1 2607 130 EPIGENETICS/EPIGENOMICS AND PREVENTION BY CURCUMIN OF EARLY STAGES OF INFLAMMATORY-DRIVEN COLON CANCER. COLORECTAL CANCER (CRC) IS ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY IN THE US AND WORLDWIDE. CRC IS THE SECOND MOST COMMON CANCER-RELATED DEATH IN BOTH MEN AND WOMEN GLOBALLY. CHRONIC INFLAMMATION HAS BEEN IDENTIFIED AS ONE OF THE MAJOR RISK FACTORS OF CRC. IT MAY DRIVE GENETIC AND EPIGENETIC/EPIGENOMIC ALTERATIONS, SUCH AS DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA REGULATION. CURRENT PREVENTION MODALITIES FOR CRC ARE LIMITED AND SOME TREATMENT REGIMENS SUCH AS USE THE NONSTEROIDAL ANTI-INFLAMMATORY DRUG ASPIRIN MAY HAVE SEVERE SIDE EFFECTS, NAMELY GASTROINTESTINAL ULCERATION AND BLEEDING. THEREFORE, THERE IS AN URGENT NEED OF DEVELOPING ALTERNATIVE STRATEGIES. RECENTLY, INCREASING EVIDENCE SUGGESTS THAT SEVERAL DIETARY CANCER CHEMOPREVENTIVE PHYTOCHEMICALS POSSESS ANTI-INFLAMMATION AND ANTIOXIDATIVE STRESS ACTIVITIES, AND MAY PREVENT CANCERS INCLUDING CRC. CURCUMIN (CUR) IS THE YELLOW PIGMENT THAT IS FOUND IN THE RHIZOMES OF TURMERIC (CURCUMA LONGA). MANY STUDIES HAVE DEMONSTRATED THAT CUR EXHIBIT STRONG ANTICANCER, ANTIOXIDATIVE STRESS, AND ANTI-INFLAMMATORY ACTIVITIES BY REGULATING SIGNALING PATHWAYS, SUCH AS NUCLEAR FACTOR ERYTHROID-2-RELATED FACTOR 2, NUCLEAR FACTOR-KAPPAB, AND EPIGENETICS/EPIGENOMICS PATHWAYS OF HISTONES MODIFICATIONS, AND DNA METHYLATION. IN THIS REVIEW, WE WILL DISCUSS THE LATEST EVIDENCE IN EPIGENETICS/EPIGENOMICS ALTERATIONS BY CUR IN CRC AND THEIR POTENTIAL CONTRIBUTION IN THE PREVENTION OF CRC. 2020 2 5043 28 PHARMACOKINETICS AND PHARMACODYNAMICS OF CURCUMIN IN REGULATING ANTI-INFLAMMATORY AND EPIGENETIC GENE EXPRESSION. CHRONIC INFLAMMATION IS A KEY DRIVER OF CANCER DEVELOPMENT. NITRITE LEVELS, WHICH ARE REGULATED BY INDUCIBLE NITRIC OXIDE SYNTHASE (INOS), PLAY A CRITICAL ROLE IN INFLAMMATION. WHILE THE ANTI-OXIDANT AND ANTI-INFLAMMATORY EFFECTS OF CURCUMIN, A NATURAL PRODUCT PRESENT IN THE ROOTS OF CURCUMA LONGA HAVE BEEN STUDIED WIDELY, THE ACUTE PHARMACOKINETICS (PK) AND PHARMACODYNAMICS (PD) OF CURCUMIN IN SUPPRESSING PRO-INFLAMMATORY MARKERS AND EPIGENETIC MODULATORS REMAIN UNCLEAR. THIS STUDY EVALUATED THE PK AND PD OF CURCUMIN-INDUCED SUPPRESSION OF LIPOPOLYSACCHARIDE (LPS)-MEDIATED INFLAMMATION IN RAT LYMPHOCYTES. LPS WAS ADMINISTERED INTRAVENOUSLY EITHER ALONE OR WITH CURCUMIN TO FEMALE SPRAGUE-DAWLEY RATS. PLASMA SAMPLES WERE ANALYSED FOR CURCUMIN CONCENTRATION AND MRNA EXPRESSION WAS QUANTIFIED IN LYMPHOCYTES. THE RELATIVE GENE EXPRESSION OF SEVERAL INFLAMMATORY AND EPIGENETIC MODULATORS WAS ANALYSED. TO INVESTIGATE THE RELATIONSHIP BETWEEN CURCUMIN CONCENTRATION AND INOS, TNF-ALPHA, AND IL-6 GENE EXPRESSION, PK/PD MODELING USING JUSKO'S INDIRECT RESPONSE MODEL (IDR) INTEGRATING TRANSIT COMPARTMENTS (TC) DESCRIBING THE DELAYED RESPONSE WAS CONDUCTED. THE CONCENTRATION-TIME PROFILE OF CURCUMIN EXHIBITED A BI-EXPONENTIAL DECLINE, WHICH WAS WELL DESCRIBED BY A TWO-COMPARTMENTAL PHARMACOKINETIC MODEL. IMPORTANTLY THE RESULTS DEMONSTRATE THAT LPS INDUCED GENE EXPRESSION OF PRO-INFLAMMATORY MARKERS IN LYMPHOCYTES, WITH PEAK EXPRESSION AT APPROXIMATELY 3 H AND CURCUMIN SUPPRESSED THE GENE EXPRESSION IN ANIMALS ADMINISTERED WITH LPS. THESE EFFECTS WERE WELL CAPTURED USING THE IDR MODEL AND AN IDR MODEL WITH THE TRANSIT COMPARTMENTS. IN SUMMARY, THE PK/PD MODELING APPROACH COULD POTENTIALLY PROVIDE A ROBUST QUANTITATIVE FRAMEWORK FOR EVALUATING THE ACUTE ANTI-INFLAMMATORY AND EPIGENETIC EFFECTS OF CURCUMIN IN FUTURE CLINICAL TRIALS. 2018 3 4149 33 MECHANISTIC INSIGHT INTO THE EFFECTS OF CURCUMIN ON NEUROINFLAMMATION-DRIVEN CHRONIC PAIN. CHRONIC PAIN IS A PERSISTENT AND UNREMITTING CONDITION THAT HAS IMMENSE EFFECTS ON PATIENTS' QUALITY OF LIFE. STUDIES HAVE SHOWN THAT NEUROINFLAMMATION IS ASSOCIATED WITH THE INDUCTION AND PROGRESSION OF CHRONIC PAIN. THE ACTIVATION OF MICROGLIA AND ASTROCYTES IS THE MAJOR HALLMARK OF SPINAL NEUROINFLAMMATION LEADING TO NEURONAL EXCITABILITY IN THE PROJECTION NEURONS. EXCESSIVE ACTIVATION OF MICROGLIA AND ASTROCYTES IS ONE OF THE MAJOR CONTRIBUTING FACTORS TO THE EXACERBATION OF PAIN. HOWEVER, THE CURRENT CHRONIC PAIN TREATMENTS, MAINLY BY TARGETING THE NEURONAL CELLS, REMAIN INEFFECTIVE AND UNABLE TO MEET THE PATIENTS' NEEDS. CURCUMIN, A NATURAL PLANT PRODUCT FOUND IN THE CURCUMA GENUS, IMPROVES CHRONIC PAIN BY DIMINISHING THE RELEASE OF INFLAMMATORY MEDIATORS FROM THE SPINAL GLIA. THIS REVIEW DETAILS THE ROLE OF CURCUMIN IN MICROGLIA AND ASTROCYTES BOTH IN VITRO AND IN VIVO AND HOW IT IMPROVES PAIN. WE ALSO DESCRIBE THE MECHANISM OF CURCUMIN BY HIGHLIGHTING THE MAJOR GLIA-MEDIATED CASCADES IN PAIN. MOREOVER, THE ROLE OF CURCUMIN ON INFLAMMASOME AND EPIGENETIC REGULATION IS DISCUSSED. FURTHERMORE, WE DISCUSS THE STRATEGIES USED TO IMPROVE THE EFFICACY OF CURCUMIN. THIS REVIEW ILLUSTRATES THAT CURCUMIN MODULATING MICROGLIA AND ASTROCYTES COULD ASSURE THE TREATMENT OF CHRONIC PAIN BY SUPPRESSING SPINAL NEUROINFLAMMATION. 2021 4 1237 52 CURCUMIN AND COLORECTAL CANCER: AN UPDATE AND CURRENT PERSPECTIVE ON THIS NATURAL MEDICINE. COLORECTAL CANCER (CRC) IS ONE OF MOST COMMON MALIGNANCIES WORLDWIDE AND ITS INCIDENCE IS STILL GROWING. IN SPITE OF RECENT ADVANCES IN TARGETED THERAPIES, THEIR CLINICAL EFFICACY HAS BEEN LIMITED, NON-CURATIVE AND UNAFFORDABLE. A GROWING BODY OF LITERATURE INDICATES THAT CRC IS A MULTI-MODAL DISEASE, WHERE A VARIETY OF FACTORS WITHIN THE TUMOR MICROENVIRONMENT PLAY A SIGNIFICANT ROLE IN ITS PATHOGENESIS. FOR INSTANCE, IMBALANCE IN GUT MICROBIAL PROFILES AND IMPAIRED INTESTINAL BARRIER FUNCTION CONTRIBUTE TO THE OVERALL INTESTINAL INFLAMMATION AND INITIATION OF CRC. MOREOVER, PERSISTENT CHRONIC INFLAMMATION FAVORS A TUMOR MICROENVIRONMENT FOR THE GROWTH OF CANCER. IN ADDITION, AUTOPHAGY OR 'SELF-EATING' IS A SURVEILLANCE MECHANISM INVOLVED IN THE DEGRADATION OF CELLULAR CONSTITUENTS THAT ARE GENERATED UNDER STRESSFUL CONDITIONS. CANCER STEM CELLS (CSCS), ON THE OTHER HAND, ENGAGE IN THE ONSET OF CRC AND ARE ABLE TO ENDOW CANCER CELLS WITH CHEMO-RESISTANCE. FURTHERMORE, THE ABERRANT EPIGENETIC ALTERATIONS PROMOTE CRC. THESE EVIDENCES HIGHLIGHT THE NEED FOR MULTI-TARGETED APPROACHES THAT ARE NOT ONLY SAFE AND INEXPENSIVE BUT OFFER A MORE EFFECTIVE ALTERNATIVE TO CURRENT GENERATION OF TARGETED DRUGS. CURCUMIN, DERIVED FROM THE PLANT CURCUMA LONGA, REPRESENTS ONE SUCH OPTION THAT HAS A LONG HISTORY OF ITS USE FOR A VARIETY OF CHRONIC DISEASE INCLUDING CANCER, IN INDIAN AYURVEDIC AND TRADITIONAL CHINESE MEDICINE. SCIENTIFIC EVIDENCE OVER THE PAST FEW DECADES HAVE OVERWHELMINGLY SHOWN THAT CURCUMIN EXHIBITS A MULTITUDE OF ANTI-CANCER ACTIVITIES ORCHESTRATED THROUGH KEY SIGNALING PATHWAYS ASSOCIATED WITH CANCER. IN THIS ARTICLE, WE WILL PRESENT A CURRENT UPDATE AND PERSPECTIVE ON THIS NATURAL MEDICINE - INCORPORATING THE BASIC CELLULAR MECHANISMS IT EFFECTS AND THE CURRENT STATE OF CLINICAL EVIDENCE, CHALLENGES AND PROMISE FOR ITS USE AS A CANCER PREVENTATIVE AND POTENTIAL ADJUNCT TOGETHER WITH MODERN THERAPIES FOR CRC PATIENTS. 2022 5 6331 40 THE ROLE OF COX-2 IN INTESTINAL INFLAMMATION AND COLORECTAL CANCER. COLORECTAL CANCER (CRC) IS A HETEROGENEOUS DISEASE, INCLUDING AT LEAST THREE MAJOR FORMS: HEREDITARY, SPORADIC AND COLITIS-ASSOCIATED CRC. A LARGE BODY OF EVIDENCE INDICATES THAT GENETIC MUTATIONS, EPIGENETIC CHANGES, CHRONIC INFLAMMATION, DIET AND LIFESTYLE ARE THE RISK FACTORS FOR CRC. AS ELEVATED CYCLOOXYGENASE-2 (COX-2) EXPRESSION WAS FOUND IN MOST CRC TISSUE AND IS ASSOCIATED WITH WORSE SURVIVAL AMONG CRC PATIENTS, INVESTIGATORS HAVE SOUGHT TO EVALUATE THE EFFECTS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) AND SELECTIVE COX-2 INHIBITORS (COXIBS) ON CRC. THE EPIDEMIOLOGICAL STUDIES, CLINICAL TRIALS AND ANIMAL EXPERIMENTS INDICATE THAT NSAIDS ARE AMONG THE MOST PROMISING CHEMOPREVENTIVE AGENTS FOR THIS DISEASE. NSAIDS EXERT THEIR ANTI-INFLAMMATORY AND ANTITUMOR EFFECTS PRIMARILY BY REDUCING PROSTAGLANDIN PRODUCTION BY INHIBITION OF COX-2 ACTIVITY. IN THIS REVIEW, WE HIGHLIGHT BREAKTHROUGHS IN OUR UNDERSTANDING OF THE ROLES OF COX-2 IN CRC AND INFLAMMATORY BOWEL DISEASE. THESE RECENT DATA PROVIDE A RATIONALE FOR RE-EVALUATING COX-2 AS BOTH THE PROGNOSTIC AND THE PREDICTIVE MARKER IN A WIDE VARIETY OF MALIGNANCIES AND FOR RENEWING THE INTEREST IN EVALUATING RELATIVE BENEFITS AND RISK OF COXIBS IN APPROPRIATELY SELECTED PATIENTS FOR CANCER PREVENTION AND TREATMENT. 2010 6 6325 33 THE ROLE OF ANTI-INFLAMMATORY DRUGS IN COLORECTAL CANCER. A LARGE BODY OF EVIDENCE INDICATES THAT GENETIC MUTATIONS, EPIGENETIC CHANGES, CHRONIC INFLAMMATION, DIET, AND LIFESTYLE ARE KEY RISK FACTORS FOR COLORECTAL CANCER (CRC). PREVENTION OF CRC HAS LONG BEEN CONSIDERED A PLAUSIBLE APPROACH FOR THE POPULATION AND INDIVIDUALS AT HIGH RISK FOR DEVELOPING THIS DISEASE. A SIGNIFICANT EFFORT HAS BEEN MADE IN THE DEVELOPMENT OF NOVEL DRUGS FOR BOTH PREVENTION AND TREATMENT OVER THE PAST TWO DECADES. THIS REVIEW HIGHLIGHTS RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS IN CRC PREVENTION AND ADJUVANT TREATMENT. MOREOVER, WE FOCUS ON THE MOLECULAR MECHANISMS UNDERLYING THE ANTITUMOR EFFECTS OF THESE DRUGS IN CRC. THE KNOWLEDGE OF HOW ANTI-INFLAMMATORY AGENTS INHIBIT CANCER FORMATION AND PROGRESSION MAY PROVIDE A RATIONALE FOR THE DEVELOPMENT OF MORE EFFECTIVE CHEMOPREVENTIVE AND CHEMOTHERAPEUTIC AGENTS WITH LESS TOXICITY. 2013 7 4671 40 NEW INSIGHTS INTO THE MECHANISM OF ACTION OF ASPIRIN IN THE PREVENTION OF COLORECTAL NEOPLASIA. THE RESULTS OF CLINICAL STUDIES HAVE SHOWN THAT THE CHRONIC ADMINISTRATION OF ASPIRIN, EVEN AT THE LOWDOSES (75-100 MG DAILY) RECOMMENDED FOR THE PREVENTION OF CARDIOVASCULAR DISEASE, IS ASSOCIATED WITH A REDUCTION OF CANCER INCIDENCE AND MORTALITY, IN PARTICULAR COLORECTAL CANCER (CRC). THE MECHANISM OF ACTION OF ASPIRIN AS AN ANTINEOPLASTIC AGENT REMAINS CONTROVERSIAL. HOWEVER, DATA OF CLINICAL PHARMACOLOGY AND SEVERAL FEATURES OF THE CHEMOPREVENTIVE EFFECT OF ASPIRIN, EMERGED FROM CLINICAL TRIALS, SUGGEST THAT THE ANTIPLATELET EFFECT OF ASPIRIN PLAYS A CENTRAL ROLE IN ITS ANTICANCER EFFECTS. IN ADDITION TO THEIR CONTRIBUTION TO TUMOR METASTASIS, PLATELETS MAY PLAY A ROLE IN THE EARLY PHASES OF TUMORIGENESIS. IN RESPONSE TO LIFESTYLE AND ENVIRONMENT FACTORS, INTESTINAL EPITHELIAL DAMAGE/ DYSFUNCTION MAY BE ASSOCIATED WITH PLATELET ACTIVATION, INITIALLY AS A MECHANISM TO REPAIR THE DAMAGE. HOWEVER, IF THE PLATELET RESPONSE IS UNCONSTRAINED, IT MAY CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC INFLAMMATION. ALTOGETHER THESE EVENTS LEAD TO ALTER THE NORMAL FUNCTIONS OF INTESTINAL EPITHELIAL CELLS AND MAY TRANSLATE INTO CELLULAR TRANSFORMATION THROUGH SEVERAL MECHANISMS, INCLUDING THE OVEREXPRESSION OF CYCLOOXYGENASE(COX)-2 AND EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR), WHICH ARE CONSIDERED EARLY EVENTS IN COLORECTAL TUMORIGENESIS. THUS, ANTIPLATELET AGENTS MAY PLAY A ROLE IN THE PREVENTION OF CRC BY MODIFYING EPIGENETIC EVENTS INVOLVED IN EARLY PHASES OF COLORECTAL TUMORIGENESIS. FINALLY, WE CARRIED OUT A CRITICAL REVIEW OF THE LITERATURE ON OFF-TARGET MECHANISMS OF ASPIRIN ACTION AS ANTICANCER DRUG. 2015 8 3804 35 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 4044 29 MACROPHAGES IN OXIDATIVE STRESS AND MODELS TO EVALUATE THE ANTIOXIDANT FUNCTION OF DIETARY NATURAL COMPOUNDS. ANTIOXIDANT TESTING OF NATURAL PRODUCTS HAS ATTRACTED INCREASING INTEREST IN RECENT YEARS, MAINLY DUE TO THE FACT THAT AN ANTIOXIDANT-RICH DIET MIGHT PROVIDE HEALTH BENEFITS. ACTIVATED MACROPHAGES ARE A MAJOR SOURCE OF REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES, AND PEROXYNITRITE GENERATED THROUGH THE SO-CALLED RESPIRATORY BURST. CONSTITUTIVELY RELEASED PROINFLAMMATORY CYTOKINE, ESPECIALLY TUMOR NECROSIS FACTOR-ALPHA, TRIGGERS NUCLEAR FACTOR-KAPPAB, AND ACTIVATOR PROTEIN-1 TRANSLOCATION LEADING TO THE OVER PRODUCTION OF REACTIVE OXYGEN SPECIES AND REACTIVE NITROGEN SPECIES IN MACROPHAGES. ACTIVATION OF TRANSCRIPTION FACTORS IN THE LONG-LIVED TISSUE-RESIDENT MACROPHAGES AND/OR MONOCYTE-DERIVED MACROPHAGES, TRIGGER EPIGENETIC MODIFICATIONS LEADING TO THE PATHOGENESIS OF CHRONIC DISEASES. NUTRACEUTICALS INCLUDING LIPID RAFT STRUCTURE DISRUPTION AGENT, CHOLESTEROL DEPLETION AGENT, FARNESYLTRANSFERASE INHIBITOR, NUCLEAR FACTOR-KAPPAB BLOCKER (ALPHA,BETA-UNSATURATED CARBONYL COMPOUNDS), GLUCOCORTICOID RECEPTOR AGONIST, AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AGONIST HAVE LONG BEEN USED TO INACTIVE MACROPHAGE. THE INHIBITION EFFECTS ON THE FORMATION OF NITRIC OXIDE, SUPEROXIDE, AND NITRITE PEROXIDE MAY BE RESPONSIBLE FOR THE ANTI-INFLAMMATORY FUNCTIONALITIES. ACTIVATED MACROPHAGE MODELS COULD BE USED TO IDENTIFY THE ACTIVE COMPONENTS FOR FUNCTIONAL DIETS DEVELOPMENT THROUGH A MULTIPLE TARGETS STRATEGY. 2017 10 4732 45 NOVEL BIOMARKERS FOR INFLAMMATORY BOWEL DISEASE AND COLORECTAL CANCER: AN INTERPLAY BETWEEN METABOLIC DYSREGULATION AND EXCESSIVE INFLAMMATION. PERSISTENT INFLAMMATION CAN TRIGGER ALTERED EPIGENETIC, INFLAMMATORY, AND BIOENERGETIC STATES. INFLAMMATORY BOWEL DISEASE (IBD) IS AN IDIOPATHIC DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE GASTROINTESTINAL TRACT, WITH EVIDENCE OF SUBSEQUENT METABOLIC SYNDROME DISORDER. STUDIES HAVE DEMONSTRATED THAT AS MANY AS 42% OF PATIENTS WITH ULCERATIVE COLITIS (UC) WHO ARE FOUND TO HAVE HIGH-GRADE DYSPLASIA, EITHER ALREADY HAD COLORECTAL CANCER (CRC) OR DEVELOP IT WITHIN A SHORT TIME. THE PRESENCE OF LOW-GRADE DYSPLASIA IS ALSO PREDICTIVE OF CRC. MANY SIGNALING PATHWAYS ARE SHARED AMONG IBD AND CRC, INCLUDING CELL SURVIVAL, CELL PROLIFERATION, ANGIOGENESIS, AND INFLAMMATORY SIGNALING PATHWAYS. CURRENT IBD THERAPEUTICS TARGET A SMALL SUBSET OF MOLECULAR DRIVERS OF IBD, WITH MANY FOCUSED ON THE INFLAMMATORY ASPECT OF THE PATHWAYS. THUS, THERE IS A GREAT NEED TO IDENTIFY BIOMARKERS OF BOTH IBD AND CRC, THAT CAN BE PREDICTIVE OF THERAPEUTIC EFFICACY, DISEASE SEVERITY, AND PREDISPOSITION TO CRC. IN THIS STUDY, WE EXPLORED THE CHANGES IN BIOMARKERS SPECIFIC FOR INFLAMMATORY, METABOLIC, AND PROLIFERATIVE PATHWAYS, TO HELP DETERMINE THE RELEVANCE TO BOTH IBD AND CRC. OUR ANALYSIS DEMONSTRATED, FOR THE FIRST TIME IN IBD, THE LOSS OF THE TUMOR SUPPRESSOR PROTEIN RAS ASSOCIATED FAMILY PROTEIN 1A (RASSF1A), VIA EPIGENETIC CHANGES, THE HYPERACTIVATION OF THE OBLIGATE KINASE OF THE NOD2 PATHOGEN RECOGNITION RECEPTOR (RECEPTOR INTERACTING PROTEIN KINASE 2 [RIPK2]), THE LOSS OF ACTIVATION OF THE METABOLIC KINASE, AMP ACTIVATED PROTEIN KINASE (AMPKALPHA1), AND, LASTLY, THE ACTIVATION OF THE TRANSCRIPTION FACTOR AND KINASE YES ASSOCIATED PROTEIN (YAP) KINASE, THAT IS INVOLVED IN PROLIFERATION OF CELLS. THE EXPRESSION AND ACTIVATION STATUS OF THESE FOUR ELEMENTS ARE MIRRORED IN IBD, CRC, AND IBD-CRC PATIENTS AND, IMPORTANTLY, IN MATCHED BLOOD AND BIOPSY SAMPLES. THE LATTER WOULD SUGGEST THAT BIOMARKER ANALYSIS CAN BE PERFORMED NON-INVASIVELY, TO UNDERSTAND IBD AND CRC, WITHOUT THE NEED FOR INVASIVE AND COSTLY ENDOSCOPIC ANALYSIS. THIS STUDY, FOR THE FIRST TIME, ILLUSTRATES THE NEED TO UNDERSTAND IBD OR CRC BEYOND AN INFLAMMATORY PERSPECTIVE AND THE VALUE OF THERAPEUTICS DIRECTED TO RESET ALTERED PROLIFERATIVE AND METABOLIC STATES WITHIN THE COLON. THE USE OF SUCH THERAPEUTICS MAY TRULY DRIVE PATIENTS INTO REMISSION. 2023 11 5566 38 ROLE OF INFLAMMATION IN THE DEVELOPMENT OF COLORECTAL CANCER. CHRONIC INFLAMMATION CAN LEAD TO THE DEVELOPMENT OF MANY DISEASES, INCLUDING CANCER. INFLAMMATORY BOWEL DISEASE (IBD) THAT INCLUDES BOTH ULCERATIVE COLITIS (UC) AND CROHNMP'S DISEASE (CD) ARE RISK FACTORS FOR THE DEVELOPMENT OF COLORECTAL CANCER (CRC). MANY CYTOKINES PRODUCED PRIMARILY BY THE GUT IMMUNE CELLS EITHER DURING OR IN RESPONSE TO LOCALIZED INFLAMMATION IN THE COLON AND RECTUM ARE KNOWN TO STIMULATE THE COMPLEX INTERACTIONS BETWEEN THE DIFFERENT CELL TYPES IN THE GUT ENVIRONMENT RESULTING IN ACUTE INFLAMMATION. SUBSEQUENTLY, CHRONIC INFLAMMATION, TOGETHER WITH GENETIC AND EPIGENETIC CHANGES, HAVE BEEN SHOWN TO LEAD TO THE DEVELOPMENT AND PROGRESSION OF CRC. VARIOUS CELL TYPES PRESENT IN THE COLON, SUCH AS ENTEROCYTES, PANETH CELLS, GOBLET CELLS, AND MACROPHAGES, EXPRESS RECEPTORS FOR INFLAMMATORY CYTOKINES AND RESPOND TO TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), INTERLEUKIN-1 BETA (IL-1BETA), IL-6, AND OTHER CYTOKINES. AMONG THE SEVERAL CYTOKINES PRODUCED, TNF-ALPHA AND IL-1BETA ARE THE KEY PRO-INFLAMMATORY MOLECULES THAT PLAY CRITICAL ROLES IN THE DEVELOPMENT OF CRC. THE CURRENT REVIEW IS INTENDED TO CONSOLIDATE THE PUBLISHED FINDINGS TO FOCUS ON THE ROLE OF PRO-INFLAMMATORY CYTOKINES, NAMELY TNF-ALPHA AND IL-1BETA, ON INFLAMMATION (AND THE ALTERED IMMUNE RESPONSE) IN THE GUT, TO BETTER UNDERSTAND THE DEVELOPMENT OF CRC IN IBD, USING VARIOUS EXPERIMENTAL MODEL SYSTEMS, PRECLINICAL AND CLINICAL STUDIES. MOREOVER, THIS REVIEW ALSO HIGHLIGHTS THE CURRENT THERAPEUTIC STRATEGIES AVAILABLE (MONOTHERAPY AND COMBINATION THERAPY) TO ALLEVIATE THE SYMPTOMS OR TREAT INFLAMMATION-ASSOCIATED CRC BY USING MONOCLONAL ANTIBODIES OR APTAMERS TO BLOCK PRO-INFLAMMATORY MOLECULES, INHIBITORS OF TYROSINE KINASES IN THE INFLAMMATORY SIGNALING CASCADE, COMPETITIVE INHIBITORS OF PRO-INFLAMMATORY MOLECULES, AND THE NUCLEIC ACID DRUGS LIKE SMALL ACTIVATING RNAS (SARNAS) OR MICRORNA (MIRNA) MIMICS TO ACTIVATE TUMOR SUPPRESSOR OR REPRESS ONCOGENE/PRO-INFLAMMATORY CYTOKINE GENE EXPRESSION. 2021 12 3689 31 INFLAMMATORY AUTO-IMMUNE DISEASES OF THE INTESTINE AND THEIR MANAGEMENT BY NATURAL BIOACTIVE COMPOUNDS. AUTOIMMUNE DISEASES ARE CAUSED BY THE OVERACTIVITY OF THE IMMUNE SYSTEM TOWARDS SELF-CONSTITUENTS. RISK FACTORS OF AUTOIMMUNE DISEASES ARE MULTIPLE AND INCLUDE GENETIC, EPIGENETIC, ENVIRONMENTAL, AND PSYCHOLOGICAL. AUTOIMMUNE CHRONIC INFLAMMATORY BOWEL DISEASES, INCLUDING CELIAC AND INFLAMMATORY DISEASES (CROHN'S DISEASE AND ULCERATIVE COLITIS), CONSTITUTE A SIGNIFICANT HEALTH PROBLEM WORLDWIDE. BESIDES THE COMPLEXITY OF THE SYMPTOMS OF THESE DISEASES, THEIR TREATMENTS HAVE ONLY BEEN PALLIATIVE. NUMEROUS INVESTIGATIONS SHOWED THAT NATURAL PHYTOCHEMICALS COULD BE PROMISING STRATEGIES TO FIGHT AGAINST THESE AUTOIMMUNE DISEASES. IN THIS RESPECT, PLANT-DERIVED NATURAL COMPOUNDS SUCH AS FLAVONOIDS, PHENOLIC ACIDS, AND TERPENOIDS EXHIBITED SIGNIFICANT EFFECTS AGAINST THREE AUTOIMMUNE DISEASES AFFECTING THE INTESTINE, PARTICULARLY BOWEL DISEASES. THIS REVIEW FOCUSES ON THE ROLE OF NATURAL COMPOUNDS OBTAINED FROM MEDICINAL PLANTS IN MODULATING INFLAMMATORY AUTO-IMMUNE DISEASES OF THE INTESTINE. IT COVERS THE MOST RECENT LITERATURE RELATED TO THE EFFECT OF THESE NATURAL COMPOUNDS IN THE TREATMENT AND PREVENTION OF AUTO-IMMUNE DISEASES OF THE INTESTINE. 2022 13 4458 36 MOLECULAR MECHANISMS OF ALCOHOL-INDUCED COLORECTAL CARCINOGENESIS. THE ETIOLOGY OF COLORECTAL CANCER (CRC) IS COMPLEX. APPROXIMATELY, 10% OF INDIVIDUALS WITH CRC HAVE PREDISPOSING GERMLINE MUTATIONS THAT LEAD TO FAMILIAL CANCER SYNDROMES, WHEREAS MOST CRC PATIENTS HAVE SPORADIC CANCER RESULTING FROM A COMBINATION OF ENVIRONMENTAL AND GENETIC RISK FACTORS. IT HAS BECOME INCREASINGLY CLEAR THAT CHRONIC ALCOHOL CONSUMPTION IS ASSOCIATED WITH THE DEVELOPMENT OF SPORADIC CRC; HOWEVER, THE EXACT MECHANISMS BY WHICH ALCOHOL CONTRIBUTES TO COLORECTAL CARCINOGENESIS ARE LARGELY UNKNOWN. SEVERAL PROPOSED MECHANISMS FROM STUDIES IN CRC MODELS SUGGEST THAT ALCOHOL METABOLITES AND/OR ENZYMES ASSOCIATED WITH ALCOHOL METABOLISM ALTER CELLULAR REDOX BALANCE, CAUSE DNA DAMAGE, AND EPIGENETIC DYSREGULATION. IN ADDITION, ALCOHOL METABOLITES CAN CAUSE A DYSBIOTIC COLORECTAL MICROBIOME AND INTESTINAL PERMEABILITY, RESULTING IN BACTERIAL TRANSLOCATION, INFLAMMATION, AND IMMUNOSUPPRESSION. ALL OF THESE EFFECTS CAN INCREASE THE RISK OF DEVELOPING CRC. THIS REVIEW AIMS TO OUTLINE SOME OF THE MOST SIGNIFICANT AND RECENT FINDINGS ON THE MECHANISMS OF ALCOHOL IN COLORECTAL CARCINOGENESIS. WE EXAMINE THE EFFECT OF ALCOHOL ON THE GENERATION OF REACTIVE OXYGEN SPECIES, THE DEVELOPMENT OF GENOTOXIC STRESS, MODULATION OF ONE-CARBON METABOLISM, DISRUPTION OF THE MICROBIOME, AND IMMUNOSUPPRESSION. 2021 14 5554 39 ROLE OF EPIGENETICS IN TRANSFORMATION OF INFLAMMATION INTO COLORECTAL CANCER. MOLECULAR MECHANISMS ASSOCIATED WITH INFLAMMATION-PROMOTED TUMORIGENESIS HAVE BECOME AN IMPORTANT TOPIC IN CANCER RESEARCH. VARIOUS ABNORMAL EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, CHROMATIN REMODELING, AND NONCODING RNA REGULATION, OCCUR DURING THE TRANSFORMATION OF CHRONIC INFLAMMATION INTO COLORECTAL CANCER (CRC). THESE CHANGES NOT ONLY ACCELERATE TRANSFORMATION BUT ALSO LEAD TO CANCER PROGRESSION AND METASTASIS BY ACTIVATING CARCINOGENIC SIGNALING PATHWAYS. THE NF-KAPPAB AND STAT3 SIGNALING PATHWAYS PLAY A PARTICULARLY IMPORTANT ROLE IN THE TRANSFORMATION OF INFLAMMATION INTO CRC, AND BOTH ARE CRITICAL TO CELLULAR SIGNAL TRANSDUCTION AND CONSTANTLY ACTIVATED IN CANCER BY VARIOUS ABNORMAL CHANGES INCLUDING EPIGENETICS. THE NF-KAPPAB AND STAT3 SIGNALS CONTRIBUTE TO THE MICROENVIRONMENT FOR TUMORIGENESIS THROUGH SECRETION OF A LARGE NUMBER OF PRO-INFLAMMATORY CYTOKINES AND THEIR CROSSTALK IN THE NUCLEUS MAKES IT EVEN MORE DIFFICULT TO TREAT CRC. COMPARED WITH GENE MUTATION THAT IS IRREVERSIBLE, EPIGENETIC INHERITANCE IS REVERSIBLE OR CAN BE ALTERED BY THE INTERVENTION. THEREFORE, UNDERSTANDING THE ROLE OF EPIGENETIC INHERITANCE IN THE INFLAMMATION-CANCER TRANSFORMATION MAY ELUCIDATE THE PATHOGENESIS OF CRC AND PROMOTE THE DEVELOPMENT OF INNOVATIVE DRUGS TARGETING TRANSFORMATION TO PREVENT AND TREAT THIS MALIGNANCY. THIS REVIEW SUMMARIZES THE LITERATURE ON THE ROLES OF EPIGENETIC MECHANISMS IN THE OCCURRENCE AND DEVELOPMENT OF INFLAMMATION-INDUCED CRC. EXPLORING THE ROLE OF EPIGENETICS IN THE TRANSFORMATION OF INFLAMMATION INTO CRC MAY HELP STIMULATE FUTURES STUDIES ON THE ROLE OF MOLECULAR THERAPY IN CRC. 2019 15 5830 41 STRESS, THYROID DYSREGULATION, AND THYROID CANCER IN CHILDREN AND ADOLESCENTS: PROPOSED IMPENDING MECHANISMS. STRESS IS A POTENTIAL CATALYST FOR THYROID DYSREGULATION THROUGH CROSS-COMMUNICATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AND HYPOTHALAMIC-PITUITARY-THYROID (HPT) AXES. STRESS AND STRESSORS EXPOSURE MOTIVATES MOLECULAR MECHANISMS AFFECTING COMPOUND FEEDBACK LOOPS OF THE HPT AXIS. WHILE THERE IS EVIDENCE OF CONNECTION BETWEEN STRESS AND THYROID DYSREGULATION, THE QUESTION WHETHER THIS CONNECTION IS IMPLICATED IN THE DEVELOPMENT OF THYROID CANCER (TC) REMAINS UNANSWERED. IN VIEW OF THE RISING INCIDENCE OF TC IN BOTH ADULTS AND CHILDREN ALONGSIDE THE INCREASING STRESS IN OUR MODERN SOCIETY, THERE IS A NEED TO UNDERSTAND POSSIBLE INTERRELATIONS BETWEEN STRESS, THYROID DYSREGULATION, AND TC. PROLONGED GLUCOCORTICOID SECRETION DUE TO STRESS INTERFERES WITH IMMUNE SYSTEM RESPONSE BY ALTERING THE CYTOKINES, INDUCING LOW-GRADE CHRONIC INFLAMMATION, AND SUPPRESSING FUNCTION OF IMMUNE-PROTECTIVE CELLS. CHRONIC INFLAMMATION IS A RISK FACTOR LINKED TO TC. THE ROLE OF AUTOIMMUNITY HAS BEEN A MATTER OF CONTROVERSY. HOWEVER, THERE IS EPIDEMIOLOGICAL CONNECTION BETWEEN AUTOIMMUNE THYROID DISEASE (AITD) AND TC; PATIENTS WITH AITD SHOW INCREASED INCIDENCE IN PAPILLARY THYROID CARCINOMA (PTC), AND THOSE WITH TC SHOW A HIGH PREVALENCE OF INTRATHYROIDAL LYMPHOCYTE INFILTRATION AND THYROID AUTOANTIBODIES. TIMING AND DURATION-DEPENDENT EXPOSURE TO SPECIFIC ENDOCRINE DISRUPTING CHEMICALS (EDCS) HAS AN IMPACT ON THYROID DEVELOPMENT, FUNCTION, AND PROLIFERATION, LEADING TO THYROID DISEASE AND POTENTIALLY CANCER. THYROID HORMONE IMBALANCE, CHRONIC INFLAMMATION, AND EDCS ARE POTENTIAL RISK FACTORS FOR OXIDATIVE STRESS. OXYGEN FREE RADICALS ARE CAPABLE OF CAUSING DNA DAMAGE VIA STIMULATION OF THE MITOGEN-ACTIVATING PROTEIN KINASE OR PHOSPHATIDYLINOSITOL-3-KINASE AND/OR NUCLEAR FACTOR KB PATHWAYS, RESULTING IN TC-ASSOCIATED GENE MUTATIONS SUCH AS RET/PTC, AKAP9-BRAF, NTRK1, RAASF, PIK3CA, AND PTEN. STRESSFUL EVENTS DURING THE CRITICAL PERIODS OF PRENATAL AND EARLY LIFE CAN INFLUENCE NEUROENDOCRINE REGULATION AND INDUCE EPIGENETIC CHANGES. ABERRANT METHYLATION OF TUMOR SUPPRESSOR GENES SUCH AS P16INK4A, RASSF, AND PTEN IS ASSOCIATED WITH PTC; HISTONE H3 ACETYLATION IS SHOWN TO BE HIGHER IN TC, AND THYROID-SPECIFIC NONCODING RNAS ARE DOWNREGULATED IN PTC. THIS REVIEW FOCUSES ON THE ABOVE PROPOSED MECHANISMS THAT POTENTIALLY LEAD TO THYROID TUMORIGENESIS WITH THE AIM TO HELP IN THE DEVELOPMENT OF NOVEL PROGNOSTIC AND THERAPEUTIC STRATEGIES FOR TC. 2023 16 4174 29 MELATONIN MEDIATED INHIBITION OF EZH2-NOS2 CROSSTALK ATTENUATES INFLAMMATORY BOWEL DISEASE IN PRECLINICAL IN VITRO AND IN VIVO MODELS. AIMS: INFLAMMATORY BOWEL DISEASE IS CHARACTERISED BY ABDOMINAL PAIN, DIARRHOEA, RECTAL BLEEDING AND WEIGHT LOSS. SOMETIMES IT MAY LEADS TO SEVERE HEALTH COMPLICATIONS RESULTING IN DEATH OF AN INDIVIDUAL. CURRENT RESEARCH EFFORTS TO HIGHLIGHT THE ROLE OF MELATONIN IN REGULATING EZH2, A MASTER EPIGENETIC REGULATOR AND ITS BENEFICIARY EFFECT IN CASE OF IBD MANAGEMENT. MATERIAL METHODS: MURINE MACROPHAGES (RAW 264.7) WERE TREATED WITH LIPOPOLYSACCHARIDES (LPS) TO ACTIVATE THEM FOR GENERATING INFLAMMATORY RESPONSE TO INVESTIGATE EFFICACY OF MELATONIN IN-VITRO MODELS. SIMILARLY, FOR DEVELOPING IN VIVO MODELS, DEXTRAN SODIUM SULPHATE (36-50 KDA) WAS USED. EVALUATIONS OF ANTI-INFLAMMATORY ACTIVITIES WERE CARRIED OUT BY NITRITE ASSAY, WESTERN BLOTTING, Q-PCR, IMMUNOFLUORESCENCE, AND HISTOLOGICAL STUDIES. KEY FINDINGS: REDUCTION OF EPIGENETIC TARGET, EZH2 BY MELATONIN SIGNIFICANTLY IMPROVES THE CLINICAL SYMPTOMS OF DEXTRAN SODIUM SULPHATE INDUCED COLITIS AND MAY BE IMPLICATED AS A POTENTIAL THERAPEUTIC TARGET IN IBD MANAGEMENT. THE PRESENT STUDY EVALUATES THE EFFICACY OF MELATONIN BY EPIGENETIC REGULATION IN IBD MODELS. DOWN REGULATION OF EZH2 BY MELATONIN REDUCED THE CHEMICAL INDUCED INFLAMMATORY INSULTS IN IN VITRO AND IN VIVO MODELS. EXPLORATION OF MOLECULAR PATHWAYS HAS REVEALED INTERLINK OF EZH2 AND NOS2, A HALLMARK OF INFLAMMATION. MOLECULAR MECHANISTIC ACTION OF MELATONIN IS ATTRIBUTED TO INHIBITION OF THE EXPRESSION AND PHYSICAL INTERACTION OF EZH2 AND NOS2. SIGNIFICANCE: OUR STUDY HIGHLIGHTS MELATONIN THERAPEUTIC EFFECT VIA ATTENUATING INTERACTION BETWEEN EZH2 AND NOS2 WHICH IS BENEFICIAL IN MANAGING IBD TREATMENT. 2022 17 1397 33 DIET PHYTOCHEMICALS AND CUTANEOUS CARCINOMA CHEMOPREVENTION: A REVIEW. CUTANEOUS CARCINOMA, WHICH HAS OCCUPIED A PECULIAR PLACE AMONG WORLDWIDE POPULATIONS, IS COMMONLY RESPONSIBLE FOR THE CONSIDERABLY INCREASING MORBIDITY AND MORTALITY RATES. CURRENTLY AVAILABLE MEDICAL PROCEDURES FAIL TO COMPLETELY AVOID CUTANEOUS CARCINOMA DEVELOPMENT OR TO PREVENT MORTALITY. CANCER CHEMOPREVENTION, AS AN ALTERNATIVE STRATEGY, IS BEING CONSIDERED TO REDUCE THE INCIDENCE AND BURDEN OF CANCERS THROUGH CHEMICAL AGENTS. DERIVED FROM DIETARY FOODS, PHYTOCHEMICALS HAVE BECOME SAFE AND RELIABLE COMPOUNDS FOR THE CHEMOPREVENTION OF CUTANEOUS CARCINOMA BY RELIEVING MULTIPLE PATHOLOGICAL PROCESSES, INCLUDING OXIDATIVE DAMAGE, EPIGENETIC ALTERATION, CHRONIC INFLAMMATION, ANGIOGENESIS, ETC. IN THIS REVIEW, WE PRESENTED COMPREHENSIVE KNOWLEDGES, MAIN MOLECULAR MECHANISMS FOR THE INITIATION AND DEVELOPMENT OF CUTANEOUS CARCINOMA AS WELL AS EFFECTS OF VARIOUS DIET PHYTOCHEMICALS ON CHEMOPREVENTION. 2017 18 688 39 BRASSICA-DERIVED PLANT BIOACTIVES AS MODULATORS OF CHEMOPREVENTIVE AND INFLAMMATORY SIGNALING PATHWAYS. A HIGH CONSUMPTION OF VEGETABLES BELONGING TO THE BRASSICACEAE FAMILY HAS BEEN RELATED TO A LOWER INCIDENCE OF CHRONIC DISEASES INCLUDING DIFFERENT KINDS OF CANCER. THESE BENEFICIAL EFFECTS OF, E.G., BROCCOLI, CABBAGE OR ROCKET (ARUGULA) INTAKE HAVE BEEN MAINLY DEDICATED TO THE SULFUR-CONTAINING GLUCOSINOLATES (GLSS)-SECONDARY PLANT COMPOUNDS NEARLY EXCLUSIVELY PRESENT IN BRASSICACEAE-AND IN PARTICULAR TO THEIR BIOACTIVE BREAKDOWN PRODUCTS INCLUDING ISOTHIOCYANATES (ITCS). OVERALL, THE CURRENT LITERATURE INDICATE THAT SELECTED BRASSICA-DERIVED ITCS EXHIBIT HEALTH-PROMOTING EFFECTS IN VITRO, AS WELL AS IN LABORATORY MICE IN VIVO. SOME STUDIES SUGGEST ANTI-CARCINOGENIC AND ANTI-INFLAMMATORY PROPERTIES FOR ITCS WHICH MAY BE COMMUNICATED THROUGH AN ACTIVATION OF THE REDOX-SENSITIVE TRANSCRIPTION FACTOR NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) THAT CONTROLS THE EXPRESSION OF ANTIOXIDANT AND PHASE II ENZYMES. FURTHERMORE, IT HAS BEEN SHOWN THAT ITCS ARE ABLE TO SIGNIFICANTLY AMELIORATE A SEVERE INFLAMMATORY PHENOTYPE IN COLITIC MICE IN VIVO. AS THERE ARE STUDIES AVAILABLE SUGGESTING AN EPIGENETIC MODE OF ACTION FOR BRASSICA-DERIVED PHYTOCHEMICALS, THE CONDUCTION OF FURTHER STUDIES WOULD BE RECOMMENDABLE TO INVESTIGATE IF THE BENEFICIAL EFFECTS OF THESE COMPOUNDS ALSO PERSIST DURING AN IRREGULAR CONSUMPTION PATTERN. 2017 19 5541 26 ROLE OF DIETARY PHENOLS IN MITIGATING MICROGLIA-MEDIATED NEUROINFLAMMATION. CHRONIC NEUROINFLAMMATION IS A PATHOLOGICAL FEATURE OF A NUMBER OF CENTRAL NERVOUS SYSTEM (CNS) DISEASES AND IS MEDIATED BY SUSTAINED ACTIVATION OF MICROGLIAL CELLS, THE INNATE IMMUNE CELLS OF THE CNS. STUDIES HAVE MAINLY FOCUSED ON IDENTIFYING THE MOLECULAR AND EPIGENETIC MECHANISMS OF MICROGLIAL ACTIVATION. THIS IS CRUCIAL IN DESIGNING THERAPEUTIC STRATEGIES FOR NEUROPATHOLOGIES IN WHICH PROLONGED MICROGLIAL ACTIVATION IS KNOWN TO EXACERBATE DISEASE CONDITION. IN RECENT YEARS, INCREASING EVIDENCE SHOW THAT NATURALLY OCCURRING COMPOUNDS PRESENT IN REGULAR DIET COULD FUNCTION AS "NUTRACEUTICALS," ARRESTING MICROGLIAL ACTIVATION, AND THUS CONFERRING NEUROPROTECTION. THIS REVIEW SUMMARIZES OUR UNDERSTANDING OF THE ROLE OF DIETARY PHENOLIC NUTRACEUTICALS IN MITIGATING MICROGLIA-MEDIATED NEUROINFLAMMATION. STUDIES SHOW THAT THESE NATURAL PHENOLS INHIBIT KEY SIGNALING PATHWAYS IN ACTIVATED MICROGLIA SUCH AS THE NFKAPPAB, MAPK AND JAK-STAT THAT TRIGGER MICROGLIA-MEDIATED INFLAMMATION IN VARIOUS NEUROPATHOLOGICAL CONDITIONS SUCH AS INJURY, INFECTION, STROKE, AUTISM AND NEURODEGENERATIVE DISEASES, I.E., ALZHEIMER'S DISEASE AND PARKINSON'S DISEASE. THE ANTI-INFLAMMATORY AND ANTIOXIDANT EFFECT EXERTED BY THESE NATURAL PHENOLS HAVE SHOWN CONSIDERABLE SUCCESS IN IMPROVING DISEASE CONDITION IN ANIMAL MODELS OF NEUROPATHOLOGIES, AND THUS SEEM TO BE SUITABLE CANDIDATES FOR DEVELOPING THERAPEUTIC STRATEGIES. 2016 20 3688 34 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008