1   871 134 CHRONIC ALCOHOL EXPOSURE AFFECTS PANCREATIC ACINAR MITOCHONDRIAL THIAMIN PYROPHOSPHATE UPTAKE: STUDIES WITH MOUSE 266-6 CELL LINE AND PRIMARY CELLS. THIAMIN IS ESSENTIAL FOR NORMAL METABOLIC ACTIVITY OF ALL MAMMALIAN CELLS, INCLUDING THOSE OF THE PANCREAS. CELLS OBTAIN THIAMIN FROM THEIR SURROUNDINGS AND ENZYMATICALLY CONVERT IT INTO THIAMIN PYROPHOSPHATE (TPP) IN THE CYTOPLASM; TPP IS THEN TAKEN UP BY MITOCHONDRIA VIA A SPECIFIC CARRIER THE MITOCHONDRIAL TPP TRANSPORTER (MTPPT; PRODUCT OF THE SLC25A19 GENE). CHRONIC ALCOHOL EXPOSURE NEGATIVELY IMPACTS THE HEALTH OF PANCREATIC ACINAR CELLS (PAC), BUT ITS EFFECT ON PHYSIOLOGICAL/MOLECULAR PARAMETERS OF MTPPT IS NOT KNOWN. WE ADDRESSED THIS ISSUE USING MOUSE PANCREATIC ACINAR TUMOR CELL LINE 266-6 AND PRIMARY PAC OF WILD-TYPE AND TRANSGENIC MICE CARRYING THE SLC25A19 PROMOTER THAT WERE FED ALCOHOL CHRONICALLY. CHRONIC ALCOHOL EXPOSURE OF 266-6 CELLS (BUT NOT TO ITS NONOXIDATIVE METABOLITES ETHYL PALMITATE AND ETHYL OLEATE) LED TO A SIGNIFICANT INHIBITION IN MITOCHONDRIAL TPP UPTAKE, WHICH WAS ASSOCIATED WITH A DECREASED EXPRESSION OF MTPPT PROTEIN, MRNA, AND ACTIVITY OF THE SLC25A19 PROMOTER. SIMILARLY, CHRONIC ALCOHOL FEEDING OF MICE LED TO A SIGNIFICANT INHIBITION IN EXPRESSION OF MTPPT PROTEIN, MRNA, HETEROGENEOUS NUCLEAR RNA, AS WELL AS IN ACTIVITY OF SLC25A19 PROMOTER IN PAC. WHILE CHRONIC ALCOHOL EXPOSURE DID NOT AFFECT DNA METHYLATION OF THE SLC25A19 PROMOTER, A SIGNIFICANT DECREASE IN HISTONE H3 EUCHROMATIN MARKERS AND AN INCREASE IN H3 HETEROCHROMATIN MARKER WERE OBSERVED. THESE FINDINGS SHOW, FOR THE FIRST TIME, THAT CHRONIC ALCOHOL EXPOSURE NEGATIVELY IMPACTS PANCREATIC MTPPT, AND THAT THIS EFFECT IS EXERTED, AT LEAST IN PART, AT THE LEVEL OF SLC25A19 TRANSCRIPTION AND APPEARS TO INVOLVE EPIGENETIC MECHANISM(S).	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
2  3727  77 INHIBITION OF PANCREATIC ACINAR MITOCHONDRIAL THIAMIN PYROPHOSPHATE UPTAKE BY THE CIGARETTE SMOKE COMPONENT 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE. THIAMIN IS ESSENTIAL FOR NORMAL METABOLISM IN PANCREATIC ACINAR CELLS (PAC) AND IS OBTAINED FROM THEIR MICROENVIRONMENT THROUGH SPECIFIC PLASMA-MEMBRANE TRANSPORTERS, CONVERTED TO THIAMIN PYROPHOSPHATE (TPP) IN THE CYTOPLASM, FOLLOWED BY UPTAKE OF TPP BY MITOCHONDRIA THROUGH THE MITOCHONDRIAL TPP (MTPP) TRANSPORTER (MTPPT; PRODUCT OF SLC25A19 GENE). TPP IS ESSENTIAL FOR NORMAL MITOCHONDRIAL FUNCTION. WE EXAMINED THE EFFECT OF LONG-TERM/CHRONIC EXPOSURE OF PAC IN VITRO (PANCREATIC ACINAR 266-6 CELLS) AND IN VIVO (WILD-TYPE OR TRANSGENIC MICE CARRYING THE SLC25A19 PROMOTER) OF THE CIGARETTE SMOKE TOXIN, 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE (NNK), ON THE MTPP UPTAKE PROCESS. OUR IN VITRO AND IN VIVO FINDINGS DEMONSTRATE THAT NNK NEGATIVELY AFFECTS MTPP UPTAKE AND REDUCED EXPRESSION OF MTPPT PROTEIN, MTPPT MRNA, AND HETEROGENOUS NUCLEAR RNA, AS WELL AS SLC25A19 PROMOTER ACTIVITY. THE EFFECT OF NNK ON SLC25A19 TRANSCRIPTION WAS NEITHER MEDIATED BY CHANGES IN EXPRESSION OF TRANSCRIPTIONAL FACTOR NFY-1 (KNOWN TO DRIVE SLC25A19 TRANSCRIPTION), NOR DUE TO CHANGES IN METHYLATION PROFILE OF THE SLC25A19 PROMOTER. RATHER, IT APPEARS TO BE DUE TO CHANGES IN HISTONE MODIFICATIONS THAT INVOLVE SIGNIFICANT DECREASES IN HISTONE H3K4-TRIMETHYLATION AND H3K9-ACETYLATION (ACTIVATION MARKERS). THE EFFECT OF NNK ON MTPPT FUNCTION IS MEDIATED THROUGH THE NONNEURONAL ALPHA7-NICOTINIC ACETYLCHOLINE RECEPTOR (ALPHA7-NACHR), AS INDICATED BY BOTH IN VITRO (USING THE NACHR ANTAGONIST MECAMYLAMINE) AND IN VIVO (USING AN ALPHA7-NACHR(-/-) MOUSE MODEL) STUDIES. THESE FINDINGS DEMONSTRATE THAT CHRONIC EXPOSURE OF PAC TO NNK NEGATIVELY IMPACTS PAC MTPP UPTAKE. THIS EFFECT APPEARS TO BE EXERTED AT THE LEVEL OF SLC25A19 TRANSCRIPTION, INVOLVE EPIGENETIC MECHANISM(S), AND IS MEDIATED THROUGH THE ALPHA7-NACHR.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
3   873  75 CHRONIC ALCOHOL EXPOSURE INHIBITS BIOTIN UPTAKE BY PANCREATIC ACINAR CELLS: POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS. CHRONIC EXPOSURE TO ALCOHOL AFFECTS DIFFERENT PHYSIOLOGICAL ASPECTS OF PANCREATIC ACINAR CELLS (PAC), BUT ITS EFFECT ON THE UPTAKE PROCESS OF BIOTIN IS NOT KNOWN. WE ADDRESSED THIS ISSUE USING MOUSE-DERIVED PANCREATIC ACINAR 266-6 CELLS CHRONICALLY EXPOSED TO ALCOHOL AND WILD-TYPE AND TRANSGENIC MICE (CARRYING THE HUMAN SLC5A6 5'-PROMOTER) FED ALCOHOL CHRONICALLY. FIRST WE ESTABLISHED THAT BIOTIN UPTAKE BY PAC IS NA(+) DEPENDENT AND CARRIER MEDIATED AND INVOLVES SODIUM-DEPENDENT MULTIVITAMIN TRANSPORTER (SMVT). CHRONIC EXPOSURE OF 266-6 CELLS TO ALCOHOL LED TO A SIGNIFICANT INHIBITION IN BIOTIN UPTAKE, EXPRESSION OF SMVT PROTEIN, AND MRNA AS WELL AS IN THE ACTIVITY OF THE SLC5A6 PROMOTER. SIMILARLY, CHRONIC ALCOHOL FEEDING OF WILD-TYPE AND TRANSGENIC MICE CARRYING THE SLC5A6 PROMOTER LED TO A SIGNIFICANT INHIBITION IN BIOTIN UPTAKE BY PAC, AS WELL AS IN THE EXPRESSION OF SMVT PROTEIN AND MRNA AND THE ACTIVITY OF THE SLC5A6 PROMOTERS EXPRESSED IN THE TRANSGENIC MICE. WE ALSO FOUND THAT CHRONIC ALCOHOL FEEDING OF MICE IS ASSOCIATED WITH A SIGNIFICANT INCREASE IN THE METHYLATION STATUS OF CPG ISLANDS PREDICTED TO BE IN THE MOUSE SLC5A6 PROMOTERS AND A DECREASE IN THE LEVEL OF EXPRESSION OF TRANSCRIPTION FACTOR KLF-4, WHICH PLAYS AN IMPORTANT ROLE IN REGULATING SLC5A6 PROMOTER ACTIVITY. THESE RESULTS DEMONSTRATE, FOR THE FIRST TIME, THAT CHRONIC ALCOHOL EXPOSURE NEGATIVELY IMPACTS BIOTIN UPTAKE IN PAC AND THAT THIS EFFECT IS EXERTED (AT LEAST IN PART) AT THE LEVEL OF TRANSCRIPTION OF THE SLC5A6 GENE AND MAY INVOLVE EPIGENETIC/MOLECULAR MECHANISMS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4  6666  72 UPTAKE OF ASCORBIC ACID BY PANCREATIC ACINAR CELLS IS NEGATIVELY IMPACTED BY CHRONIC ALCOHOL EXPOSURE. VITAMIN C (ASCORBIC ACID, AA) IS INDISPENSABLE FOR NORMAL METABOLISM OF ALL MAMMALIAN CELLS INCLUDING PANCREATIC ACINAR CELLS (PACS). PACS OBTAIN AA FROM THEIR SURROUNDINGS VIA TRANSPORT ACROSS THE CELL MEMBRANE. CHRONIC ALCOHOL EXPOSURE NEGATIVELY AFFECTS BODY AA HOMEOSTASIS; IT ALSO INHIBITS UPTAKE OF OTHER MICRONUTRIENTS INTO PACS, BUT ITS EFFECT ON AA UPTAKE IS NOT CLEAR. WE EXAMINED THIS ISSUE USING BOTH IN VITRO (266-6 CELLS) AND IN VIVO (MICE) MODELS OF CHRONIC ALCOHOL EXPOSURE. FIRST, WE DETERMINED THE RELATIVE EXPRESSION OF THE AA TRANSPORTERS 1 AND 2 [I.E., SODIUM-DEPENDENT VITAMIN C TRANSPORTER-1 (SVCT-1) AND SVCT-2] IN MOUSE AND HUMAN PACS AND FOUND SVCT-2 TO BE THE PREDOMINANT TRANSPORTER. CHRONIC EXPOSURE OF 266-6 CELLS TO ALCOHOL SIGNIFICANTLY INHIBITED AA UPTAKE AND CAUSED A MARKED REDUCTION IN SVCT-2 EXPRESSION AT THE PROTEIN, MRNA, AND HETEROGENEOUS NUCLEAR RNA (HNRNA) LEVELS. SIMILARLY, CHRONIC ALCOHOL FEEDING OF MICE SIGNIFICANTLY INHIBITED AA UPTAKE AND CAUSED A MARKED REDUCTION IN LEVEL OF EXPRESSION OF THE SVCT-2 PROTEIN, MRNA, AND HNRNA. THESE FINDINGS SUGGEST POSSIBLE INVOLVEMENT OF TRANSCRIPTIONAL MECHANISM(S) IN MEDIATING CHRONIC ALCOHOL EFFECT ON AA UPTAKE BY PACS. WE ALSO OBSERVED SIGNIFICANT EPIGENETIC CHANGES (HISTONE MODIFICATIONS) IN THE SLC23A2 GENE (REDUCTION IN H3K4ME3 LEVEL AND AN INCREASE IN H3K27ME3 LEVEL) IN THE ALCOHOL-EXPOSED 266-6 CELLS. THESE FINDINGS SHOW THAT CHRONIC ALCOHOL EXPOSURE INHIBITS PAC AA UPTAKE AND THAT THE EFFECT IS MEDIATED, IN PART, AT THE LEVEL OF TRANSCRIPTION OF THE SLC23A2 GENE AND MAY INVOLVE EPIGENETIC MECHANISM(S).	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5  1158  41 CONTEXT-DEPENDENT EPIGENETIC REGULATION OF NUCLEAR FACTOR OF ACTIVATED T CELLS 1 IN PANCREATIC PLASTICITY. BACKGROUND & AIMS: THE ABILITY OF EXOCRINE PANCREATIC CELLS TO CHANGE THE CELLULAR PHENOTYPE IS REQUIRED FOR TISSUE REGENERATION UPON INJURY, BUT ALSO CONTRIBUTES TO THEIR MALIGNANT TRANSFORMATION AND TUMOR PROGRESSION. WE INVESTIGATED CONTEXT-DEPENDENT SIGNALING AND TRANSCRIPTION MECHANISMS THAT DETERMINE PANCREATIC CELL FATE DECISIONS TOWARD REGENERATION AND MALIGNANCY. IN PARTICULAR, WE STUDIED THE FUNCTION AND REGULATION OF THE INFLAMMATORY TRANSCRIPTION FACTOR NUCLEAR FACTOR OF ACTIVATED T CELLS 1 (NFATC1) IN PANCREATIC CELL PLASTICITY AND TISSUE ADAPTATION. METHODS: WE ANALYZED CELL PLASTICITY DURING PANCREATIC REGENERATION AND TRANSFORMATION IN MICE WITH PANCREAS-SPECIFIC EXPRESSION OF A CONSTITUTIVELY ACTIVE FORM OF NFATC1, OR DEPLETION OF ENHANCER OF ZESTE 2 HOMOLOGUE 2 (EZH2), IN THE CONTEXT OF WILD-TYPE OR CONSTITUTIVELY ACTIVATE KRAS, RESPECTIVELY. ACUTE AND CHRONIC PANCREATITIS WERE INDUCED BY INTRAPERITONEAL INJECTION OF CAERULEIN. EZH2-DEPENDENT REGULATION OF NFATC1 EXPRESSION WAS STUDIED IN MOUSE IN HUMAN PANCREATIC TISSUE AND CELLS BY IMMUNOHISTOCHEMISTRY, IMMUNOBLOTTING, AND QUANTITATIVE REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION. WE USED GENETIC AND PHARMACOLOGIC APPROACHES OF EZH2 AND NFATC1 INHIBITION TO STUDY THE CONSEQUENCES OF PATHWAY DISRUPTION ON PANCREATIC MORPHOLOGY AND FUNCTION. EPIGENETIC MODIFICATIONS ON THE NFATC1 GENE WERE INVESTIGATED BY CHROMATIN IMMUNOPRECIPITATION ASSAYS. RESULTS: NFATC1 WAS RAPIDLY AND TRANSIENTLY INDUCED IN EARLY ADAPTATION TO ACINAR CELL INJURY IN HUMAN SAMPLES AND IN MICE, WHERE IT PROMOTED ACINAR CELL TRANSDIFFERENTIATION AND BLOCKED PROLIFERATION OF METAPLASTIC PANCREATIC CELLS. HOWEVER, IN LATE STAGES OF REGENERATION, NFATC1 WAS EPIGENETICALLY SILENCED BY EZH2-DEPENDENT HISTONE METHYLATION, TO ENABLE ACINAR CELL REDIFFERENTIATION AND PREVENT ORGAN ATROPHY AND EXOCRINE INSUFFICIENCY. IN CONTRAST, ONCOGENIC ACTIVATION OF KRAS SIGNALING IN PANCREATIC DUCTAL ADENOCARCINOMA CELLS REVERSED THE EZH2-DEPENDENT EFFECTS ON THE NFATC1 GENE AND WAS REQUIRED FOR EZH2-MEDIATED TRANSCRIPTIONAL ACTIVATION OF NFATC1. CONCLUSIONS: IN STUDIES OF HUMAN AND MOUSE PANCREATIC CELLS AND TISSUE, WE IDENTIFIED CONTEXT-SPECIFIC EPIGENETIC REGULATION OF NFATC1 ACTIVITY AS AN IMPORTANT MECHANISM OF PANCREATIC CELL PLASTICITY. INHIBITORS OF EZH2 MIGHT THEREFORE INTERFERE WITH ONCOGENIC ACTIVITY OF NFATC1 AND BE USED IN TREATMENT OF PANCREATIC DUCTAL ADENOCARCINOMA.	2017	

6  6132  35 THE EPIGENETIC REGULATORS BMI1 AND RING1B ARE DIFFERENTIALLY REGULATED IN PANCREATITIS AND PANCREATIC DUCTAL ADENOCARCINOMA. CHRONIC PANCREATITIS AND PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) ARE ASSOCIATED WITH MAJOR CHANGES IN CELL DIFFERENTIATION. THESE CHANGES MAY BE AT THE BASIS OF THE INCREASED RISK FOR PDAC AMONG PATIENTS WITH CHRONIC PANCREATITIS. POLYCOMB PROTEINS ARE EPIGENETIC SILENCERS EXPRESSED IN ADULT STEM CELLS; UP-REGULATION OF POLYCOMB PROTEINS HAS BEEN REPORTED TO OCCUR IN A VARIETY OF SOLID TUMOURS SUCH AS COLON AND BREAST CANCER. WE HYPOTHESIZED THAT POLYCOMB MIGHT PLAY A ROLE IN PRENEOPLASTIC STATES IN THE PANCREAS AND IN TUMOUR DEVELOPMENT/PROGRESSION. TO TEST THESE IDEAS, WE DETERMINED THE EXPRESSION OF PRC1 COMPLEX PROTEINS (BMI1 AND RING1B) DURING PANCREATIC DEVELOPMENT AND IN PANCREATIC TISSUE FROM MOUSE MODELS OF DISEASE: ACUTE AND CHRONIC PANCREATIC INJURY, DUCT LIGATION, AND IN K-RAS(G12V) CONDITIONAL KNOCK-IN AND CAERULEIN-TREATED K-RAS(G12V) MICE. THE STUDY WAS EXTENDED TO HUMAN PANCREATIC TISSUE SAMPLES. TO OBTAIN MECHANISTIC INSIGHTS, BMI1 EXPRESSION IN CELLS UNDERGOING IN VITRO EXOCRINE CELL METAPLASIA AND THE EFFECTS OF BMI1 DEPLETION IN AN ACINAR CANCER CELL LINE WERE STUDIED. WE FOUND THAT BMI1 AND RING1B ARE EXPRESSED IN PANCREATIC EXOCRINE PRECURSOR CELLS DURING EARLY DEVELOPMENT AND IN DUCTAL AND ISLET CELLS-BUT NOT ACINAR CELLS-IN THE ADULT PANCREAS. BMI1 EXPRESSION WAS INDUCED IN ACINAR CELLS DURING ACUTE INJURY, IN ACINAR-DUCTAL METAPLASTIC LESIONS, AS WELL AS IN PANCREATIC INTRAEPITHELIAL NEOPLASIA (PANIN) AND PDAC. IN CONTRAST, RING1B EXPRESSION WAS ONLY SIGNIFICANTLY AND PERSISTENTLY UP-REGULATED IN HIGH-GRADE PANINS AND IN PDAC. BMI1 KNOCKDOWN IN CULTURED ACINAR TUMOUR CELLS LED TO CHANGES IN THE EXPRESSION OF VARIOUS DIGESTIVE ENZYMES. OUR RESULTS SUGGEST THAT BMI1 AND RING1B ARE MODULATED IN PANCREATIC DISEASES AND COULD CONTRIBUTE DIFFERENTLY TO TUMOUR DEVELOPMENT.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7  1035  42 CLASS I HISTONE DEACETYLASE INHIBITION IMPROVES PANCREATITIS OUTCOME BY LIMITING LEUKOCYTE RECRUITMENT AND ACINAR-TO-DUCTAL METAPLASIA. BACKGROUND AND PURPOSE: PANCREATITIS IS A COMMON INFLAMMATION OF THE PANCREAS WITH RISING INCIDENCE IN MANY COUNTRIES. DESPITE IMPROVEMENTS IN DIAGNOSTIC TECHNIQUES, THE DISEASE IS ASSOCIATED WITH HIGH RISK OF SEVERE MORBIDITY AND MORTALITY AND THERE IS AN URGENT NEED FOR NEW THERAPEUTIC INTERVENTIONS. IN THIS STUDY, WE EVALUATED WHETHER HISTONE DEACETYLASES (HDACS), KEY EPIGENETIC REGULATORS OF GENE TRANSCRIPTION, ARE INVOLVED IN THE DEVELOPMENT OF THE DISEASE. EXPERIMENTAL APPROACH: WE ANALYSED HDAC REGULATION DURING CERULEIN-INDUCED ACUTE, CHRONIC AND AUTOIMMUNE PANCREATITIS USING DIFFERENT TRANSGENIC MOUSE MODELS. THE FUNCTIONAL RELEVANCE OF CLASS I HDACS WAS TESTED WITH THE SELECTIVE INHIBITOR MS-275 IN VIVO UPON PANCREATITIS INDUCTION AND IN VITRO IN ACTIVATED MACROPHAGES AND PRIMARY ACINAR CELL EXPLANTS. KEY RESULTS: HDAC EXPRESSION AND ACTIVITY WERE UP-REGULATED IN A TIME-DEPENDENT MANNER FOLLOWING INDUCTION OF PANCREATITIS, WITH THE HIGHEST ABUNDANCE OBSERVED FOR CLASS I HDACS. CLASS I HDAC INHIBITION DID NOT PREVENT THE INITIAL ACINAR CELL DAMAGE. HOWEVER, IT EFFECTIVELY REDUCED THE INFILTRATION OF INFLAMMATORY CELLS, INCLUDING MACROPHAGES AND T CELLS, IN BOTH ACUTE AND CHRONIC PHASES OF THE DISEASE, AND DIRECTLY DISRUPTED MACROPHAGE ACTIVATION. IN ADDITION, MS-275 TREATMENT REDUCED DNA DAMAGE IN ACINAR CELLS AND LIMITED ACINAR DE-DIFFERENTIATION INTO ACINAR-TO-DUCTAL METAPLASIA IN A CELL-AUTONOMOUS MANNER BY IMPEDING THE EGF RECEPTOR SIGNALLING AXIS. CONCLUSIONS AND IMPLICATIONS: THESE RESULTS DEMONSTRATE THAT CLASS I HDACS ARE CRITICALLY INVOLVED IN THE DEVELOPMENT OF ACUTE AND CHRONIC FORMS OF PANCREATITIS AND SUGGEST THAT BLOCKADE OF CLASS I HDAC ISOFORMS IS A PROMISING TARGET TO IMPROVE THE OUTCOME OF THE DISEASE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8  1787  57 EFFECT OF CHRONIC ALCOHOL EXPOSURE ON GUT VITAMIN B7 UPTAKE: INVOLVEMENT OF EPIGENETIC MECHANISMS AND EFFECT OF ALCOHOL METABOLITES. VITAMIN B7 (BIOTIN) IS ESSENTIAL FOR NORMAL HEALTH AND ITS DEFICIENCY/SUBOPTIMAL LEVELS OCCUR IN A VARIETY OF CONDITIONS INCLUDING CHRONIC ALCOHOLISM. MAMMALS, INCLUDING HUMANS, OBTAIN BIOTIN FROM DIET AND GUT-MICROBIOTA VIA ABSORPTION ALONG THE INTESTINAL TRACT. THE ABSORPTION PROCESS IS CARRIER MEDIATED AND INVOLVES THE SODIUM-DEPENDENT MULTIVITAMIN TRANSPORTER (SMVT; SLC5A6). WE HAVE PREVIOUSLY SHOWN THAT CHRONIC ALCOHOL EXPOSURE SIGNIFICANTLY INHIBITS INTESTINAL/COLONIC BIOTIN UPTAKE VIA SUPPRESSION OF SLC5A6 TRANSCRIPTION IN ANIMAL AND CELL LINE MODELS. HOWEVER, LITTLE IS KNOWN ABOUT THE TRANSCRIPTIONAL/EPIGENETIC FACTORS THAT MEDIATE THIS SUPPRESSION. IN ADDITION, THE EFFECT OF ALCOHOL METABOLITES (GENERATED VIA ALCOHOL METABOLISM BY GUT MICROBIOTA AND HOST TISSUES) ON BIOTIN UPTAKE IS STILL UNKNOWN. TO ADDRESS THESE QUESTIONS, WE FIRST DEMONSTRATED THAT CHRONIC ALCOHOL EXPOSURE INHIBITS SMALL INTESTINAL AND COLONIC BIOTIN UPTAKE AND SMVT EXPRESSION IN HUMAN DIFFERENTIATED ENTEROID AND COLONOID MONOLAYERS. WE THEN SHOWED THAT CHRONIC ALCOHOL EXPOSURES OF BOTH, CACO-2 CELLS AND MICE, ARE ASSOCIATED WITH A SIGNIFICANT SUPPRESSION IN EXPRESSION OF THE NUCLEAR FACTOR KLF-4 (NEEDED FOR SLC5A6 PROMOTER ACTIVITY), AS WELL AS WITH EPIGENETIC ALTERATIONS (HISTONE MODIFICATIONS). WE ALSO FOUND THAT CHRONIC EXPOSURE OF NCM460 HUMAN COLONIC EPITHELIAL CELLS AS WELL AS HUMAN DIFFERENTIATED COLONOID MONOLAYERS, TO ALCOHOL METABOLITES (ACETALDEHYDE, ETHYL PALMITATE, ETHYL OLEATE) SIGNIFICANTLY INHIBITED BIOTIN UPTAKE AND SMVT EXPRESSION. THESE FINDINGS SHED LIGHT ONTO THE MOLECULAR/EPIGENETIC MECHANISMS THAT MEDIATE THE INHIBITORY EFFECT OF CHRONIC ALCOHOL EXPOSURE ON INTESTINAL BIOTIN UPTAKE. THEY FURTHER SHOW THAT ALCOHOL METABOLITES ARE ALSO CAPABLE OF INHIBITING BIOTIN UPTAKE IN THE GUT.NEW & NOTEWORTHY USING COMPLEMENTARY MODELS, INCLUDING HUMAN DIFFERENTIATED ENTEROID AND COLONOID MONOLAYERS, THIS STUDY SHOWS THE INVOLVEMENT OF MOLECULAR AND EPIGENETIC MECHANISMS IN MEDIATING THE INHIBITORY EFFECT OF CHRONIC ALCOHOL EXPOSURE ON BIOTIN UPTAKE ALONG THE INTESTINAL TRACT. THE STUDY ALSO SHOWS THAT ALCOHOL METABOLITES (GENERATED BY GUT MICROBIOTA AND HOST TISSUES) CAUSE INHIBITION IN GUT BIOTIN UPTAKE.	2021	
                                                                                                                                                                                       
9  3720  31 INHIBITION OF CLASS I HISTONE DEACETYLASES ABROGATES TUMOR GROWTH FACTOR BETA EXPRESSION AND DEVELOPMENT OF FIBROSIS DURING CHRONIC PANCREATITIS. PANCREATIC FIBROSIS IS THE HALLMARK OF CHRONIC PANCREATITIS, A HIGHLY DEBILITATING DISEASE FOR WHICH THERE IS CURRENTLY NO CURE. THE KEY EVENT AT THE BASIS OF PANCREATIC FIBROSIS IS THE DEPOSITION OF EXTRACELLULAR MATRIX PROTEINS BY ACTIVATED PANCREATIC STELLATE CELLS (PSCS). TRANSFORMING GROWTH FACTOR BETA (TGFBETA) IS A POTENT PROFIBROTIC FACTOR IN THE PANCREAS AS IT PROMOTES THE ACTIVATION OF PSC; THUS, PHARMACOLOGIC INTERVENTIONS THAT EFFECTIVELY REDUCE TGFBETA EXPRESSION HARBOR CONSIDERABLE THERAPEUTIC POTENTIAL IN THE TREATMENT OF CHRONIC PANCREATITIS. IN THIS STUDY, WE INVESTIGATED WHETHER TGFBETA EXPRESSION IS REDUCED BY PHARMACOLOGIC INHIBITION OF THE EPIGENETIC MODIFIERS HISTONE DEACETYLASES (HDACS). TO ADDRESS THIS AIM, CHRONIC PANCREATITIS WAS INDUCED IN C57BL/6 MICE WITH SERIAL INJECTIONS OF CERULEIN, AND THE SELECTIVE CLASS 1 HDAC INHIBITOR MS-275 WAS ADMINISTERED IN VIVO IN A PREVENTIVE AND THERAPEUTIC MANNER. BOTH MS-275 REGIMENS POTENTLY REDUCED DEPOSITION OF EXTRACELLULAR MATRIX AND DEVELOPMENT OF FIBROSIS IN THE PANCREAS AFTER 4 WEEKS OF CHRONIC PANCREATITIS. REDUCED PANCREATIC FIBROSIS WAS CONCOMITANT WITH LOWER EXPRESSION OF PANCREATIC TGFBETA AND CONSEQUENT REDUCED PSC ACTIVATION. IN SEARCH OF THE CELL TYPES TARGETED BY THE INHIBITOR, WE FOUND THAT MS-275 TREATMENT ABROGATED THE EXPRESSION OF TGFBETA IN ACINAR CELLS STIMULATED BY CERULEIN TREATMENT. OUR STUDY DEMONSTRATES THAT MS-275 IS AN EFFECTIVE ANTIFIBROTIC AGENT IN THE CONTEXT OF EXPERIMENTAL CHRONIC PANCREATITIS AND THUS MAY CONSTITUTE A VALID THERAPEUTIC INTERVENTION FOR THIS SEVERE DISEASE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  1141  27 CONCERTED CELL AND IN VIVO SCREEN FOR PANCREATIC DUCTAL ADENOCARCINOMA (PDA) CHEMOTHERAPEUTICS. PDA IS A MAJOR CAUSE OF US CANCER-RELATED DEATHS. ONCOGENIC KRAS PRESENTS IN 90% OF HUMAN PDAS. KRAS MUTATIONS OCCUR EARLY IN PRE-NEOPLASTIC LESIONS BUT ARE INSUFFICIENT TO CAUSE PDA. OTHER CONTRIBUTING FACTORS EARLY IN DISEASE PROGRESSION INCLUDE CHRONIC PANCREATITIS, ALTERATIONS IN EPIGENETIC REGULATORS, AND TUMOR SUPPRESSOR GENE MUTATION. GPCRS ACTIVATE HETEROTRIMERIC G-PROTEINS THAT STIMULATE INTRACELLULAR CALCIUM AND ONCOGENIC KRAS SIGNALING, THEREBY PROMOTING PANCREATITIS AND PROGRESSION TO PDA. BY CONTRAST, RGS PROTEINS INHIBIT GI/Q-COUPLED GPCRS TO NEGATIVELY REGULATE PDA PROGRESSION. RGS16::GFP IS EXPRESSED IN RESPONSE TO CAERULEIN-INDUCED ACINAR CELL DEDIFFERENTIATION, EARLY NEOPLASIA, AND THROUGHOUT PDA PROGRESSION. IN GENETICALLY ENGINEERED MOUSE MODELS OF PDA, RGS16::GFP IS USEFUL FOR PRE-CLINICAL RAPID IN VIVO VALIDATION OF NOVEL CHEMOTHERAPEUTICS TARGETING EARLY LESIONS IN PATIENTS FOLLOWING SUCCESSFUL RESECTION OR AT HIGH RISK FOR PROGRESSING TO PDA. CULTURED PRIMARY PDA CELLS EXPRESS RGS16::GFP IN RESPONSE TO CYTOTOXIC DRUGS. A HISTONE DEACETYLASE INHIBITOR, TSA, STIMULATED RGS16::GFP EXPRESSION IN PDA PRIMARY CELLS, POTENTIATED GEMCITABINE AND JQ1 CYTOTOXICITY IN CELL CULTURE, AND GEM + TSA + JQ1 INHIBITED TUMOR INITIATION AND PROGRESSION IN VIVO. HERE WE ESTABLISH THE USE OF RGS16::GFP EXPRESSION FOR TESTING DRUG COMBINATIONS IN CELL CULTURE AND VALIDATION OF BEST CANDIDATES IN OUR RAPID IN VIVO SCREEN.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
11  5868  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12  2030  39 EPIGENETIC CHANGES IN INFLAMMATORY GENES AND THE PROTECTIVE EFFECT OF COOKED RHUBARB ON PANCREATIC TISSUE OF RATS WITH CHRONIC ALCOHOL EXPOSURE. CHRONIC ALCOHOL CONSUMPTION, WHICH IS OBSERVED WORLDWIDE, CAN DAMAGE PANCREATIC TISSUE AND PROMOTE PANCREATITIS. RHUBARB IS A WIDELY USED TRADITIONAL CHINESE HERBAL MEDICINE FOR TREATING PANCREATITIS IN CHINA. HOWEVER, FEW PHARMACOLOGICAL STUDIES HAVE INVESTIGATED ITS EPIGENETIC REGULATION. IN THIS STUDY, WE INVESTIGATED WHETHER CHRONIC EXPOSURE TO ALCOHOL CAN ALTER INFLAMMATORY GENE EXPRESSION AND THE EPIGENETIC REGULATION EFFECT OF COOKED RHUBARB IN THE PANCREATIC TISSUE OF RATS. FIRST, CHANGES IN INFLAMMATORY CYTOKINE DNA METHYLATION (IL-10, IL-1ALPHA, TNF-ALPHA, NF-KAPPAB AND TGF-BETA) WERE DETECTED IN PANCREATIC TISSUE OF SPRAGUE-DAWLEY RATS WITH VARYING ALCOHOL EXPOSURE TIMES (4, 6, 8, OR 12 WEEKS), AND THEN WITH VARYING DOSES OF COOKED RHUBARB TREATMENT (3, 6, OR 12 G/DAY). DNA METHYLATION LEVELS, RELATED RNA CONCENTRATIONS AND PROTEIN EXPRESSION OF SPECIFIC INFLAMMATORY CYTOKINES, AND HISTOPATHOLOGICAL SCORE WERE ANALYSED IN PANCREATIC TISSUE OF SPRAGUE-DAWLEY RATS. THE RESULTS SHOWED THAT CHRONIC ALCOHOL EXPOSURE (8 WEEKS) REDUCED THE LEVEL OF IL-1ALPHA DNA METHYLATION AND INCREASED ITS PROTEIN EXPRESSION IN ACINAR CELLS (P < 0.05). IN THE ACINAR CELLS, THE LEVEL OF IL-10 DNA METHYLATION INCREASED, RESULTING IN A REDUCTION OF PROTEIN EXPRESSION (P < 0.05). SIMULTANEOUSLY, CHRONIC ALCOHOL EXPOSURE INCREASED THE PATHOLOGICAL DAMAGE TO THE PANCREAS (P < 0.05). FINALLY, COOKED RHUBARB TREATMENT (3 G/KG/DAY) EFFECTIVELY ALLEVIATED THESE CHANGES IN PANCREATIC TISSUE FROM CHRONIC ALCOHOL EXPOSURE (P < 0.05). THESE RESULTS INDICATE THAT CHRONIC EXPOSURE TO ALCOHOL LEADS TO CHANGES IN DNA METHYLATION AND PROTEIN EXPRESSION OF INFLAMMATORY GENES, AND COOKED RHUBARB MAY HAVE A PROTECTIVE EFFECT ON THE PANCREATIC TISSUE OF RATS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13  1826  33 EFFECTS OF HISTONE DEACETYLASE INHIBITOR ON EXTRACELLULAR MATRIX PRODUCTION IN HUMAN NASAL POLYP ORGAN CULTURES. BACKGROUND: NASAL POLYPOSIS IS ASSOCIATED WITH A CHRONIC INFLAMMATORY CONDITION OF THE SINONASAL MUCOSA AND INVOLVES MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLULAR MATRIX (ECM) ACCUMULATION. EPIGENETIC MODULATION BY HISTONE DEACETYLASE (HDAC) INHIBITORS INCLUDING TRICHOSTATIN A (TSA) HAS BEEN REPORTED TO HAVE INHIBITORY EFFECTS ON MYOFIBROBLAST DIFFERENTIATION IN LUNG AND RENAL FIBROBLASTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE INHIBITORY EFFECT OF TSA ON MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION IN NASAL POLYP ORGAN CULTURES. METHODS: NASAL POLYP TISSUES FROM 18 PATIENTS WERE ACQUIRED DURING ENDOSCOPIC SINUS SURGERY. AFTER ORGAN CULTURE, NASAL POLYPS WERE STIMULATED WITH TGF-BETA1 AND THEN TREATED WITH TSA. ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), FIBRONECTIN, AND COLLAGEN TYPE I EXPRESSION LEVELS WERE EXAMINED BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION (PCR), REAL-TIME PCR, WESTERN BLOT, AND IMMUNOFLUORESCENT STAINING. HDAC2, HDAC4, AND ACETYLATED H4 EXPRESSION LEVELS WERE ASSAYED BY WESTERN BLOT. CYTOTOXICITY WAS ANALYZED BY THE TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE BIOTIN-DUTP NICK END LABELING ASSAY. RESULTS: THE EXPRESSION LEVELS OF ALPHA-SMA, FIBRONECTIN, AND COLLAGEN TYPE 1 WERE INCREASED IN NASAL POLYP AFTER TRANSFORMING GROWTH FACTOR (TGF) BETA1 TREATMENT. TSA-INHIBITED TGF-BETA1 INDUCED THESE GENE AND PROTEIN EXPRESSION LEVELS. FURTHERMORE, TSA SUPPRESSED PROTEIN EXPRESSION LEVELS OF HDAC2 AND HDAC4. HOWEVER, TSA INDUCED HYPERACETYLATION OF HISTONES H4. TREATMENT WITH TGF-BETA1 WITH OR WITHOUT TSA DID NOT HAVE CYTOTOXIC EFFECT. CONCLUSION: THESE FINDINGS PROVIDE NOVEL INSIGHTS INTO THE EPIGENETIC REGULATION IN MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION OF NASAL POLYP. TSA COULD BE A CANDIDATE OF A THERAPEUTIC AGENT FOR REVERSING THE TGF-BETA1-INDUCED ECM SYNTHESIS THAT LEADS TO NASAL POLYP DEVELOPMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
14  1906  35 ENHANCER OF ZESTE HOMOLOG 2-CATALYSED H3K27 TRIMETHYLATION PLAYS A KEY ROLE IN ACUTE-ON-CHRONIC LIVER FAILURE VIA TNF-MEDIATED PATHWAY. ACUTE-ON-CHRONIC LIVER FAILURE IS MAINLY DUE TO HOST IMMUNITY SELF-DESTRUCTION. THE HISTONE H3 LYSINE 27 (H3K27) TRIMETHYLATING ENZYME, ENHANCER OF ZESTE HOMOLOG 2 (EZH2) MEDIATES EPIGENETIC SILENCING OF GENE EXPRESSION AND REGULATES IMMUNITY, ALSO INVOLVES PATHOGENESIS OF SEVERAL LIVER DISEASES. THE CURRENT STUDY WAS TO DETERMINE THE ROLE OF METHYLTRANSFERASE EZH2 AND ITS CATALYSED H3K27 TRIMETHYLATION (H3K27ME3) IN LIVER FAILURE, AND TO FURTHER INVESTIGATE THE POTENTIAL TARGET FOR LIVER FAILURE TREATMENT. EZH2 AND ITS CATALYSED H3K27ME3 WERE DETERMINED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM LIVER FAILURE PATIENTS AND KUPFFER CELLS FROM EXPERIMENTAL MICE. FURTHERMORE, GSK126 (AN INHIBITOR FOR EZH2 TRIMETHYLATION FUNCTION) WAS APPLIED IN LIVER FAILURE MICE IN VIVO, AND LIPOPOLYSACCHARIDE-STIMULATED MONONUCLEAR CELLS IN VITRO. EZH2 AND H3K27ME3 WERE SIGNIFICANTLY UPREGULATED IN HUMAN PBMC FROM LIVER FAILURE PATIENTS OR MURINE KUPFFER CELLS FROM THE LIVER FAILURE ANIMALS, RESPECTIVELY. GSK126 AMELIORATED DISEASE SEVERITY IN LIVER FAILURE MICE, WHICH MAYBE ATTRIBUTE TO DOWN-REGULATE CIRCULATING AND HEPATIC PROINFLAMMATORY CYTOKINES, ESPECIALLY TNF VIA REDUCING H3K27ME3. IN-DEPTH CHROMATIN IMMUNOPRECIPITATION ANALYSIS UNRAVELLED THAT DECREASED ENRICHMENT OF H3K27ME3 ON TNF PROMOTOR, RESULTING IN TNF ELEVATION IN KUPFFER CELLS FROM LIVER FAILURE MICE. NUCLEAR FACTOR KAPPA B (NF-KAPPAB) AND PROTEIN KINASE B (AKT) SIGNALLING PATHWAYS WERE ACTIVATED UPON LIPOPOLYSACCHARIDE STIMULATION, BUT ATTENUATED BY USING GSK126, ACCOMPANIED WITH DECREASED TNF IN VITRO. IN CONCLUSION, EZH2 AND H3K27ME3 CONTRIBUTED TO THE PATHOGENESIS OF LIVER FAILURE VIA TRIGGERING TNF AND OTHER INDISPENSABLE PROINFLAMMATORY CYTOKINES. EZH2 WAS TO MODIFY H3K27ME3 ENRICHMENT, AS WELL AS, ACTIVATION OF THE DOWNSTREAM NF-KAPPAB AND AKT SIGNALLING PATHWAYS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15  2326  35 EPIGENETIC REGULATION OF HOTAIR IN ADVANCED CHRONIC MYELOID LEUKEMIA. PURPOSE: CHRONIC MYELOID LEUKEMIA (CML) ACCOUNTS FOR ~10% OF LEUKEMIA CASES, AND ITS PROGRESSION INVOLVES EPIGENETIC GENE REGULATION. THIS STUDY INVESTIGATED EPIGENETIC REGULATION OF HOTAIR AND ITS TARGET MICRORNA, MIR-143, IN ADVANCED CML. PATIENTS AND METHODS: WE FIRST ISOLATED BONE MARROW MONONUCLEAR CELLS FROM 70 PATIENTS WITH DIFFERENT PHASES OF CML AND FROM HEALTHY DONORS AS NORMAL CONTROL; WE ALSO CULTURED K562 AND KCL22 CELLS, TREATED WITH DEMETHYLATION DRUG; MTT ASSAY, FLOW CYTOMETRY, QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR), METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), WESTERN BLOT, LUCIFERASE ASSAY, RNA PULL-DOWN ASSAY AND RNA-BINDING PROTEIN IMMUNOPRECIPITATION (RIP) ASSAY WERE PERFORMED. RESULT: AS MEASURED BY QPCR, HOTAIR EXPRESSION IN K562 CELLS, KCL22 CELLS, AND SAMPLES FROM CASES OF ADVANCED-STAGE CML INCREASED WITH LEVELS OF SEVERAL DNA METHYLTRANSFERASES AND HISTONE DEACETYLATES, INCLUDING DNMT1, DNMT3A, HDAC1, EZH2, AND LSD1, AND MIR-143 LEVELS WERE DECREASED AND HOTAIR LEVELS WERE INCREASED. TREATMENT WITH 5-AZACYTIDINE, A DNA METHYLATION INHIBITOR, DECREASED DNMT1, DNMT3A, HDAC1, EZH2, LSD1 MRNA, PROTEIN LEVELS, AND HOTAIR MRNA LEVELS BUT INCREASED MIR-143 LEVELS. HOTAIR KNOCKDOWN AND MIR-143 OVEREXPRESSION BOTH INHIBITED PROLIFERATION AND PROMOTED APOPTOSIS IN KCL22 AND K562 CELLS THROUGH THE PI3K/AKT PATHWAY. RNA PULL-DOWN, MASS SPECTROMETRY, AND RIP ASSAYS SHOWED THAT HOTAIR INTERACTED WITH EZH2 AND LSD1. A DUAL-LUCIFERASE ASSAY DEMONSTRATED THAT HOTAIR INTERACTED WITH MIR-143. CONCLUSION: OUR FINDINGS DEMONSTRATE THE KEY EPIGENETIC INTERACTIONS OF HOTAIR RELATED TO CML PROGRESSION AND SUGGEST HOTAIR AS A POTENTIAL THERAPEUTIC TARGET FOR ADVANCED CML. FURTHERMORE, OUR RESULTS SUPPORT THE USE OF DEMETHYLATION DRUGS AS A CML TREATMENT STRATEGY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16  3175  34 H2AX PHOSPHORYLATION REGULATED BY P38 IS INVOLVED IN BIM EXPRESSION AND APOPTOSIS IN CHRONIC MYELOGENOUS LEUKEMIA CELLS INDUCED BY IMATINIB. INCREASING EVIDENCE SUGGESTS THAT HISTONE H2AX PLAYS A CRITICAL ROLE IN REGULATION OF TUMOR CELL APOPTOSIS AND ACTS AS A NOVEL HUMAN TUMOR SUPPRESSOR PROTEIN. HOWEVER, THE ACTION OF H2AX IN CHRONIC MYELOGENOUS LEUKEMIA (CML) CELLS IS UNKNOWN. THE DETAILED MECHANISM AND EPIGENETIC REGULATION BY H2AX REMAIN ELUSIVE IN CANCER CELLS. HERE, WE REPORT THAT H2AX WAS INVOLVED IN APOPTOSIS OF CML CELLS. OVEREXPRESSION OF H2AX INCREASED APOPTOTIC SENSITIVITY OF CML CELLS (K562) INDUCED BY IMATINIB. HOWEVER, OVEREXPRESSION OF SER139-MUTATED H2AX (BLOCKING PHOSPHORYLATION) DECREASED SENSITIVITY OF K562 CELLS TO APOPTOSIS. SIMILARLY, KNOCKDOWN OF H2AX MADE K562 CELLS RESISTANT TO APOPTOTIC INDUCTION. THESE RESULTS REVEALED THAT THE FUNCTION OF H2AX INVOLVED IN APOPTOSIS IS STRICTLY RELATED TO ITS PHOSPHORYLATION (SER139). OUR DATA FURTHER INDICATED THAT IMATINIB MAY STIMULATE MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) FAMILY MEMBER P38, AND H2AX PHOSPHORYLATION FOLLOWED A SIMILAR TIME COURSE, SUGGESTING A PARALLEL RESPONSE. H2AX PHOSPHORYLATION CAN BE BLOCKED BY P38 SIRNA OR ITS INHIBITOR. THESE DATA DEMONSTRATED THAT H2AX PHOSPHORYLATION WAS REGULATED BY P38 MAPK PATHWAY IN K562 CELLS. HOWEVER, THE P38 MAPK DOWNSTREAM, MITOGEN- AND STRESS-ACTIVATED PROTEIN KINASE-1 AND -2, WHICH PHOSPHORYLATED HISTONE H3, WERE NOT REQUIRED FOR H2AX PHOSPHORYLATION DURING APOPTOSIS. FINALLY, WE PROVIDED EPIGENETIC EVIDENCE THAT H2AX PHOSPHORYLATION REGULATED APOPTOSIS-RELATED GENE BIM EXPRESSION. BLOCKING OF H2AX PHOSPHORYLATION INHIBITED BIM GENE EXPRESSION. TAKEN TOGETHER, THESE DATA DEMONSTRATED THAT H2AX PHOSPHORYLATION REGULATED BY P38 IS INVOLVED IN BIM EXPRESSION AND APOPTOSIS IN CML CELLS INDUCED BY IMATINIB.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17  1945  32 EPIGALLOCATECHIN-3-GALLATE, A HISTONE ACETYLTRANSFERASE INHIBITOR, INHIBITS EBV-INDUCED B LYMPHOCYTE TRANSFORMATION VIA SUPPRESSION OF RELA ACETYLATION. BECAUSE THE P300/CBP-MEDIATED HYPERACETYLATION OF RELA (P65) IS CRITICAL FOR NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) ACTIVATION, THE ATTENUATION OF P65 ACETYLATION IS A POTENTIAL MOLECULAR TARGET FOR THE PREVENTION OF CHRONIC INFLAMMATION. DURING OUR ONGOING SCREENING STUDY TO IDENTIFY NATURAL COMPOUNDS WITH HISTONE ACETYLTRANSFERASE INHIBITOR (HATI) ACTIVITY, WE IDENTIFIED EPIGALLOCATECHIN-3-GALLATE (EGCG) AS A NOVEL HATI WITH GLOBAL SPECIFICITY FOR THE MAJORITY OF HAT ENZYMES BUT WITH NO ACTIVITY TOWARD EPIGENETIC ENZYMES INCLUDING HDAC, SIRT1, AND HMTASE. AT A DOSE OF 100 MICROMOL/L, EGCG ABROGATES P300-INDUCED P65 ACETYLATION IN VITRO AND IN VIVO, INCREASES THE LEVEL OF CYTOSOLIC IKAPPABALPHA, AND SUPPRESSES TUMOR NECROSIS FACTOR ALPHA (TNFALPHA)-INDUCED NF-KAPPAB ACTIVATION. WE ALSO SHOWED THAT EGCG PREVENTS TNFALPHA-INDUCED P65 TRANSLOCATION TO THE NUCLEUS, CONFIRMING THAT HYPERACETYLATION IS CRITICAL FOR NF-KAPPAB TRANSLOCATION AS WELL AS ACTIVITY. FURTHERMORE, EGCG TREATMENT INHIBITED THE ACETYLATION OF P65 AND THE EXPRESSION OF NF-KAPPAB TARGET GENES IN RESPONSE TO DIVERSE STIMULI. FINALLY, EGCG REDUCED THE BINDING OF P300 TO THE PROMOTER REGION OF INTERLEUKIN-6 GENE WITH AN INCREASED RECRUITMENT OF HDAC3, WHICH HIGHLIGHTS THE IMPORTANCE OF THE BALANCE BETWEEN HATS AND HISTONE DEACETYLASES IN THE NF-KAPPAB-MEDIATED INFLAMMATORY SIGNALING PATHWAY. IMPORTANTLY, EGCG AT 50 MICROMOL/L DOSE COMPLETELY BLOCKS EBV INFECTION-INDUCED CYTOKINE EXPRESSION AND SUBSEQUENTLY THE EBV-INDUCED B LYMPHOCYTE TRANSFORMATION. THESE RESULTS SHOW THE CRUCIAL ROLE OF ACETYLATION IN THE DEVELOPMENT OF INFLAMMATORY-RELATED DISEASES.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  1667  33 DOWNREGULATION OF PCAF BY MIR-181A/B PROVIDES FEEDBACK REGULATION TO TNF-ALPHA-INDUCED TRANSCRIPTION OF PROINFLAMMATORY GENES IN LIVER EPITHELIAL CELLS. ABERRANT CELLULAR RESPONSES TO PROINFLAMMATORY CYTOKINES, SUCH AS TNF-ALPHA, ARE PATHOGENIC FEATURES IN MOST CHRONIC INFLAMMATORY DISEASES. A VARIETY OF EXTRACELLULAR AND INTRACELLULAR FEEDBACK PATHWAYS HAS EVOLVED TO PREVENT AN INAPPROPRIATE CELLULAR REACTION TO THESE PROINFLAMMATORY CYTOKINES. IN THIS STUDY, WE REPORT THAT TNF-ALPHA TREATMENT OF HUMAN AND MOUSE CHOLANGIOCYTES AND HEPATOCYTES DOWNREGULATED EXPRESSION OF P300/CBP-ASSOCIATED FACTOR (PCAF), A COACTIVATOR AND AN ACETYLTRANSFERASE THAT PROMOTES HISTONE ACETYLATION AND GENE TRANSCRIPTION. OF THESE UPREGULATED MICRORNAS IN TNF-ALPHA-TREATED CELLS, MIR-181A/B (MIR-181A AND MIR-181B) SUPPRESSED TRANSLATION OF PCAF MRNA. FUNCTIONAL MANIPULATION OF MIR-181A/B CAUSED RECIPROCAL ALTERATIONS IN PCAF PROTEIN EXPRESSION IN CULTURED CHOLANGIOCYTES AND HEPATOCYTES. INHIBITION OF MIR-181A/B FUNCTION WITH ANTI-MIRS BLOCKED TNF-ALPHA-INDUCED SUPPRESSION OF PCAF EXPRESSION. PROMOTER RECRUITMENT OF PCAF WAS SHOWN TO BE ASSOCIATED WITH TNF-ALPHA-INDUCED TRANSCRIPTION OF INFLAMMATORY GENES. INTRIGUINGLY, PRETREATMENT OF CELLS WITH TNF-ALPHA INHIBITED TRANSCRIPTION OF INFLAMMATORY GENES IN RESPONSE TO SUBSEQUENT TNF-ALPHA STIMULATION. OVEREXPRESSION OF PCAF OR INHIBITION OF MIR-181A/B FUNCTION WITH ANTI-MIRS ATTENUATED THE INHIBITORY EFFECTS OF TNF-ALPHA PRETREATMENT ON EPITHELIAL INFLAMMATORY RESPONSE TO SUBSEQUENT TNF-ALPHA STIMULATION. DOWNREGULATION OF PCAF AND THE INHIBITORY EFFECTS OF TNF-ALPHA PRETREATMENT ON LIVER EPITHELIAL INFLAMMATORY RESPONSE WERE FURTHER CONFIRMED IN A MOUSE MODEL OF TNF-ALPHA I.P. INJECTION. THESE DATA SUGGEST THAT PCAF IS A TARGET FOR MIR-181A/B, AND DOWNREGULATION OF PCAF BY TNF-ALPHA PROVIDES NEGATIVE FEEDBACK REGULATION TO INFLAMMATORY REACTIONS IN LIVER EPITHELIAL CELLS, A PROCESS THAT MAY BE RELEVANT TO THE EPIGENETIC FINE-TUNING OF EPITHELIAL INFLAMMATORY PROCESSES IN GENERAL.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19  5850  39 SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) REDUCES FIBROSIS MARKERS AND DEACTIVATES HUMAN STELLATE CELLS VIA THE EPITHELIAL-MESENCHYMAL TRANSITION (EMT). HEPATIC FIBROSIS IS KNOWN AS THE ACCUMULATION OF CONNECTIVE TISSUE SECONDARY TO CHRONIC DAMAGE TO THE LIVER. EPITHELIAL-MESENCHYMAL TRANSITION (EMT) CORRESPONDING INCREASE IN LIVER FIBROGENESIS WAS SHOWN WITH IMMUNOHISTOCHEMISTRY AND PCR-BASED STUDIES. SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), A SYNTHETIC COMPOUND APPROVED AS A HISTONE DEACETYLASE INHIBITOR (HDAC) BY THE FDA TO TREAT CUTANEOUS T-CELL LYMPHOMA IS UNDER INVESTIGATION FOR THE TREATMENT OF LUNG AND RENAL FIBROSIS. EXPERIMENTAL MODELING FOR HEPATIC FIBROSIS CAN BE CONSTRUCTED WITH AN LX2 CELL LINE ISOLATED FROM HUMAN HEPATIC STELLATE CELLS (HSCS). IN THIS STUDY, WE AIMED TO INVESTIGATE THE MODULATION OF SAHA IN THE PATHOGENESIS OF LIVER FIBROSIS BY DETECTING THE LEVELS OF PROTEINS; (E-CADHERIN (E-CAD), N-CADHERIN (N-CAD), VIMENTIN (VIM), AND GENES; E-CAD, N-CAD, VIM, TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA), ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), TYPE 1 COLLAGEN (COL1A1), TYPE 3 COLLAGEN (COL3A1)) THAT PLAY A SIGNIFICANT ROLE IN EMT WITH THE LX2 CELL LINE. WE ALSO EVALUATED THE ACTION OF SAHA WITH CELL PROLIFERATION, CLONOGENIC, AND MIGRATION ASSAY. CELL PROLIFERATION WAS PERFORMED BY FLOW CYTOMETRY. ALL THE PROTEIN LEVELS WERE DETERMINED BY WESTERN BLOT ANALYSIS, AND GENE EXPRESSION LEVELS WERE MEASURED BY REAL-TIME PCR. OUR STUDY OBSERVED THAT SAHA TREATMENT DECREASED CELL VIABILITY, COLONY FORMATION AND MIGRATION IN LX2 CELLS. WE FOUND THAT SAHA INCREASED E-CAD EXPRESSION LEVEL, WHILE IT DECREASED N-CAD, VIM, COL1A1, COL3A1, ALPHA-SMA TGF-BETA GENES EXPRESSION LEVELS. SAHA DECREASED THE LEVEL OF E-CAD, N-CAD, AND VIM PROTEIN LEVELS. WE THOUGHT THAT SAHA POSSESSES POTENT ANTIFIBROTIC AND ANTI-EMT PROPERTIES IN LX2.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20  6020  37 THE ATTENUATION OF RENAL FIBROSIS BY HISTONE DEACETYLASE INHIBITORS IS ASSOCIATED WITH THE PLASTICITY OF FOXP3(+)IL-17(+) T CELLS. BACKGROUND: THE HISTONE DEACETYLASE (HDAC) INHIBITOR, WHICH HAS POTENTIAL EFFECTS ON EPIGENETIC MODIFICATIONS, HAD BEEN REPORTED TO ATTENUATE RENAL FIBROSIS. CD4(+) FORKHEAD BOX P3 (FOXP3)(+) T REGULATORY (TREG) CELLS MAY BE CONVERTED TO INFLAMMATION-ASSOCIATED T HELPER 17 CELLS (TH17) WITH TISSUE FIBROSIS PROPERTIES. THE ASSOCIATION BETWEEN FOXP3(+)IL-17(+) T CELLS AND THE ATTENUATION OF RENAL FIBROSIS BY THE HDAC INHIBITOR IS NOT CLEAR. METHODS: THIS STUDY EVALUATED THE ROLES OF THE HDAC INHIBITOR, TREG CELLS AND THEIR DIFFERENTIATION INTO TH17 CELLS, WHICH AGGRAVATE CHRONIC INFLAMMATION AND RENAL FIBROSIS IN A UNILATERAL URETERAL OBSTRUCTION (UUO) MOUSE MODEL. THE STUDY GROUPS INCLUDED CONTROL AND UUO MICE THAT WERE MONITORED FOR 7, 14 OR 21 DAYS. RESULTS: JUXTAGLOMERULAR (JG) HYPERPLASIA, ANGIOTENSIN II TYPE 1 RECEPTOR (AT1R) EXPRESSION AND LYMPHOCYTE INFILTRATION WERE OBSERVED IN RENAL TISSUES AFTER UUO BUT WERE DECREASED AFTER TRICHOSTATIN A (TSA) TREATMENT, A HDAC INHIBITOR. THE NUMBER OF CD4(+)FOXP3(+) T CELLS INCREASED PROGRESSIVELY, ALONG WITH THE NUMBER OF FOXP3(+)INTERLEUKIN (IL)-17(+) T CELLS, AFTER 14 DAYS, AND THEIR NUMBERS THEN PROGRESSIVELY DECREASED WITH INCREASING CD4(+)IL-17(+) T CELL NUMBERS, AS DEMONSTRATED BY DOUBLE IMMUNOHISTOCHEMISTRY. PROGRESSIVE RENAL FIBROSIS WAS ASSOCIATED WITH THE LOSS OF CD4(+)FOXP3(+)IL-17(+) T CELLS IN SPLENIC SINGLE-CELL SUSPENSIONS. FOXP3(+)IL-17(+) T CELLS EXPRESSED TGF-BETA1 BOTH IN VITRO AND IN VIVO, AND TGF-BETA1 EXPRESSION WAS SIGNIFICANTLY KNOCKDOWN BY IL-17 SIRNA IN VITRO. THESE CELLS WERE FOUND TO PLAY A ROLE IN CONVERTING TREGS INTO IL-17- AND TGF-BETA1-PRODUCING CELLS. CONCLUSIONS: TSA TREATMENT DECREASED JG HYPERPLASIA, THE PERCENTAGE OF FOXP3(+)IL-17(+) CELLS AND THE DEGREE OF FIBROSIS, SUGGESTING THAT THERAPEUTIC BENEFITS MAY RESULT FROM EPIGENETIC MODIFICATIONS.	2017