1 5105 139 POLYCYSTIC OVARIAN SYNDROME: A COMPLEX DISEASE WITH A GENETICS APPROACH. POLYCYSTIC OVARIAN SYNDROME (PCOS) IS A COMPLEX ENDOCRINE DISORDER AFFECTING FEMALES IN THEIR REPRODUCTIVE AGE. THE EARLY DIAGNOSIS OF PCOS IS COMPLICATED AND COMPLEX DUE TO OVERLAPPING SYMPTOMS OF THIS DISEASE. THE MOST ACCEPTED DIAGNOSTIC APPROACH TODAY IS THE ROTTERDAM CONSENSUS (2003), WHICH SUPPORTS THE POSITIVE DIAGNOSIS OF PCOS WHEN PATIENTS PRESENT TWO OUT OF THE FOLLOWING THREE SYMPTOMS: BIOCHEMICAL AND CLINICAL SIGNS OF HYPERANDROGENISM, OLIGO, AND ANOVULATION, ALSO POLYCYSTIC OVARIAN MORPHOLOGY ON SONOGRAPHY. GENETIC VARIANCE, EPIGENETIC CHANGES, AND DISTURBED LIFESTYLE LEAD TO THE DEVELOPMENT OF PATHOPHYSIOLOGICAL DISTURBANCES, WHICH INCLUDE HYPERANDROGENISM, INSULIN RESISTANCE, AND CHRONIC INFLAMMATION IN PCOS FEMALES. AT THE MOLECULAR LEVEL, DIFFERENT PROTEINS AND MOLECULAR AND SIGNALING PATHWAYS ARE INVOLVED IN DISEASE PROGRESSION, WHICH LEADS TO THE FAILURE OF A SINGLE GENETIC DIAGNOSTIC APPROACH. THE GENETIC APPROACH TO ELUCIDATE THE MECHANISM OF PATHOGENESIS OF PCOS WAS RECENTLY DEVELOPED, WHEREBY FOUR PHENOTYPIC VARIANCES OF PCOS CATEGORIZE PCOS PATIENTS INTO CLASSIC, OVULATORY, AND NON-HYPERANDROGENIC TYPES. GENETIC STUDIES HELP TO IDENTIFY THE ROOT CAUSE FOR THE DEVELOPMENT OF THIS PCOS. PCOS GENETIC INHERITANCE IS AUTOSOMAL DOMINANT BUT THE LATEST INVESTIGATIONS REVEALED IT AS A MULTIGENE ORIGIN DISEASE. DIFFERENT GENETIC LOCI AND SPECIFIC GENES HAVE BEEN IDENTIFIED SO FAR AS BEING ASSOCIATED WITH THIS DISEASE. GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND RELATED GENETIC STUDIES HAVE CHANGED THE SCENARIO FOR THE DIAGNOSIS AND TREATMENT OF THIS REPRODUCTIVE AND METABOLIC CONDITION KNOWN AS PCOS. THIS REVIEW ARTICLE BRIEFLY DISCUSSES DIFFERENT GENES ASSOCIATED DIRECTLY OR INDIRECTLY WITH DISEASE DEVELOPMENT AND PROGRESSION. 2022 2 4403 46 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 3 4892 38 OXIDATIVE STRESS AND REPRODUCTIVE FUNCTION: OXIDATIVE STRESS IN POLYCYSTIC OVARY SYNDROME. IN BRIEF: A GENETIC, EPIGENETIC, AND ENVIRONMENTAL ASSOCIATION EXISTS BETWEEN OXIDATIVE STRESS (OS) AND POLYCYSTIC OVARY SYNDROME (PCOS), EXPRESSED IN A MULTIFACETED CLINICAL PROFILE. THIS REVIEW SUMMARIZES AND DISCUSSES THE ROLE OF OS IN THE PATHOGENESIS OF PCOS SYNDROME, FOCUSING ON METABOLIC, REPRODUCTIVE, AND CANCER COMPLICATIONS. ABSTRACT: OXIDATIVE STRESS (OS), AN IMBALANCE BETWEEN OXIDANTS AND ANTIOXIDANTS IN CELLS, IS ONE OF MANY FACTORS PLAYING ESSENTIAL ROLES IN THE PATHOGENESIS OF POLYCYSTIC OVARY SYNDROME (PCOS). PCOS IS DESCRIBED MAINLY AS A DISPROPORTION OF REPRODUCTIVE HORMONES, LEADING TO CHRONIC ANOVULATION AND INFERTILITY IN WOMEN. INTERESTINGLY, OS IN PCOS MAY BE ASSOCIATED WITH MANY DISORDERS AND DISEASES. THIS REVIEW FOCUSES ON CHARACTERISTIC MARKERS OF OS IN PCOS AND THE RELATIONSHIP BETWEEN OS AND PCOS RELATED TO INSULIN RESISTANCE (IR), HYPERANDROGENEMIA, OBESITY, CHRONIC INFLAMMATION, CARDIOVASCULAR DISEASES, AND CANCER. INTERESTINGLY, IN PATIENTS WITH PCOS, AN INCREASE IN OXIDATIVE STATUS AND INSUFFICIENT COMPENSATION OF THE INCREASE IN ANTIOXIDANT STATUS BEFORE ANY CARDIOVASCULAR COMPLICATIONS ARE OBSERVED. MOREOVER, FREE RADICALS PROMOTE CARCINOGENESIS IN PCOS PATIENTS. HOWEVER, DESPITE THESE DATA, IT HAS NOT BEEN ESTABLISHED WHETHER OXYGEN STRESS INFLUENCES PCOS DEVELOPMENT OR A SECONDARY DISORDER RESULTING FROM HYPERGLYCEMIA, IR, AND CARDIOVASCULAR AND CANCER COMPLICATIONS IN WOMEN. 2022 4 259 42 ADVANCES IN PCOS PATHOGENESIS AND PROGRESSION-MITOCHONDRIAL MUTATIONS AND DYSFUNCTION. POLYCYSTIC OVARY SYNDROME (PCOS) IS A COMMON FEMALE ENDOCRINE DISORDER, WHICH STILL REMAINS LARGELY UNSOLVED IN TERMS OF ETIOLOGY AND PATHOGENESIS DESPITE IMPORTANT ADVANCES IN OUR UNDERSTANDING OF ITS GENETIC, EPIGENETIC, OR ENVIRONMENTAL FACTOR IMPLICATIONS. IT IS A HETEROGENEOUS DISEASE, FREQUENTLY ASSOCIATED WITH INSULIN RESISTANCE, CHRONIC INFLAMMATION, AND OXIDATIVE STRESS AND PROBABLY ACCOMPANIED WITH SUBCLINICAL CARDIOVASCULAR DISEASE (CVD) AND SOME MALIGNANT LESIONS AS WELL, SUCH AS ENDOMETRIAL CANCER. DISCREPANCIES IN THE CLINICAL PHENOTYPE AND PROGRESSION OF PCOS EXIST BETWEEN DIFFERENT POPULATION GROUPS, WHICH NUCLEAR GENETIC STUDIES HAVE SO FAR FAILED TO EXPLAIN. OVER THE LAST YEARS, MITOCHONDRIAL DYSFUNCTION HAS BEEN INCREASINGLY RECOGNIZED AS AN IMPORTANT CONTRIBUTOR TO AN ARRAY OF DISEASES. BECAUSE MITOCHONDRIA ARE UNDER THE DUAL GENETIC CONTROL OF BOTH THE MITOCHONDRIAL AND NUCLEAR GENOMES, MUTATIONS WITHIN EITHER DNA MOLECULE MAY RESULT IN DEFICIENCY IN RESPIRATORY CHAIN FUNCTION THAT LEADS TO A REDUCED ABILITY TO PRODUCE CELLULAR ADENOSINE-5'-TRIPHOSPHATE AND TO AN EXCESSIVE PRODUCTION OF REACTIVE OXYGEN SPECIES. HOWEVER, THE ASSOCIATION BETWEEN VARIANTS IN MITOCHONDRIAL GENOME, MITOCHONDRIAL DYSFUNCTION, AND PCOS HAS BEEN INVESTIGATED TO A LESSER EXTENT. MAY MUTATIONS IN MITOCHONDRIAL DNA (MTDNA) BECOME AN ADDITIONAL TARGET OF INVESTIGATIONS ON THE MISSING PCOS HERITABILITY? ARE MUTATIONS IN MTDNA IMPLICATED IN THE INITIATION AND PROGRESSION OF PCOS COMPLICATIONS, E.G., CVDS, DIABETES MELLITUS, CANCERS? 2018 5 6116 30 THE EPIGENETIC CORRELATION AMONG OVARIAN CANCER, ENDOMETRIOSIS AND PCOS: A REVIEW. OVARIAN CANCER IS A FREQUENT MALIGNANCY THAT AFFECTS A LARGE PERCENTAGE OF WOMEN. ENDOMETRIOSIS IS A CHRONIC CONDITION, WHERE THERE IS A PRODUCTION OF BENIGN LESIONS WERE OBSERVED IN THE UTERINE ENVIRONMENT. PCOS IS A METABOLIC DISORDER CHARACTERIZED BY THE PRESENCE OF NUMEROUS CYSTS IN THE OVARIES. THE RELATION BETWEEN OVARIAN MALIGNANCIES AND PCOS, BY AN INCREASED RATIO OF OVARIAN STROMAL TISSUES IN PCOS PATIENTS. THE DIRECT CORRELATION IS NOT YET CONFIRMED AMONG THE THREE DISORDERS, BUT IT IS OFTEN NOTED THAT THEY SHARE RISK FACTORS, SUCH AS OBESITY, HORMONAL IMBALANCES. EPIGENETIC FACTORS HAVE SHOWN TO BE AN IMPORTANT REASON FOR CANCER PROGRESSION. OUR FINDINGS AT THE EPIGENETIC LEVEL INCLUDES A COMPARATIVE ANALYSIS, POINT MUTATIONS IN GENES, OVERACTIVATION OF SIGNALING PATHWAYS. THIS REVIEW PAPER, HIGHLIGHT THE POSSIBLE CORRELATION BETWEEN THE THREE DISORDERS IN TERMS OF GENETIC AND EPIGENETIC FACTORS AND HOW IT COULD TOGETHER TRIGGER THE CANCER PROGRESSION AND METASTASIS. 2022 6 5106 32 POLYCYSTIC OVARY SYNDROME IN ADULT WOMEN. POLYCYSTIC OVARY SYNDROME IS THE MOST PREVALENT ENDOCRINE-METABOLIC PATHOLOGY IN PRE-MENOPAUSAL WOMEN. ITS ETIOPATHOGENESIS IS COMPLEX, MULTIFACTORIAL AND HETEROGENEOUS, INCLUDING THE INTERACTION OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. ANDROGENIC EXCESS CONSTITUTES THE DISEASE'S MAIN PHYSIOPATHOLOGICAL MECHANISM AND RESULTS IN REPRODUCTIVE, METABOLIC AND COSMETIC ALTERATIONS WHICH NEGATIVELY IMPACT THESE PATIENTS' QUALITY OF LIFE. THE CRITERIA ESTABLISHED IN THE ROTTERDAM CONSENSUS AND THEIR CORRECT APPLICATION FORM THE NECESSARY BASIS FOR THIS SYNDROME'S PROPER DIAGNOSIS. IN THE ABSENCE OF AN AETIOLOGICAL TREATMENT, THE AIM IS TO IMPROVE THE CLINICAL SIGNS AND SYMPTOMS DERIVED FROM HYPERANDROGENISM, OVARIAN DYSFUNCTION AND EXISTING METABOLIC COMPLICATIONS, AND, THEREFORE, THEY MUST BE CHRONIC AND INDIVIDUALISED. 2019 7 5104 29 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 8 4973 46 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 9 5643 37 SEX AND AUTOIMMUNITY: PROPOSED MECHANISMS OF DISEASE ONSET AND SEVERITY. CHRONIC AUTOIMMUNE DISEASES AFFECT 5-10% OF THE POPULATION WORLDWIDE AND ARE LARGELY PREDOMINANT IN WOMEN. SEX HORMONE CHANGES HAVE BEEN WIDELY INVESTIGATED BASED ON CHANGES IN THE CLINICAL PHENOTYPES OBSERVED DURING PREGNANCY AND MENOPAUSE. IT IS KNOWN THAT FEMALES WITH AUTOIMMUNE DISEASES MANIFEST A HIGHER RATE OF CIRCULATING LEUKOCYTES WITH A SINGLE X CHROMOSOME, AND THERE HAVE BEEN SEVERAL REPORTS ON THE ROLE OF X CHROMOSOME GENE DOSAGE THROUGH INACTIVATION OR DUPLICATION IN AUTOIMMUNITY. HOWEVER, IT IS ALSO IMPORTANT NOT TO OVERLOOK MEN WITH AUTOIMMUNE DISEASES, WHO MIGHT MANIFEST A MORE FREQUENT LOSS OF THE Y CHROMOSOME IN CIRCULATING LEUKOCYTES. AREAS COVERED: IN THE PRESENT REVIEW, WE WILL DISCUSS THE CURRENT EVIDENCE SUPPORTING THE MECHANISMS OF FEMALE PREDOMINANCE IN RHEUMATIC DISEASES, BY DISCUSSING THE ROLE OF REPRODUCTIVE HISTORY, SEX HORMONES AND ABNORMALITIES RELATED TO THEM, CLINICAL DIFFERENCES BETWEEN MALE AND FEMALE PATIENTS, AND EPIGENETIC CHANGES THAT HAVE BEEN EVALUATED THROUGH TWIN STUDIES ON GENETIC AND ENVIRONMENTAL CHANGES IN RHEUMATIC PATIENTS. EXPERT OPINION: THE INFLUENCE OF SEX HORMONES AND CHROMOSOMES ON THE FUNCTION OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMS NEEDS TO BE CLARIFIED, TO BETTER UNDERSTAND THE RISK OF AUTOIMMUNE DISEASES, EARLY DIAGNOSTIC TOOLS, AND THERAPEUTIC RESPONSE. 2019 10 3750 39 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 11 6812 32 [EPIGENETICS, INTERFACE BETWEEN ENVIRONMENT AND GENES: ROLE IN COMPLEX DISEASES]. EPIGENETICS IS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION OR CELLULAR PHENOTYPE CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE. EPIGENETICS IS ONE OF THE MAJOR MECHANISMS EXPLAINING THE "DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASES" (DOHAD). BESIDES GENETIC BACKGROUND INHERITED FROM PARENTS, WHICH CONFERS SUSCEPTIBILITY TO CERTAIN PATHOLOGIES, EPIGENETIC CHANGES CONSTITUTE THE MEMORY OF PREVIOUS EVENTS, EITHER POSITIVE OR NEGATIVE, ALONG THE LIFE CYCLE, INCLUDING AT THE IN UTERO STAGE. THE LATER EXPOSITION TO HOSTILE ENVIRONMENT MAY REVEAL SUCH SUSCEPTIBILITY, WITH THE DEVELOPMENT OF VARIOUS PATHOLOGIES, AMONG THEM NUMEROUS CHRONIC COMPLEX DISEASES. THE DEMONSTRATION OF SUCH A SEQUENCE OF EVENTS HAS BEEN SHOWN FOR METABOLIC DISEASES AS OBESITY, METABOLIC SYNDROME AND TYPE 2 DIABETES, CARDIOVASCULAR DISEASE AND CANCER. IN CONTRAST TO GENETIC PREDISPOSITION, WHICH IS IRREVERSIBLE, EPIGENETIC CHANGES ARE POTENTIALLY REVERSIBLE, THUS GIVING TARGETS NOT ONLY FOR PREVENTION, BUT POSSIBLY ALSO FOR THE TREATMENT OF CERTAIN COMPLEX DISEASES. 2012 12 738 29 CANCER SUSCEPTIBILITY: EPIGENETIC MANIFESTATION OF ENVIRONMENTAL EXPOSURES. CANCER IS A DISEASE THAT RESULTS FROM BOTH GENETIC AND EPIGENETIC CHANGES. DISCORDANT PHENOTYPES AND VARYING INCIDENCES OF COMPLEX DISEASES SUCH AS CANCER IN MONOZYGOTIC TWINS AS WELL AS GENETICALLY IDENTICAL LABORATORY ANIMALS HAVE LONG BEEN ATTRIBUTED TO DIFFERENCES IN ENVIRONMENTAL EXPOSURES. ACCUMULATING EVIDENCE INDICATES, HOWEVER, THAT DISPARITIES IN GENE EXPRESSION RESULTING FROM VARIABLE MODIFICATIONS IN DNA METHYLATION AND CHROMATIN STRUCTURE IN RESPONSE TO THE ENVIRONMENT ALSO PLAY A ROLE IN DIFFERENTIAL SUSCEPTIBILITY TO DISEASE. DESPITE A GROWING CONSENSUS ON THE IMPORTANCE OF EPIGENETICS IN THE ETIOLOGY OF CHRONIC HUMAN DISEASES, THE GENES MOST PRONE TO EPIGENETIC DYSREGULATION ARE INCOMPLETELY DEFINED. MOREOVER, NEITHER THE ENVIRONMENTAL AGENTS MOST STRONGLY AFFECTING THE EPIGENOME NOR THE CRITICAL WINDOWS OF VULNERABILITY TO ENVIRONMENTALLY INDUCED EPIGENETIC ALTERATIONS ARE ADEQUATELY CHARACTERIZED. THESE MAJOR DEFICITS IN KNOWLEDGE MARKEDLY IMPAIR OUR ABILITY TO UNDERSTAND FULLY THE ETIOLOGY OF CANCER AND THE IMPORTANCE OF THE EPIGENOME IN DIAGNOSING AND PREVENTING THIS DEVASTATING DISEASE. 2007 13 506 32 ASSOCIATION OF ENDOMETRIOSIS WITH CARDIOVASCULAR DISEASE: GENETIC ASPECTS (REVIEW). CARDIOVASCULAR DISEASE (CVD) COMPRISES A BROAD SPECTRUM OF PATHOLOGICAL CONDITIONS THAT AFFECT THE HEART OR BLOOD VESSELS, INCLUDING SEQUELAE THAT ARISE FROM DAMAGED VASCULATURE IN OTHER ORGANS OF THE BODY, SUCH AS THE BRAIN, KIDNEYS OR EYES. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE OF THE ARTERIAL INTIMA AND IS THE PRIMARY CAUSE OF CORONARY ARTERY DISEASE, PERIPHERAL VASCULAR DISEASE, HEART ATTACK, STROKE AND RENAL PATHOLOGY. IT REPRESENTS A LEADING CAUSE OF MORTALITY WORLDWIDE AND THE LOSS OF HUMAN PRODUCTIVITY THAT IS MARKED BY AN ALTERED IMMUNE RESPONSE. ENDOMETRIOSIS IS A HERITABLE, HETEROGENEOUS, COMMON GYNECOLOGICAL CONDITION INFLUENCED BY MULTIPLE GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS, AFFECTING UP TO 10% OF THE FEMALE POPULATION OF CHILDBEARING AGE, CAUSING PAIN AND INFERTILITY; IT IS CHARACTERIZED BY THE ECTOPIC GROWTH OF ENDOMETRIAL TISSUE OUTSIDE THE UTERINE CAVITY. OF NOTE, EPIDEMIOLOGICAL DATA OBTAINED THUS FAR HAVE SUGGESTED A LINK BETWEEN ENDOMETRIOSIS AND THE RISK OF DEVELOPING CVD. THE SIMILARITIES OBSERVED IN SPECIFIC MOLECULAR AND CELLULAR PATHWAYS OF ENDOMETRIOSIS AND CVD MAY BE PARTIALLY EXPLAINED BY A SHARED GENETIC BACKGROUND. THE PRESENT REVIEW PRESENTS AND DISCUSSES THE SHARED GENETIC FACTORS WHICH HAVE BEEN REPORTED TO BE ASSOCIATED WITH THE DEVELOPMENT OF BOTH DISORDERS. 2023 14 5646 26 SEX DIFFERENCES AND EMERGING NEW RISK FACTORS FOR ATHEROSCLEROSIS AND ITS THROMBOTIC COMPLICATIONS. CARDIOVASCULAR DISEASES (CVD) REMAIN THE WORLD'S LEADING CAUSE OF DEATH AND DISABILITY IN BOTH MEN AND WOMEN, BUT WITH DIFFERENT PROGNOSTICS AND OUTCOMES BETWEEN SEXES. ALTHOUGH THE BURDEN OF CVD IS GENERALLY RELATED TO THE CONVENTIONAL RISK FACTORS, THE RELEVANCE OF NON-TRADITIONAL RISK FACTORS IS INCREASINGLY BEING RECOGNIZED TO EXPLAIN THE SO-CALLED "RESIDUAL RISK". MEN AND WOMEN SHARE MANY SIMILARITIES REGARDING CLASSICAL CARDIOVASCULAR RISK FACTORS BUT HAVE DIFFERENT DISEASE PATHOPHYSIOLOGY, CLINICAL PRESENTATIONS, PREVALENCE, AND OUTCOMES OF CVDS. HOW SEX-SPECIFICITIES REGARDING THE EFFECTS OF NON-TRADITIONAL RISK FACTORS MAY CONTRIBUTE TO THE EVOLUTION OF ATHEROSCLEROSIS AND ITS CLINICAL MANIFESTATIONS IN MALES AND FEMALES REMAIN LARGELY UNDERANALYZED. THE PRESENT REVIEW SUMMARIZES THE CURRENT KNOWLEDGE FOR SEX DIFFERENCES IN ATHEROSCLEROTIC PLAQUE COMPOSITION AND CLINICAL EVOLUTION IN ASSOCIATION WITH RISK FACTORS, SUCH AS INFLAMMATION, LIPOPROTEIN(A), HEMOSTASIS, INTRAPLAQUE CALCIFICATION, AND DEPRESSION. WE FURTHER DISCUSS THE POTENTIAL SEX-DIFFERENTIAL IMPACT OF CHRONIC INFECTIOUS DISEASES, GUT MICROBIOME AND, EPIGENETIC GENE EXPRESSION REGULATION FOR ATHEROSCLEROSIS AND THE EFFECT OF FEMALE-SPECIFIC DISORDERS IN CVD. 2021 15 6791 28 [DOES THE NUMBER OF PATIENTS WITH AUTOIMMUNE DISORDERS AND THE FREQUENCY OF AUTOIMMUNE DISEASES INCREASE?]. AUTOIMMUNE DISEASES GENERALLY BELONG TO THE RARE DISEASES, HOWEVER, SOME OF THEM ARE FREQUENT IN THE POPULATION. IN THE PRESENT WORK THE AUTHORS ANALYSE WHETHER CAN ANY INCREASE BE OBSERVED IN THE NUMBER OF PATIENTS SUFFERING FROM AUTOIMMUNE DISEASES AND WHETHER DO THE FREQUENCY OF CERTAIN AUTOIMMUNE DISORDERS INCREASE. DUE MAINLY TO EPIGENETIC FACTORS THE INCIDENCE OF AUTOIMMUNE DISEASES ARE INCREASING, THEREFORE THERE ARE MORE PATIENTS RECOGNISED WITH PARTICULAR DISORDERS. ON THE OTHER HAND THE INCIDENCE IS INCREASED BY IMPROVING DIAGNOSTIC POSSIBILITIES, BY THE USE OF MORE SPECIFIC AND SENSITIVE CLASSIFICATION CRITERIA AND MORE SOPHISTICATED LABORATORY TESTS, RESULTED IN THE RECOGNITION OF MILDER AND ATYPICAL DISEASE VARIANTS AS WELL. THE PREVALENCE IS ALSO INCREASING IN CONSEQUENCE OF NOVEL IMMUNE SUPPRESSIVE THERAPEUTIC POSSIBILITIES AND THE CONSEQUENT IMPROVEMENT OF SURVIVAL IN THE MOST OF THESE DISEASES. BESIDES, MORE AND MORE DISEASES HAVE BEEN REVEALED TO HAVE AUTOIMMUNE BACKGROUND, AND LOT OF NEW AUTOIMMUNE SYNDROMES, DISEASES HAVE BEEN CHARACTERISED RECENTLY. THIS INCREASES THE NUMBER OF THE KNOWN AUTOIMMUNE RHEUMATIC DISORDERS WITH A CONSEQUENT INCREASE IN THE NUMBER OF AUTOIMMUNE PATIENTS. ASSIGNED TO THE INCREASING NUMBER OF VARIABLE CHRONIC AUTOIMMUNE DISORDERS, AND THE INCREASING NUMBER OF DISABLED PATIENTS WITH SUCH DISEASES INCREASING MEDICAL AND SOCIAL ATTENTION HAS TO BE FOCUSED ON. 2007 16 3676 33 INFLAMMATION AND NEUTROPHIL IMMUNOSENESCENCE IN HEALTH AND DISEASE: TARGETED TREATMENTS TO IMPROVE CLINICAL OUTCOMES IN THE ELDERLY. DESPITE INCREASING LONGEVITY, MANY OLD PEOPLE ARE NOT IN GOOD HEALTH. THERE HAS BEEN AN INCREASE IN THE PREVALENCE OF AGE-ASSOCIATED MULTI-MORBIDITY (TWO OR MORE CHRONIC CONDITIONS IN THE SAME PERSON). ALSO, SEVERE INFECTIONS, SUCH AS PNEUMONIA, REMAIN SIGNIFICANT CAUSES OF MORTALITY AND MORBIDITY IN THIS AGING GROUP. MANY CHRONIC HEALTH CONDITIONS SHARE RISK FACTORS SUCH AS INCREASING AGE, SMOKING, A SEDENTARY LIFE STYLE AND BEING PART OF A LOWER SOCIOECONOMIC GROUP. HOWEVER, DESPITE THIS, MULTI-MORBIDITIES OFTEN CO-OCCUR MORE COMMONLY THAN WOULD BE PREDICTED. THIS HAS LED TO THE HYPOTHESIS THAT THEY SHARE COMMON UNDERLYING MECHANISMS. THIS IS AN IMPORTANT CONCEPT, FOR IF IT WERE TRUE, TREATMENTS COULD BE DEVISED WHICH TARGET THESE COMMON PATHWAYS AND IMPROVE A NUMBER OF AGE-ASSOCIATED HEALTH CONDITIONS. MANY CHRONIC ILLNESSES ASSOCIATED WITH MULTI-MORBIDITY AND SEVERE INFECTIONS ARE CHARACTERIZED BY AN ABNORMAL AND SUSTAINED INFLAMMATORY RESPONSE, WITH NEUTROPHILS BEING KEY EFFECTOR CELLS IN THE PATHOLOGICAL PROCESS. STUDIES HAVE DESCRIBED ABERRANT NEUTROPHIL FUNCTIONS ACROSS THESE CONDITIONS, AND SOME HAVE HIGHLIGHTED POTENTIAL MECHANISMS FOR ALTERED CELL BEHAVIOURS WHICH APPEAR SHARED ACROSS DISEASE STATES. IT HAS BEEN SUGGESTED THAT ALTERED FUNCTIONS MAY REPRESENT NEUTROPHIL "SENESCENCE". THIS REVIEW CONSIDERS HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE CELL AGES, AND HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE HOST AGES IN HEALTH AND DISEASE AND DISCUSSES WHETHER NEUTROPHIL FUNCTIONS COULD BE TARGETED TO IMPROVE HEALTH OUTCOMES IN OLDER ADULTS. 2018 17 5076 32 PHYSIOLOGICAL AND ENVIRONMENTAL FACTORS AFFECTING CANCER RISK AND PROGNOSIS IN OBESITY. OBESITY RESULTS FROM A CHRONIC EXCESSIVE ACCUMULATION OF ADIPOSE TISSUE DUE TO A LONG-TERM IMBALANCE BETWEEN ENERGY INTAKE AND EXPENDITURE. AVAILABLE EPIDEMIOLOGICAL AND CLINICAL DATA STRONGLY SUPPORT THE LINKS BETWEEN OBESITY AND CERTAIN CANCERS. EMERGING CLINICAL AND EXPERIMENTAL FINDINGS HAVE IMPROVED OUR UNDERSTANDING OF THE ROLES OF KEY PLAYERS IN OBESITY-ASSOCIATED CARCINOGENESIS SUCH AS AGE, SEX (MENOPAUSE), GENETIC AND EPIGENETIC FACTORS, GUT MICROBIOTA AND METABOLIC FACTORS, BODY SHAPE TRAJECTORY OVER LIFE, DIETARY HABITS, AND GENERAL LIFESTYLE. IT IS NOW WIDELY ACCEPTED THAT THE CANCER-OBESITY RELATIONSHIP DEPENDS ON THE SITE OF CANCER, THE SYSTEMIC INFLAMMATORY STATUS, AND MICRO ENVIRONMENTAL PARAMETERS SUCH AS LEVELS OF INFLAMMATION AND OXIDATIVE STRESS IN TRANSFORMING TISSUES. WE HEREBY REVIEW RECENT ADVANCES IN OUR UNDERSTANDING OF CANCER RISK AND PROGNOSIS IN OBESITY WITH RESPECT TO THESE PLAYERS. WE HIGHLIGHT HOW THE LACK OF THEIR CONSIDERATION CONTRIBUTED TO THE CONTROVERSY OVER THE LINK BETWEEN OBESITY AND CANCER IN EARLY EPIDEMIOLOGICAL STUDIES. FINALLY, THE LESSONS AND CHALLENGES OF INTERVENTIONS FOR WEIGHT LOSS AND BETTER CANCER PROGNOSIS, AND THE MECHANISMS OF WEIGHT GAIN IN SURVIVORS ARE ALSO DISCUSSED. 2023 18 3848 23 IS EPIGENETICS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE? BACKGROUND: EPIGENETIC MECHANISMS PROVIDE ONE POTENTIAL EXPLANATION FOR HOW ENVIRONMENTAL INFLUENCES IN EARLY LIFE CAUSE LONG-TERM CHANGES IN CHRONIC DISEASE SUSCEPTIBILITY. WHEREAS EPIGENETIC DYSREGULATION IS INCREASINGLY IMPLICATED IN VARIOUS RARE DEVELOPMENTAL SYNDROMES AND CANCER, THE ROLE OF EPIGENETICS IN COMPLEX CHRONIC DISEASES, SUCH AS CARDIOVASCULAR DISEASE, TYPE 2 DIABETES AND OBESITY, REMAINS LARGELY UNCHARACTERIZED. EXTENSIVE WORK IN ANIMAL MODELS IS REQUIRED TO DEVELOP SPECIFIC HYPOTHESES THAT CAN BE PRACTICABLY TESTED IN HUMANS. ANIMAL MODELS: WE HAVE DEVELOPED A MOUSE MODEL SHOWING THAT METHYL DONOR SUPPLEMENTATION PREVENTS TRANSGENERATIONAL AMPLIFICATION OF OBESITY, SUGGESTING A ROLE FOR DNA METHYLATION IN THE DEVELOPMENTAL ESTABLISHMENT OF BODY WEIGHT REGULATION. CONCLUSIONS: COUPLING SUCH MODELS WITH RECENTLY DEVELOPED EPIGENOMIC TECHNOLOGIES SHOULD ULTIMATELY ENABLE US TO DETERMINE IF EPIGENETICS IS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE. 2009 19 3743 47 INSIGHTS FROM GENOMIC STUDIES ON THE ROLE OF SEX STEROIDS IN THE AETIOLOGY OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A CHRONIC NEURO-INFLAMMATORY DISORDER THE DEFINING FEATURE OF WHICH IS THE GROWTH OF TISSUE (LESIONS) THAT RESEMBLES THE ENDOMETRIUM OUTSIDE THE UTERUS. ESTIMATES OF PREVALENCE QUOTE RATES OF ~10% OF WOMEN OF REPRODUCTIVE AGE, EQUATING TO AT LEAST 190 MILLION WOMEN WORLD-WIDE. GENETIC, HORMONAL AND IMMUNOLOGICAL FACTORS HAVE ALL BEEN PROPOSED AS CONTRIBUTING TO RISK FACTORS ASSOCIATED WITH THE DEVELOPMENT OF LESIONS. TWIN STUDIES REPORT THE HERITABLE COMPONENT OF ENDOMETRIOSIS AS ~50%. GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) THAT APPEAR OVER-REPRESENTED IN PATIENTS WITH ENDOMETRIOSIS, PARTICULARLY THOSE WITH MORE EXTENSIVE DISEASE (STAGE III/IV). IN DIFFERENT SAMPLE POPULATIONS, THERE HAS BEEN REPLICATION OF SNPS NEAR GENES INVOLVED IN OESTROGEN AND OTHER STEROID REGULATED PATHWAYS INCLUDING ESR1 (OESTROGEN RECEPTOR ALPHA), GREB1, HOXA10, WNT4 AND MAPK KINASE SIGNALLING. COMPARISONS WITH GWAS CONDUCTED ON OTHER PATIENT COHORTS HAVE FOUND LINKS WITH REPRODUCTIVE TRAITS (AGE AT MENARCHE) AND DISORDERS (FIBROIDS, ENDOMETRIAL AND OVARIAN CANCER) AND COMMON CO-MORBIDITIES (MIGRAINE, DEPRESSION, ASTHMA). IN SUMMARY, GENETIC ANALYSES HAVE PROVIDED NEW INSIGHTS INTO THE HORMONE-REGULATED PATHWAYS THAT MAY CONTRIBUTE TO INCREASED RISK OF DEVELOPING ENDOMETRIOSIS SOME OF WHICH MAY ACT IN EARLY LIFE. NEW STUDIES ARE NEEDED TO CLARIFY THE RELATIONSHIP BETWEEN THE MANY SNPS IDENTIFIED, THE GENES THAT THEY REGULATE AND THEIR CONTRIBUTION(S) TO DEVELOPMENT OF DIFFERENT FORMS OF ENDOMETRIOSIS. WE HOPE THAT MORE ADVANCED METHODS ALLOWING INTEGRATION BETWEEN GWAS, EPIGENETIC AND TISSUE EXPRESSION DATA WILL IMPROVE RISK ANALYSIS AND REDUCE DIAGNOSITIC DELAY. LAY SUMMARY: ENDOMETRIOSIS IS A DEBILITATING REPRODUCTIVE DISORDER AFFECTING ~10% OF REPRODUCTIVE-AGE WOMEN, AND THOSE ASSIGNED FEMALE AT BIRTH, WHICH CAUSES A RANGE OF SYMPTOMS INCLUDING CHRONIC PAIN AND INFERTILITY. THE REASON WHY SOME, BUT NOT ALL THESE INDIVIDUALS, DEVELOP THE LESIONS THAT CHARACTERISE THE DISEASE ARE POORLY UNDERSTOOD, BUT RECENTLY ATTENTION HAS FOCUSED ON GENETIC RISK FACTORS TO EXPLAIN WHY THE INCIDENCE IS HIGHER IN SOME FAMILIES. STUDIES ON LARGE COHORTS OF PATIENTS WITH COMPARISON OF THEIR DNA TO WOMEN WITHOUT ENDOMETRIOSIS OR WITH OTHER DISORDERS HAVE DOCUMENTED CHANGES IN GENES ASSOCIATED WITH STEROID HORMONE PRODUCTION OR ACTION. THE RESULTS PROVIDE FURTHER EVIDENCE THAT ENDOMETRIOSIS SHARES GENETIC RISK FACTORS WITH OTHER DISORDERS OF THE REPRODUCTIVE SYSTEM AND A PLATFORM FOR NEW IDEAS RELATED TO RISK, BIOMARKERS AND THERAPIES. 2022 20 3404 35 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023