1 5334 148 QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EPIGENETIC PROFILE IN ADVANCED COPD. EPIGENETIC MECHANISMS REGULATE MUSCLE MASS AND FUNCTION IN MODELS OF MUSCLE DYSFUNCTION AND ATROPHY. WE ASSESSED WHETHER QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EXPRESSION PROFILE OF EPIGENETIC EVENTS IN PATIENTS WITH ADVANCED COPD (CHRONIC OBSTRUCTIVE PULMONARY DISEASE). IN VASTUS LATERALIS (VL) OF SEDENTARY SEVERE COPD PATIENTS (N=41), WHO WERE FURTHER SUBDIVIDED INTO THOSE WITH (N=25) AND WITHOUT (N=16) MUSCLE WEAKNESS AND HEALTHY CONTROLS (N=19), EXPRESSION OF MUSCLE-ENRICHED MIRNAS, HISTONE ACETYLTRANSFERASES (HATS) AND DEACETYLASES (HDACS), GROWTH AND ATROPHY SIGNALLING MARKERS, TOTAL PROTEIN AND HISTONE ACETYLATION, TRANSCRIPTION FACTORS, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE CLINICALLY EVALUATED. COMPARED WITH CONTROLS, IN VL OF ALL COPD TOGETHER AND IN MUSCLE-WEAKNESS PATIENTS, EXPRESSION OF MIR-1, MIR-206 AND MIR-27A, LEVELS OF LYSINE-ACETYLATED PROTEINS AND HISTONES AND ACETYLATED HISTONE 3 WERE INCREASED, WHEREAS EXPRESSION OF HDAC3, HDAC4, SIRTUIN-1 (SIRT-1), IGF-1 (INSULIN-LIKE GROWTH FACTOR-1) WERE DECREASED, AKT (V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOGUE 1) EXPRESSION DID NOT DIFFER, FOLLISTATIN EXPRESSION WAS GREATER, WHEREAS MYOSTATIN EXPRESSION WAS LOWER, SERUM REPONSE FACTOR (SRF) EXPRESSION WAS INCREASED AND FIBRE SIZE OF FAST-TWITCH FIBRES WAS SIGNIFICANTLY REDUCED. IN VL OF SEVERE COPD PATIENTS WITH MUSCLE WEAKNESS AND ATROPHY, EPIGENETIC EVENTS REGULATE MUSCLE DIFFERENTIATION RATHER THAN PROLIFERATION AND MUSCLE GROWTH AND ATROPHY SIGNALLING, PROBABLY AS FEEDBACK MECHANISMS TO PREVENT THOSE MUSCLES FROM UNDERGOING FURTHER ATROPHY. LYSINE-HYPERACETYLATION OF HISTONES MAY DRIVE ENHANCED PROTEIN CATABOLISM IN THOSE MUSCLES. THESE FINDINGS MAY HELP DESIGN NOVEL THERAPEUTIC STRATEGIES (ENHANCERS OF MIRNAS PROMOTING MYOGENESIS AND ACETYLATION INHIBITORS) TO SELECTIVELY TARGET MUSCLE WEAKNESS AND ATROPHY IN SEVERE COPD. 2015 2 1633 71 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 3 2170 69 EPIGENETIC MECHANISMS IN RESPIRATORY MUSCLE DYSFUNCTION OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. EPIGENETIC EVENTS ARE DIFFERENTIALLY EXPRESSED IN THE LUNGS AND AIRWAYS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). MOREOVER, EPIGENETIC MECHANISMS ARE INVOLVED IN THE SKELETAL (PERIPHERAL) MUSCLE DYSFUNCTION OF COPD PATIENTS. WHETHER EPIGENETIC EVENTS MAY ALSO REGULATE RESPIRATORY MUSCLE DYSFUNCTION IN COPD REMAINS UNKNOWN. WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS WOULD BE DIFFERENTIALLY EXPRESSED IN THE MAIN INSPIRATORY MUSCLE (DIAPHRAGM) OF PATIENTS WITH COPD OF A WIDE RANGE OF DISEASE SEVERITY COMPARED TO HEALTHY CONTROLS. IN DIAPHRAGM MUSCLE SPECIMENS (THORACOTOMY DUE TO LUNG LOCALIZED NEOPLASMS) OF SEDENTARY PATIENTS WITH MILD-TO-MODERATE AND SEVERE COPD, WITH PRESERVED BODY COMPOSITION, AND SEDENTARY HEALTHY CONTROLS, EXPRESSION OF MUSCLE-ENRICHED MICRORNAS, HISTONE ACETYLTRANSFERASES (HATS) AND DEACETYLASES (HDACS), TOTAL DNA METHYLATION AND PROTEIN ACETYLATION, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES, MUSCLE-SPECIFIC TRANSCRIPTION FACTORS, AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE ALSO CLINICALLY EVALUATED: LUNG AND MUSCLE FUNCTIONS AND EXERCISE CAPACITY. COMPARED TO HEALTHY CONTROLS, PATIENTS EXHIBITED MODERATE AIRFLOW LIMITATION AND DIFFUSION CAPACITY, AND REDUCED EXERCISE TOLERANCE AND TRANSDIAPHRAGMATIC STRENGTH. MOREOVER, IN THE DIAPHRAGM OF THE COPD PATIENTS, MUSCLE-SPECIFIC MICRORNA EXPRESSION WAS DOWNREGULATED, WHILE HDAC4 AND MYOCYTE ENHANCER FACTOR (MEF)2C PROTEIN LEVELS WERE HIGHER, AND DNA METHYLATION LEVELS, MUSCLE FIBER TYPES AND SIZES DID NOT DIFFER BETWEEN PATIENTS AND CONTROLS. IN THE MAIN RESPIRATORY MUSCLE OF COPD PATIENTS WITH A WIDE RANGE OF DISEASE SEVERITY AND NORMAL BODY COMPOSITION, MUSCLE-SPECIFIC MICRORNAS WERE DOWNREGULATED, WHILE HDAC4 AND MEF2C LEVELS WERE UPREGULATED. IT IS LIKELY THAT THESE EPIGENETIC EVENTS ACT AS BIOLOGICAL ADAPTIVE MECHANISMS TO BETTER OVERCOME THE CONTINUOUS INSPIRATORY LOADS OF THE RESPIRATORY SYSTEM IN COPD. THESE FINDINGS MAY OFFER NOVEL THERAPEUTIC STRATEGIES TO SPECIFICALLY TARGET RESPIRATORY MUSCLE DYSFUNCTION IN PATIENTS WITH COPD. 2014 4 4577 33 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 5 4101 14 MDCT AND MR UROGRAM SPECTRUM OF CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT DIAGNOSED IN ADULTHOOD. OBJECTIVE: CONGENITAL ANOMALIES OF THE KIDNEYS AND URINARY TRACT (CAKUT) ENCOMPASS A SPECTRUM OF ANOMALIES THAT RESULT FROM GENETIC, EPIGENETIC, ENVIRONMENTAL, AND MOLECULAR SIGNAL ABERRATIONS AT KEY STAGES OF URINARY TRACT DEVELOPMENT. CAKUT CAN BE SEEN INCIDENTALLY ON CROSS-SECTIONAL IMAGING OF THE ABDOMEN OR CAN BE A CAUSE FOR ADULT-ONSET CHRONIC KIDNEY DISEASE, POSING NEW CHALLENGES FOR NEPHROLOGISTS, UROLOGISTS, AND RADIOLOGISTS. CONCLUSION: AWARENESS OF CAKUT AND FAMILIARITY WITH THEIR IMAGING FINDINGS PERMIT OPTIMAL PATIENT MANAGEMENT AND THOROUGH WORKUP TO PREVENT HYPERTENSION AND PROGRESSION FROM CAKUT TO RENAL FAILURE. THE PURPOSE OF THIS ARTICLE IS TO REVIEW THE CROSS-SECTIONAL IMAGING FINDINGS OF CAKUT THAT MAY PRESENT IN ADULTHOOD. 2015 6 1265 25 CYSTINURIA POORLY RESPONDING TO TREATMENT - THE RISK OF CHRONIC KIDNEY DISEASE. CYSTINURIA IS THE GENETIC CONDITION FOR THE INCREASED EXCRETION OF CYSTINE IN THE URINE. PATIENTS MAINLY SUFFER FROM AFFLICTIONS RELATED TO THE PRESENCE AND PASSAGE OF KIDNEY STONES. THE CURRENTLY AVAILABLE TREATMENT METHODS INCLUDE CONSERVATIVE TREATMENT BASED ON INCREASED FLUID INTAKE, APPROPRIATE DIET, MEDICATIONS AND UROLOGICAL PROCEDURES. THE CAUSAL TREATMENT HAS NOT YET BEEN INVENTED. A CASE REPORT: A PATIENT CASE WAS DESCRIBED WHOSE FIRST SYMPTOMATIC KIDNEY STONES APPEARED AFTER THE SECOND YEAR OF LIFE. URINARY CYSTINE EXCRETION WAS SIGNIFICANTLY INCREASED - 25,431 MUMOL/1G CREATININE (NORM: 167-333 MUMOL/1G CREATININE), WHICH WAS ALSO SHOWN, BUT LOWER, IN BOTH PARENTS OF THE PATIENT. DESPITE THE EARLY INITIATION OF THERAPY INCLUDING LOW SODIUM DIET, ABUNDANT HYDRATION, ALKALIZATION, CAPTOPRIL AND COMPLIANCE WITH STRINGENT RESTRICTIONS, THE LEVEL OF URINARY CYSTINE EXCRETION WAS STILL NOT WITHIN THE NORMAL RANGE. THERE HAVE BEEN MANY MODIFICATIONS TO THE THERAPY AND DOSE INCREASES OF DRUGS, BUT WITHOUT VISIBLE RESULTS. THE PATIENT UNDERWENT SEVERAL UROLOGICAL PROCEDURES, INCLUDING: ESWL (EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY), URSL (URETEROSCOPIC LITHOTRIPSY), PCNL (PERCUTANEOUS NEPHROLITHOTOMY) AND OPEN SURGERY TO REMOVE CYSTINE DEPOSITS THAT WERE STILL PRODUCED IN THE KIDNEYS. IN ADDITION, FOR MANY YEARS THE DISEASE WAS COMPLICATED BY RECURRENT URINARY TRACT INFECTIONS, UNDERWEIGHT AND LESIONS LIKE EPITHELIAL METAPLASIA IN THE BLADDER. RENAL PARAMETERS WERE REPEATEDLY EXAMINED. ELEVATED RESULTS SUCH AS: SERUM CREATININE 0.9 MG/DL, CYSTATIN C CONCENTRATION 1.10 MG/L, ALBUMIN-CREATININE INDEX 0.197, CREATININE CLEARANCE 50.7 ML/MIN /1.73 M2 AND EGFR 73 ML/MIN/1.73 M2 ALLOWED FOR THE DIAGNOSIS OF CHRONIC KIDNEY DISEASE BEFORE THE AGE OF 18. AFTER MANY YEARS OF CONSERVATIVE TREATMENT, ONLY THE INTRODUCTION OF THIOPRONINE, STILL LITTLE KNOWN IN POLAND, REDUCED THE LEVEL OF CYSTINE EXCRETED IN THE URINE. THE INCLUSION OF THE DRUG REDUCED THE TENDENCY TO PRODUCE KIDNEY STONES, WHICH ALLOWED TO INHIBIT THE PROGRESSION OF RENAL FAILURE. CONCLUSIONS: DESPITE MANY YEARS OF RESEARCH AND MODERN DRUGS, CYSTINURIA IS STILL A DISEASE WITH WHICH PATIENTS ARE ASSOCIATED FOR THE REST OF THEIR LIVES. THE ONGOING RESEARCH, ALONG WITH ATTEMPTS TO UNDERSTAND THE GENETIC AND EPIGENETIC MECHANISMS RESPONSIBLE FOR THE EMERGENCE OF MUTATIONS IN THE MAIN GENES CAUSING THE DISEASE AND THE COURSE OF THE DISEASE, GIVES HOPE FOR FINDING A METHOD OF CAUSAL TREATMENT FOR CYSTINURIA. 2021 7 2505 37 EPIGENETICS AND MUSCLE DYSFUNCTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMMON, PREVENTABLE, AND TREATABLE DISEASE AND A MAJOR LEADING CAUSE OF MORBIDITY AND MORTALITY WORLDWIDE. IN COPD, COMORBIDITIES, ACUTE EXACERBATIONS, AND SYSTEMIC MANIFESTATIONS NEGATIVELY INFLUENCE DISEASE SEVERITY AND PROGRESSION REGARDLESS OF THE RESPIRATORY CONDITION. SKELETAL MUSCLE DYSFUNCTION, WHICH IS ONE OF THE COMMONEST SYSTEMIC MANIFESTATIONS IN PATIENTS WITH COPD, HAS A TREMENDOUS IMPACT ON THEIR EXERCISE CAPACITY AND QUALITY OF LIFE. SEVERAL PATHOPHYSIOLOGICAL AND MOLECULAR UNDERLYING MECHANISMS INCLUDING EPIGENETICS (THE PROCESS WHEREBY GENE EXPRESSION IS REGULATED BY HERITABLE MECHANISMS THAT DO NOT AFFECT DNA SEQUENCE) HAVE BEEN SHOWN TO PARTICIPATE IN THE ETIOLOGY OF COPD MUSCLE DYSFUNCTION. THE EPIGENETIC MODIFICATIONS IDENTIFIED SO FAR IN CELLS INCLUDE DNA METHYLATION, HISTONE ACETYLATION AND METHYLATION, AND NONCODING RNAS SUCH AS MICRORNAS. HEREIN, WE FIRST REVIEW THE ROLE OF EPIGENETIC MECHANISMS IN MUSCLE DEVELOPMENT AND ADAPTATION TO ENVIRONMENTAL FACTORS IN SEVERAL MODELS. MOREOVER, THE EPIGENETIC EVENTS REPORTED SO FAR TO BE POTENTIALLY INVOLVED IN MUSCLE DYSFUNCTION AND MASS LOSS OF PATIENTS WITH COPD ARE ALSO DISCUSSED. FURTHERMORE, THE DIFFERENT EXPRESSION PROFILE OF SEVERAL MUSCLE-ENRICHED MICRORNAS IN THE DIAPHRAGM AND VASTUS LATERALIS MUSCLES OF PATIENTS WITH COPD ARE ALSO REVIEWED FROM RESULTS RECENTLY OBTAINED IN OUR GROUP. THE ROLE OF PROTEIN HYPERACETYLATION IN ENHANCED MUSCLE PROTEIN CATABOLISM OF LIMB MUSCLES IS ALSO DISCUSSED. FUTURE RESEARCH SHOULD FOCUS ON THE FULL ELUCIDATION OF THE TRIGGERS OF EPIGENETIC MECHANISMS AND THEIR SPECIFIC DOWNSTREAM BIOLOGICAL PATHWAYS IN COPD MUSCLE DYSFUNCTION AND WASTING. 2015 8 6840 17 [MALE INFERTILITY AND UROLOGIC CANCERS: ADVANCES IN STUDIES]. MALE INFERTILITY IS ONE OF THE MOST COMMON DISEASES IN ANDROLOGY. STUDIES SHOW THAT MALE INFERTILITY IS SIGNIFICANTLY CORRELATED WITH THE INCIDENCE AND MORTALITY OF TUMORS, ESPECIALLY MALIGNANT TUMORS IN THE GENITOURINARY SYSTEM, SUCH AS TESTIS CANCER AND PROSTATE CANCER. THE RELATIONSHIP OF MALE INFERTILITY WITH GENITOURINARY SYSTEM TUMORS INVOLVES VARIOUS ASPECTS, MAINLY INCLUDING CHANGES IN CHROMOSOME MUTATIONS, EPIGENETIC MARKS, HORMONAL IMBALANCE, AND CONGENITAL DEFORMITY. BESIDES, SOME CHRONIC DISEASES ARE SHOWN TO BE SIGNIFICANTLY ASSOCIATED WITH MALE INFERTILITY, AND SEMEN QUALITY OR FERTILITY STATUS MAY BE BIOMARKERS OF THE OVERALL HEALTH OF MALES. IN-DEPTH STUDIES OF THE CORRELATION BETWEEN MALE INFERTILITY AND THESE FACTORS ARE VERY IMPORTANT FOR AN INSIGHT INTO THE PATHOGENESIS AND PREVENTION OF THE RELATED DISEASES. 2022 9 6436 29 THERAPEUTIC ACTIONS OF TEA PHENOLIC COMPOUNDS AGAINST OXIDATIVE STRESS AND INFLAMMATION AS CENTRAL MEDIATORS IN THE DEVELOPMENT AND PROGRESSION OF HEALTH PROBLEMS: A REVIEW FOCUSING ON MICRORNA REGULATION. MANY HEALTH PROBLEMS INCLUDING CHRONIC DISEASES ARE CLOSELY ASSOCIATED WITH OXIDATIVE STRESS AND INFLAMMATION. TEA HAS ABUNDANT PHENOLIC COMPOUNDS WITH VARIOUS HEALTH BENEFITS INCLUDING ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES. THIS REVIEW FOCUSES ON THE PRESENT UNDERSTANDING OF THE IMPACT OF TEA PHENOLIC COMPOUNDS ON THE EXPRESSION OF MIRNAS, AND ELUCIDATES THE BIOCHEMICAL AND MOLECULAR MECHANISMS UNDERLYING THE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL PROTECTIVE ACTIONS OF TEA PHENOLIC COMPOUNDS AGAINST OXIDATIVE STRESS- AND/OR INFLAMMATION-MEDIATED DISEASES. CLINICAL STUDIES SHOWED THAT DRINKING TEA OR TAKING CATECHIN SUPPLEMENT ON A DAILY BASIS PROMOTED THE ENDOGENOUS ANTIOXIDANT DEFENSE SYSTEM OF THE BODY WHILE INHIBITING INFLAMMATORY FACTORS. THE REGULATION OF CHRONIC DISEASES BASED ON EPIGENETIC MECHANISMS, AND THE EPIGENETIC-BASED THERAPIES INVOLVING DIFFERENT TEA PHENOLIC COMPOUNDS, HAVE BEEN INSUFFICIENTLY STUDIED. THE MOLECULAR MECHANISMS AND APPLICATION STRATEGIES OF MIR-27 AND MIR-34 INVOLVED IN OXIDATIVE STRESS RESPONSE AND MIR-126 AND MIR-146 INVOLVED IN INFLAMMATION PROCESS WERE PRELIMINARILY INVESTIGATED. SOME EMERGING EVIDENCE SUGGESTS THAT TEA PHENOLIC COMPOUNDS MAY PROMOTE EPIGENETIC CHANGES, INVOLVING NON-CODING RNA REGULATION, DNA METHYLATION, HISTONE MODIFICATION, UBIQUITIN AND SUMO MODIFICATIONS. HOWEVER, EPIGENETIC MECHANISMS AND EPIGENETIC-BASED DISEASE THERAPIES INVOLVING PHENOLIC COMPOUNDS FROM DIFFERENT TEAS, AND THE POTENTIAL CROSS-TALKS AMONG THE EPIGENETIC EVENTS, REMAIN UNDERSTUDIED. 2023 10 4543 31 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 11 4410 36 MOLECULAR AND BIOLOGICAL PATHWAYS OF SKELETAL MUSCLE DYSFUNCTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) WILL BE A MAJOR LEADING CAUSE OF DEATH WORLDWIDE IN THE NEAR FUTURE. WEAKNESS AND ATROPHY OF THE QUADRICEPS ARE ASSOCIATED WITH A SIGNIFICANTLY POORER PROGNOSIS AND INCREASED MORTALITY IN COPD. DESPITE THAT SKELETAL MUSCLE DYSFUNCTION MAY AFFECT BOTH RESPIRATORY AND LIMB MUSCLE GROUPS IN COPD, THE LATTER ARE FREQUENTLY MORE SEVERELY AFFECTED. THEREFORE, MUSCLE DYSFUNCTION IN COPD IS A COMMON SYSTEMIC MANIFESTATION THAT SHOULD BE EVALUATED ON ROUTINE BASIS IN CLINICAL SETTINGS. IN THE PRESENT REVIEW, SEVERAL ASPECTS OF COPD MUSCLE DYSFUNCTION ARE BEING REVIEWED, WITH SPECIAL EMPHASIS ON THE UNDERLYING BIOLOGICAL MECHANISMS. FIGURES ON THE PREVALENCE OF COPD MUSCLE DYSFUNCTION AND THE MOST RELEVANT ETIOLOGIC CONTRIBUTORS ARE ALSO PROVIDED. DESPITE THAT ONGOING RESEARCH WILL SHED LIGHT INTO THE CONTRIBUTION OF ADDITIONAL MECHANISMS TO COPD MUSCLE DYSFUNCTION, CURRENT KNOWLEDGE POINTS TOWARD THE INVOLVEMENT OF A WIDE SPECTRUM OF CELLULAR AND MOLECULAR EVENTS THAT ARE DIFFERENTIALLY EXPRESSED IN RESPIRATORY AND LIMB MUSCLES. SUCH MECHANISMS ARE THOROUGHLY DESCRIBED IN THE ARTICLE. THE CONTRIBUTION OF EPIGENETIC EVENTS ON COPD MUSCLE DYSFUNCTION IS ALSO REVIEWED. WE CONCLUDE THAT IN VIEW OF THE LATEST DISCOVERIES, FROM NOW, ON NEW AVENUES OF RESEARCH SHOULD BE DESIGNED TO SPECIFICALLY TARGET CELLULAR MECHANISMS AND PATHWAYS THAT IMPAIR MUSCLE MASS AND FUNCTION IN COPD USING PHARMACOLOGICAL STRATEGIES AND/OR EXERCISE TRAINING MODALITIES. 2016 12 3519 32 IGF-1 SIGNALING IN NEONATAL HYPOXIA-INDUCED PULMONARY HYPERTENSION: ROLE OF EPIGENETIC REGULATION. PULMONARY HYPERTENSION IS A FATAL DISEASE CHARACTERIZED BY A PROGRESSIVE INCREASE IN PULMONARY ARTERY PRESSURE ACCOMPANIED BY PULMONARY VASCULAR REMODELING AND INCREASED VASOMOTOR TONE. ALTHOUGH SOME BIOLOGICAL PATHWAYS HAVE BEEN IDENTIFIED IN NEONATAL HYPOXIA-INDUCED PULMONARY HYPERTENSION (PH), LITTLE IS KNOWN REGARDING THE ROLE OF GROWTH FACTORS IN THE PATHOGENESIS OF PH IN NEONATES. IN THIS STUDY, USING A MODEL OF HYPOXIA-INDUCED PH IN NEONATAL MICE, WE DEMONSTRATE THAT THE GROWTH FACTOR INSULIN-LIKE GROWTH FACTOR-1 (IGF-1), A POTENT ACTIVATOR OF THE AKT SIGNALING PATHWAY, IS INVOLVED IN NEONATAL PH. AFTER EXPOSURE TO HYPOXIA, IGF-1 SIGNALING IS ACTIVATED IN PULMONARY ENDOTHELIAL AND SMOOTH MUSCLE CELLS IN VITRO, AND THE IGF-1 DOWNSTREAM SIGNAL PAKT(S473) IS UPREGULATED IN LUNGS OF NEONATAL MICE. WE FOUND THAT IGF-1 REGULATES ET-1 EXPRESSION IN PULMONARY ENDOTHELIAL CELLS AND THAT IGF-1 EXPRESSION IS REGULATED BY HISTONE DEACETYLASES (HDACS). IN ADDITION, THERE IS A DIFFERENTIAL CYTOSINE METHYLATION SITE IN THE IGF-1 PROMOTER REGION IN RESPONSE TO NEONATAL HYPOXIA. MOREOVER, INHIBITION OF HDACS WITH APICIDIN DECREASES NEONATAL HYPOXIA-INDUCED GLOBAL DNA METHYLATION LEVELS IN LUNGS AND SPECIFIC CYTOSINE METHYLATION LEVELS AROUND THE PULMONARY IGF-1 PROMOTER REGION. FINALLY, HDAC INHIBITION WITH APICIDIN REDUCES CHRONIC HYPOXIA-INDUCED ACTIVATION OF IGF-1/PAKT SIGNALING IN LUNGS AND ATTENUATES RIGHT VENTRICULAR HYPERTROPHY AND PULMONARY VASCULAR REMODELING. TAKEN TOGETHER, WE CONCLUDE THAT IGF-1, WHICH IS EPIGENETICALLY REGULATED, IS INVOLVED IN THE PATHOGENESIS OF PULMONARY HYPERTENSION IN NEONATAL MICE. THIS STUDY IMPLICATES A NOVEL HDAC/IGF-1 EPIGENETIC PATHWAY IN THE REGULATION OF HYPOXIA-INDUCED PH AND WARRANTS FURTHER STUDY OF THE ROLE OF IGF-1 IN NEONATAL PULMONARY HYPERTENSIVE DISEASE. 2015 13 5679 43 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 14 2348 35 EPIGENETIC REGULATION OF MUSCLE PHENOTYPE AND ADAPTATION: A POTENTIAL ROLE IN COPD MUSCLE DYSFUNCTION. QUADRICEPS MUSCLE DYSFUNCTION OCCURS IN ONE-THIRD OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IN VERY EARLY STAGES OF THEIR CONDITION, EVEN PRIOR TO THE DEVELOPMENT OF AIRWAY OBSTRUCTION. AMONG SEVERAL FACTORS, DECONDITIONING AND MUSCLE MASS LOSS ARE THE MOST RELEVANT CONTRIBUTING FACTORS LEADING TO THIS DYSFUNCTION. MOREOVER, EPIGENETICS, DEFINED AS THE PROCESS WHEREBY GENE EXPRESSION IS REGULATED BY HERITABLE MECHANISMS THAT DO NOT AFFECT DNA SEQUENCE, COULD BE INVOLVED IN THE SUSCEPTIBILITY TO MUSCLE DYSFUNCTION, PATHOGENESIS, AND PROGRESSION. HEREIN, WE REVIEW THE ROLE OF EPIGENETIC MECHANISMS IN MUSCLE DEVELOPMENT AND ADAPTATION TO ENVIRONMENTAL FACTORS SUCH AS IMMOBILIZATION AND EXERCISE, AND THEIR IMPLICATIONS IN THE PATHOPHYSIOLOGY AND SUSCEPTIBILITY TO MUSCLE DYSFUNCTION IN COPD. THE EPIGENETIC MODIFICATIONS IDENTIFIED SO FAR INCLUDE DNA METHYLATION, HISTONE ACETYLATION AND METHYLATION, AND NON-CODING RNAS SUCH AS MICRORNAS (MIRNAS). IN THE PRESENT REVIEW, WE DESCRIBE THE SPECIFIC CONTRIBUTION OF EPIGENETIC MECHANISMS TO THE REGULATION OF EMBRYONIC MYOGENESIS, MUSCLE STRUCTURE AND METABOLISM, IMMOBILIZATION, AND EXERCISE, AND IN MUSCLES OF COPD PATIENTS. EVENTS RELATED TO MUSCLE DEVELOPMENT AND REGENERATION AND THE RESPONSE TO EXERCISE AND IMMOBILIZATION ARE TIGHTLY REGULATED BY EPIGENETIC MECHANISMS. THESE ENVIRONMENTAL FACTORS PLAY A KEY ROLE IN THE OUTCOME OF MUSCLE MASS AND FUNCTION AS WELL AS IN THE SUSCEPTIBILITY TO MUSCLE DYSFUNCTION IN COPD. FUTURE RESEARCH REMAINS TO BE DONE TO SHED LIGHT ON THE SPECIFIC TARGET PATHWAYS OF MIRNA FUNCTION AND OTHER EPIGENETIC MECHANISMS IN THE SUSCEPTIBILITY, PATHOGENESIS, AND PROGRESSION OF COPD MUSCLE DYSFUNCTION. 2013 15 2555 20 EPIGENETICS IN RENAL DISEASES. WITH AGING, PREVALENCE OF OBESITY, HYPERTENSION, DIABETES AND RENAL DISEASES HAVE INCREASED GLOBALLY. OVER THE LAST TWO DECADES, THE PREVALENCE OF RENAL DISEASES HAS BEEN INTENSELY INCREASING. RENAL DISEASE AND RENAL PROGRAMMING ARE REGULATED BY EPIGENETIC MODIFICATIONS LIKE DNA METHYLATION AND HISTONE MODIFICATIONS. ENVIRONMENTAL FACTORS HAVE SIGNIFICANT ROLE IN THE PATHOPHYSIOLOGY OF RENAL DISEASE PROGRESSION. UNDERSTANDING THE POTENTIAL OF EPIGENETIC REGULATION OF GENE EXPRESSION MAY BE USEFUL IN RENAL DISEASE PROGNOSIS, DIAGNOSIS AND PROVIDES NOVEL THERAPEUTIC MEASURES. IN A NUTSHELL, THIS CHAPTER TALKS ABOUT THE ROLE OF EPIGENETIC MECHANISMS-DNA METHYLATION, HISTONE MODIFICATION, AND NONCODING RNA IN DIFFERENT RENAL DISEASES. THESE INCLUDE DIABETIC KIDNEY DISEASE, DIABETIC NEPHROPATHY, RENAL FIBROSIS, ETC. 2023 16 2982 25 GENETIC CONSIDERATIONS IN PEDIATRIC CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IN CHILDREN IS AN IRREVERSIBLE PROCESS THAT, IN SOME CASES, MAY LEAD TO END-STAGE RENAL DISEASE. THE MAJORITY OF CHILDREN WITH CKD HAVE A CONGENITAL DISORDER OF THE KIDNEY OR UROLOGICAL TRACT ARISING FROM BIRTH. THERE IS STRONG EVIDENCE FOR BOTH A GENETIC AND EPIGENETIC COMPONENT TO PROGRESSION OF CKD. UTILIZATION OF GENE-MAPPING STRATEGIES, RANGING FROM GENOME-WIDE ASSOCIATION STUDIES TO SINGLE-NUCLEOTIDE POLYMORPHISM ANALYSIS, SERVES TO IDENTIFY POTENTIAL GENETIC VARIANTS THAT MAY LEND TO DISEASE VARIATION. GENOME-WIDE ASSOCIATION STUDIES EVALUATING POPULATION-BASED DATA HAVE IDENTIFIED DIFFERENT LOCI ASSOCIATED WITH CKD PROGRESSION. ANALYSIS OF SINGLE-NUCLEOTIDE POLYMORPHISMS ON AN INDIVIDUAL LEVEL SUGGESTS THAT SECONDARY SYSTEMIC SEQUELAE OF CKD ARE CLOSELY RELATED TO DYSFUNCTION OF THE CARDIOVASCULAR-INFLAMMATORY AXIS AND MAY LEAD TO ADVANCED CARDIOVASCULAR DISEASE THROUGH ABNORMAL VASCULAR CALCIFICATION AND ACTIVATION OF THE RENIN-ANGIOTENSIN SYSTEM. SIMILARLY, GENETIC VARIANTS AFFECTING CYTOKINE CONTROL, FIBROSIS, AND PARENCHYMAL DEVELOPMENT MAY MODULATE CKD THROUGH DEVELOPMENT AND ACCELERATION OF RENAL INTERSTITIAL FIBROSIS. EPIGENETIC STUDIES EVALUATE MODIFICATION OF THE GENOME THROUGH DNA METHYLATION, HISTONE MODIFICATION, OR RNA INTERFERENCE, WHICH MAY BE DIRECTLY INFLUENCED BY EXTERNAL OR ENVIRONMENTAL FACTORS DIRECTING GENOMIC EXPRESSION. LASTLY, IMPROVED UNDERSTANDING OF THE GENETIC AND EPIGENETIC CONTRIBUTION TO CKD PROGRESSION MAY ALLOW PROVIDERS TO IDENTIFY A POPULATION AT ACCELERATED RISK FOR DISEASE PROGRESSION AND APPLY NOVEL THERAPIES TARGETED AT THE GENETIC MECHANISM OF DISEASE. 2016 17 5363 13 RECENT ADVANCES IN DIABETIC KIDNEY DISEASES: FROM KIDNEY INJURY TO KIDNEY FIBROSIS. DIABETIC KIDNEY DISEASE (DKD) IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE. THE NATURAL HISTORY OF DKD INCLUDES GLOMERULAR HYPERFILTRATION, PROGRESSIVE ALBUMINURIA, DECLINING ESTIMATED GLOMERULAR FILTRATION RATE, AND, ULTIMATELY, KIDNEY FAILURE. IT IS KNOWN THAT DKD IS ASSOCIATED WITH METABOLIC CHANGES CAUSED BY HYPERGLYCEMIA, RESULTING IN GLOMERULAR HYPERTROPHY, GLOMERULOSCLEROSIS, AND TUBULOINTERSTITIAL INFLAMMATION AND FIBROSIS. HYPERGLYCEMIA IS ALSO KNOWN TO CAUSE PROGRAMMED EPIGENETIC MODIFICATION. HOWEVER, THE DETAILED MECHANISMS INVOLVED IN THE ONSET AND PROGRESSION OF DKD REMAIN ELUSIVE. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES REGARDING THE PATHOGENIC MECHANISMS INVOLVED IN DKD. 2021 18 4017 30 LOW-DOSE HYDRALAZINE REDUCES ALBUMINURIA AND GLOMERULOSCLEROSIS IN A MOUSE MODEL OF OBESITY-RELATED CHRONIC KIDNEY DISEASE. AIM: TO DETERMINE, USING A MOUSE MODEL OF OBESITY, WHETHER LOW-DOSE HYDRALAZINE PREVENTS OBESITY-RELATED CHRONIC KIDNEY DISEASE (CKD). METHODS: FROM 8 WEEKS OF AGE, MALE C57BL/6 MICE RECEIVED A HIGH-FAT DIET (HFD) OR CHOW, WITH OR WITHOUT LOW-DOSE HYDRALAZINE (25 MG/L) IN DRINKING WATER, FOR 24 WEEKS. BIOMETRIC AND METABOLIC VARIABLES, RENAL FUNCTION AND STRUCTURAL CHANGES, RENAL GLOBAL DNA METHYLATION, DNA METHYLATION PROFILE AND MARKERS OF RENAL FIBROSIS, INJURY, INFLAMMATION AND OXIDATIVE STRESS WERE ASSESSED. RESULTS: THE HFD-FED MICE DEVELOPED OBESITY, WITH GLUCOSE INTOLERANCE, HYPERINSULINAEMIA AND DYSLIPIDAEMIA. OBESITY INCREASED ALBUMINURIA AND GLOMERULOSCLEROSIS, WHICH WERE SIGNIFICANTLY AMELIORATED BY LOW-DOSE HYDRALAZINE IN THE ABSENCE OF A BLOOD PRESSURE-LOWERING EFFECT. OBESITY INCREASED RENAL GLOBAL DNA METHYLATION AND THIS WAS ATTENUATED BY LOW-DOSE HYDRALAZINE. HFD-INDUCED CHANGES IN METHYLATION OF INDIVIDUAL LOCI WERE ALSO SIGNIFICANTLY REVERSED BY LOW-DOSE HYDRALAZINE. OBESE MICE DEMONSTRATED INCREASED MARKERS OF KIDNEY FIBROSIS, INFLAMMATION AND OXIDATIVE STRESS, BUT THESE MARKERS WERE NOT SIGNIFICANTLY IMPROVED BY HYDRALAZINE. CONCLUSION: LOW-DOSE HYDRALAZINE AMELIORATED HFD-INDUCED ALBUMINURIA AND GLOMERULOSCLEROSIS, INDEPENDENT OF ALTERATIONS IN BIOMETRIC AND METABOLIC VARIABLES OR BLOOD PRESSURE REGULATION. ALTHOUGH THE PRECISE MECHANISM OF RENOPROTECTION IN OBESITY IS UNCLEAR, AN EPIGENETIC BASIS MAY BE IMPLICATED. THESE DATA SUPPORT REPURPOSING HYDRALAZINE AS A NOVEL THERAPY TO PREVENT CKD PROGRESSION IN OBESE PATIENTS. 2022 19 2001 23 EPIGENETIC AND NON-EPIGENETIC REGULATION OF KLOTHO IN KIDNEY DISEASE. KLOTHO IS A NOVEL RENOPROTECTIVE ANTI-AGING PROTEIN AVAILABLE IN MEMBRANE-BOUND OR SOLUBLE FORM. KLOTHO IS EXPRESSED IN BRAIN, PANCREAS, AND OTHER SOLID ORGANS BUT SHOWS HIGHEST EXPRESSION LEVELS IN THE KIDNEY. KLOTHO SUSTAINS NORMAL KIDNEY PHYSIOLOGY BUT KLOTHO REGULATION ALSO CONTRIBUTES TO THE PROGRESSION OF KIDNEY DISEASE. SYSTEMIC AND INTRARENAL LEVELS OF KLOTHO FALL DRASTICALLY DURING ACUTE KIDNEY INJURY, KIDNEY FIBROSIS, DIABETIC NEPHROPATHY, AND OTHER FORMS OF CHRONIC KIDNEY DISEASE, ETC. MOREOVER, EXOGENOUS SUPPLEMENTATION OR OVEREXPRESSION OF ENDOGENOUS KLOTHO ATTENUATES KIDNEY DISEASE. THE REGULATION OF ENDOGENOUS KLOTHO EXPRESSION INVOLVES EPIGENETIC AS WELL AS NON-EPIGENETIC MECHANISMS. THE EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION, POST-TRANSLATIONAL HISTONE MODIFICATIONS, MIRNAS REGULATE THE CHANGE IN KLOTHO EXPRESSION IN KIDNEY DISEASE. NON-EPIGENETIC MECHANISMS SUCH AS ER STRESS, WNT SIGNALING, ACTIVATION OF THE RENIN ANGIOTENSIN SYSTEM (RAS), EXCESSIVE REACTIVE OXYGEN SPECIES AND CYTOKINE GENERATION, ALBUMIN OVERLOAD, AND PPAR-GAMMA SIGNALING ALSO CONTRIBUTE TO KLOTHO REGULATION. EVOLVING EVIDENCE HIGHLIGHT THE CAPACITY OF NATURAL PRODUCTS TO REGULATE KLOTHO EXPRESSION IN KIDNEY DISEASE. ALL THESE PRECLINICAL DATA SUGGEST THAT KLOTHO COULD BE A NOVEL BIOMARKER AS WELL AS THERAPEUTIC TARGET. HERE WE REVIEW THE DIFFERENT MECHANISMS OF KLOTHO REGULATION IN THE CONTEXT OF KLOTHO AS A BIOMARKER AND POTENTIAL THERAPEUTIC AGENT. 2021 20 3889 23 KLOTHO RECOVERY BY GENISTEIN VIA PROMOTER HISTONE ACETYLATION AND DNA DEMETHYLATION MITIGATES RENAL FIBROSIS IN MICE. RENAL FIBROSIS IS A COMMON HISTOMORPHOLOGICAL FEATURE OF RENAL AGING AND CHRONIC KIDNEY DISEASES OF ALL ETIOLOGIES, AND ITS INITIATION AND PROGRESSION ARE SUBSTANTIALLY INFLUENCED BY ABERRANT EPIGENETIC MODIFICATIONS OF FIBROSIS-SUSCEPTIBLE GENES, YET WITHOUT EFFECTIVE THERAPY. "EPIGENETIC DIETS" EXHIBIT TISSUE-PROTECTIVE AND EPIGENETIC-MODULATING PROPERTIES; HOWEVER, THEIR ANTI-RENAL FIBROSIS FUNCTIONS AND THE UNDERLYING MECHANISMS ARE LESS UNDERSTOOD. IN THIS STUDY, WE SHOW THAT GENISTEIN, A PHYTOESTROGENIC ISOFLAVONE ENRICHED IN DIETARY SOY PRODUCTS, EXHIBITS IMPRESSIVE ANTI-RENAL FIBROSIS ACTIVITIES BY RECOVERING EPIGENETIC LOSS OF KLOTHO, A KIDNEY-ENRICHED ANTI-AGING AND FIBROSIS-SUPPRESSING PROTEIN. MOUSE FIBROTIC KIDNEYS INDUCED BY UUO (UNILATERAL URETERAL OCCLUSION) DISPLAYED SEVERER KLOTHO SUPPRESSION AND ADVERSE EXPRESSION OF RENAL FIBROSIS-ASSOCIATED PROTEINS, BUT GENISTEIN ADMINISTRATION MARKEDLY RECOVERED THE KLOTHO LOSS AND ATTENUATED RENAL FIBROSIS AND THE PROTEIN EXPRESSION ABNORMALITIES. THE EXAMINATION OF POSSIBLE CAUSES OF THE KLOTHO RECOVERY REVEALED THAT GENISTEIN SIMULTANEOUSLY INHIBITED HISTONE 3 DEACETYLATION OF KLOTHO PROMOTER AND NORMALIZED THE PROMOTER DNA HYPERMETHYLATION BY SUPPRESSING ELEVATED DNA METHYLTRANSFERASE DNMT1 AND DNMT3A. MORE IMPORTANTLY, GENISTEIN'S ANTI-RENAL FIBROSIS EFFECTS ON THE RENAL FIBROTIC LESIONS AND THE ABNORMAL EXPRESSIONS OF FIBROSIS-ASSOCIATED PROTEINS WERE ABROGATED WHEN KLOTHO IS KNOCKDOWN BY RNA INTERFERENCES IN UUO MICE. THUS, OUR RESULTS IDENTIFY KLOTHO RESTORATION VIA EPIGENETIC HISTONE ACETYLATION AND DNA DEMETHYLATION AS A CRITICAL MECHANISM OF GENISTEIN'S ANTI-FIBROSIS FUNCTION AND SHED NEW LIGHTS ON THE POTENTIALS OF EPIGENETIC DIETS IN PREVENTING OR TREATING AGING OR RENAL FIBROSIS-ASSOCIATED KIDNEY DISEASES. KEY MESSAGES: GENISTEIN PREVENTS RENAL FIBROSIS AND THE ASSOCIATED KLOTHO SUPPRESSION IN UUO MICE. GENISTEIN UPREGULATES KLOTHO IN PART BY REVERSING THE PROMOTER HISTONE 3 HYPOACETYLATION. GENISTEIN ALSO PRESERVES KLOTHO VIA RELIEVING KLOTHO PROMOTER HYPERMETHYLATION. GENISTEIN DEMETHYLATES KLOTHO PROMOTER BY INHIBITING ABERRANT DNMT1/3A EXPRESSION. GENISTEIN RESTORATION OF KLOTHO IS ESSENTIAL FOR ITS ANTI-RENAL FIBROSIS FUNCTION. 2019