1 5679 133 SHORT- AND LONG-TERM HINDLIMB IMMOBILIZATION AND RELOADING: PROFILE OF EPIGENETIC EVENTS IN GASTROCNEMIUS. SKELETAL MUSCLE DYSFUNCTION AND ATROPHY ARE CHARACTERISTIC FEATURES ACCOMPANYING CHRONIC CONDITIONS. EPIGENETIC EVENTS REGULATE MUSCLE MASS AND FUNCTION MAINTENANCE. WE HYPOTHESIZED THAT THE PATTERN OF EPIGENETIC EVENTS (MUSCLE-ENRICHED MICRORNAS AND HISTONE ACETYLATION) AND ACETYLATION OF TRANSCRIPTION FACTORS KNOWN TO SIGNAL MUSCLE WASTING MAY DIFFER BETWEEN EARLY- AND LATE-TIME POINTS IN SKELETAL MUSCLES OF MICE EXPOSED TO HINDLIMB IMMOBILIZATION (I) AND RECOVERY FOLLOWING I. BODY AND MUSCLE WEIGHTS, GRIP STRENGTH, MUSCLE-ENRICHED MICRORNAS, HISTONE DEACETYLASES (HDACS), ACETYLATION OF PROTEINS, HISTONES, AND TRANSCRIPTION FACTORS (TF), MYOGENIC TF FACTORS, AND MUSCLE PHENOTYPE WERE ASSESSED IN GASTROCNEMIUS OF MICE EXPOSED TO PERIODS (1, 2, 3, 7, 15, AND 30 DAYS, I GROUPS) OF HINDLIMB IMMOBILIZATION, AND IN THOSE EXPOSED TO RELOADING FOR DIFFERENT PERIODS OF TIME (1, 3, 7, 15, AND 30 DAYS, R GROUPS) FOLLOWING 7-DAY IMMOBILIZATION. COMPARED TO NON-IMMOBILIZED CONTROLS, MUSCLE WEIGHT, LIMB STRENGTH, MICRORNAS, ESPECIALLY MIR-486, SIRT1 LEVELS, AND SLOW- AND FAST-TWITCH CROSS-SECTIONAL AREAS WERE DECREASED IN MICE OF I GROUPS, WHEREAS PAX7 AND ACETYLATED FOXO1 AND FOXO3 LEVELS WERE INCREASED. MUSCLE RELOADING FOLLOWING SPLINT REMOVAL IMPROVED MUSCLE MASS LOSS, STRENGTH, AND FIBER ATROPHY, BY INCREASING MICRORNAS, PARTICULARLY MIR-486, AND SIRT1 CONTENT, WHILE DECREASING ACETYLATED FOXO1 AND FOXO3 LEVELS. IN THIS MOUSE MODEL OF DISUSE MUSCLE ATROPHY, MUSCLE-ENRICHED MICRORNAS, ESPECIALLY MIR-486, THROUGH PAX7 REGULATION DELAYED MUSCLE CELL DIFFERENTIATION FOLLOWING UNLOADING OF GASTROCNEMIUS MUSCLE. ACETYLATION OF FOXO1 AND 3 SEEMED TO DRIVE MUSCLE MASS LOSS AND ATROPHY, WHILE DEACETYLATION OF THESE FACTORS THROUGH SIRT1 WOULD ENABLE THE MUSCLE FIBERS TO REGENERATE. J. CELL. PHYSIOL. 232: 1415-1427, 2017. (C) 2016 WILEY PERIODICALS, INC. 2017 2 4543 33 MUSCLE DYSFUNCTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE: UPDATE ON CAUSES AND BIOLOGICAL FINDINGS. RESPIRATORY AND/OR LIMB MUSCLE DYSFUNCTION, WHICH ARE FREQUENTLY OBSERVED IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS, CONTRIBUTE TO THEIR DISEASE PROGNOSIS IRRESPECTIVE OF THE LUNG FUNCTION. MUSCLE DYSFUNCTION IS CAUSED BY THE INTERACTION OF LOCAL AND SYSTEMIC FACTORS. THE KEY DELETERIOUS ETIOLOGIC FACTORS ARE PULMONARY HYPERINFLATION FOR THE RESPIRATORY MUSCLES AND DECONDITIONING SECONDARY TO REDUCED PHYSICAL ACTIVITY FOR LIMB MUSCLES. NONETHELESS, CIGARETTE SMOKE, SYSTEMIC INFLAMMATION, NUTRITIONAL ABNORMALITIES, EXERCISE, EXACERBATIONS, ANABOLIC INSUFFICIENCY, DRUGS AND COMORBIDITIES ALSO SEEM TO PLAY A RELEVANT ROLE. ALL THESE FACTORS MODIFY THE PHENOTYPE OF THE MUSCLES, THROUGH THE INDUCTION OF SEVERAL BIOLOGICAL PHENOMENA IN PATIENTS WITH COPD. WHILE RESPIRATORY MUSCLES IMPROVE THEIR AEROBIC PHENOTYPE (PERCENTAGE OF OXIDATIVE FIBERS, CAPILLARIZATION, MITOCHONDRIAL DENSITY, ENZYME ACTIVITY IN THE AEROBIC PATHWAYS, ETC.), LIMB MUSCLES EXHIBIT THE OPPOSITE PHENOTYPE. IN ADDITION, BOTH MUSCLE GROUPS SHOW OXIDATIVE STRESS, SIGNS OF DAMAGE AND EPIGENETIC CHANGES. HOWEVER, FIBER ATROPHY, INCREASED NUMBER OF INFLAMMATORY CELLS, ALTERED REGENERATIVE CAPACITY; SIGNS OF APOPTOSIS AND AUTOPHAGY, AND AN IMBALANCE BETWEEN PROTEIN SYNTHESIS AND BREAKDOWN ARE RATHER CHARACTERISTIC FEATURES OF THE LIMB MUSCLES, MOSTLY IN PATIENTS WITH REDUCED BODY WEIGHT. DESPITE THAT SIGNIFICANT PROGRESS HAS BEEN ACHIEVED IN THE LAST DECADES, FULL ELUCIDATION OF THE SPECIFIC ROLES OF THE TARGET BIOLOGICAL MECHANISMS INVOLVED IN COPD MUSCLE DYSFUNCTION IS STILL REQUIRED. SUCH AN ACHIEVEMENT WILL BE CRUCIAL TO ADEQUATELY TACKLE WITH THIS RELEVANT CLINICAL PROBLEM OF COPD PATIENTS IN THE NEAR-FUTURE. 2015 3 6774 23 [AGE-RELATED VASCULAR CHANGES EXEMPLIFIED BY THE CAROTID ARTERY]. ONE OF THE MAIN RISK FACTORS FOR THE PRESENCE OF CAROTID STENOSIS AND CAROTID-RELATED STROKE IS AGE. THE AIM OF THIS REVIEW ARTICLE IS TO PRESENT THE CURRENT STATE OF KNOWLEDGE ON AGE-RELATED VASCULAR CHANGES USING CAROTID STENOSIS AS AN EXAMPLE.VASCULAR AGING (VASCULAR SENESCENCE) IS A DECREASE OF STRUCTURAL AND FUNCTIONAL PROPERTIES OF THE VESSEL WALL THAT TAKES PLACE ON DIFFERENT LEVELS. AT THE MULTICELLULAR LEVEL AN INCREASE IN VESSEL VOLUME AND DIAMETER AS WELL AS INTIMA MEDIA THICKNESS OCCURS WITH AGE MAINLY DUE TO ATHEROSCLEROTIC CHANGES IN THE VESSEL WALL. AT THE CELLULAR AND EXTRACELLULAR LEVELS THERE IS A DECREASE IN ELASTIN FIBERS, SMOOTH MUSCLE CELLS, AND TOTAL CELLULARITY, AN INCREASE IN LIPID, CHOLESTEROL, AND CALCIUM PHOSPHATE DEPOSITION AS WELL AS NEOVASCULARIZATION. THE CAUSES OF VASCULAR AGING AT THE MOLECULAR LEVEL INCLUDE, IN PARTICULAR OXIDATIVE STRESS, CHRONIC INFLAMMATORY RESPONSE, MITOCHONDRIAL DYSFUNCTION, EPIGENETIC CHANGES, DYSREGULATION OF THE EXPRESSION OF NON-CODING RNAS (NCRNAS), AND THE INCREASE IN SENESCENCE. AGE-RELATED LOSS OF TISSUE HEALING AND REPAIR CAPACITY MAKE PLAQUES MORE VULNERABLE AND, IN THE CASE OF THE CAROTID ARTERY, MORE SUSCEPTIBLE TO ISCHEMIC STROKE.INCREASING KNOWLEDGE OF THE INFLUENCE OF AGING ON THE EPIGENETICS AND NCRNAS IN ATHEROSCLEROTIC PLAQUES CAN IN THE FUTURE MORE ACCURATELY QUANTIFY INDIVIDUAL PATIENT RISK AND CONTRIBUTE TO THE DEVELOPMENT OF TARGETED THERAPEUTIC STRATEGIES; HOWEVER, FURTHER STUDIES ARE NEEDED IN THIS FIELD TO UNDERSTAND THE FULL EXTENT OF VASCULAR AGING AND ITS ASSOCIATED DISEASES SO THAT THESE CAN THEN BE SPECIFICALLY TARGETED. 2022 4 4779 16 NUTRIENTS, GENETIC FACTORS, AND THEIR INTERACTION IN NON-ALCOHOLIC FATTY LIVER DISEASE AND CARDIOVASCULAR DISEASE. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CHRONIC LIVER DISEASE IN WESTERN COUNTRIES AND EXPOSE PATIENTS TO INCREASED RISK OF HEPATIC AND CARDIOVASCULAR (CV) MORBIDITY AND MORTALITY. BOTH ENVIRONMENTAL FACTORS AND GENETIC PREDISPOSITION CONTRIBUTE TO THE RISK. AN INAPPROPRIATE DIET, RICH IN REFINED CARBOHYDRATES, ESPECIALLY FRUCTOSE, AND SATURATED FATS, AND POOR IN FIBERS, POLYUNSATURATED FATS, AND VITAMINS IS ONE OF THE MAIN KEY FACTORS, AS WELL AS THE POLYMORPHISM OF PATATIN-LIKE PHOSPHOLIPASE DOMAIN CONTAINING 3 (PNPLA3 GENE) FOR NAFLD AND THE APOLIPOPROTEINS AND THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) FAMILY FOR THE CARDIOVASCULAR DAMAGE. BEYOND GENETIC INFLUENCE, ALSO EPIGENETICS MODIFICATIONS ARE RESPONSIBLE FOR VARIOUS CLINICAL MANIFESTATIONS OF BOTH HEPATIC AND CV DISEASE. INTERESTINGLY, DATA ARE ACCUMULATING ON THE INTERPLAY BETWEEN DIET AND GENETIC AND EPIGENETIC MODIFICATIONS, MODULATING PATHOGENETIC PATHWAYS IN NAFLD AND CV DISEASE. WE REPORT THE MAIN EVIDENCE FROM LITERATURE ON THE INFLUENCE OF BOTH MACRO AND MICRONUTRIENTS IN NAFLD AND CV DAMAGE AND THE ROLE OF GENETICS EITHER ALONE OR COMBINED WITH DIET IN INCREASING THE RISK OF DEVELOPING BOTH DISEASES. UNDERSTANDING THE INTERACTION BETWEEN METABOLIC ALTERATIONS, GENETICS AND DIET ARE ESSENTIAL TO TREAT THE DISEASES AND TAILORING NUTRITIONAL THERAPY TO CONTROL NAFLD AND CV RISK. 2020 5 615 20 BIOACTIVE COMPONENTS AND POSSIBLE ACTIVITIES OF MEDICINAL MUSHROOMS IN ALLEVIATING THE PATHOGENESIS OF NONALCOHOLIC FATTY LIVER DISEASE (REVIEW). NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A GLOBAL DISEASE THAT IS CLOSELY ASSOCIATED WITH OBESITY, TYPE 2 DIABETES MELLITUS, AND CARDIOVASCULAR DISEASE. EXCESSIVE FAT ACCUMULATION, FATTY DEGENERATION, AND CHRONIC INFLAMMATION OF THE LIVER ACTIVATE THE PROGRESSION OF NAFLD FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS AND FURTHER TO LIVER FIBROSIS, CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. THE UNDERLYING MECHANISM FOR THE DEVELOPMENT AND PROGRESSION OF NAFLD IS COMPLEX AND A MULTIPLE-HIT HYPOTHESIS INCLUDING DIETARY, ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS HAS BEEN RAISED. INCREASED DE NOVO LIPOGENESIS, DECREASED LIPOLYSIS, AND INSULIN RESISTANCE ARE ASSOCIATED WITH THE DEVELOPMENT OF NAFLD. CURRENTLY, NO EFFECTIVE DRUG THERAPIES ARE APPROVED FOR THE TREATMENT OF NAFLD. SEVERAL MEDICINAL MUSHROOMS HAVE BEEN FOUND TO HAVE SIGNIFICANT WEIGHT CONTROL AND GUT MICROBE MODULATION ACTIVITIES AND ANTIHYPERTRIGLYCERIDEMIC, ANTIHYPERGLYCEMIC, ANTIOXIDANT, AND ANTI-INFLAMMATORY EFFECTS, WHICH MAY BE USEFUL TO PREVENT AND ATTENUATE THE DEVELOPMENT AND PROGRESSION OF NAFLD. THESE BENEFICIAL EFFECTS ARE ASSOCIATED WITH MUSHROOMS' BIOACTIVE COMPONENTS, SUCH AS POLYSACCHARIDES, DIETARY FIBERS, ANTIOXIDANTS, AND OTHER COMPOUNDS DERIVED FROM FRUITING BODIES, CULTURED MYCELIUM, AND/OR BROTH OF MEDICINAL MUSHROOMS. THIS ARTICLE PRESENTS AN OVERVIEW OF MULTIPLE ASPECTS OF NAFLD, INCLUDING THE EPIDEMIOLOGY, PATHOGENESIS, MANAGEMENT, AND TREATMENT. THE BIOACTIVE COMPONENTS AND POSSIBLE ACTIVITIES OF MEDICINAL MUSHROOMS IN ALLEVIATING THE PATHOGENESIS OF NAFLD ARE ALSO REVIEWED. 2021 6 4115 18 MECHANISMS OF AGING OF THE EXTRACELLULAR MATRIX: ROLE OF THE ELASTIN-LAMININ RECEPTOR. AGING OF CONNECTIVE TISSUES IS IMPORTANT FOR THE UNDERSTANDING OF AGING MECHANISMS OF TISSUES RICH IN EXTRACELLULAR MATRIX AND OF AGE-DEPENDENT DISEASES OFTEN AFFECTING SUCH TISSUES. AGING MECHANISMS OF SUCH TISSUES CAN BE DIVIDED AS FOLLOWS: (1) AGE-DEPENDENT MODIFICATIONS OF MATRIX BIOSYNTHESIS; (2) POSTSYNTHETIC MODIFICATIONS OF EXTRACELLULAR MATRIX, AND (3) MODIFICATIONS OF CELL-MATRIX INTERACTIONS. EXAMPLES ARE DISCUSSED FOR ALL THREE ASPECTS OF TISSUE AGING, WITH SPECIAL EMPHASIS ON THE ROLE OF EPIGENETIC REACTIONS. THESE REACTIONS INCLUDE THE MAILLARD REACTION, UNCONTROLLED PROTEOLYTIC DEGRADATION, AND FREE RADICAL RELEASE. PROTEOLYTIC FRAGMENTS OF FIBRONECTIN AND OF ELASTIC FIBERS WERE SHOWN TO PRODUCE NOXIOUS EFFECTS AND TO BE ENGAGED IN VICIOUS CIRCLES OF AUTOENTERTAINED AND SELF-AMPLIFIED MECHANISMS. WE STUDIED IN PARTICULAR THE ROLE OF THE ELASTIN-LAMININ RECEPTOR IN TISSUE AGING AND IN ATHEROGENESIS. THE PRESENCE OF SATURATING CONCENTRATIONS OF ELASTIN PEPTIDES IN THE CIRCULATION RESULTS IN A CHRONIC OVERSTIMULATION OF THE RECEPTOR WITH SUSTAINED FREE RADICAL AND LYTIC ENZYME PRODUCTION. OTHER EXAMPLES OF AGE-DEPENDENT UNCOUPLING OF RECEPTORS ALSO ILLUSTRATE THE IMPORTANCE OF ALTERED RECEPTOR FUNCTION IN TISSUE AGING AND RELATED PATHOLOGIES. 1998 7 4675 17 NEW INSIGHTS INTO UNDERSTANDING THE MECHANISMS, PATHOGENESIS, AND MANAGEMENT OF MALIGNANT MESOTHELIOMAS. MALIGNANT MESOTHELIOMA (MM) IS A RELATIVELY RARE BUT DEVASTATING TUMOR THAT IS INCREASING WORLDWIDE. YET, BECAUSE OF DIFFICULTIES IN EARLY DIAGNOSIS AND RESISTANCE TO CONVENTIONAL THERAPIES, MM REMAINS A CHALLENGE FOR PATHOLOGISTS AND CLINICIANS TO TREAT. IN RECENT YEARS, MUCH HAS BEEN REVEALED REGARDING THE MECHANISMS OF INTERACTIONS OF PATHOGENIC FIBERS WITH MESOTHELIAL CELLS, CRUCIAL SIGNALING PATHWAYS, AND GENETIC AND EPIGENETIC EVENTS THAT MAY OCCUR DURING THE PATHOGENESIS OF THESE UNUSUAL, PLEIOMORPHIC TUMORS. THESE OBSERVATIONS SUPPORT A SCENARIO WHEREBY MESOTHELIAL CELLS UNDERGO A SERIES OF CHRONIC INJURY, INFLAMMATION, AND PROLIFERATION IN THE LONG LATENCY PERIOD OF MM DEVELOPMENT THAT MAY BE PERPETUATED BY DURABLE FIBERS, THE TUMOR MICROENVIRONMENT, AND INFLAMMATORY STIMULI. ONE CULPRIT IN SUSTAINED INFLAMMATION IS THE ACTIVATED INFLAMMASOME, A COMPONENT OF MACROPHAGES OR MESOTHELIAL CELLS THAT LEADS TO PRODUCTION OF CHEMOTACTIC, GROWTH-PROMOTING, AND ANGIOGENIC CYTOKINES. THIS INFORMATION HAS BEEN VITAL TO DESIGNING NOVEL THERAPEUTIC APPROACHES FOR PATIENTS WITH MM THAT FOCUS ON IMMUNOTHERAPY, TARGETING GROWTH FACTOR RECEPTORS AND PATHWAYS, OVERCOMING RESISTANCE TO APOPTOSIS, AND MODIFYING EPIGENETIC CHANGES. 2013 8 386 24 AN IN VIVO IMMUNOHISTOCHEMICAL STUDY ON MACROH2A.1 IN LUNG AND LYMPH-NODE TISSUES EXPOSED TO AN ASBESTIFORM FIBER. AIMS: THE AIM OF THIS STUDY WAS TO INVESTIGATE MACROH2A.1 IMMUNOEXPRESSION IN TISSUES OF SHEEP EXPOSED TO FE. BACKGROUND: THE CORRELATION BETWEEN ASBESTIFORM FIBERS, LUNG CANCER, PLEURAL MESOTHELIOMA, AND OTHER LUNG DISEASES IS ALREADY WELL ESTABLISHED AS THE PATHOPHISIOLOGICAL PATHOPHYSIOLOGICAL RESPIRATORY MECHANISMS INVOLVED BY INHALATION OF FLUORO-EDENITE (FE). THE LATTER IS REPRESENTED BY CELL PROLIFERATION AND INDUCING THE RELEASE OF GROWTH FACTORS, CYTOKINES, AND REACTIVE OXYGEN AND NITRITE SPECIES, WITH DNA DAMAGE THAT CAUSES CHRONIC INFLAMMATION AND CARCINOGENESIS. MACROH2A.1, AND HISTONE VARIANT, SEEMS TO PLAY A ROLE IN SENSING THE METABOLIC STATE OF THE CELL AND LINKING IT WITH CHROMATIN. PHYSIOLOGICALLY, MACROH2A.1 IS EXPRESSED AT LOW LEVELS IN STEM CELLS AND IT BECAME UPREGULATED DURING DIFFERENTIATION, PREVENTING REPROGRAMMING OF INDUCED PLURIPOTENT STEM CELLS AND AFTER NUCLEAR TRANSFER. IN PARTICULAR, MACROH2A.1 HAS BEEN SHOWN TO EXPLICATE A POTENT ANTITUMOR MECHANISM IN VIVO AS IT RESULTS UPREGULATED IN SENESCENT CELLS DETERMINING A PERMANENT GROWTH-ARREST. OBJECTIVE: EVALUATE THE POSSIBLE ROLE OF THE HISTONE VARIANT IN THE ORGANISM IN RESPONSE TO DEEP INSIGHT UNDERSTANDING THE MECHANISMS OF TOXICITY AND THE CELLULAR RESPONSE TO FE. METHODS: LUNG AND LYMPH NODES OF EXPOSED SHEEP WERE SELECTED. SAMPLES WERE PROCESSED FOR HISTOLOGICAL AND IMMUNIHISTOCHEMICAL IMMUNOHISTOCHEMICAL EVALUATIONS. DENSITOMETRIC, MORPHOMETRIC, AND STATISTICAL ANALYSIS ANALYSES WERE CONDUCTED. RESULTS: TISSUE SECTIONS OF FE EXPOSED SHEEP DEMONSTRATED OVEREXPRESSION OF MACROH2A.1 VS UNEXPOSED SAMPLES. THE DATA SUGGEST AN INVOLVEMENT OF THESE THIS MOLECULE IN THE CELLULAR RESPONSE TRIGGERED BY FE DIRECTED EXPOSURE. CONCLUSION: IN THIS CONTEST, MACROH2A.1 OVEREXPRESSION SUPPORTS ITS FUNCTION AS AN EPIGENETIC STABILIZER THAT HELPS TO ESTABLISH AND MAINTAIN DIFFERENTIATED STATES. 2020 9 2403 25 EPIGENETIC REPROGRAMMING: A POSSIBLE ETIOLOGICAL FACTOR IN BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS? PURPOSE: THE ETIOLOGY OF BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS IS POORLY UNDERSTOOD. THE POSSIBILITY THAT EPIGENETIC REPROGRAMMING MAY HAVE A ROLE IS DISCUSSED. MATERIALS AND METHODS: A LITERATURE SEARCH WAS PERFORMED WITH THE ENTREZ-PUBMED(R) DATABASE USING THE KEY WORDS URINARY BLADDER, EPIGENETICS, EPIGENETIC MECHANISMS, INTERSTITIAL CYSTITIS, DIAGNOSIS, ETIOLOGY, UROTHELIAL CELLS, MAST CELLS, NERVE FIBERS, NERVES, NERVE GROWTH FACTOR, RECURRENT INJURY, STEM CELLS, INFLAMMATORY MEDIATORS AND DEMETHYLASES. RESULTS: THE UROEPITHELIUM IS INTIMATELY ASSOCIATED WITH THE NERVOUS SYSTEM. SENSORY INPUT AT THE APICAL SURFACE OF UMBRELLA CELLS REGULATES BLADDER FUNCTION VIA A TRANSMURAL SIGNALING PATHWAY. WHEN UMBRELLA CELLS ARE SHED IN RESPONSE TO NOXIOUS STIMULI, STEM CELLS IN THE BASAL LAYER BECOME EXPOSED. THE POLYCOMB GROUP GENES ARE KEY IN THE MAINTENANCE OF ADULT STEM CELLS. THE POLYCOMB GROUP GENES MEDIATE GENE SILENCING AND REPRESS TRANSDIFFERENTIATION BY METHYLATING LYSINE 27 OF HISTONE H3 (H3K27ME3). JMJD3, AN ENZYME DEMETHYLATING H3K27ME3, ANTAGONIZES POLYCOMB GROUP GENES MEDIATED SILENCING. INFLAMMATORY STIMULI ARE STRONG INDUCERS OF JMJD3 AND MAY REVERSE GENE SILENCING IN STEM CELLS, MODIFYING THE DIFFERENTIATION PATTERN. EPIGENETIC PROCESSES INVOLVING H3K27 METHYLATION ARE MULTISTABLE PROCESSES. TRANSIENT SIGNALING, EG BY LIPOPOLYSACCHARIDE, TRIGGERS EPIGENETIC REPROGRAMMING AND ESTABLISHES ONE OF THE ALTERNATIVE REGULATORY STATES. ONCE ESTABLISHED SUCH STATES CAN BE MAINTAINED AND PROPAGATED EVEN IN THE ABSENCE OF THE INITIAL SIGNAL. CONCLUSIONS: WE POSTULATE THAT SIMILAR EPIGENETIC REPROGRAMMING MECHANISMS IN THE BLADDER MAY PROVIDE AN EXPLANATION FOR UROEPITHELIAL, MAST CELLS AND NERVE CELL ABNORMALITIES IN BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS, AS WELL AS PROPAGATION OF THIS ALTERED STATE IN THE ABSENCE OF THE SIGNAL THAT MAY HAVE TRIGGERED IT. IT ALSO PROVIDES A NEW EXPERIMENTAL PARADIGM FOR EXPLORING THE ETIOLOGY OF BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS. DATA SUPPORTING THIS HYPOTHESIS WOULD PROVIDE A RATIONALE FOR NEW DIAGNOSTIC AS WELL AS TREATMENT OPTIONS FOR BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS. 2009 10 5074 20 PHYSIOLOGIC AND EPIGENETIC EFFECTS OF NUTRIENTS ON DISEASE PATHWAYS. BACKGROUND/OBJECTIVES: EPIGENETIC REGULATION BY NUTRIENTS CAN INFLUENCE THE DEVELOPMENT OF SPECIFIC DISEASES. THIS STUDY SOUGHT TO EXAMINE THE EFFECT OF INDIVIDUAL NUTRIENTS AND NUTRIENT FAMILIES IN THE CONTEXT OF PREVENTING CHRONIC METABOLIC DISEASES VIA EPIGENETIC REGULATION. THE INHIBITION OF LIPID ACCUMULATION AND INFLAMMATION BY NUTRIENTS INCLUDING PROTEINS, LIPIDS, VITAMINS, AND MINERALS WERE OBSERVED, AND HISTONE ACETYLATION BY HISTONE ACETYLTRANSFERASE (HAT) WAS MEASURED. CORRELATIVE ANALYSES WERE ALSO PERFORMED. MATERIALS/METHODS: NUTRIENTS WERE SELECTED ACCORDING TO INFORMATION FROM THE KOREAN MINISTRY OF FOOD AND DRUG SAFETY. SELECTED NUTRIENT FUNCTIONALITIES, INCLUDING THE ATTENUATION OF FATTY ACID-INDUCED LIPID ACCUMULATION AND LIPOPOLYSACCHARIDE-MEDIATED ACUTE INFLAMMATION WERE EVALUATED IN MOUSE MACROPHAGE RAW264.7 AND MOUSE HEPATOCYTE AML-12 CELLS. EFFECTS OF THE SELECTED NUTRIENTS ON IN VITRO HAT INHIBITION WERE ALSO EVALUATED. RESULTS: NITRIC OXIDE (NO) PRODUCTION CORRELATED WITH HAT ACTIVITY, WHICH WAS REGULATED BY THE AMINO ACIDS GROUP, SUGGESTING THAT AMINO ACIDS POTENTIALLY CONTRIBUTE TO THE ATTENUATION OF NO PRODUCTION VIA THE INHIBITION OF HAT ACTIVITY. UNSATURATED FATTY ACIDS TENDED TO ATTENUATE INFLAMMATION BY INHIBITING NO PRODUCTION, WHICH MAY BE ATTRIBUTABLE TO THE INHIBITION OF IN VITRO HAT ACTIVITY. IN CONTRAST TO WATER-SOLUBLE VITAMINS, THE LIPID-SOLUBLE VITAMINS SIGNIFICANTLY DECREASED NO PRODUCTION. WATER- AND LIPID-SOLUBLE VITAMINS BOTH EXHIBITED SIGNIFICANT INHIBITORY ACTIVITIES AGAINST HAT. IN ADDITION, CALCIUM AND MANGANESE SIGNIFICANTLY INHIBITED LIPID ACCUMULATION, NO PRODUCTION, AND HAT ACTIVITY. CONCLUSIONS: SEVERAL CANDIDATE NUTRIENTS AND THEIR FAMILY MEMBERS MAY HAVE ROLES IN THE PREVENTION OF DISEASES, INCLUDING HEPATIC STEATOSIS AND INFLAMMATION-RELATED DISEASES (I.E., NONALCOHOLIC STEATOHEPATITIS) VIA EPIGENETIC REGULATION. FURTHER STUDIES ARE WARRANTED TO DETERMINE WHICH SPECIFIC AMINO ACIDS, UNSATURATED FATTY ACIDS AND LIPID-SOLUBLE VITAMINS OR SPECIFIC MINERALS INFLUENCE THE DEVELOPMENT OF STEATOSIS AND INFLAMMATORY-RELATED DISEASES. 2023 11 4711 23 NON-ALCOHOLIC FATTY LIVER DISEASE IN OBESE CHILDREN AND ADOLESCENTS: A ROLE FOR NUTRITION? NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) HAS BECOME THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE IN CHILDREN, PARALLELING THE INCREASING PREVALENCE OF OBESITY WORLDWIDE. THE PATHOGENESIS OF PAEDIATRIC NAFLD IS NOT FULLY UNDERSTOOD, BUT IT IS KNOWN THAT OBESITY, NUTRITION, LIFESTYLE VARIABLES, GENETIC AND EPIGENETIC FACTORS MAY BE CAUSALLY INVOLVED IN THE DEVELOPMENT OF THIS COMMON METABOLIC LIVER DISEASE. IN PARTICULAR, OBESITY AND NUTRITION ARE AMONG THE STRONGEST RISK FACTORS FOR PAEDIATRIC NAFLD, WHICH MAY EXERT THEIR ADVERSE HEPATIC EFFECTS ALREADY BEFORE BIRTH. EXCESS ENERGY INTAKE INDUCES HYPERTROPHY AND HYPERPLASIA OF ADIPOSE TISSUE WITH SUBSEQUENT DEVELOPMENT OF SYSTEMIC INSULIN RESISTANCE, WHICH IS ANOTHER IMPORTANT RISK FACTOR FOR NAFLD. DIET COMPOSITION AND IN PARTICULAR SIMPLE CARBOHYDRATE INTAKE (ESPECIALLY HIGH FRUCTOSE INTAKE) MAY PROMOTE THE DEVELOPMENT OF NAFLD, WHEREAS NON-DIGESTIBLE CARBOHYDRATES (DIETARY FIBER), BY AFFECTING GUT MICROBIOTA, MAY FAVOUR THE INTEGRITY OF GUT WALL AND REDUCE INFLAMMATION, OPPOSING THIS PROCESS. SATURATED FAT INTAKE MAY ALSO PROMOTE NAFLD DEVELOPMENT, WHEREAS UNSATURATED FAT INTAKE HAS SOME BENEFICIAL EFFECTS. PROTEIN INTAKE DOES NOT SEEM TO AFFECT THE DEVELOPMENT OF NAFLD, BUT FURTHER INVESTIGATION IS NEEDED. IN CONCLUSION, LIFESTYLE MODIFICATIONS TO INDUCE WEIGHT LOSS, THROUGH DIET AND PHYSICAL ACTIVITY, REMAIN THE MAINSTAY OF TREATMENT FOR PAEDIATRIC NAFLD. THE USE OF DIETARY SUPPLEMENTS, SUCH AS OMEGA-3 FATTY ACIDS AND PROBIOTICS, NEEDS FURTHER STUDY BEFORE RECOMMENDATION. 2022 12 1395 20 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 13 2735 26 EXPLORING THE RELATIONSHIP BETWEEN EPIGENETIC DNA METHYLATION AND CARDIAC FIBROSIS THROUGH RAMAN MICROSPECTROSCOPY. CARDIOMYOPATHIES ARE ASSOCIATED WITH FIBROTIC REMODELING OF THE HEART, WHICH IS CHARACTERIZED BY THE EXCESSIVE ACCUMULATION OF COLLAGEN TYPE I (COL I) DUE TO CHRONIC INFLAMMATION AND SUSPECTED EPIGENETIC INFLUENCES. DESPITE THE SEVERITY AND HIGH MORTALITY RATE OF CARDIAC FIBROSIS, CURRENT TREATMENT OPTIONS ARE OFTEN INADEQUATE, UNDERSCORING THE IMPORTANCE OF GAINING A DEEPER UNDERSTANDING OF THE DISEASE'S UNDERLYING MOLECULAR AND CELLULAR MECHANISMS. IN THIS STUDY, THE EXTRACELLULAR MATRIX (ECM) AND NUCLEI IN FIBROTIC AREAS OF DIFFERENT CARDIOMYOPATHIES WERE MOLECULARLY CHARACTERIZED BY RAMAN MICROSPECTROSCOPY AND IMAGING AND COMPARED WITH THE CONTROL MYOCARDIUM. PATIENT SAMPLES WERE OBTAINED FROM HEART TISSUE AFFECTED BY ISCHEMIA, HYPERTROPHY, AND DILATED CARDIOMYOPATHY AND ANALYZED FOR FIBROSIS THROUGH CONVENTIONAL HISTOLOGY AND MARKER-INDEPENDENT RAMAN MICROSPECTROSCOPY (RMS). PROMINENT DIFFERENCES BETWEEN CONTROL MYOCARDIUM AND CARDIOMYOPATHIES WERE REVEALED BY SPECTRAL DECONVOLUTION OF COL I RAMAN SPECTRA. STATISTICALLY SIGNIFICANT DIFFERENCES WERE IDENTIFIED IN THE AMIDE I REGION OF SPECTRAL SUBPEAK AT 1,608 CM(-1), WHICH IS A REPRESENTATIVE ENDOGENOUS MARKER FOR ALTERATIONS IN THE STRUCTURAL CONFORMATION OF COL I FIBERS. MOREOVER, EPIGENETIC 5MC DNA MODIFICATION WAS IDENTIFIED WITHIN CELL NUCLEI BY MULTIVARIATE ANALYSIS. A STATISTICALLY SIGNIFICANT INCREASE IN SIGNAL INTENSITIES OF SPECTRAL FEATURES INDICATIVE OF DNA METHYLATION WAS DETECTED IN CARDIOMYOPATHIES IN ACCORDANCE WITH IMMUNOFLUORESCENCE 5MC STAINING. OVERALL, RMS IS A VERSATILE TECHNOLOGY IN THE DISCRIMINATION OF CARDIOMYOPATHIES BASED ON MOLECULAR EVALUATION OF COL I AND NUCLEI WHILE PROVIDING INSIGHTS INTO THE PATHOGENESIS OF THE DISEASES.NEW & NOTEWORTHY CARDIOMYOPATHIES ARE ASSOCIATED WITH SEVERE FIBROTIC REMODELING OF THE HEART, WHICH IS CHARACTERIZED BY THE EXCESSIVE ACCUMULATION OF COLLAGEN TYPE I (COL I). IN THIS STUDY, WE USED MARKER-INDEPENDENT RAMAN MICROSPECTROSCOPY (RMS) TO GAIN A DEEPER UNDERSTANDING OF THE DISEASE'S UNDERLYING MOLECULAR AND CELLULAR MECHANISMS. 2023 14 446 24 APABETALONE DOWNREGULATES FIBROTIC, INFLAMMATORY AND CALCIFIC PROCESSES IN RENAL MESANGIAL CELLS AND PATIENTS WITH RENAL IMPAIRMENT. EPIGENETIC MECHANISMS ARE IMPLICATED IN TRANSCRIPTIONAL PROGRAMS DRIVING CHRONIC KIDNEY DISEASE (CKD). APABETALONE IS AN ORALLY AVAILABLE INHIBITOR OF BROMODOMAIN AND EXTRATERMINAL (BET) PROTEINS, WHICH ARE EPIGENETIC READERS THAT MODULATE GENE EXPRESSION. IN THE PHASE 3 BETONMACE TRIAL, APABETALONE REDUCED RISK OF MAJOR ADVERSE CARDIAC EVENTS (MACE) BY 50% IN THE CKD SUBPOPULATION, INDICATING FAVORABLE EFFECTS ALONG THE KIDNEY-HEART AXIS. ACTIVATION OF HUMAN RENAL MESANGIAL CELLS (HRMCS) TO A CONTRACTILE PHENOTYPE THAT OVERPRODUCES EXTRACELLULAR MATRIX (ECM) AND INFLAMMATORY CYTOKINES, AND PROMOTES CALCIFICATION, FREQUENTLY ACCOMPANIES CKD TO DRIVE PATHOLOGY. HERE, WE SHOW APABETALONE DOWNREGULATED HRMC ACTIVATION WITH TGF-BETA1 STIMULATION BY SUPPRESSING TGF-BETA1-INDUCED ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA) EXPRESSION, ALPHA-SMA ASSEMBLY INTO STRESS FIBERS, ENHANCED CONTRACTION, COLLAGEN OVERPRODUCTION, AND EXPRESSION OF KEY DRIVERS OF FIBROSIS, INFLAMMATION, OR CALCIFICATION INCLUDING THROMBOSPONDIN, FIBRONECTIN, PERIOSTIN, SPARC, INTERLEUKIN 6, AND ALKALINE PHOSPHATASE. LIPOPOLYSACCHARIDE-STIMULATED EXPRESSION OF INFLAMMATORY GENES IL6, IL1B, AND PTGS2 WAS ALSO SUPPRESSED. TRANSCRIPTOMICS CONFIRMED APABETALONE AFFECTED GENE SETS OF ECM REMODELING AND INTEGRINS. CLINICAL TRANSLATION OF IN VITRO RESULTS WAS INDICATED IN CKD PATIENTS WHERE A SINGLE DOSE OF APABETALONE REDUCED PLASMA LEVELS OF KEY PRO-FIBROTIC AND INFLAMMATORY MARKERS, AND INDICATED INHIBITION OF TGF-BETA1 SIGNALING. WHILE PLASMA PROTEINS CANNOT BE TRACED TO THE KIDNEY ALONE, ANTI-FIBROTIC AND ANTI-INFLAMMATORY EFFECTS OF APABETALONE IDENTIFIED IN THIS STUDY ARE CONSISTENT WITH THE OBSERVED DECREASE IN CARDIOVASCULAR RISK IN CKD PATIENTS. 2023 15 3585 20 IMPACT OF THE EXPOSOME ON THE EPIGENOME IN INFLAMMATORY BOWEL DISEASE PATIENTS AND ANIMAL MODELS. INFLAMMATORY BOWEL DISEASES (IBD) ARE CHRONIC INFLAMMATORY DISORDERS OF THE GASTROINTESTINAL TRACT THAT ENCOMPASS TWO MAIN PHENOTYPES, NAMELY CROHN'S DISEASE AND ULCERATIVE COLITIS. THESE CONDITIONS OCCUR IN GENETICALLY PREDISPOSED INDIVIDUALS IN RESPONSE TO ENVIRONMENTAL FACTORS. EPIGENETICS, ACTING BY DNA METHYLATION, POST-TRANSLATIONAL HISTONES MODIFICATIONS OR BY NON-CODING RNAS, COULD EXPLAIN HOW THE EXPOSOME (OR ALL ENVIRONMENTAL INFLUENCES OVER THE LIFE COURSE, FROM CONCEPTION TO DEATH) COULD INFLUENCE THE GENE EXPRESSION TO CONTRIBUTE TO INTESTINAL INFLAMMATION. WE PERFORMED A SCOPING SEARCH USING MEDLINE TO IDENTIFY ALL THE ELEMENTS OF THE EXPOSOME THAT MAY PLAY A ROLE IN INTESTINAL INFLAMMATION THROUGH EPIGENETIC MODIFICATIONS, AS WELL AS THE UNDERLYING MECHANISMS. THE ENVIRONMENTAL FACTORS EPIGENETICALLY INFLUENCING THE OCCURRENCE OF INTESTINAL INFLAMMATION ARE THE MATERNAL LIFESTYLE (MAINLY DIET, THE OCCURRENCE OF INFECTION DURING PREGNANCY AND SMOKING); BREASTFEEDING; MICROBIOTA; DIET (INCLUDING A LOW-FIBER DIET, HIGH-FAT DIET AND DEFICIENCY IN MICRONUTRIENTS); SMOKING HABITS, VITAMIN D AND DRUGS (E.G., IBD TREATMENTS, ANTIBIOTICS AND PROBIOTICS). INFLUENCED BY BOTH MICROBIOTA AND DIET, SHORT-CHAIN FATTY ACIDS ARE GUT MICROBIOTA-DERIVED METABOLITES RESULTING FROM THE ANAEROBIC FERMENTATION OF NON-DIGESTIBLE DIETARY FIBERS, PLAYING AN EPIGENETICALLY MEDIATED ROLE IN THE INTEGRITY OF THE EPITHELIAL BARRIER AND IN THE DEFENSE AGAINST INVADING MICROORGANISMS. ALTHOUGH THE IMPACT OF SOME ENVIRONMENTAL FACTORS HAS BEEN IDENTIFIED, THE EXPOSOME-INDUCED EPIMUTATIONS IN IBD REMAIN A LARGELY UNDEREXPLORED FIELD. HOW THESE ENVIRONMENTAL EXPOSURES INDUCE EPIGENETIC MODIFICATIONS (IN TERMS OF DURATION, FREQUENCY AND THE TIMING AT WHICH THEY OCCUR) AND HOW OTHER ENVIRONMENTAL FACTORS ASSOCIATED WITH IBD MODULATE EPIGENETICS DESERVE TO BE FURTHER INVESTIGATED. 2022 16 1633 41 DO EPIGENETIC EVENTS TAKE PLACE IN THE VASTUS LATERALIS OF PATIENTS WITH MILD CHRONIC OBSTRUCTIVE PULMONARY DISEASE? MUSCLE DYSFUNCTION IS A MAJOR COMORBIDITY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). SEVERAL BIOLOGICAL MECHANISMS INCLUDING EPIGENETIC EVENTS REGULATE MUSCLE MASS AND FUNCTION IN MODELS OF MUSCLE ATROPHY. INVESTIGATIONS CONDUCTED SO FAR HAVE FOCUSED ON THE ELUCIDATION OF BIOLOGICAL MECHANISMS INVOLVED IN MUSCLE DYSFUNCTION IN ADVANCED COPD. WE ASSESSED WHETHER THE EPIGENETIC PROFILE MAY BE ALTERED IN THE VASTUS LATERALIS OF PATIENTS WITH MILD COPD, NORMAL BODY COMPOSITION, AND MILDLY IMPAIRED MUSCLE FUNCTION AND EXERCISE CAPACITY. IN VASTUS LATERALIS (VL) OF MILD COPD PATIENTS WITH WELL-PRESERVED BODY COMPOSITION AND IN HEALTHY AGE-MATCHED CONTROLS, EXPRESSION OF DNA METHYLATION, MUSCLE-ENRICHED MICRORNAS, HISTONE ACETYLTRANSFERASES (HTAS) AND DEACETYLASES (HDACS), PROTEIN ACETYLATION, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES, AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE CLINICALLY EVALUATED. COMPARED TO HEALTHY CONTROLS, IN THE VL OF MILD COPD PATIENTS, MUSCLE FUNCTION AND EXERCISE CAPACITY WERE MODERATELY REDUCED, DNA METHYLATION LEVELS DID NOT DIFFER, MIR-1 EXPRESSION LEVELS WERE INCREASED AND POSITIVELY CORRELATED WITH BOTH FORCED EXPIRATORY VOLUME IN ONE SECOND (FEV1) AND QUADRICEPS FORCE, HDAC4 PROTEIN LEVELS WERE INCREASED, AND MUSCLE FIBER TYPES AND SIZES WERE NOT DIFFERENT. MODERATE SKELETAL MUSCLE DYSFUNCTION IS A RELEVANT FEATURE IN PATIENTS WITH MILD COPD AND PRESERVED BODY COMPOSITION. SEVERAL EPIGENETIC EVENTS ARE DIFFERENTIALLY EXPRESSED IN THE LIMB MUSCLES OF THESE PATIENTS, PROBABLY AS AN ATTEMPT TO COUNTERBALANCE THE UNDERLYING MECHANISMS THAT ALTER MUSCLE FUNCTION AND MASS. THE STUDY OF PATIENTS AT EARLY STAGES OF THEIR DISEASE IS OF INTEREST AS THEY ARE A TARGET FOR TIMELY THERAPEUTIC INTERVENTIONS THAT MAY SLOW DOWN THE COURSE OF THE DISEASE AND PREVENT THE DELETERIOUS EFFECTS OF MAJOR COMORBIDITIES. 2014 17 4577 24 MYOSTATIN: BASIC BIOLOGY TO CLINICAL APPLICATION. MYOSTATIN IS A MEMBER OF THE TRANSFORMING GROWTH FACTOR (TGF)-BETA SUPERFAMILY. IT IS EXPRESSED BY ANIMAL AND HUMAN SKELETAL MUSCLE CELLS WHERE IT LIMITS MUSCLE GROWTH AND PROMOTES PROTEIN BREAKDOWN. ITS EFFECTS ARE INFLUENCED BY COMPLEX MECHANISMS INCLUDING TRANSCRIPTIONAL AND EPIGENETIC REGULATION AND MODULATION BY EXTRACELLULAR BINDING PROTEINS. DUE TO ITS ACTIONS IN PROMOTING MUSCLE ATROPHY AND CACHEXIA, MYOSTATIN HAS BEEN INVESTIGATED AS A PROMISING THERAPEUTIC TARGET TO COUNTERACT MUSCLE MASS LOSS IN EXPERIMENTAL MODELS AND PATIENTS AFFECTED BY DIFFERENT MUSCLE-WASTING CONDITIONS. MOREOVER, GROWING EVIDENCE INDICATES THAT MYOSTATIN, BEYOND TO REGULATE SKELETAL MUSCLE GROWTH, MAY HAVE A ROLE IN MANY PHYSIOLOGIC AND PATHOLOGIC PROCESSES, SUCH AS OBESITY, INSULIN RESISTANCE, CARDIOVASCULAR AND CHRONIC KIDNEY DISEASE. IN THIS CHAPTER, WE REVIEW MYOSTATIN BIOLOGY, INCLUDING INTRACELLULAR AND EXTRACELLULAR REGULATORY PATHWAYS, AND THE ROLE OF MYOSTATIN IN MODULATING PHYSIOLOGIC PROCESSES, SUCH AS MUSCLE GROWTH AND AGING. MOREOVER, WE DISCUSS THE MOST RELEVANT EXPERIMENTAL AND CLINICAL EVIDENCE SUPPORTING THE EXTRA-MUSCLE EFFECTS OF MYOSTATIN. FINALLY, WE CONSIDER THE MAIN STRATEGIES DEVELOPED AND TESTED TO INHIBIT MYOSTATIN IN CLINICAL TRIALS AND DISCUSS THE LIMITS AND FUTURE PERSPECTIVES OF THE RESEARCH ON MYOSTATIN. 2022 18 706 25 BUTYRATE AND DIETARY SOLUBLE FIBER IMPROVE NEUROINFLAMMATION ASSOCIATED WITH AGING IN MICE. AGING RESULTS IN CHRONIC SYSTEMIC INFLAMMATION THAT CAN ALTER NEUROINFLAMMATION OF THE BRAIN. SPECIFICALLY, MICROGLIA SHIFT TO A PRO-INFLAMMATORY PHENOTYPE PREDISPOSING THEM TO HYPERACTIVATION UPON STIMULATION BY PERIPHERAL IMMUNE SIGNALS. IT IS PROPOSED THAT CERTAIN NUTRIENTS CAN DELAY BRAIN AGING BY PREVENTING OR REVERSING MICROGLIAL HYPERACTIVATION. BUTYRATE, A SHORT-CHAIN FATTY ACID (SCFA) PRODUCED PRIMARILY BY BACTERIAL FERMENTATION OF FIBER IN THE COLON, HAS BEEN EXTENSIVELY STUDIED PHARMACOLOGICALLY AS A HISTONE DEACETYLASE INHIBITOR AND SERVES AS AN ATTRACTIVE THERAPEUTIC CANDIDATE, AS BUTYRATE HAS ALSO BEEN SHOWN TO BE ANTI-INFLAMMATORY AND IMPROVE MEMORY IN ANIMAL MODELS. IN THIS STUDY, WE DEMONSTRATE THAT BUTYRATE CAN ATTENUATE PRO-INFLAMMATORY CYTOKINE EXPRESSION IN MICROGLIA IN AGED MICE. IT IS STILL NOT FULLY UNDERSTOOD, HOWEVER, IF AN INCREASE IN BUTYRATE-PRODUCING BACTERIA IN THE GUT AS A CONSEQUENCE OF A DIET HIGH IN SOLUBLE FIBER COULD AFFECT MICROGLIAL ACTIVATION DURING AGING. ADULT AND AGED MICE WERE FED EITHER A 1% CELLULOSE (LOW FIBER) OR 5% INULIN (HIGH FIBER) DIET FOR 4 WEEKS. FINDINGS INDICATE THAT MICE FED INULIN HAD AN ALTERED GUT MICROBIOME AND INCREASED BUTYRATE, ACETATE, AND TOTAL SCFA PRODUCTION. IN ADDITION, HISTOLOGICAL SCORING OF THE DISTAL COLON DEMONSTRATED THAT AGED ANIMALS ON THE LOW FIBER DIET HAD INCREASED INFLAMMATORY INFILTRATE THAT WAS SIGNIFICANTLY REDUCED IN ANIMALS CONSUMING THE HIGH FIBER DIET. FURTHERMORE, GENE EXPRESSION OF INFLAMMATORY MARKERS, EPIGENETIC REGULATORS, AND THE MICROGLIAL SENSORY APPARATUS (I.E., THE SENSOME) WERE ALTERED BY BOTH DIET AND AGE, WITH AGED ANIMALS EXHIBITING A MORE ANTI-INFLAMMATORY MICROGLIAL PROFILE ON THE HIGH FIBER DIET. TAKEN TOGETHER, HIGH FIBER SUPPLEMENTATION IN AGING IS A NON-INVASIVE STRATEGY TO INCREASE BUTYRATE LEVELS, AND THESE DATA SUGGEST THAT AN INCREASE IN BUTYRATE THROUGH ADDED SOLUBLE FIBER SUCH AS INULIN COULD COUNTERBALANCE THE AGE-RELATED MICROBIOTA DYSBIOSIS, POTENTIALLY LEADING TO NEUROLOGICAL BENEFITS. 2018 19 4047 25 MAIN PATHOGENIC MECHANISMS AND RECENT ADVANCES IN COPD PERIPHERAL SKELETAL MUSCLE WASTING. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A WORLDWIDE PREVALENT RESPIRATORY DISEASE MAINLY CAUSED BY TOBACCO SMOKE EXPOSURE. COPD IS NOW CONSIDERED AS A SYSTEMIC DISEASE WITH SEVERAL COMORBIDITIES. AMONG THEM, SKELETAL MUSCLE DYSFUNCTION AFFECTS AROUND 20% OF COPD PATIENTS AND IS ASSOCIATED WITH HIGHER MORBIDITY AND MORTALITY. ALTHOUGH THE HISTOLOGICAL ALTERATIONS ARE WELL CHARACTERIZED, INCLUDING MYOFIBER ATROPHY, A DECREASED PROPORTION OF SLOW-TWITCH MYOFIBERS, AND A DECREASED CAPILLARIZATION AND OXIDATIVE PHOSPHORYLATION CAPACITY, THE MOLECULAR BASIS FOR MUSCLE ATROPHY IS COMPLEX AND REMAINS PARTLY UNKNOWN. MAJOR DIFFICULTIES LIE IN PATIENT HETEROGENEITY, ACCESSING PATIENTS' SAMPLES, AND COMPLEX MULTIFACTORIAL PROCESS INCLUDING EXTRINSIC MECHANISMS, SUCH AS TOBACCO SMOKE OR DISUSE, AND INTRINSIC MECHANISMS, SUCH AS OXIDATIVE STRESS, HYPOXIA, OR SYSTEMIC INFLAMMATION. MUSCLE WASTING IS ALSO A HIGHLY DYNAMIC PROCESS WHOSE INVESTIGATION IS HAMPERED BY THE DIFFERENTIAL PROTEIN REGULATION ACCORDING TO THE STAGE OF ATROPHY. IN THIS REVIEW, WE REPORT AND DISCUSS RECENT DATA REGARDING THE MOLECULAR ALTERATIONS IN COPD LEADING TO IMPAIRED MUSCLE MASS, INCLUDING INFLAMMATION, HYPOXIA AND HYPERCAPNIA, MITOCHONDRIAL DYSFUNCTION, DIVERSE METABOLIC CHANGES SUCH AS OXIDATIVE AND NITROSATIVE STRESS AND GENETIC AND EPIGENETIC MODIFICATIONS, ALL LEADING TO AN IMPAIRED ANABOLIC/CATABOLIC BALANCE IN THE MYOCYTE. WE RECAPITULATE DATA CONCERNING SKELETAL MUSCLE DYSFUNCTION OBTAINED IN THE DIFFERENT RODENT MODELS OF COPD. FINALLY, WE PROPOSE SEVERAL PATHWAYS THAT SHOULD BE INVESTIGATED IN COPD SKELETAL MUSCLE DYSFUNCTION IN THE FUTURE. 2023 20 350 29 ALTERED DYNAMICS OF LIPID METABOLISM IN MUSCLE CELLS FROM PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHY IS AMELIORATED BY 6 MONTHS OF TRAINING. KEY POINTS: REGULAR EXERCISE IMPROVES MUSCLE FUNCTIONAL CAPACITY AND CLINICAL STATE OF PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHY (IIM). IN OUR STUDY, WE USED AN IN VITRO MODEL OF HUMAN PRIMARY MUSCLE CELL CULTURES, DERIVED FROM IIM PATIENTS BEFORE AND AFTER A 6-MONTH INTENSIVE SUPERVISED TRAINING INTERVENTION TO ASSESS THE IMPACT OF DISEASE AND EXERCISE ON LIPID METABOLISM DYNAMICS. WE PROVIDE EVIDENCE THAT MUSCLE CELLS FROM IIM PATIENTS DISPLAY ALTERED DYNAMICS OF LIPID METABOLISM AND IMPAIRED ADAPTIVE RESPONSE TO SATURATED FATTY ACID LOAD COMPARED TO HEALTHY CONTROLS. A 6-MONTH INTENSIVE SUPERVISED EXERCISE TRAINING INTERVENTION IN PATIENTS WITH IIM MITIGATED DISEASE EFFECTS IN THEIR CULTURED MUSCLE CELLS, IMPROVING OR NORMALIZING THEIR CAPACITY TO HANDLE LIPIDS. THESE FINDINGS HIGHLIGHT THE PUTATIVE ROLE OF INTRINSIC METABOLIC DEFECTS OF SKELETAL MUSCLE IN THE PATHOGENESIS OF IIM AND THE POSITIVE IMPACT OF EXERCISE, MAINTAINED IN VITRO BY YET UNKNOWN EPIGENETIC MECHANISMS. ABSTRACT: EXERCISE IMPROVES SKELETAL MUSCLE FUNCTION, CLINICAL STATE AND QUALITY OF LIFE IN PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHY (IIM). OUR AIM WAS TO IDENTIFY DISEASE-RELATED METABOLIC PERTURBATIONS AND THE IMPACT OF EXERCISE IN SKELETAL MUSCLE CELLS OF IIM PATIENTS. PATIENTS UNDERWENT A 6-MONTH INTENSIVE SUPERVISED TRAINING INTERVENTION. MUSCLE FUNCTION, ANTHROPOMETRIC AND METABOLIC PARAMETERS WERE EXAMINED AND MUSCLE CELL CULTURES WERE ESTABLISHED (M. VASTUS LATERALIS; BERGSTROM NEEDLE BIOPSY) BEFORE AND AFTER TRAINING FROM PATIENTS AND SEDENTARY AGE/SEX/BODY MASS INDEX-MATCHED CONTROLS. [(14) C]PALMITATE WAS USED TO DETERMINE FAT OXIDATION AND LIPID SYNTHESIS (THIN LAYER CHROMATOGRAPHY). CELLS WERE EXPOSED TO A CHRONIC (3 DAYS) AND ACUTE (3 H) METABOLIC CHALLENGE (THE SATURATED FATTY ACID PALMITATE, 100 MUM). REDUCED OXIDATIVE (INTERMEDIATE METABOLITES, -49%, P = 0.034) AND NON-OXIDATIVE (DIGLYCERIDES, -38%, P = 0.013) LIPID METABOLISM WAS IDENTIFIED IN PALMITATE-TREATED MUSCLE CELLS FROM IIM PATIENTS COMPARED TO CONTROLS. THREE DAYS OF PALMITATE EXPOSURE ELICITED DISTINCT REGULATION OF OXIDATIVE PHOSPHORYLATION (OXPHOS) COMPLEX IV AND COMPLEX V/ATP SYNTHASE (P = 0.012/0.005) AND ADIPOSE TRIGLYCERIDE LIPASE IN PATIENTS COMPARED TO CONTROLS (P = 0.045) (IMMUNOBLOTTING). IMPORTANTLY, 6 MONTHS OF TRAINING IN IIM PATIENTS IMPROVED LIPID METABOLISM (CO(2) , P = 0.010; INTERMEDIATE METABOLITES, P = 0.041) AND ACTIVATION OF AMP KINASE (P = 0.007), AND NEARLY NORMALIZED PALMITATE-INDUCED CHANGES IN OXPHOS PROTEINS IN MYOTUBES FROM IIM PATIENTS, IN PARALLEL WITH IMPROVEMENTS OF PATIENTS' CLINICAL STATE. MYOTUBES FROM IIM PATIENTS DISPLAYED ALTERED DYNAMICS OF LIPID METABOLISM AND IMPAIRED RESPONSE TO METABOLIC CHALLENGE WITH SATURATED FATTY ACID. OUR OBSERVATIONS SUGGEST THAT METABOLIC DEFECTS INTRINSIC TO SKELETAL MUSCLE COULD REPRESENT NON-IMMUNE PATHOMECHANISMS, WHICH CAN CONTRIBUTE TO MUSCLE WEAKNESS IN IIM. A 6-MONTH TRAINING INTERVENTION MITIGATED DISEASE EFFECTS IN MUSCLE CELLS IN VITRO, INDICATING THE EXISTENCE OF EPIGENETIC REGULATORY MECHANISMS. 2021