1 3233 91 HELICOBACTER, INFLAMMATION, AND GASTRIC CANCER. HELICOBACTER PYLORI INFECTION LEADS TO LONG-LASTING CHRONIC INFLAMMATION AND REPRESENTS THE MOST COMMON RISK FACTOR UNDERLYING GASTRIC CANCER. RECENTLY, NEW INSIGHTS INTO THE MECHANISMS THROUGH WHICH H. PYLORI AND MUCOSAL INFLAMMATION LEAD TO CANCER DEVELOPMENT HAVE EMERGED. H. PYLORI VIRULENCE FACTORS, IN PARTICULAR SPECIFIC CAGA GENOTYPES, REPRESENT MAIN FACTORS IN GASTRIC CANCER, INDUCING ALTERED INTRACELLULAR SIGNALING IN EPITHELIAL CELLS. THE CHRONIC NATURE OF H. PYLORI INFECTION APPEARS TO RELATE TO THE VACA VIRULENCE FACTOR AND TH17/TREG MECHANISMS. A ROLE OF H. PYLORI INFECTION IN EPIGENETIC AND MICRORNA DEREGULATION HAS BEEN SHOWN. MUTATION OF THE EPITHELIAL CELL GENOME, A HALLMARK OF CANCER, WAS DEMONSTRATED TO ACCUMULATE IN H. PYLORI INFECTED STOMACH PARTLY DUE TO INADEQUATE DNA REPAIR. GASTRIC STEM CELLS WERE SHOWN TO BE TARGETS OF OXIDATIVE INJURY IN THE HELICOBACTER-INFLAMMATORY MILIEU. RECENT ADVANCES EMPHASIZING THE CONTRIBUTION OF BACTERIAL FACTORS, INFLAMMATORY MEDIATORS, AND THE HOST EPITHELIAL RESPONSE IN GASTRIC CARCINOGENESIS ARE REVIEWED. 2013 2 4154 27 MECHANISTIC ROLES OF EPITHELIAL AND IMMUNE CELL SIGNALING DURING THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER. TO DATE, SUBSTANTIAL EVIDENCE HAS SHOWN A SIGNIFICANT ASSOCIATION BETWEEN INFLAMMATORY BOWEL DISEASES (IBD) AND DEVELOPMENT OF COLITIS-ASSOCIATED CANCER (CAC). THE INCIDENCE/PREVALENCE OF IBD IS HIGHER IN WESTERN COUNTRIES INCLUDING THE US, AUSTRALIA, AND THE UK. ALTHOUGH CAC DEVELOPMENT IS GENERALLY CHARACTERIZED BY STEPWISE ACCUMULATION OF GENETIC AS WELL AS EPIGENETIC CHANGES, PRECISE MECHANISMS OF HOW CHRONIC INFLAMMATION LEADS TO THE DEVELOPMENT OF CAC ARE LARGELY UNKNOWN. PRECEDING INTESTINAL INFLAMMATION IS ONE OF THE MAJOR INFLUENTIAL FACTORS FOR CAC TUMORIGENESIS. MUCOSAL IMMUNE RESPONSES INCLUDING ACTIVATION OF ABERRANT SIGNALING PATHWAYS BOTH IN INNATE AND ADAPTIVE IMMUNE CELLS PLAY A PIVOTAL ROLE IN CAC. TUMOR PROGRESSION AND METASTASIS ARE SHAPED BY A TIGHTLY CONTROLLED TUMOR MICROENVIRONMENT WHICH IS ORCHESTRATED BY SEVERAL IMMUNE CELLS AND STROMAL CELLS INCLUDING MACROPHAGES, NEUTROPHILS, DENDRITIC CELLS, MYELOID DERIVED SUPPRESSOR CELLS, T CELLS, AND MYOFIBROBLASTS. IN THIS ARTICLE, WE WILL DISCUSS THE CONTRIBUTING FACTORS OF EPITHELIAL AS WELL AS IMMUNE CELL SIGNALING IN INITIATION OF CAC TUMORIGENESIS AND MUCOSAL IMMUNE REGULATORY FACTORS IN THE COLONIC TUMOR MICROENVIRONMENT. IN DEPTH UNDERSTANDING OF THESE FACTORS IS NECESSARY TO DEVELOP NOVEL ANTI-INFLAMMATORY AND ANTI-CANCER THERAPIES FOR CAC IN THE NEAR FUTURE. 2016 3 3920 18 LINKING IMMUNITY, EPIGENETICS, AND CANCER IN INFLAMMATORY BOWEL DISEASE. MOST OF WHAT IS KNOWN ABOUT THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE (IBD) PERTAINS TO COMPLEX INTERPLAY BETWEEN HOST GENETICS, IMMUNITY, AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS PLAY PIVOTAL ROLES IN INTESTINAL IMMUNITY AND MUCOSAL HOMEOSTASIS AS WELL AS MEDIATING GENE-ENVIRONMENT INTERACTIONS. IN THIS ARTICLE, WE PROVIDE A HISTORICAL ACCOUNT OF EPIGENETIC RESEARCH EITHER DIRECTLY RELATED OR PERTINENT TO THE PATHOGENESIS AND MANAGEMENT OF IBD. WE FURTHER COLLATE EMERGING EVIDENCE SUPPORTING ROLES FOR EPIGENETIC MECHANISMS IN RELEVANT ASPECTS OF IBD BIOLOGY, INCLUDING DEREGULATED IMMUNITY, HOST-PATHOGEN RECOGNITION AND MUCOSAL INTEGRITY. FINALLY, WE HIGHLIGHT KEY EPIGENETIC MECHANISMS THAT LINK CHRONIC INFLAMMATION TO SPECIFIC IBD COMORBIDITIES, INCLUDING COLITIS-ASSOCIATED CANCER AND DISCUSS THEIR POTENTIAL UTILITY AS NOVEL BIOMARKERS OR PHARMACOLOGIC TARGETS IN IBD THERAPY. 2014 4 3232 28 HELICOBACTER PYLORI-INDUCED SIGNALING PATHWAYS CONTRIBUTE TO INTESTINAL METAPLASIA AND GASTRIC CARCINOGENESIS. HELICOBACTER PYLORI (H. PYLORI) INDUCES CHRONIC GASTRIC INFLAMMATION, ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND CANCER. ALTHOUGH THE RISK OF GASTRIC CANCER INCREASES EXPONENTIALLY WITH THE EXTENT OF ATROPHIC GASTRITIS, THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS HAVE NOT BEEN FULLY ELUCIDATED. H. PYLORI INDUCES GENETIC AND EPIGENETIC CHANGES IN GASTRIC EPITHELIAL CELLS THROUGH ACTIVATING INTRACELLULAR SIGNALING PATHWAYS IN A CAGPAI-DEPENDENT MANNER. H. PYLORI EVENTUALLY INDUCES GASTRIC CANCER WITH CHROMOSOMAL INSTABILITY (CIN) OR MICROSATELLITE INSTABILITY (MSI), WHICH ARE CLASSIFIED AS TWO MAJOR SUBTYPES OF GASTRIC CANCER. ELUCIDATION OF THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS WILL ALSO BE IMPORTANT FOR CANCER THERAPY. 2015 5 2368 27 EPIGENETIC REGULATION OF T HELPER CELLS AND INTESTINAL PATHOGENICITY. INFLAMMATORY BOWEL DISEASES (IBDS) ARE CHARACTERIZED BY RELAPSING AND REMITTING CHRONIC INTESTINAL INFLAMMATION. PREVIOUS STUDIES HAVE DEMONSTRATED THE CONTRIBUTIONS OF GENETIC BACKGROUND, ENVIRONMENTAL FACTORS (FOOD, MICROBIOTA, USE OF ANTIBIOTICS), AND HOST IMMUNITY IN THE DEVELOPMENT OF IBDS. MORE THAN 200 GENES HAVE BEEN SHOWN TO INFLUENCE IBD SUSCEPTIBILITY, MOST OF WHICH ARE INVOLVED IN IMMUNITY. THE VERTEBRATE IMMUNE SYSTEM COMPRISES A COMPLEX NETWORK OF INNATE AND ADAPTIVE IMMUNE CELLS THAT PROTECT THE HOST FROM INFECTION AND CANCER. DYSREGULATION OF THE MUTUALISTIC RELATIONSHIP BETWEEN THE IMMUNE SYSTEM AND THE GUT ENVIRONMENT RESULTS IN IBD. CONSIDERING THE FUNDAMENTAL ROLE OF EPIGENETIC REGULATION IN IMMUNE CELLS, EPIGENETIC MECHANISMS, PARTICULARLY IN T HELPER (TH) CELLS, MAY PLAY A MAJOR ROLE IN THE COMPLEX REGULATION OF MUCOSAL IMMUNITY. EPIGENETIC REGULATION AND DYSREGULATION OF TH CELLS ARE INVOLVED IN THE MAINTENANCE OF INTESTINAL HOMEOSTASIS AND ITS BREAKDOWN IN IBD. 2019 6 3221 26 HELICOBACTER PYLORI AND THE MOLECULAR PATHOGENESIS OF INTESTINAL-TYPE GASTRIC CARCINOMA. GASTRIC CARCINOMA IS AN INFLAMMATION-RELATED CANCER CAUSED BY LONG-TERM INFECTION WITH THE HUMAN BACTERIAL PATHOGEN, HELICOBACTER PYLORI. THE PATTERN OF ACUTE-ON-CHRONIC INFLAMMATION CAUSES PROGRESSIVE MUCOSAL DAMAGE WHICH MAY RESULT IN ATROPHY WITH METAPLASTIC EPITHELIA AND EVENTUALLY GASTRIC CANCER. RECENTLY, IT HAS BEEN RECOGNIZED THAT H. PYLORI CAN ALSO CAUSE GENETIC INSTABILITY SUCH AS DOUBLE-STRANDED DNA BREAKS AND CAN PRODUCE GENE ACTIVATION AND SILENCING VIA EPIGENETIC PATHWAYS. AS GENETIC INSTABILITY IS THE HALLMARK OF CANCER, WE HIGHLIGHT RECENT PROGRESS IN UNDERSTANDING THE GASTRIC CARCINOGENESIS IN RELATION TO H. PYLORI-RELATED INFLAMMATION, H. PYLORI-INDUCED DOUBLE-STRANDED DNA BREAKAGE AND ABERRANT GENE EXPRESSION AS WELL AS THE MECHANISMS AND ROLE OF H. PYLORI-ASSOCIATED EPIGENETIC CHANGE IN GENE EXPRESSION. 2014 7 2852 24 FROM GASTRIC INFLAMMATION TO GASTRIC CANCER. THE MAJORITY OF GASTRIC ADENOCARCINOMAS ARE RELATED TO CHRONIC INFLAMMATION INDUCED BY HELICOBACTER PYLORI INFECTION. FOR INTESTINAL-TYPE GASTRIC CANCER, A MULTISTEP PROCESS OF MUCOSAL ALTERATIONS LEADING FROM GASTRITIS VIA GLANDULAR ATROPHY, INTESTINAL METAPLASIA AND DYSPLASIA TO INVASIVE CARCINOMA IS WELL RECOGNIZED. ONGOING CLINICAL STUDIES FOCUS ON A 'POINT OF NO RETURN'. IT IS DEFINED AS A SITUATION WHEN CERTAIN ALTERATIONS ARE NO LONGER REVERSIBLE BY H. PYLORI ERADICATION AND PROGRESSION TO GASTRIC CANCER MAY CONTINUE. H. PYLORI AFFECTS THE MUCOSAL AS WELL AS THE SYSTEMIC IMMUNE RESPONSE BY SECRETION OF CYTOKINES AND THE RECRUITMENT OF DISTINCT INFLAMMATORY CELLS. THE IMMUNE RESPONSE IS CHARACTERIZED BY A BALANCE BETWEEN A TH1-DOMINATED RESPONSE AND THE RECRUITMENT OF ANTIGEN-SPECIFIC REGULATORY T CELLS THAT ALLOW THE BACTERIA TO PERSIST IN HUMAN GASTRIC MUCOSA. BESIDES IMMUNE-MEDIATED EFFECTS, H. PYLORI INDUCES CELLULAR ALTERATIONS AS WELL AS GENETIC ALTERATIONS IN GENES THAT ARE ESSENTIAL FOR THE EPIGENETIC INTEGRITY AND MUCOSAL HOMEOSTASIS. THESE GENETIC ALTERATIONS DURING GASTRIC CANCER DEVELOPMENT ARE IN FOCUS OF INTENSIVE RESEARCH AND SHOULD ULTIMATELY ALLOW THE IDENTIFICATION OF RISK FACTORS INVOLVED IN GASTRIC CARCINOGENESIS. THE DETECTION OF INDIVIDUALS AT HIGH RISK FOR GASTRIC CANCER WOULD HELP TO DESIGN APPROPRIATE STRATEGIES FOR PREVENTION AND SURVEILLANCE. 2010 8 3804 17 INTESTINAL MICROBIOTA, CHRONIC INFLAMMATION, AND COLORECTAL CANCER. IN ADDITION TO GENETIC AND EPIGENETIC FACTORS, VARIOUS ENVIRONMENTAL FACTORS, INCLUDING DIET, PLAY IMPORTANT ROLES IN THE DEVELOPMENT OF COLORECTAL CANCER (CRC). RECENTLY, THERE IS INCREASING INTEREST IN THE INTESTINAL MICROBIOTA AS AN ENVIRONMENTAL RISK FACTOR FOR CRC, BECAUSE DIET ALSO INFLUENCES THE COMPOSITION OF THE INTESTINAL MICROBIOTA. THE HUMAN INTESTINAL MICROBIOTA COMPRISES ABOUT 100 TRILLION MICROBES. THIS MICROBIOME THRIVES ON UNDIGESTED DIETARY RESIDUES IN THE INTESTINAL LUMEN AND PRODUCES VARIOUS METABOLITES. IT IS WELL KNOWN THAT THE DIETARY RISK FACTORS FOR CRC ARE MEDIATED BY DYSBIOSIS OF THE INTESTINAL MICROBIOTA AND THEIR METABOLITES. IN THIS REVIEW, WE DESCRIBE THE BACTERIAL TAXA ASSOCIATED WITH CRC, INCLUDING FUSOBACTERIUM NUCLEATUM, ENTEROTOXIGENIC BACTEROIDES FRAGILIS, ESCHERICHIA COLI, AND BUTYRATE-PRODUCING BACTERIA. WE ALSO DISCUSS THE HOST-DIET INTERACTION IN COLORECTAL CARCINOGENESIS. 2018 9 3170 21 GUT INFLAMMATION AND TUMORIGENESIS: EVERY SITE HAS A DIFFERENT TALE TO TELL. GUT INFLAMMATION HAS BEEN CORRELATED WITH CANCEROGENESIS BY DISRUPTING GASTROINTESTINAL HOMEOSTASIS. NUMEROUS CHRONIC INFLAMMATORY DISORDERS OF THE TUBULAR GASTROINTESTINAL TRACT (E.G., GASTROESOPHAGEAL REFLUX DISEASE, HELICOBACTER PYLORI-INDUCED AND AUTOIMMUNE CHRONIC GASTRITIS, CELIAC DISEASE, AND INFLAMMATORY BOWEL DISEASES) HAVE BEEN VARIABLY ASSOCIATED WITH AN INCREASED NEOPLASTIC RISK. GASTROINTESTINAL INFLAMMATION-INDUCED NEOPLASMS INCLUDE EPITHELIAL TUMORS (ESOPHAGEAL SQUAMOUS CELL CARCINOMA AND ADENOCARCINOMA, GASTRIC ADENOCARCINOMA AND NEUROENDOCRINE TUMORS, SMALL BOWEL ADENOCARCINOMA AND NEUROENDOCRINE TUMORS, AND COLORECTAL CANCER) AND LYMPHOMAS (SUCH AS GASTRIC MARGINAL ZONE LYMPHOMAS AND ENTEROPATHY-ASSOCIATED T CELL LYMPHOMA). IN THE LAST DECADES, NUMEROUS STUDIES HAVE INVESTIGATED THE PATHOGENETIC MECHANISMS AND THE MICROENVIRONMENTAL/MICROBIOME CHANGES THAT TRIGGER GENETIC AND/OR EPIGENETIC ALTERATIONS EVENTUALLY LEADING TO TUMORIGENESIS, OFTEN THROUGH A HISTOLOGICALLY RECOGNIZABLE INFLAMMATION-DYSPLASIA-CARCINOMA CANCEROGENIC SEQUENCE. IN THE PRESENT REVIEW, AN OVERVIEW OF THE CURRENT KNOWLEDGE ON THE LINKS BETWEEN INFLAMMATORY DISEASES AND NEOPLASMS OF THE TUBULAR GI TRACT, APPLYING A SITE-BY-SITE APPROACH, IS PROVIDED. 2023 10 3229 33 HELICOBACTER PYLORI-INDUCED GASTRIC INFLAMMATION AND GASTRIC CANCER. HELICOBACTER PYLORI (H. PYLORI) INFECT OVER HALF OF THE WORLD'S POPULATION. THE PREVALENCE OF H. PYLORI INFECTION AND THE PREDOMINANT GENOTYPE OF H. PYLORI VIRULENCE FACTORS VARY CONSIDERABLY ACROSS DIFFERENT GEOGRAPHICAL REGIONS. H. PYLORI COULD UNIQUELY PERSIST FOR DECADES IN THE HARSH STOMACH ENVIRONMENT, WHERE IT DAMAGES THE GASTRIC MUCOSA AND CHANGES THE PATTERN OF GASTRIC HORMONE RELEASE, THEREBY AFFECTS GASTRIC PHYSIOLOGY. BY UTILIZING VARIOUS VIRULENCE FACTORS, H. PYLORI TARGETS DIFFERENT CELLULAR PROTEINS TO MODULATE THE HOST INFLAMMATORY RESPONSE AND INITIATE MULTIPLE "HITS" ON THE GASTRIC MUCOSA, RESULTING IN CHRONIC GASTRITIS AND PEPTIC ULCERATION. AMONG THE LONG-TERM CONSEQUENCES OF H. PYLORI INFECTION IS GASTRIC MALIGNANCIES, PARTICULARLY GASTRIC CANCER (GC) AND GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA. AS SUCH, H. PYLORI HAS BEEN RECOGNIZED AS A CLASS I CARCINOGEN BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. DESPITE A CLOSE CAUSAL LINK BETWEEN H. PYLORI INFECTION AND THE DEVELOPMENT OF GASTRIC MALIGNANCIES, THE PRECISE MECHANISMS INVOLVED IN THIS PROCESS ARE STILL OBSCURE. STUDIES OVER THE PAST TWO DECADES HAVE REVEALED THAT H. PYLORI EXERT ONCOGENIC EFFECTS ON GASTRIC MUCOSA THROUGH A COMPLEX INTERACTION BETWEEN BACTERIAL FACTORS, HOST FACTORS, AND ENVIRONMENTAL FACTORS. NUMEROUS SIGNALING PATHWAYS CAN BE ACTIVATED BY H. PYLORI. IN THIS REVIEW, WE AIM TO ELABORATE ON THE RECENT DEVELOPMENTS IN THE PATHOPHYSIOLOGICAL MECHANISMS OF H. PYLORI-INDUCED GASTRIC INFLAMMATION AND GASTRIC CANCER. 2014 11 4535 22 MULTIPLE ROLES OF TOLL-LIKE RECEPTOR 4 IN COLORECTAL CANCER. TOLL-LIKE RECEPTOR (TLR) SIGNALING HAS BEEN IMPLICATED IN THE INFLAMMATORY RESPONSES IN INTESTINAL EPITHELIAL CELLS (IECS). SUCH INFLAMMATORY SIGNALS MEDIATE COMPLEX INTERACTIONS BETWEEN COMMENSAL BACTERIA AND TLRS AND ARE REQUIRED FOR IEC PROLIFERATION, IMMUNE RESPONSE, REPAIR, AND HOMEOSTASIS. THE UPREGULATION OF CERTAIN TLRS IN COLORECTAL CANCER (CRC) TISSUES SUGGESTS THAT TLRS MAY PLAY AN ESSENTIAL ROLE IN THE PROGNOSIS OF CHRONIC AND INFLAMMATORY DISEASES THAT ULTIMATELY CULMINATE IN CRC. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE LITERATURE ON THE INVOLVEMENT OF THE TLR PATHWAY IN THE INITIATION, PROGRESSION, AND METASTASIS OF CRC, AS WELL AS INHERITED GENETIC VARIATION AND EPIGENETIC REGULATION. THE DIFFERENTIAL EXPRESSION OF TLRS IN EPITHELIAL CELLS HAS ALSO BEEN DISCUSSED. IN PARTICULAR, WE EMPHASIZE THE PHYSIOLOGICAL ROLE OF TLR4 IN CRC DEVELOPMENT AND PATHOGENESIS, AND PROPOSE NOVEL AND PROMISING APPROACHES FOR CRC THERAPEUTICS WITH THE AID OF TLR LIGANDS. 2014 12 3226 36 HELICOBACTER PYLORI INFECTION, ONCOGENIC PATHWAYS AND EPIGENETIC MECHANISMS IN GASTRIC CARCINOGENESIS. CHRONIC COLONIZATION OF THE HUMAN STOMACH BY HELICOBACTER PYLORI, A GRAM-NEGATIVE BACTERIUM, IS THE MAJOR CAUSE OF CHRONIC GASTRITIS, PEPTIC ULCERS AND GASTRIC CANCER. RECENT PROGRESS HAS ELUCIDATED IMPORTANT BACTERIAL AND HOST FACTORS THAT ARE RESPONSIBLE FOR H. PYLORI-INDUCED GASTRIC INFLAMMATION AND GASTRIC MALIGNANCY. H. PYLORI CYTOTOXIN-ASSOCIATED ANTIGEN A IS THE MAJOR ONCOGENIC FACTOR INJECTED INTO HOST CELLS FROM BACTERIA AND IT DISRUPTS EPITHELIAL CELL FUNCTIONS. TOGETHER WITH H. PYLORI CAG PATHOGENICITY ISLAND, IT CAUSES GENERAL INFLAMMATORY STRESS WITHIN GASTRIC MUCOSA AND ACTIVATES MULTIPLE ONCOGENIC PATHWAYS IN EPITHELIAL CELLS. A GROWING LIST OF THESE PATHWAYS INCLUDES NF-KAPPAB, ACTIVATOR PROTEIN-1, PI3K, SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION 3, WNT/BETA-CATENIN AND CYCLOOXYGENASE 2. H. PYLORI INDUCES EPIGENETIC ALTERATIONS, SUCH AS DNA METHYLATION AND HISTONE MODIFICATION, WHICH PLAY CRITICAL ROLES IN ONCOGENIC TRANSFORMATION. IN ADDITION, INVESTIGATIONS INTO GASTRIC STEM CELL OR PROGENITOR CELL BIOLOGY HAVE SHED LIGHT ON THE MECHANISMS THROUGH WHICH GASTRIC CANCER MAY ORIGINATE. CONTINUED INVESTIGATION IN THESE AREAS WILL YIELD NOVEL INSIGHTS AND HELP TO ELUCIDATE THE MECHANISMS OF BACTERIA-INDUCED CARCINOGENESIS. 2010 13 2853 27 FROM HELICOBACTER PYLORI INFECTION TO GASTRIC CANCER: CURRENT EVIDENCE ON THE IMMUNE RESPONSE. GASTRIC CANCER (GC) IS THE RESULT OF A MULTIFACTORIAL PROCESS WHOSE MAIN COMPONENTS ARE INFECTION BY HELICOBACTER PYLORI (H. PYLORI), BACTERIAL VIRULENCE FACTORS, HOST IMMUNE RESPONSE AND ENVIRONMENTAL FACTORS. THE DEVELOPMENT OF THE NEOPLASTIC MICROENVIRONMENT ALSO DEPENDS ON GENETIC AND EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES, WHICH RESULTS IN DEREGULATION OF CELL SIGNALING PATHWAYS AND APOPTOSIS PROCESS. THIS REVIEW SUMMARIZES THE MAIN ASPECTS OF THE PATHOGENESIS OF GC AND THE IMMUNE RESPONSE INVOLVED IN CHRONIC INFLAMMATION GENERATED BY H. PYLORI. 2022 14 3411 20 HP1GAMMA PREVENTS ACTIVATION OF THE CGAS/STING PATHWAY BY PRESERVING NUCLEAR ENVELOPE AND GENOMIC INTEGRITY IN COLON ADENOCARCINOMA CELLS. CHRONIC INFLAMMATORY PROCESSES IN THE INTESTINE RESULT IN SERIOUS CONDITIONS SUCH AS INFLAMMATORY BOWEL DISEASE (IBD) AND CANCER. AN INCREASED DETECTION OF CYTOPLASMIC DNA SENSORS HAS BEEN REPORTED IN THE IBD COLON MUCOSA, SUGGESTING THEIR CONTRIBUTION IN MUCOSAL INFLAMMATION. YET, THE MECHANISMS ALTERING DNA HOMEOSTASIS AND TRIGGERING THE ACTIVATION OF DNA SENSORS REMAIN POORLY UNDERSTOOD. IN THIS STUDY, WE SHOW THAT THE EPIGENETIC REGULATOR HP1GAMMA PLAYS A ROLE IN PRESERVING NUCLEAR ENVELOPE AND GENOMIC INTEGRITY IN ENTEROCYTIC CELLS, THEREBY PROTECTING AGAINST THE PRESENCE OF CYTOPLASMIC DNA. ACCORDINGLY, HP1 LOSS OF FUNCTION LED TO THE INCREASED DETECTION OF CGAS/STING, A CYTOPLASMIC DNA SENSOR THAT TRIGGERS INFLAMMATION. THUS, IN ADDITION TO ITS ROLE AS A TRANSCRIPTIONAL SILENCER, HP1GAMMA MAY ALSO EXERT ANTI-INFLAMMATORY PROPERTIES BY PREVENTING THE ACTIVATION OF THE ENDOGENOUS CYTOPLASMIC DNA RESPONSE IN THE GUT EPITHELIUM. 2023 15 6871 23 [PATHOGENETIC IMPORTANCE OF HELICOBACTER PYLORI INFECTION]. H. PYLORI ARE ETIOLOGICAL FACTOR OF HUMAN ACUTE AND CHRONIC GASTRITIS. DEPENDING ON PATHOGENIC FACTORS OF MICROORGANISM AND POLYMORPHISM OF HUMAN GENES, CHRONIC GASTRITIS CAN BE A CAUSE FOR ULCERATIVE ENTERITIS OF THE DUODENUM OR STOMACH, GASTRIC ADENOCARCINOMA AND MALT-LYMPHOMA DEVELOPMENT. WE REVEALED GENETIC FEATURES OF BACTERIA, DETERMINED THE INTENSITY OF INFLAMMATION, SUCH AS PATHOGENIC FACTORS--CAG, PLASTIC REGION OF THE GENOME AND ADHESIN CODING GENES. EPIGENETIC CHANGES, FOR EXAMPLE THE METHYLATION OF E-CADHERIN GENE ASSOCIATED WITH H PYLORI, ARE CRUCIAL FOR CARCINOGENESIS. THEREBY, PREDISPOSITION OF CHRONIC GASTRITIS ASSOCIATED WITH H. PYLORI TO ULCERATIVE ENTERITIS OF THE DUODENUM, ULCERATIVE STOMACH DISEASE OR GASTRIC ADENOCARCINOMA DEPENDS ON TOPOGRAPHY, THE INTENSITY OF INFLAMMATION AND CHANGES OF ACID PRODUCTION IN THE STOMACH. 2012 16 4984 31 PATHWAYS OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI VIRULENCE AND INTERACTIONS WITH ANTIOXIDANT SYSTEMS, VITAMIN C AND PHYTOCHEMICALS. HELICOBACTER PYLORI IS A CLASS ONE CARCINOGEN WHICH CAUSES CHRONIC ATROPHIC GASTRITIS, GASTRIC INTESTINAL METAPLASIA, DYSPLASIA AND ADENOCARCINOMA. THE MECHANISMS BY WHICH H. PYLORI INTERACTS WITH OTHER RISK AND PROTECTIVE FACTORS, PARTICULARLY VITAMIN C IN GASTRIC CARCINOGENESIS ARE COMPLEX. GASTRIC CARCINOGENESIS INCLUDES METABOLIC, ENVIRONMENTAL, EPIGENETIC, GENOMIC, INFECTIVE, INFLAMMATORY AND ONCOGENIC PATHWAYS. THE MOLECULAR CLASSIFICATION OF GASTRIC CANCER SUBTYPES HAS REVOLUTIONIZED THE UNDERSTANDING OF GASTRIC CARCINOGENESIS. THIS INCLUDES THE TUMOUR MICROENVIRONMENT, GERMLINE MUTATIONS, AND THE ROLE OF HELICOBACTER PYLORI BACTERIA, EPSTEIN BARR VIRUS AND EPIGENETICS IN SOMATIC MUTATIONS. THERE IS EVIDENCE THAT ASCORBIC ACID, PHYTOCHEMICALS AND ENDOGENOUS ANTIOXIDANT SYSTEMS CAN MODIFY THE RISK OF GASTRIC CANCER. GASTRIC JUICE ASCORBATE LEVELS DEPEND ON DIETARY INTAKE OF ASCORBIC ACID BUT CAN ALSO BE DECREASED BY H. PYLORI INFECTION, H. PYLORI CAGA SECRETION, TOBACCO SMOKING, ACHLORHYDRIA AND CHRONIC ATROPHIC GASTRITIS. ASCORBIC ACID MAY BE PROTECTIVE AGAINST GASTRIC CANCER BY ITS ANTIOXIDANT EFFECT IN GASTRIC CYTOPROTECTION, REGENERATING ACTIVE VITAMIN E AND GLUTATHIONE, INHIBITING ENDOGENOUS N-NITROSATION, REDUCING TOXIC EFFECTS OF INGESTED NITROSODIMETHYLAMINES AND HETEROCYCLIC AMINES, AND PREVENTING H. PYLORI INFECTION. THE EFFECTIVENESS OF SUCH CYTOPROTECTION IS RELATED TO H. PYLORI STRAIN VIRULENCE, PARTICULARLY CAGA EXPRESSION. THE ROLE OF VITAMIN C IN EPIGENETIC REPROGRAMMING IN GASTRIC CANCER IS STILL EVOLVING. OTHER FACTORS IN CONJUNCTION WITH VITAMIN C ALSO PLAY A ROLE IN GASTRIC CARCINOGENESIS. ERADICATION OF H. PYLORI MAY LEAD TO RECOVERY OF VITAMIN C SECRETION BY GASTRIC EPITHELIUM AND ENABLE REGRESSION OF PREMALIGNANT GASTRIC LESIONS, THEREBY INTERRUPTING THE CORREA CASCADE OF GASTRIC CARCINOGENESIS. 2020 17 3601 23 IMPORTANCE OF PROBIOTICS IN THE PREVENTION AND TREATMENT OF COLORECTAL CANCER. COLORECTAL CANCER (CRC) REMAINS ONE OF THE MOST COMMON AND DEADLY CANCERS. INTESTINAL GUT MICROFLORA IS IMPORTANT TO MAINTAIN AND CONTRIBUTES TO SEVERAL INTESTINAL FUNCTIONS, INCLUDING THE DEVELOPMENT OF THE MUCOSAL IMMUNE SYSTEM, ABSORPTION OF COMPLEX MACROMOLECULES, SYNTHESIS OF AMINO ACIDS/VITAMINS AND THE PROTECTION AGAINST PATHOGENIC MICROORGANISMS. IT IS WELL KNOWN THAT THE GUT MICROBIOTA CHANGES OR DYSBIOSIS MAY HAVE AN ESSENTIAL IMPACT IN THE INITIATION AND PROMOTION OF CHRONIC INFLAMMATORY PATHWAYS AND ALSO HAVE A PROFOUND DIFFERENT GENETIC AND EPIGENETIC ALTERATIONS LEADING TO DYSPLASIA, CLONAL EXPANSION, AND MALIGNANT TRANSFORMATION. PROBIOTIC BACTERIA HAS ANTITUMOR ACTIVITY WITH VARIOUS MECHANISMS SUCH AS NONSPECIFIC PHYSIOLOGICAL AND IMMUNOLOGICAL MECHANISMS. THIS REVIEW EVALUATES THE EFFECTS OF MICROBIOTA AND PROBIOTICS IN CLINICAL TRIALS, IN VITRO AND ANIMAL MODEL STUDIES THAT HAVE EXPLORED HOW PROBIOTIC AGAINST CANCER DEVELOPMENT AND ALSO DISCUSSES THE POSSIBLE IMMUNOMODULATORY MECHANISMS. SEVERAL MECHANISMS ALTERATION OF THE INTESTINAL MICROFLORA; INACTIVATION OF CANCEROGENIC COMPOUNDS; COMPETITION WITH PUTREFACTIVE AND PATHOGENIC MICROBIOTA; IMPROVEMENT OF THE HOST'S IMMUNE RESPONSE; ANTIPROLIFERATIVE EFFECTS VIA REGULATION OF APOPTOSIS AND CELL DIFFERENTIATION; FERMENTATION OF UNDIGESTED FOOD; INHIBITION OF TYROSINE KINASE; REDUCES THE ENTEROPATHOGENIC COMPLICATIONS BEFORE AND AFTER COLON CANCER SURGERY AND IMPROVE DIARRHEA AND IT'S HAVE BEEN ABLE TO CREATE THE INTEGRITY OF GUT MUCOSAL AND HAVE STIMULATORY EFFECTS ON THE SYSTEMIC IMMUNE SYSTEM AND PREVENT THE CRC METASTASIS. RESEARCH IN CLINICAL TRIALS ENCOURAGING FINDINGS THAT SUPPORT A ROLE OF PROBIOTICS IN CRC PREVENTION AND IMPROVE THE SAFETY AND EFFECTIVENESS OF CANCER THERAPY EVEN THOUGH ADDITIONAL CLINICAL RESEARCH IS STILL NECESSARY. 2019 18 700 19 BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4): A KEY PLAYER IN INFLAMMATORY BOWEL DISEASE AND POTENTIAL TO INSPIRE EPIGENETIC THERAPEUTICS. INTRODUCTION: INFLAMMATORY BOWEL DISEASES (IBDS) ARE DEBILITATING CHRONIC INFLAMMATORY DISORDERS WITH INCREASING PREVALENCE WORLDWIDE. EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) IS CRITICAL IN CONTROLLING GENE EXPRESSION OF IBD-ASSOCIATED INFLAMMATORY CYTOKINE NETWORKS. BRD4 AS A PROMISING THERAPEUTIC TARGET IS ALSO TIGHTLY ASSOCIATED WITH MANY OTHER DISEASES, SUCH AS AIRWAY INFLAMMATION AND FIBROSIS, CANCERS, INFECTIOUS DISEASES AND CENTRAL NERVOUS SYSTEM DISORDERS. AREAS COVERED: THIS REVIEW BRIEFLY SUMMARIZED THE CRITICAL ROLE OF BRD4 IN THE PATHOGENESIS OF IBDS AND THE CURRENT CLINICAL LANDSCAPE OF DEVELOPING BROMODOMAIN AND EXTRA TERMINAL DOMAIN (BET) INHIBITORS. THE CHALLENGES AND OPPORTUNITIES AS WELL AS FUTURE DIRECTIONS OF TARGETING BRD4 INHIBITION FOR POTENTIAL IBD MEDICATIONS WERE ALSO DISCUSSED. EXPERT OPINION: TARGETING BRD4 WITH POTENT AND SPECIFIC INHIBITORS MAY OFFER NOVEL EFFECTIVE THERAPEUTICS FOR IBD PATIENTS, PARTICULARLY THOSE WHO ARE REFRACTORY TO ANTI-TNFALPHA THERAPY AND IBD-RELATED PROFIBROTIC. DEVELOPING HIGHLY SPECIFIC BRD4 INHIBITORS FOR IBD MEDICATIONS MAY HELP ERASE THE DRAWBACKS OF MOST CURRENT PAN-BET/BRD4 INHIBITORS, SUCH AS OFF-TARGET EFFECTS, POOR ORAL BIOAVAILABILITY, AND LOW GUT MUCOSAL ABSORBANCE. NOVEL STRATEGIES SUCH AS COMBINATORIAL THERAPY, BRD4-BASED DUAL INHIBITORS AND PROTEOLYSIS TARGETING CHIMERAS (PROTACS) MAY ALSO HAVE GREAT POTENTIAL TO MITIGATE SIDE EFFECTS AND OVERCOME DRUG RESISTANCE DURING IBD TREATMENT. 2023 19 5180 17 PREMALIGNANT CONDITIONS OF GASTRIC CANCER. PREMALIGNANT LESIONS OF GASTRIC CANCER ENCOMPASS A VARIETY OF CONDITIONS SUCH AS CHRONIC GASTRITIS, INTESTINAL METAPLASIA AND DYSPLASIA, IN WHICH ELEVATED RISK OF DEVELOPING GASTRIC CANCER HAVE BEEN DOCUMENTED. AMONG THEM, INTESTINAL METAPLASIA IS FREQUENTLY ENCOUNTERED IN OUR DAILY ENDOSCOPIC EXAMINATION, YET ITS CLINICAL SIGNIFICANCE IS OFTEN UNDERESTIMATED DESPITE OF A NUMBER OF REPORTS DEMONSTRATING GENETIC AND EPIGENETIC ALTERATIONS IN THE INTESTINAL METAPLASTIC MUCOSA. IN THIS REVIEW, I WILL DESCRIBE THE MOLECULAR MECHANISMS OF PHENOTYPIC CHANGES FROM GASTRIC MUCOSA TO INTESTINAL METAPLASIA BASED ON OUR ANALYSIS OF MOUSE MODEL OF INTESTINAL METAPLASIA GENERATED BY ECTOPIC EXPRESSION OF CDX2 IN CONJUNCTION WITH THE STUDIES WITH HUMAN INTESTINAL METAPLASIA. 2013 20 6841 32 [MECHANISMS OF H. PYLORI INFECTION-INDUCED GASTRIC CARCINOGENESIS]. MANY EPIDEMIOLOGICAL STUDIES HAVE DEMONSTRATED A STRONG ASSOCIATION BETWEEN H. PYLORI (HELICOBACTER PYLORI) INFECTION AND HUMAN GASTRIC CANCER DEVELOPMENT. THE PRECISE MECHANISMS ACCOUNTING FOR GASTRIC CANCER DEVELOPMENT INDUCED BY H. PYLORI INFECTION ARE STILL NOT COMPLETELY UNDERSTOOD. HOWEVER, IT SHOULD BE REASONABLE TO ASSUME THAT THERE ARE TWO DISTINCT MOLECULAR PATHWAYS FOR GASTRIC CARCINOGENESIS BY H. PYLORI INFECTION; THE DIRECT ACTION OF THE BACTERIA ITSELF ON GASTRIC EPITHELIAL CELLS, AND THE ACCUMULATION OF GENETIC CHANGES CAUSED BY PROLONGED BACTERIAL INFECTION AND CHRONIC INFLAMMATION. AS A DIRECT ACTION OF H. PYLORI, BACTERIAL PROTEINS SUCH AS CAGA COULD BE DELIVERED INTO GASTRIC EPITHELIAL CELLS VIA THE TYPE IV SECRETION APPARATUS AND MODIFY THE HOST CELL FUNCTIONS RELATED TO CELL PROLIFERATION. IN ADDITION TO THE DIRECT BACTERIAL ACTION, H. PYLORI INFECTION AND THE RESULTANT INFLAMMATORY RESPONSE CAUSE VARIOUS GENETIC AND EPIGENETIC CHANGES IN TUMOR-RELATED GENES OF THE GASTRIC EPITHELIAL CELLS. NOTABLY, EXPRESSION OF AID (ACTIVATION-INDUCED CYTIDINE DEAMINASE), A DNA EDITING ENZYME THAT UNDERGOES SOMATIC HYPERMUTATION ON HUMAN GENES, IS INDUCED IN RESPONSE TO H. PYLORI INFECTION AND PROINFLAMMATORY CYTOKINE STIMULATION IN HUMAN GASTRIC EPITHELIAL CELLS. AS A RESULT, THE ACCUMULATION OF GENETIC ALTERATIONS WOULD PERSIST UNTIL THE CLINICAL STAGE OF ATROPHIC GASTRITIS AND EVENTUALLY TRIGGER THE MALIGNANT TRANSFORMATION OF GASTRIC CELLS. 2010