEIN IN THE SPINAL CORD. CO-IMMUNOPRECIPITATION WAS APPLIED TO DETECT THE INTERACTION BETWEEN JMJD6 AND WNT3A. RESULTS: COMPARED WITH THE SHAM GROUP, THE PWMT OF THE RATS IN EACH GROUP AFTER CCI WAS SIGNIFICANTLY DECREASED AND THE PWTL WAS SIGNIFICANTLY SHORTENED (P<0.05). COMPARED WITH THE CCI GROUP AND THE CCI+LV-NC GROUP, PWMT IN THE CCI+LV-JMJD6 GROUP WAS INCREASED SIGNIFICANTLY ON THE 10TH DAY AND THE 14TH DAY AFTER CCI, AND THE PWTL WAS SIGNIFICANTLY PROLONGED ON THE 14TH DAY AFTER CCI (P<0.05). ON THE 14TH DAY AFTER CCI, THE EXPRESSION LEVELS OF WNT3A AND NR2B IN THE CCI GROUP AND THE CCI+LV-NC GROUP WERE SIGNIFICANTLY HIGHER THAN THOSE IN THE SHAM GROUP. AFTER INTRATHECAL INJECTION OF LENTIVIRAL VECTOR, WNT3A AND NR2B PROTEIN EXPRESSION LEVELS IN THE CCI+LV-JMJD6 GROUP WERE LOWER COMPARED WITH THE CCI+LV-NC GROUP (P<0.05). THE RESULTS OF CO-IMMUNOPRECIPITATION SHOWED NO DIRECT INTERACTION BETWEEN WNT3A AND JMJD6. CONCLUSION: WNT3A IS INVOLVED IN MEDIATING NEUROPATHIC PAIN, AND ITS EFFECT MAY BE RELATED TO THE EPIGENETIC MODIFICATION OF JMJD6, WHICH IS LIKELY REGULATED THROUGH INDIRECT INTERACTION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  6085  23 THE EFFECTS OF ACARBOSE ON CHEMOKINE AND CYTOKINE PRODUCTION IN HUMAN MONOCYTIC THP-1 CELLS. BACKGROUND AND OBJECTIVES: CHRONIC INFLAMMATION INDUCED BY PROINFLAMMATORY CYTOKINES AND CHEMOKINES IS POSTULATED TO BE INVOLVED IN INSULIN RESISTANCE AND BETA-CELL DYSFUNCTION IN TYPE 2 DIABETES MELLITUS (T2DM). ACARBOSE, THE ALPHA-GLUCOSIDASE INHIBITOR, IS AN ORAL ANTIDIABETIC DRUG FOR T2DM. ACARBOSE SUPPRESSES INFLAMMATORY CYTOKINE PRODUCTION IN PATIENTS WITH T2DM, THOUGH THE UNDERLYING MECHANISMS ARE UNCLEAR. IN THE PRESENT STUDY, WE AIMED TO INVESTIGATE THE ANTI-INFLAMMATORY EFFECTS AND THE EXACT MECHANISMS OF ACARBOSE IN HUMAN MONOCYTIC THP-1 CELLS. METHODS: THP-1 CELLS WERE PRETREATED WITH ACARBOSE AND THEN STIMULATED WITH LIPOPOLYSACCHARIDE (LPS). THE LEVELS OF TH1-RELATED CHEMOKINES, INCLUDING INTERFERON-GAMMA-INDUCIBLE PROTEIN-10 (IP-10), MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1), TH2-RELATED CHEMOKINE MACROPHAGE-DERIVED CHEMOKINE (MDC), AND PROINFLAMMATORY CYTOKINE TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), WERE DETERMINED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. INTRACELLULAR SIGNALING PATHWAYS WERE EXPLORED BY WESTERN BLOT ANALYSIS AND USING A CHROMATIN IMMUNOPRECIPITATION ASSAY. RESULTS: ACARBOSE SUPPRESSED THE LEVELS OF IP-10, MCP-1, MDC, AND TNF-ALPHA AND DOWNREGULATED PHOSPHORYLATION OF P38, C-JUN N-TERMINAL KINASE (JNK), EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK), AND NUCLEAR FACTOR-KAPPA B-P65 (NF-KAPPAB-P65) IN LPS-STIMULATED THP-1 CELLS. ACARBOSE SUPPRESSED LPS-INDUCED ACETYLATION OF HISTONES H3 (H3) AND H4 IN THE IP-10 AND MCP-1 PROMOTER REGIONS. THESE FINDINGS REVEALED THE SUPPRESSIVE EFFECTS OF ACARBOSE ON IP-10, MCP-1, MDC, AND TNF-ALPHA PRODUCTION IN THP-1 CELLS VIA, AT LEAST PARTIALLY, THE P38, JNK, ERK, AND NF-KAPPAB-P65 PATHWAYS, AS WELL AS THROUGH EPIGENETIC REGULATION VIA HISTONE H3 AND H4 ACETYLATION. CONCLUSION: OUR STUDY POINTS TO THE THERAPEUTIC ANTI-INFLAMMATORY POTENTIAL OF ACARBOSE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6   809  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7  3868  26 JMJD6 EXERTS FUNCTION IN NEUROPATHIC PAIN BY REGULATING NF?KAPPAB FOLLOWING PERIPHERAL NERVE INJURY IN RATS. TREATMENT OF NEUROPATHIC PAIN (NPP) CONTINUES TO BE A MAJOR CHALLENGE, AND THE UNDERLYING MECHANISMS REMAIN TO BE ELUCIDATED. PREVIOUS STUDIES HAVE DEMONSTRATED THAT HISTONE METHYLATION IS IMPORTANT IN SYNAPTIC PLASTICITY OF THE NERVOUS SYSTEM AND MAY AFFECT NUCLEAR FACTOR?KAPPAB (NF?KAPPAB) SIGNALING THROUGH EPIGENETIC MECHANISMS. THE PRESENT STUDY AIMED TO INVESTIGATE THE ROLE OF JUMONJI C DOMAIN 6 (JMJD6), A HISTONE DEMETHYLASE, IN A CHRONIC CONSTRICTION INJURY (CCI) MODEL OF NPP. ON THE THIRD DAY POST?CCI SURGERY, A JMJD6 OVEREXPRESSING LENTIVIRAL VECTOR (LV?JMJD6) WAS INTRATHECALLY INJECTED IN THE RATS. MECHANICAL WITHDRAWAL THRESHOLD AND THERMAL WITHDRAWAL LATENCY WERE ASSESSED PRIOR SURGERY AND ON DAYS 3, 7, 10 AND 14 POST?CCI. THE RESULTS SHOWED THAT INTRATHECAL INJECTION WITH THE LV?JMJD6 ATTENUATED CCI?INDUCED PAIN FACILITATION. THE EXPRESSION OF JMJD6 WAS LOWER FOLLOWING CCI SURGERY, AND ITS EXPRESSION WAS SIGNIFICANTLY INCREASED FOLLOWING INTRATHECAL INJECTION WITH LV?JMJD6, COMPARED WITH LEVELS IN NORMAL SALINE (NS)? AND NEGATIVE CONTROL LENTIVIRAL VECTOR (NC)?TREATED RATS. THE EXPRESSION OF SPINAL NF?KAPPAB PHOSPHORYLATED (P?)P65 SUBUNIT AND ITS DOWNSTREAM PAIN?ASSOCIATED EFFECTORS, INCLUDING INTERLEUKIN 1BETA (IL?1BETA), TUMOR NECROSIS FACTOR?ALPHA (TNF?ALPHA) AND VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), WERE INCREASED FOLLOWING CCI SURGERY. INTRATHECAL INJECTION WITH LV?JMJD6 SUPPRESSED ACTIVATION OF THE P?P65 SUBUNIT IN CCI RATS. IN ADDITION, EXPRESSION LEVELS OF ITS DOWNSTREAM EFFECTORS IL?1BETA, TNF?ALPHA AND VEGF WERE ATTENUATED BY INTRATHECAL TREATMENT WITH LV?JMJD6, COMPARED WITH THOSE IN THE NS? AND NC?TREATED CCI RATS. FURTHERMORE, THE JMJD6? AND P65?IMMUNOREACTIVE CELLS OVERLAPPED IN THE SPINAL DORSAL HORN, HOWEVER, CO?IMMUNOPRECIPITATION SHOWED THAT JMJD6 AND THE NF?KAPPAB P65 SUBUNIT DID NOT DIRECTLY INTERACT, INDICATING OTHER FUNCTIONAL CONNECTIONS MAY EXIST BETWEEN THESE FACTORS FOLLOWING CCI SURGERY. COLLECTIVELY, THESE FINDINGS INDICATED AN IMPORTANT MECHANISM UNDERLYING THE PATHOGENESIS OF NPP. JMJD6 MAY EXERT ITS THERAPEUTIC FUNCTION IN NPP BY REGULATING NF?KAPPAB FOLLOWING CCI.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                     
8  5868  22 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9  2311  21 EPIGENETIC REGULATION OF CYTOSOLIC PHOSPHOLIPASE A2 IN SH-SY5Y HUMAN NEUROBLASTOMA CELLS. GROUP IVA CYTOSOLIC PHOSPHOLIPASE A2 (CPLA2 OR PLA2G4A) IS A KEY ENZYME THAT CONTRIBUTES TO INFLAMMATION VIA THE GENERATION OF ARACHIDONIC ACID AND EICOSANOIDS. WHILE MUCH IS KNOWN ABOUT REGULATION OF CPLA2 BY POSTTRANSLATIONAL MODIFICATION SUCH AS PHOSPHORYLATION, LITTLE IS KNOWN ABOUT ITS EPIGENETIC REGULATION. IN THIS STUDY, TREATMENT WITH HISTONE DEACETYLASE (HDAC) INHIBITORS, TRICHOSTATIN A (TSA), VALPROIC ACID, TUBACIN AND THE CLASS I HDAC INHIBITOR, MS-275, WERE FOUND TO INCREASE CPLA2ALPHA MESSENGER RNA (MRNA) EXPRESSION IN SH-SY5Y HUMAN NEUROBLASTOMA CELLS. CO-TREATMENT OF THE HISTONE ACETYLTRANSFERASE (HAT) INHIBITOR, ANACARDIC ACID, MODULATED UPREGULATION OF CPLA2ALPHA INDUCED BY TSA. SPECIFIC INVOLVEMENT OF CLASS I HDACS AND HAT IN CPLA2ALPHA REGULATION WAS FURTHER SHOWN, AND A TIP60-SPECIFIC HAT INHIBITOR, NU9056, MODULATED THE UPREGULATION OF CPLA2ALPHA INDUCED BY MS-275. IN ADDITION, CO-TREATMENT OF WITH HISTONE METHYLTRANSFERASE (HMT) INHIBITOR, 5'-DEOXY-5'-METHYLTHIOADENOSINE (MTA) SUPPRESSED TSA-INDUCED CPLA2ALPHA UPREGULATION. THE ABOVE CHANGES IN CPLA2 MRNA EXPRESSION WERE REFLECTED AT THE PROTEIN LEVEL BY WESTERN BLOTS AND IMMUNOCYTOCHEMISTRY. CHROMATIN IMMUNOPRECIPITATION (CHIP) SHOWED TSA INCREASED BINDING OF TRIMETHYLATED H3K4 TO THE PROXIMAL PROMOTER REGION OF THE CPLA2ALPHA GENE. CELL INJURY AFTER TSA TREATMENT AS INDICATED BY LACTATE DEHYDROGENASE (LDH) RELEASE WAS MODULATED BY ANACARDIC ACID, AND A ROLE OF CPLA2 IN MEDIATING TSA-INDUCED INJURY SHOWN, AFTER CO-INCUBATION WITH THE CPLA2 SELECTIVE INHIBITOR, ARACHIDONOYL TRIFLUOROMETHYL KETONE (AACOCF3). TOGETHER, RESULTS INDICATE EPIGENETIC REGULATION OF CPLA2 AND THE POTENTIAL OF SUCH REGULATION FOR TREATMENT OF CHRONIC INFLAMMATION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
10   428  20 ANTI-INFLAMMATORY ACTIVITY OF MIODESIN: MODULATION OF INFLAMMATORY MARKERS AND EPIGENETIC EVIDENCE. PURPOSE: TO INVESTIGATE THE EFFECTS OF A COMBINED HERBAL MEDICINE MIODESIN ON THE INFLAMMATORY RESPONSE OF KEY CELLS INVOLVED IN THE ACUTE AND CHRONIC INFLAMMATORY PROCESSES AS WELL AS THE POSSIBLE EPIGENETIC INVOLVEMENT. METHODS: AFTER THE ESTABLISHMENT OF THE IC(50) DOSE, THE CHONDROCYTE, KERATINOCYTE, AND MACROPHAGE CELL LINES WERE PRETREATED FOR 2 HOURS WITH MIODESIN (200 MUG/ML) AND STIMULATED WITH LPS (1 MUG/ML) FOR 24 HOURS. THE SUPERNATANT WAS USED TO MEASURE THE LEVELS OF CYTOKINES (IL-1BETA, IL-6, IL-8, AND TNF-ALPHA) AND CHEMOKINES (CCL2, CCL3, AND CCL5), AND THE CELLS WERE USED TO EXTRACT THE MRNA FOR THE TRANSCRIPTION FACTOR (NF-KAPPABETA), INFLAMMATORY ENZYMES (COX-1, COX-2, PLA2, AND INOS), AND CHEMOKINES (CCL2, CCL3, AND CCL5). RESULTS: MIODESIN INHIBITED THE RELEASE OF LPS-INDUCED CYTOKINES (IL-1BETA, IL-6, IL-8, AND TNF-ALPHA; P < 0.01) AND CHEMOKINES (CCL2, CCL3, AND CCL5; P < 0.01) AND THE EXPRESSION OF THE TRANSCRIPTION FACTOR (NF-KAPPABETA; P < 0.01), INFLAMMATORY ENZYMES (COX-1, COX-2, PLA2, INOS; P < 0.01), AND CHEMOKINES (CCL2, CCL3, AND CCL5; P < 0.01). IN ADDITION, THE EVALUATION OF EPIGENETIC MECHANISM REVEALED THAT MIODESIN DID NOT INDUCE CHANGES IN DNA METHYLATION, ASSURING THE GENETIC SAFENESS OF THE COMPOUND IN TERMS OF THE INFLAMMATORY RESPONSE. CONCLUSIONS: MIODESIN PRESENTS ANTI-INFLAMMATORY PROPERTIES, INHIBITING HYPERACTIVATION OF CHONDROCYTES, KERATINOCYTES, AND MACROPHAGES, INVOLVING EPIGENETICS IN SUCH EFFECTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
11  6612  27 ULTRA-LOW-DOSE NALOXONE ENHANCES THE ANTINOCICEPTIVE EFFECT OF MORPHINE IN PTX-TREATED RATS: REGULATION ON GLOBAL HISTONE METHYLATION. OBJECTIVE: EPIGENETIC REPROGRAMMING MAY HAVE A POSSIBLE ROLE IN NEUROPATHIC PAIN DEVELOPMENT; THE PRESENT STUDY EXAMINED THE GLOBAL PATTERNS OF LYSINE HISTONE MODIFICATION. IN THIS SERIAL STUDY WE ANALYZED THE LEVELS OF HISTONE 3 LYSINE 4 MONOMETHYLATION, HISTONE 3 LYSINE 4 DIMETHYLATION, AND HISTONE 3 LYSINE 9 TRIMETHYLATION IN PERTUSSIS TOXIN (PTX)-INDUCED THERMAL HYPERALGESIC RAT SPINAL CORDS. METHODS: MALE WISTAR RATS IMPLANTED WITH AN INTRATHECAL CATHETER RECEIVED A SINGLE INTRATHECAL PTX (1 MUG IN 5 MUL SALINE) INJECTION. FOUR DAYS LATER, THEY WERE RANDOMLY ASSIGNED TO RECEIVE EITHER A SINGLE INJECTION OF SALINE, OR ULTRA-LOW-DOSE NALOXONE (15 NG IN 5 MUL SALINE), FOLLOWED BY MORPHINE (10 MUG IN 5 MUL SALINE) INJECTION 30 MINUTES LATER. RESULTS: THE RESULTS SHOWED THAT PTX INJECTION INDUCED THERMAL HYPERALGESIA AND SIGNIFICANT INCREASE OF GLOBAL HISTONE METHYLATION IN THE SPINAL CORDS. INTRATHECAL MORPHINE ALONE DID NOT AFFECT THE THERMAL HYPERALGESIA AND GLOBAL HISTONE METHYLATION. IN CONTRAST, INTRATHECAL ADMINISTRATION OF ULTRA-LOW-DOSE NALOXONE PLUS MORPHINE SIGNIFICANTLY ATTENUATED THE PTX-INDUCED THERMAL HYPERALGESIA AND DOWN-REGULATED THE GLOBAL HISTONE METHYLATION. CONCLUSION: THE RESULTS SUGGEST THAT ULTRA-LOW-DOSE NALOXONE MIGHT BE CLINICAL VALUABLE FOR NEUROPATHIC PAIN MANAGEMENT VIA REGULATING GLOBAL HISTONE MODIFICATION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12  5781  23 SPINAL SIRT1 ACTIVATION ATTENUATES NEUROPATHIC PAIN IN MICE. ABNORMAL HISTONE ACETYLATION OCCURS DURING NEUROPATHIC PAIN THROUGH AN EPIGENETIC MECHANISM. SILENT INFORMATION REGULATOR 1 (SIR2 OR SIRT1), A NAD-DEPENDENT DEACETYLASE, PLAYS COMPLEX SYSTEMIC ROLES IN A VARIETY OF PROCESSES THROUGH DEACETYLATING ACETYLATED HISTONE AND OTHER SPECIFIC SUBSTRATES. BUT THE ROLE OF SIRT1 IN NEUROPATHIC PAIN IS NOT WELL ESTABLISHED YET. THE PRESENT STUDY WAS INTENDED TO DETECT SIRT1 CONTENT AND ACTIVITY, NICOTINAMIDE (NAM) AND NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD) IN THE SPINAL CORD USING IMMUNOBLOTTING OR MASS SPECTROSCOPY OVER TIME IN MICE FOLLOWING CHRONIC CONSTRICTION INJURY (CCI) OR SHAM SURGERY. IN ADDITION, THE EFFECT OF INTRATHECAL INJECTION OF NAD OR RESVERATROL ON THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA WAS EVALUATED IN CCI MICE. FINALLY, WE INVESTIGATED WHETHER SIRT1 INHIBITOR EX-527 COULD REVERSE THE ANTI-NOCICEPTIVE EFFECT OF NAD OR RESVERATROL. IT WAS FOUND THAT SPINAL SIRT1 EXPRESSION, DEACETYLASE ACTIVITY AND NAD/NAM DECREASED SIGNIFICANTLY 1, 3, 7, 14 AND 21 DAYS AFTER CCI SURGERY AS COMPARED WITH SHAM GROUP. IN ADDITION, DAILY INTRATHECAL INJECTION OF 5 MICROL 800 MM NAD 1 H BEFORE AND 1 DAY AFTER CCI SURGERY OR SINGLE INTRATHECAL INJECTION OF 5 MICROL 90 MM RESVERATROL 1 H BEFORE CCI SURGERY PRODUCED A TRANSIENT INHIBITORY EFFECT ON THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA IN CCI MICE. FINALLY, AN INTRATHECAL INJECTION OF 5 MICROL 1.2 MM EX-527 1 H BEFORE NAD OR RESVERATROL ADMINISTRATION REVERSED THE ANTI-NOCICEPTIVE EFFECT OF NAD OR RESVERATROL. THESE DATA INDICATE THAT THE REDUCTION IN SIRT1 DEACETYLASE ACTIVITY MAY BE A FACTOR CONTRIBUTING TO THE DEVELOPMENT OF NEUROPATHIC PAIN IN CCI MICE. OUR FINDINGS SUGGEST THAT THE ENHANCEMENT OF SPINAL NAD/NAM AND/OR SIRT1 ACTIVITY MAY BE A POTENTIALLY PROMISING STRATEGY FOR THE PREVENTION OR TREATMENT OF NEUROPATHIC PAIN.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13  2006  18 EPIGENETIC AUGMENTATION OF THE MACROPHAGE INFLAMMATORY PROTEIN 2/C-X-C CHEMOKINE RECEPTOR TYPE 2 AXIS THROUGH HISTONE H3 ACETYLATION IN INJURED PERIPHERAL NERVES ELICITS NEUROPATHIC PAIN. ALTHOUGH THERE IS GROWING EVIDENCE SHOWING THAT THE INVOLVEMENT OF CHEMOKINES IN THE PATHOGENESIS OF NEUROPATHIC PAIN IS ASSOCIATED WITH NEUROINFLAMMATION, THE DETAILS ARE UNCLEAR. WE INVESTIGATED THE C-X-C CHEMOKINE LIGAND TYPE 2 [MACROPHAGE INFLAMMATORY PROTEIN 2 (MIP-2)]/C-X-C CHEMOKINE RECEPTOR TYPE 2 (CXCR2) AXIS AND EPIGENETIC REGULATION OF THESE MOLECULES IN NEUROPATHIC PAIN AFTER PERIPHERAL NERVE INJURY. EXPRESSION OF MIP-2 AND CXCR2 WERE UP-REGULATED AND LOCALIZED ON ACCUMULATED NEUTROPHILS AND MACROPHAGES IN THE INJURED SCIATIC NERVE (SCN) AFTER PARTIAL SCIATIC NERVE LIGATION (PSL). PERINEURAL INJECTION OF MIP-2-NEUTRALIZING ANTIBODY (ANTI-MIP-2) OR THE CXCR2 ANTAGONIST N-(2-BROMOPHENYL)-N'-(2-HYDROXY-4-NITROPHENYL)UREA (SB225002) PREVENTED PSL-INDUCED TACTILE ALLODYNIA AND THERMAL HYPERALGESIA. PERINEURAL INJECTION OF RECOMBINANT MIP-2 ELICITED NEUROPATHIC PAIN-LIKE BEHAVIORS. ANTI-MIP-2 SUPPRESSED NEUTROPHIL ACCUMULATION IN THE SCN AFTER PSL. NEUTROPHIL DEPLETION BY INTRAPERITONEAL INJECTION OF LY6G ANTIBODY ATTENUATED PSL-INDUCED NEUROPATHIC PAIN. BOTH ANTI-MIP-2 AND SB225002 SUPPRESSED UP-REGULATION OF INFLAMMATORY CYTOKINES AND CHEMOKINES IN THE INJURED SCN. IN ADDITION, ACETYLATION OF HISTONE H3 [LYSINE (LYS9)-ACETYLATED HISTONE H3 (ACK9-H3)] ON THE PROMOTER REGION OF MIP-2 AND CXCR2 WAS INCREASED IN THE INJURED SCN AFTER PSL. EXPRESSION OF ACK9-H3 WAS OBSERVED IN THE NUCLEI OF NEUTROPHILS AND MACROPHAGES SURROUNDING THE EPINEURIUM. ADMINISTRATION OF THE HISTONE ACETYLTRANSFERASE INHIBITOR ANACARDIC ACID SUPPRESSED THE UP-REGULATION OF MIP-2 AND CXCR2 IN THE SCN AFTER PSL AND RESULTED IN THE PREVENTION OF PSL-INDUCED NEUROPATHIC PAIN. TAKEN TOGETHER, THESE RESULTS SHOW THAT AUGMENTATION OF THE MIP-2/CXCR2 AXIS BY HYPERACETYLATION OF HISTONE H3 ON THE PROMOTER REGION OF MIP-2 AND CXCR2 LOCATED IN THE INJURED PERIPHERAL NERVE ELICITS CHRONIC NEUROINFLAMMATION THROUGH NEUTROPHIL ACCUMULATION, LEADING TO NEUROPATHIC PAIN.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
14  1038  20 CLINACANTHUS NUTANS EXTRACTS MODULATE EPIGENETIC LINK TO CYTOSOLIC PHOSPHOLIPASE A2 EXPRESSION IN SH-SY5Y CELLS AND PRIMARY CORTICAL NEURONS. CLINACANTHUS NUTANS LINDAU (C. NUTANS), COMMONLY KNOWN AS SABAH SNAKE GRASS IN SOUTHEAST ASIA, IS WIDELY USED IN FOLK MEDICINE DUE TO ITS ANALGESIC, ANTIVIRAL, AND ANTI-INFLAMMATORY PROPERTIES. OUR RECENT STUDY PROVIDED EVIDENCE FOR THE REGULATION OF CYTOSOLIC PHOSPHOLIPASE A2 (CPLA2) MRNA EXPRESSION BY EPIGENETIC FACTORS (TAN ET AL. IN MOL NEUROBIOL. DOI: 10.1007/S12035-015-9314-Z , 2015). THIS ENZYME CATALYZES THE RELEASE OF ARACHIDONIC ACID FROM GLYCEROPHOSPHOLIPIDS, AND FORMATION OF PRO-INFLAMMATORY EICOSANOIDS OR TOXIC LIPID PEROXIDATION PRODUCTS SUCH AS 4-HYDROXYNONENAL. IN THIS STUDY, WE EXAMINED THE EFFECTS OF C. NUTANS ETHANOL LEAF EXTRACTS ON EPIGENETIC REGULATION OF CPLA2 MRNA EXPRESSION IN SH-SY5Y HUMAN NEUROBLASTOMA CELLS AND MOUSE PRIMARY CORTICAL NEURONS. C. NUTANS MODULATED INDUCTION OF CPLA2 EXPRESSION IN SH-SY5Y CELLS BY HISTONE DEACETYLASE (HDAC) INHIBITORS, MS-275, MC-1568, AND TSA. C. NUTANS EXTRACTS ALSO INHIBITED HISTONE ACETYLASE (HAT) ACTIVITY. LEVELS OF CPLA2 MRNA EXPRESSION WERE INCREASED IN PRIMARY CORTICAL NEURONS SUBJECTED TO 0.5-H OXYGEN-GLUCOSE DEPRIVATION INJURY (OGD). THIS INCREASE WAS SIGNIFICANTLY INHIBITED BY C. NUTANS TREATMENT. TREATMENT OF PRIMARY NEURONS WITH THE HDAC INHIBITOR MS-275 AUGMENTED OGD-INDUCED CPLA2 MRNA EXPRESSION, AND THIS INCREASE WAS MODULATED BY C. NUTANS EXTRACTS. OGD-STIMULATED INCREASE IN CPLA2 MRNA EXPRESSION WAS ALSO REDUCED BY A TIP60 HAT INHIBITOR, NU9056. IN VIEW OF A KEY ROLE OF CPLA2 IN THE PRODUCTION OF PRO-INFLAMMATORY EICOSANOIDS AND FREE RADICAL DAMAGE, AND THE FACT THAT EPIGENETIC EFFECTS ON GENES ARE OFTEN LONG-LASTING, RESULTS SUGGEST A ROLE FOR C. NUTANS AND PHYTOCHEMICALS TO INHIBIT THE PRODUCTION OF ARACHIDONIC ACID-DERIVED PRO-INFLAMMATORY EICOSANOIDS AND CHRONIC INFLAMMATION, THROUGH EPIGENETIC REGULATION OF CPLA2 EXPRESSION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15  6472  24 TNFALPHA IN THE TRIGEMINAL NOCICEPTIVE SYSTEM IS CRITICAL FOR TEMPOROMANDIBULAR JOINT PAIN. PREVIOUS STUDIES HAVE SHOWN THAT TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) IS SIGNIFICANTLY INCREASED IN COMPLETE FREUND'S ADJUVANT (CFA)-TREATED TEMPOROMANDIBULAR JOINT (TMJ) TISSUES. HOWEVER, IT IS UNCLEAR WHETHER TNFALPHA IN THE TRIGEMINAL NOCICEPTIVE SYSTEM CONTRIBUTES TO THE DEVELOPMENT OF TMJ PAIN. IN THE PRESENT STUDY, WE INVESTIGATED THE ROLE OF TNFALPHA IN TRIGEMINAL GANGLIA (TG) AND SPINAL TRIGEMINAL NUCLEUS CAUDALIS (SP5C) IN CFA-INDUCED INFLAMMATORY TMJ PAIN. INTRA-TMJ INJECTION OF CFA (10 MUL, 5 MG/ML) INDUCED INFLAMMATORY PAIN IN THE TRIGEMINAL NERVE V2- AND V3-INNERVATED SKIN AREAS OF WT MICE, WHICH WAS PRESENT ON DAY 1 AFTER CFA AND PERSISTED FOR AT LEAST 10 DAYS. TNFALPHA IN BOTH TG AND SP5C OF WT MICE WAS UPREGULATED AFTER CFA INJECTION. THE CFA-INDUCED TMJ PAIN WAS SIGNIFICANTLY INHIBITED IN TNFALPHA KO MICE. THE IMMUNOFLUORESCENCE STAINING SHOWED THAT INTRA-TMJ CFA INJECTION NOT ONLY ENHANCED CO-LOCALIZATION OF TNFALPHA WITH IBA1 (A MARKER FOR MICROGLIA) IN BOTH TG AND SP5C BUT ALSO MARKEDLY INCREASED THE EXPRESSION OF TNFALPHA IN THE SP5C NEURONS. BY THE METHYLATED DNA IMMUNOPRECIPITATION ASSAY, WE ALSO FOUND THAT DNA METHYLATION AT THE TNF GENE PROMOTER REGION IN THE TG WAS DRAMATICALLY DIMINISHED AFTER CFA INJECTION, INDICATING THAT EPIGENETIC REGULATION MAY BE INVOLVED IN THE CFA-ENHANCED TNFALPHA EXPRESSION IN OUR MODEL. OUR RESULTS SUGGEST THAT TNFALPHA IN THE TRIGEMINAL NOCICEPTIVE SYSTEM PLAYS A CRITICAL ROLE IN CFA-INDUCED INFLAMMATORY TMJ PAIN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16  1777  25 EDIBLE BLUE-GREEN ALGAE REDUCE THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES BY INHIBITING NF-KAPPAB PATHWAY IN MACROPHAGES AND SPLENOCYTES. BACKGROUND: CHRONIC INFLAMMATION CONTRIBUTES TO THE DEVELOPMENT OF PATHOLOGICAL DISORDERS INCLUDING INSULIN RESISTANCE AND ATHEROSCLEROSIS. IDENTIFICATION OF ANTI-INFLAMMATORY NATURAL PRODUCTS CAN PREVENT THE INFLAMMATORY DISEASES. METHODS: ANTI-INFLAMMATORY EFFECTS OF BLUE-GREEN ALGAE (BGA), I.E., NOSTOC COMMUNE VAR. SPHAEROIDES KUTZING (NO) AND SPIRULINA PLATENSIS (SP), WERE COMPARED IN RAW 264.7 AND MOUSE BONE MARROW-DERIVED MACROPHAGES (BMM) AS WELL AS SPLENOCYTES FROM APOLIPOPROTEIN E KNOCKOUT (APOE(-/-)) MICE FED BGA. RESULTS: WHEN MACROPHAGES PRETREATED WITH 100MUG/ML NO LIPID EXTRACT (NOE) OR SP LIPID EXTRACT (SPE) WERE ACTIVATED BY LIPOPOLYSACCHARIDE (LPS), EXPRESSION AND SECRETION OF PRO-INFLAMMATORY CYTOKINES, SUCH AS TUMOR NECROSIS FACTOR ALPHA (TNFALPHA), INTERLEUKIN 1BETA (IL-1BETA), AND IL-6, WERE SIGNIFICANTLY REPRESSED. NOE AND SPE ALSO SIGNIFICANTLY REPRESSED THE EXPRESSION OF TNFALPHA AND IL-1BETA IN BMM. LPS-INDUCED SECRETION OF IL-6 WAS LOWER IN SPLENOCYTES FROM APOE(-/-) FED AN ATHEROGENIC DIET CONTAINING 5% NO OR SP FOR 12WEEKS. IN RAW 264.7 MACROPHAGES, NOE AND SPE MARKEDLY DECREASED NUCLEAR TRANSLOCATION OF NF-KAPPAB. THE DEGREE OF REPRESSION OF PRO-INFLAMMATORY GENE EXPRESSION BY ALGAL EXTRACTS WAS MUCH STRONGER THAN THAT OF SN50, AN INHIBITOR OF NF-KAPPAB NUCLEAR TRANSLOCATION. TRICHOSTATIN A, A PAN HISTONE DEACETYLASE INHIBITOR, INCREASED BASAL EXPRESSION OF IL-1BETA AND ATTENUATED THE REPRESSION OF THE GENE EXPRESSION BY SPE. SPE SIGNIFICANTLY DOWN-REGULATED MRNA ABUNDANCE OF 11 HDAC ISOFORMS, CONSEQUENTLY INCREASING ACETYLATED HISTONE 3 LEVELS. CONCLUSION: NOE AND SPE REPRESS PRO-INFLAMMATORY CYTOKINE EXPRESSION AND SECRETION IN MACROPHAGES AND SPLENOCYTES VIA INHIBITION OF NF-KAPPAB PATHWAY. HISTONE ACETYLATION STATE IS LIKELY INVOLVED IN THE INHIBITION. GENERAL SIGNIFICANCE: THIS STUDY UNDERSCORES NATURAL PRODUCTS CAN EXERT ANTI-INFLAMMATORY EFFECTS BY EPIGENETIC MODIFICATIONS SUCH AS HISTONE ACETYLATION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17  5625  20 SELECTIVE CLASS I HISTONE DEACETYLASE INHIBITORS SUPPRESS PERSISTENT SPONTANEOUS NOCICEPTION AND THERMAL HYPERSENSITIVITY IN A RAT MODEL OF BEE VENOM-INDUCED INFLAMMATORY PAIN. TO CONFIRM WHETHER CLASS I HISTONE DEACETYLASE INHIBITORS (HDACIS) ARE EFFECTIVE IN RELIEF OF PERIPHERAL INFLAMMATORY PAIN, THE EFFECTS OF TWO SELECTIVE INHIBITORS, MS-275 AND MGCD0103, WERE STUDIED IN RATS INFLAMED BY SUBCUTANEOUS (S.C.) INJECTION OF BEE VENOM (BV). THE BV TEST IS CHARACTERIZED BY DISPLAYING BOTH PERSISTENT SPONTANEOUS NOCICEPTION (PSN) AND PRIMARY HYPERSENSITIVITY. INTRATHECAL (I.T.) PRE-TREATMENT OF EITHER MS-275 OR MGCD0103 WITH A SINGLE DOSE OF 60 NMOL/20 MUL RESULTED IN PROFOUND SUPPRESSION OF BOTH PSN AND PRIMARY THERMAL HYPERSENSITIVITY BUT WITHOUT SIGNIFICANT INFLUENCE UPON THE PRIMARY MECHANICAL HYPERSENSITIVITY AND MIRROR-IMAGE THERMAL HYPERSENSITIVITY. MOREOVER, THE UP-REGULATION OF BOTH HDAC1 AND HDAC2 INDUCED BY S.C. BV INJECTION WAS COMPLETELY SUPPRESSED BY I.T. PRE-TREATMENT OF MS-275. THE PRESENT RESULTS PROVIDE WITH ANOTHER NEW LINE OF EVIDENCE SHOWING INVOLVEMENT OF EPIGENETIC REGULATION OF CHROMATIN STRUCTURE BY HDAC1/2-MEDIATED HISTONE HYPOACETYLATION IN THE BV-INDUCED PSN AND THERMAL HYPERSENSITIVITY AND DEMONSTRATE THE BENEFICIAL EFFECTS OF CLASS I HDACIS IN PREVENTION OF PERIPHERAL INFLAMMATORY PAIN FROM OCCURRING.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18   532  15 ASTROCYTIC C-JUN N-TERMINAL KINASE-HISTONE DEACETYLASE-2 CASCADE CONTRIBUTES TO GLUTAMATE TRANSPORTER-1 DECREASE AND MECHANICAL ALLODYNIA FOLLOWING PERIPHERAL NERVE INJURY IN RATS. DECREASE OF GLUTAMATE TRANSPORTER-1 (GLT-1) IN THE SPINAL DORSAL HORN AFTER NERVE INJURY INDUCES ENHANCED EXCITATORY TRANSMISSION AND CAUSES PERSISTENT PAIN. HISTONE DEACETYLASES (HDACS)-CATALYZED DEACETYLATION MIGHT CONTRIBUTE TO THE DECREASE OF GLT-1, WHILE THE DETAILED MECHANISMS HAVE YET TO BE FULLY ELABORATED. SPINAL NERVE LIGATION (SNL) INDUCED SIGNIFICANT INCREASES OF HDAC2 AND DECREASES OF GLT-1 IN SPINAL ASTROCYTES. INTRATHECAL INFUSION OF THE HDAC2 INHIBITORS ATTENUATED THE DECREASE OF GLT-1 AND ENHANCED PHOSPHORYLATION OF GLUTAMATE RECEPTORS. GLT-1 AND PHOSPHORYLATED C-JUN N-TERMINAL KINASE (JNK) WERE HIGHLY COLOCALIZED IN THE SPINAL CORD, AND A LARGE NUMBER OF PJNK POSITIVE CELLS WERE HDAC2 POSITIVE. INTRATHECALLY INFUSION OF THE JNK INHIBITOR SP600125 SIGNIFICANTLY INHIBITED SNL-INDUCED UPREGULATION OF HDAC2. SNL-INDUCED HDAC2 UP-REGULATION COULD BE INHIBITED BY THE NEUTRALIZING ANTI-TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) BINDING PROTEIN ETANERCEPT OR THE MICROGLIAL INHIBITOR MINOCYCLINE. IN CULTURED ASTROCYTES, TNF-ALPHA INDUCED ENHANCED PHOSPHORYLATION OF JNK AND A SIGNIFICANT INCREASE OF HDAC2, AS WELL AS A REMARKABLE DECREASE OF GLT-1, WHICH COULD BE PREVENTED BY SP600125 OR THE HDAC2 SPECIFIC INHIBITOR CAY10683. OUR DATA SUGGEST THAT ASTROCYTIC JNK-HDAC2 CASCADE CONTRIBUTES TO GLT-1 DECREASE AND MECHANICAL ALLODYNIA FOLLOWING PERIPHERAL NERVE INJURY. NEUROIMMUNE ACTIVATION AFTER PERIPHERAL NERVE INJURY COULD INDUCE EPIGENETIC MODIFICATION CHANGES IN ASTROCYTES AND CONTRIBUTE TO CHRONIC PAIN MAINTENANCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19  4993  17 PENTOXIFYLLINE-INDUCED PROTEIN EXPRESSION CHANGE IN RAW 264.7 CELLS AS DETERMINED BY IMMUNOPRECIPITATION-BASED HIGH PERFORMANCE LIQUID CHROMATOGRAPHY. ALTHOUGH PENTOXIFYLLINE (PTX) WAS IDENTIFIED AS A COMPETITIVE NON-SELECTIVE PHOSPHODIESTERASE INHIBITOR, ITS PHARMACOLOGICAL EFFECT HAS NOT BEEN CLEARLY ELUCIDATED. THE PRESENT STUDY EXPLORED THE EFFECT OF LOW DOSE 10 MUG/ML PTX (THERAPEUTIC DOSE) COMPARED TO HIGH DOSE 300 MUG/ML PTX (EXPERIMENTAL DOSE) IN RAW 264.7 CELLS THROUGH IMMUNOPRECIPITATION-BASED HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (IP-HPLC), IMMUNOHISTOCHEMISTRY, AND WESTERN BLOT. 10 MUG/ML PTX INCREASED THE EXPRESSION OF PROLIFERATION (KI-67, PCNA, CYCLIN D2, CDC25A), EPIGENETIC MODIFICATION (KDM4D, PCAF, HMGB1), PROTEIN TRANSLATION (DOHH, DHPS, EIF5A1), RAS SIGNALING (KRAS, PAKT1/2/3, PI3K), NFKB SIGNALING (NFKB, GADD45, P38), PROTECTION (HSP70, SOD1, GSTO1/2), SURVIVAL (PAKT1/2/3, SP1, SIRTUIN 6), NEUROMUSCULAR DIFFERENTIATION (NSEGAMMA, MYOSIN-1A, DESMIN), OSTEOBLASTIC DIFFERENTIATION (BMP2, RUNX2, OSTERIX), ACUTE INFLAMMATION (TNFALPHA, IL-1, CXCR4), INNATE IMMUNITY (BETA-DEFENSIN 1, LACTOFERRIN, TLR-3, -4), CELL-MEDIATED IMMUNITY (CD4, CD8, CD80), WHILE DECREASED THE EXPRESSION OF ER STRESS (EIF2ALPHA, EIF2AK3, ATF6ALPHA), FIBROSIS (FGF2, CTGF, COLLAGEN 3A1), AND CHRONIC INFLAMMATION (CD68, MMP-2, -3, COX2) VERSUS THE UNTREATED CONTROLS. THE ACTIVATION OF PROLIFERATION BY 10 MUG/ML PTX WAS ALSO SUPPORTED BY THE INCREASE OF CMYC-MAX HETERODIMER AND BETA-CATENIN-TCF1 COMPLEX IN DOUBLE IP-HPLC. 10 MUG/ML PTX ENHANCED FAS-MEDIATED APOPTOSIS BUT DIMINISHED P53-MEDIATED APOPTOSIS, AND DOWNREGULATED MANY ANGIOGENESIS PROTEINS (ANGIOGENIN, VEGF-A, AND FLT4), BUT UPREGULATED HIF1ALPHA, VEGFR2, AND CMG2 REACTIVELY. WHEREAS, 300 MUG/ML PTX CONSISTENTLY DECREASED PROLIFERATION, EPIGENETIC MODIFICATION, RAS AND NFKB SIGNALING, NEUROMUSCULAR AND OSTEOBLASTIC DIFFERENTIATION, BUT INCREASED APOPTOSIS, ER STRESS, AND FIBROSIS COMPARED TO 10 MUG/ML PTX. THESE DATA SUGGEST PTX HAS DIFFERENT BIOLOGICAL EFFECT ON RWA 264.7 CELLS DEPENDING ON THE CONCENTRATION OF 10 MUG/ML AND 300 MUG/ML PTX. THE LOW DOSE 10 MUG/ML PTX ENHANCED RAS/NFKB SIGNALING, PROLIFERATION, DIFFERENTIATION, AND INFLAMMATION, PARTICULARLY, IT STIMULATED NEUROMUSCULAR AND OSTEOBLASTIC DIFFERENTIATION, INNATE IMMUNITY, AND CELL-MEDIATED IMMUNITY, BUT ATTENUATED ER STRESS, FIBROSIS, ANGIOGENESIS, AND CHRONIC INFLAMMATION, WHILE THE HIGH DOSE 300 MUG/ML PTX WAS FOUND TO ALLEVIATE THE 10 MUG/ML PTX-INDUCED BIOLOGICAL EFFECTS, RESULTED IN THE SUPPRESSION OF RAS/NFKB SIGNALING, PROLIFERATION, NEUROMUSCULAR AND OSTEOBLASTIC DIFFERENTIATION, AND INFLAMMATION.	2022	

20  3126  16 GINSENOSIDE REDUCES COGNITIVE IMPAIRMENT DURING CHRONIC CEREBRAL HYPOPERFUSION THROUGH BRAIN-DERIVED NEUROTROPHIC FACTOR REGULATED BY EPIGENETIC MODULATION. INCREASED EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN ASSOCIATED WITH MEMORY-ENHANCING AND NEUROPROTECTIVE PROPERTIES OF SOME DRUGS UNDER CHRONIC CEREBRAL HYPOPERFUSION (CCH) CONDITION. GINSENOSIDE RD (GSRD), ONE OF THE MAIN ACTIVE INGREDIENTS IN PANAX GINSENG, IS WIDELY USED FOR BRAIN PROTECTION. HOWEVER, IT IS POORLY UNDERSTOOD WHETHER EPIGENETIC MECHANISMS IMPLIED IN THE BDNF MODULATION AFTER GSRD TREATMENT FOR CCH REMAIN ELUSIVE. HERE, WE INVESTIGATED THE NEUROPROTECTIVE EFFECTS OF GSRD AND THE INVOLVED MECHANISMS. WE DEMONSTRATED THAT GSRD ADMINISTRATION AMELIORATED CCH-INDUCED IMPAIRMENT OF LEARNING AND MEMORY BEHAVIORS, EVIDENCED BY DECREASED ESCAPE LATENCY AND INCREASED NUMBER OF CROSSING THE PLATFORM IN MORRIS WATER MAZE TEST. THIS IMPROVEMENT WAS ASSOCIATED WITH PROMOTED NEURON SURVIVAL AND INCREASED BDNF EXPRESSION IN THE HIPPOCAMPUS AND PREFRONTAL CORTEX OF CCH MICE. GSRD IMPROVED NEURON SURVIVAL AND DECREASED NEURON APOPTOSIS AND THE LEVEL OF CASPASE-3 UNDER OXYGEN-GLUCOSE DEPRIVATION/REOXYGENATION (OGD/R) BY UPREGULATION OF BDNF AS WELL AS IN VITRO. THE LEVELS OF ACETYLATED HISTONE H3 (AC-H3) AND HISTONE DEACETYLASE (HISTONE DEACETYLASE 2 (HDAC2)) WERE ALTERED UNDER OGD/R IN A TIME-DEPENDENT MANNER, AND GSRD REESTABLISHED THE BALANCE BETWEEN AC-H3 AND HDAC2 WHICH RESULTED IN UPREGULATION OF BDNF AND INCREASED NEURON SURVIVAL. MS-275, AN INHIBITOR OF CLASS I HDACS, ABOLISHED THE LEVELS OF AC-H3 AT THE BDNF PROMOTERS AND ENHANCED UPREGULATION OF BDNF AFTER GSRD ADMINISTRATION, SUGGESTING A SYNERGISTIC EFFECT BETWEEN GSRD AND MS-275. ALL THE DATA SUGGESTED THAT GSRD PROVIDED NEUROPROTECTION BY EPIGENETIC MODULATION WHICH ACCOUNTED FOR THE REGULATION OF BDNF IN CCH MICE.	2017