1 4306 123 MICRORNA-29A MITIGATES LAMINECTOMY-INDUCED SPINAL EPIDURAL FIBROSIS AND GAIT DYSREGULATION BY REPRESSING TGF-BETA1 AND IL-6. SPINAL EPIDURAL FIBROSIS IS ONE OF THE TYPICAL FEATURES ATTRIBUTABLE TO FAILED BACK SURGERY SYNDROME, WITH EXCESSIVE SCAR DEVELOPMENT IN THE DURA AND NERVE ROOTS. THE MICRORNA-29 FAMILY (MIR-29S) HAS BEEN FOUND TO ACT AS A FIBROGENESIS-INHIBITORY FACTOR THAT REDUCES FIBROTIC MATRIX OVERPRODUCTION IN VARIOUS TISSUES. HOWEVER, THE MECHANISTIC BASIS OF MIRNA-29A UNDERLYING THE OVERABUNDANT FIBROTIC MATRIX SYNTHESIS IN SPINAL EPIDURAL SCARS POST-LAMINECTOMY REMAINED ELUSIVE. THIS STUDY REVEALED THAT MIR-29A ATTENUATED LUMBAR LAMINECTOMY-INDUCED FIBROGENIC ACTIVITY, AND EPIDURAL FIBROTIC MATRIX FORMATION WAS SIGNIFICANTLY LESSENED IN THE TRANSGENIC MICE (MIR-29ATG) AS COMPARED WITH WILD-TYPE MICE (WT). MOREOVER, MIR-29ATG LIMITS LAMINECTOMY-INDUCED DAMAGE AND HAS ALSO BEEN DEMONSTRATED TO DETECT WALKING PATTERNS, FOOTPRINT DISTRIBUTION, AND MOVING ACTIVITY. IMMUNOHISTOCHEMISTRY STAINING OF EPIDURAL TISSUE SHOWED THAT MIR-29ATG WAS A REMARKABLY WEAK SIGNAL OF IL-6, TGF-BETA1, AND DNA METHYLTRANSFERASE MARKER, DNMT3B, COMPARED TO THE WILD-TYPE MICE. TAKEN TOGETHER, THESE RESULTS HAVE FURTHER STRENGTHENED THE EVIDENCE THAT MIR-29A EPIGENETIC REGULATION REDUCES FIBROTIC MATRIX FORMATION AND SPINAL EPIDURAL FIBROTIC ACTIVITY IN SURGERY SCARS TO PRESERVE THE INTEGRITY OF THE SPINAL CORD CORE. THIS STUDY ELUCIDATES AND HIGHLIGHTS THE MOLECULAR MECHANISMS THAT REDUCE THE INCIDENCE OF SPINAL EPIDURAL FIBROSIS, ELIMINATING THE RISK OF GAIT ABNORMALITIES AND PAIN ASSOCIATED WITH LAMINECTOMY. 2023 2 1398 23 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 3 3750 17 INSULIN RESISTANCE IN POLYCYSTIC OVARY SYNDROME ACROSS VARIOUS TISSUES: AN UPDATED REVIEW OF PATHOGENESIS, EVALUATION, AND TREATMENT. POLYCYSTIC OVARY SYNDROME (PCOS) IS A COMMON ENDOCRINE DISORDER CHARACTERIZED BY CHRONIC OVULATION DYSFUNCTION AND OVERABUNDANCE OF ANDROGENS; IT AFFECTS 6-20% OF WOMEN OF REPRODUCTIVE AGE. PCOS INVOLVES VARIOUS PATHOPHYSIOLOGICAL FACTORS, AND AFFECTED WOMEN USUALLY HAVE SIGNIFICANT INSULIN RESISTANCE (IR), WHICH IS A MAJOR CAUSE OF PCOS. IR AND COMPENSATORY HYPERINSULINAEMIA HAVE DIFFERING PATHOGENESES IN VARIOUS TISSUES, AND IR VARIES AMONG DIFFERENT PCOS PHENOTYPES. GENETIC AND EPIGENETIC CHANGES, HYPERANDROGENAEMIA, AND OBESITY AGGRAVATE IR. INSULIN SENSITIZATION DRUGS ARE A NEW TREATMENT MODALITY FOR PCOS. WE SEARCHED PUBMED, GOOGLE SCHOLAR, ELSEVIER, AND UPTODATE DATABASES IN THIS REVIEW, AND FOCUSED ON THE PATHOGENESIS OF IR IN WOMEN WITH PCOS AND THE PATHOPHYSIOLOGY OF IR IN VARIOUS TISSUES. IN ADDITION, THE REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF THE CURRENT PROGRESS IN THE EFFICACY OF INSULIN SENSITIZATION THERAPY IN THE MANAGEMENT OF PCOS, PROVIDING THE LATEST EVIDENCE FOR THE CLINICAL TREATMENT OF WOMEN WITH PCOS AND IR. 2023 4 6254 18 THE MICROBIOME AND IRRITABLE BOWEL SYNDROME - A REVIEW ON THE PATHOPHYSIOLOGY, CURRENT RESEARCH AND FUTURE THERAPY. IRRITABLE BOWEL SYNDROME (IBS) IS A FUNCTIONAL DISORDER WHICH AFFECTS A LARGE PROPORTION OF THE POPULATION GLOBALLY. THE PRECISE ETIOLOGY OF IBS IS STILL UNKNOWN, ALTHOUGH CONSENSUS UNDERSTANDING PROPOSES IBS TO BE OF MULTIFACTORIAL ORIGIN WITH YET UNDEFINED SUBTYPES. GENETIC AND EPIGENETIC FACTORS, STRESS-RELATED NERVOUS AND ENDOCRINE SYSTEMS, IMMUNE DYSREGULATION AND THE BRAIN-GUT AXIS SEEM TO BE CONTRIBUTING FACTORS THAT PREDISPOSE INDIVIDUALS TO IBS. IN ADDITION TO FOOD HYPERSENSITIVITY, TOXINS AND ADVERSE LIFE EVENTS, CHRONIC INFECTIONS AND DYSBIOTIC GUT MICROBIOTA HAVE BEEN SUGGESTED TO TRIGGER IBS SYMPTOMS IN TANDEM WITH THE PREDISPOSING FACTORS. THIS REVIEW WILL SUMMARIZE THE PATHOPHYSIOLOGY OF IBS AND THE ROLE OF GUT MICROBIOTA IN RELATION TO IBS. CURRENT METHODOLOGIES FOR MICROBIOME STUDIES IN IBS SUCH AS GENOME SEQUENCING, METAGENOMICS, CULTUROMICS AND ANIMAL MODELS WILL BE DISCUSSED. THE MYRIAD OF THERAPY OPTIONS SUCH AS IMMUNOGLOBULINS (IMMUNE-BASED THERAPY), PROBIOTICS AND PREBIOTICS, DIETARY MODIFICATIONS INCLUDING FODMAP RESTRICTION DIET AND GLUTEN-FREE DIET, AS WELL AS FECAL TRANSPLANTATION WILL BE REVIEWED. FINALLY THIS REVIEW WILL HIGHLIGHT FUTURE DIRECTIONS IN IBS THERAPY RESEARCH, INCLUDING IDENTIFICATION OF NEW MOLECULAR TARGETS, APPLICATION OF 3-D GUT MODEL, GUT-ON-A-CHIP AND PERSONALIZED THERAPY. 2019 5 6872 27 [POLYPHENOLS AS PROMISING BIOACTIVE COMPOUNDS]. POLYPHENOLS ARE DIVERSE AND WIDESPREAD BIOACTIVE PLANT-BASED COMPOUNDS. THESE COMPOUNDS ARE FOUND IN VARIOUS FOODS SUCH AS BERRIES, FRUITS, VEGETABLES, CEREALS, NUTS, COFFEE, CACAO, SPICES, SEEDS. THEY ARE DIVIDED INTO PHENOLIC ACIDS, STILBENES, FLAVONOIDS, LIGNANS DEPENDING ON THEIR MOLECULAR STRUCTURE. THEY ATTRACT THE ATTENTION OF RESEARCHERS DUE TO WIDE RANGE OF BIOLOGICAL EFFECTS ON HUMAN BODY. THE PURPOSE OF THIS WORK WAS TO ANALYZE MODERN SCIENTIFIC PUBLICATIONS ON THE BIOLOGICAL EFFECTS OF POLYPHENOLS. MATERIAL AND METHODS. THE REVIEW IS BASED ON PUBLICATIONS PRESENTED IN THE PUBMED, GOOGLE SCHOLAR, RESEARCHGATE, ELSEVIER, ELIBRARY, CYBERLENINKA DATABASES USING "POLYPHENOLS", "FLAVONOIDS", "RESVERATROL", "QUERCETIN", "CATECHINS" AS KEY WORDS. PREFERENCE WAS GIVEN TO ORIGINAL RESEARCHES OVER THE PAST 10 YEARS PUBLISHED IN REFEREED JOURNALS. RESULTS. OXIDATIVE STRESS, CHRONIC INFLAMMATION, MICROBIOME DISORDERS, INSULIN RESISTANCE, EXCESSIVE PROTEIN GLYCATION, AND GENOTOXIC EFFECTS ARE AT THE HEART OF THE PATHOGENESIS OF MANY DISEASES, INCLUDING THOSE ASSOCIATED WITH AGE. A LARGE AMOUNT OF MATERIAL HAS BEEN ACCUMULATED ON THE ANTIOXIDANT, ANTICARCINOGENIC, EPIGENETIC, METABOLIC, GEROPROTECTIVE, ANTI-INFLAMMATORY AND ANTIVIRAL EFFECTS OF POLYPHENOLS. THIS GIVES REASONS TO CONSIDER POLYPHENOLS AS VERY PROMISING MICRONUTRIENTS, WHICH INCLUSION IN THE DIET CAN REDUCE THE RISK OF DEVELOPING CARDIOVASCULAR, ONCOLOGICAL, NEURODEGENERATIVE DISEASES, DIABETES MELLITUS, OBESITY, METABOLIC SYNDROME, PREMATURE AGING, THAT IS, THE MAIN CAUSES OF DEATH, A DECREASE IN THE DURATION AND QUALITY OF LIFE OF A MODERN PERSON. CONCLUSION. EXPANDING THE RANGE OF PRODUCTS ENRICHED WITH POLYPHENOLS WITH THEIR HIGH BIOAVAILABILITY IS A PROMISING AREA OF SCIENTIFIC RESEARCH AND DEVELOPMENT OF PRODUCTION IN ORDER TO PREVENT SOCIALLY SIGNIFICANT AGE-ASSOCIATED DISEASES. 2023 6 1395 25 DIET AND MICROBIOME IN THE BEGINNING OF THE SEQUENCE OF GUT INFLAMMATION. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC INFLAMMATORY CONDITION OF THE GASTROINTESTINAL TRACT DUE, AT LEAST PARTIALLY, TO AN ABERRANT AND EXCESSIVE MUCOSAL IMMUNE RESPONSE TO GUT BACTERIA IN GENETICALLY-PREDISPOSED INDIVIDUALS UNDER CERTAIN ENVIRONMENTAL FACTORS. THE INCIDENCE OF IBD IS RISING IN WESTERN AND NEWLY INDUSTRIALIZED COUNTRIES, PARALLELING THE INCREASE OF WESTERNIZED DIETARY PATTERNS, THROUGH NEW ANTIGENS, EPITHELIAL FUNCTION AND PERMEABILITY, EPIGENETIC MECHANISMS (E.G., DNA METHYLATION), AND ALTERATION OF THE GUT MICROBIOME. ALTERATION IN THE COMPOSITION AND FUNCTIONALITY OF THE GUT MICROBIOME (INCLUDING BACTERIA, VIRUSES AND FUNGI) SEEMS TO BE A NUCLEAR PATHOGENIC FACTOR. THE MICROBIOME ITSELF IS DYNAMIC, AND THE CHANGES IN FOOD QUALITY, DIETARY HABITS, LIVING CONDITIONS AND HYGIENE OF THESE WESTERN SOCIETIES, COULD INTERACT IN A COMPLEX MANNER AS MODULATORS OF DYSBIOSIS, THEREBY INFLUENCING THE ACTIVATION OF IMMUNE CELLS' PROMOTING INFLAMMATION. THE MICROBIOME PRODUCES DIVERSE SMALL MOLECULES VIA SEVERAL METABOLIC WAYS, WITH THE FIBER-DERIVED SHORT-CHAIN FATTY ACIDS (I.E., BUTYRATE) AS MAIN ELEMENTS AND HAVING ANTI-INFLAMMATORY EFFECTS. THESE METABOLITES AND SOME MICRONUTRIENTS OF THE DIET (I.E., VITAMINS, FOLIC ACID, BETA CAROTENE AND TRACE ELEMENTS) ARE REGULATORS OF INNATE AND ADAPTIVE INTESTINAL IMMUNE HOMEOSTASIS. AN EXCESSIVE AND UNHEALTHY CONSUMPTION OF SUGAR, ANIMAL FAT AND A LOW-VEGETABLE AND -FIBER DIET ARE RISK FACTORS FOR IBD APPEARANCE. FURTHERMORE, METABOLISM OF NUTRIENTS IN INTESTINAL EPITHELIUM AND IN GUT MICROBIOTA IS ALTERED BY INFLAMMATION, CHANGING THE DEMAND FOR NUTRIENTS NEEDED FOR HOMEOSTASIS. THIS ROLE OF FOOD AND A REDUCED GUT MICROBIAL DIVERSITY IN CAUSING IBD MIGHT ALSO HAVE A PROPHYLACTIC OR THERAPEUTIC ROLE FOR IBD. THE RELATIONSHIP BETWEEN DIETARY INTAKE, SYMPTOMS, AND BOWEL INFLAMMATION COULD LEAD TO DIETARY AND LIFESTYLE RECOMMENDATIONS, INCLUDING DIETS WITH ABUNDANT FRUITS, VEGETABLES, OLIVE OIL AND OILY FISH, WHICH HAVE ANTI-INFLAMMATORY EFFECTS AND COULD PREVENT DYSBIOSIS AND IBD. DIETARY MODULATION AND APPROPRIATE EXCLUSION DIETS MIGHT BE A NEW COMPLEMENTARY MANAGEMENT FOR TREATMENT AT DISEASE FLARES AND IN REFRACTORY PATIENTS, EVEN REDUCING COMPLICATIONS, HOSPITALIZATIONS AND SURGERY, THROUGH MODIFYING THE LUMINAL INTESTINAL ENVIRONMENT. 2021 7 4761 20 NRF2 SENSITIZES FERROPTOSIS THROUGH L-2-HYDROXYGLUTARATE-MEDIATED CHROMATIN MODIFICATIONS IN SICKLE CELL DISEASE. SICKLE CELL DISEASE (SCD) IS A CHRONIC HEMOLYTIC AND SYSTEMIC HYPOXIA CONDITION WITH CONSTANT OXIDATIVE STRESS AND SIGNIFICANT METABOLIC ALTERATIONS. HOWEVER, LITTLE IS KNOWN ABOUT THE CORRELATION BETWEEN METABOLIC ALTERATIONS AND THE PATHOPHYSIOLOGICAL SYMPTOMS. HERE, WE REPORT THAT NRF2, A MASTER REGULATOR OF CELLULAR ANTIOXIDANT RESPONSES, REGULATES THE PRODUCTION OF THE METABOLITE L-2-HYDROXYGLUTARATE (L2HG) TO MEDIATE EPIGENETIC HISTONE HYPERMETHYLATION FOR GENE EXPRESSION INVOLVED IN METABOLIC, OXIDATIVE, AND FERROPTOTIC STRESS RESPONSES IN SCD. MECHANISTICALLY, NRF2 WAS FOUND TO REGULATE THE EXPRESSION OF L2HG DEHYDROGENASE (L2HGDH) TO MEDIATE L2HG PRODUCTION UNDER HYPOXIA. GENE EXPRESSION PROFILE ANALYSIS INDICATED THAT REACTIVE OXYGEN SPECIES (ROS) AND FERROPTOSIS RESPONSES WERE THE MOST SIGNIFICANTLY AFFECTED SIGNALING PATHWAYS AFTER NRF2 ABLATION IN SCD. NRF2 SILENCING AND L2HG SUPPLEMENTATION SENSITIZE HUMAN SICKLE ERYTHROID CELLS TO ROS AND FERROPTOSIS STRESS. THE ABSENCE OF NRF2 AND ACCUMULATION OF L2HG SIGNIFICANTLY AFFECT HISTONE METHYLATION FOR CHROMATIN STRUCTURE MODIFICATION AND REDUCE THE ASSEMBLY OF TRANSCRIPTION COMPLEXES ON DOWNSTREAM TARGET GENES TO REGULATE ROS AND FERROPTOSIS RESPONSES. FURTHERMORE, PHARMACOLOGICAL ACTIVATION OF NRF2 WAS FOUND TO HAVE PROTECTIVE EFFECTS AGAINST ROS AND FERROPTOSIS STRESS IN SCD MICE. OUR DATA SUGGEST A NOVEL MECHANISM BY WHICH NRF2 REGULATES L2HG LEVELS TO MEDIATE SCD SEVERITY THROUGH ROS AND FERROPTOSIS STRESS RESPONSES, SUGGESTING THAT TARGETING NRF2 IS A VIABLE THERAPEUTIC STRATEGY FOR AMELIORATING SCD SYMPTOMS. 2023 8 5104 10 POLYCYSTIC OVARIAN SYNDROME. WOMEN WITH PCOS PRESENT WITH SIGNS OF CHRONIC ANOVULATION, HYPERANDROGENISM, AND METABOLIC ABNORMALITIES. THE NIH RECENTLY EMBRACED THE ROTTERDAM CRITERIA TO BROADLY IDENTIFY ALL THE PHENOTYPES OF PCOS. WOMEN WITH PCOS ARE OFTEN OBESE WITH INSULIN RESISTANCE AND HENCE HAVE AN INCREASED SUSCEPTIBILITY TO GLUCOSE INTOLERANCE AND TYPE 2 DIABETES. FUTURE RESEARCH SHOULD FOCUS ON THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL DETERMINANTS OF PCOS TO DEVELOP NEW THERAPIES TO ADDRESS THE PREVENTION OF THIS DISORDER AND ITS LONG-TERM COMPLICATIONS. 2015 9 1403 18 DIETARY APPROACHES TO WOMEN'S SEXUAL AND REPRODUCTIVE HEALTH. OVER THE COURSE OF THE REPRODUCTIVE LIFE SPAN, IT IS COMMON FOR WOMEN TO EXPERIENCE ONE OR MORE OF THE MOST COMMON GYNECOLOGIC CONDITIONS, INCLUDING SEXUAL DYSFUNCTION, POLYCYSTIC OVARY SYNDROME, FIBROIDS, ENDOMETRIOSIS, AND INFERTILITY. ALTHOUGH CURRENT MANAGEMENT GUIDELINES OFTEN TURN TO THE ESTABLISHED PHARMACEUTICAL APPROACHES FOR EACH OF THESE DIAGNOSES, THE SCIENTIFIC LITERATURE ALSO SUPPORTS AN EVIDENCE-BASED APPROACH ROOTED IN THE PARADIGM OF FOOD AS MEDICINE. ACHIEVING HEALTHY DIETARY PATTERNS IS A CORE GOAL OF LIFESTYLE MEDICINE, AND A PLANT-FORWARD APPROACH AKIN TO THE MEDITERRANEAN DIET HOLDS GREAT PROMISE FOR IMPROVING MANY CHRONIC GYNECOLOGIC DISEASES. FURTHERMORE, CREATING AN OPTIMAL PRECONCEPTION ENVIRONMENT FROM A NUTRITIONAL STANDPOINT MAY FACILITATE EPIGENETIC SIGNALING, THUS IMPROVING THE HEALTH OF FUTURE GENERATIONS. THIS STATE-OF-THE-ART REVIEW EXPLORES THE LITERATURE CONNECTING DIET WITH SEXUAL AND REPRODUCTIVE HEALTH IN PREMENOPAUSAL WOMEN. 2021 10 757 22 CARTILAGE REPAIR BY MESENCHYMAL STEM CELLS: CLINICAL TRIAL UPDATE AND PERSPECTIVES. OSTEOARTHRITIS IS A DEGENERATIVE DISEASE OF JOINTS WITH DESTRUCTION OF ARTICULAR CARTILAGE ASSOCIATED WITH SUBCHONDRAL BONE HYPERTROPHY AND INFLAMMATION. OA IS THE LEADING CAUSE OF JOINT PAIN RESULTING IN SIGNIFICANT WORSENING OF THE QUALITY-OF-LIFE IN THE ELDERLY. NUMEROUS EFFORTS HAVE BEEN SPENT TO OVERCOME THE INHERENTLY POOR HEALING ABILITY OF ARTICULAR CARTILAGE. MESENCHYMAL STEM CELLS (MSCS) HAVE BEEN IN THE LIMELIGHT OF CELL-BASED THERAPIES TO PROMOTE CARTILAGE REPAIR. DESPITE PROGRESSIVE ADVANCEMENTS IN MSC MANIPULATION AND THE INTRODUCTION OF VARIOUS BIOACTIVE SCAFFOLDS AND GROWTH FACTORS IN PRECLINICAL STUDIES, CURRENT CLINICAL TRIALS ARE STILL AT EARLY STAGES WITH PRELIMINARY AIMS TO EVALUATE SAFETY, FEASIBILITY AND EFFICACY. THIS REVIEW SUMMARISES RECENTLY REPORTED MSC-BASED CLINICAL TRIALS AND DISCUSSES NEW RESEARCH DIRECTIONS WITH PARTICULAR FOCUS ON THE POTENTIAL APPLICATION OF MSC-DERIVED EXTRACELLULAR VEHICLES, MIRNAS AND ADVANCED GENE EDITING TECHNIQUES WHICH MAY SHED LIGHT ON THE DEVELOPMENT OF NOVEL TREATMENT STRATEGIES. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: THIS REVIEW SUMMARISES RECENT MSC-RELATED CLINICAL RESEARCH THAT FOCUSES ON CARTILAGE REPAIR. WE ALSO PROPOSE A NOVEL POSSIBLE TRANSLATIONAL DIRECTION FOR HYALINE CARTILAGE FORMATION AND A NEW PARADIGM MAKING USE OF EXTRA-CELLULAR SIGNALLING AND EPIGENETIC REGULATION IN THE APPLICATION OF MSCS FOR CARTILAGE REPAIR. 2017 11 5231 16 PROBIOTICS AND AMELIORATION OF RHEUMATOID ARTHRITIS: SIGNIFICANT ROLES OF LACTOBACILLUS CASEI AND LACTOBACILLUS ACIDOPHILUS. RHEUMATOID ARTHRITIS IS A CHRONIC AUTOIMMUNE DISORDER THAT CAN LEAD TO DISABILITY CONDITIONS WITH SWOLLEN JOINTS, PAIN, STIFFNESS, CARTILAGE DEGRADATION, AND OSTEOPOROSIS. GENETIC, EPIGENETIC, SEX-SPECIFIC FACTORS, SMOKING, AIR POLLUTION, FOOD, ORAL HYGIENE, PERIODONTITIS, PREVOTELLA, AND IMBALANCE IN THE GASTROINTESTINAL MICROBIOTA ARE POSSIBLE SOURCES OF THE INITIATION OR PROGRESSION OF RHEUMATOID ARTHRITIS, ALTHOUGH THE DETAILED MECHANISMS STILL NEED TO BE ELUCIDATED. PROBIOTICS CONTAINING LACTOBACILLUS SPP. ARE COMMONLY USED AS ALLEVIATING AGENTS OR FOOD SUPPLEMENTS TO MANAGE DIARRHEA, DYSENTERY, DEVELOP IMMUNITY, AND MAINTAIN GENERAL HEALTH. THE MECHANISM OF ACTION OF LACTOBACILLUS SPP. AGAINST RHEUMATOID ARTHRITIS IS STILL NOT CLEARLY KNOWN TO DATE. IN THIS NARRATIVE REVIEW, WE RECAPITULATE THE FINDINGS OF RECENT STUDIES TO UNDERSTAND THE OVERALL PATHOGENESIS OF RHEUMATOID ARTHRITIS AND THE ROLES OF PROBIOTICS, PARTICULARLY L. CASEI OR L. ACIDOPHILUS, IN THE MANAGEMENT OF RHEUMATOID ARTHRITIS IN CLINICAL AND PRECLINICAL STUDIES. 2021 12 4274 22 MICROBIOTA IN INFLAMMATORY BOWEL DISEASE PATHOGENESIS AND THERAPY: IS IT ALL ABOUT DIET? INFLAMMATORY BOWEL DISEASE (IBD), INCLUDING ULCERATIVE COLITIS, CROHN'S DISEASE, AND UNCLASSIFIED IBD, CONTINUES TO CAUSE SIGNIFICANT MORBIDITY. WHILE ITS INCIDENCE IS INCREASING, NO CLEAR ETIOLOGY AND NO CURE HAVE YET BEEN DISCOVERED. RECENT FINDINGS SUGGEST THAT IBD MAY HAVE A MULTIFACTORIAL ETIOLOGY, WHERE COMPLEX INTERACTIONS BETWEEN GENETICS, EPIGENETICS, ENVIRONMENTAL FACTORS (INCLUDING DIET BUT ALSO INFECTIONS, ANTIBIOTICS, AND SANITATION), AND HOST IMMUNE SYSTEM LEAD TO ABNORMAL IMMUNE RESPONSES AND CHRONIC INFLAMMATION. OVER THE PAST YEARS, THE ROLE OF ALTERED GUT MICROBIOTA (IN BOTH COMPOSITION AND FUNCTION) IN IBD PATHOGENESIS HAS EMERGED AS AN OUTSTANDING AREA OF INTEREST. ACCORDING TO NEW FINDINGS, GUT DYSBIOSIS MAY APPEAR AS A KEY ELEMENT IN INITIATION OF INFLAMMATION IN IBD AND ITS COMPLICATIONS. MOREOVER, COMPLEX METAGENOMIC STUDIES PROVIDE POSSIBILITIES TO DISTINGUISH BETWEEN IBD TYPES AND APPRECIATE SEVERITY AND PROGNOSIS OF THE DISEASE, AS WELL AS RESPONSE TO THERAPY. THIS REVIEW PROVIDES AN UPDATED KNOWLEDGE OF RECENT FINDINGS LINKING ALTERED BACTERIAL COMPOSITION AND FUNCTIONS, VIRUSES, AND FUNGI TO IBD PATHOGENESIS. IT ALSO HIGHLIGHTS THE COMPLEX GENETIC, EPIGENETIC, IMMUNE, AND MICROBIAL INTERACTIONS IN RELATION TO ENVIRONMENTAL FACTORS (INCLUDING DIET). WE OVERVIEW THE ACTUAL OPTIONS TO MANIPULATE THE ALTERED MICROBIOTA, SUCH AS MODIFIED DIET, PROBIOTICS, PREBIOTICS, SYNBIOTICS, ANTIBIOTICS, AND FECAL TRANSPLANTATION. FUTURE POSSIBLE THERAPIES ARE ALSO INCLUDED. TARGETING ALTERED MICROBIOTA COULD BE THE NEXT THERAPEUTIC PERSONALIZED APPROACH, BUT MORE RESEARCH AND WELL-DESIGNED COMPARATIVE PROSPECTIVE STUDIES ARE REQUIRED TO FORMULATE ADEQUATE DIRECTIONS FOR PREVENTION AND THERAPY. 2015 13 5107 22 POLYCYSTIC OVARY SYNDROME: A BRAIN DISORDER CHARACTERIZED BY EATING PROBLEMS ORIGINATING DURING PUBERTY AND ADOLESCENCE. POLYCYSTIC OVARY SYNDROME (PCOS) IS AN ENDOCRINE CONDITION ASSOCIATED WITH REPRODUCTIVE AND PSYCHIATRIC DISORDERS, AND WITH OBESITY. EATING DISORDERS, SUCH AS BULIMIA AND RECURRENT DIETING, ARE ALSO LINKED TO PCOS. THEY CAN LEAD TO THE EPIGENETIC DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AXIS, THEREBY IMPACTING ON OVARIAN FOLLICULOGENESIS. WE POSTULATE THAT PCOS IS INDUCED BY PSYCHOLOGICAL DISTRESS AND EPISODES OF OVEREATING AND/OR DIETING DURING PUBERTY AND ADOLESCENCE, WHEN BODY DISSATISFACTION AND EMOTIONAL DISTRESS ARE OFTEN PRESENT. WE PROPOSE THAT UPREGULATED ACTIVATION OF THE CENTRAL HPG AXIS DURING THIS PERIOD CAN BE EPIGENETICALLY ALTERED BY PSYCHOLOGICAL STRESSORS AND BY BULIMIA/RECURRENT DIETING, WHICH ARE COMMON DURING ADOLESCENCE AND WHICH CAN LEAD TO PCOS. THIS HYPOTHESIS IS BASED ON EVENTS THAT OCCUR DURING A LARGELY NEGLECTED STAGE OF FEMALE REPRODUCTIVE DEVELOPMENT. TO DATE, MOST RESEARCH INTO THE ORIGINS OF PCOS HAS FOCUSED ON THE PRENATAL INDUCTION OF THIS DISORDER, PARTICULARLY IN UTERO ANDROGENIZATION AND THE ROLE OF ANTI-MULLERIAN HORMONE. ESTABLISHING CAUSALITY IN OUR PERIPUBERTAL MODEL REQUIRES PROSPECTIVE COHORT STUDIES FROM INFANCY. MECHANISTIC STUDIES SHOULD CONSIDER THE ROLE OF THE GUT MICROBIOTA IN ADDITION TO THE EPIGENETIC REGULATION OF (NEURO) HORMONES. FINALLY, CLINICIANS SHOULD CONSIDER THE IMPORTANCE OF UNDERLYING CHRONIC PSYCHOLOGICAL DISTRESS AND EATING DISORDERS IN PCOS. 2020 14 4136 26 MECHANISMS OF MANGANESE-INDUCED NEUROTOXICITY AND THE PURSUIT OF NEUROTHERAPEUTIC STRATEGIES. CHRONIC EXPOSURE TO ELEVATED LEVELS OF MANGANESE VIA OCCUPATIONAL OR ENVIRONMENTAL SETTINGS CAUSES A NEUROLOGICAL DISORDER KNOWN AS MANGANISM, RESEMBLING THE SYMPTOMS OF PARKINSON'S DISEASE, SUCH AS MOTOR DEFICITS AND COGNITIVE IMPAIRMENT. NUMEROUS STUDIES HAVE BEEN CONDUCTED TO CHARACTERIZE MANGANESE'S NEUROTOXICITY MECHANISMS IN SEARCH OF EFFECTIVE THERAPEUTICS, INCLUDING NATURAL AND SYNTHETIC COMPOUNDS TO TREAT MANGANESE TOXICITY. SEVERAL POTENTIAL MOLECULAR TARGETS OF MANGANESE TOXICITY AT THE EPIGENETIC AND TRANSCRIPTIONAL LEVELS HAVE BEEN IDENTIFIED RECENTLY, WHICH MAY CONTRIBUTE TO DEVELOP MORE PRECISE AND EFFECTIVE GENE THERAPIES. THIS REVIEW UPDATES FINDINGS ON MANGANESE-INDUCED NEUROTOXICITY MECHANISMS ON INTRACELLULAR INSULTS SUCH AS OXIDATIVE STRESS, INFLAMMATION, EXCITOTOXICITY, AND MITOPHAGY, AS WELL AS TRANSCRIPTIONAL DYSREGULATIONS INVOLVING YIN YANG 1, RE1-SILENCING TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR EB, AND NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 THAT COULD BE TARGETS OF MANGANESE NEUROTOXICITY THERAPIES. THIS REVIEW ALSO FEATURES INTRACELLULAR PROTEINS SUCH AS PTEN-INDUCIBLE KINASE 1, PARKIN, SIRTUINS, LEUCINE-RICH REPEAT KINASE 2, AND ALPHA-SYNUCLEIN, WHICH ARE ASSOCIATED WITH MANGANESE-INDUCED DYSREGULATION OF AUTOPHAGY/MITOPHAGY. IN ADDITION, NEWER THERAPEUTIC APPROACHES TO TREAT MANGANESE'S NEUROTOXICITY INCLUDING NATURAL AND SYNTHETIC COMPOUNDS MODULATING EXCITOTOXICITY, AUTOPHAGY, AND MITOPHAGY, WERE REVIEWED. TAKEN TOGETHER, IN-DEPTH MECHANISTIC KNOWLEDGE ACCOMPANIED BY ADVANCES IN GENE AND DRUG DELIVERY STRATEGIES WILL MAKE SIGNIFICANT PROGRESS IN THE DEVELOPMENT OF RELIABLE THERAPEUTIC INTERVENTIONS AGAINST MANGANESE-INDUCED NEUROTOXICITY. 2022 15 2731 20 EXPLORING THE COMPLEX RELATIONSHIP BETWEEN MICROBIOTA AND SYSTEMIC LUPUS ERYTHEMATOSUS. PURPOSE OF REVIEW: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY VARIOUS AUTOANTIBODIES AND MULTI-ORGAN. MICROBIOTA DYSBIOSIS IN THE GUT, SKIN, ORAL, AND OTHER SURFACES HAS A SIGNIFICANT IMPACT ON SLE DEVELOPMENT. THIS ARTICLE SUMMARIZES RELEVANT RESEARCH AND PROVIDES NEW MICROBIOME-RELATED STRATEGIES FOR EXPLORING THE MECHANISMS AND TREATING PATIENTS WITH SLE. RECENT FINDINGS: SLE PATIENTS HAVE DISRUPTIONS IN MULTIPLE MICROBIOMES, WITH THE GUT MICROBIOTA (BACTERIA, VIRUSES, AND FUNGI) AND THEIR METABOLITES BEING THE MOST THOROUGHLY RESEARCHED. THIS DYSBIOSIS CAN PROMOTE SLE PROGRESSION THROUGH MECHANISMS SUCH AS THE LEAKY GUT, MOLECULAR MIMICRY, AND EPIGENETIC REGULATION. NOTWITHSTANDING STUDY CONSTRAINTS ON THE RELATIONSHIP BETWEEN MICROBIOTA AND SLE, SPECIFIC INTERVENTIONS TARGETING THE GUT MICROBIOTA, SUCH AS PROBIOTICS, DIETARY MANAGEMENT, AND FECAL MICROBIOTA TRANSPLANTATION, HAVE EMERGED AS PROMISING SLE THERAPEUTICS. 2023 16 1401 11 DIETARY AND PHARMACOLOGICAL TREATMENT OF ABDOMINAL PAIN IN IBS. THIS REVIEW INTRODUCES THE PRINCIPLES OF VISCERAL SENSATION AND APPRAISES THE CURRENT APPROACHES TO MANAGEMENT OF VISCERAL PAIN IN FUNCTIONAL GI DISEASES, PRINCIPALLY IBS. THESE APPROACHES INCLUDE DIETARY MEASURES INCLUDING FIBRE SUPPLEMENTATION, LOW FERMENTABLE OLIGOSACCHARIDES, DISACCHARIDES, MONOSACCHARIDES AND POLYOLS DIET, AND PHARMACOLOGICAL APPROACHES SUCH AS ANTISPASMODICS, PEPPERMINT OIL, ANTIDEPRESSANTS (TRICYCLIC AGENTS, SELECTIVE SEROTONIN REUPTAKE INHIBITORS), 5-HT(3) RECEPTOR ANTAGONISTS (ALOSETRON, ONDANSETRON, RAMOSETRON), NON-ABSORBED ANTIBIOTIC (RIFAXIMIN), SECRETAGOGUES (LUBIPROSTONE, LINACLOTIDE), MU-OPIOID RECEPTOR (OR) AND KAPPA-OR AGONIST, DELTA-OR ANTAGONIST (ELUXADOLINE), HISTAMINE H1 RECEPTOR ANTAGONIST (EBASTINE), NEUROKININ-2 RECEPTOR ANTAGONIST (IBODUTANT) AND GABAERGIC AGENTS (GABAPENTIN AND PREGABALIN). EFFICACY AND SAFETY ARE DISCUSSED BASED ON PIVOTAL TRIALS OR PUBLISHED SYSTEMATIC REVIEWS AND META-ANALYSIS, EXPRESSING ORS OR RELATIVE RISKS AND THEIR 95% CIS. POTENTIAL NEW APPROACHES MAY BE BASED ON RECENT INSIGHTS ON MUCOSAL EXPRESSION OF GENES, AND MICRORNA AND EPIGENETIC MARKERS IN HUMAN BIOPSIES AND IN ANIMAL MODELS OF VISCERAL HYPERSENSITIVITY.THE OBJECTIVES OF THIS REVIEW ARE TO APPRAISE THE PHYSIOLOGY AND ANATOMY OF GUT SENSATION AND THE EFFICACY IN THE RELIEF OF VISCERAL PAIN (TYPICALLY IN IBS) OF SEVERAL CLASSES OF THERAPIES. THESE INCLUDE FERMENTABLE OLIGOSACCHARIDES, DISACCHARIDES, MONOSACCHARIDES AND POLYOLS (FODMAPS) AND DIFFERENT CLASSES OF MEDICATIONS (BOX 1). BOX 1CLASSES OF PHARMACOLOGICAL AGENTS FOR VISCERAL PAINANTIDEPRESSANTS (TRICYCLIC AGENTS, SELECTIVE SEROTONIN REUPTAKE INHIBITORS)PEPPERMINT OIL5-HT(3) RECEPTOR ANTAGONISTS (ALOSETRON, ONDANSETRON, RAMOSETRON)NON-ABSORBED ANTIBIOTIC (RIFAXIMIN)SECRETAGOGUES (LUBIPROSTONE, LINACLOTIDE)MU-OPIOID RECEPTOR (OR) AND KAPPA-OR AGONIST AND DELTA-OR ANTAGONIST (ELUXADOLINE)HISTAMINE H1 RECEPTOR ANTAGONIST (EBASTINE)NEUROKININ-2 RECEPTOR ANTAGONIST (IBODUTANT)GABAERGIC AGENTS (GABAPENTIN AND PREGABALIN). 2017 17 1692 31 DURATION OF EXPOSURE TO EPIDURAL ANESTHESIA AT DELIVERY, DNA METHYLATION IN UMBILICAL CORD BLOOD AND THEIR ASSOCIATION WITH OFFSPRING ASTHMA IN NON-HISPANIC BLACK WOMEN. EPIDURAL ANESTHESIA IS AN EFFECTIVE PAIN RELIEF MODALITY, WIDELY USED FOR LABOR ANALGESIA. CHILDHOOD ASTHMA IS ONE OF THE COMMONEST CHRONIC MEDICAL ILLNESSES IN THE USA WHICH PLACES A SIGNIFICANT BURDEN ON THE HEALTH-CARE SYSTEM. WE RECENTLY DEMONSTRATED A NEGATIVE ASSOCIATION BETWEEN THE DURATION OF EPIDURAL ANESTHESIA AND THE DEVELOPMENT OF CHILDHOOD ASTHMA; HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS STILL REMAIN UNCLEAR. IN THIS STUDY OF 127 MOTHER-CHILD PAIRS COMPRISED OF 75 NON-HISPANIC BLACK (NHB) AND 52 NON-HISPANIC WHITE (NHW) FROM THE NEWBORN EPIGENETIC STUDY, WE TESTED THE HYPOTHESIS THAT UMBILICAL CORD BLOOD DNA METHYLATION MEDIATES THE ASSOCIATION BETWEEN THE DURATION OF EXPOSURE TO EPIDURAL ANESTHESIA AT DELIVERY AND THE DEVELOPMENT OF CHILDHOOD ASTHMA AND WHETHER THIS DIFFERED BY RACE/ETHNICITY. IN THE MOTHER-CHILD PAIRS OF NHB ANCESTRY, THE DURATION OF EXPOSURE TO EPIDURAL ANESTHESIA WAS ASSOCIATED WITH A MARGINALLY LOWER RISK OF ASTHMA (ODDS RATIO = 0.88, 95% CONFIDENCE INTERVAL = 0.76-1.01) FOR EACH 1-H INCREASE IN EXPOSURE TO EPIDURAL ANESTHESIA. OF THE 20 CPGS IN THE NHB POPULATION SHOWING THE STRONGEST MEDIATION EFFECT, 50% DEMONSTRATED AN AVERAGE MEDIATION PROPORTION OF 52%, WITH DIRECTIONAL CONSISTENCY OF DIRECT AND INDIRECT EFFECTS. THESE TOP 20 CPGS MAPPED TO 21 GENES ENRICHED FOR PATHWAYS ENGAGED IN ANTIGEN PROCESSING, ANTIGEN PRESENTATION, PROTEIN UBIQUITINATION AND REGULATORY NETWORKS RELATED TO THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS I COMPLEX AND NUCLEAR FACTOR KAPPA-B (NFKB) COMPLEX. OUR FINDINGS SUGGEST THAT DNA METHYLATION IN IMMUNE-RELATED PATHWAYS CONTRIBUTES TO THE EFFECTS OF THE DURATION OF EXPOSURE TO EPIDURAL ANESTHESIA ON CHILDHOOD ASTHMA RISK IN NHB OFFSPRING. 2023 18 105 18 A REVIEW OF MICROBIOTA AND IRRITABLE BOWEL SYNDROME: FUTURE IN THERAPIES. IRRITABLE BOWEL SYNDROME (IBS), ONE OF THE MOST FREQUENT DIGESTIVE DISORDERS, IS CHARACTERIZED BY CHRONIC AND RECURRENT ABDOMINAL PAIN AND ALTERED BOWEL HABIT. THE ORIGIN SEEMS TO BE MULTIFACTORIAL AND IS STILL NOT WELL DEFINED FOR THE DIFFERENT SUBTYPES. GENETIC, EPIGENETIC AND SEX-RELATED MODIFICATIONS OF THE FUNCTIONING OF THE NERVOUS AND IMMUNE-ENDOCRINE SUPERSYSTEMS AND REGULATION OF BRAIN-GUT PHYSIOLOGY AND BILE ACID PRODUCTION AND ABSORPTION ARE CERTAINLY INVOLVED. ACQUIRED PREDISPOSITION MAY ACT IN CONJUNCTION WITH INFECTIOUS, TOXIC, DIETARY AND LIFE EVENT-RELATED FACTORS TO ENHANCE EPITHELIAL PERMEABILITY AND ELICIT MUCOSAL MICROINFLAMMATION, IMMUNE ACTIVATION AND DYSBIOSIS. NOTABLY, STRONG EVIDENCE SUPPORTS THE ROLE OF BACTERIAL, VIRAL AND PARASITIC INFECTIONS IN TRIGGERING IBS, AND TARGETING MICROBIOTA SEEMS PROMISING IN VIEW OF THE POSITIVE RESPONSE TO MICROBIOTA-RELATED THERAPIES IN SOME PATIENTS. HOWEVER, THE LACK OF HIGHLY PREDICTIVE DIAGNOSTIC BIOMARKERS AND THE COMPLEXITY AND HETEROGENEITY OF IBS PATIENTS MAKE MANAGEMENT DIFFICULT AND UNSATISFACTORY IN MANY CASES, REDUCING PATIENT HEALTH-RELATED QUALITY OF LIFE AND INCREASING THE SANITARY BURDEN. THIS ARTICLE REVIEWS SPECIFIC ALTERATIONS AND INTERVENTIONS TARGETING THE GUT MICROBIOTA IN IBS, INCLUDING PREBIOTICS, PROBIOTICS, SYNBIOTICS, NON-ABSORBABLE ANTIBIOTICS, DIETS, FECAL TRANSPLANTATION AND OTHER POTENTIAL FUTURE APPROACHES USEFUL FOR THE DIAGNOSIS, PREVENTION AND TREATMENT OF IBS. 2018 19 1390 14 DIAGNOSING NOCIPLASTIC PAIN IN CANCER SURVIVORS: A MAJOR STEP FORWARD. NOCIPLASTIC PAIN SYNDROMES INCLUDE PARTICULAR FIBROMYALGIA, IRRITABLE BOWEL SYNDROME, HEADACHE, COMPLEX REGIONAL PAIN SYNDROME, AND IDIOPATHIC OROFACIAL PAIN. SEVERAL MECHANISMS HAVE BEEN PROPOSED TO ACCOUNT FOR NOCIPLASTIC PAIN INCLUDING CENTRAL SENSITISATION, ALTERATIONS OF PAIN MODULATORY CONTROLS, EPIGENETIC CHANGES, AND PERIPHERAL MECHANISMS. IMPORTANTLY, NOCIPLASTIC PAIN MIGHT ALSO BE PRESENT IN PATIENTS WITH CANCER PAIN, PARTICULARLY THOSE WITH PAIN RELATED TO COMPLICATIONS OF CANCER TREATMENT. INCREASED AWARENESS OF NOCIPLASTIC PAIN ASSOCIATED WITH CANCER SHOULD HAVE IMPORTANT IMPLICATIONS FOR MONITORING AND MANAGING SUCH PATIENTS. 2023 20 4403 22 MODULATION OF THE INFLAMMATORY RESPONSE IN POLYCYSTIC OVARY SYNDROME (PCOS)-SEARCHING FOR EPIGENETIC FACTORS. POLYCYSTIC OVARY SYNDROME (PCOS) IS THE MOST COMMON ENDOCRINE DISORDER IN WOMEN OF REPRODUCTIVE AGE. DESPITE ITS INCIDENCE, THE SYNDROME IS POORLY UNDERSTOOD AND REMAINS UNDERDIAGNOSED, AND FEMALE PATIENTS ARE DIAGNOSED WITH A DELAY. THE HETEROGENOUS NATURE OF THIS COMPLEX DISORDER RESULTS FROM THE COMBINED OCCURRENCE OF GENETIC, ENVIRONMENTAL, ENDOCRINE, AND BEHAVIORAL FACTORS. PRIMARY CLINICAL MANIFESTATIONS OF PCOS ARE DERIVED FROM THE EXCESS OF ANDROGENS (ANOVULATION, POLYCYSTIC OVARY MORPHOLOGY, LACK OF OR SCANTY, IRREGULAR MENSTRUAL PERIODS, ACNE AND HIRSUTISM), WHEREAS THE SECONDARY MANIFESTATIONS INCLUDE MULTIPLE METABOLIC, CARDIOVASCULAR, AND PSYCHOLOGICAL DISORDERS. DIETARY AND LIFESTYLE FACTORS PLAY IMPORTANT ROLES IN THE DEVELOPMENT AND COURSE OF PCOS, WHICH SUGGESTS STRONG EPIGENETIC AND ENVIRONMENTAL INFLUENCES. MANY STUDIES HAVE SHOWN A STRONG ASSOCIATION BETWEEN PCOS AND CHRONIC, LOW-GRADE INFLAMMATION BOTH IN THE OVARIAN TISSUE AND THROUGHOUT THE BODY. IN THE VAST MAJORITY OF PCOS PATIENTS, ELEVATED VALUES OF INFLAMMATORY MARKERS OR THEIR GENE MARKERS HAVE BEEN REPORTED. DEVELOPMENT OF THE VICIOUS CYCLE OF THE CHRONIC INFLAMMATORY STATE IN PCOS IS ADDITIONALLY STIMULATED BY HYPERINSULINEMIA AND OBESITY. CHANGES IN DNA METHYLATION, HISTONE ACETYLATION AND NONCODING RNA LEVELS ARE PRESENTED IN THIS REVIEW IN THE CONTEXT OF OXIDATIVE STRESS, REACTIVE OXYGEN SPECIES, AND INFLAMMATORY SIGNALING IN PCOS. EPIGENETIC MODULATION OF ANDROGENIC ACTIVITY IN RESPONSE TO INFLAMMATORY SIGNALING IS ALSO DISCUSSED. 2022