1 3635 122 INCREASED DNA METHYLATION, CELLULAR SENESCENCE AND PREMATURE EPIGENETIC AGING IN GUINEA PIGS AND HUMANS WITH TUBERCULOSIS. BACKGROUND: TUBERCULOSIS (TB) IS THE ARCHETYPICAL CHRONIC INFECTION, WITH PATIENTS HAVING MONTHS OF SYMPTOMS BEFORE DIAGNOSIS. IN THE TWO YEARS AFTER SUCCESSFUL THERAPY, SURVIVORS OF TB HAVE A THREE-FOLD INCREASED RISK OF DEATH. METHODS: GUINEA PIGS WERE INFECTED WITH MYCOBACTERIUM TUBERCULOSIS (MTB) FOR 45 DAYS, FOLLOWED BY RRBS DNA METHYLATION ANALYSIS. IN HUMANS, NETWORK ANALYSIS OF DIFFERENTIALLY EXPRESSED GENES ACROSS THREE TB COHORTS WERE VISUALIZED AT THE PATHWAY-LEVEL. SERUM LEVELS OF INFLAMMATION WERE MEASURED BY ELISA. HORVATH (DNA METHYLATION) AND RNA-SEQ BIOLOGICAL CLOCKS WERE USED TO INVESTIGATE SHIFTS IN CHRONOLOGICAL AGE AMONG HUMANS WITH TB. RESULTS: GUINEA PIGS WITH TB DEMONSTRATED DNA HYPERMETHYLATION AND SHOWED SYSTEM-LEVEL SIMILARITY TO HUMANS WITH TB (P-VALUE = 0.002). THE TRANSCRIPTOME IN TB IN MULTIPLE COHORTS WAS ENRICHED FOR DNA METHYLATION AND CELLULAR SENESCENCE. SENESCENCE ASSOCIATED PROTEINS CXCL9, CXCL10, AND TNF WERE ELEVATED IN TB PATIENTS COMPARED TO HEALTHY CONTROLS. HUMANS WITH TB DEMONSTRATE 12.7 YEARS (95% CI: 7.5, 21.9) AND 14.38 YEARS (95% CI: 10.23-18.53) OF CELLULAR AGING AS MEASURED BY EPIGENETIC AND GENE EXPRESSION BASED CELLULAR CLOCKS, RESPECTIVELY. CONCLUSIONS: IN BOTH GUINEA PIGS AND HUMANS, TB PERTURBS EPIGENETIC PROCESSES, PROMOTING PREMATURE CELLULAR AGING AND INFLAMMATION, A PLAUSIBLE MEANS TO EXPLAIN THE LONG-TERM DETRIMENTAL HEALTH OUTCOMES AFTER TB. 2022 2 5350 23 RATIONAL DEVELOPMENT OF ADJUNCT IMMUNE-BASED THERAPIES FOR DRUG-RESISTANT TUBERCULOSIS: HYPOTHESES AND EXPERIMENTAL DESIGNS. THE POOR TREATMENT OUTCOMES FOR EXTENSIVELY DRUG-RESISTANT AND MULTIDRUG-RESISTANT TUBERCULOSIS AND THE SLOW PROGRESS IN DEVELOPMENT AND EVALUATION OF NEW TUBERCULOSIS DRUGS GAVE RISE TO DEVELOPMENT OF SEVERAL POTENTIAL IMMUNE-BASED THERAPIES FOR ADJUNCT USE WITH DRUG TREATMENT. HOWEVER, NONE OF THESE THERAPIES HAVE BEEN SHOWN TO BE OF BENEFIT IN CONTROLLED CLINICAL TRIALS IN HUMANS. THERE IS AN URGENT NEED TO RETHINK THE IMMUNOLOGY OF MYCOBACTERIUM TUBERCULOSIS INFECTION AND TO ASCERTAIN PROTECTIVE IMMUNE MECHANISMS THAT COULD BE EXPLOITED TO DEVELOP MORE EFFECTIVE ADJUNCT IMMUNE THERAPIES. T CELLS OBTAINED FROM THE PERIPHERAL BLOOD CIRCULATION MAY NOT REFLECT THE BIOLOGICALLY RELEVANT RECOGNITION OF ANTI-M. TUBERCULOSIS T-CELL RESPONSES IN SITU. THUS, T CELLS THAT MEDIATE PROTECTIVE ANTI-M. TUBERCULOSIS IMMUNE RESPONSES RECOGNIZE AN AS-YET UNDISCOVERED SET OF M. TUBERCULOSIS ANTIGENS THAT REQUIRE DEFINITION. THE BIOLOGICALLY AND CLINICALLY RELEVANT M. TUBERCULOSIS TARGETS THAT ELICIT PROTECTIVE IMMUNE RESPONSES MAY HAVE YET TO BE DISCOVERED. THE ENTIRE M. TUBERCULOSIS PROTEOME IS NOW ACCESSIBLE FOR SCREENING BY ANTIBODY RECOGNITION AND CAN THEREFORE BE USED TO IDENTIFY SPECIFIC T-CELL M. TUBERCULOSIS TARGET ANTIGENS. INHIBITORY CYTOKINES AND LYMPHOCYTOSIS PRESENT IN CHRONIC TUBERCULOSIS INFLAMMATION MAY BE DELETERIOUS IN MOUNTING AN EFFECTIVE M. TUBERCULOSIS T-CELL RESPONSE. CONSEQUENTLY, ABERRANT AND NONEFFECTIVE IMMUNE RESPONSES COULD BE REFOCUSED WITH ANTICYTOKINE OR CELLULAR THERAPY. EPIGENETIC CHANGES DUE TO CHRONIC INFLAMMATION MAY BE RESPONSIBLE, IN PART, FOR IMPAIRED IMMUNE RESPONSES IN TUBERCULOSIS AND THESE CHANGES COULD BE REVERSED. WE PRESENT FEASIBLE EXPERIMENTAL DESIGNS TO TEST THESE HYPOTHESES; THE RESULTS OF WHICH MAY GUIDE AND REFOCUS DEVELOPMENT OF NOVEL IMMUNE-BASED THERAPIES FOR ADJUNCT TREATMENT OF DRUG-RESISTANT TUBERCULOSIS. INSIGHTS FROM CANCER IMMUNOLOGY WILL CROSS-FERTILIZE TUBERCULOSIS IMMUNOLOGY AND HELP TO DEVISE MORE EFFECTIVE ADJUNCT TREATMENT AND VACCINATION STRATEGIES. 2012 3 1308 23 DEFINING A RESEARCH AGENDA TO ADDRESS THE CONVERGING EPIDEMICS OF TUBERCULOSIS AND DIABETES: PART 2: UNDERLYING BIOLOGIC MECHANISMS. THERE IS GROWING INTEREST IN THE RE-EMERGING INTERACTION BETWEEN TYPE 2 DIABETES (DM) AND TB, BUT THE UNDERLYING BIOLOGIC MECHANISMS ARE POORLY UNDERSTOOD DESPITE THEIR POSSIBLE IMPLICATIONS IN CLINICAL MANAGEMENT. EXPERTS IN EPIDEMIOLOGIC, PUBLIC HEALTH, BASIC SCIENCE, AND CLINICAL STUDIES RECENTLY CONVENED AND IDENTIFIED RESEARCH PRIORITIES FOR ELUCIDATING THE UNDERLYING MECHANISMS FOR THE CO-OCCURRENCE OF TB AND DM. WE IDENTIFIED GAPS IN CURRENT KNOWLEDGE OF ALTERED IMMUNITY IN PATIENTS WITH DM DURING TB, WHERE MOST STUDIES SUGGEST AN UNDERPERFORMING INNATE IMMUNITY, BUT EXAGGERATED ADAPTIVE IMMUNITY TO MYCOBACTERIUM TUBERCULOSIS. VARIOUS MOLECULAR MECHANISMS AND PATHWAYS MAY UNDERLIE THESE OBSERVATIONS IN THE DM HOST. THESE INCLUDE SIGNALING INDUCED BY EXCESS ADVANCED GLYCATION END PRODUCTS AND THEIR RECEPTOR, HIGHER LEVELS OF REACTIVE OXIDATIVE SPECIES AND OXIDATIVE STRESS, EPIGENETIC CHANGES DUE TO CHRONIC HYPERGLYCEMIA, ALTERED NUCLEAR RECEPTORS, AND/OR DIFFERENCES IN CELL METABOLISM (IMMUNOMETABOLISM). STUDIES IN HUMANS AT DIFFERENT STAGES OF DM (NO DM, PRE-DM, AND DM) OR TB (LATENT OR ACTIVE TB) SHOULD BE COMPLEMENTED WITH FINDINGS IN ANIMAL MODELS, WHICH PROVIDE THE UNIQUE OPPORTUNITY TO STUDY EARLY EVENTS IN THE HOST-PATHOGEN INTERACTION. SUCH STUDIES COULD ALSO HELP IDENTIFY BIOMARKERS THAT WILL COMPLEMENT CLINICAL STUDIES IN ORDER TO TAILOR THE PREVENTION OF TB-DM, OR TO AVOID THE ADVERSE TB TREATMENT OUTCOMES THAT ARE MORE LIKELY IN THESE PATIENTS. SUCH STUDIES WILL ALSO INFORM NEW APPROACHES TO HOST-DIRECTED THERAPIES. 2017 4 858 27 CHROMATIN DECONDENSATION AND T CELL HYPERRESPONSIVENESS IN DIABETES-ASSOCIATED HYPERGLYCEMIA. DIABETES IS LINKED TO INCREASED INFLAMMATION AND SUSCEPTIBILITY TO CERTAIN INFECTIOUS DISEASES INCLUDING TUBERCULOSIS (TB). WE PREVIOUSLY REPORTED THAT AEROSOL TB IN MICE WITH CHRONIC (>/= 12 WK) HYPERGLYCEMIA FEATURES INCREASED BACTERIAL LOAD, OVERPRODUCTION OF SEVERAL CYTOKINES, AND INCREASED IMMUNE PATHOLOGY COMPARED WITH NORMOGLYCEMIC CONTROLS. A SIMILAR PHENOTYPE EXISTS IN HUMAN PATIENTS WITH DIABETES WITH TB. THE MECHANISMS OF INCREASED T CELL ACTIVATION IN DIABETES ARE UNKNOWN. IN THE CURRENT STUDY, WE TESTED THE HYPOTHESIS THAT HYPERGLYCEMIA MODIFIES THE INTRINSIC RESPONSIVENESS OF NAIVE T CELLS TO TCR STIMULATION. PURIFIED T CELLS FROM CHRONICALLY HYPERGLYCEMIC (HG) MICE PRODUCED HIGHER LEVELS OF TH1, TH2, AND TH17 CYTOKINES AND PROLIFERATED MORE THAN T CELLS FROM NORMOGLYCEMIC CONTROLS AFTER ANTI-CD3E OR AG STIMULATION. IN THIS WAY, NAIVE T CELLS FROM HG MICE RESEMBLED AG-EXPERIENCED CELLS, ALTHOUGH CD44 EXPRESSION WAS NOT INCREASED. CHROMATIN DECONDENSATION, ANOTHER CHARACTERISTIC OF AG-EXPERIENCED T CELLS, WAS INCREASED IN NAIVE T CELLS FROM HG MICE. THAT PHENOTYPE DEPENDED ON EXPRESSION OF THE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS AND COULD BE REVERSED BY INHIBITING P38 MAPK. CHROMATIN DECONDENSATION AND HYPERRESPONSIVENESS TO TCR STIMULATION PERSISTED FOLLOWING TRANSFER OF T CELLS FROM HG MICE INTO NORMOGLYCEMIC MICE. WE PROPOSE THAT CHRONIC HYPERGLYCEMIA CAUSES RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS-MEDIATED EPIGENETIC MODIFICATION OF NAIVE T CELLS LEADING TO P38 MAPK-DEPENDENT CHROMATIN DECONDENSATION. THIS PREACTIVATION STATE FACILITATES TRANSCRIPTION FACTOR ACCESS TO DNA, INCREASING CYTOKINE PRODUCTION AND PROLIFERATION FOLLOWING TCR STIMULATION. THIS MECHANISM MAY CONTRIBUTE TO PATHOLOGICAL INFLAMMATION ASSOCIATED WITH DIABETES AND MIGHT OFFER A NOVEL THERAPEUTIC TARGET. 2014 5 2563 19 EPIGENETICS IN TUBERCULOSIS: IMMUNOMODULATION OF HOST IMMUNE RESPONSE. TUBERCULOSIS IS A STERN, DIFFICULT TO TREAT CHRONIC INFECTION CAUSED BY ACID-FAST BACILLI THAT TEND TO TAKE A LONG TIME TO BE ERADICATED FROM THE HOST'S ENVIRONMENT. IT REQUIRES THE ACTION OF BOTH INNATE AND ADAPTIVE IMMUNE SYSTEMS BY THE HOST. THERE ARE VARIOUS PATTERN RECOGNITION RECEPTORS PRESENT ON IMMUNE CELLS, WHICH RECOGNIZE FOREIGN PATHOGENS OR ITS PRODUCT AND TRIGGER THE IMMUNE RESPONSE. THE EPIGENETIC MODIFICATION PLAYS A CRUCIAL ROLE IN TRIGGERING THE SUSCEPTIBILITY OF THE HOST TOWARDS THE PATHOGEN AND ACTIVATING THE HOST'S IMMUNE SYSTEM AGAINST THE INVADING PATHOGEN. IT ALTERS THE GENE EXPRESSION MODIFYING THE GENETIC MATERIAL OF THE HOST'S CELL. EPIGENETIC MODIFICATION SUCH AS HISTONE ACETYLATION, ALTERATION IN NON-CODING RNA, DNA METHYLATION AND ALTERATION IN MIRNA HAS BEEN STUDIED FOR THEIR INFLUENCE ON THE PATHOPHYSIOLOGY OF TUBERCULOSIS TO CONTROL THE SPREAD OF INFECTION. DESPITE SEVERAL STUDIES BEING CONDUCTED, MANY GAPS STILL EXIST. HEREIN, WE DISCUSS THE IMMUNOPATHOPHYSIOLOGICAL MECHANISM OF TUBERCULOSIS, THE ESSENTIALS OF EPIGENETICS AND THE RECENT ENCROACHMENT OF EPIGENETICS IN THE FIELD OF TUBERCULOSIS AND ITS INFLUENCE ON THE OUTCOME AND PATHOPHYSIOLOGY OF THE INFECTION. 2022 6 1053 25 CLINICAL IMPLICATIONS OF INTERFERON-GAMMA GENETIC AND EPIGENETIC VARIANTS. INTERFERON-GAMMA (IFN-GAMMA) IS AN INTEGRAL AND CRITICAL MOLECULE OF THE IMMUNE SYSTEM, WITH MULTIPLE FUNCTIONS, MOSTLY RELATED TO THE T HELPER TYPE 1 (TH1) RESPONSE TO INFECTION. IT IS CRITICAL FOR DEFENCE AGAINST MYCOBACTERIAL INFECTION AND IS OF INCREASING INTEREST IN DEFENCE AGAINST FUNGI. IN THIS ARTICLE, WE REVIEW THE GENETIC AND EPIGENETIC VARIANTS AFFECTING IFN-GAMMA EXPRESSION AND INVESTIGATE ITS ROLE IN DISEASE, WITH AN EMPHASIS ON FUNGAL DISEASES SUCH AS INVASIVE AND CHRONIC PULMONARY ASPERGILLOSIS. OVER 347 IFN-GAMMA GENE VARIANTS HAVE BEEN DESCRIBED, IN MULTIPLE ETHNIC POPULATIONS. MANY APPEAR TO CONFER A SUSCEPTIBILITY TO DISEASE, ESPECIALLY TUBERCULOSIS (TB) AND HEPATITIS, BUT ALSO SOME NON-INFECTIOUS CONDITIONS SUCH AS APLASTIC ANAEMIA, CERVICAL CANCER AND PSORIASIS. SEVERAL EPIGENETIC MODIFICATIONS ARE ALSO DESCRIBED, INCREASING IFN-GAMMA EXPRESSION IN TH1 LYMPHOCYTES AND REDUCING IFN-GAMMA EXPRESSION IN TH2 LYMPHOCYTES. RECOMBINANT IFN-GAMMA ADMINISTRATION IS LICENSED FOR THE PROPHYLAXIS OF INFECTION (BACTERIAL AND FUNGAL) IN PATIENTS WITH THE PHAGOCYTE FUNCTIONAL DEFICIENCY SYNDROME CHRONIC GRANULOMATOUS DISEASE, ALTHOUGH THE BENEFITS APPEAR LIMITED. INTERFERON-GAMMA THERAPY IS GIVEN TO PATIENTS WITH PROFOUND DEFECTS IN IFN-GAMMA AND INTERLEUKIN-12 PRODUCTION AND APPEARS TO BE BENEFICIAL FOR PATIENTS WITH INVASIVE ASPERGILLOSIS AND CRYPTOCOCCAL MENINGITIS, BUT THE STUDIES ARE NOT DEFINITIVE. A HIGH PROPORTION OF PATIENTS WITH CHRONIC PULMONARY ASPERGILLOSIS ARE POOR PRODUCERS OF IFN-GAMMA IN RESPONSE TO MULTIPLE STIMULI AND COULD ALSO BENEFIT FROM IFN-GAMMA ADMINISTRATION. THE INVESTIGATION AND MANAGEMENT OF PATIENTS WITH POSSIBLE OR DEMONSTRATED IFN-GAMMA DEFICIENCY IN ADULTHOOD IS POORLY STUDIED AND COULD BE GREATLY ENHANCED WITH THE INTEGRATION OF GENETIC DATA. 2014 7 5800 19 STEPWISE PATHOGENIC EVOLUTION OF MYCOBACTERIUM ABSCESSUS. ALTHOUGH ALMOST ALL MYCOBACTERIAL SPECIES ARE SAPROPHYTIC ENVIRONMENTAL ORGANISMS, A FEW, SUCH AS MYCOBACTERIUM TUBERCULOSIS, HAVE EVOLVED TO CAUSE TRANSMISSIBLE HUMAN INFECTION. BY ANALYZING THE RECENT EMERGENCE AND SPREAD OF THE ENVIRONMENTAL ORGANISM M. ABSCESSUS THROUGH THE GLOBAL CYSTIC FIBROSIS POPULATION, WE HAVE DEFINED KEY, GENERALIZABLE STEPS INVOLVED IN THE PATHOGENIC EVOLUTION OF MYCOBACTERIA. WE SHOW THAT EPIGENETIC MODIFIERS, ACQUIRED THROUGH HORIZONTAL GENE TRANSFER, CAUSE SALTATIONAL INCREASES IN THE PATHOGENIC POTENTIAL OF SPECIFIC ENVIRONMENTAL CLONES. ALLOPATRIC PARALLEL EVOLUTION DURING CHRONIC LUNG INFECTION THEN PROMOTES RAPID INCREASES IN VIRULENCE THROUGH MUTATIONS IN A DISCRETE GENE NETWORK; THESE MUTATIONS ENHANCE GROWTH WITHIN MACROPHAGES BUT IMPAIR FOMITE SURVIVAL. AS A CONSEQUENCE, WE OBSERVE CONSTRAINED PATHOGENIC EVOLUTION WHILE PERSON-TO-PERSON TRANSMISSION REMAINS INDIRECT, BUT POSTULATE ACCELERATED PATHOGENIC ADAPTATION ONCE DIRECT TRANSMISSION IS POSSIBLE, AS OBSERVED FOR M. TUBERCULOSIS OUR FINDINGS INDICATE HOW KEY INTERVENTIONS, SUCH AS EARLY TREATMENT AND CROSS-INFECTION CONTROL, MIGHT RESTRICT THE SPREAD OF EXISTING MYCOBACTERIAL PATHOGENS AND PREVENT NEW, EMERGENT ONES. 2021 8 5489 25 REVERSING POST-INFECTIOUS EPIGENETIC-MEDIATED IMMUNE SUPPRESSION. THE IMMUNE RESPONSE MUST BALANCE THE PRO-INFLAMMATORY, CELL-MEDIATED CYTOTOXICITY WITH THE ANTI-INFLAMMATORY AND WOUND REPAIR RESPONSE. EPIGENETIC MECHANISMS MEDIATE THIS BALANCE AND LIMIT HOST IMMUNITY FROM INDUCING EXUBERANT COLLATERAL DAMAGE TO HOST TISSUE AFTER SEVERE AND CHRONIC INFECTIONS. HOWEVER, FOLLOWING TREATMENT FOR THESE INFECTIONS, INCLUDING SEPSIS, PNEUMONIA, HEPATITIS B, HEPATITIS C, HIV, TUBERCULOSIS (TB) OR SCHISTOSOMIASIS, DETRIMENTAL EPIGENETIC SCARS PERSIST, AND RESULT IN LONG-LASTING IMMUNE SUPPRESSION. THIS IS HYPOTHESIZED TO BE ONE OF THE CONTRIBUTING MECHANISMS EXPLAINING WHY SURVIVORS OF INFECTION HAVE INCREASED ALL-CAUSE MORTALITY AND INCREASED RATES OF UNRELATED SECONDARY INFECTIONS. THE MECHANISMS THAT INDUCE EPIGENETIC-MEDIATED IMMUNE SUPPRESSION HAVE BEEN DEMONSTRATED IN-VITRO AND IN ANIMAL MODELS. MODULATION OF THE AMP-ACTIVATED PROTEIN KINASE (AMPK)-MAMMALIAN TARGET OF RAPAMYCIN (MTOR), NUCLEAR FACTOR OF ACTIVATED T CELLS (NFAT) OR NUCLEAR RECEPTOR (NR4A) PATHWAYS IS ABLE TO BLOCK OR REVERSE THE DEVELOPMENT OF DETRIMENTAL EPIGENETIC SCARS. SIMILARLY, DRUGS THAT DIRECTLY MODIFY EPIGENETIC ENZYMES, SUCH AS THOSE THAT INHIBIT HISTONE DEACETYLASES (HDAC) INHIBITORS, DNA HYPOMETHYLATING AGENTS OR MODIFIERS OF THE NUCLEOSOME REMODELING AND DNA METHYLATION (NURD) COMPLEX OR POLYCOMB REPRESSIVE COMPLEX (PRC) HAVE DEMONSTRATED CAPACITY TO RESTORE HOST IMMUNITY IN THE SETTING OF CANCER-, LCMV- OR MURINE SEPSIS-INDUCED EPIGENETIC-MEDIATED IMMUNE SUPPRESSION. A THIRD CLINICALLY FEASIBLE STRATEGY FOR REVERSING DETRIMENTAL EPIGENETIC SCARS INCLUDES BIOENGINEERING APPROACHES TO EITHER DIRECTLY REVERSE THE DETRIMENTAL EPIGENETIC MARKS OR TO MODIFY THE EPIGENETIC ENZYMES OR TRANSCRIPTION FACTORS THAT INDUCE DETRIMENTAL EPIGENETIC SCARS. EACH OF THESE APPROACHES, ALONE OR IN COMBINATION, HAVE ABLATED OR REVERSED DETRIMENTAL EPIGENETIC MARKS IN IN-VITRO OR IN ANIMAL MODELS; TRANSLATIONAL STUDIES ARE NOW REQUIRED TO EVALUATE CLINICAL APPLICABILITY. 2021 9 453 24 APPLICATIONS OF CRISPR SYSTEMS IN RESPIRATORY HEALTH: ENTERING A NEW 'RED PEN' ERA IN GENOME EDITING. RESPIRATORY DISEASES, SUCH AS INFLUENZA INFECTION, ACUTE TRACHEAL BRONCHITIS, PNEUMONIA, TUBERCULOSIS, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ASTHMA, LUNG CANCER AND NASOPHARYNGEAL CARCINOMA, CONTINUE TO SIGNIFICANTLY IMPACT HUMAN HEALTH. DISEASES OF THE LUNG AND RESPIRATORY TRACT ARE INFLUENCED BY ENVIRONMENTAL CONDITIONS AND SOCIO-ECONOMIC FACTORS; HOWEVER, MANY OF THESE SERIOUS RESPIRATORY DISORDERS ARE ALSO ROOTED IN GENETIC OR EPIGENETIC CAUSES. CLUSTERED REGULARLY INTERSPACED PALINDROMIC REPEATS (CRISPR) AND CRISPR-ASSOCIATED (CAS) PROTEINS, ISOLATED FROM THE IMMUNE SYSTEM OF PROKARYOTES, PROVIDE A TOOL TO MANIPULATE GENE SEQUENCES AND GENE EXPRESSION WITH SIGNIFICANT IMPLICATIONS FOR RESPIRATORY RESEARCH. CRISPR/CAS SYSTEMS ALLOW PRECLINICAL MODELLING OF CAUSAL FACTORS INVOLVED IN MANY RESPIRATORY DISEASES, PROVIDING NEW INSIGHTS INTO THEIR UNDERLYING MECHANISMS. CRISPR CAN ALSO BE USED TO SCREEN FOR GENES INVOLVED IN RESPIRATORY PROCESSES, DEVELOPMENT AND PATHOLOGY, IDENTIFYING NOVEL DISEASE DRIVERS OR DRUG TARGETS. FINALLY, CRISPR/CAS SYSTEMS CAN POTENTIALLY CORRECT GENETIC MUTATIONS AND EDIT EPIGENETIC MARKS THAT CONTRIBUTE TO RESPIRATORY DISORDERS, PROVIDING A FORM OF PERSONALIZED MEDICINE THAT COULD BE USED IN CONJUNCTION WITH OTHER TECHNOLOGIES SUCH AS STEM CELL REPROGRAMMING AND TRANSPLANTATION. CRISPR GENE EDITING IS A YOUNG FIELD OF RESEARCH, AND CONCERNS REGARDING ITS SPECIFICITY, AS WELL AS THE NEED FOR EFFICIENT AND SAFE DELIVERY METHODS, NEED TO BE ADDRESSED FURTHER. HOWEVER, CRISPR/CAS SYSTEMS REPRESENT A SIGNIFICANT STEP FORWARD FOR RESEARCH AND THERAPY IN RESPIRATORY HEALTH, AND IT IS LIKELY WE WILL SEE THE BREAKTHROUGHS GENERATED FROM THIS TECHNOLOGY CONTINUE. 2019 10 4211 23 METFORMIN FOR CARDIOVASCULAR PROTECTION, INFLAMMATORY BOWEL DISEASE, OSTEOPOROSIS, PERIODONTITIS, POLYCYSTIC OVARIAN SYNDROME, NEURODEGENERATION, CANCER, INFLAMMATION AND SENESCENCE: WHAT IS NEXT? DIABETES IS ACCOMPANIED BY SEVERAL COMPLICATIONS. HIGHER PREVALENCE OF CANCERS, CARDIOVASCULAR DISEASES, CHRONIC KIDNEY DISEASE (CKD), OBESITY, OSTEOPOROSIS, AND NEURODEGENERATIVE DISEASES HAS BEEN REPORTED AMONG PATIENTS WITH DIABETES. METFORMIN IS THE OLDEST ORAL ANTIDIABETIC DRUG AND CAN IMPROVE COEXISTING COMPLICATIONS OF DIABETES. CLINICAL TRIALS AND OBSERVATIONAL STUDIES UNCOVERED THAT METFORMIN CAN REMARKABLY PREVENT OR ALLEVIATE CARDIOVASCULAR DISEASES, OBESITY, POLYCYSTIC OVARIAN SYNDROME (PCOS), OSTEOPOROSIS, CANCER, PERIODONTITIS, NEURONAL DAMAGE AND NEURODEGENERATIVE DISEASES, INFLAMMATION, INFLAMMATORY BOWEL DISEASE (IBD), TUBERCULOSIS, AND COVID-19. IN ADDITION, METFORMIN HAS BEEN PROPOSED AS AN ANTIAGING AGENT. NUMEROUS MECHANISMS WERE SHOWN TO BE INVOLVED IN THE PROTECTIVE EFFECTS OF METFORMIN. METFORMIN ACTIVATES THE LKB1/AMPK PATHWAY TO INTERACT WITH SEVERAL INTRACELLULAR SIGNALING PATHWAYS AND MOLECULAR MECHANISMS. THE DRUG MODIFIES THE BIOLOGIC FUNCTION OF NF-KAPPAB, PI3K/AKT/MTOR, SIRT1/PGC-1ALPHA, NLRP3, ERK, P38 MAPK, WNT/BETA-CATENIN, NRF2, JNK, AND OTHER MAJOR MOLECULES IN THE INTRACELLULAR SIGNALING NETWORK. IT ALSO REGULATES THE EXPRESSION OF NONCODING RNAS. THEREBY, METFORMIN CAN REGULATE METABOLISM, GROWTH, PROLIFERATION, INFLAMMATION, TUMORIGENESIS, AND SENESCENCE. ADDITIONALLY, METFORMIN MODULATES IMMUNE RESPONSE, AUTOPHAGY, MITOPHAGY, ENDOPLASMIC RETICULUM (ER) STRESS, AND APOPTOSIS AND EXERTS EPIGENETIC EFFECTS. FURTHERMORE, METFORMIN PROTECTS AGAINST OXIDATIVE STRESS AND GENOMIC INSTABILITY, PRESERVES TELOMERE LENGTH, AND PREVENTS STEM CELL EXHAUSTION. IN THIS REVIEW, THE PROTECTIVE EFFECTS OF METFORMIN ON EACH DISEASE WILL BE DISCUSSED USING THE RESULTS OF RECENT META-ANALYSES, CLINICAL TRIALS, AND OBSERVATIONAL STUDIES. THEREAFTER, IT WILL BE METICULOUSLY EXPLAINED HOW METFORMIN REPROGRAMS INTRACELLULAR SIGNALING PATHWAYS AND ALTERS MOLECULAR AND CELLULAR INTERACTIONS TO MODIFY THE CLINICAL PRESENTATIONS OF SEVERAL DISEASES. 2021 11 2169 23 EPIGENETIC MECHANISMS IN PARENCHYMAL LUNG DISEASES: BYSTANDERS OR THERAPEUTIC TARGETS? EPIGENETIC RESPONSES DUE TO ENVIRONMENTAL CHANGES ALTER CHROMATIN STRUCTURE, WHICH IN TURN MODIFIES THE PHENOTYPE, GENE EXPRESSION PROFILE, AND ACTIVITY OF EACH CELL TYPE THAT HAS A ROLE IN THE PATHOPHYSIOLOGY OF A DISEASE. PULMONARY DISEASES ARE ONE OF THE MAJOR CAUSES OF DEATH IN THE WORLD, INCLUDING LUNG CANCER, IDIOPATHIC PULMONARY FIBROSIS (IPF), CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), PULMONARY HYPERTENSION (PH), LUNG TUBERCULOSIS, PULMONARY EMBOLISM, AND ASTHMA. SEVERAL LINES OF EVIDENCE INDICATE THAT EPIGENETIC MODIFICATIONS MAY BE ONE OF THE MAIN FACTORS TO EXPLAIN THE INCREASING INCIDENCE AND PREVALENCE OF LUNG DISEASES INCLUDING IPF AND COPD. INTERESTINGLY, ISOLATED FIBROBLASTS AND SMOOTH MUSCLE CELLS FROM PATIENTS WITH PULMONARY DISEASES SUCH AS IPF AND PH THAT WERE CULTURED EX VIVO MAINTAINED THE DISEASE PHENOTYPE. THE CELLS OFTEN SHOW A HYPER-PROLIFERATIVE, APOPTOSIS-RESISTANT PHENOTYPE WITH INCREASED EXPRESSION OF EXTRACELLULAR MATRIX (ECM) AND ACTIVATED FOCAL ADHESIONS SUGGESTING THE PRESENCE OF AN EPIGENETICALLY IMPRINTED PHENOTYPE. MOREOVER, MANY ABNORMALITIES OBSERVED IN MOLECULAR PROCESSES IN IPF PATIENTS ARE SHOWN TO BE EPIGENETICALLY REGULATED, SUCH AS INNATE IMMUNITY, CELLULAR SENESCENCE, AND APOPTOTIC CELL DEATH. DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNA REGULATION CONSTITUTE THE MOST COMMON EPIGENETIC MODIFICATION MECHANISMS. 2022 12 5324 26 PULMONARY MICRORNA PROFILING: IMPLICATIONS IN UPPER LOBE PREDOMINANT LUNG DISEASE. BACKGROUND: NUMEROUS PULMONARY DISEASES MANIFEST WITH UPPER LOBE PREDOMINANCE INCLUDING CYSTIC FIBROSIS, SMOKING-RELATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND TUBERCULOSIS. ZONAL HYPOXIA, CHARACTERISTIC OF THESE PULMONARY MALADIES, AND OXYGEN STRESS IN GENERAL IS KNOWN TO EXERT PROFOUND EFFECTS ON VARIOUS IMPORTANT ASPECTS OF CELL BIOLOGY. LUNG MACROPHAGES ARE MAJOR PARTICIPANTS IN THE PULMONARY INNATE IMMUNE RESPONSE AND REGIONAL DIFFERENCES IN MACROPHAGE RESPONSIVENESS TO HYPOXIA MAY CONTRIBUTE IN THE DEVELOPMENT OF LUNG DISEASE. MICRORNAS ARE UBIQUITOUS REGULATORS OF HUMAN BIOLOGY AND EMERGING EVIDENCE INDICATES ALTERED MICRORNA EXPRESSION MODULATES RESPIRATORY DISEASE PROCESSES. THE OBJECTIVE OF THIS STUDY IS TO GAIN INSIGHT INTO THE EPIGENETIC AND CELLULAR MECHANISMS INFLUENCING REGIONAL DIFFERENCES IN LUNG DISEASE BY INVESTIGATING EFFECT OF HYPOXIA ON REGIONAL MICRORNA EXPRESSION IN THE LUNG. ALL STUDIES WERE PERFORMED USING PRIMARY ALVEOLAR MACROPHAGES (N = 10) OR BRONCHOALVEOLAR LAVAGE FLUID (N = 16) ISOLATED FROM HUMAN SUBJECTS. MICRORNA WAS ASSAYED VIA THE NANOSTRING NCOUNTER MICRORNA ASSAY. RESULTS: DIVERGENT MOLECULAR PATTERNS OF MICRORNA EXPRESSION WERE OBSERVED IN ALTERNATE LUNG LOBES, SPECIFICALLY NOTED WAS DISPARATE EXPRESSION OF MIR-93 AND MIR-4454 IN ALVEOLAR MACROPHAGES ALONG WITH ALTERED EXPRESSION OF MIR-451A AND MIR-663A IN BRONCHOALVEOLAR LAVAGE FLUID. GENE ONTOLOGY WAS USED TO IDENTIFY POTENTIAL DOWNSTREAM TARGETS OF DIVERGENT MICRORNAS. TARGETS INCLUDE CYTOKINES AND MATRIX METALLOPROTEINASES, MOLECULES THAT COULD HAVE A SIGNIFICANT IMPACT ON PULMONARY INFLAMMATION AND FIBROSIS. CONCLUSIONS: OUR FINDINGS SHOW VARIANT REGIONAL MICRORNA EXPRESSION ASSOCIATED WITH HYPOXIA IN ALVEOLAR MACROPHAGES AND BAL FLUID IN THE LUNG-UPPER VS LOWER LOBE. FUTURE STUDIES SHOULD ADDRESS WHETHER THESE SPECIFIC MICRORNAS MAY ACT INTRACELLULARLY, IN A PARACRINE/ENDOCRINE MANNER TO DIRECT THE INNATE IMMUNE RESPONSE OR MAY ULTIMATELY BE INVOLVED IN PULMONARY HOST-TO-PATHOGEN TRANS-KINGDOM CROSS-TALK. 2017 13 6120 19 THE EPIGENETIC IMPLICATION IN CORONAVIRUS INFECTION AND THERAPY. EPIGENETICS IS A RELATIVELY NEW FIELD OF SCIENCE THAT STUDIES THE GENETIC AND NON-GENETIC ASPECTS RELATED TO HERITABLE PHENOTYPIC CHANGES, FREQUENTLY CAUSED BY ENVIRONMENTAL AND METABOLIC FACTORS. IN THE HOST, THE EPIGENETIC MACHINERY CAN REGULATE GENE EXPRESSION THROUGH A SERIES OF REVERSIBLE EPIGENETIC MODIFICATIONS, SUCH AS HISTONE METHYLATION AND ACETYLATION, DNA/RNA METHYLATION, CHROMATIN REMODELING, AND NON-CODING RNAS. THE CORONAVIRUS DISEASE 19 (COVID-19) IS A HIGHLY TRANSMITTABLE AND PATHOGENIC VIRAL INFECTION. THE SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2), WHICH EMERGED IN WUHAN, CHINA, AND SPREAD WORLDWIDE, CAUSES IT. COVID-19 SEVERITY AND CONSEQUENCES LARGELY DEPEND ON PATIENT AGE AND HEALTH STATUS. IN THIS REVIEW, WE WILL SUMMARIZE AND COMPARATIVELY ANALYZE HOW VIRUSES REGULATE THE HOST EPIGENOME. MAINLY, WE WILL BE FOCUSING ON HIGHLY PATHOGENIC RESPIRATORY RNA VIRUS INFECTIONS SUCH AS CORONAVIRUSES. IN THIS CONTEXT, EPIGENETIC ALTERATIONS MIGHT PLAY AN ESSENTIAL ROLE IN THE ONSET OF CORONAVIRUS DISEASE COMPLICATIONS. ALTHOUGH MANY THERAPEUTIC APPROACHES ARE UNDER STUDY, MORE RESEARCH IS URGENTLY NEEDED TO IDENTIFY EFFECTIVE VACCINE OR SAFER CHEMOTHERAPEUTIC DRUGS, INCLUDING EPIGENETIC DRUGS, TO COPE WITH THIS VIRAL OUTBREAK AND TO DEVELOP PRE- AND POST-EXPOSURE PROPHYLAXIS AGAINST COVID-19. 2020 14 6502 17 TRAINED IMMUNITY: LONG-TERM ADAPTATION IN INNATE IMMUNE RESPONSES. ADAPTIVE IMMUNE RESPONSES ARE CHARACTERIZED BY ANTIGEN SPECIFICITY AND INDUCTION OF LIFELONG IMMUNOLOGIC MEMORY. RECENTLY, IT HAS BEEN REPORTED THAT INNATE IMMUNE CELLS CAN ALSO BUILD IMMUNE MEMORY CHARACTERISTICS-A PROCESS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY DESCRIBES THE PERSISTENT HYPERRESPONSIVE PHENOTYPE THAT INNATE IMMUNE CELLS CAN DEVELOP AFTER BRIEF STIMULATION. PATHOGENIC STIMULI SUCH AS MICROORGANISMS, AND ALSO ENDOGENOUS MOLECULES INCLUDING URIC ACID, OXIDIZED LDL (LOW-DENSITY LIPOPROTEIN), AND CATECHOLAMINES, ARE CAPABLE OF INDUCING MEMORY IN MONOCYTES AND MACROPHAGES. WHILE TRAINED IMMUNITY PROVIDES FAVORABLE CROSS-PROTECTION IN THE CONTEXT OF INFECTIOUS DISEASES, THE HEIGHTENED IMMUNE RESPONSE CAN BE MALADAPTIVE IN DISEASES DRIVEN BY CHRONIC SYSTEMIC INFLAMMATION, SUCH AS ATHEROSCLEROSIS. TRAINED IMMUNITY IS MAINTAINED BY DISTINCT EPIGENETIC AND METABOLIC MECHANISMS AND PERSISTS FOR AT LEAST SEVERAL MONTHS IN VIVO DUE TO REPROGRAMMING OF MYELOID PROGENITOR CELLS. ADDITIONALLY, CERTAIN NONIMMUNE CELLS ARE ALSO FOUND TO EXHIBIT TRAINED IMMUNITY CHARACTERISTICS. THUS, TRAINED IMMUNITY PRESENTS AN EXCITING FRAMEWORK TO DEVELOP NEW APPROACHES TO VACCINATION AND ALSO NOVEL PHARMACOLOGICAL TARGETS IN THE TREATMENT OF INFLAMMATORY DISEASES. 2021 15 5135 22 POTENTIAL MECHANISMS FOR LUNG FIBROSIS ASSOCIATED WITH COVID-19 INFECTION. PULMONARY FIBROSIS IS A SEQUELAE OF SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2) INFECTION THAT CURRENTLY LACKS EFFECTIVE PREVENTATIVE OR THERAPEUTIC MEASURES. POST-VIRAL LUNG FIBROSIS DUE TO SARS-COV-2 HAS BEEN SHOWN TO BE PROGRESSIVE ON SELECTED PATIENTS USING IMAGING STUDIES. PERSISTENT INFILTRATION OF MACROPHAGES AND MONOCYTES, A MAIN FEATURE OF SARS-COV-2 PULMONARY FIBROSIS, AND LONG-LIVED CIRCULATING INFLAMMATORY MONOCYTES MIGHT BE DRIVING FACTORS PROMOTING THE PROFIBROTIC MILIEU IN THE LUNG. THE UPSTREAM SIGNAL(S) THAT REGULATES THE PRESENCE OF THESE IMMUNE CELLS (DESPITE COMPLETE VIRAL CLEARANCE) REMAINS TO BE EXPLORED. CURRENT DATA INDICATE THAT MUCH OF THE STIMULATING SIGNALS ARE LOCALIZED IN THE LUNGS. HOWEVER, AN ONGOING LOW-GRADE SYSTEMIC INFLAMMATION IN LONG CORONAVIRUS DISEASE 2019 (COVID-19) SYMPTOMS SUGGESTS THAT CERTAIN NON-PULMONARY REGULATORS SUCH AS EPIGENETIC CHANGES IN HEMATOPOIETIC STEM CELLS MIGHT BE CRITICAL TO THE CHRONIC INFLAMMATORY RESPONSE. SINCE NEARLY ONE-THIRD OF THE WORLD POPULATION HAVE BEEN INFECTED, A TIMELY UNDERSTANDING OF THE UNDERLYING PATHOGENESIS LEADING TO TISSUE REMODELING IS REQUIRED. HEREIN, WE REVIEW THE POTENTIAL PATHOGENIC MECHANISMS DRIVING LUNG FIBROSIS FOLLOWING SARS-COV-2 INFECTION BASED UPON AVAILABLE STUDIES AND OUR PRELIMINARY FINDINGS (GRAPHICAL ABSTRACT). 2023 16 2357 19 EPIGENETIC REGULATION OF PULMONARY INFLAMMATION. PULMONARY DISEASE SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), ASTHMA, PULMONARY FIBROSIS AND PULMONARY HYPERTENSION ARE THE LEADING CAUSE OF DEATHS. MORE IMPORTANTLY, LUNG DISEASES ARE ON THE RISE AND ENVIRONMENTAL FACTORS INDUCED EPIGENETIC MODIFICATIONS ARE MAJOR PLAYERS ON THIS INCREASED PREVALENCE. IT HAS BEEN REPORTED THAT DYSREGULATION OF GENES INVOLVED IN EPIGENETIC REGULATION SUCH AS THE HISTONE DEACETYLASE (HDACS) AND HISTONE ACETYLTRANSFERASE (HATS) PLAY IMPORTANT ROLE IN LUNG HEALTH AND PULMONARY DISEASE PATHOGENESIS. INFLAMMATION IS AN ESSENTIAL COMPONENT OF RESPIRATORY DISEASES. INJURY AND INFLAMMATION TRIGGER RELEASE OF EXTRACELLULAR VESICLES THAT CAN ACT AS EPIGENETIC MODIFIERS THROUGH TRANSFER OF EPIGENETIC REGULATORS SUCH AS MICRORNAS (MIRNAS), LONG NON-CODING RNAS (LNCRNAS), PROTEINS AND LIPIDS, FROM ONE CELL TO ANOTHER. THE IMMUNE DYSREGULATIONS CAUSED BY THE CARGO CONTENTS ARE IMPORTANT CONTRIBUTORS OF RESPIRATORY DISEASE PATHOGENESIS. N6 METHYLATION OF RNA IS ALSO EMERGING TO BE A CRITICAL MECHANISM OF EPIGENETIC ALTERATION AND UPREGULATION OF IMMUNE RESPONSES TO ENVIRONMENTAL STRESSORS. EPIGENETIC CHANGES SUCH AS DNA METHYLATION ARE STABLE AND OFTEN LONG TERM AND CAUSE ONSET OF CHRONIC LUNG CONDITIONS. THESE EPIGENETIC PATHWAYS ARE ALSO BEING UTILIZED FOR THERAPEUTIC INTERVENTION IN SEVERAL LUNG CONDITIONS. 2023 17 6500 15 TRAINED IMMUNITY IN TYPE 2 IMMUNE RESPONSES. IMMUNOLOGICAL MEMORY OF INNATE IMMUNE CELLS, ALSO TERMED "TRAINED IMMUNITY", ALLOWS FOR CROSS-PROTECTION AGAINST DISTINCT PATHOGENS, BUT MAY ALSO DRIVE CHRONIC INFLAMMATION. RECENT STUDIES HAVE SHOWN THAT MEMORY RESPONSES ASSOCIATED WITH TYPE 2 IMMUNITY DO NOT SOLELY RELY ON ADAPTIVE IMMUNE CELLS, SUCH AS T- AND B CELLS, BUT ALSO INVOLVE THE INNATE IMMUNE SYSTEM AND EPITHELIAL CELLS. MEMORY RESPONSES HAVE BEEN DESCRIBED FOR MONOCYTES, MACROPHAGES AND AIRWAY EPITHELIAL CELLS OF ASTHMATIC PATIENTS AS WELL AS FOR MACROPHAGES AND GROUP 2 INNATE LYMPHOID CELLS (ILC2) FROM ALLERGEN-SENSITIZED OR HELMINTH-INFECTED MICE. THE METABOLIC AND EPIGENETIC MECHANISMS THAT MEDIATE ALLERGEN- OR HELMINTH-INDUCED REPROGRAMMING OF INNATE IMMUNE CELLS ARE ONLY BEGINNING TO BE UNCOVERED. TRAINED IMMUNITY HAS BEEN IMPLICATED IN HELMINTH-DRIVEN IMMUNE REGULATION AND ALLERGEN-SPECIFIC IMMUNOTHERAPY, SUGGESTING ITS EXPLOITATION IN FUTURE THERAPIES. HERE, WE DISCUSS RECENT ADVANCES AND KEY REMAINING QUESTIONS REGARDING THE MECHANISMS AND FUNCTIONS OF TRAINED TYPE 2 IMMUNITY IN INFECTION AND INFLAMMATION. 2022 18 6053 16 THE CRUCIAL ROLE OF NLRP3 INFLAMMASOME IN VIRAL INFECTION-ASSOCIATED FIBROSING INTERSTITIAL LUNG DISEASES. IDIOPATHIC PULMONARY FIBROSIS (IPF), ONE OF THE MOST COMMON FIBROSING INTERSTITIAL LUNG DISEASES (ILD), IS A CHRONIC-AGE-RELATED RESPIRATORY DISEASE THAT RISES FROM REPEATED MICRO-INJURY OF THE ALVEOLAR EPITHELIUM. ENVIRONMENTAL INFLUENCES, INTRINSIC FACTORS, GENETIC AND EPIGENETIC RISK FACTORS THAT LEAD TO CHRONIC INFLAMMATION MIGHT BE IMPLICATED IN THE DEVELOPMENT OF IPF. THE EXACT TRIGGERS THAT INITIATE THE FIBROTIC RESPONSE IN IPF REMAIN ENIGMATIC, BUT THERE IS NOW INCREASING EVIDENCE SUPPORTING THE ROLE OF CHRONIC EXPOSURE OF VIRAL INFECTION. DURING VIRAL INFECTION, ACTIVATION OF THE NLRP3 INFLAMMASOME BY INTEGRATING MULTIPLE CELLULAR AND MOLECULAR SIGNALING IMPLICATES ROBUST INFLAMMATION, FIBROBLAST PROLIFERATION, ACTIVATION OF MYOFIBROBLAST, MATRIX DEPOSITION, AND ABERRANT EPITHELIAL-MESENCHYMAL FUNCTION. OVERALL, THE CROSSTALK OF THE NLRP3 INFLAMMASOME AND VIRUSES CAN ACTIVATE IMMUNE RESPONSES AND INFLAMMASOME-ASSOCIATED MOLECULES IN THE DEVELOPMENT, PROGRESSION, AND EXACERBATION OF IPF. 2021 19 3678 22 INFLAMMATION AND REGENERATION IN THE DENTIN-PULP COMPLEX: A DOUBLE-EDGED SWORD. DENTAL TISSUE INFECTION AND DISEASE RESULT IN ACUTE AND CHRONIC ACTIVATION OF THE INNATE IMMUNE RESPONSE, WHICH IS MEDIATED BY MOLECULAR AND CELLULAR SIGNALING. DIFFERENT CELL TYPES WITHIN THE DENTIN-PULP COMPLEX ARE ABLE TO DETECT INVADING BACTERIA AT ALL STAGES OF THE INFECTION. INDEED, AT RELATIVELY EARLY DISEASE STAGES, ODONTOBLASTS WILL RESPOND TO BACTERIAL COMPONENTS, AND AS THE DISEASE PROGRESSES, CORE PULPAL CELLS INCLUDING FIBROBLASTS, STEMS CELLS, ENDOTHELIAL CELLS, AND IMMUNE CELLS WILL BECOME INVOLVED. PATTERN RECOGNITION RECEPTORS, SUCH AS TOLL-LIKE RECEPTORS EXPRESSED ON THESE CELL TYPES, ARE RESPONSIBLE FOR DETECTING BACTERIAL COMPONENTS, AND THEIR LIGAND BINDING LEADS TO THE ACTIVATION OF THE NUCLEAR FACTOR-KAPPA B AND P38 MITOGEN-ACTIVATED PROTEIN (MAP) KINASE INTRACELLULAR SIGNALING CASCADES. SUBSEQUENT NUCLEAR TRANSLOCATION OF THE TRANSCRIPTION FACTOR SUBUNITS FROM THESE PATHWAYS WILL LEAD TO PROINFLAMMATORY MEDIATOR EXPRESSION, INCLUDING INCREASES IN CYTOKINES AND CHEMOKINES, WHICH TRIGGER HOST CELLULAR DEFENSE MECHANISMS. THE COMPLEX MOLECULAR SIGNALING WILL RESULT IN THE RECRUITMENT OF IMMUNE SYSTEM CELLS TARGETED AT COMBATING THE INVADING MICROBES; HOWEVER, THE TRAFFICKING AND ANTIBACTERIAL ACTIVITY OF THESE CELLS CAN LEAD TO COLLATERAL TISSUE DAMAGE. RECENT EVIDENCE SUGGESTS THAT IF INFLAMMATION IS RESOLVED RELATIVELY LOW LEVELS OF PROINFLAMMATORY MEDIATORS MAY PROMOTE TISSUE REPAIR, WHEREAS IF CHRONIC INFLAMMATION ENSUES REPAIR MECHANISMS BECOME INHIBITED. THUS, THE EFFECTS OF MEDIATORS ARE TEMPORAL CONTEXT DEPENDENT. ALTHOUGH CONTAINMENT AND REMOVAL OF THE INFECTION ARE KEYS TO ENABLE DENTAL TISSUE REPAIR, IT IS FEASIBLE THAT THE DEVELOPMENT OF ANTI-INFLAMMATORY AND IMMUNOMODULATORY APPROACHES, BASED ON MOLECULAR, EPIGENETIC, AND PHOTOBIOMODULATORY TECHNOLOGIES, MAY ALSO BE BENEFICIAL FOR FUTURE ENDODONTIC TREATMENTS. 2014 20 1640 14 DOES EPIGENETICS PLAY A ROLE IN HUMAN ASTHMA? ASTHMA AND OTHER ALLERGIC DISEASES ARE AMONG THE MOST PREVALENT CHRONIC NON-COMMUNICABLE DISEASES OF CHILDHOOD. ACCORDING TO THE WORLD HEALTH ORGANIZATION, ASTHMA AFFECTS >7.0 MILLION CHILDREN UNDER 18 IN THE UNITED STATES, WITH AN ECONOMIC BURDEN THAT IS ESTIMATED TO EXCEED THAT OF TUBERCULOSIS AND HIV/AIDS COMBINED. DESPITE MUCH RESEARCH, THE NATURAL HISTORY OF ASTHMA AND ITS PATHOGENESIS ARE STILL IN MANY WAYS ELUSIVE. THIS REVIEW DISCUSSES OUR CURRENT UNDERSTANDING OF THE ROLE EPIGENETIC PROCESSES PLAY IN ASTHMA PATHOGENESIS, FOCUSING ON GENOME-WIDE, POPULATION-BASED STUDIES. 2016