1 5416 89 REGULATION OF CELLULAR METABOLISM: PROGRAMMING AND MAINTAINING METABOLIC HOMEOSTASIS. MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION IS PROGRAMMED TO SET AND MAINTAIN METABOLIC HOMEOSTASIS. THIS IS ACCOMPLISHED THROUGH AN INTRINSIC PROGRAM THAT DETERMINES THE METABOLIC [ATP]/[ADP]/[PI], WHERE [PI] IS THE CONCENTRATION OF INORGANIC PHOSPHATE (ENERGY STATE) AND MAINTAINS IT THROUGH A BIDIRECTIONAL SENSORY/SIGNALING CONTROL NETWORK THAT REACHES EVERY ASPECT OF CELLULAR METABOLISM. THE PROGRAM SETS THE ENERGY STATE WITH HIGH PRECISION (TO BETTER THAN ONE PART IN 10(9)) AND CAN RESPOND TO TRANSIENT CHANGES IN ENERGY DEMAND (ATP USE) TO MORE THAN 100 TIMES THE RESTING RATE. EPIGENETIC AND ENVIRONMENTAL FACTORS ARE ABLE TO "FINE TUNE" THE PROGRAMMED SET POINT OVER A NARROW RANGE TO MEET THE SPECIAL NEEDS ASSOCIATED WITH CELL DIFFERENTIATION AND CHRONIC CHANGES IN METABOLIC REQUIREMENTS. THE RESULT IS ROBUST, ACROSS PLATFORM CONTROL OF METABOLISM, ESSENTIAL TO CELLULAR DIFFERENTIATION AND THE EVOLUTION OF COMPLEX ORGANISMS. 2013 2 1341 18 DETANGLING THE INTERRELATIONS BETWEEN MAFLD, INSULIN RESISTANCE, AND KEY HORMONES. METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASE (MAFLD) HAS INCREASINGLY BECOME A SIGNIFICANT AND HIGHLY PREVALENT CAUSE OF CHRONIC LIVER DISEASE, DISPLAYING A WIDE ARRAY OF RISK FACTORS AND PATHOPHYSIOLOGIC MECHANISMS OF WHICH ONLY A FEW HAVE SO FAR BEEN CLEARLY ELUCIDATED. A BIDIRECTIONAL INTERACTION BETWEEN HORMONAL DISCREPANCIES AND METABOLIC-RELATED DISORDERS, INCLUDING OBESITY, TYPE 2 DIABETES MELLITUS (T2DM), AND POLYCYSTIC OVARIAN SYNDROME (PCOS) HAS BEEN DESCRIBED. SINCE THE CHANGE IN NOMENCLATURE FROM NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) TO MAFLD IS BASED ON THE CLEAR IMPACT OF METABOLIC ELEMENTS ON THE DISEASE, THE RECIPROCAL INTERACTIONS OF HORMONES SUCH AS INSULIN, ADIPOKINES (LEPTIN AND ADIPONECTIN), AND ESTROGENS HAVE STRONGLY POINTED TO THE INTRINSIC LINKS THAT LEAD TO THE HETEROGENEOUS EPIDEMIOLOGY, CLINICAL PRESENTATIONS, AND RISK FACTORS INVOLVED IN MAFLD IN DIFFERENT POPULATIONS. THE OBJECTIVE OF THIS WORK IS TWOFOLD. FIRSTLY, THERE IS A BRIEF DISCUSSION REGARDING THE CHANGE IN NOMENCLATURE AS WELL AS EPIDEMIOLOGY, RISK FACTORS, AND PATHOPHYSIOLOGIC MECHANISMS OTHER THAN HORMONAL EFFECTS, WHICH INCLUDE NUTRITION AND THE GUT MICROBIOME, AS WELL AS GENETIC AND EPIGENETIC INFLUENCES. SECONDLY, WE REVIEW THE BASIS OF THE MOST IMPORTANT HORMONAL FACTORS INVOLVED IN THE DEVELOPMENT AND PROGRESSION OF MAFLD THAT ACT BOTH INDEPENDENTLY AND IN AN INTERRELATED MANNER. 2022 3 5252 70 PROGRAMMING AND REGULATION OF METABOLIC HOMEOSTASIS. EVIDENCE IS PRESENTED THAT THE RATE AND EQUILIBRIUM CONSTANTS IN MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION SET AND MAINTAIN METABOLIC HOMEOSTASIS IN EUKARYOTIC CELLS. THESE INTERNAL CONSTANTS DETERMINE THE ENERGY STATE ([ATP]/[ADP][PI]), AND THE ENERGY STATE MAINTAINS HOMEOSTASIS THROUGH A BIDIRECTIONAL SENSORY/SIGNALING CONTROL NETWORK THAT REACHES EVERY ASPECT OF CELLULAR METABOLISM. THE ENERGY STATE IS MAINTAINED WITH HIGH PRECISION (TO APPROXIMATELY 1 PART IN 10(10)), AND THE CONTROL SYSTEM CAN RESPOND TO TRANSIENT CHANGES IN ENERGY DEMAND (ATP UTILIZATION) OF MORE THAN 100 TIMES THE RESTING RATE. EPIGENETIC AND ENVIRONMENTAL FACTORS ARE ABLE TO "FINE-TUNE" THE PROGRAMMED SET POINT OVER A NARROW RANGE TO MEET THE SPECIAL NEEDS ASSOCIATED WITH CELL DIFFERENTIATION AND CHRONIC CHANGES IN METABOLIC REQUIREMENTS. THE RESULT IS ROBUST ACROSS-PLATFORM CONTROL OF METABOLISM, WHICH IS ESSENTIAL TO CELLULAR DIFFERENTIATION AND THE EVOLUTION OF COMPLEX ORGANISMS. A MODEL OF OXIDATIVE PHOSPHORYLATION IS PRESENTED, FOR WHICH THE STEADY-STATE RATE EXPRESSION HAS BEEN DERIVED AND COMPUTER PROGRAMMED. THE BEHAVIOR OF OXIDATIVE PHOSPHORYLATION PREDICTED BY THE MODEL IS SHOWN TO FIT THE EXPERIMENTAL DATA AVAILABLE FOR ISOLATED MITOCHONDRIA AS WELL AS FOR CELLS AND TISSUES. THIS INCLUDES MEASUREMENTS FROM SEVERAL DIFFERENT MAMMALIAN TISSUES AS WELL AS FROM INSECT FLIGHT MUSCLE AND PLANTS. THE RESPIRATORY CHAIN AND OXIDATIVE PHOSPHORYLATION IS REMARKABLY SIMILAR FOR ALL HIGHER PLANTS AND ANIMALS. THIS IS CONSISTENT WITH THE EFFICIENT SYNTHESIS OF ATP AND PRECISE CONTROL OF METABOLIC HOMEOSTASIS PROVIDED BY OXIDATIVE PHOSPHORYLATION BEING A KEY TO CELLULAR DIFFERENTIATION AND THE EVOLUTION OF STRUCTURES WITH SPECIALIZED FUNCTION. 2015 4 6713 27 VISCERAL ADIPOSITY SYNDROME. THE ASSOCIATION OF ANTHROPOMETRIC (WAIST CIRCUMFERENCE) AND HEMODYNAMIC (BLOOD PRESSURE) CHANGES WITH ABNORMALITIES IN GLUCOSE AND LIPID METABOLISM HAS BEEN MOTIVATION FOR A LOT OF DISCUSSIONS IN THE LAST 30 YEARS. NOWADAYS, BLOOD PRESSURE, BODY MASS INDEX/ABDOMINAL CIRCUMFERENCE, GLYCEMIA, TRIGLYCERIDEMIA, AND HDL-CHOLESTEROL CONCENTRATIONS ARE CONSIDERED IN THE DEFINITION OF METABOLIC SYNDROME, REFERRED AS VISCERAL ADIPOSITY SYNDROME (VAS) IN THE PRESENT REVIEW. HOWEVER, MORE THAN 250 YEARS AGO AN ASSOCIATION BETWEEN VISCERAL AND MEDIASTINAL OBESITY WITH HYPERTENSION, GOUT, AND OBSTRUCTIVE APNEA HAD ALREADY BEEN RECOGNIZED. EXPANSION OF VISCERAL ADIPOSE TISSUE SECONDARY TO CHRONIC OVER-CONSUMPTION OF CALORIES STIMULATES THE RECRUITMENT OF MACROPHAGES, WHICH ASSUME AN INFLAMMATORY PHENOTYPE AND PRODUCE CYTOKINES THAT DIRECTLY INTERFERE WITH INSULIN SIGNALING, RESULTING IN INSULIN RESISTANCE. IN TURN, INSULIN RESISTANCE (IR) MANIFESTS ITSELF IN VARIOUS TISSUES, CONTRIBUTING TO THE OVERALL PHENOTYPE OF VAS. FOR EXAMPLE, IN WHITE ADIPOSE TISSUE, IR RESULTS IN LIPOLYSIS, INCREASED FREE FATTY ACIDS RELEASE AND WORSENING OF INFLAMMATION, SINCE FATTY ACIDS CAN BIND TO TOLL-LIKE RECEPTORS. IN THE LIVER, IR RESULTS IN INCREASED HEPATIC GLUCOSE PRODUCTION, CONTRIBUTING TO HYPERGLYCEMIA; IN THE VASCULAR ENDOTHELIUM AND KIDNEY, IR RESULTS IN VASOCONSTRICTION, SODIUM RETENTION AND, CONSEQUENTLY, ARTERIAL HYPERTENSION. OTHER PLAYERS HAVE BEEN RECOGNIZED IN THE DEVELOPMENT OF VAS, SUCH AS GENETIC PREDISPOSITION, EPIGENETIC FACTORS ASSOCIATED WITH EXPOSURE TO AN UNFAVOURABLE INTRAUTERINE ENVIRONMENT AND THE GUT MICROBIOTA. MORE RECENTLY, EXPERIMENTAL AND CLINICAL STUDIES HAVE SHOWN THE AUTONOMIC NERVOUS SYSTEM PARTICIPATES IN MODULATING VISCERAL ADIPOSE TISSUE. THE SYMPATHETIC NERVOUS SYSTEM IS RELATED TO ADIPOSE TISSUE FUNCTION AND DIFFERENTIATION THROUGH BETA1, BETA2, BETA3, ALPHA1, AND ALPHA2 ADRENERGIC RECEPTORS. THE RELATION IS BIDIRECTIONAL: SYMPATHETIC DENERVATION OF ADIPOSE TISSUE BLOCKS LIPOLYSIS TO A VARIETY OF LIPOLYTIC STIMULI AND ADIPOSE TISSUE SEND INPUTS TO THE BRAIN. AN IMBALANCE OF SYMPATHETIC/PARASYMPATHETIC AND ALPHA2 ADRENERGIC/BETA3 RECEPTOR IS RELATED TO VISCERAL ADIPOSE TISSUE STORAGE AND INSULIN SENSITIVITY. THUS, IN ADDITION TO THE WELL-KNOWN FACTORS CLASSICALLY ASSOCIATED WITH VAS, ABNORMAL AUTONOMIC ACTIVITY ALSO EMERGES AS AN IMPORTANT FACTOR REGULATING WHITE ADIPOSE TISSUE, WHICH HIGHLIGHTS COMPLEX ROLE OF ADIPOSE TISSUE IN THE VAS. 2016 5 4050 18 MALADAPTIVE TRAINED IMMUNITY AND CLONAL HEMATOPOIESIS AS POTENTIAL MECHANISTIC LINKS BETWEEN PERIODONTITIS AND INFLAMMATORY COMORBIDITIES. PERIODONTITIS IS BIDIRECTIONALLY ASSOCIATED WITH SYSTEMIC INFLAMMATORY DISORDERS. THE PREVALENCE AND SEVERITY OF THIS ORAL DISEASE AND LINKED COMORBIDITIES INCREASES WITH AGING. HERE, WE REVIEW TWO NEWLY EMERGED CONCEPTS, TRAINED INNATE IMMUNITY (TII) AND CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP), WHICH TOGETHER SUPPORT A POTENTIAL HYPOTHESIS ON HOW PERIODONTITIS AFFECTS AND IS AFFECTED BY COMORBIDITIES AND WHY THE SUSCEPTIBILITY TO PERIODONTITIS AND COMORBIDITIES INCREASES WITH AGING. GIVEN THAT CHRONIC DISEASES ARE LARGELY TRIGGERED BY THE ACTION OF INFLAMMATORY IMMUNE CELLS, MODULATION OF THEIR BONE MARROW PRECURSORS, THE HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS), MAY AFFECT MULTIPLE DISORDERS THAT EMERGE AS COMORBIDITIES. SUCH ALTERATIONS IN HSPCS CAN BE MEDIATED BY TII AND/OR CHIP, TWO NON-MUTUALLY EXCLUSIVE PROCESSES SHARING A BIAS FOR ENHANCED MYELOPOIESIS AND PRODUCTION OF INNATE IMMUNE CELLS WITH HEIGHTENED PROINFLAMMATORY POTENTIAL. TII IS A STATE OF ELEVATED IMMUNE RESPONSIVENESS BASED ON INNATE IMMUNE (EPIGENETIC) MEMORY. SYSTEMIC INFLAMMATION CAN INITIATE TII IN THE BONE MARROW VIA SUSTAINED REWIRING OF HSPCS, WHICH THEREBY DISPLAY A SKEWING TOWARD THE MYELOID LINEAGE, RESULTING IN GENERATION OF HYPER-REACTIVE OR "TRAINED" MYELOID CELLS. CHIP ARISES FROM AGING-RELATED SOMATIC MUTATIONS IN HSPCS, WHICH CONFER A SURVIVAL AND PROLIFERATION ADVANTAGE TO THE MUTANT HSPCS AND GIVE RISE TO AN OUTSIZED FRACTION OF HYPER-INFLAMMATORY MUTANT MYELOID CELLS IN THE CIRCULATION AND TISSUES. THIS REVIEW DISCUSSES EMERGING EVIDENCE THAT SUPPORTS THE NOTION THAT TII AND CHIP MAY UNDERLIE A CAUSAL AND AGE-RELATED ASSOCIATION BETWEEN PERIODONTITIS AND COMORBIDITIES. A HOLISTIC MECHANISTIC UNDERSTANDING OF THE PERIODONTITIS-SYSTEMIC DISEASE CONNECTION MAY OFFER NOVEL DIAGNOSTIC AND THERAPEUTIC TARGETS FOR TREATING INFLAMMATORY COMORBIDITIES. 2022 6 375 17 AN ENERGETIC VIEW OF STRESS: FOCUS ON MITOCHONDRIA. ENERGY IS REQUIRED TO SUSTAIN LIFE AND ENABLE STRESS ADAPTATION. AT THE CELLULAR LEVEL, ENERGY IS LARGELY DERIVED FROM MITOCHONDRIA - UNIQUE MULTIFUNCTIONAL ORGANELLES WITH THEIR OWN GENOME. FOUR MAIN ELEMENTS CONNECT MITOCHONDRIA TO STRESS: (1) ENERGY IS REQUIRED AT THE MOLECULAR, (EPI)GENETIC, CELLULAR, ORGANELLAR, AND SYSTEMIC LEVELS TO SUSTAIN COMPONENTS OF STRESS RESPONSES; (2) GLUCOCORTICOIDS AND OTHER STEROID HORMONES ARE PRODUCED AND METABOLIZED BY MITOCHONDRIA; (3) RECIPROCALLY, MITOCHONDRIA RESPOND TO NEUROENDOCRINE AND METABOLIC STRESS MEDIATORS; AND (4) EXPERIMENTALLY MANIPULATING MITOCHONDRIAL FUNCTIONS ALTERS PHYSIOLOGICAL AND BEHAVIORAL RESPONSES TO PSYCHOLOGICAL STRESS. THUS, MITOCHONDRIA ARE ENDOCRINE ORGANELLES THAT PROVIDE BOTH THE ENERGY AND SIGNALS THAT ENABLE AND DIRECT STRESS ADAPTATION. NEURAL CIRCUITS REGULATING SOCIAL BEHAVIOR - AS WELL AS PSYCHOPATHOLOGICAL PROCESSES - ARE ALSO INFLUENCED BY MITOCHONDRIAL ENERGETICS. AN INTEGRATIVE VIEW OF STRESS AS AN ENERGY-DRIVEN PROCESS OPENS NEW OPPORTUNITIES TO STUDY MECHANISMS OF ADAPTATION AND REGULATION ACROSS THE LIFESPAN. 2018 7 6169 18 THE GUT MICROBIOTA AND HEALTHY AGING: A MINI-REVIEW. THE GUT MICROBIOTA SHOWS A WIDE INTER-INDIVIDUAL VARIATION, BUT ITS WITHIN-INDIVIDUAL VARIATION IS RELATIVELY STABLE OVER TIME. A FUNCTIONAL CORE MICROBIOME, PROVIDED BY ABUNDANT BACTERIAL TAXA, SEEMS TO BE COMMON TO VARIOUS HUMAN HOSTS REGARDLESS OF THEIR GENDER, GEOGRAPHIC LOCATION, AND AGE. WITH ADVANCING CHRONOLOGICAL AGE, THE GUT MICROBIOTA BECOMES MORE DIVERSE AND VARIABLE. HOWEVER, WHEN MEASURES OF BIOLOGICAL AGE ARE USED WITH ADJUSTMENT FOR CHRONOLOGICAL AGE, OVERALL RICHNESS DECREASES, WHILE A CERTAIN GROUP OF BACTERIA ASSOCIATED WITH FRAILTY INCREASES. THIS HIGHLIGHTS THE IMPORTANCE OF CONSIDERING BIOLOGICAL OR FUNCTIONAL MEASURES OF AGING. STUDIES USING MODEL ORGANISMS INDICATE THAT AGE-RELATED GUT DYSBIOSIS MAY CONTRIBUTE TO UNHEALTHY AGING AND REDUCED LONGEVITY. THE GUT MICROBIOME DEPENDS ON THE HOST NUTRIENT SIGNALING PATHWAYS FOR ITS BENEFICIAL EFFECTS ON HOST HEALTH AND LIFESPAN, AND GUT DYSBIOSIS DISRUPTING THE INTERDEPENDENCE MAY DIMINISH THE BENEFICIAL EFFECTS OR EVEN HAVE REVERSE EFFECTS. GUT DYSBIOSIS CAN TRIGGER THE INNATE IMMUNE RESPONSE AND CHRONIC LOW-GRADE INFLAMMATION, LEADING TO MANY AGE-RELATED DEGENERATIVE PATHOLOGIES AND UNHEALTHY AGING. THE GUT MICROBIOTA COMMUNICATES WITH THE HOST THROUGH VARIOUS BIOMOLECULES, NUTRIENT SIGNALING-INDEPENDENT PATHWAYS, AND EPIGENETIC MECHANISMS. DISTURBANCE OF THESE COMMUNICATIONS BY AGE-RELATED GUT DYSBIOSIS CAN AFFECT THE HOST HEALTH AND LIFESPAN. THIS MAY EXPLAIN THE IMPACT OF THE GUT MICROBIOME ON HEALTH AND AGING. 2018 8 611 16 BIDIRECTIONAL RESCUE OF EXTREME GENETIC PREDISPOSITIONS TO ANXIETY: IMPACT OF CRH RECEPTOR 1 AS EPIGENETIC PLASTICITY GENE IN THE AMYGDALA. THE CONTINUUM OF PHYSIOLOGICAL ANXIETY UP TO PSYCHOPATHOLOGY IS NOT MERELY DEPENDENT ON GENES, BUT IS ORCHESTRATED BY THE INTERPLAY OF GENETIC PREDISPOSITION, GENE X ENVIRONMENT AND EPIGENETIC INTERACTIONS. ACCORDINGLY, INBORN ANXIETY IS CONSIDERED A POLYGENIC, MULTIFACTORIAL TRAIT, LIKELY TO BE SHAPED BY ENVIRONMENTALLY DRIVEN PLASTICITY AT THE GENOMIC LEVEL. WE HERE TOOK ADVANTAGE OF THE EXTREME GENETIC PREDISPOSITION OF THE SELECTIVELY BRED HIGH (HAB) AND LOW ANXIETY (LAB) MOUSE MODEL EXHIBITING HIGH VS LOW ANXIETY-RELATED BEHAVIOR AND TESTED WHETHER AND HOW BENEFICIAL (ENRICHED ENVIRONMENT) VS DETRIMENTAL (CHRONIC MILD STRESS) ENVIRONMENTAL MANIPULATIONS ARE CAPABLE OF RESCUING PHENOTYPES FROM BOTH ENDS OF THE ANXIETY CONTINUUM. WE PROVIDE EVIDENCE THAT (I) EVEN INBORN AND SEEMINGLY RIGID BEHAVIORAL AND NEUROENDOCRINE PHENOTYPES CAN BIDIRECTIONALLY BE RESCUED BY APPROPRIATE ENVIRONMENTAL STIMULI, (II) CORTICOTROPIN-RELEASING HORMONE RECEPTOR 1 (CRHR1), CRITICALLY INVOLVED IN TRAIT ANXIETY, SHOWS BIDIRECTIONAL ALTERATIONS IN ITS EXPRESSION IN THE BASOLATERAL AMYGDALA (BLA) UPON ENVIRONMENTAL STIMULATION, (III) THESE ALTERATIONS ARE LINKED TO AN INCREASED METHYLATION STATUS OF ITS PROMOTER AND, FINALLY, (IV) BINDING OF THE TRANSCRIPTION FACTOR YIN YANG 1 (YY1) TO THE CRHR1 PROMOTER CONTRIBUTES TO ITS GENE EXPRESSION IN A METHYLATION-SENSITIVE MANNER. THUS, CRHR1 IN THE BLA IS CRITICALLY INVOLVED AS PLASTICITY GENE IN THE BIDIRECTIONAL EPIGENETIC RESCUE OF EXTREMES IN TRAIT ANXIETY. 2014 9 4973 22 PATHOPHYSIOLOGICAL EFFECTS OF CONTEMPORARY LIFESTYLE ON EVOLUTIONARY-CONSERVED SURVIVAL MECHANISMS IN POLYCYSTIC OVARY SYNDROME. POLYCYSTIC OVARY SYNDROME (PCOS) IS INCREASINGLY BEING CHARACTERIZED AS AN EVOLUTIONARY MISMATCH DISORDER THAT PRESENTS WITH A COMPLEX MIXTURE OF METABOLIC AND ENDOCRINE SYMPTOMS. THE EVOLUTIONARY MODEL PROPOSES THAT PCOS ARISES FROM A COLLECTION OF INHERITED POLYMORPHISMS THAT HAVE BEEN CONSISTENTLY DEMONSTRATED IN A VARIETY OF ETHNIC GROUPS AND RACES. IN UTERO DEVELOPMENTAL PROGRAMMING OF SUSCEPTIBLE GENOMIC VARIANTS ARE THOUGHT TO PREDISPOSE THE OFFSPRING TO DEVELOP PCOS. POSTNATAL EXPOSURE TO LIFESTYLE AND ENVIRONMENTAL RISK FACTORS RESULTS IN EPIGENETIC ACTIVATION OF DEVELOPMENTALLY PROGRAMMED GENES AND DISTURBANCE OF THE HALLMARKS OF HEALTH. THE RESULTING PATHOPHYSIOLOGICAL CHANGES REPRESENT THE CONSEQUENCES OF POOR-QUALITY DIET, SEDENTARY BEHAVIOUR, ENDOCRINE DISRUPTING CHEMICALS, STRESS, CIRCADIAN DISRUPTION, AND OTHER LIFESTYLE FACTORS. EMERGING EVIDENCE SUGGESTS THAT LIFESTYLE-INDUCED GASTROINTESTINAL DYSBIOSIS PLAYS A CENTRAL ROLE IN THE PATHOGENESIS OF PCOS. LIFESTYLE AND ENVIRONMENTAL EXPOSURES INITIATE CHANGES THAT RESULT IN DISTURBANCE OF THE GASTROINTESTINAL MICROBIOME (DYSBIOSIS), IMMUNE DYSREGULATION (CHRONIC INFLAMMATION), ALTERED METABOLISM (INSULIN RESISTANCE), ENDOCRINE AND REPRODUCTIVE IMBALANCE (HYPERANDROGENISM), AND CENTRAL NERVOUS SYSTEM DYSFUNCTION (NEUROENDOCRINE AND AUTONOMIC NERVOUS SYSTEM). PCOS CAN BE A PROGRESSIVE METABOLIC CONDITION THAT LEADS TO OBESITY, GESTATIONAL DIABETES, TYPE TWO DIABETES, METABOLIC-ASSOCIATED FATTY LIVER DISEASE, METABOLIC SYNDROME, CARDIOVASCULAR DISEASE, AND CANCER. THIS REVIEW EXPLORES THE MECHANISMS THAT UNDERPIN THE EVOLUTIONARY MISMATCH BETWEEN ANCIENT SURVIVAL PATHWAYS AND CONTEMPORARY LIFESTYLE FACTORS INVOLVED IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF PCOS. 2023 10 4786 21 NUTRITION AND HEALTH DURING MID-LIFE: SEARCHING FOR SOLUTIONS AND MEETING CHALLENGES FOR THE AGING POPULATION. INTERACTIONS BETWEEN GENETIC (GENOME) AND ENVIRONMENTAL FACTORS (EPIGENOME) OPERATE DURING A PERSON'S ENTIRE LIFESPAN. THE AGING PROCESS IS ASSOCIATED WITH SEVERAL CELLULAR AND ORGANIC FUNCTIONAL ALTERATIONS THAT, AT THE END, CAUSE MULTI-ORGANIC CELL FAILURE. EPIGENETIC MECHANISMS OF AGING ARE MODIFIABLE BY APPROPRIATE PREVENTIVE ACTIONS MEDIATED BY SIRTUINS, CALORIC INPUT, DIET COMPONENTS, ADIPOSE TISSUE-RELATED INFLAMMATORY REACTIONS, AND PHYSICAL ACTIVITY. THE MEDITERRANEAN LIFESTYLE HAS BEEN FOR MANY MILLENNIA A DAILY HABIT FOR PEOPLE IN WESTERN CIVILIZATIONS LIVING AROUND THE MEDITERRANEAN SEA WHO WORKED INTENSIVELY AND SURVIVED WITH VERY FEW SEASONAL FOODS. A HIGH ADHERENCE TO THE TRADITIONAL MEDITERRANEAN DIET IS ASSOCIATED WITH LOW MORTALITY (HIGHER LONGEVITY) AND REDUCED RISK OF DEVELOPING CHRONIC DISEASES, INCLUDING CANCER, THE METABOLIC SYNDROME, DEPRESSION AND CARDIOVASCULAR AND NEURODEGENERATIVE DISEASES. REPORTS INDICATE THAT SOME DIETARY COMPONENTS, SUCH AS OLIVE OIL, ANTIOXIDANTS, OMEGA-3 AND -6 POLYUNSATURATED ACIDS, POLYPHENOLS AND FLAVONOIDS, MEDIATE BENEFICIAL ANTI-AGING EFFECTS (ANTI-CHRONIC DISEASES AND INCREASED LONGEVITY). EQUALLY, PHYSICAL ACTIVITY DISPLAYS A POSITIVE EFFECT, PRODUCING CALORIC CONSUMPTION AND REGULATION OF ADIPOSE AND PANCREATIC FUNCTION. THE PREDICTIVE STRENGTH OF SOME FOOD PATTERNS MAY BE A WAY OF DEVELOPING RECOMMENDATIONS FOR FOOD AND HEALTH POLICIES. THIS PAPER WILL DISCUSS SEVERAL WAYS OF IMPROVING HEALTH DURING MID-LIFE, FOCUSING ON CERTAIN GROUPS OF FUNCTIONAL FOODS AND HEALTHY HABITS WHICH MAY REDUCE OR PREVENT AGE-RELATED CHRONIC DISEASES. 2013 11 4151 21 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 12 4891 19 OXIDATIVE STRESS AND INFLAMMATORY MARKERS IN PREDIABETES AND DIABETES. PREDIABETES IS A STATE OF ELEVATED PLASMA GLUCOSE IN WHICH THE THRESHOLD FOR DIABETES HAS NOT YET BEEN REACHED AND CAN PREDISPOSE TO THE DEVELOPMENT OF TYPE 2 DIABETES AND CARDIOVASCULAR DISEASES. INSULIN RESISTANCE AND IMPAIRED BETA-CELL FUNCTION ARE OFTEN ALREADY PRESENT IN PREDIABETES. HYPERGLYCEMIA CAN UPREGULATE MARKERS OF CHRONIC INFLAMMATION AND CONTRIBUTE TO INCREASED REACTIVE OXYGEN SPECIES (ROS) GENERATION, WHICH ULTIMATELY CAUSE VASCULAR DYSFUNCTION. CONVERSELY, INCREASED OXIDATIVE STRESS AND INFLAMMATION CAN LEAD TO INSULIN RESISTANCE AND IMPAIRED INSULIN SECRETION. PROPER TREATMENT OF HYPERGLYCEMIA AND INHIBITION OF ROS OVERPRODUCTION IS CRUCIAL FOR DELAYING ONSET OF DIABETES AND FOR PREVENTION OF CARDIOVASCULAR COMPLICATIONS. THUS, IT IS IMPERATIVE TO DETERMINE THE MECHANISMS INVOLVED IN THE PROGRESSION FROM PREDIABETES TO DIABETES INCLUDING A CLARIFICATION OF HOW OLD AND NEW MEDICATIONS AFFECT OXIDATIVE AND IMMUNE MECHANISMS OF DIABETES. IN THIS REVIEW, WE DISCUSS THE RELATIONSHIP BETWEEN OXIDATIVE STRESS AND HYPERGLYCEMIA ALONG WITH LINKS BETWEEN INFLAMMATION AND PREDIABETES. ADDITIONALLY, THE EFFECTS OF HYPERGLYCEMIC MEMORY, MICROVESICLES, MICRO-RNA, AND EPIGENETIC REGULATION ON INFLAMMATION, OXIDATIVE STATE, AND GLYCEMIC CONTROL ARE HIGHLIGHTED. ADIPOSE TISSUE AND THEIR INFLUENCE ON CHRONIC INFLAMMATION ARE ALSO BRIEFLY REVIEWED. FINALLY, THE ROLE OF IMMUNE-TARGETED THERAPIES AND ANTI-DIABETIC MEDICATION ON GLYCEMIC CONTROL AND OXIDATIVE STRESS ARE DISCUSSED. 2019 13 4806 19 OBESITY AND METABOLIC SYNDROME ASSOCIATED WITH SYSTEMIC INFLAMMATION AND THE IMPACT ON THE MALE REPRODUCTIVE SYSTEM. OBESITY AND METABOLIC SYNDROME (METS) ARE GLOBAL EPIDEMICS, DRIVEN BY AN OBESOGENIC ENVIRONMENT. THIS IS MEDIATED BY COMPLEX UNDERLYING PATHOPHYSIOLOGY, IN WHICH CHRONIC INFLAMMATION IS AN IMPORTANT AETIOLOGICAL AND MECHANISTIC PHENOMENON. A SHIFT TOWARDS A SUBCLINICAL T(H) 1-LYMPHOCYTE MEDIATED INNATE AND CHRONIC INFLAMMATORY RESPONSE IS WELL DEFINED IN OBESITY AND METS, DEMONSTRATED IN MULTIPLE SYSTEMS INCLUDING VISCERAL ADIPOSITY, BRAIN (HYPOTHALAMUS), MUSCLES, VASCULATURE, LIVER, PANCREAS, TESTES, EPIDIDYMIS, PROSTATE AND SEMINAL FLUID. INFLAMMATORY CYTOKINES DISRUPT THE HYPOTHALAMIC-PITUITARY-TESTES AXIS AND STEROIDOGENESIS CASCADES (HYPOGONADOTROPIC HYPOGONADISM), SPERMATOGENESIS (POOR SEMEN PARAMETERS, INCLUDING DNA FRAGMENTATION AND DETRIMENTAL EPIGENETIC MODIFICATION) AND RESULTS IN SUBCLINICAL PROSTATITIS AND PROSTATE HYPERPLASIA. THIS REVIEW AIMS TO HIGHLIGHT THE ROLE OF CHRONIC INFLAMMATION IN OBESITY AND METS, CYTOKINES IN MALE REPRODUCTIVE PHYSIOLOGY AND PATHOPHYSIOLOGY, THE IMPACT ON STEROIDOGENESIS AND SPERMATOGENESIS, PROSTATE PATHOLOGY AND ERECTILE DYSFUNCTION. CURRENTLY, IT IS RECOMMENDED THAT CLINICAL ASSESSMENT OF MALE INFERTILITY AND REPRODUCTIVE DYSFUNCTION IN OBESE AND METS PATIENTS INCLUDES INFLAMMATION ASSESSMENT (HIGHLY SENSITIVE C-REACTIVE PROTEIN), AND APPROPRIATE ADVICE AND THERAPEUTIC OPTIONS ARE INCORPORATED IN THE MANAGEMENT OPTIONS. HOWEVER, THE MECHANISMS AND THERAPEUTIC OPTIONS REMAIN POORLY UNDERSTOOD AND REQUIRE SIGNIFICANT INTERDISCIPLINARY RESEARCH TO IDENTIFY POTENTIAL NOVEL THERAPEUTIC STRATEGIES. 2019 14 5558 17 ROLE OF GUT MICROBIOTA IN THE AETIOLOGY OF OBESITY: PROPOSED MECHANISMS AND REVIEW OF THE LITERATURE. THE AETIOLOGY OF OBESITY HAS BEEN ATTRIBUTED TO SEVERAL FACTORS (ENVIRONMENTAL, DIETARY, LIFESTYLE, HOST, AND GENETIC FACTORS); HOWEVER NONE OF THESE FULLY EXPLAIN THE INCREASE IN THE PREVALENCE OF OBESITY WORLDWIDE. GUT MICROBIOTA LOCATED AT THE INTERFACE OF HOST AND ENVIRONMENT IN THE GUT ARE A NEW AREA OF RESEARCH BEING EXPLORED TO EXPLAIN THE EXCESS ACCUMULATION OF ENERGY IN OBESE INDIVIDUALS AND MAY BE A POTENTIAL TARGET FOR THERAPEUTIC MANIPULATION TO REDUCE HOST ENERGY STORAGE. SEVERAL MECHANISMS HAVE BEEN SUGGESTED TO EXPLAIN THE ROLE OF GUT MICROBIOTA IN THE AETIOLOGY OF OBESITY SUCH AS SHORT CHAIN FATTY ACID PRODUCTION, STIMULATION OF HORMONES, CHRONIC LOW-GRADE INFLAMMATION, LIPOPROTEIN AND BILE ACID METABOLISM, AND INCREASED ENDOCANNABINOID RECEPTOR SYSTEM TONE. HOWEVER, EVIDENCE FROM ANIMAL AND HUMAN STUDIES CLEARLY INDICATES CONTROVERSIES IN DETERMINING THE CAUSE OR EFFECT RELATIONSHIP BETWEEN THE GUT MICROBIOTA AND OBESITY. METAGENOMICS BASED STUDIES INDICATE THAT FUNCTIONALITY RATHER THAN THE COMPOSITION OF GUT MICROBIOTA MAY BE IMPORTANT. FURTHER MECHANISTIC STUDIES CONTROLLING FOR ENVIRONMENTAL AND EPIGENETIC FACTORS ARE THEREFORE REQUIRED TO HELP UNRAVEL OBESITY PATHOGENESIS. 2016 15 2699 16 EXCESS BODY WEIGHT: NOVEL INSIGHTS INTO ITS ROLES IN OBESITY COMORBIDITIES. EXCESS BODY WEIGHT IS A GLOBAL HEALTH PROBLEM DUE TO SEDENTARY LIFESTYLE AND UNHEALTHY DIET, AFFECTING 2 BILLION POPULATION WORLDWIDE. OBESITY IS A MAJOR RISK FACTOR FOR METABOLIC DISEASES. NOTABLY, THE METABOLIC RISK OF OBESITY LARGELY DEPENDS ON BODY WEIGHT DISTRIBUTION, OF WHICH VISCERAL ADIPOSE TISSUES BUT NOT SUBCUTANEOUS FATS ARE CLOSELY ASSOCIATED WITH OBESITY COMORBIDITIES, INCLUDING TYPE 2 DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, CARDIOVASCULAR DISEASE AND CERTAIN TYPES OF CANCER. LATEST MULTI-OMICS AND MECHANISTICAL STUDIES REPORTED THE CRUCIAL INVOLVEMENT OF GENETIC AND EPIGENETIC ALTERATIONS, ADIPOKINES DYSREGULATION, IMMUNITY CHANGES, IMBALANCE OF WHITE AND BROWN ADIPOSE TISSUES, AND GUT MICROBIAL DYSBIOSIS IN MEDIATING THE PATHOGENIC ASSOCIATION BETWEEN VISCERAL ADIPOSE TISSUES AND COMORBIDITIES. IN THIS REVIEW, WE EXPLORE THE EPIDEMIOLOGY OF EXCESS BODY WEIGHT AND THE UP-TO-DATE MECHANISM OF HOW EXCESS BODY WEIGHT AND OBESITY LEAD TO CHRONIC COMPLICATIONS. WE ALSO EXAMINE THE UTILIZATION OF VISCERAL FAT MEASUREMENT AS AN ACCURATE CLINICAL PARAMETER FOR RISK ASSESSMENT IN HEALTHY INDIVIDUALS AND CLINICAL OUTCOME PREDICTION IN OBESE SUBJECTS. IN ADDITION, CURRENT APPROACHES FOR THE PREVENTION AND TREATMENT OF EXCESS BODY WEIGHT AND ITS RELATED METABOLIC COMORBIDITIES ARE FURTHER DISCUSSED. 2023 16 1149 21 CONNECTING THE IMMUNE SYSTEM, SYSTEMIC CHRONIC INFLAMMATION AND THE GUT MICROBIOME: THE ROLE OF SEX. UNRESOLVED LOW GRADE SYSTEMIC INFLAMMATION REPRESENTS THE UNDERLYING PATHOLOGICAL MECHANISM DRIVING IMMUNE AND METABOLIC PATHWAYS INVOLVED IN AUTOIMMUNE DISEASES (AID). MECHANISTIC STUDIES IN ANIMAL MODELS OF AID AND OBSERVATIONAL STUDIES IN PATIENTS HAVE FOUND ALTERATIONS IN GUT MICROBIOTA COMMUNITIES AND THEIR METABOLITES, SUGGESTING A MICROBIAL CONTRIBUTION TO THE ONSET OR PROGRESSION OF AID. THE GUT MICROBIOTA AND ITS METABOLITES HAVE BEEN SHOWN TO INFLUENCE IMMUNE FUNCTIONS AND IMMUNE HOMEOSTASIS BOTH WITHIN THE GUT AND SYSTEMATICALLY. MICROBIAL DERIVED-SHORT CHAIN FATTY ACID (SCFA) AND BIO-TRANSFORMED BILE ACID (BA) HAVE BEEN SHOWN TO INFLUENCE THE IMMUNE SYSTEM ACTING AS LIGANDS SPECIFIC CELL SIGNALING RECEPTORS LIKE GPRCS, TGR5 AND FXR, OR VIA EPIGENETIC PROCESSES. SIMILARLY, INTESTINAL PERMEABILITY (LEAKY GUT) AND BACTERIAL TRANSLOCATION ARE IMPORTANT CONTRIBUTORS TO CHRONIC SYSTEMIC INFLAMMATION AND, WITHOUT REPAIR OF THE INTESTINAL BARRIER, MIGHT REPRESENT A CONTINUOUS INFLAMMATORY STIMULUS CAPABLE OF TRIGGERING AUTOIMMUNE PROCESSES. RECENT STUDIES INDICATE GENDER-SPECIFIC DIFFERENCES IN IMMUNITY, WITH THE GUT MICROBIOTA SHAPING AND BEING CONCOMITANTLY SHAPED BY THE HORMONAL MILIEU GOVERNING DIFFERENCES BETWEEN THE SEXES. A BI-DIRECTIONAL CROSS-TALK BETWEEN MICROBIOTA AND THE ENDOCRINE SYSTEM IS EMERGING WITH BACTERIA BEING ABLE TO PRODUCE HORMONES (E.G. SEROTONIN, DOPAMINE AND SOMATOSTATINE), RESPOND TO HOST HORMONES (E.G. ESTROGENS) AND REGULATE HOST HORMONES' HOMEOSTASIS (E.G BY INHIBITING GENE PROLACTIN TRANSCRIPTION OR CONVERTING GLUCOCORTICOIDS TO ANDROGENS). WE REVIEW HEREIN HOW GUT MICROBIOTA AND ITS METABOLITES REGULATE IMMUNE FUNCTION, INTESTINAL PERMEABILITY AND POSSIBLY AID PATHOLOGICAL PROCESSES. FURTHER, WE DESCRIBE THE DYSBIOSIS WITHIN THE GUT MICROBIOTA OBSERVED IN DIFFERENT AID AND SPECULATE HOW RESTORING GUT MICROBIOTA COMPOSITION AND ITS REGULATORY METABOLITES BY DIETARY INTERVENTION INCLUDING PREBIOTICS AND PROBIOTICS COULD HELP IN PREVENTING OR AMELIORATING AID. FINALLY, WE SUGGEST THAT, GIVEN CONSISTENT OBSERVATIONS OF MICROBIOTA DYSBIOSIS ASSOCIATED WITH AID AND THE ABILITY OF SCFA AND BA TO REGULATE INTESTINAL PERMEABILITY AND INFLAMMATION, FURTHER MECHANISTIC STUDIES, EXAMINING HOW DIETARY MICROBIOTA MODULATION CAN PROTECT AGAINST AID, HOLD CONSIDERABLE POTENTIAL TO TACKLE INCREASED INCIDENCE OF AID AT THE POPULATION LEVEL. 2018 17 4205 26 METABOLO-EPIGENETIC INTERPLAY PROVIDES TARGETED NUTRITIONAL INTERVENTIONS IN CHRONIC DISEASES AND AGEING. EPIGENETIC MODIFICATIONS ARE CHEMICAL MODIFICATIONS THAT AFFECT GENE EXPRESSION WITHOUT ALTERING DNA SEQUENCES. IN PARTICULAR, EPIGENETIC CHEMICAL MODIFICATIONS CAN OCCUR ON HISTONE PROTEINS -MAINLY ACETYLATION, METHYLATION-, AND ON DNA AND RNA MOLECULES -MAINLY METHYLATION-. ADDITIONAL MECHANISMS, SUCH AS RNA-MEDIATED REGULATION OF GENE EXPRESSION AND DETERMINANTS OF THE GENOMIC ARCHITECTURE CAN ALSO AFFECT GENE EXPRESSION. IMPORTANTLY, DEPENDING ON THE CELLULAR CONTEXT AND ENVIRONMENT, EPIGENETIC PROCESSES CAN DRIVE DEVELOPMENTAL PROGRAMS AS WELL AS FUNCTIONAL PLASTICITY. HOWEVER, MISBALANCED EPIGENETIC REGULATION CAN RESULT IN DISEASE, PARTICULARLY IN THE CONTEXT OF METABOLIC DISEASES, CANCER, AND AGEING. NON-COMMUNICABLE CHRONIC DISEASES (NCCD) AND AGEING SHARE COMMON FEATURES INCLUDING ALTERED METABOLISM, SYSTEMIC META-INFLAMMATION, DYSFUNCTIONAL IMMUNE SYSTEM RESPONSES, AND OXIDATIVE STRESS, AMONG OTHERS. IN THIS SCENARIO, UNBALANCED DIETS, SUCH AS HIGH SUGAR AND HIGH SATURATED FATTY ACIDS CONSUMPTION, TOGETHER WITH SEDENTARY HABITS, ARE RISK FACTORS IMPLICATED IN THE DEVELOPMENT OF NCCD AND PREMATURE AGEING. THE NUTRITIONAL AND METABOLIC STATUS OF INDIVIDUALS INTERACT WITH EPIGENETICS AT DIFFERENT LEVELS. THUS, IT IS CRUCIAL TO UNDERSTAND HOW WE CAN MODULATE EPIGENETIC MARKS THROUGH BOTH LIFESTYLE HABITS AND TARGETED CLINICAL INTERVENTIONS -INCLUDING FASTING MIMICKING DIETS, NUTRACEUTICALS, AND BIOACTIVE COMPOUNDS- WHICH WILL CONTRIBUTE TO RESTORE THE METABOLIC HOMEOSTASIS IN NCCD. HERE, WE FIRST DESCRIBE KEY METABOLITES FROM CELLULAR METABOLIC PATHWAYS USED AS SUBSTRATES TO "WRITE" THE EPIGENETIC MARKS; AND COFACTORS THAT MODULATE THE ACTIVITY OF THE EPIGENETIC ENZYMES; THEN, WE BRIEFLY SHOW HOW METABOLIC AND EPIGENETIC IMBALANCES MAY RESULT IN DISEASE; AND, FINALLY, WE SHOW SEVERAL EXAMPLES OF NUTRITIONAL INTERVENTIONS - DIET BASED INTERVENTIONS, BIOACTIVE COMPOUNDS, AND NUTRACEUTICALS- AND EXERCISE TO COUNTERACT EPIGENETIC ALTERATIONS. 2023 18 5697 19 SIMILARITIES IN PATHOGENETIC MECHANISMS UNDERLYING THE BIDIRECTIONAL RELATIONSHIP BETWEEN ENDOMETRIOSIS AND PELVIC INFLAMMATORY DISEASE. BACKGROUND: ENDOMETRIOSIS IS A COMMON INFLAMMATORY DISEASE CHARACTERIZED BY THE PRESENCE OF ENDOMETRIAL CELLS OUTSIDE OF THE UTERINE CAVITY. ENDOMETRIOSIS AFFECTS 10% OF WOMEN OF REPRODUCTIVE AGE AND SIGNIFICANTLY REDUCES THEIR QUALITY OF LIFE AS A RESULT OF CHRONIC PELVIC PAIN AND INFERTILITY. BIOLOGIC MECHANISMS, INCLUDING PERSISTENT INFLAMMATION, IMMUNE DYSFUNCTION, AND EPIGENETIC MODIFICATIONS, HAVE BEEN PROPOSED AS THE PATHOGENESIS OF ENDOMETRIOSIS. IN ADDITION, ENDOMETRIOSIS CAN POTENTIALLY BE ASSOCIATED WITH AN INCREASED RISK OF PELVIC INFLAMMATORY DISEASE (PID). CHANGES IN THE VAGINAL MICROBIOTA ASSOCIATED WITH BACTERIAL VAGINOSIS (BV) RESULT IN PID OR A SEVERE FORM OF ABSCESS FORMATION, TUBO-OVARIAN ABSCESS (TOA). THIS REVIEW AIMS TO SUMMARIZE THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS AND PID AND TO DISCUSS WHETHER ENDOMETRIOSIS MAY PREDISPOSE TO PID AND VICE VERSA. METHODS: PAPERS PUBLISHED BETWEEN 2000 AND 2022 IN THE PUBMED AND GOOGLE SCHOLAR DATABASES WERE INCLUDED. RESULTS: AVAILABLE EVIDENCE SUPPORTS THAT WOMEN WITH ENDOMETRIOSIS ARE AT INCREASED RISK OF COMORBID PID AND VICE VERSA, SUPPORTING THAT ENDOMETRIOSIS AND PID ARE LIKELY TO COEXIST. THERE IS A BIDIRECTIONAL RELATIONSHIP BETWEEN ENDOMETRIOSIS AND PID THAT SHARES A SIMILAR PATHOPHYSIOLOGY, WHICH INCLUDES THE DISTORTED ANATOMY FAVORABLE TO BACTERIA PROLIFERATION, HEMORRHAGE FROM ENDOMETRIOTIC LESIONS, ALTERATIONS TO THE REPRODUCTIVE TRACT MICROBIOME, AND IMPAIRED IMMUNE RESPONSE MODULATED BY ABERRANT EPIGENETIC PROCESSES. HOWEVER, WHETHER ENDOMETRIOSIS PREDISPOSES TO PID OR VICE VERSA HAS NOT BEEN IDENTIFIED. CONCLUSIONS: THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF THE PATHOGENESIS OF ENDOMETRIOSIS AND PID AND DISCUSSES THE SIMILARITIES BETWEEN THEM. 2023 19 4792 18 NUTRITIONAL EPIGENETICS AND PHYTOCHEMICALS IN CANCER FORMATION. NUTRIGENETICS AND NUTRIGENOMICS ARE TWO CONCEPTS IN THE AREA OF NUTRITIONAL GENOMICS. EPIGENETICS IS A NEW DISCIPLINE WITH SIGNIFICANT POTENTIAL IN THE PREVENTION AND MANAGEMENT OF CERTAIN CARCINOMAS AND DISEASES. EPIGENETICS CONSISTS OF DNA METHYLATION, HISTONE MODIFICATION, NON-CODING RNAS, AND TELOMERASE ACTIVITY. EPIGENETIC-BASED MECHANISMS ACT ON THE INHIBITION OF CANCER CELLS BY MODULATING ENZYMES SUCH AS DNA METHYLTRANSFERASE AND HISTONE DEACETYLASE, AS WELL AS NON-CODING RNAS. PHYTOCHEMICALS ARE NATURAL BIOACTIVE COMPONENTS OF PLANT ORIGIN THAT HAVE ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTI-ANGIOGENIC EFFECTS ON VARIOUS DISEASES, ESPECIALLY CANCER. THE EPIGENETIC DIET IS A NUTRITIONAL MODEL BASED ON THE CONSUMPTION OF VARIOUS PHYTOCHEMICALS SUCH AS EPIGALLOCATECHIN-3-GALLATE, MORIN, CAFFEIC ACID PHENYL ESTER, APIGENIN, GENISTEIN, CURCUMIN, RESVERATROL, AND SULFORAPHANE. PHYTOCHEMICALS EXERT THEIR EFFECTS ON CANCER-BASED BY REDUCING CELL PROLIFERATION, INVASION, AND METASTASIS AND INCREASING CELL APOPTOSIS. SIMULTANEOUSLY, IT HAS FUNCTIONS SUCH AS REDUCING ONCOGENES THAT HAVE EFFECTS ON CANCER ETIOLOGY AND INCREASING TUMOR SUPPRESSOR GENES.KEY TEACHING POINTSCANCER IS A CHRONIC DISEASE WITH A HIGH MORTALITY RATE, IN WHICH VARIOUS GENETIC AND ENVIRONMENTAL FACTORS ARE INVOLVED IN ITS ETIOLOGY.PROTOONCOGENES, TUMOR SUPPRESSOR GENES, AND DNA REPAIR GENES ARE AMONG THE GENE GROUPS THAT FORM THE BASIS OF CANCER AND GENETIC STRUCTURE.THE BIDIRECTIONAL INTERACTION BETWEEN NUTRITION AND THE HUMAN GENOME HAS BEEN EFFECTIVE IN THE EMERGENCE OF THE CONCEPTS OF NUTRIGENETICS AND NUTRIGENOMICS.EPIGENETIC DIET IS A DIET BASED ON THE CONSUMPTION OF FOODS SUCH AS SOY, GRAPES, BLUEBERRIES, TURMERIC, CRUCIFEROUS VEGETABLES, AND GREEN TEA, WHICH INDUCE EPIGENETIC MECHANISMS THAT PROTECT AGAINST CANCER AND AGING. 2023 20 2617 28 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