1 1237 175 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 2 232 27 ADAPTIVE PLASTICITY IN THE RETINA: PROTECTION AGAINST ACUTE INJURY AND NEURODEGENERATIVE DISEASE BY CONDITIONING STIMULI. ALTHOUGH BOTH PRECLINICAL AND CLINICAL CONDITIONING STUDIES IN HEART AND BRAIN LEAD THE FIELD OF CONDITIONING MEDICINE, INVESTIGATIONS OF RETINAL CONDITIONING STILL NUMBER MORE THAN 100. IN THIS BRIEF REVIEW, WE HIGHLIGHT FINDINGS TO DATE FROM ANIMAL AND CELL CULTURE MODELS OF CONDITIONING THAT PROVIDE DEMONSTRATED PROTECTION IN ACUTE AND CHRONIC RETINAL INJURY AND DISEASE MODELS. THE MULTITUDE OF STIMULI USED TO CONDITION THE RETINA, THE SIGNALING MEDIATORS AND PATHWAYS IDENTIFIED, AND THE INJURY- AND DISEASE-RESILIENT PHENOTYPES DOCUMENTED ARE DISCUSSED HEREIN, ALONG WITH OUR RECOMMENDATIONS FOR THE KINDS OF STUDIES NEEDED TO CONTINUE TO ADVANCE THIS PROMISING FIELD. IN OUR VIEW, THE ROBUST PROTECTION AFFORDED BY THESE ADAPTIVE EPIGENETIC RESPONSES TO CONDITIONING STRESS PROVIDES SIGNIFICANT INCENTIVES FOR BOTH FURTHERING OUR INVESTMENT IN BENCH RESEARCH AND UNDERWRITING CLINICAL TRIALS, SO THAT THE FULL POTENTIAL OF THIS THERAPY CAN BE REALIZED. 2018 3 5078 37 PHYSIOLOGY AND PATHOPHYSIOLOGY OF MATRIX METALLOPROTEASES. MATRIX METALLOPROTEASES (MMPS) COMPRISE A FAMILY OF ENZYMES THAT CLEAVE PROTEIN SUBSTRATES BASED ON A CONSERVED MECHANISM INVOLVING ACTIVATION OF AN ACTIVE SITE-BOUND WATER MOLECULE BY A ZN(2+) ION. ALTHOUGH THE CATALYTIC DOMAIN OF MMPS IS STRUCTURALLY HIGHLY SIMILAR, THERE ARE MANY DIFFERENCES WITH RESPECT TO SUBSTRATE SPECIFICITY, CELLULAR AND TISSUE LOCALIZATION, MEMBRANE BINDING AND REGULATION THAT MAKE THIS A VERY VERSATILE FAMILY OF ENZYMES WITH A MULTITUDE OF PHYSIOLOGICAL FUNCTIONS, MANY OF WHICH ARE STILL NOT FULLY UNDERSTOOD. ESSENTIALLY, ALL MEMBERS OF THE MMP FAMILY HAVE BEEN LINKED TO DISEASE DEVELOPMENT, NOTABLY TO CANCER METASTASIS, CHRONIC INFLAMMATION AND THE ENSUING TISSUE DAMAGE AS WELL AS TO NEUROLOGICAL DISORDERS. THIS HAS STIMULATED A FLURRY OF STUDIES INTO MMP INHIBITORS AS THERAPEUTIC AGENTS, AS WELL AS INTO MEASURING MMP LEVELS AS DIAGNOSTIC OR PROGNOSTIC MARKERS. AS WITH MOST PROTEIN FAMILIES, DECIPHERING THE FUNCTION(S) OF MMPS IS DIFFICULT, AS THEY CAN MODIFY MANY PROTEINS. WHICH OF THESE REACTIONS ARE PHYSIOLOGICALLY OR PATHOPHYSIOLOGICALLY RELEVANT IS OFTEN NOT CLEAR, ALTHOUGH STUDIES ON KNOCKOUT ANIMALS, HUMAN GENETIC AND EPIGENETIC, AS WELL AS BIOCHEMICAL STUDIES USING NATURAL OR SYNTHETIC INHIBITORS HAVE PROVIDED INSIGHT TO A GREAT EXTENT. IN THIS REVIEW, WE WILL GIVE AN OVERVIEW OF 23 MEMBERS OF THE HUMAN MMP FAMILY AND DESCRIBE FUNCTIONS, LINKAGES TO DISEASE AND STRUCTURAL AND MECHANISTIC FEATURES. MMPS CAN BE GROUPED INTO SOLUBLE (INCLUDING MATRILYSINS) AND MEMBRANE-ANCHORED SPECIES. WE ADHERE TO THE 'MMP NOMENCLATURE' AND PROVIDE THE READER WITH REFERENCE TO THE MANY, OFTEN DIVERSE, NAMES FOR THIS ENZYME FAMILY IN THE INTRODUCTION. 2011 4 3920 31 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 5 2675 41 ETIOPATHOGENESIS OF INFLAMMATORY BOWEL DISEASE: TODAY AND TOMORROW. PURPOSE OF REVIEW: CROHN'S DISEASE AND ULCERATIVE COLITIS, THE TWO MAJOR FORMS OF INFLAMMATORY BOWEL DISEASE (IBD), REPRESENT CHRONIC DISEASES OF UNKNOWN CAUSE, AND THEY ARE REGARDED AS PROTOTYPICAL COMPLEX DISEASES. DESPITE ALL THE RECENT ADVANCES, A COMPLETE APPRECIATION OF THE PATHOGENESIS OF IBD IS STILL LIMITED. IN THIS REVIEW, WE PRESENT RECENT INFORMATION CONTRIBUTING TO A BETTER UNDERSTANDING OF MECHANISMS UNDERLYING IBD. RECENT FINDINGS: HERE, WE ATTEMPT TO HIGHLIGHT NOVEL ENVIRONMENTAL TRIGGERS, DATA ON THE GUT MICROBIOTA, ITS INTERACTION WITH THE HOST, AND THE POTENTIAL INFLUENCE OF DIET AND FOOD COMPONENTS. WE DISCUSS RECENT FINDINGS ON DEFECTIVE SIGNALING PATHWAYS AND THE POTENTIAL EFFECTS ON THE IMMUNE RESPONSE, AND WE PRESENT NEW DATA ON EPIGENETIC CHANGES, INFLAMMASOME, AND DAMAGE-ASSOCIATED MOLECULAR PATTERNS ASSOCIATED WITH IBD. SUMMARY: THE CONTINUING IDENTIFICATION OF SEVERAL EPIGENETIC, TRANSCRIPTOMIC, PROTEOMIC, AND METABOLOMIC ALTERATIONS IN PATIENTS WITH IBD REFLECTS THE COMPLEX NATURE OF THE DISEASE AND SUGGESTS THE NEED FOR INNOVATIVE APPROACHES SUCH AS SYSTEMS BIOLOGY FOR IDENTIFYING NOVEL RELEVANT TARGETS IN IBD. 2017 6 2342 34 EPIGENETIC REGULATION OF MACROPHAGE POLARIZATION AND FUNCTION. MACROPHAGE POLARIZATION REFERS TO DEVELOPMENT OF A SPECIFIC PHENOTYPE IMPORTANT FOR TISSUE HOMEOSTASIS OR HOST DEFENSE IN RESPONSE TO ENVIRONMENTAL CUES. ENVIRONMENTAL FACTORS THAT INDUCE MACROPHAGE POLARIZATION INCLUDE CYTOKINES AND MICROBIAL FACTORS PRODUCED BY PATHOGENS OR COMMENSAL MICROBIOTA. SIGNALING PATHWAYS UTILIZED BY THESE POLARIZING FACTORS HAVE BEEN WELL CHARACTERIZED, BUT IT IS LESS CLEAR HOW SIGNALS ARE CONVERTED INTO COMPLEX AND SUSTAINED PATTERNS OF GENE EXPRESSION, AND HOW MACROPHAGES ARE REPROGRAMMED DURING POLARIZATION TO ALTER THEIR RESPONSES TO SUBSEQUENT ENVIRONMENTAL CHALLENGES. EMERGING EVIDENCE, REVIEWED HERE, SUGGESTS AN IMPORTANT ROLE FOR EPIGENETIC MECHANISMS IN MODULATING AND TRANSMITTING SIGNALS DURING MACROPHAGE POLARIZATION AND REPROGRAMMING. DEEPER UNDERSTANDING OF EPIGENETIC REGULATION OF MACROPHAGE PHENOTYPE WILL ENABLE DEVELOPMENT OF GENE-SPECIFIC THERAPEUTIC APPROACHES TO ENHANCE HOST DEFENSE WHILE PRESERVING TISSUE INTEGRITY AND PREVENTING CHRONIC INFLAMMATORY DISEASES. 2013 7 5551 35 ROLE OF EPIGENETICS IN MODULATION OF IMMUNE RESPONSE AT THE JUNCTION OF HOST-PATHOGEN INTERACTION AND DANGER MOLECULE SIGNALING. EPIGENETIC MECHANISMS HAVE RAPIDLY AND CONTROVERSIALLY EMERGED AS SILENT MODULATORS OF HOST DEFENSES THAT CAN LEAD TO A MORE PROMINENT IMMUNE RESPONSE AND SHAPE THE COURSE OF INFLAMMATION IN THE HOST. THUS, THE EPIGENETICS CAN BOTH DRIVE THE PRODUCTION OF SPECIFIC INFLAMMATORY MEDIATORS AND CONTROL THE MAGNITUDE OF THE HOST RESPONSE. THE EPIGENETIC ACTIONS THAT ARE PREDOMINANTLY SHOWN TO MODULATE THE HOST DEFENSE AGAINST MICROBIAL PATHOGENS ARE DNA METHYLATION, HISTONE MODIFICATION AND THE ACTIVITY OF NON-CODING RNAS. THERE IS ALSO GROWING EVIDENCE THAT OPPORTUNISTIC CHRONIC PATHOGENS, SUCH AS PORPHYROMONAS GINGIVALIS, AS A MICROBIAL HOST SUBVERSION STRATEGY, CAN EPIGENETICALLY INTERFERE WITH THE HOST DNA MACHINERY FOR SUCCESSFUL COLONIZATION. SIMILARLY, THE NOVEL INVOLVEMENT OF SMALL MOLECULE 'DANGER SIGNALS', WHICH ARE RELEASED BY STRESSED OR INFECTED CELLS, AT THE CENTER OF HOST-PATHOGEN INTERPLAY AND EPIGENETICS IS DEVELOPING. IN THIS REVIEW, WE SYSTEMATICALLY EXAMINE THE LATEST KNOWLEDGE WITHIN THE FIELD OF EPIGENETICS IN THE CONTEXT OF HOST-DERIVED DANGER MOLECULE AND PURINERGIC SIGNALING, WITH A PARTICULAR FOCUS ON HOST MICROBIAL DEFENSES AND INFECTION-DRIVEN CHRONIC INFLAMMATION. 2016 8 4274 46 MICROBIOTA IN INFLAMMATORY BOWEL DISEASE PATHOGENESIS AND THERAPY: IS IT ALL ABOUT DIET? INFLAMMATORY BOWEL DISEASE (IBD), INCLUDING ULCERATIVE COLITIS, CROHN'S DISEASE, AND UNCLASSIFIED IBD, CONTINUES TO CAUSE SIGNIFICANT MORBIDITY. WHILE ITS INCIDENCE IS INCREASING, NO CLEAR ETIOLOGY AND NO CURE HAVE YET BEEN DISCOVERED. RECENT FINDINGS SUGGEST THAT IBD MAY HAVE A MULTIFACTORIAL ETIOLOGY, WHERE COMPLEX INTERACTIONS BETWEEN GENETICS, EPIGENETICS, ENVIRONMENTAL FACTORS (INCLUDING DIET BUT ALSO INFECTIONS, ANTIBIOTICS, AND SANITATION), AND HOST IMMUNE SYSTEM LEAD TO ABNORMAL IMMUNE RESPONSES AND CHRONIC INFLAMMATION. OVER THE PAST YEARS, THE ROLE OF ALTERED GUT MICROBIOTA (IN BOTH COMPOSITION AND FUNCTION) IN IBD PATHOGENESIS HAS EMERGED AS AN OUTSTANDING AREA OF INTEREST. ACCORDING TO NEW FINDINGS, GUT DYSBIOSIS MAY APPEAR AS A KEY ELEMENT IN INITIATION OF INFLAMMATION IN IBD AND ITS COMPLICATIONS. MOREOVER, COMPLEX METAGENOMIC STUDIES PROVIDE POSSIBILITIES TO DISTINGUISH BETWEEN IBD TYPES AND APPRECIATE SEVERITY AND PROGNOSIS OF THE DISEASE, AS WELL AS RESPONSE TO THERAPY. THIS REVIEW PROVIDES AN UPDATED KNOWLEDGE OF RECENT FINDINGS LINKING ALTERED BACTERIAL COMPOSITION AND FUNCTIONS, VIRUSES, AND FUNGI TO IBD PATHOGENESIS. IT ALSO HIGHLIGHTS THE COMPLEX GENETIC, EPIGENETIC, IMMUNE, AND MICROBIAL INTERACTIONS IN RELATION TO ENVIRONMENTAL FACTORS (INCLUDING DIET). WE OVERVIEW THE ACTUAL OPTIONS TO MANIPULATE THE ALTERED MICROBIOTA, SUCH AS MODIFIED DIET, PROBIOTICS, PREBIOTICS, SYNBIOTICS, ANTIBIOTICS, AND FECAL TRANSPLANTATION. FUTURE POSSIBLE THERAPIES ARE ALSO INCLUDED. TARGETING ALTERED MICROBIOTA COULD BE THE NEXT THERAPEUTIC PERSONALIZED APPROACH, BUT MORE RESEARCH AND WELL-DESIGNED COMPARATIVE PROSPECTIVE STUDIES ARE REQUIRED TO FORMULATE ADEQUATE DIRECTIONS FOR PREVENTION AND THERAPY. 2015 9 6360 38 THE ROLE OF INFLAMMATORY PATHWAYS IN CANCER-ASSOCIATED CACHEXIA AND RADIATION RESISTANCE. DYSREGULATED INFLAMMATORY RESPONSES ARE KEY CONTRIBUTORS TO A MULTITUDE OF CHRONIC AILMENTS, INCLUDING CANCER. EVIDENCE INDICATES THAT DISEASE PROGRESSION IN CANCER IS DEPENDENT ON THE COMPLEX INTERACTION BETWEEN THE TUMOR AND THE HOST MICROENVIRONMENT. MOST RECENTLY, THE INFLAMMATORY RESPONSE HAS BEEN SUGGESTED TO BE CRITICAL, AS BOTH THE TUMOR AND MICROENVIRONMENT COMPARTMENTS PRODUCE CYTOKINES THAT ACT ON NUMEROUS TARGET SITES, WHERE THEY FOSTER A COMPLEX CASCADE OF BIOLOGIC OUTCOMES. PATIENTS WITH CANCER-ASSOCIATED CACHEXIA (CAC) SUFFER FROM A DRAMATIC LOSS OF SKELETAL MUSCLE AND ADIPOSE TISSUE, ULTIMATELY PRECLUDING THEM FROM MANY FORMS OF THERAPEUTIC INTERVENTION, INCLUDING RADIOTHERAPY. THE CYTOKINES THAT HAVE BEEN LINKED TO THE PROMOTION OF THE CACHECTIC RESPONSE MAY ALSO PARTICIPATE IN RADIATION RESISTANCE. THE MAJOR CHANGES AT THE CYTOKINE LEVEL ARE, IN PART, DUE TO TRANSCRIPTIONAL REGULATORY ALTERATIONS POSSIBLY DUE TO EPIGENETIC MODIFICATIONS. HEREIN WE DISCUSS THE ROLE OF INFLAMMATORY PATHWAYS IN CAC AND EXAMINE THE POTENTIAL LINK BETWEEN CACHEXIA INDUCTION AND RADIATION RESISTANCE. 2013 10 1136 38 COMPREHENSIVE OVERVIEW OF MICRORNA FUNCTION IN RHEUMATOID ARTHRITIS. MICRORNAS (MIRNAS), A CLASS OF ENDOGENOUS SINGLE-STRANDED SHORT NONCODING RNAS, HAVE EMERGED AS VITAL EPIGENETIC REGULATORS OF BOTH PATHOLOGICAL AND PHYSIOLOGICAL PROCESSES IN ANIMALS. THEY DIRECT FUNDAMENTAL CELLULAR PATHWAYS AND PROCESSES BY FINE-TUNING THE EXPRESSION OF MULTIPLE GENES AT THE POSTTRANSCRIPTIONAL LEVEL. GROWING EVIDENCE SUGGESTS THAT MIRNAS ARE IMPLICATED IN THE ONSET AND DEVELOPMENT OF RHEUMATOID ARTHRITIS (RA). RA IS A CHRONIC INFLAMMATORY DISEASE THAT MAINLY AFFECTS SYNOVIAL JOINTS. THIS COMMON AUTOIMMUNE DISORDER IS CHARACTERIZED BY A COMPLEX AND MULTIFACETED PATHOGENESIS, AND ITS MORBIDITY, DISABILITY AND MORTALITY RATES REMAIN CONSISTENTLY HIGH. MORE IN-DEPTH INSIGHTS INTO THE UNDERLYING MECHANISMS OF RA ARE REQUIRED TO ADDRESS UNMET CLINICAL NEEDS AND OPTIMIZE TREATMENT. HEREIN, WE COMPREHENSIVELY REVIEW THE DEREGULATED MIRNAS AND IMPAIRED CELLULAR FUNCTIONS IN RA TO SHED LIGHT ON SEVERAL ASPECTS OF RA PATHOGENESIS, WITH A FOCUS ON EXCESSIVE INFLAMMATION, SYNOVIAL HYPERPLASIA AND PROGRESSIVE JOINT DAMAGE. THIS REVIEW ALSO PROVIDES PROMISING TARGETS FOR INNOVATIVE THERAPIES OF RA. IN ADDITION, WE DISCUSS THE REGULATORY ROLES AND CLINICAL POTENTIAL OF EXTRACELLULAR MIRNAS IN RA, HIGHLIGHTING THEIR PROSPECTIVE APPLICATIONS AS DIAGNOSTIC AND PREDICTIVE BIOMARKERS. 2023 11 5372 44 RECENT ADVANCES IN UNDERSTANDING THE PATHOGENESIS OF RHEUMATOID ARTHRITIS: NEW TREATMENT STRATEGIES. RHEUMATOID ARTHRITIS (RA) IS CONSIDERED A CHRONIC SYSTEMIC, MULTI-FACTORIAL, INFLAMMATORY, AND PROGRESSIVE AUTOIMMUNE DISEASE AFFECTING MANY PEOPLE WORLDWIDE. WHILE PATIENTS SHOW VERY INDIVIDUAL COURSES OF DISEASE, WITH RA FOCUSING ON THE MUSCULOSKELETAL SYSTEM, JOINTS ARE OFTEN SEVERELY AFFECTED, LEADING TO LOCAL INFLAMMATION, CARTILAGE DESTRUCTION, AND BONE EROSION. TO PREVENT JOINT DAMAGE AND PHYSICAL DISABILITY AS ONE OF MANY SYMPTOMS OF RA, EARLY DIAGNOSIS IS CRITICAL. AUTO-ANTIBODIES PLAY A PIVOTAL CLINICAL ROLE IN PATIENTS WITH SYSTEMIC RA. AS BIOMARKERS, THEY COULD HELP TO MAKE A MORE EFFICIENT DIAGNOSIS, PROGNOSIS, AND TREATMENT DECISION. BESIDES AUTO-ANTIBODIES, SEVERAL OTHER FACTORS ARE INVOLVED IN THE PROGRESSION OF RA, SUCH AS EPIGENETIC ALTERATIONS, POST-TRANSLATIONAL MODIFICATIONS, GLYCOSYLATION, AUTOPHAGY, AND T-CELLS. UNDERSTANDING THE INTERPLAY BETWEEN THESE FACTORS WOULD CONTRIBUTE TO A DEEPER INSIGHT INTO THE CAUSES, MECHANISMS, PROGRESSION, AND TREATMENT OF THE DISEASE. IN THIS REVIEW, THE LATEST RA RESEARCH FINDINGS ARE DISCUSSED TO BETTER UNDERSTAND THE PATHOGENESIS, AND FINALLY, TREATMENT STRATEGIES FOR RA THERAPY ARE PRESENTED, INCLUDING BOTH CONVENTIONAL APPROACHES AND NEW METHODS THAT HAVE BEEN DEVELOPED IN RECENT YEARS OR ARE CURRENTLY UNDER INVESTIGATION. 2021 12 4422 47 MOLECULAR AND GENETIC INFLAMMATION NETWORKS IN MAJOR HUMAN DISEASES. IT HAS BEEN WELL-RECOGNIZED THAT INFLAMMATION ALONGSIDE TISSUE REPAIR AND DAMAGE MAINTAINING TISSUE HOMEOSTASIS DETERMINES THE INITIATION AND PROGRESSION OF COMPLEX DISEASES. ALBEIT WITH THE ACCOMPLISHMENT OF HAVING CAPTURED THE MOST CRITICAL INFLAMMATION-INVOLVED MOLECULES, GENETIC SUSCEPTIBILITIES, EPIGENETIC FACTORS, AND ENVIRONMENTAL FACTORS, OUR SCHEMATA ON THE ROLE OF INFLAMMATION IN COMPLEX DISEASES REMAIN LARGELY PATCHY, IN PART DUE TO THE SUCCESS OF REDUCTIONISM IN TERMS OF RESEARCH METHODOLOGY PER SE. OMICS DATA ALONGSIDE THE ADVANCES IN DATA INTEGRATION TECHNOLOGIES HAVE ENABLED RECONSTRUCTION OF MOLECULAR AND GENETIC INFLAMMATION NETWORKS WHICH SHED LIGHT ON THE UNDERLYING PATHOPHYSIOLOGY OF COMPLEX DISEASES OR CLINICAL CONDITIONS. GIVEN THE PROVEN BENEFICIAL ROLE OF ANTI-INFLAMMATION IN CORONARY HEART DISEASE AS WELL AS OTHER COMPLEX DISEASES AND IMMUNOTHERAPY AS A REVOLUTIONARY TRANSITION IN ONCOLOGY, IT BECOMES TIMELY TO REVIEW OUR CURRENT UNDERSTANDING OF THE MOLECULAR AND GENETIC INFLAMMATION NETWORKS UNDERLYING MAJOR HUMAN DISEASES. IN THIS REVIEW, WE FIRST BRIEFLY DISCUSS THE COMPLEXITY OF INFECTIOUS DISEASES AND THEN HIGHLIGHT RECENTLY UNCOVERED MOLECULAR AND GENETIC INFLAMMATION NETWORKS IN OTHER MAJOR HUMAN DISEASES INCLUDING OBESITY, TYPE II DIABETES, CORONARY HEART DISEASE, LATE ONSET ALZHEIMER'S DISEASE, PARKINSON'S DISEASE, AND SPORADIC CANCER. THE COMMONALITY AND SPECIFICITY OF THESE MOLECULAR NETWORKS ARE ADDRESSED IN THE CONTEXT OF GENETICS BASED ON GENOME-WIDE ASSOCIATION STUDY (GWAS). THE DOUBLE-SWORD ROLE OF INFLAMMATION, SUCH AS HOW THE ABERRANT TYPE 1 AND/OR TYPE 2 IMMUNITY LEADS TO CHRONIC AND SEVERE CLINICAL CONDITIONS, REMAINS OPEN IN TERMS OF THE INFLAMMASOME AND THE CORE INFLAMMATOME NETWORK FEATURES. INCREASINGLY AVAILABLE LARGE OMICS AND CLINICAL DATA IN TANDEM WITH SYSTEMS BIOLOGY APPROACHES HAVE OFFERED AN EXCITING YET CHALLENGING OPPORTUNITY TOWARD RECONSTRUCTION OF MORE COMPREHENSIVE AND DYNAMIC MOLECULAR AND GENETIC INFLAMMATION NETWORKS, WHICH HOLD GREAT PROMISE IN TRANSITING NETWORK SNAPSHOTS TO VIDEO-STYLE MULTI-SCALE INTERPLAYS OF DISEASE MECHANISMS, IN TURN LEADING TO EFFECTIVE CLINICAL INTERVENTION. 2016 13 566 38 BASES FOR THE ADEQUATE DEVELOPMENT OF NUTRITIONAL RECOMMENDATIONS FOR PATIENTS WITH INFLAMMATORY BOWEL DISEASE. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC AND RELAPSING INFLAMMATORY CONDITION OF THE GASTROINTESTINAL TRACT; IT IS A HETEROGENEOUS AND MULTIFACTORIAL DISORDER RESULTING FROM A COMPLEX INTERPLAY BETWEEN GENETIC VARIATION, INTESTINAL MICROBIOTA, THE HOST IMMUNE SYSTEM AND ENVIRONMENTAL FACTORS SUCH AS DIET, DRUGS, BREASTFEEDING AND SMOKING. THE INTERACTIONS BETWEEN DIETARY NUTRIENTS AND INTESTINAL IMMUNITY ARE COMPLEX. THERE IS A COMPELLING ARGUMENT FOR ENVIRONMENTAL FACTORS SUCH AS DIET PLAYING A ROLE IN THE CAUSE AND COURSE OF IBD, GIVEN THAT THREE IMPORTANT FACTORS IN THE PATHOGENESIS OF IBD CAN BE MODULATED AND CONTROLLED BY DIET: INTESTINAL MICROBIOTA, THE IMMUNE SYSTEM AND EPITHELIAL BARRIER FUNCTION. THE AIM OF THIS REVIEW IS TO SUMMARIZE THE EPIDEMIOLOGICAL FINDINGS REGARDING DIET AND TO FOCUS ON THE EFFECTS THAT NUTRIENTS EXERT ON THE INTESTINAL MUCOSA-MICROBIOTA-PERMEABILITY INTERACTION. THE NATURE OF THESE INTERACTIONS IN IBD IS INFLUENCED BY ALTERATIONS IN THE NUTRITIONAL METABOLISM OF THE GUT MICROBIOTA AND HOST CELLS THAT CAN INFLUENCE THE OUTCOME OF NUTRITIONAL INTERVENTION. A BETTER UNDERSTANDING OF DIET-HOST-MICROBIOTA INTERACTIONS IS ESSENTIAL FOR UNRAVELLING THE COMPLEX MOLECULAR BASIS OF EPIGENETIC, GENETIC AND ENVIRONMENTAL INTERACTIONS UNDERLYING IBD PATHOGENESIS AS WELL AS FOR OFFERING NEW THERAPEUTIC APPROACHES FOR THE TREATMENT OF IBD. 2019 14 5309 32 PSORIASIS PATHOGENESIS AND TREATMENT. RESEARCH ON PSORIASIS PATHOGENESIS HAS LARGELY INCREASED KNOWLEDGE ON SKIN BIOLOGY IN GENERAL. IN THE PAST 15 YEARS, BREAKTHROUGHS IN THE UNDERSTANDING OF THE PATHOGENESIS OF PSORIASIS HAVE BEEN TRANSLATED INTO TARGETED AND HIGHLY EFFECTIVE THERAPIES PROVIDING FUNDAMENTAL INSIGHTS INTO THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES WITH A DOMINANT IL-23/TH17 AXIS. THIS REVIEW DISCUSSES THE MECHANISMS INVOLVED IN THE INITIATION AND DEVELOPMENT OF THE DISEASE, AS WELL AS THE THERAPEUTIC OPTIONS THAT HAVE ARISEN FROM THE DISSECTION OF THE INFLAMMATORY PSORIATIC PATHWAYS. OUR DISCUSSION BEGINS BY ADDRESSING THE INFLAMMATORY PATHWAYS AND KEY CELL TYPES INITIATING AND PERPETUATING PSORIATIC INFLAMMATION. NEXT, WE DESCRIBE THE ROLE OF GENETICS, ASSOCIATED EPIGENETIC MECHANISMS, AND THE INTERACTION OF THE SKIN FLORA IN THE PATHOPHYSIOLOGY OF PSORIASIS. FINALLY, WE INCLUDE A COMPREHENSIVE REVIEW OF WELL-ESTABLISHED WIDELY AVAILABLE THERAPIES AND NOVEL TARGETED DRUGS. 2019 15 2525 44 EPIGENETICS AND TRAINED IMMUNITY. SIGNIFICANCE: A GROWING BODY OF CLINICAL AND EXPERIMENTAL EVIDENCE HAS CHALLENGED THE TRADITIONAL UNDERSTANDING THAT ONLY THE ADAPTIVE IMMUNE SYSTEM CAN MOUNT IMMUNOLOGICAL MEMORY. RECENT FINDINGS DESCRIBE THE ADAPTIVE CHARACTERISTICS OF THE INNATE IMMUNE SYSTEM, UNDERSCORED BY ITS ABILITY TO REMEMBER ANTECEDENT FOREIGN ENCOUNTERS AND RESPOND IN A NONSPECIFIC SENSITIZED MANNER TO REINFECTION. THIS HAS BEEN TERMED TRAINED INNATE IMMUNITY. ALTHOUGH BENEFICIAL IN THE CONTEXT OF RECURRENT INFECTIONS, THIS MIGHT ACTUALLY CONTRIBUTE TO CHRONIC IMMUNE-MEDIATED DISEASES, SUCH AS ATHEROSCLEROSIS. RECENT ADVANCES: IN LINE WITH ITS PROPOSED ROLE IN SUSTAINING CELLULAR MEMORIES, EPIGENETIC REPROGRAMMING HAS EMERGED AS A CRITICAL DETERMINANT OF TRAINED IMMUNITY. RECENT TECHNOLOGICAL AND COMPUTATIONAL ADVANCES THAT IMPROVE UNBIASED ACQUISITION OF EPIGENOMIC PROFILES HAVE SIGNIFICANTLY ENHANCED OUR APPRECIATION FOR THE COMPLEXITIES OF CHROMATIN ARCHITECTURE IN THE CONTEXTS OF DIVERSE IMMUNOLOGICAL CHALLENGES. CRITICAL ISSUES: KEY TO RESOLVING THE DISTINCT CHROMATIN SIGNATURES OF INNATE IMMUNE MEMORY IS A COMPREHENSIVE UNDERSTANDING OF THE PRECISE PHYSIOLOGICAL TARGETS OF REGULATORY PROTEINS THAT RECOGNIZE, DEPOSIT, AND REMOVE CHEMICAL MODIFICATIONS FROM CHROMATIN AS WELL AS OTHER GENE-REGULATING FACTORS. DRAWING FROM A RAPIDLY EXPANDING COMPENDIUM OF EXPERIMENTAL AND CLINICAL STUDIES, THIS REVIEW DETAILS A CURRENT PERSPECTIVE OF THE EPIGENETIC PATHWAYS THAT SUPPORT THE ADAPTED PHENOTYPES OF MONOCYTES AND MACROPHAGES. FUTURE DIRECTIONS: WE EXPLORE FUTURE STRATEGIES THAT ARE AIMED AT EXPLOITING THE MECHANISM OF TRAINED IMMUNITY TO IMPROVE THE PREVENTION AND TREATMENT OF INFECTIONS AND IMMUNE-MEDIATED CHRONIC DISORDERS. 2018 16 6592 46 TUMOR-ASSOCIATED MACROPHAGES IN HEPATOCELLULAR CARCINOMA PATHOGENESIS, PROGNOSIS AND THERAPY. HEPATOCELLULAR CARCINOMA (HCC) CONSTITUTES A MAJOR HEALTH BURDEN GLOBALLY, AND IT IS CAUSED BY INTRINSIC GENETIC MUTATIONS ACTING IN CONCERT WITH A MULTITUDE OF EPIGENETIC AND EXTRINSIC RISK FACTORS. CANCER INDUCES MYELOPOIESIS IN THE BONE MARROW, AS WELL AS THE MOBILIZATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS, WHICH RESIDE IN THE SPLEEN. MONOCYTES PRODUCED IN THE BONE MARROW AND THE SPLEEN FURTHER INFILTRATE TUMORS, WHERE THEY DIFFERENTIATE INTO TUMOR-ASSOCIATED MACROPHAGES (TAMS). THE RELATIONSHIP BETWEEN CHRONIC INFLAMMATION AND HEPATOCARCINOGENESIS HAS BEEN THOROUGHLY INVESTIGATED OVER THE PAST DECADE; HOWEVER, SEVERAL ASPECTS OF THE ROLE OF TAMS IN HCC DEVELOPMENT ARE YET TO BE DETERMINED. IN RESPONSE TO CERTAIN STIMULI AND SIGNALING, MONOCYTES DIFFERENTIATE INTO MACROPHAGES WITH ANTITUMOR PROPERTIES, WHICH ARE CLASSIFIED AS M1-LIKE. ON THE OTHER HAND, UNDER DIFFERENT STIMULI AND SIGNALING, THE POLARIZATION OF MACROPHAGES SHIFTS TOWARDS AN M2-LIKE PHENOTYPE WITH A TUMOR PROMOTING CAPACITY. M2-LIKE MACROPHAGES DRIVE TUMOR GROWTH BOTH DIRECTLY AND INDIRECTLY, VIA THE SUPPRESSION OF CYTOTOXIC CELL POPULATIONS, INCLUDING CD8+ T CELLS AND NK CELLS. THE TUMOR MICROENVIRONMENT AFFECTS THE RESPONSE TO IMMUNOTHERAPIES. THEREFORE, AN ENHANCED UNDERSTANDING OF ITS IMMUNOBIOLOGY IS ESSENTIAL FOR THE DEVELOPMENT OF NEXT-GENERATION IMMUNOTHERAPIES. THE UTILIZATION OF VARIOUS MONOCYTE-CENTERED ANTICANCER TREATMENT MODALITIES HAS BEEN UNDER CLINICAL INVESTIGATION, SELECTIVELY TARGETING AND MODULATING THE PROCESSES OF MONOCYTE RECRUITMENT, ACTIVATION AND MIGRATION. THIS REVIEW SUMMARIZES THE CURRENT EVIDENCE ON THE ROLE OF TAMS IN HCC PATHOGENESIS AND PROGRESSION, AS WELL AS IN THEIR POTENTIAL INVOLVEMENT IN TUMOR THERAPY, SHEDDING LIGHT ON EMERGING ANTICANCER TREATMENT METHODS TARGETING MONOCYTES. 2022 17 792 37 CELLULAR MECHANISMS PROMOTING CACHEXIA AND HOW THEY ARE OPPOSED BY SIRTUINS (1). MANY CHRONIC DISEASES ARE ASSOCIATED WITH UNINTENTIONAL LOSS OF BODY WEIGHT, WHICH IS TERMED "CACHEXIA". CACHEXIA IS A COMPLEX MULTIFACTORIAL SYNDROME ASSOCIATED WITH THE UNDERLYING PRIMARY DISEASE, AND CHARACTERIZED BY LOSS OF SKELETAL MUSCLE WITH OR WITHOUT LOSS OF FAT TISSUE. PATIENTS WITH CACHEXIA FACE DIRE SYMPTOMS LIKE DYSPNEA, FATIGUE, EDEMA, EXERCISE INTOLERANCE, AND LOW RESPONSIVENESS TO MEDICAL THERAPY, WHICH WORSEN QUALITY OF LIFE. BECAUSE CACHEXIA IS NOT A STAND-ALONE DISORDER, TREATING PRIMARY DISEASE - SUCH AS CANCER - TAKES PRECEDENCE FOR THE PHYSICIAN, AND IT REMAINS MOSTLY A NEGLECTED ILLNESS. EXISTING CLINICAL TRIALS HAVE DEMONSTRATED LIMITED SUCCESS MOSTLY BECAUSE OF THEIR MONOTHERAPEUTIC APPROACH AND LATE DETECTION OF THE SYNDROME. TO CONQUER CACHEXIA, IT IS ESSENTIAL TO IDENTIFY AS MANY MOLECULAR TARGETS AS POSSIBLE USING THE LATEST TECHNOLOGIES WE HAVE AT OUR DISPOSAL. IN THIS REVIEW, WE HAVE DISCUSSED DIFFERENT ASPECTS OF CACHEXIA, WHICH INCLUDE VARIOUS DISEASE SETTINGS, ACTIVE MOLECULAR PATHWAYS, AND RECENT NOVEL ADVANCES MADE IN THIS FIELD TO UNDERSTAND CONSEQUENCES OF THIS ILLNESS. WE ALSO DISCUSS ROLES OF THE SIRTUINS, THE NAD(+)-DEPENDENT LYSINE DEACETYLASES, MICRORNAS, CERTAIN DIETARY OPTIONS, AND EPIGENETIC DRUGS AS POTENTIAL APPROACHES, WHICH CAN BE USED TO TACKLE CACHEXIA AS EARLY AS POSSIBLE IN ITS COURSE. 2019 18 1404 34 DIETARY COMPOSITION AND EFFECTS IN INFLAMMATORY BOWEL DISEASE. DRAMATIC CHANGES IN THE ENVIRONMENT AND HUMAN LIFESTYLE HAVE BEEN ASSOCIATED WITH THE RISE OF VARIOUS CHRONIC COMPLEX DISEASES, SUCH AS INFLAMMATORY BOWEL DISEASE (IBD). A DYSBIOTIC GUT MICROBIOTA HAS BEEN PROPOSED AS A CRUCIAL PATHOGENIC ELEMENT, CONTRIBUTING TO IMMUNE IMBALANCES AND FOSTERING A PROINFLAMMATORY MILIEU, WHICH MAY BE ASSOCIATED WITH DISEASE RELAPSES OR EVEN THE INITIATION OF IBD. IN ADDITION TO REPRESENTING IMPORTANT REGULATORS OF THE MUCOSAL IMMUNITY AND THE COMPOSITION OF THE GUT MICROBIOTA, FOOD COMPONENTS HAVE BEEN SHOWN TO BE POTENTIAL ENVIRONMENTAL TRIGGERS OF EPIGENETIC MODIFICATIONS. IN THE CONTEXT OF CHRONIC INTESTINAL INFLAMMATION, DIETARY HABITS AND SPECIFIC FOOD COMPONENTS HAVE BEEN IMPLICATED AS IMPORTANT MODULATORS OF EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, WHICH MAY PREDISPOSE A PERSON TO THE INCREASED RISK OF THE INITIATION AND EVOLUTION OF IBD. THIS REVIEW PROVIDES NOVEL INSIGHTS ABOUT HOW DIETARY FACTORS MAY INTERACT WITH THE INTESTINAL MUCOSA AND MODULATE IMMUNE HOMEOSTASIS BY SHAPING THE INTESTINAL ECOSYSTEM, AS WELL AS THE POTENTIAL INFLUENCE OF DIET IN THE ETIOPATHOGENESIS AND MANAGEMENT OF IBD. 2019 19 6303 52 THE PUZZLE OF IMMUNE PHENOTYPES OF CHILDHOOD ASTHMA. ASTHMA REPRESENTS THE MOST COMMON CHRONIC CHILDHOOD DISEASE WORLDWIDE. WHEREAS PRESCHOOL CHILDREN PRESENT WITH WHEEZING TRIGGERED BY DIFFERENT FACTORS (MULTITRIGGER AND VIRAL WHEEZE), CLINICAL ASTHMA MANIFESTATION IN SCHOOL CHILDREN HAS PREVIOUSLY BEEN CLASSIFIED AS ALLERGIC AND NON-ALLERGIC ASTHMA. FOR BOTH, THE UNDERLYING IMMUNOLOGICAL MECHANISMS ARE NOT YET UNDERSTOOD IN DEPTH IN CHILDREN. TREATMENT IS STILL PRESCRIBED REGARDLESS OF UNDERLYING MECHANISMS, AND CHILDREN ARE NOT ALWAYS TREATED SUCCESSFULLY. THIS REVIEW SUMMARIZES RECENT KEY FINDINGS ON THE COMPLEX MECHANISMS OF THE DEVELOPMENT AND MANIFESTATION OF CHILDHOOD ASTHMA. WHEREAS TRADITIONAL CLASSIFICATION OF CHILDHOOD ASTHMA IS PRIMARILY BASED ON CLINICAL SYMPTOMS LIKE WHEEZING AND ATOPY, NOVEL APPROACHES TO SPECIFY ASTHMA PHENOTYPES ARE UNDER WAY AND FACE CHALLENGES SUCH AS INCLUDING THE STABILITY OF PHENOTYPES OVER TIME AND TRANSITION INTO ADULTHOOD. EPIDEMIOLOGICAL STUDIES ENCLOSE MORE INFORMATION ON THE PATIENT'S DISEASE HISTORY AND ENVIRONMENTAL INFLUENCES. LATEST STUDIES DEFINE ENDOTYPES BASED ON MOLECULAR AND CELLULAR MECHANISMS, FOR EXAMPLE DEFINING RISK AND PROTECTIVE SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AND NEW IMMUNE PHENOTYPES, SHOWING PROMISING RESULTS. ALSO, REGULATORY T CELLS AND RECENTLY DISCOVERED T HELPER CELL SUBTYPES SUCH AS TH9 AND TH17 CELLS WERE SHOWN TO BE IMPORTANT FOR THE DEVELOPMENT OF ASTHMA. INNATE LYMPHOID CELLS (ILC) COULD PLAY A CRITICAL ROLE IN ASTHMA PATIENTS AS THEY PRODUCE DIFFERENT CYTOKINES ASSOCIATED WITH ASTHMA. EPIGENETIC FINDINGS SHOWED DIFFERENT ACETYLATION AND METHYLATION PATTERNS FOR CHILDREN WITH ALLERGIC AND NON-ALLERGIC ASTHMA. ON A POSTTRANSCRIPTIONAL LEVEL, MIRNAS ARE REGULATING FACTORS IDENTIFIED TO DIFFER BETWEEN ASTHMA PATIENTS AND HEALTHY CONTROLS AND ALSO INDICATE DIFFERENCES WITHIN ASTHMA PHENOTYPES. METABOLOMICS IS ANOTHER EXCITING CHAPTER IMPORTANT FOR ENDOTYPING ASTHMATIC CHILDREN. DESPITE THE DEVELOPMENT OF NEW BIOMARKERS AND THE DISCOVERY OF NEW IMMUNOLOGICAL MOLECULES, THE COMPLEX PUZZLE OF CHILDHOOD ASTHMA IS STILL FAR FROM BEING COMPLETED. ADDRESSING THE CURRENT CHALLENGES OF DISTINCT CLINICAL ASTHMA AND WHEEZE PHENOTYPES, INCLUDING THEIR STABILITY AND UNDERLYING ENDOTYPES, INVOLVES ADDRESSING THE INTERPLAY OF INNATE AND ADAPTIVE IMMUNE REGULATORY MECHANISMS IN LARGE, INTERDISCIPLINARY COHORTS. 2016 20 4151 38 MECHANISTIC INSIGHTS INTO GLUCOSE INDUCED VASCULAR EPIGENETIC REPROGRAMMING IN TYPE 2 DIABETES. ENDOTHELIAL CELLS LINING THE VESSEL WALL REGULATE THROMBOSIS, INFLAMMATION, ANGIOGENESIS AND BALANCE BETWEEN VASOCONSTRICTION AND VASODILATORY FUNCTIONS. SUBJECTS WITH TYPE 2 DIABETES (T2D) ACCRUE A MULTITUDE OF VASCULOPATHIES CAUSING HIGH MORBIDITY AND MORTALITY ACROSS THE GLOBE. HIGH GLUCOSE AND ITS MODIFIED PRODUCTS SUCH AS ADVANCED GLYCATION END PRODUCTS LEAD TO A BIDIRECTIONAL ACTIVATION OF INFLAMMATORY AND EPIGENETIC MACHINERY IN ENDOTHELIAL CELLS RESULTING IN A STATE OF CHRONIC INFLAMMATORY MILIEU AND EVENTUALLY INTO VASCULAR COMPLICATIONS. CLINICAL AND EXPERIMENTAL STUDIES HAVE SHOWN THAT DESPITE THE THERAPEUTIC NORMALIZATION OF GLUCOSE LEVELS, SUBJECTS WITH T2D OVERT TO VASCULAR COMPLICATIONS THROUGH A PROCESS OF METABOLIC MEMORY WHICH IS ASSOCIATED WITH SIGNIFICANT EPIGENETIC REPROGRAMMING IN ENDOTHELIAL CELLS. IN NORMAL PHYSIOLOGICAL CONDITIONS, VASCULAR ENDOTHELIAL CELLS DISPLAY A QUIESCENT STATE AND ONLY IN RESPONSE TO EITHER PHYSIOLOGICAL OR PATHOLOGICAL RESPONSE, ENDOTHELIAL CELLS UNDERGO PROLIFERATION. DURING THE PATHOGENESIS OF T2D, DNA METHYLATION, HISTONE MARKS AND NON-CODING RNAS FORMING THE EPIGENETIC LANDSCAPE ARE DYSREGULATED AND ACTIVATE QUIESCENT ENDOTHELIAL CELLS TO SWITCH ON A DIVERSE SET OF MOLECULAR ACTIVITIES AND LEAD TO ENDOTHELIAL DYSFUNCTION. IN THE PRESENT REVIEW, WE PROVIDE A COMPREHENSIVE OVERVIEW OF HOW HYPERGLYCEMIA IN T2D REPROGRAMS ENDOTHELIAL EPIGENOME AND LEAD TO FUNCTIONAL CONSEQUENCES IN THE PATHOGENESIS OF VASCULAR COMPLICATIONS. FURTHER, WE CATALOGUE AND DISCUSS EPI-DRUGS THAT MAY AMELIORATE ENDOTHELIAL FUNCTIONS DURING T2D. 2022