1 2692 115 EVOLUTION OF THE CONCEPTS OF ENDOMETROSIS, POST BREEDING ENDOMETRITIS, AND SUSCEPTIBILITY OF MARES. IN THIS PAPER, THE EVOLUTION OF OUR UNDERSTANDING ABOUT POST BREEDING ENDOMETRITIS (PBE), THE SUSCEPTIBILITY OF MARES, AND EVENTS LEADING TO ENDOMETROSIS ARE REVIEWED. WHEN SPERM ARRIVE IN THE UTERUS, PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES ARE RELEASED. THEY ATTRACT NEUTROPHILS AND INDUCE MODULATORY CYTOKINES WHICH CONTROL INFLAMMATION. IN SUSCEPTIBLE MARES, THIS PHYSIOLOGICAL DEFENSE CAN BE PROLONGED SINCE THE PATTERN OF CYTOKINE RELEASE DIFFERS FROM THAT OF RESISTANT MARES BEING DELAYED AND WEAKER FOR ANTI-INFLAMMATORY CYTOKINES. DELAYED UTERINE CLEARANCE DUE TO CONFORMATIONAL DEFECTS, DEFICIENT MYOMETRIAL CONTRACTIONS, AND FAILURE OF THE CERVIX TO RELAX IS DETECTED BY INTRAUTERINE FLUID ACCUMULATION AND IS AN IMPORTANT REASON FOR SUSCEPTIBILITY TO ENDOMETRITIS. MULTIPAROUS AGED MARES ARE MORE LIKELY TO BE SUSCEPTIBLE. UNTREATED PROLONGED PBE CAN LEAD TO BACTERIAL OR FUNGAL ENDOMETRITIS CALLED PERSISTENT OR CHRONIC ENDOMETRITIS. EXUBERANT OR PROLONGED NEUTROPHILIA AND CYTOKINE RELEASE CAN HAVE DELETERIOUS AND PERMANENT EFFECTS IN INDUCING ENDOMETROSIS. INTERACTIONS OF NEUTROPHILS, CYTOKINES, AND PROSTAGLANDINS IN THE FORMATION OF COLLAGEN AND EXTRACELLULAR MATRIX IN THE PATHOGENESIS OF FIBROSIS ARE DISCUSSED. ENDOMETRITIS AND ENDOMETROSIS ARE INTERCONNECTED, INFLUENCING EACH OTHER. IT IS SUGGESTED THAT THEY REPRESENT EPIGENETIC CHANGES INDUCED BY AGE AND HOSTILE UTERINE ENVIRONMENT. 2022 2 5489 23 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 3 3464 28 HYPOTHESIS. BYSTANDERS OR BAD SEEDS? MANY AUTOIMMUNE-TARGET CELLS MAY BE TRANSFORMING TO CANCER AND SIGNALLING "DANGER" TO THE IMMUNE SYSTEM. AUTOIMMUNE-TARGET CELLS IN AUTOIMMUNE DISEASE (AID) ARE USUALLY CONSTRUED AS CONSTITUTIONALLY NORMAL HEALTHY CELLS. A RELATED ASSUMPTION IS THAT OTHER CELLS IN THE BODY OF AID PATIENTS, EXCEPT FOR CERTAIN IMMUNOCYTES, ARE HEALTHY CELLS. AN IMPLICATION OF THAT VIEW IS THAT ANY SYSTEMIC PATHOLOGY IN ORGAN-SPECIFIC AID IS RELATED TO METABOLIC DERANGEMENTS SECONDARY TO TISSUE DESTRUCTION. HOWEVER, MUCH DATA ON TARGET AND OTHER CELLS IN AID SUGGEST WIDESPREAD PRIMARY CELLULAR DEFECTS. IN INSULIN-DEPENDENT DIABETES MELLITUS (IDDM), FOR EXAMPLE, MANY "COMPLICATIONS" SUCH AS ATHEROSCLEROSIS, PREMATURE ARTERIAL STIFFENING, SENESCENCE OF FIBROBLASTS IN VITRO, AND EXUBERANT GROWTH OF SMOOTH MUSCLE AND MESANGIAL CELLS IN VIVO ARE NOT STRICTLY ATTRIBUTABLE TO GLUCOSE ELEVATION. ALSO UNEXPLAINED IS THE SIMILAR APPEARANCE OF IDDM BETA-CELLS AND CELLS FROM INSULINOMA AND WHY THE PRODROMAL PHASE OF IDDM HAS MANY INSULINOMA-LIKE FEATURES. WHILE AID TARGET CELLS HAVE OFTEN BEEN LIKENED TO NEOPLASTIC CELLS, INVESTIGATORS HAVE RARELY EXPLORED THE POSSIBILITY THAT AUTOIMMUNITY IN AID IS FUNDAMENTALLY ANTINEOPLASTIC. THIS IS LIKELY BECAUSE THE DOMINANT IDEAS IN ONCOLOGY AND IMMUNOLOGY-SOMATIC MUTATION AND CLONAL DELETION, RESPECTIVELY-HAVE PREVENTED EXPLANATIONS FOR HOW NORMAL IMMUNITY COULD DETECT TRANSFORMING CELLS NOT EXPRESSING NON-SELF ANTIGENS. NEW AND LESS CONVENTIONAL THEORIES OF CANCER AND IMMUNITY HAVE FACILITATED SUCH AN EXPLANATION. I USE RUBIN'S "EPIGENETIC" AGING MODEL OF CARCINOGENESIS AND MATZINGER'S "DANGER" MODEL OF IMMUNITY TO INTEGRATE THE IMMUNOLOGICAL AND ONCOLOGICAL SIDES OF AID. IN PARTICULAR, I POSTULATE THAT INDIVIDUALS SUFFERING FROM AID HAVE INHERITED MANY FOCI OF PREMATURELY AGING CELLS. THOSE INHERENTLY DAMAGED CELLS ADAPT TO IN VIVO CHALLENGES BY BEGINNING TO TRANSFORM INTO CANCER CELLS. HOWEVER, AS LONG AS THOSE STRESSED CELLS HAVE NOT FULLY TRANSFORMED, THEY WILL CONTINUE TO SIGNAL "DANGER" TO THE INNATE IMMUNE SYSTEM. THE CLINICAL OUTCOME OF THAT STRUGGLE BETWEEN INCIPIENT NEOPLASIA AND IMMUNITY WILL VARY DEPENDING UPON THE DEGREE OF TUMOR-PRONENESS AND RESISTANCE OF THE INDIVIDUAL. BORROWING FROM CANCER GENETICIST HENRY LYNCH, I POSTULATE THAT TUMOR-RESISTANCE IS INHERITED AS A QUANTITATIVE POLYGENIC TRAIT IN DIRECT PROPORTION TO TUMOR-PRONENESS. I FURTHER CONTEND THAT TUMOR-PRONENESS AND IMMUNITY ARE LINKED POLYGENIC TRAITS SUCH THAT THE GREATER ONE'S TUMOR-PRONENESS, THE MORE POWERFUL HIS/HER ANTITUMOR IMMUNITY. I POINT TO THE SHARED DNA REPAIR DEFICIENCY OF CERTAIN CANCER-PRONE SYNDROMES AND HLA-LINKED AID, THEIR OCCASIONAL CO-OCCURRENCE, AND THEIR DEMONSTRABLY EXCEPTIONAL IMMUNITY AGAINST SOLID TUMORS. I PROPOSE THAT HLA-LINKED AID CONSTITUTE "CHRONIC HYPERSENSITIVITY SYNDROMES" DUE TO IMMUNITY'S LARGELY HIDDEN BATTLE TO SUPPRESS MULTIPLE INCIPIENT NEOPLASTIC MICROFOCI. MUCH OF THE PHYSIOPATHOLOGY OF AID IS EXPLICABLE AS A SUSTAINED SYSTEMIC RESPONSE TO THREATENED NEOPLASTIC TRANSFORMATION. 2001 4 1066 24 CLINICAL USE OF AMINO ACIDS AS DIETARY SUPPLEMENT: PROS AND CONS. NITROGEN SUPPLY IS PIVOTAL FOR THE MAINTENANCE OF LIFE. AMINO ACIDS CAN BE UTILIZED TO SYNTHESIZE BOTH GLUCOSE AND LIPIDS. THE OPPOSITE, I.E., PRODUCTION OF AMINO ACIDS FROM EITHER ONE OF THEM, IS NOT POSSIBLE IN THE ABSENCE OF OTHER AMINO ACIDS AS DONORS OF NITROGEN. THE QUALITY OF AMINO ACID CONTENT IN PROTEIN HAS BEEN RE-EVALUATED RECENTLY, AND THE RELEVANCE OF ESSENTIAL AMINO ACIDS HAS BEEN REPEATEDLY UNDERLINED. ESSENTIAL AMINO ACID REQUIREMENTS IN DIFFERENT MAMMALS ARE NOT IDENTICAL, AND RATIOS AMONG THEM SHOULD BE TAKEN INTO ACCOUNT WHEN PROJECTING AN EFFICIENT FORMULATION. RECENT RESEARCH HAS DEMONSTRATED THAT GENES RESPOND TO DIFFERENT QUALITIES AND QUANTITIES OF NUTRITIONAL SUPPLY, AND INCREASED PROVISION OF ESSENTIAL AMINO ACIDS INCREASES LIFESPAN IN ANIMAL EXPERIMENTS THROUGH MITOCHONDRIOGENESIS AND MAINTENANCE OF ELEVATED RATES OF SYNTHESIS OF ANTI-OXIDANT MOLECULES. MOREOVER, GENETIC EXPRESSION OF KEY CONTROLLERS OF SYNTHESIS, LIKE MTOR, MAY BE PARTICULARLY IMPORTANT FOR UNDERSTANDING SKELETAL MUSCLE MAINTENANCE. LOSSES OF MUSCLE MASS AND IMPAIRED IMMUNE FUNCTION ARE RELATED TO REDUCED PROTEIN SUPPLY, AND THERE IS INCREASING EVIDENCE THAT REGULAR ESSENTIAL AMINO ACID INTAKE AS PART OF AN ORAL DIET IS EFFECTIVE IN REVERSING MUSCLE CATABOLISM, PROMOTING MUSCLE ANABOLISM, AND RESTORING IMMUNOLOGICAL FUNCTION. THEREFORE, THE USE OF AMINO ACIDS AS SUPPLEMENTS TO DIET WOULD BE EXPANDING IN THE NEAR FUTURE. IS THIS SAFE? FEW DATA ARE AVAILABLE ON AMINO ACID TOXICITY, AND ONLY ONE ESSENTIAL AMINO ACID MAY BE CONSIDERED TO HAVE CLINICALLY RELEVANT TOXICITY: METHIONINE, BECAUSE IT IS TRANSFORMED INTO A TOXIC INTERMEDIATE, HOMOCYSTEINE, WHEN CYSTEINE SYNTHESIS IS REQUIRED BY METABOLIC NEEDS. MATCHING OF STOICHIOMETRIC RATIOS BETWEEN METHIONINE AND CYSTEINE MAY SOLVE THE PROBLEM OF SUPPLYING SUFFICIENT AMOUNTS OF SULFUR TO THE BODY. ARGININE AND GLUTAMINE ARE TWO NON-ESSENTIAL AMINO ACIDS THAN CAN BECOME "CONDITIONALLY ESSENTIAL" BECAUSE OF ELEVATED NEEDS DURING PATHOLOGICAL CONDITIONS, AND METABOLISM MAY NOT BE ABLE TO MAINTAIN THEIR CONCENTRATIONS AT SUFFICIENT LEVELS TO MATCH METABOLIC REQUIREMENTS. CHRONIC EXOGENOUS ARGININE SUPPLEMENTATION HAS NOT PROVEN TO EXERT POSITIVE CLINICAL EFFECTS IN DIFFERENT TRIALS, AND SEQUENTIAL ARTICULATION OF THE KNOWLEDGE OF INTRODUCTION OF ARGININE-DRIVEN TRANSCRIPTIONAL, TRANSLATIONAL, AND EPIGENETIC ADAPTATIONS MAY GIVE US A KEY FOR INTERPRETING THOSE PUZZLING RESULTS. 2011 5 4663 30 NEW HORIZONS: NOVEL APPROACHES TO ENHANCE HEALTHSPAN THROUGH TARGETING CELLULAR SENESCENCE AND RELATED AGING MECHANISMS. THE ELDERLY POPULATION IS INCREASING FASTER THAN OTHER SEGMENTS OF THE POPULATION THROUGHOUT THE WORLD. AGE IS THE LEADING PREDICTOR FOR MOST CHRONIC DISEASES AND DISORDERS, MULTIMORBIDITY, GERIATRIC SYNDROMES, AND IMPAIRED ABILITY TO RECOVER FROM ACCIDENTS OR ILLNESSES. ENHANCING THE DURATION OF HEALTH AND INDEPENDENCE, TERMED HEALTHSPAN, WOULD BE MORE DESIRABLE THAN EXTENDING LIFESPAN MERELY BY PROLONGING THE PERIOD OF MORBIDITY TOWARD THE END OF LIFE. THE GEROSCIENCE HYPOTHESIS POSITS THAT HEALTHSPAN CAN BE EXTENDED BY TARGETING FUNDAMENTAL AGING MECHANISMS, RATHER THAN ATTEMPTING TO ADDRESS EACH AGE-RELATED DISEASE ONE AT A TIME, ONLY SO THE AFFLICTED INDIVIDUAL SURVIVES DISABLED AND DIES SHORTLY AFTERWARD OF ANOTHER AGE-RELATED DISEASE. THESE FUNDAMENTAL AGING MECHANISMS INCLUDE, AMONG OTHERS, CHRONIC INFLAMMATION, FIBROSIS, STEM CELL/ PROGENITOR DYSFUNCTION, DNA DAMAGE, EPIGENETIC CHANGES, METABOLIC SHIFTS, DESTRUCTIVE METABOLITE GENERATION, MITOCHONDRIAL DYSFUNCTION, MISFOLDED OR AGGREGATED PROTEIN ACCUMULATION, AND CELLULAR SENESCENCE. THESE PROCESSES APPEAR TO BE TIGHTLY INTERLINKED, AS TARGETING ANY ONE APPEARS TO AFFECT MANY OF THE REST, UNDERLYING OUR UNITARY THEORY OF FUNDAMENTAL AGING MECHANISMS. INTERVENTIONS TARGETING MANY FUNDAMENTAL AGING PROCESSES ARE BEING DEVELOPED, INCLUDING DIETARY MANIPULATIONS, METFORMIN, MTOR (MECHANISTIC TARGET OF RAPAMYCIN) INHIBITORS, AND SENOLYTICS, WHICH ARE IN EARLY HUMAN TRIALS. THESE INTERVENTIONS COULD LEAD TO GREATER HEALTHSPAN BENEFITS THAN TREATING AGE-RELATED DISEASES ONE AT A TIME. TO ILLUSTRATE THESE POINTS, WE FOCUS ON CELLULAR SENESCENCE AND THERAPIES IN DEVELOPMENT TO TARGET SENESCENT CELLS. COMBINING INTERVENTIONS TARGETING AGING MECHANISMS WITH DISEASE-SPECIFIC DRUGS COULD RESULT IN MORE THAN ADDITIVE BENEFITS FOR CURRENTLY DIFFICULT-TO-TREAT OR INTRACTABLE DISEASES. MORE RESEARCH ATTENTION NEEDS TO BE DEVOTED TO TARGETING FUNDAMENTAL AGING PROCESSES. 2021 6 621 24 BIOENERGETIC EVOLUTION EXPLAINS PREVALENCE OF LOW NEPHRON NUMBER AT BIRTH: RISK FACTOR FOR CKD. THERE IS GREATER THAN TENFOLD VARIATION IN NEPHRON NUMBER OF THE HUMAN KIDNEY AT BIRTH. ALTHOUGH LOW NEPHRON NUMBER IS A RECOGNIZED RISK FACTOR FOR CKD, ITS DETERMINANTS ARE POORLY UNDERSTOOD. EVOLUTIONARY MEDICINE REPRESENTS A NEW DISCIPLINE THAT SEEKS EVOLUTIONARY EXPLANATIONS FOR DISEASE, BROADENING PERSPECTIVES ON RESEARCH AND PUBLIC HEALTH INITIATIVES. EVOLUTION OF THE KIDNEY, AN ORGAN RICH IN MITOCHONDRIA, HAS BEEN DRIVEN BY NATURAL SELECTION FOR REPRODUCTIVE FITNESS CONSTRAINED BY ENERGY AVAILABILITY. OVER THE PAST 2 MILLION YEARS, RAPID GROWTH OF AN ENERGY-DEMANDING BRAIN IN HOMO SAPIENS ENABLED HOMINID ADAPTATION TO ENVIRONMENTAL EXTREMES THROUGH SELECTION FOR MUTATIONS IN MITOCHONDRIAL AND NUCLEAR DNA EPIGENETICALLY REGULATED BY ALLOCATION OF ENERGY TO DEVELOPING ORGANS. MATERNAL UNDERNUTRITION OR HYPOXIA RESULTS IN INTRAUTERINE GROWTH RESTRICTION OR PRETERM BIRTH, RESULTING IN LOW BIRTH WEIGHT AND LOW NEPHRON NUMBER. REGULATED THROUGH PLACENTAL TRANSFER, ENVIRONMENTAL OXYGEN AND NUTRIENTS SIGNAL NEPHRON PROGENITOR CELLS TO REPROGRAM METABOLISM FROM GLYCOLYSIS TO OXIDATIVE PHOSPHORYLATION. THESE PROCESSES ARE MODULATED BY COUNTERBALANCING ANABOLIC AND CATABOLIC METABOLIC PATHWAYS THAT EVOLVED FROM PROKARYOTE HOMOLOGS AND BY HYPOXIA-DRIVEN AND AUTOPHAGY PATHWAYS THAT EVOLVED IN EUKARYOTES. REGULATION OF NEPHRON DIFFERENTIATION BY HISTONE MODIFICATIONS AND DNA METHYLTRANSFERASES PROVIDE EPIGENETIC CONTROL OF NEPHRON NUMBER IN RESPONSE TO ENERGY AVAILABLE TO THE FETUS. DEVELOPMENTAL PLASTICITY OF NEPHROGENESIS REPRESENTS AN EVOLVED LIFE HISTORY STRATEGY THAT PRIORITIZES ENERGY TO EARLY BRAIN GROWTH WITH ADEQUATE KIDNEY FUNCTION THROUGH REPRODUCTIVE YEARS, THE TRADE-OFF BEING INCREASING PREVALENCE OF CKD DELAYED UNTIL LATER ADULTHOOD. THE RESEARCH IMPLICATIONS OF THIS EVOLUTIONARY ANALYSIS ARE TO IDENTIFY REGULATORY PATHWAYS OF ENERGY ALLOCATION DIRECTING NEPHROGENESIS WHILE ACCOUNTING FOR THE DIFFERENT LIFE HISTORY STRATEGIES OF ANIMAL MODELS SUCH AS THE MOUSE. THE CLINICAL IMPLICATIONS ARE TO OPTIMIZE NUTRITION AND MINIMIZE HYPOXIC/TOXIC STRESSORS IN CHILDBEARING WOMEN AND CHILDREN IN EARLY POSTNATAL DEVELOPMENT. 2020 7 5145 24 POTENTIAL ROLE OF NUTRACEUTICALS VIA TARGETING A WNT/BETA-CATENIN AND NF-KAPPAB PATHWAY IN TREATMENT OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A DISEASE DUE TO THE AGING OF THE ARTICULAR CARTILAGE, A POST-MITOTIC TISSUE THAT STAYS FUNCTIONING UNTIL PRIMARY HOMEOSTATIC PROCESSES FAIL. BECAUSE OF PAIN AND DISABILITY, OA SIGNIFICANTLY INFLUENCES NATIONAL HEALTHCARE EXPENSES AND PATIENT QUALITY OF LIFE. IT IS A WHOLE-JOINT ILLNESS CHARACTERIZED BY INFLAMMATORY AND OXIDATIVE SIGNALING PATHWAYS AND SIGNIFICANT EPIGENETIC ALTERATIONS THAT CAUSE CARTILAGE EXTRACELLULAR MATRIX DEGRADATION. THE CANONICAL WNT PATHWAY (WNT/BETA-CATENIN PATHWAY) AND NUCLEAR FACTOR KAPPA B (NF-KAPPAB) SIGNALING PATHWAYS MAY FUNCTION IN JOINT TISSUES BY MODULATING THE ACTIVITY OF SYNOVIAL CELLS, OSTEOBLASTS, AND CHONDROCYTES. HOWEVER, FINDING INNOVATIVE WAYS TO TREAT OSTEOARTHRITIS AND GET THE JOINT BACK TO AVERAGE BALANCE IS STILL A STRUGGLE. NUTRACEUTICALS ARE DIETARY SUPPLEMENTS THAT PROMOTE JOINT HEALTH BY BALANCING ANABOLIC AND CATABOLIC SIGNALS. NEW THERAPEUTIC METHODS FOR OA TREATMENT HAVE BEEN DEVELOPED BASED ON MANY RESEARCH FINDINGS THAT SHOW NUTRACEUTICALS HAVE STRONG ANTI-INFLAMMATION, ANTIOXIDANT, ANTI-BONE RESORPTION, AND ANABOLIC PROPERTIES. FOR THE TREATMENT OF OSTEOARTHRITIS, WE EXPLORE THE POSSIBLE INVOLVEMENT OF NUTRACEUTICALS THAT TARGET THE WNT/BETA-CATENIN AND NF-KAPPAB PATHWAYS. PRACTICAL APPLICATIONS: IN KEEPING WITH THE AGING POPULATION, OSTEOARTHRITIS IS BECOMING MORE WIDESPREAD. IN THIS EXTENSIVE RESEARCH, WE STUDIED THE ROLE OF THE WNT/BETA-CATENIN AND NF-KAPPAB PATHWAY IN OA FORMATION AND PROGRESSION. NUTRACEUTICALS THAT TARGET THESE OA-RELATED SIGNALING PATHWAYS ARE A VIABLE THERAPY OPTION. WNT/BETA-CATENIN AND NF-KAPPAB SIGNALING PATHWAY ARE INHIBITED BY POLYPHENOLS, FLAVONOIDS, ALKALOIDS, AND VITAMINS FROM THE NUTRACEUTICAL CATEGORY, MAKING THEM POSSIBLE THERAPEUTIC DRUGS FOR OA THERAPY. 2022 8 4798 28 NUTRITIONALLY MEDIATED PROGRAMMING OF THE DEVELOPING IMMUNE SYSTEM. A GROWING BODY OF EVIDENCE HIGHLIGHTS THE IMPORTANCE OF A MOTHER'S NUTRITION FROM PRECONCEPTION THROUGH LACTATION IN PROGRAMMING THE EMERGING ORGAN SYSTEMS AND HOMEOSTATIC PATHWAYS OF HER OFFSPRING. THE DEVELOPING IMMUNE SYSTEM MAY BE PARTICULARLY VULNERABLE. INDEED, EXAMPLES OF NUTRITION-MEDIATED IMMUNE PROGRAMMING CAN BE FOUND IN THE LITERATURE ON INTRA-UTERINE GROWTH RETARDATION, MATERNAL MICRONUTRIENT DEFICIENCIES, AND INFANT FEEDING. CURRENT MODELS OF IMMUNE ONTOGENY DEPICT A "LAYERED" EXPANSION OF INCREASINGLY COMPLEX DEFENSES, WHICH MAY BE PERMANENTLY ALTERED BY MATERNAL MALNUTRITION. ONE PROGRAMMING MECHANISM INVOLVES ACTIVATION OF THE MATERNAL HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN RESPONSE TO NUTRITIONAL STRESS. FETAL OR NEONATAL EXPOSURE TO ELEVATED STRESS HORMONES IS LINKED IN ANIMAL STUDIES TO PERMANENT CHANGES IN NEUROENDOCRINE-IMMUNE INTERACTIONS, WITH DIVERSE MANIFESTATIONS SUCH AS AN ATTENUATED INFLAMMATORY RESPONSE OR REDUCED RESISTANCE TO TUMOR COLONIZATION. MATERNAL MALNUTRITION MAY ALSO HAVE A DIRECT INFLUENCE, AS EVIDENCED BY NUTRIENT-DRIVEN EPIGENETIC CHANGES TO DEVELOPING T REGULATORY CELLS AND SUBSEQUENT RISK OF ALLERGY OR ASTHMA. A 3RD PROGRAMMING PATHWAY INVOLVES PLACENTAL OR BREAST MILK TRANSFER OF MATERNAL IMMUNE FACTORS WITH IMMUNOMODULATORY FUNCTIONS (E.G. CYTOKINES). MATERNAL MALNUTRITION CAN DIRECTLY AFFECT TRANSFER MECHANISMS OR INFLUENCE THE QUALITY OR QUANTITY OF TRANSFERRED FACTORS. THE PUBLIC HEALTH IMPLICATIONS OF NUTRITION-MEDIATED IMMUNE PROGRAMMING ARE OF PARTICULAR IMPORTANCE IN THE DEVELOPING WORLD, WHERE PREVALENT MATERNAL UNDERNUTRITION IS COUPLED WITH PERSISTENT INFECTIOUS CHALLENGES. HOWEVER, EARLY ALTERATIONS TO THE IMMUNE SYSTEM, RESULTING FROM EITHER NUTRITIONAL DEFICIENCIES OR EXCESSES, HAVE BROAD RELEVANCE FOR IMMUNE-MEDIATED DISEASES, SUCH AS ASTHMA, AND CHRONIC INFLAMMATORY CONDITIONS LIKE CARDIOVASCULAR DISEASE. 2011 9 1308 24 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 10 4568 22 MYELOID-DERIVED SUPPRESSOR CELLS (MDSC): WHEN GOOD INTENTIONS GO AWRY. MDSC ARE A HETEROGENEOUS POPULATION OF IMMATURE MYELOID CELLS THAT ARE RELEASED BY BIOLOGICAL STRESS SUCH AS TISSUE DAMAGE AND INFLAMMATION. CONVENTIONALLY, MDSC ARE KNOWN FOR THEIR DETRIMENTAL ROLE IN CHRONIC INFLAMMATION AND NEOPLASTIC CONDITIONS. HOWEVER, THEIR INTRINSIC FUNCTIONS IN IMMUNOREGULATION, WOUND HEALING, AND ANGIOGENESIS ARE INTENDED TO PROTECT FROM OVER-REACTIVE IMMUNE RESPONSES, MAINTENANCE OF IMMUNOTOLERANCE, TISSUE REPAIR, AND HOMEOSTASIS. PARADOXICALLY, UNDER CERTAIN CONDITIONS, MDSC CAN IMPAIR PROTECTIVE IMMUNE RESPONSES AND EXACERBATE THE DISEASE. THE TRANSITION FROM PROTECTIVE TO HARMFUL MDSC IS MOST LIKELY DRIVEN BY ENVIRONMENTAL AND EPIGENETIC MECHANISMS INDUCED BY PROLONGED EXPOSURE TO UNRESOLVED INFLAMMATORY TRIGGERS. HERE, WE REVIEW SEVERAL EXAMPLES OF THE DUAL IMPACT OF MDSC IN CONDITIONS SUCH AS MATERNAL-FETAL TOLERANCE, SELF-ANTIGENS IMMUNOTOLERANCE, OBESITY-ASSOCIATED CANCER, SEPSIS AND TRAUMA. MOREOVER, WE ALSO HIGHLIGHTED THE EVIDENCE INDICATING THAT MDSC HAVE A ROLE IN COVID-19 PATHOPHYSIOLOGY. FINALLY, WE HAVE SUMMARIZED THE EVIDENCE INDICATING EPIGENETIC MECHANISMS ASSOCIATED WITH MDSC FUNCTION. 2021 11 4044 22 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 12 6883 30 [RESOLUTION OF INFLAMMATION--PHARMACOLOGICAL ASPECTS]. INFLAMMATION IS A FUNDAMENTAL BIOLOGIC PROCESS EVOLUTIONALLY PRESERVED BY A GERM LINE CODE. THE INTERPLAY OF THE EPIGENETIC WITH THE ENVIRONMENT DIRECTS THE CODE TO TEMPORALLY DISTINCT INFLAMMATORY RESPONSES, WHICH CAN BE ACUTE OR CHRONIC. THE AIM OF THIS STUDY IS TO PRESENT NEW ASPECTS REGARDING THE RESOLUTION OF INFLAMMATION. ACUTE INFLAMMATION NORMALLY RESOLVES BY MECHANISMS STILL SOMEWHAT ELUSIVE. CURRENT EVIDENCE SUGGESTS THAT AN ACTIVE COORDINATED PROGRAM INITIATED THE FIRST FEW HOURS AFTER THE INFLAMMATORY RESPONSE BEGINS AND ITS FAILURE LEAD TO CHRONIC INFLAMMATION. THIS PROCESS IS ESSENTIAL FOR APPROPRIATE HOST RESPONSES, TISSUE PROTECTION AND THE RETURN TO HOMEOSTASIS. PROSTAGLANDINS AND LEUKOTRIENES ARE LIPID MEDIATORS THAT PLAY IMPORTANT ROLES IN HOST DEFENSE AND ACUTE INFLAMMATION. GRANULOCYTES PROMOTE THE SWITCH OF ARACHIDONIC ACID-DERIVED PROSTAGLANDINS AND LEUKOTRIENES TO LIPOXINS, ACTIVE ANTIINFLAMMATORY AND PRO-RESOLUTION MEDIATORS. THE APOPTOSIS OF THE NEUTROPHILS COINCIDES WITH THE BIOSYNTHESIS OF RESOLVINS AND PROTECTINS FROM OMEGA-3 POLYUNSATURATED FATTY ACIDS AND RELEASES ANTI-INFLAMMATORY AND REPARATIVE CYTOKINES. THIS INFORMATION COULD LEAD TO NEW TREATMENTS FOR INFLAMMATORY DISEASES. 2011 13 6394 29 THE ROLE OF THE HOST-NEUTROPHIL BIOLOGY. NEUTROPHILIC POLYMORPHONUCLEAR LEUKOCYTES (NEUTROPHILS) ARE MYELOID CELLS PACKED WITH LYSOSOMAL GRANULES (HENCE ALSO CALLED GRANULOCYTES) THAT CONTAIN A FORMIDABLE ANTIMICROBIAL ARSENAL. THEY ARE TERMINALLY DIFFERENTIATED CELLS THAT PLAY A CRITICAL ROLE IN ACUTE AND CHRONIC INFLAMMATION, AS WELL AS IN THE RESOLUTION OF INFLAMMATION AND WOUND HEALING. NEUTROPHILS EXPRESS A DENSE ARRAY OF SURFACE RECEPTORS FOR MULTIPLE LIGANDS, RANGING FROM INTEGRINS TO SUPPORT THEIR EGRESS FROM BONE MARROW INTO THE CIRCULATION AND FROM THE CIRCULATION INTO TISSUES, TO CYTOKINE/CHEMOKINE RECEPTORS THAT DRIVE THEIR NAVIGATION TO THE SITE OF INFECTION OR TISSUE DAMAGE AND ALSO PRIME THEM FOR A SECOND STIMULUS, TO PATTERN RECOGNITION RECEPTORS AND IMMUNOGLOBULIN RECEPTORS TO FACILITATE THE DESTRUCTION AND REMOVAL OF INFECTIVE AGENTS OR DEBRIDEMENT OF DAMAGED TISSUES. WHEN AFFERENT NEUTROPHIL SIGNALS ARE PROPORTIONATE AND COORDINATED THEY WILL PHAGOCYTOSE OPSONIZED AND UNOPSONIZED BACTERIA, ACTIVATING THE NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE (RESPIRATORY BURST) TO GENERATE REACTIVE OXYGEN SPECIES, WHICH AUGMENT THE PROTEOLYTIC DESTRUCTION OF MICROBES SECURED WITHIN THE PHAGOSOME. A HIGHLY ORCHESTRATED PROCESS OF APOPTOSIS FOLLOWS, FORMING MEMBRANE-BOUND SUBSTRUCTURES THAT ARE REMOVED BY MACROPHAGES. NEUTROPHILS ARE CAPABLE OF VARIOUS OTHER FORMS OF PROGRAMMED CELL DEATH, SUCH AS NETOSIS AND PYROPTOTIC CELL DEATH, AS WELL AS NONPROGRAMMED CELL DEATH BY NECROSIS. IN RECENT YEARS, RESEARCH HAS REVEALED THAT NEUTROPHILS ARE CAPABLE OF FAR MORE SUBTLE CELL-CELL INTERACTIONS THAN PREVIOUSLY THOUGHT POSSIBLE. THIS INCLUDES SYNTHESIS OF VARIOUS INFLAMMATORY MEDIATORS AND ALSO MYELOID CELL TRAINING WITHIN BONE MARROW, WHERE EPIGENETIC AND METABOLIC SIGNALS ASSOCIATED WITH RETURNING NEUTROPHILS THAT UNDERGO REVERSE EGRESS FROM TISSUES INTO THE VASCULATURE AND BACK TO BONE MARROW PROGRAM A HYPERREACTIVE SUBSET OF NEUTROPHILS DURING MYELOPOIESIS THAT ARE CAPABLE OF HYPERSENSITIVE REACTIONS TO MICROBIAL AGGRESSORS. THESE CHARACTERISTICS ARE EVIDENT IN VARIOUS NEUTROPHIL SUBSETS/SUBPOPULATIONS, CREATING BROAD HETEROGENEITY IN THE BEHAVIOR AND BIOLOGICAL REPERTOIRE OF THESE SEEMINGLY SCHIZOPHRENIC IMMUNE CELLS. MOREOVER, NEUTROPHILS ARE CRITICAL EFFECTOR CELLS OF ADAPTIVE AND INNATE IMMUNITY, BINDING TO OPSONIZED BACTERIA AND DESTROYING THEM BY EXTRACELLULAR AND INTRACELLULAR METHODS. THE FORMER CREATES SUBSTANTIAL COLLATERAL HOST TISSUE DAMAGE, AS THEY ARE LESS SPECIFIC THAN T-CYTOTOXIC CELL-KILLING MECHANISMS, AND IN CONDITIONS SUCH AS PERI-IMPLANTITIS, WHERE PLASMA CELLS AND NEUTROPHILS DOMINATE THE IMMUNE INFILTRATE, BONE AND TISSUE DESTRUCTION ARE RAPID AND APPEAR RELENTLESS. FINALLY, THE ROLE OF NEUTROPHILS AS CONDUITS FOR PERIODONTAL-SYSTEMIC DISEASE CONNECTIONS AND FOR OXIDATIVE DAMAGE TO ACT AS A CAUSAL LINK BETWEEN THE TWO HAS ONLY RECENTLY BEEN REALIZED. IN THIS CHAPTER, WE ATTEMPT TO EXPAND ON THESE ISSUES, EMPHASIZING THE CONTRIBUTIONS OF EUROPEAN SCIENTISTS THROUGHOUT A DETAILED APPRAISAL OF THE BENEFITS AND SIDE EFFECTS OF NEUTROPHILIC INFLAMMATION AND IMMUNE FUNCTION. 2023 14 1398 33 DIET, GUT MICROBIOME AND EPIGENETICS: EMERGING LINKS WITH INFLAMMATORY BOWEL DISEASES AND PROSPECTS FOR MANAGEMENT AND PREVENTION. INFLAMMATORY BOWEL DISEASES (IBD) REPRESENT A GROWING PUBLIC HEALTH CONCERN DUE TO INCREASING INCIDENCE WORLDWIDE. THE CURRENT NOTION ON THE PATHOGENESIS OF IBD IS THAT GENETICALLY SUSCEPTIBLE INDIVIDUALS DEVELOP INTOLERANCE TO DYSREGULATED GUT MICROFLORA (DYSBIOSIS) AND CHRONIC INFLAMMATION DEVELOPS AS A RESULT OF ENVIRONMENTAL TRIGGERS. AMONG THE ENVIRONMENTAL FACTORS ASSOCIATED WITH IBD, DIET PLAYS AN IMPORTANT ROLE IN MODULATING THE GUT MICROBIOME, INFLUENCING EPIGENETIC CHANGES, AND, THEREFORE, COULD BE APPLIED AS A THERAPEUTIC TOOL TO IMPROVE THE DISEASE COURSE. NEVERTHELESS, THE CURRENT DIETARY RECOMMENDATIONS FOR DISEASE PREVENTION AND MANAGEMENT ARE SCARCE AND HAVE WEAK EVIDENCE. THIS REVIEW SUMMARISES THE CURRENT KNOWLEDGE ON THE COMPLEX INTERACTIONS BETWEEN DIET, MICROBIOME AND EPIGENETICS IN IBD. WHEREAS AN OVERABUNDANCE OF CALORIES AND SOME MACRONUTRIENTS INCREASE GUT INFLAMMATION, SEVERAL MICRONUTRIENTS HAVE THE POTENTIAL TO MODULATE IT. IMMUNONUTRITION HAS EMERGED AS A NEW CONCEPT PUTTING FORWARD THE IMPORTANCE OF VITAMINS SUCH AS VITAMINS A, C, E, AND D, FOLIC ACID, BETA CAROTENE AND TRACE ELEMENTS SUCH AS ZINC, SELENIUM, MANGANESE AND IRON. HOWEVER, WHEN ASSESSED IN CLINICAL TRIALS, SPECIFIC MICRONUTRIENTS EXERTED A LIMITED BENEFIT. BEYOND NUTRIENTS, AN ANTI-INFLAMMATORY DIETARY PATTERN AS A COMPLEX INTERVENTION APPROACH HAS BECOME POPULAR IN RECENT YEARS. HENCE, EXCLUSIVE ENTERAL NUTRITION IN PAEDIATRIC CROHN'S DISEASE IS THE ONLY NUTRITIONAL INTERVENTION CURRENTLY RECOMMENDED AS A FIRST-LINE THERAPY. OTHER NUTRITIONAL INTERVENTIONS OR SPECIFIC DIETS INCLUDING THE SPECIFIC CARBOHYDRATE DIET (SCD), THE LOW FERMENTABLE OLIGOSACCHARIDES, DISACCHARIDES, MONOSACCHARIDES, AND POLYOL (FODMAP) DIET AND, MOST RECENTLY, THE MEDITERRANEAN DIET HAVE SHOWN STRONG ANTI-INFLAMMATORY PROPERTIES AND SHOW PROMISE FOR IMPROVING DISEASE SYMPTOMS. MORE WORK IS REQUIRED TO EVALUATE THE ROLE OF INDIVIDUAL FOOD COMPOUNDS AND COMPLEX NUTRITIONAL INTERVENTIONS WITH THE POTENTIAL TO DECREASE INFLAMMATION AS A MEANS OF PREVENTION AND MANAGEMENT OF IBD. 2017 15 5214 20 PRETERM BEHAVIORAL EPIGENETICS: A SYSTEMATIC REVIEW. BEHAVIORAL EPIGENETICS IS REVEALING NEW PATHWAYS THAT LEAD INDIVIDUALS FROM EARLY ADVERSITY EXPOSURES TO LATER-IN-LIFE DETRIMENTAL OUTCOMES. PRETERM BIRTH CONSTITUTES ONE OF THE MAJOR ADVERSE EVENTS IN HUMAN DEVELOPMENT. PRETERM INFANTS ARE HOSPITALIZED IN THE NEONATAL INTENSIVE CARE UNIT (NICU) WHERE THEY ARE EXPOSED TO LIFE-SAVING YET PAIN-INDUCING PROCEDURES AND TO PROTECTIVE CARE. THE APPLICATION OF BEHAVIORAL EPIGENETICS TO THE FIELD OF PRETERM STUDIES (I.E., PRETERM BEHAVIORAL EPIGENETICS, PBE) IS RAPIDLY GROWING AND HOLDS PROMISES TO PROVIDE VALID INSIGHTS FOR RESEARCH AND CLINICAL ACTIVITY. HERE, THE EVIDENCE OF THE EPIGENETIC CORRELATES OF PRENATAL ADVERSITIES, NICU-RELATED ENVIRONMENT AND DEVELOPMENT OF PRETERM INFANTS IS SYSTEMATICALLY REVIEWED. THE FINDINGS SUGGEST THAT A NUMBER OF PRENATAL ADVERSE (E.G., MATERNAL DEPRESSION AND STRESS) AND POST-NATAL (E.G., NICU-RELATED PAIN-RELATED STRESS) EVENTS AFFECT THE DEVELOPMENTAL TRAJECTORIES OF PRETERM INFANTS AND CHILDREN VIA EPIGENETIC ALTERATIONS OF IMPRINTED AND STRESS-RELATED GENES. NONETHELESS, THE POTENTIAL EPIGENETIC VESTIGES OF EARLY CARE AND PROTECTIVE INTERVENTIONS IN NICU HAVE NOT BEEN INVESTIGATED YET AND THIS REPRESENTS A FASCINATING CHALLENGE FOR FUTURE PBE RESEARCH. 2018 16 2617 31 EPIGENOME TARGETING BY PROBIOTIC METABOLITES. BACKGROUND: THE INTESTINAL MICROBIOTA PLAYS AN IMPORTANT ROLE IN IMMUNE DEVELOPMENT AND HOMEOSTASIS. A DISTURBED MICROBIOTA DURING EARLY INFANCY IS ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING INFLAMMATORY AND ALLERGIC DISEASES LATER IN LIFE. THE MECHANISMS UNDERLYING THESE EFFECTS ARE POORLY UNDERSTOOD BUT ARE LIKELY TO INVOLVE ALTERATIONS IN MICROBIAL PRODUCTION OF FERMENTATION-DERIVED METABOLITES, WHICH HAVE POTENT IMMUNE MODULATING PROPERTIES AND ARE REQUIRED FOR MAINTENANCE OF HEALTHY MUCOSAL IMMUNE RESPONSES. PROBIOTICS ARE BENEFICIAL BACTERIA THAT HAVE THE CAPACITY TO ALTER THE COMPOSITION OF BACTERIAL SPECIES IN THE INTESTINE THAT CAN IN TURN INFLUENCE THE PRODUCTION OF FERMENTATION-DERIVED METABOLITES. PRINCIPAL AMONG THESE METABOLITES ARE THE SHORT-CHAIN FATTY ACIDS BUTYRATE AND ACETATE THAT HAVE POTENT ANTI-INFLAMMATORY ACTIVITIES IMPORTANT IN REGULATING IMMUNE FUNCTION AT THE INTESTINAL MUCOSAL SURFACE. THEREFORE STRATEGIES AIMED AT RESTORING THE MICROBIOTA PROFILE MAY BE EFFECTIVE IN THE PREVENTION OR TREATMENT OF ALLERGIC AND INFLAMMATORY DISEASES. PRESENTATION OF THE HYPOTHESIS: PROBIOTIC BACTERIA HAVE DIVERSE EFFECTS INCLUDING ALTERING MICROBIOTA COMPOSITION, REGULATING EPITHELIAL CELL BARRIER FUNCTION AND MODULATING OF IMMUNE RESPONSES. THE PRECISE MOLECULAR MECHANISMS MEDIATING THESE PROBIOTIC EFFECTS ARE NOT WELL UNDERSTOOD. SHORT-CHAIN FATTY ACIDS SUCH AS BUTYRATE ARE A CLASS OF HISTONE DEACETYLASE INHIBITORS IMPORTANT IN THE EPIGENETIC CONTROL OF HOST CELL RESPONSES. IT IS HYPOTHESIZED THAT THE BIOLOGICAL FUNCTION OF PROBIOTICS MAY BE A RESULT OF EPIGENETIC MODIFICATIONS THAT MAY EXPLAIN THE WIDE RANGE OF EFFECTS OBSERVED. STUDIES DELINEATING THE EFFECTS OF PROBIOTICS ON SHORT-CHAIN FATTY ACID PRODUCTION AND THE EPIGENETIC ACTIONS OF SHORT-CHAIN FATTY ACIDS WILL ASSIST IN UNDERSTANDING THE ASSOCIATION BETWEEN MICROBIOTA AND ALLERGIC OR AUTOIMMUNE DISORDERS. TESTING THE HYPOTHESIS: WE PROPOSE THAT TREATMENT WITH SPECIFIC PROBIOTIC BACTERIA UNDER IN VIVO CONDITIONS WOULD OFFER THE IDEAL CONDITIONS TO EXAMINE THE MICROBIOLOGICAL, IMMUNOLOGICAL AND EPIGENETIC MECHANISMS OF ACTION. ADVANCES IN EPIGENETIC TECHNOLOGY NOW ALLOW INVESTIGATORS TO BETTER UNDERSTAND THE COMPLEX BIOLOGICAL PROPERTIES OF PROBIOTICS AND THEIR METABOLITES. IMPLICATIONS OF THE HYPOTHESIS: DETERMINING THE PRECISE MECHANISMS OF PROBIOTIC ACTION WILL LEAD TO MORE SPECIFIC AND EFFICACIOUS THERAPEUTIC STRATEGIES IN THE PREVENTION OR TREATMENT OF CHRONIC INFLAMMATORY CONDITIONS. 2010 17 3701 25 INFLAMMATORY RESPONSE TO REGULATED CELL DEATH IN GOUT AND ITS FUNCTIONAL IMPLICATIONS. GOUT, A CHRONIC INFLAMMATORY ARTHRITIS DISEASE, IS CHARACTERIZED BY HYPERURICEMIA AND CAUSED BY INTERACTIONS BETWEEN GENETIC, EPIGENETIC, AND METABOLIC FACTORS. ACUTE GOUT SYMPTOMS ARE TRIGGERED BY THE INFLAMMATORY RESPONSE TO MONOSODIUM URATE CRYSTALS, WHICH IS MEDIATED BY THE INNATE IMMUNE SYSTEM AND IMMUNE CELLS (E.G., MACROPHAGES AND NEUTROPHILS), THE NACHT, LRR, AND PYD DOMAINS-CONTAINING PROTEIN 3 (NLRP3) INFLAMMASOME ACTIVATION, AND PRO-INFLAMMATORY CYTOKINE (E.G., IL-1BETA) RELEASE. RECENT STUDIES HAVE INDICATED THAT THE MULTIPLE PROGRAMMED CELL DEATH PATHWAYS INVOLVED IN THE INFLAMMATORY RESPONSE INCLUDE PYROPTOSIS, NETOSIS, NECROPTOSIS, AND APOPTOSIS, WHICH INITIATE INFLAMMATORY REACTIONS. IN THIS REVIEW, WE EXPLORE THE CORRELATION AND INTERACTIONS AMONG THESE FACTORS AND THEIR ROLES IN THE PATHOGENESIS OF GOUT TO PROVIDE FUTURE RESEARCH DIRECTIONS AND POSSIBILITIES FOR IDENTIFYING POTENTIAL NOVEL THERAPEUTIC TARGETS AND ENHANCING OUR UNDERSTANDING OF GOUT PATHOGENESIS. 2022 18 620 35 BIOCHEMISTRY AND MOLECULAR BIOLOGY OF GELATINASE B OR MATRIX METALLOPROTEINASE-9 (MMP-9): THE NEXT DECADE. RESEARCH ON MATRIX METALLOPROTEINASES (MMPS) AND IN PARTICULAR ON GELATINASE B, ALIAS MMP-9, HAS GROWN EXPONENTIALLY IN THE DECADE 2003-2012. STRUCTURAL DETAILS ABOUT FLEXIBILITY OF MMP-9 MONOMERS, TOGETHER WITH GLYCOSYLATION, OLIGOMERIZATION, HETEROGENEITY AND INSTABILITY OF THE WILDTYPE ENZYME EXPLAIN WHY CRYSTALLOGRAPHY EXPERIMENTS HAVE NOT YET BEEN SUCCESSFUL FOR THE INTACT ENZYME. MMP-9 MAY BE VIEWED AS A MULTIDOMAIN ENZYME IN WHICH THE HEMOPEXIN, THE O-GLYCOSYLATED AND THE CATALYTIC DOMAINS YIELD SUPPORT FOR ATTACHMENT, ARTICULATION AND CATALYSIS, RESPECTIVELY. THE STEPWISE PROTEOLYTIC ACTIVATION OF THE INACTIVE ZYMOGEN INTO A CATALYTICALLY ACTIVE FORM BECOMES GRADUALLY BETTER UNDERSTOOD. PRIMING OF ACTIVATION BY MMP-3 MAY BE EXECUTED BY MEPRINS THAT DESTABILIZE THE INTERACTION OF THE AMINOTERMINUS WITH THE THIRD FIBRONECTIN REPEAT. ALTERNATIVELY, AUTOCATALYTIC ACTIVATION MAY OCCUR IN THE PRESENCE OF MOLECULES THAT TIGHTLY BIND TO THE CATALYTIC SITE AND THAT PUSH THE CYSTEIN RESIDUE IN THE PRODOMAIN AWAY FROM THE CATALYTIC ZINC ION. THANKS TO THE DEVELOPMENT OF DEGRADOMICS TECHNOLOGIES, SUBSTRATE REPERTOIRES OF MMP-9 HAVE BEEN DEFINED, BUT IT REMAINS A CHALLENGE TO DETERMINE AND PROVE WHICH SUBSTRATES ARE BIOLOGICALLY RELEVANT. THE SUBSTRATE REPERTOIRE HAS BEEN ENLARGED FROM EXTRACELLULAR TO MEMBRANE-BOUND AND EFFICIENT INTRACELLULAR SUBSTRATES, SUCH AS CRYSTALLINS, TUBULINS AND ACTINS. BIOLOGICAL STUDIES OF MMP-9 HAVE TUNED THE FIELD FROM BEING PRIMARILY CANCER-ORIENTED TOWARDS VASCULAR AND INFLAMMATORY RESEARCH. IN TUMOR BIOLOGY, IT HAS BEEN INCREASINGLY APPRECIATED THAT MMP-9 FROM INFLAMMATORY CELLS, PARTICULARLY NEUTROPHILS, CO-DETERMINES PROGNOSIS AND OUTCOME. ASIDE FROM THE CATALYTIC FUNCTIONS EXECUTED BY AMINOTERMINAL DOMAINS OF MMP-9, THE CARBOXYTERMINAL HEMOPEXIN (PEX) DOMAIN OF GELATINASE B EXERTS NON-CATALYTIC ANTI-APOPTOTIC SIGNALING EFFECTS. THE RECOGNITION THAT GELATINASE B IS INDUCED BY MANY PRO-INFLAMMATORY CYTOKINES, WHEREAS ITS INHIBITORS ARE INCREASED BY ANTI-INFLAMMATORY CYTOKINES, HAS GENERATED INTEREST TO TARGET MMP-9 IN ACUTE LETHAL CONDITIONS, SUCH AS BACTERIAL MENINGITIS, SEPSIS AND ENDOTOXIN SHOCK, AND IN ACUTE EXACERBATIONS OF CHRONIC DISEASES. PREVIOUSLY DESCRIBED TRANSCRIPTIONAL REGULATION OF MMP-9 IS COMPLEMENTED BY EPIGENETIC CHECKPOINTS, INCLUDING HISTONE MODIFICATIONS AND MICRORNAS. BECAUSE ACTIVATION OF PROMMP-9 MAY BE EXECUTED BY OTHER MMPS, THE THERAPEUTIC DOGMA THAT MMP INHIBITORS NEED TO BE HIGHLY SELECTIVE MAY BE KEYED DOWN FOR THE TREATMENT OF LIFE-THREATENING CONDITIONS. WHEN INFLAMMATION AND MMP-9 FULFILL BENEFICIAL FUNCTIONS TO CLEAR DAMAGING PROTEIN COMPLEXES, SUCH AS IN SYSTEMIC AUTOIMMUNE DISEASES, THERAPEUTIC MMP INHIBITION HAS TO BE AVOIDED. IN MMP9 GENE KNOCKOUT MICE, SPECIFIC SPONTANEOUS PHENOTYPES EMERGED WITH EFFECTS ON THE SKELETAL, REPRODUCTIVE AND NERVOUS SYSTEMS. THESE FINDINGS NOT ONLY HAVE CLINICAL CORRELATES IN BONE GROWTH AND FERTILITY, BUT ALSO STIMULATE RESEARCH ON THE ROLES OF MMPS AND MMP-9 IN ENDOCRINOLOGY, IMMUNOLOGY AND THE NEUROSCIENCES. MMP9-DEFICIENT MICE ARE VALUABLE TOOLS TO DEFINE MMP-9 SUBSTRATES IN VIVO AND TO STUDY THE ROLE OF THIS ENZYME IN ANIMAL MODELS OF INFLAMMATORY, VASCULAR, NEOPLASTIC AND DEGENERATIVE DISEASES. FUTURE CHALLENGES INCLUDE SOLVING THE CRYSTAL STRUCTURE, DEFINITION OF THE FUNCTIONS OF COVALENT OLIGOMERS AND HETEROMERS IN BIOLOGY AND PATHOLOGY, LIFE-IMAGING OF MMP-9 ACTIVITY, SUBSTRATE DETERMINATION IN SITU AND THE STUDY OF INHIBITOR EFFECTS ON FERTILITY, CANCER AND INFLAMMATION AND IN NEUROBIOLOGY AND REGENERATIVE MEDICINE. SUCH STUDIES WILL BETTER DEFINE CONDITIONS IN WHICH INHIBITION OF MMP-9 IS BENEFICIAL OR HAS TO BE AVOIDED. 2013 19 5469 24 RESOLUTION OF INFLAMMATION AS A NOVEL CHEMOPREVENTIVE STRATEGY. ACUTE INFLAMMATION, A PHYSIOLOGIC RESPONSE TO PROTECT CELLS FROM MICROBIAL INFECTION AND OTHER NOXIOUS STIMULI, IS AUTOMATICALLY TERMINATED BY ENDOGENOUS ANTI-INFLAMMATORY AND PRO-RESOLVING MEDIATORS TO RESTORE HOMEOSTATIC CONDITIONS. HOWEVER, IF TIMELY RESOLUTION OF INFLAMMATION IS FAILED, INFLAMMATION PERSISTS AND CAN PROGRESS TO A CHRONIC INFLAMMATION WHICH HAS LONG BEEN THOUGHT AS A PREDISPOSING FACTOR TO CARCINOGENESIS. EXCESSIVE AND PATHOLOGIC INFLAMMATION CAUSES DNA DAMAGE, GENOMIC INSTABILITY, EPIGENETIC DYSREGULATION, AND ALTERATION OF INTRACELLULAR SIGNALING, ALL OF WHICH ARE INVOLVED IN NEOPLASTIC TRANSFORMATION. TO PREVENT CHRONIC INFLAMMATION AND RESULTING INFLAMMATION-PROMOTED CANCER DEVELOPMENT, UNDERSTANDING THE PROCESS THAT RESOLVES INFLAMMATION IS ESSENTIAL. RESOLUTION OF INFLAMMATION IS AN ACTIVE COORDINATED PROCESS REGULATED BY DISTINCT ANTI-INFLAMMATORY AND PRO-RESOLVING ENDOGENOUS LIPID MEDIATORS, SUCH AS RESOLVINS AND LIPOXINS. THE ROLE OF PRO-INFLAMMATORY SIGNALING IN CARCINOGENESIS HAS BECOME MORE AND MORE EVIDENT AND WELL CHARACTERIZED, BUT THE POTENTIAL ROLE OF PRO-RESOLVING MEDIATORS IN CANCER PREVENTION REMAINS STILL ELUSIVE. IN SEARCHING FOR AN EFFICACIOUS WAY TO PREVENT CHRONIC INFLAMMATION-ASSOCIATED CANCER, THE PRO-RESOLVING SIGNAL TRANSDUCTION PATHWAYS AND THEIR REGULATORS SHOULD BE UNRAVELED. 2013 20 601 20 BETA-GLUCAN "TRAINED IMMUNITY" IMMUNOMODULATORY PROPERTIES POTENTIATE TISSUE WOUND MANAGEMENT AND ACCELERATE FITNESS RECOVER. INTRODUCTION: IT IS WELL ESTABLISHED THAT MODERATE PHYSICAL ACTIVITY CAN IMPROVE THE IMMUNE STATUS, RATHER EXCESS OR HIGH-INTENSITY PHYSICAL EXERCISE CAN CAUSE DAMAGE TO THE IMMUNE SYSTEM. IN ADDITION, MUSCLE INJURIES RESULTING FROM INCREASED FREQUENCY AND INTENSITY OF EXERCISES COMPROMISE INNATE IMMUNE ACTIVITY AND MAY DECREASE TISSUE REGENERATION. THUS, BETA-GLUCANS, A NATURAL COMPOUND, MAY REPRESENT AN IMPORTANT SUBSTANCE WITH STRONG IMMUNOMODULATORY PROPERTIES ACTING AS AN IMMUNOSTIMULANT THERAPY KNOWN AS "TRAINED IMMUNITY". THIS IMMUNE STIMULATING THERAPEUTIC IS AN IMMUNOLOGICAL MEMORY PHENOMENON LINKED TO THE INNATE IMMUNE SYSTEM, TRIGGERING CELLULAR CHANGES AT EPIGENETIC, TRANSCRIPTIONAL, AND FUNCTIONAL LEVELS, TO REGULATE THE IMMUNE SYSTEM AND RECOVER ITS HOMEOSTASIS WITH CLINICAL BENEFITS. CONCLUSION: THIS NARRATIVE REVIEW WORKS WITH THE CURRENT EVIDENCE REGARDING BETA-GLUCANS AS A POSSIBLE ALTERNATIVE THERAPY FOR WOUND HEALING AND ITS SAFETY AND EFFICACY IN THE TREATMENT OF MUSCLE INJURIES AND PHYSICAL RECOVERY INCLUDING OTHER CHRONIC CONDITIONS AND DISEASES. 2022