1 322 144 ALKALINE PHOSPHATASE: AN OLD FRIEND AS TREATMENT TARGET FOR CARDIOVASCULAR AND MINERAL BONE DISORDERS IN CHRONIC KIDNEY DISEASE. ALKALINE PHOSPHATASE (ALP) IS AN EVOLUTIONARY CONSERVED ENZYME AND WIDELY USED BIOMARKER IN CLINICAL PRACTICE. TISSUE-NONSPECIFIC ALKALINE PHOSPHATASE (TNALP) IS ONE OF FOUR HUMAN ISOZYMES THAT ARE EXPRESSED AS DISTINCT TNALP ISOFORMS AFTER POSTTRANSLATIONAL MODIFICATIONS, MAINLY IN BONE, LIVER, AND KIDNEY TISSUES. BEYOND THE WELL-KNOWN EFFECTS ON BONE MINERALIZATION, THE BONE ALP (BALP) ISOFORMS (B/I, B1, B1X, AND B2) ARE ALSO INVOLVED IN THE PATHOGENESIS OF ECTOPIC CALCIFICATION. THIS NARRATIVE REVIEW SUMMARIZES THE RECENT CLINICAL INVESTIGATIONS AND MECHANISMS THAT LINK ALP AND BALP TO INFLAMMATION, METABOLIC SYNDROME, VASCULAR CALCIFICATION, ENDOTHELIAL DYSFUNCTION, FIBROSIS, CARDIOVASCULAR DISEASE, AND MORTALITY. THE ASSOCIATION BETWEEN ALP, VITAMIN K, BONE METABOLISM, AND FRACTURE RISK IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) IS ALSO DISCUSSED. RECENT ADVANCES IN DIFFERENT PHARMACOLOGICAL STRATEGIES ARE HIGHLIGHTED, WITH THE POTENTIAL TO MODULATE THE EXPRESSION OF ALP DIRECTLY AND INDIRECTLY IN CKD-MINERAL AND BONE DISORDER (CKD-MBD), E.G., EPIGENETIC MODULATION, PHOSPHATE BINDERS, CALCIMIMETICS, VITAMIN D, AND OTHER ANTI-FRACTURE TREATMENTS. WE CONCLUDE THAT THE SIGNIFICANT EVIDENCE FOR ALP AS A PATHOGENIC FACTOR AND RISK MARKER IN CKD-MBD SUPPORTS THE INCLUSION OF CONCRETE TREATMENT TARGETS FOR ALP IN CLINICAL GUIDELINES. WHILE A TARGET VALUE BELOW 120 U/L IS ASSOCIATED WITH IMPROVED SURVIVAL, FURTHER EXPERIMENTAL AND CLINICAL RESEARCH SHOULD EXPLORE INTERVENTIONAL STRATEGIES WITH OPTIMAL RISK-BENEFIT PROFILES. THE FUTURE HOLDS GREAT PROMISE FOR NOVEL DRUG THERAPIES MODULATING ALP. 2022 2 1391 33 DIAGNOSTIC APPROACH TO PATIENTS WITH LOW SERUM ALKALINE PHOSPHATASE. INCREASED SERUM LEVELS OF ALKALINE PHOSPHATASE (ALP) ARE WIDELY RECOGNIZED AS A BIOCHEMICAL MARKER OF MANY DISORDERS AFFECTING THE LIVER OR BONE. HOWEVER, THE APPROACH FOR PATIENTS WITH LOW ALP PHOSPHATASE IS NOT WELL-ESTABLISHED. LOW SERUM ALP IS AN EPIPHENOMENON OF MANY SEVERE ACUTE INJURIES AND DISEASES. PERSISTENTLY LOW SERUM ALP MAY BE SECONDARY TO DRUG THERAPY (INCLUDING ANTIRESORPTIVES) OR A VARIETY OF ACQUIRED DISORDERS, SUCH AS MALNUTRITION, VITAMIN AND MINERAL DEFICIENCIES, ENDOCRINE DISORDERS, ETC. HYPOPHOSPHATASIA, DUE TO PATHOGENIC VARIANTS OF THE ALPL GENE, WHICH ENCODES TISSUE NON-SPECIFIC ALP, IS THE MOST COMMON GENETIC CAUSE OF LOW SERUM ALP. MARKED BONE HYPOMINERALIZATION IS FREQUENT IN SEVERE PEDIATRIC-ONSET CASES. HOWEVER, ADULT FORMS OF HYPOPHOSPHATASIA USUALLY PRESENT WITH MILDER MANIFESTATIONS, SUCH AS SKELETAL PAIN, CHONDROCALCINOSIS, CALCIFIC PERIARTHRITIS, DENTAL PROBLEMS, AND STRESS FRACTURES. THE DIAGNOSTIC APPROACH TO THESE PATIENTS IS DISCUSSED. MEASURING SEVERAL ALP SUBSTRATES, SUCH AS PYROPHOSPHATE, PYRIDOXAL PHOSPHATE, OR PHOSPHOETHANOLAMINE, MAY HELP TO ESTABLISH ENZYME DEFICIENCY. GENE ANALYSIS SHOWING A PATHOGENIC VARIANT IN ALPL MAY CONFIRM THE DIAGNOSIS. HOWEVER, A SUBSTANTIAL PROPORTION OF PATIENTS SHOW NORMAL RESULTS AFTER SEQUENCING ALPL EXONS. IT IS STILL UNKNOWN IF THOSE PATIENTS CARRY UNIDENTIFIED MUTATIONS IN REGULATORY REGIONS OF ALPL, EPIGENETIC CHANGES, OR ABNORMALITIES IN OTHER GENES. 2023 3 5045 38 PHARMACOLOGIC EPIGENETIC MODULATORS OF ALKALINE PHOSPHATASE IN CHRONIC KIDNEY DISEASE. PURPOSE OF REVIEW: IN CHRONIC KIDNEY DISEASE (CKD), DISTURBANCE OF SEVERAL METABOLIC REGULATORY MECHANISMS CAUSE PREMATURE AGEING, ACCELERATED CARDIOVASCULAR DISEASE (CVD), AND MORTALITY. SINGLE-TARGET INTERVENTIONS HAVE REPEATEDLY FAILED TO IMPROVE THE PROGNOSIS FOR CKD PATIENTS. EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL TO MODULATE SEVERAL PATHOGENETIC PROCESSES SIMULTANEOUSLY. ALKALINE PHOSPHATASE (ALP) IS A ROBUST PREDICTOR OF CVD AND ALL-CAUSE MORTALITY AND IMPLICATED IN PATHOGENIC PROCESSES ASSOCIATED WITH CVD IN CKD. RECENT FINDINGS: IN EXPERIMENTAL STUDIES, EPIGENETIC MODULATION OF ALP BY MICRORNAS OR BROMODOMAIN AND EXTRATERMINAL (BET) PROTEIN INHIBITION HAS SHOWN PROMISING RESULTS FOR THE TREATMENT OF CVD AND OTHER CHRONIC METABOLIC DISEASES. THE BET INHIBITOR APABETALONE IS CURRENTLY BEING EVALUATED FOR CARDIOVASCULAR RISK REDUCTION IN A PHASE III CLINICAL STUDY IN HIGH-RISK CVD PATIENTS, INCLUDING PATIENTS WITH CKD (CLINICALTRIALS.GOV IDENTIFIER: NCT02586155). PHASE II STUDIES DEMONSTRATE AN ALP-LOWERING POTENTIAL OF APABETALONE, WHICH WAS ASSOCIATED WITH IMPROVED CARDIOVASCULAR AND RENAL OUTCOMES. SUMMARY: ALP IS A PREDICTOR OF CVD AND MORTALITY IN CKD. EPIGENETIC MODULATION OF ALP HAS THE POTENTIAL TO AFFECT SEVERAL PATHOGENETIC PROCESSES IN CKD AND THEREBY IMPROVE CARDIOVASCULAR OUTCOME. 2020 4 220 43 ACUTE KIDNEY DISEASE: AN OVERVIEW OF THE EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND MANAGEMENT. ACUTE KIDNEY INJURY (AKI) INCREASES THE RISK OF CHRONIC KIDNEY DISEASE (CKD), AND AKI AND CKD ARE SEEN AS INTERCONNECTED SYNDROMES. ACUTE KIDNEY DISEASE (AKD) IS DEFINED AS SUBACUTE DAMAGE AND/OR LOSS OF KIDNEY FUNCTION OCCURRING 7 TO 90 DAYS AFTER AKI, DURING WHICH PERIOD KEY INTERVENTIONS MAY BE INITIATED TO HINDER THE DEVELOPMENT OF CKD. WHILE AKD IS USUALLY UNDER-RECOGNIZED, IT IS ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY GLOBALLY. THIS REVIEW ARTICLE AIMS TO SUMMARIZE THE CURRENT KNOWLEDGE CONCERNING THE EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND MANAGEMENT OF AKD WITH THE AIM TO DEVELOP MONITORING STRATEGIES AND THERAPEUTIC AGENTS OF AKD. GENERALLY, AKD TENDS TO OCCUR MORE FREQUENTLY IN THE ELDERLY AND THOSE WITH CHRONIC DISEASES, SUCH AS HYPERTENSION, DIABETES MELLITUS, AND METABOLIC SYNDROME. IN ADDITION, THE SEVERITY, DURATION, AND FREQUENCY OF AKI ARE INDEPENDENT RISK FACTORS FOR AKD. INVESTIGATIONS OF SEVERAL MECHANISMS OF AKD, SUCH AS RENAL TUBULAR EPITHELIUM CELL-CYCLE ARREST, EPIGENETIC CHANGE, CHRONIC INFLAMMATION, MITOCHONDRIA DYSFUNCTION, FAILED REGENERATION OF TUBULAR CELLS, METABOLIC REPROGRAMMING, AND RENIN-ANGIOTENSIN SYSTEM (RAS) ACTIVATION, HAVE IDENTIFIED ADDITIONAL POTENTIAL PHARMACOTHERAPY TARGETS. MANAGEMENT OF AKD INCLUDES PREVENTION OF REPEATED AKI, EARLY AND REGULAR FOLLOW-UP BY A NEPHROLOGIST, RESUMPTION AND ADJUSTMENT OF ESSENTIAL MEDICATION, OPTIMIZATION OF BLOOD PRESSURE CONTROL AND NUTRITION MANAGEMENT, AND DEVELOPMENT OF NEW PHARMACEUTICAL AGENTS INCLUDING RAS INHIBITORS. FINALLY, WE OUTLINE A CARE BUNDLE FOR AKD PATIENTS BASED ON IMPORTANT LESSONS LEARNED FROM STUDIES AND REGISTRIES AND IDENTIFY THE NEED FOR CLINICAL TRIALS OF RAS INHIBITORS OR OTHER NOVEL AGENTS TO IMPEDE ENSUING CKD DEVELOPMENT. 2023 5 1898 32 ENDOTHELINS IN CARDIOVASCULAR BIOLOGY AND THERAPEUTICS. CARDIOVASCULAR DISEASE IS A MAJOR CONTRIBUTOR TO GLOBAL MORBIDITY AND MORTALITY AND IS THE COMMON END POINT OF MANY CHRONIC DISEASES. THE ENDOTHELINS COMPRISE THREE STRUCTURALLY SIMILAR PEPTIDES OF 21 AMINO ACIDS IN LENGTH. ENDOTHELIN 1 (ET-1) AND ET-2 ACTIVATE TWO G PROTEIN-COUPLED RECEPTORS - ENDOTHELIN RECEPTOR TYPE A (ET(A)) AND ENDOTHELIN RECEPTOR TYPE B (ET(B)) - WITH EQUAL AFFINITY, WHEREAS ET-3 HAS A LOWER AFFINITY FOR ET(A). ET-1 IS THE MOST POTENT VASOCONSTRICTOR IN THE HUMAN CARDIOVASCULAR SYSTEM AND HAS REMARKABLY LONG-LASTING ACTIONS. ET-1 CONTRIBUTES TO VASOCONSTRICTION, VASCULAR AND CARDIAC HYPERTROPHY, INFLAMMATION, AND TO THE DEVELOPMENT AND PROGRESSION OF CARDIOVASCULAR DISEASE. ENDOTHELIN RECEPTOR ANTAGONISTS HAVE REVOLUTIONIZED THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION. CLINICAL TRIALS CONTINUE TO EXPLORE NEW APPLICATIONS OF ENDOTHELIN RECEPTOR ANTAGONISTS, PARTICULARLY IN TREATMENT-RESISTANT HYPERTENSION, CHRONIC KIDNEY DISEASE AND PATIENTS RECEIVING ANTIANGIOGENIC THERAPIES. TRANSLATIONAL STUDIES HAVE IDENTIFIED IMPORTANT ROLES FOR THE ENDOTHELIN ISOFORMS AND NEW THERAPEUTIC TARGETS DURING DEVELOPMENT, IN FLUID-ELECTROLYTE HOMEOSTASIS, AND IN CARDIOVASCULAR AND NEURONAL FUNCTION. NOVEL PHARMACOLOGICAL STRATEGIES ARE EMERGING IN THE FORM OF SMALL-MOLECULE EPIGENETIC MODULATORS, BIOLOGICS (SUCH AS MONOCLONAL ANTIBODIES FOR ET(B)) AND POSSIBLY SIGNALLING PATHWAY-BIASED AGONISTS AND ANTAGONISTS. 2019 6 2373 33 EPIGENETIC REGULATION OF THE N-TERMINAL TRUNCATED ISOFORM OF MATRIX METALLOPROTEINASE-2 (NTT-MMP-2) AND ITS PRESENCE IN RENAL AND CARDIAC DISEASES. SEVERAL CLINICAL AND EXPERIMENTAL STUDIES HAVE DOCUMENTED A COMPELLING AND CRITICAL ROLE FOR THE FULL-LENGTH MATRIX METALLOPROTEINASE-2 (FL-MMP-2) IN ISCHEMIC RENAL INJURY, PROGRESSIVE RENAL FIBROSIS, AND DIABETIC NEPHROPATHY. A NOVEL N-TERMINAL TRUNCATED ISOFORM OF MMP-2 (NTT-MMP-2) WAS RECENTLY DISCOVERED, WHICH IS INDUCED BY HYPOXIA AND OXIDATIVE STRESS BY THE ACTIVATION OF A LATENT PROMOTER LOCATED IN THE FIRST INTRON OF THE MMP2 GENE. THIS NTT-MMP-2 ISOFORM IS ENZYMATICALLY ACTIVE BUT REMAINS INTRACELLULAR IN OR NEAR THE MITOCHONDRIA. IN THIS PERSPECTIVE ARTICLE, WE FIRST PRESENT THE FINDINGS ABOUT THE DISCOVERY OF THE NTT-MMP-2 ISOFORM, AND ITS FUNCTIONAL AND STRUCTURAL DIFFERENCES AS COMPARED WITH THE FL-MMP-2 ISOFORM. BASED ON PUBLICLY AVAILABLE EPIGENOMICS DATA FROM THE ENCYCLOPEDIA OF DNA ELEMENTS (ENCODE) PROJECT, WE PROVIDE INSIGHTS INTO THE EPIGENETIC REGULATION OF THE LATENT PROMOTER LOCATED IN THE FIRST INTRON OF THE MMP2 GENE, WHICH SUPPORT THE ACTIVATION OF THE NTT-MMP-2 ISOFORM. WE THEN FOCUS ON ITS FUNCTIONAL ASSESSMENT BY COVERING THE ALTERATIONS FOUND IN THE KIDNEY OF TRANSGENIC MICE EXPRESSING THE NTT-MMP-2 ISOFORM. NEXT, WE HIGHLIGHT RECENT FINDINGS REGARDING THE PRESENCE OF THE NTT-MMP-2 ISOFORM IN RENAL DYSFUNCTION, IN KIDNEY AND CARDIAC DISEASES, INCLUDING DAMAGE OBSERVED IN AGING, ACUTE ISCHEMIA-REPERFUSION INJURY (IRI), CHRONIC KIDNEY DISEASE, DIABETIC NEPHROPATHY, AND HUMAN RENAL TRANSPLANTS WITH DELAYED GRAFT FUNCTION. FINALLY, WE BRIEFLY DISCUSS HOW OUR INSIGHTS MAY GUIDE FURTHER EXPERIMENTAL AND CLINICAL STUDIES THAT ARE NEEDED TO ELUCIDATE THE UNDERLYING MECHANISMS AND THE ROLE OF THE NTT-MMP-2 ISOFORM IN RENAL DYSFUNCTION, WHICH MAY HELP TO ESTABLISH IT AS A POTENTIAL THERAPEUTIC TARGET IN KIDNEY DISEASES. 2021 7 6398 35 THE ROLE OF VITAMIN D AND VDR IN CARCINOGENESIS: THROUGH EPIDEMIOLOGY AND BASIC SCIENCES. IN THE LAST TWO DECADES VITAMIN D (VD) RESEARCH HAS DEMONSTRATED NEW EXTRASKELETAL ACTIONS OF THIS PRE-HORMONE, SUGGESTING A PROTECTIVE ROLE OF THIS SECOSTEROID IN THE ONSET, PROGRESSION AND PROGNOSIS OF SEVERAL CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS CARDIOVASCULAR DISEASE, DIABETES MELLITUS OR CANCER. REGARDING CARCINOGENESIS, BOTH PRECLINICAL AND EPIDEMIOLOGICAL EVIDENCE AVAILABLE SHOW ONCOPROTECTIVE ACTIONS OF VD AND ITS RECEPTOR, THE VDR. HOWEVER, IN LATE NEOPLASTIC STAGES THE VD SYSTEM (VDS) SEEMS TO BE LESS FUNCTIONAL, WHICH APPEARS TO BE DUE TO AN EPIGENETIC SILENCING OF THE SYSTEM. IN PRECLINICAL EXPERIMENTAL STUDIES, VD PRESENTS ONCOPROTECTIVE ACTIONS THROUGH MODULATION OF INFLAMMATION, CELL PROLIFERATION, CELL DIFFERENTIATION, ANGIOGENESIS, INVASIVE AND METASTATIC POTENTIAL, APOPTOSIS, MIRNA EXPRESSION REGULATION AND MODULATION OF THE HEDGEHOG SIGNALLING PATHWAY. MOREOVER, EPIDEMIOLOGICAL EVIDENCE POINTS TOWARDS AN ONCOPROTECTIVE ROLE OF VITAMIN D AND VDR IN COLORECTAL CANCER. THIS ASSOCIATION IS MORE CONTROVERSIAL WITH BREAST, OVARIAN AND PROSTATE CANCERS, ALTHOUGH WITH A FEW ADVERSE EFFECTS. NONETHELESS, WE SHOULD CONSIDER OTHER FACTORS TO DETERMINE THE BENEFIT OF INCREASED SERUM CONCENTRATION OF VD. MUCH OF THE EPIDEMIOLOGICAL EVIDENCE IS STILL INCONCLUSIVE, AND WE WILL HAVE TO WAIT FOR NEW, BETTER-DESIGNED ONGOING RCTS AND THEIR RESULTS TO DISCERN THE REAL EFFECT OF VITAMIN D IN CANCER RISK REDUCTION AND THERAPY. THE OBJECTIVE OF THIS LITERATURE REVIEW IS TO OFFER AN UP-TO-DATE ANALYSIS OF THE ROLE OF THE VD AND VDR, IN THE ONSET, PROGRESSION AND PROGNOSIS OF ALL TYPES OF CANCER. WE FURTHER DISCUSS THE AVAILABLE LITERATURE AND SUGGEST NEW HYPOTHESES AND FUTURE CHALLENGES IN THE FIELD OF VD RESEARCH. 2017 8 2616 26 EPIGENOME MODULATION INDUCED BY KETOGENIC DIETS. KETOGENIC DIETS (KD) ARE DIETARY STRATEGIES LOW IN CARBOHYDRATES, NORMAL IN PROTEIN, AND HIGH, NORMAL, OR REDUCED IN FAT WITH OR WITHOUT (VERY LOW-CALORIES KETOGENIC DIET, VLCKD) A REDUCED CALORIC INTAKE. KDS HAVE BEEN SHOWN TO BE USEFUL IN THE TREATMENT OF OBESITY, METABOLIC DISEASES AND RELATED DISORDERS, NEUROLOGICAL DISEASES, AND VARIOUS PATHOLOGICAL CONDITIONS SUCH AS CANCER, NONALCOHOLIC LIVER DISEASE, AND CHRONIC PAIN. SEVERAL STUDIES HAVE INVESTIGATED THE INTRACELLULAR METABOLIC PATHWAYS THAT CONTRIBUTE TO THE BENEFICIAL EFFECTS OF THESE DIETS. ALTHOUGH EPIGENETIC CHANGES ARE AMONG THE MOST IMPORTANT DETERMINANTS OF AN ORGANISM'S ABILITY TO ADAPT TO ENVIRONMENTAL CHANGES, DATA ON THE EPIGENETIC CHANGES ASSOCIATED WITH THESE DIETARY PATHWAYS ARE STILL LIMITED. THIS REVIEW PROVIDES AN OVERVIEW OF THE MAJOR EPIGENETIC CHANGES ASSOCIATED WITH KDS. 2022 9 3933 30 LIVER SINUSOIDAL ENDOTHELIAL CELLS ARE IMPLICATED IN MULTIPLE FIBROTIC MECHANISMS. CHRONIC LIVER DISEASES ARE ATTRIBUTED TO LIVER INJURY. DEVELOPMENT OF FIBROSIS FROM CHRONIC LIVER DISEASES IS A DYNAMIC PROCESS THAT INVOLVES MULTIPLE MOLECULAR AND CELLULAR PROCESSES. AS THE FIRST TO BE IMPACTED BY INJURY, LIVER SINUSOIDAL ENDOTHELIAL CELLS (LSECS) ARE INVOLVED IN THE PATHOGENESIS OF LIVER DISEASES CAUSED BY A VARIETY OF ETIOLOGIES. MOREOVER, CAPILLARIZATION OF LSECS HAS BEEN RECOGNIZED AS AN IMPORTANT EVENT IN THE DEVELOPMENT OF CHRONIC LIVER DISEASES AND FIBROSIS. STUDIES HAVE REPORTED THAT VARIOUS CYTOKINES (SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR, TRANSFORMING GROWTH FACTOR-BETA), AND PATHWAYS (SUCH AS HEDGEHOG, AND NOTCH), AS WELL AS EPIGENETIC AND METABOLIC FACTORS ARE INVOLVED IN THE DEVELOPMENT OF LSEC-MEDIATED LIVER FIBROSIS. THIS REVIEW DESCRIBES THE COMPLEXITY AND PLASTICITY OF LSECS IN FIBROTIC LIVER DISEASES FROM SEVERAL PERSPECTIVES, INCLUDING THE CROSS-TALK BETWEEN LSECS AND OTHER INTRA-HEPATIC CELLS. MOREOVER, IT SUMMARIZES THE MECHANISMS OF SEVERAL KINDS OF LSECS-TARGETING ANTI-FIBROSIS CHEMICALS, AND PROVIDES A THEORETICAL BASIS FOR FUTURE STUDIES. 2021 10 3152 31 GLUCOSE VARIABILITY: HOW DOES IT WORK? A GROWING BODY OF EVIDENCE POINTS TO THE ROLE OF GLUCOSE VARIABILITY (GV) IN THE DEVELOPMENT OF THE MICROVASCULAR AND MACROVASCULAR COMPLICATIONS OF DIABETES. IN THIS REVIEW, WE SUMMARIZE DATA ON GV-INDUCED BIOCHEMICAL, CELLULAR AND MOLECULAR EVENTS INVOLVED IN THE PATHOGENESIS OF DIABETIC COMPLICATIONS. CURRENT DATA INDICATE THAT THE DETERIORATING EFFECT OF GV ON TARGET ORGANS CAN BE REALIZED THROUGH OXIDATIVE STRESS, GLYCATION, CHRONIC LOW-GRADE INFLAMMATION, ENDOTHELIAL DYSFUNCTION, PLATELET ACTIVATION, IMPAIRED ANGIOGENESIS AND RENAL FIBROSIS. THE EFFECTS OF GV ON OXIDATIVE STRESS, INFLAMMATION, ENDOTHELIAL DYSFUNCTION AND HYPERCOAGULABILITY COULD BE AGGRAVATED BY HYPOGLYCEMIA, ASSOCIATED WITH HIGH GV. OSCILLATING HYPERGLYCEMIA CONTRIBUTES TO BETA CELL DYSFUNCTION, WHICH LEADS TO A FURTHER INCREASE IN GV AND COMPLETES THE VICIOUS CIRCLE. IN CELLS, THE GV-INDUCED CYTOTOXIC EFFECT INCLUDES MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS AND DISTURBANCES IN AUTOPHAGIC FLUX, WHICH ARE ACCOMPANIED BY REDUCED VIABILITY, ACTIVATION OF APOPTOSIS AND ABNORMALITIES IN CELL PROLIFERATION. THESE EFFECTS ARE REALIZED THROUGH THE UP- AND DOWN-REGULATION OF A LARGE NUMBER OF GENES AND THE ACTIVITY OF SIGNALING PATHWAYS SUCH AS PI3K/AKT, NF-KAPPAB, MAPK (ERK), JNK AND TGF-BETA/SMAD. EPIGENETIC MODIFICATIONS MEDIATE THE POSTPONED EFFECTS OF GLUCOSE FLUCTUATIONS. THE MULTIPLE DETERIORATIVE EFFECTS OF GV PROVIDE FURTHER SUPPORT FOR CONSIDERING IT AS A THERAPEUTIC TARGET IN DIABETES. 2021 11 3591 31 IMPAIRED ONE CARBON METABOLISM AND DNA METHYLATION IN ALCOHOL TOXICITY. EXCESSIVE ALCOHOL CONSUMPTION IS A PROMINENT PROBLEM AND ONE OF THE MAJOR CAUSES OF MORTALITY AND MORBIDITY AROUND THE WORLD. LONG-TERM, HEAVY ALCOHOL CONSUMPTION IS ASSOCIATED WITH A NUMBER OF DELETERIOUS HEALTH CONSEQUENCES, SUCH AS CANCER, HEART AND LIVER DISEASE, A VARIETY OF NEUROLOGICAL, COGNITIVE, AND BEHAVIORAL DEFICITS. ALCOHOL CONSUMPTION IS ALSO ASSOCIATED WITH DEVELOPMENTAL DEFECTS. THE CAUSES OF ALCOHOL-INDUCED TOXICITY ARE PRESENTLY UNCLEAR. ONE OF THE MECHANISMS UNDERLYING ALCOHOL TOXICITY HAS TO DO WITH ITS INTERACTION WITH FOLIC ACID/HOMOCYSTEINE OR ONE-CARBON METABOLISM (OCM). OCM IS A MAJOR DONOR OF METHYL GROUPS FOR METHYLATION, PARTICULARLY DNA METHYLATION CRITICAL FOR EPIGENETIC REGULATION OF GENE EXPRESSION, AND ITS DISTURBANCE MAY COMPROMISE DNA METHYLATION, THEREBY AFFECTING GENE EXPRESSION. OCM DISTURBANCE MEDIATED BY NUTRIENT DEFICITS IS A WELL-KNOWN RISK FACTOR FOR VARIOUS DISORDERS AND DEVELOPMENTAL DEFECTS (E.G., NEURAL TUBE DEFECTS). IN THIS REVIEW, WE SUMMARIZE THE ROLE OF OCM DISTURBANCE AND ASSOCIATED EPIGENETIC ABERRATIONS IN CHRONIC ALCOHOL-INDUCED TOXICITY. IN THIS REVIEW, WE SUMMARIZE THE ROLE OF ONE-CARBON METABOLISM (OCM) ABERRATIONS IN CHRONIC ALCOHOL-INDUCED TOXICITY. OCM IS A MAJOR DONOR OF METHYL GROUPS FOR METHYLATION REACTIONS, PARTICULARLY DNA METHYLATION CRITICAL FOR EPIGENETIC REGULATION OF GENE EXPRESSION. ALCOHOL INTERFERENCE WITH OCM AND CONSEQUENT REDUCED AVAILABILITY OF METHYL GROUPS, IMPROPER DNA METHYLATION, AND ABERRANT GENE EXPRESSION CAN PLAY A CAUSATIVE ROLE IN ALCOHOL TOXICITY. 2014 12 5890 33 SYSTEMS BIOLOGY ELUCIDATES COMMON PATHOGENIC MECHANISMS BETWEEN NONALCOHOLIC AND ALCOHOLIC-FATTY LIVER DISEASE. THE ABNORMAL ACCUMULATION OF FAT IN THE LIVER IS OFTEN RELATED EITHER TO METABOLIC RISK FACTORS ASSOCIATED WITH METABOLIC SYNDROME IN THE ABSENCE OF ALCOHOL CONSUMPTION (NONALCOHOLIC FATTY LIVER DISEASE, NAFLD) OR TO CHRONIC ALCOHOL CONSUMPTION (ALCOHOLIC FATTY LIVER DISEASE, AFLD). CLINICAL AND HISTOLOGICAL STUDIES SUGGEST THAT NAFLD AND AFLD SHARE PATHOGENIC MECHANISMS. NEVERTHELESS, CURRENT DATA ARE STILL INCONCLUSIVE AS TO WHETHER THE UNDERLYING BIOLOGICAL PROCESS AND DISEASE PATHWAYS OF NAFLD AND AFLD ARE ALIKE. OUR PRIMARY AIM WAS TO INTEGRATE OMICS AND PHYSIOLOGICAL DATA TO ANSWER THE QUESTION OF WHETHER NAFLD AND AFLD SHARE MOLECULAR PROCESSES THAT LEAD TO DISEASE DEVELOPMENT. WE ALSO EXPLORED THE EXTENT TO WHICH INSULIN RESISTANCE (IR) IS A DISTINCTIVE FEATURE OF NAFLD. TO ANSWER THESE QUESTIONS, WE USED SYSTEMS BIOLOGY APPROACHES, SUCH AS GENE ENRICHMENT ANALYSIS, PROTEIN-PROTEIN INTERACTION NETWORKS, AND GENE PRIORITIZATION, BASED ON MULTI-LEVEL DATA EXTRACTED BY COMPUTATIONAL DATA MINING. WE OBSERVED THAT THE LEADING DISEASE PATHWAYS ASSOCIATED WITH NAFLD DID NOT SIGNIFICANTLY DIFFER FROM THOSE OF AFLD. HOWEVER, SYSTEMS BIOLOGY REVEALED THE IMPORTANCE OF EACH MOLECULAR PROCESS BEHIND EACH OF THE TWO DISEASES, AND DISSECTED DISTINCTIVE MOLECULAR NAFLD AND AFLD-SIGNATURES. COMPARATIVE CO-ANALYSIS OF NAFLD AND AFLD CLARIFIED THE PARTICIPATION OF NAFLD, BUT NOT AFLD, IN CARDIOVASCULAR DISEASE, AND SHOWED THAT INSULIN SIGNALING IS IMPAIRED IN FATTY LIVER REGARDLESS OF THE NOXA, BUT THE PUTATIVE REGULATORY MECHANISMS ASSOCIATED WITH NAFLD SEEM TO ENCOMPASS A COMPLEX NETWORK OF GENES AND PROTEINS, PLAUSIBLE OF EPIGENETIC MODIFICATIONS. GENE PRIORITIZATION SHOWED A CANCER-RELATED FUNCTIONAL MAP THAT SUGGESTS THAT THE FATTY TRANSFORMATION OF THE LIVER TISSUE IS REGARDLESS OF THE CAUSE, AN EMERGING MECHANISM OF UBIQUITOUS ONCOGENIC ACTIVATION. IN CONCLUSION, SIMILAR UNDERLYING DISEASE MECHANISMS LEAD TO NAFLD AND AFLD, BUT SPECIFIC ONES DEPICT A PARTICULAR DISEASE SIGNATURE THAT HAS A DIFFERENT IMPACT ON THE SYSTEMIC CONTEXT. 2013 13 3963 33 LONG NONCODING RNA UC.98 STABILIZES ATHEROSCLEROTIC PLAQUES BY PROMOTING THE PROLIFERATION AND ADHESIVE CAPACITY IN MURINE AORTIC ENDOTHELIAL CELLS. PATHOLOGICAL STUDIES HAVE SHOWN THAT THE VULNERABILITY OF PLAQUES AFFECTS OUTCOMES IN PATIENTS WITH ATHEROSCLEROSIS (AS), A CHRONIC INFLAMMATORY DISEASE AND COMMON CAUSE OF MORBIDITY AND MORTALITY WORLDWIDE. ALTHOUGH EMERGING TECHNOLOGIES HAVE ENABLED EARLY DIAGNOSIS OF AS WITH HIGH-RISK VULNERABLE PLAQUES, MORE ACCURATE AND NONINVASIVE DIAGNOSTIC METHODS ARE URGENTLY REQUIRED. TO THIS END, MOLECULES INVOLVED IN GENETIC OR EPIGENETIC REGULATION OF THE VULNERABILITY OF ATHEROSCLEROTIC PLAQUES HAVE BEEN EXTENSIVELY STUDIED. HERE, WE EVALUATED LONG NONCODING RNA (LNCRNA) VARIABILITY BY MICROARRAY ASSAY IN MURINE AORTIC ENDOTHELIAL CELLS (MAECS) BEARING VULNERABLE PLAQUES AND IDENTIFIED THE NOVEL FUNCTIONAL LNCRNA UC.98, WHOSE EXPRESSION PATTERN WAS ASSOCIATED WITH THE VULNERABILITY OF ATHEROSCLEROTIC PLAQUES. CONSISTENT WITH THIS, CLINICAL STATISTICS COMPARING THE PERIPHERAL BLOOD SPECIMENS FROM SETS OF PATIENTS WITH AS WITH OR WITHOUT VULNERABLE PLAQUES CONFIRMED THE LINEAR RELATIONSHIP BETWEEN THE EXPRESSION PATTERN OF UC.98 AND PLAQUE INSTABILITY. MOREOVER, MTT ASSAYS AND WESTERN BLOT ANALYSIS SHOWED THAT SILENCING OF INTRINSIC UC.98 IN MAECS NOT ONLY SUPPRESSED CELL PROLIFERATION BUT ALSO DECREASED THE EXPRESSIONS OF VASCULAR CELL ADHESION MOLECULE-1 AND INTERCELLULAR ADHESION MOLECULE-1, THEREBY INACTIVATING THE NUCLEAR FACTOR-KAPPAB PATHWAY. IN CONCLUSION, OUR RESULTS HIGHLIGHTED THE PIVOTAL ROLE OF UC.98 IN REGULATING THE VULNERABILITY OF PLAQUES DURING AS PROGRESSION AND SUGGESTED THAT UC.98 MAY BE A BIOMARKER OF THE EARLY DIAGNOSIS AND PROGNOSIS OF AS WITH VULNERABLE PLAQUES AND A POTENTIAL THERAPEUTIC TARGET FOR SLOWING AS PROGRESSION. 2020 14 4719 32 NONCODING RNA AND EPIGENETIC GENE REGULATION IN RENAL DISEASES. KIDNEYS HAVE A MAJOR ROLE IN NORMAL PHYSIOLOGY AND METABOLIC HOMEOSTASIS. LOSS OR IMPAIRMENT OF KIDNEY FUNCTION IS A COMMON OCCURRENCE IN SEVERAL METABOLIC DISORDERS, INCLUDING HYPERTENSION AND DIABETES. CHRONIC KIDNEY DISEASE (CKD) AFFECT NEARLY 10% OF THE POPULATION WORLDWIDE; RANKS 18TH IN THE LIST OF CAUSES OF DEATH; AND CONTRIBUTES TO A SIGNIFICANT PROPORTION OF HEALTHCARE COSTS. THE TISSUE REPAIR AND REGENERATIVE POTENTIAL OF KIDNEYS ARE LIMITED AND THEY DECLINE DURING AGING. RECENT STUDIES HAVE DEMONSTRATED A KEY ROLE FOR EPIGENETIC PROCESSES AND PLAYERS, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, NONCODING (NC)RNA, AND SO ON, IN BOTH KIDNEY DEVELOPMENT AND DISEASE. IN THIS REVIEW, WE HIGHLIGHT THESE RECENT FINDINGS WITH AN EMPHASIS ON ABERRANT EPIGENETIC CHANGES THAT ACCOMPANY RENAL DISEASES, KEY TARGETS, AND THEIR THERAPEUTIC VALUE. 2017 15 4198 28 METABOLIC PROFILING DISTINGUISHES THREE SUBTYPES OF ALZHEIMER'S DISEASE. THE CAUSE OF ALZHEIMER'S DISEASE IS INCOMPLETELY DEFINED, AND NO TRULY EFFECTIVE THERAPY EXISTS. HOWEVER, MULTIPLE STUDIES HAVE IMPLICATED METABOLIC ABNORMALITIES SUCH AS INSULIN RESISTANCE, HORMONAL DEFICIENCIES, AND HYPERHOMOCYSTEINEMIA. OPTIMIZING METABOLIC PARAMETERS IN A COMPREHENSIVE WAY HAS YIELDED COGNITIVE IMPROVEMENT, BOTH IN SYMPTOMATIC AND ASYMPTOMATIC INDIVIDUALS. THEREFORE, EXPANDING THE STANDARD LABORATORY EVALUATION IN PATIENTS WITH DEMENTIA MAY BE REVEALING. HERE I REPORT THAT METABOLIC PROFILING REVEALS THREE ALZHEIMER'S DISEASE SUBTYPES. THE FIRST IS INFLAMMATORY, IN WHICH MARKERS SUCH AS HS-CRP AND GLOBULIN:ALBUMIN RATIO ARE INCREASED. THE SECOND TYPE IS NON-INFLAMMATORY, IN WHICH THESE MARKERS ARE NOT INCREASED, BUT OTHER METABOLIC ABNORMALITIES ARE PRESENT. THE THIRD TYPE IS A VERY DISTINCTIVE CLINICAL ENTITY THAT AFFECTS RELATIVELY YOUNG INDIVIDUALS, EXTENDS BEYOND THE TYPICAL ALZHEIMER'S DISEASE INITIAL DISTRIBUTION TO AFFECT THE CORTEX WIDELY, IS CHARACTERIZED BY EARLY NON-AMNESTIC FEATURES SUCH AS DYSCALCULIA AND APHASIA, IS OFTEN MISDIAGNOSED OR LABELED ATYPICAL ALZHEIMER'S DISEASE, TYPICALLY AFFECTS APOE4-NEGATIVE INDIVIDUALS, AND IS ASSOCIATED WITH STRIKING ZINC DEFICIENCY. GIVEN THE INVOLVEMENT OF ZINC IN MULTIPLE ALZHEIMER'S-RELATED METABOLIC PROCESSES, SUCH AS INSULIN RESISTANCE, CHRONIC INFLAMMATION, ADAM10 PROTEOLYTIC ACTIVITY, AND HORMONAL SIGNALING, THIS SYNDROME OF ALZHEIMER'S-PLUS WITH LOW ZINC (APLZ) WARRANTS FURTHER METABOLIC, GENETIC, AND EPIGENETIC CHARACTERIZATION. 2015 16 6595 31 TUMOR-SPECIFIC GROWTH FACTOR (TSGF): A FUTURISTIC TUMOR BIOMARKER IN EARLY DIAGNOSIS OF CANCER. DESPITE THE SIGNIFICANT IMPROVEMENT IN THE TREATMENT MODALITIES, CANCER IS ONE OF THE FASTEST-GROWING CHRONIC DISEASE CONDITIONS ALL OVER THE WORLD. GENETIC AND EPIGENETIC ALTERATIONS IN THE NORMAL PHYSIOLOGY OF THE CELL ARE THE KEY FACTOR FOR TUMOR DEVELOPMENT. THESE CHANGES CAN TRIGGER THE PRODUCTION OF ABNORMAL PROTEIN EXPRESSIONS THROUGH STIMULATION OF DIFFERENT SIGNALING PATHWAYS AND CAN DEEPLY AFFECT NORMAL CELL GROWTH AND PROLIFERATION. ANY ALTERED PROTEIN EXPRESSION, GENETIC VARIATION, MICRO-RNA OR POST-TRANSLATIONAL PROTEIN MODIFICATIONS THAT INDICATE TUMORIGENESIS CAN ACT AS AN EARLY SIGNAL TERMED AS BIOMARKER. CANCER, BEING A MULTISTEP PROCESS WITH ACCUMULATING GENETIC AND EPIGENETIC ALTERATIONS, COULD BE DETECTED EARLY WITH SUITABLE BIOMARKERS. THERE ARE SEVERAL PROTEINS SUCH AS AFP, CA-125, PSA, TROPONIN, CEA, OSTEOPONTIN, CA 19-9 THAT ACT AS BIOMARKERS WHICH HELP IN EARLY DETECTION, PROGNOSIS, AND MONITORING OF DISEASE PROGRESSION, A HUNT FOR NEWER BIOMARKERS WITH HIGHER SPECIFICITY AND SENSITIVITY IS STILL ONGOING. TUMOR-SPECIFIC GROWTH FACTOR (TSGF) IS ONE SUCH BUDDING AND PREVAILING TUMOR BIOMARKER USED FOR THE EARLY-STAGE DETECTION OF SEVERAL TYPES OF CARCINOMAS. TSGF IS A GENE THAT HELPS IN TUMOR ANGIOGENESIS AND GETS RELEASED DURING THE PRELIMINARY STAGES FROM CANCER CELLS THAT ENSURE THE VASCULAR PROLIFERATION OF THE SAME. IN THIS REVIEW, THE CLINICAL INVESTIGATIONS OF TSGF IN DIFFERENT KINDS OF MALIGNANCY IS DISCUSSED IN DETAIL AND SUGGESTS THE POSSIBILITY OF USING TSGF AS A BIOMARKER IN EARLY DIAGNOSIS OF CANCER. 2023 17 2597 28 EPIGENETICS OF SUBCELLULAR STRUCTURE FUNCTIONING IN THE ORIGIN OF RISK OR RESILIENCE TO COMORBIDITY OF NEUROPSYCHIATRIC AND CARDIOMETABOLIC DISORDERS. MECHANISMS CONTROLLING MITOCHONDRIAL FUNCTION, PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM (ER) AND NUCLEAR PROCESSES SUCH AS TELOMERE LENGTH AND DNA REPAIR MAY BE SUBJECT TO EPIGENETIC CUES THAT RELATE THE GENOMIC EXPRESSION AND ENVIRONMENTAL EXPOSURES IN EARLY STAGES OF LIFE. THEY MAY ALSO BE INVOLVED IN THE COMORBID APPEARANCE OF CARDIOMETABOLIC (CMD) AND NEUROPSYCHIATRIC DISORDERS (NPD) DURING ADULTHOOD. MITOCHONDRIAL FUNCTION AND PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM ARE ASSOCIATED WITH OXIDATIVE STRESS AND ELEVATED INTRACELLULAR CALCIUM LEVELS AND MAY ALSO UNDERLIE THE VULNERABILITY FOR COMORBID CMD AND NPD. MITOCHONDRIA PROVIDE KEY METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+), ATP, ALPHA-KETOGLUTARATE AND ACETYL COENZYME A THAT ARE REQUIRED FOR MANY TRANSCRIPTIONAL AND EPIGENETIC PROCESSES. THEY ARE ALSO A SOURCE OF FREE RADICALS. ON THE OTHER HAND, EPIGENETIC MARKERS IN NUCLEAR DNA DETERMINE MITOCHONDRIAL BIOGENESIS. THE ER IS THE SUBCELLULAR ORGANELLE IN WHICH SECRETORY PROTEINS ARE FOLDED. MANY ENVIRONMENTAL FACTORS STOP THE ABILITY OF CELLS TO PROPERLY FOLD PROTEINS AND MODIFY POST-TRANSLATIONALLY SECRETORY AND TRANSMEMBRANE PROTEINS LEADING TO ENDOPLASMIC RETICULUM STRESS AND OXIDATIVE STRESS. ER FUNCTIONING MAY BE EPIGENETICALLY DETERMINED. CHRONIC ER STRESS IS EMERGING AS A KEY CONTRIBUTOR TO A GROWING LIST OF HUMAN DISEASES, INCLUDING CMD AND NPD. TELOMERE LOSS CAUSES CHROMOSOMAL FUSION, ACTIVATION OF THE CONTROL OF DNA DAMAGE-RESPONSES, UNSTABLE GENOME AND ALTERED STEM CELL FUNCTION, WHICH MAY UNDERLIE THE COMORBIDITY OF CMD AND NPD. THE LENGTH OF TELOMERES IS RELATED TO OXIDATIVE STRESS AND MAY BE EPIGENETICALLY PROGRAMMED. PATHWAYS INVOLVED IN DNA REPAIR MAY BE EPIGENETICALLY PROGRAMMED AND MAY CONTRIBUTE TO DISEASES. IN THIS PAPER, WE DESCRIBE SUBCELLULAR MECHANISMS THAT ARE DETERMINED BY EPIGENETIC MARKERS AND THEIR POSSIBLE RELATION TO THE DEVELOPMENT OF INCREASED SUSCEPTIBILITY TO DEVELOP CMD AND NPD. 2018 18 4187 43 METABOLIC AND VASCULAR EFFECT OF THE MEDITERRANEAN DIET. SEVERAL STUDIES INDICATED HOW DIETARY PATTERNS THAT WERE OBTAINED FROM NUTRITIONAL CLUSTER ANALYSIS CAN PREDICT DISEASE RISK OR MORTALITY. LOW-GRADE CHRONIC INFLAMMATION REPRESENTS A BACKGROUND PATHOGENETIC MECHANISM LINKING METABOLIC RISK FACTORS TO INCREASED RISK OF CHRONIC DEGENERATIVE DISEASES. A MEDITERRANEAN DIET (MEDI) STYLE HAS BEEN REPORTED AS ASSOCIATED WITH A LOWER DEGREE OF INFLAMMATION BIOMARKERS AND WITH A PROTECTIVE ROLE ON CARDIOVASCULAR AND CEREBROVASCULAR EVENTS. THERE IS HETEROGENEITY IN DEFINING THE MEDDIET, AND IT CAN, OWING TO ITS COMPLEXITY, BE CONSIDERED AS AN EXPOSOME WITH THOUSANDS OF NUTRIENTS AND PHYTOCHEMICALS. RECENTLY, IT HAS BEEN REPORTED A NOVEL POSITIVE ASSOCIATION BETWEEN BASELINE PLASMA CERAMIDE CONCENTRATIONS AND CARDIOVASCULAR EVENTS AND HOW ADHERENCE TO A MEDITERRANEAN DIET-STYLE MAY INFLUENCE THE POTENTIAL NEGATIVE RELATIONSHIP BETWEEN ELEVATED PLASMA CERAMIDE CONCENTRATIONS AND CARDIOVASCULAR DISEASES (CVD). SEVERAL RANDOMIZED CONTROLLED TRIALS (RCTS) SHOWED THE POSITIVE EFFECTS OF THE MEDI DIET STYLE ON SEVERAL CARDIOVASCULAR RISK FACTORS, SUCH AS BODY MASS INDEX, WAIST CIRCUMFERENCE, BLOOD LIPIDS, BLOOD PRESSURE, INFLAMMATORY MARKERS AND ADHESION MOLECULES, AND DIABETES AND HOW THESE ADVANTAGES OF THE MEDI ARE MAINTAINED IN COMPARISON OF A LOW-FAT DIET. SOME STUDIES REPORTED A POSITIVE EFFECT OF ADHERENCE TO A MEDITERRANEAN DIET AND HEART FAILURE INCIDENCE, WHEREAS SOME RECENT STUDIES, SUCH AS THE PREDIMED STUDY, SHOWED THAT THE INCIDENCE OF MAJOR CARDIOVASCULAR EVENTS WAS LOWER AMONG THOSE ASSIGNED TO MEDI SUPPLEMENTED WITH EXTRA-VIRGIN OLIVE OIL OR NUTS THAN AMONG THOSE ASSIGNED TO A REDUCED-FAT DIET. NEW STUDIES ARE NEEDED TO BETTER UNDERSTAND THE MOLECULAR MECHANISMS, WHEREBY THE MEDDIET MAY EXERCISE ITS EFFECTS. HERE, WE PRESENT RECENT ADVANCES IN UNDERSTANDING THE MOLECULAR BASIS OF MEDDIET EFFECTS, MAINLY FOCUSING ON CARDIOVASCULAR DISEASES, BUT ALSO DISCUSSING OTHER RELATED DISEASES. WE REVIEW MEDDIET COMPOSITION AND ASSESSMENT AS WELL AS THE LATEST ADVANCES IN THE GENOMIC, EPIGENOMIC (DNA METHYLATION, HISTONE MODIFICATIONS, MICRORNAS, AND OTHER EMERGING REGULATORS), TRANSCRIPTOMIC (SELECTED GENES AND WHOLE TRANSCRIPTOME), AND METABOLOMIC AND METAGENOMIC ASPECTS OF THE MEDDIET EFFECTS (AS A WHOLE AND FOR ITS MOST TYPICAL FOOD COMPONENTS). WE ALSO PRESENT A REVIEW OF THE CLINICAL EFFECTS OF THIS DIETARY STYLE UNDERLYING THE BIOCHEMICAL AND MOLECULAR EFFECTS OF THE MEDITERRANEAN DIET. OUR PURPOSE IS TO REVIEW THE MAIN FEATURES OF THE MEDITERRANEAN DIET IN PARTICULAR ITS BENEFITS ON HUMAN HEALTH, UNDERLING THE ANTI-INFLAMMATORY, ANTI-OXIDANT AND ANTI-ATHEROSCLEROTIC EFFECTS TO WHICH NEW KNOWLEDGE ABOUT EPIGENETIC AND GUT-MICROBIOTA RELATIONSHIP IS RECENTLY ADDED. 2019 19 2533 37 EPIGENETICS IN AUTOIMMUNE CONNECTIVE TISSUE DISEASES. BACKGROUND. AUTOIMMUNE CONNECTIVE TISSUE DISEASES (ACTDS) ENCOMPASS A HETEROGENEOUS GROUP OF CHRONIC IMMUNE-MEDIATED INFLAMMATORY DISORDERS, PRIMARILY AFFECTING CONNECTIVE TISSUES AND CLINICALLY CHARACTERIZED BY VARIABLE MULTISYSTEM MANIFESTATIONS, FREQUENTLY OVERLAPPING. ENVIRONMENTAL FACTORS ARE THOUGHT TO PROMOTE ACTD DEVELOPMENT IN GENETIC PREDISPOSING/ENDOCRINE PERMISSIVE BACKGROUND THROUGH THE INDUCTION OF EPIGENETIC MODIFICATIONS, CONSISTING OF STABLE, HERITABLE, BUT POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION, OCCURRING WITHOUT ALTERATIONS OF THE DNA SEQUENCE. ACTUALLY, EPIGENETIC MECHANISMS (SUCH AS HISTONE MODIFICATIONS, DNA METHYLATION, NUCLEOSOME POSITIONING, AND RNA INTERFERENCE) LINK GENOTYPE UPSTREAM AND PHENOTYPE DOWNSTREAM, AND, IF PERSISTENTLY ABERRANT, MAY CAUSE A VARIETY OF HUMAN DISEASES, INCLUDING ACTDS. WE AIMED TO REVIEW THE RECENT ADVANCES IN THE KNOWLEDGE OF THE ACTD EPIGENETIC ALTERATIONS. METHODS: A DETAILED SEARCH OF THE AVAILABLE LITERATURE WAS PERFORMED IN THE PUBMED (U.S. NATIONAL LIBRARY OF MEDICINE) DATABASE. RESULTS: GROWING EVIDENCE UNDERLINES THE RELEVANT ROLE OF EPIGENETIC DEFECTS IN THE ACTD PATHOGENESIS, AND SPECIFIC EPIGENETIC PATTERNS CAN REPRESENT DISEASE BIOMARKERS. IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA), EPIGENETIC VARIATIONS INTERACT DETERMINING THE TYPICAL "AGGRESSIVE" PHENOTYPE DISPLAYED BY RA SYNOVIAL FIBROBLASTS. EPIGENETIC MODIFICATIONS ARE INVOLVED IN THE PROFIBROTIC PROCESS THAT CHARACTERIZES SYSTEMIC SCLEROSIS. IN SYSTEMIC LUPUS ERYTHEMATOSUS AND SJOGREN'S SYNDROME, COMPLEX EPIGENETIC CHANGES ALTERING GENE EXPRESSION HAVE BEEN DEMONSTRATED. CONCLUSIONS: COMPREHENSIVE STUDIES WILL CONTRIBUTE TO FURTHER DEFINE THE ABERRANT EPIGENETIC MECHANISMS INVOLVED IN THE ACTDS ETIOPATHOGENESIS. MOREOVER, BEING EPIGENETIC CHANGES POTENTIALLY REVERSIBLE, THE IDENTIFICATION OF ACTDS EPIGENETIC BIOMARKERS WILL ALLOW THE DEVELOPMENT OF THERAPEUTIC STRATEGIES ADDRESSED TO TARGET DYSREGULATED GENES AND CORRECT ABERRANT EPIGENOMIC ALTERATIONS. 2014 20 4399 32 MODULATION OF GENOMIC AND POSTGENOMIC ALTERATIONS IN NONCANCER DISEASES AND CRITICAL PERIODS OF LIFE. GENOMIC AND POSTGENOMIC CHANGES ARE EXTENSIVELY INVESTIGATED IN CANCER RESEARCH. SIMILAR ALTERATIONS, AFFECTING GENOME, TRANSCRIPTOME, MIRNOME AND/OR PROTEOME END-POINTS, HAVE BEEN DETECTED IN A VARIETY OF OTHER CHRONIC DEGENERATIVE DISEASES, SUCH AS ATHEROSCLEROSIS, DEGENERATIVE HEART DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEUROLOGICAL DISORDERS, EYE DISEASES, DIABETES, METABOLIC SYNDROME, SKIN AGEING AND ALOPECIA. NO GENERALIZATION CAN BE MADE DUE TO THE MYRIAD OF DIVERSE CLINICAL ENTITIES CLASSIFIED AS CHRONIC DEGENERATIVE DISEASES. MOREOVER, THE DETECTION OF MOLECULAR CHANGES DOES NOT AUTOMATICALLY IMPLY THEIR CAUSAL ROLE. NEVERTHELESS, COMMON MECHANISMS, SUCH AS DNA DAMAGE, EPIGENETIC ALTERATIONS, OXIDATIVE STRESS, AND CHRONIC INFLAMMATION, IN ADDITION TO GENETIC PREDISPOSITION, ARE OFTEN INVOLVED IN NONCANCER DISEASES. WE DEBATE HERE IN MORE DETAIL THE SUBJECTS OF CARDIOVASCULAR DISEASES AND OF SKIN DISEASES. MOREOVER, WE DISCUSS OUR EXPERIMENTAL STUDIES SUGGESTING THAT GENOMIC AND POSTGENOMIC CHANGES DO ALSO OCCUR DURING CRITICAL PERIODS OF LIFE, INCLUDING THE PRENATAL LIFE, THE PERINATAL PERIOD, AND AGEING. IN ADDITION, WE COMMENT ON THE FINDING THAT STEM-DERIVED CELLS ARE MORE SUSCEPTIBLE TO MOLECULAR DAMAGE THAN MORE DIFFERENTIATED CELLS. ALL THESE DATA ARE VIEWED IN THE PERSPECTIVE OF PREVENTIVE MEDICINE. IN FACT, THERE IS EVIDENCE THAT THE GENOMIC AND POSTGENOMIC ALTERATIONS OCCURRING NOT ONLY IN SEVERAL PATHOLOGICAL CONDITIONS BUT ALSO IN PARAPHYSIOLOGICAL SITUATIONS THAT AFFECT CRITICAL PERIODS OF LIFE CAN BE MODULATED BY MEANS OF DIETARY AND PHARMACOLOGICAL AGENTS. THE DISCOVERY THAT CHEMOPREVENTIVE AGENTS ARE ALSO ABLE TO ATTENUATE NUCLEOTIDE DAMAGE IN STEM-DERIVED CELLS WARRANTS FURTHER STUDIES IN VIEW OF POSSIBLE CLINICAL APPLICATIONS. 2009