1 4974 132 PATHOPHYSIOLOGICAL MECHANISMS LEADING TO MUSCLE LOSS IN CHRONIC KIDNEY DISEASE. LOSS OF MUSCLE PROTEINS IS A DELETERIOUS CONSEQUENCE OF CHRONIC KIDNEY DISEASE (CKD) THAT CAUSES A DECREASE IN MUSCLE STRENGTH AND FUNCTION, AND CAN LEAD TO A REDUCTION IN QUALITY OF LIFE AND INCREASED RISK OF MORBIDITY AND MORTALITY. THE EFFECTIVENESS OF CURRENT TREATMENT STRATEGIES IN PREVENTING OR REVERSING MUSCLE PROTEIN LOSSES IS LIMITED. THE LIMITATIONS LARGELY STEM FROM THE SYSTEMIC NATURE OF DISEASES SUCH AS CKD, WHICH STIMULATE SKELETAL MUSCLE PROTEIN DEGRADATION PATHWAYS WHILE SIMULTANEOUSLY ACTIVATING MECHANISMS THAT IMPAIR MUSCLE PROTEIN SYNTHESIS AND REPAIR. STIMULI THAT INITIATE MUSCLE PROTEIN LOSS INCLUDE METABOLIC ACIDOSIS, INSULIN AND IGF1 RESISTANCE, CHANGES IN HORMONES, CYTOKINES, INFLAMMATORY PROCESSES AND DECREASED APPETITE. A GROWING BODY OF EVIDENCE SUGGESTS THAT SIGNALLING MOLECULES SECRETED FROM MUSCLE CAN ENTER THE CIRCULATION AND SUBSEQUENTLY INTERACT WITH RECIPIENT ORGANS, INCLUDING THE KIDNEYS, WHILE CONVERSELY, PATHOLOGICAL EVENTS IN THE KIDNEY CAN ADVERSELY INFLUENCE PROTEIN METABOLISM IN SKELETAL MUSCLE, DEMONSTRATING THE EXISTENCE OF CROSSTALK BETWEEN KIDNEY AND MUSCLE. TOGETHER, THESE SIGNALS, WHETHER DIRECT OR INDIRECT, INDUCE CHANGES IN THE LEVELS OF REGULATORY AND EFFECTOR PROTEINS VIA ALTERATIONS IN MRNAS, MICRORNAS AND CHROMATIN EPIGENETIC RESPONSES. ADVANCES IN OUR UNDERSTANDING OF THE SIGNALS AND PROCESSES THAT MEDIATE MUSCLE LOSS IN CKD AND OTHER MUSCLE WASTING CONDITIONS WILL SUPPORT THE FUTURE DEVELOPMENT OF THERAPEUTIC STRATEGIES TO REDUCE MUSCLE LOSS. 2022 2 2360 25 EPIGENETIC REGULATION OF SKELETAL MUSCLE METABOLISM. NORMAL SKELETAL MUSCLE METABOLISM IS ESSENTIAL FOR WHOLE BODY METABOLIC HOMOEOSTASIS AND DISRUPTIONS IN MUSCLE METABOLISM ARE ASSOCIATED WITH A NUMBER OF CHRONIC DISEASES. TRANSCRIPTIONAL CONTROL OF METABOLIC ENZYME EXPRESSION IS A MAJOR REGULATORY MECHANISM FOR MUSCLE METABOLIC PROCESSES. SUBSTANTIAL EVIDENCE IS EMERGING THAT HIGHLIGHTS THE IMPORTANCE OF EPIGENETIC MECHANISMS IN THIS PROCESS. THIS REVIEW WILL EXAMINE THE IMPORTANCE OF EPIGENETICS IN THE REGULATION OF MUSCLE METABOLISM, WITH A PARTICULAR EMPHASIS ON DNA METHYLATION AND HISTONE ACETYLATION AS EPIGENETIC CONTROL POINTS. THE EMERGING CROSS-TALK BETWEEN METABOLISM AND EPIGENETICS IN THE CONTEXT OF HEALTH AND DISEASE WILL ALSO BE EXAMINED. THE CONCEPT OF INHERITANCE OF SKELETAL MUSCLE METABOLIC PHENOTYPES WILL BE DISCUSSED, IN ADDITION TO EMERGING EPIGENETIC THERAPIES THAT COULD BE USED TO ALTER MUSCLE METABOLISM IN CHRONIC DISEASE STATES. 2016 3 3581 31 IMPACT OF PHYSICAL ACTIVITY AND EXERCISE ON THE EPIGENOME IN SKELETAL MUSCLE AND EFFECTS ON SYSTEMIC METABOLISM. EXERCISE AND PHYSICAL ACTIVITY INDUCES PHYSIOLOGICAL RESPONSES IN ORGANISMS, AND ADAPTATIONS IN SKELETAL MUSCLE, WHICH IS BENEFICIAL FOR MAINTAINING HEALTH AND PREVENTING AND/OR TREATING MOST CHRONIC DISEASES. THESE ADAPTATIONS ARE MAINLY INSTIGATED BY TRANSCRIPTIONAL RESPONSES THAT ENSUE IN REACTION TO EACH INDIVIDUAL EXERCISE, EITHER RESISTANCE OR ENDURANCE. CONSEQUENTLY, CHANGES IN KEY METABOLIC, REGULATORY, AND MYOGENIC GENES IN SKELETAL MUSCLE OCCUR AS BOTH AN EARLY AND LATE RESPONSE TO EXERCISE, AND THESE EPIGENETIC MODIFICATIONS, WHICH ARE INFLUENCED BY ENVIRONMENTAL AND GENETIC FACTORS, TRIGGER THOSE ALTERATIONS IN THE TRANSCRIPTIONAL RESPONSES. DNA METHYLATION AND HISTONE MODIFICATIONS ARE THE MOST SIGNIFICANT EPIGENETIC CHANGES DESCRIBED IN GENE TRANSCRIPTION, LINKED TO THE SKELETAL MUSCLE TRANSCRIPTIONAL RESPONSE TO EXERCISE, AND MEDIATING THE EXERCISE ADAPTATIONS. NEVERTHELESS, OTHER ALTERATIONS IN THE EPIGENETICS MARKERS, SUCH AS EPITRANSCRIPTOMICS, MODIFICATIONS MEDIATED BY MIRNAS, AND LACTYLATION AS A NOVEL EPIGENETIC MODIFICATION, ARE EMERGING AS KEY EVENTS FOR GENE TRANSCRIPTION. HERE, WE PROVIDE AN OVERVIEW AND UPDATE OF THE IMPACT OF EXERCISE ON EPIGENETIC MODIFICATIONS, INCLUDING THE WELL-DESCRIBED DNA METHYLATIONS AND HISTONE MODIFICATIONS, AND THE EMERGING MODIFICATIONS IN THE SKELETAL MUSCLE. IN ADDITION, WE DESCRIBE THE EFFECTS OF EXERCISE ON EPIGENETIC MARKERS IN OTHER METABOLIC TISSUES; ALSO, WE PROVIDE INFORMATION ABOUT HOW SYSTEMIC METABOLISM OR ITS METABOLITES INFLUENCE EPIGENETIC MODIFICATIONS IN THE SKELETAL MUSCLE. 2022 4 5660 37 SEX-SPECIFIC EPIGENETIC PROGRAMMING IN RENAL FIBROSIS AND INFLAMMATION. THE GROWING PREVALENCE OF HYPERTENSION, HEART DISEASE, DIABETES, AND OBESITY ALONG WITH AN AGING POPULATION, IS LEADING TO HIGHER INCIDENCE OF RENAL DISEASES IN THE SOCIETY. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED MAINLY BY PERSISTENT INFLAMMATION, FIBROSIS, AND GRADUAL LOSS OF RENAL FUNCTION LEADING TO RENAL FAILURE. SEX IS A KNOWN CONTRIBUTOR TO THE DIFFERENCES IN INCIDENCE AND PROGRESSION OF CKD. EPIGENETIC PROGRAMMING IS AN ESSENTIAL REGULATOR OF RENAL PHYSIOLOGY AND IS CRITICALLY INVOLVED IN THE PATHOPHYSIOLOGY OF RENAL INJURY AND FIBROSIS. EPIGENETIC SIGNALING INTEGRATES INTRINSIC AND EXTRINSIC SIGNALS ONTO THE GENOME, AND VARIOUS ENVIRONMENTAL AND HORMONAL STIMULI, INCLUDING SEX HORMONES, WHICH REGULATE GENE EXPRESSION AND DOWNSTREAM CELLULAR RESPONSES. THE MOST EXTENSIVELY STUDIED EPIGENETIC ALTERATIONS THAT PLAY A CRITICAL ROLE IN RENAL DAMAGE INCLUDE HISTONE MODIFICATIONS AND DNA METHYLATION. NOTABLY, THESE EPIGENETIC ALTERATIONS ARE REVERSIBLE, MAKING THEM CANDIDATES FOR POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OF RENAL DISEASES. HERE, WE WILL SUMMARIZE THE CURRENT KNOWLEDGE ON SEX-DIFFERENCES IN EPIGENETIC MODULATION OF RENAL FIBROSIS AND INFLAMMATION AND HIGHLIGHT SOME POSSIBLE EPIGENETIC THERAPEUTIC STRATEGIES FOR CKD TREATMENT. 2023 5 5581 31 ROLE OF NF-KAPPAB IN AGEING AND AGE-RELATED DISEASES: LESSONS FROM GENETICALLY MODIFIED MOUSE MODELS. AGEING IS A COMPLEX PROCESS, INDUCED BY MULTIFACETED INTERACTION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. IT IS MANIFESTED BY A DECLINE IN THE PHYSIOLOGICAL FUNCTIONS OF ORGANISMS AND ASSOCIATED TO THE DEVELOPMENT OF AGE-RELATED CHRONIC DISEASES AND CANCER DEVELOPMENT. IT IS CONSIDERED THAT AGEING FOLLOWS A STRICTLY-REGULATED PROGRAM, IN WHICH SOME SIGNALING PATHWAYS CRITICALLY CONTRIBUTE TO THE ESTABLISHMENT AND MAINTENANCE OF THE AGED STATE. CHRONIC INFLAMMATION IS A MAJOR MECHANISM THAT PROMOTES THE BIOLOGICAL AGEING PROCESS AND COMORBIDITY, WITH THE TRANSCRIPTION FACTOR NF-KAPPAB (NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS) AS A CRUCIAL MEDIATOR OF INFLAMMATORY RESPONSES. THIS, TOGETHER WITH THE FINDING THAT THE ACTIVATION OR INHIBITION OF NF-KAPPAB CAN INDUCE OR REVERSE RESPECTIVELY THE MAIN FEATURES OF AGED ORGANISMS, HAS BROUGHT IT UNDER CONSIDERATION AS A KEY TRANSCRIPTION FACTOR THAT ACTS AS A DRIVER OF AGEING. IN THIS REVIEW, WE FOCUSED ON THE DATA OBTAINED ENTIRELY THROUGH THE GENERATION OF KNOCKOUT AND TRANSGENIC MOUSE MODELS OF EITHER PROTEIN INVOLVED IN THE NF-KAPPAB SIGNALING PATHWAY THAT HAVE PROVIDED RELEVANT INFORMATION ABOUT THE INTRICATE PROCESSES OR MOLECULAR MECHANISMS THAT CONTROL AGEING. WE HAVE REVIEWED THE RELATIONSHIP OF NF-KAPPAB AND PREMATURE AGEING; THE DEVELOPMENT OF CANCER ASSOCIATED WITH AGEING AND THE IMPLICATION OF NF-KAPPAB ACTIVATION IN THE DEVELOPMENT OF AGE-RELATED DISEASES, SOME OF WHICH GREATLY INCREASE THE RISK OF DEVELOPING CANCER. 2021 6 6715 31 VITAMIN A AND THE EPIGENOME. THE EPIGENETIC PHENOMENA REFER TO HERITABLE CHANGES IN GENE EXPRESSION OTHER THAN THOSE IN THE DNA SEQUENCE, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS. MAJOR RESEARCH PROGRESS IN THE LAST FEW YEARS HAS PROVIDED FURTHER PROOF THAT ENVIRONMENTAL FACTORS, INCLUDING DIET AND NUTRITION, CAN INFLUENCE PHYSIOLOGIC AND PATHOLOGIC PROCESSES THROUGH EPIGENETIC ALTERATIONS, WHICH IN TURN INFLUENCE GENE EXPRESSION. THIS INFLUENCE IS TERMED NUTRITIONAL EPIGENETICS, AND ONE PROMINENT EXAMPLE IS THE REGULATION OF GENE TRANSCRIPTION BY VITAMIN A THROUGH INTERACTION TO ITS NUCLEAR RECEPTOR. VITAMIN A IS CRITICAL THROUGHOUT LIFE. TOGETHER WITH ITS DERIVATIVES, IT REGULATES DIVERSE PROCESSES INCLUDING REPRODUCTION, EMBRYOGENESIS, VISION, GROWTH, CELLULAR DIFFERENTIATION AND PROLIFERATION, MAINTENANCE OF EPITHELIAL CELLULAR INTEGRITY AND IMMUNE FUNCTION. HERE WE REVIEW THE EPIGENETIC ROLE OF VITAMIN A IN CANCER, STEM CELLS DIFFERENTIATION, PROLIFERATION, AND IMMUNITY. THE DATA PRESENTED HERE SHOW THAT RETINOIC ACID IS A POTENT AGENT CAPABLE OF INDUCING ALTERATIONS IN EPIGENETIC MODIFICATIONS THAT PRODUCE VARIOUS EFFECTS ON THE PHENOTYPE. MEDICAL BENEFITS OF VITAMIN A AS AN EPIGENETIC MODULATOR, ESPECIALLY WITH RESPECT TO ITS CHRONIC USE AS NUTRITIONAL SUPPLEMENT, SHOULD RELY ON OUR FURTHER UNDERSTANDING OF ITS EPIGENETIC EFFECTS DURING HEALTH AND DISEASE, AS WELL AS THROUGH DIFFERENT GENERATIONS. 2017 7 1604 40 DNA METHYLATION SUSTAINS "INFLAMED" MEMORY OF PERIPHERAL IMMUNE CELLS AGGRAVATING KIDNEY INFLAMMATORY RESPONSE IN CHRONIC KIDNEY DISEASE. THE INCIDENCE OF CHRONIC KIDNEY DISEASE (CKD) HAS RAPIDLY INCREASED IN THE PAST DECADES. A PROGRESSIVE LOSS OF KIDNEY FUNCTION CHARACTERIZES A PART OF CKD EVEN WITH INTENSIVE SUPPORTIVE TREATMENT. IRRESPECTIVE OF ITS ETIOLOGY, CKD PROGRESSION IS GENERALLY ACCOMPANIED WITH THE DEVELOPMENT OF CHRONIC KIDNEY INFLAMMATION THAT IS PATHOLOGICALLY FEATURED BY THE LOW-GRADE BUT CHRONIC ACTIVATION OF RECRUITED IMMUNE CELLS. CUMULATIVE EVIDENCE SUPPORT THAT ABERRANT DNA METHYLATION PATTERN OF DIVERSE PERIPHERAL IMMUNE CELLS, INCLUDING T CELLS AND MONOCYTES, IS CLOSELY ASSOCIATED WITH CKD DEVELOPMENT IN MANY CHRONIC DISEASE SETTINGS. THE CHANGE OF DNA METHYLATION PROFILE CAN SUSTAIN FOR A LONG TIME AND AFFECT THE FUTURE GENES EXPRESSION IN THE CIRCULATING IMMUNE CELLS EVEN AFTER THEY MIGRATE FROM THE CIRCULATION INTO THE INVOLVED KIDNEY. IT IS OF CLINICAL INTEREST TO REVEAL THE UNDERLYING MECHANISM OF HOW ALTERED DNA METHYLATION REGULATES THE INTENSITY AND THE TIME LENGTH OF THE INFLAMMATORY RESPONSE IN THE RECRUITED EFFECTOR CELLS. WE AND OTHERS RECENTLY DEMONSTRATED THAT ALTERED DNA METHYLATION OCCURS IN PERIPHERAL IMMUNE CELLS AND PROFOUNDLY CONTRIBUTES TO CKD DEVELOPMENT IN SYSTEMIC CHRONIC DISEASES, SUCH AS DIABETES AND HYPERTENSION. THIS REVIEW WILL SUMMARIZE THE CURRENT FINDINGS ABOUT THE INFLUENCE OF ABERRANT DNA METHYLATION ON CIRCULATING IMMUNE CELLS AND HOW IT POTENTIALLY DETERMINES THE OUTCOME OF CKD. 2021 8 2499 24 EPIGENETICS AND EXERCISE. EPIGENETICS CAN BE DEFINED AS 'THE STRUCTURAL ADAPTATION OF CHROMOSOMAL REGIONS SO AS TO REGISTER, SIGNAL, OR PERPETUATE ALTERED ACTIVITY STATES.' INCREASED TRANSCRIPTION OF KEY REGULATORY, METABOLIC, AND MYOGENIC GENES IS AN EARLY RESPONSE TO EXERCISE AND IS IMPORTANT IN MEDIATING SUBSEQUENT ADAPTATIONS IN SKELETAL MUSCLE. DNA HYPOMETHYLATION AND HISTONE HYPERACETYLATION ARE EMERGING AS IMPORTANT CRUCIAL EVENTS FOR INCREASED TRANSCRIPTION. THE COMPLEX INTERACTIONS BETWEEN MULTIPLE EPIGENETIC MODIFICATIONS AND THEIR REGULATION BY METABOLIC CHANGES AND SIGNALING EVENTS DURING EXERCISE, WITH IMPLICATIONS FOR ENHANCED UNDERSTANDING OF THE ACUTE AND CHRONIC ADAPTATIONS TO EXERCISE, ARE QUESTIONS FOR FURTHER INVESTIGATION. 2019 9 607 34 BEYOND GENETICS: EPIGENETIC CODE IN CHRONIC KIDNEY DISEASE. EPIGENETICS REFERS TO A HERITABLE CHANGE IN THE PATTERN OF GENE EXPRESSION THAT IS MEDIATED BY A MECHANISM SPECIFICALLY NOT DUE TO ALTERATIONS IN THE PRIMARY NUCLEOTIDE SEQUENCE. WELL-KNOWN EPIGENETIC MECHANISMS ENCOMPASS DNA METHYLATION, CHROMATIN REMODELING (HISTONE MODIFICATIONS), AND RNA INTERFERENCE. FUNCTIONALLY, EPIGENETICS PROVIDES AN EXTRA LAYER OF TRANSCRIPTIONAL CONTROL AND PLAYS A CRUCIAL ROLE IN NORMAL PHYSIOLOGICAL DEVELOPMENT, AS WELL AS IN PATHOLOGICAL CONDITIONS. ABERRANT DNA METHYLATION IS IMPLICATED IN IMMUNE DYSFUNCTION, INFLAMMATION, AND INSULIN RESISTANCE. EPIGENETIC CHANGES MAY BE RESPONSIBLE FOR 'METABOLIC MEMORY' AND DEVELOPMENT OF MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES. MICRORNAS ARE CRITICAL IN THE MAINTENANCE OF GLOMERULAR HOMEOSTASIS AND HENCE RNA INTERFERENCE MAY BE IMPORTANT IN THE PROGRESSION OF RENAL DISEASE. RECENT STUDIES HAVE SHOWN THAT EPIGENETIC MODIFICATIONS ORCHESTRATE THE EPITHELIAL-MESENCHYMAL TRANSITION AND EVENTUALLY FIBROSIS OF THE RENAL TISSUE. OXIDATIVE STRESS, INFLAMMATION, HYPERHOMOCYSTEINEMIA, AND UREMIC TOXINS COULD INDUCE EPIMUTATIONS IN CHRONIC KIDNEY DISEASE. EPIGENETIC ALTERATIONS ARE ASSOCIATED WITH INFLAMMATION AND CARDIOVASCULAR DISEASE IN PATIENTS WITH CHRONIC KIDNEY DISEASE. REVERSIBLE NATURE OF THE EPIGENETIC CHANGES GIVES A UNIQUE OPPORTUNITY TO HALT OR EVEN REVERSE THE DISEASE PROCESS THROUGH TARGETED THERAPEUTIC STRATEGIES. 2011 10 5471 27 RESPIRATORY MUSCLE SENESCENCE IN AGEING AND CHRONIC LUNG DISEASES. AGEING IS A PROGRESSIVE CONDITION THAT USUALLY LEADS TO THE LOSS OF PHYSIOLOGICAL PROPERTIES. THIS PROCESS IS ALSO PRESENT IN RESPIRATORY MUSCLES, WHICH ARE AFFECTED BY BOTH SENESCENT CHANGES OCCURRING IN THE WHOLE ORGANISM AND THOSE THAT ARE MORE SPECIFIC FOR MUSCLES. THE MECHANISMS OF THE LATTER CHANGES INCLUDE OXIDATIVE STRESS, DECREASE IN NEUROTROPHIC FACTORS AND DNA ABNORMALITIES. AGEING NORMALLY COEXISTS WITH COMORBIDITIES, INCLUDING RESPIRATORY DISEASES, WHICH FURTHER DETERIORATE THE STRUCTURE AND FUNCTION OF RESPIRATORY MUSCLES. IN THIS CONTEXT, CHANGES INTRINSIC TO AGEING BECOME ENHANCED BY MORE SPECIFIC FACTORS SUCH AS THE IMPAIRMENT IN LUNG MECHANICS AND GAS EXCHANGE, EXACERBATIONS AND HYPOXIA. HYPOXIA IN PARTICULAR HAS A DIRECT EFFECT ON MUSCLES, MAINLY THROUGH THE EXPRESSION OF INDUCIBLE FACTORS (HYPOXIC-INDUCIBLE FACTOR), AND CAN RESULT IN OXIDATIVE STRESS AND CHANGES IN DNA, DECREASE IN MITOCHONDRIAL BIOGENESIS AND DEFECTS IN THE TISSUE REPAIR MECHANISMS. INTENSE EXERCISE CAN ALSO CAUSE DAMAGE IN RESPIRATORY MUSCLES OF ELDERLY RESPIRATORY PATIENTS, BUT THIS CAN BE FOLLOWED BY TISSUE REPAIR AND REMODELLING. HOWEVER, AGEING INTERFERES WITH MUSCLE REPAIR BY TAMPERING WITH THE FUNCTION OF SATELLITE CELLS, MAINLY DUE TO OXIDATIVE STRESS, DNA DAMAGE AND EPIGENETIC MECHANISMS. IN ADDITION TO THE NORMAL PROCESS OF AGEING, STRESS-INDUCED PREMATURE SENESCENCE CAN ALSO OCCUR, INVOLVING CHANGES IN THE EXPRESSION OF MULTIPLE GENES BUT WITHOUT MODIFICATIONS IN TELOMERE LENGTH. 2020 11 5258 33 PROGRESSION OF TUBULOINTERSTITIAL FIBROSIS AND THE CHRONIC KIDNEY DISEASE PHENOTYPE - ROLE OF RISK FACTORS AND EPIGENETICS. ALTHOUGH THE KIDNEY HAS CAPACITY TO REPAIR AFTER MILD INJURY, ONGOING OR SEVERE DAMAGE RESULTS IN SCARRING (FIBROSIS) AND AN ASSOCIATED PROGRESSIVE LOSS OF KIDNEY FUNCTION. HOWEVER, DESPITE ITS UNIVERSAL SIGNIFICANCE, EVIDENCE HIGHLIGHTS A POPULATION BASED HETEROGENEITY IN THE TRAJECTORY OF CHRONIC KIDNEY DISEASE (CKD) IN THESE PATIENTS. TO EXPLAIN THE HETEROGENEITY OF THE CKD PHENOTYPE REQUIRES AN UNDERSTANDING OF THE RELEVANT RISK FACTORS FOR FIBROSIS. THESE FACTORS INCLUDE BOTH THE EXTRINSIC NATURE OF INJURY, AND INTRINSIC FACTORS SUCH AS AGE, GENDER, GENETICS, AND PERPETUAL ACTIVATION OF FIBROBLASTS THROUGH PRIMING. IN MANY CASES AN ADDITIONAL LEVEL OF REGULATION IS PROVIDED BY EPIGENETIC MECHANISMS WHICH INTEGRATE THE VARIOUS PRO-FIBROTIC AND ANTI-FIBROTIC TRIGGERS IN FIBROGENESIS. IN THIS REVIEW WE THEREFORE EXAMINE THE VARIOUS MOLECULAR AND STRUCTURAL CHANGES OF FIBROSIS, AND HOW THEY ARE INFLUENCED BY EXTRINSIC AND INTRINSIC FACTORS. OUR AIM IS TO PROVIDE A UNIFYING HYPOTHESIS TO HELP EXPLAIN THE TRANSITION FROM ACUTE TO CKD. 2017 12 2348 32 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 13 2195 40 EPIGENETIC MODIFICATION MECHANISMS INVOLVED IN INFLAMMATION AND FIBROSIS IN RENAL PATHOLOGY. THE GROWING INCIDENCE OF OBESITY, HYPERTENSION, AND DIABETES, COUPLED WITH THE AGING OF THE POPULATION, IS INCREASING THE PREVALENCE OF RENAL DISEASES IN OUR SOCIETY. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED BY PERSISTENT INFLAMMATION, FIBROSIS, AND LOSS OF RENAL FUNCTION LEADING TO END-STAGE RENAL DISEASE. NOWADAYS, CKD TREATMENT HAS LIMITED EFFECTIVENESS UNDERSCORING THE IMPORTANCE OF THE DEVELOPMENT OF INNOVATIVE THERAPEUTIC OPTIONS. RECENT STUDIES HAVE IDENTIFIED HOW EPIGENETIC MODIFICATIONS PARTICIPATE IN THE SUSCEPTIBILITY TO CKD AND HAVE EXPLAINED HOW THE ENVIRONMENT INTERACTS WITH THE RENAL CELL EPIGENOME TO CONTRIBUTE TO RENAL DAMAGE. EPIGENETIC MECHANISMS REGULATE CRITICAL PROCESSES INVOLVED IN GENE REGULATION AND DOWNSTREAM CELLULAR RESPONSES. THE MOST RELEVANT EPIGENETIC MODIFICATIONS THAT PLAY A CRITICAL ROLE IN RENAL DAMAGE INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND CHANGES IN MIRNA LEVELS. IMPORTANTLY, THESE EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND, THEREFORE, A SOURCE OF POTENTIAL THERAPEUTIC TARGETS. HERE, WE WILL EXPLAIN HOW EPIGENETIC MECHANISMS MAY REGULATE ESSENTIAL PROCESSES INVOLVED IN RENAL PATHOLOGY AND HIGHLIGHT SOME POSSIBLE EPIGENETIC THERAPEUTIC STRATEGIES FOR CKD TREATMENT. 2018 14 859 23 CHROMATIN DYNAMICS IN KIDNEY DEVELOPMENT AND FUNCTION. EPIGENETIC MECHANISMS ARE FUNDAMENTAL KEY FEATURES OF DEVELOPING CELLS CONNECTING DEVELOPMENTAL REGULATORY FACTORS TO CHROMATIN MODIFICATION. CHANGES IN THE ENVIRONMENT DURING RENAL DEVELOPMENT CAN HAVE LONG-LASTING EFFECTS ON THE PERMANENT TISSUE STRUCTURE AND THE LEVEL OF EXPRESSION OF IMPORTANT FUNCTIONAL GENES. THESE CHANGES ARE BELIEVED TO CONTRIBUTE TO KIDNEY DISEASE OCCURRENCE AND PROGRESSION. ALTHOUGH THE MECHANISMS OF EARLY PATTERNING AND CELL FATE HAVE BEEN WELL DESCRIBED FOR RENAL DEVELOPMENT, LITTLE IS KNOWN ABOUT ASSOCIATED EPIGENETIC MODIFICATIONS AND THEIR IMPACT ON HOW GENES INTERACT TO SPECIFY THE RENAL EPITHELIAL CELLS OF NEPHRONS AND HOW THIS SPECIFICATION IS RELEVANT TO MAINTAINING NORMAL RENAL FUNCTION. A BETTER UNDERSTANDING OF THE RENAL CELL-SPECIFIC EPIGENETIC MODIFICATIONS AND THE INTERACTION OF DIFFERENT CELL TYPES TO FORM THIS HIGHLY COMPLEX ORGAN WILL NOT ONLY HELP TO BETTER UNDERSTAND DEVELOPMENTAL DEFECTS AND EARLY LOSS OF KIDNEY FUNCTION IN CHILDREN, BUT ALSO HELP TO UNDERSTAND AND IMPROVE CHRONIC DISEASE PROGRESSION, CELL REGENERATION AND RENAL AGING. 2014 15 4882 31 OVERVIEW OF THE CELLULAR AND MOLECULAR BASIS OF KIDNEY FIBROSIS. THE COMMON PATHOGENETIC PATHWAY OF PROGRESSIVE INJURY IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) IS EPITOMIZED AS NORMAL KIDNEY PARENCHYMAL DESTRUCTION DUE TO SCARRING (FIBROSIS). UNDERSTANDING THE FUNDAMENTAL PATHWAYS THAT LEAD TO RENAL FIBROSIS IS ESSENTIAL IN ORDER TO DEVELOP BETTER THERAPEUTIC OPTIONS FOR HUMAN CKD. ALTHOUGH COMPLEX, FOUR CELLULAR RESPONSES ARE PIVOTAL. (1) AN INTERSTITIAL INFLAMMATORY RESPONSE THAT HAS MULTIPLE CONSEQUENCES-SOME HARMFUL AND OTHERS HEALING. (2) THE APPEARANCE OF A UNIQUE INTERSTITIAL CELL POPULATION OF MYOFIBROBLASTS, PRIMARILY DERIVED FROM KIDNEY STROMAL CELLS (FIBROBLASTS AND PERICYTES), THAT ARE THE PRIMARY SOURCE OF THE VARIOUS EXTRACELLULAR MATRIX PROTEINS THAT FORM INTERSTITIAL SCARS. (3) TUBULAR EPITHELIAL CELLS THAT HAVE VARIABLE AND TIME-DEPENDENT ROLES AS EARLY RESPONDERS TO INJURY AND LATER AS VICTIMS OF FIBROSIS DUE TO THE LOSS OF THEIR REGENERATIVE ABILITIES. (4) LOSS OF INTERSTITIAL CAPILLARY INTEGRITY THAT COMPROMISES OXYGEN DELIVERY AND LEADS TO A VICIOUS CASCADE OF HYPOXIA-OXIDANT STRESS THAT ACCENTUATES INJURY AND FIBROSIS. IN THE ABSENCE OF ADEQUATE ANGIOGENIC RESPONSES, A HEALTHY INTERSTITIAL CAPILLARY NETWORK IS NOT MAINTAINED. THE FIBROTIC 'SCAR' THAT TYPIFIES CKD IS AN INTERESTING CONSORTIUM OF MULTIFUNCTIONAL MACROMOLECULES THAT NOT ONLY CHANGE IN COMPOSITION AND STRUCTURE OVER TIME, BUT CAN BE DEGRADED VIA EXTRACELLULAR AND INTRACELLULAR PROTEASES. ALTHOUGH TRANSFORMING GROWTH FACTOR BETA APPEARS TO BE THE PRIMARY DRIVER OF KIDNEY FIBROSIS, A VAST ARRAY OF ADDITIONAL MOLECULES MAY HAVE MODULATING ROLES. THE IMPORTANCE OF GENETIC AND EPIGENETIC FACTORS IS INCREASINGLY APPRECIATED. AN INTRIGUING BUT INCOMPLETELY UNDERSTOOD CARDIORENAL SYNDROME UNDERLIES THE HIGH MORBIDITY AND MORTALITY RATES THAT DEVELOP IN ASSOCIATION WITH PROGRESSIVE KIDNEY FIBROSIS. 2014 16 2577 33 EPIGENETICS OF INFLAMMATION, MATERNAL INFECTION, AND NUTRITION. STUDIES HAVE DEMONSTRATED THAT EPIGENETIC CHANGES SUCH AS DNA METHYLATION, HISTONE MODIFICATION, AND CHROMATIN REMODELING ARE LINKED TO AN INCREASED INFLAMMATORY RESPONSE AS WELL AS INCREASED RISK OF CHRONIC DISEASE DEVELOPMENT. A FEW STUDIES HAVE BEGUN TO INVESTIGATE WHETHER DIETARY NUTRIENTS PLAY A BENEFICIAL ROLE BY MODIFYING OR REVERSING EPIGENETICALLY INDUCED INFLAMMATION. RESULTS OF THESE STUDIES SHOW THAT NUTRIENTS MODIFY EPIGENETIC PATHWAYS. HOWEVER, LITTLE IS KNOWN ABOUT HOW NUTRIENTS MODULATE INFLAMMATION BY REGULATING IMMUNE CELL FUNCTION AND/OR IMMUNE CELL DIFFERENTIATION VIA EPIGENETIC PATHWAYS. THIS OVERVIEW WILL PROVIDE INFORMATION ABOUT THE CURRENT UNDERSTANDING OF THE ROLE OF NUTRIENTS IN THE EPIGENETIC CONTROL MECHANISMS OF IMMUNE FUNCTION. 2015 17 2562 26 EPIGENETICS IN THE PRIMARY AND SECONDARY PREVENTION OF CARDIOVASCULAR DISEASE: INFLUENCE OF EXERCISE AND NUTRITION. INCREASING EVIDENCE LINKS CHANGES IN EPIGENETIC SYSTEMS, SUCH AS DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA EXPRESSION, TO THE OCCURRENCE OF CARDIOVASCULAR DISEASE (CVD). THESE EPIGENETIC MODIFICATIONS CAN CHANGE GENETIC FUNCTION UNDER INFLUENCE OF EXOGENOUS STIMULI AND CAN BE TRANSFERRED TO NEXT GENERATIONS, PROVIDING A POTENTIAL MECHANISM FOR INHERITANCE OF BEHAVIOURAL INTERVENTION EFFECTS. THE BENEFITS OF EXERCISE AND NUTRITIONAL INTERVENTIONS IN THE PRIMARY AND SECONDARY PREVENTION OF CVD ARE WELL ESTABLISHED, BUT THE MECHANISMS ARE NOT COMPLETELY UNDERSTOOD. IN THIS REVIEW, WE DESCRIBE THE ACUTE AND CHRONIC EPIGENETIC EFFECTS OF PHYSICAL ACTIVITY AND DIETARY CHANGES. WE PROPOSE EXERCISE AND NUTRITION AS POTENTIAL TRIGGERS OF EPIGENETIC SIGNALS, PROMOTING THE RESHAPING OF TRANSCRIPTIONAL PROGRAMMES WITH EFFECTS ON CVD PHENOTYPES. FINALLY, WE HIGHLIGHT RECENT DEVELOPMENTS IN EPIGENETIC THERAPEUTICS WITH IMPLICATIONS FOR PRIMARY AND SECONDARY CVD PREVENTION. 2022 18 4273 35 MICROBIOTA AND EPIGENETICS: HEALTH IMPACT. EPIGENETIC CHANGES ASSOCIATED WITH DISEASE DEVELOPMENT AND PROGRESSIONS ARE OF INCREASING IMPORTANCE BECAUSE OF THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. SEVERAL EPIGENETIC CHANGES ASSOCIATED WITH CHRONIC METABOLIC DISORDERS HAVE BEEN STUDIED IN VARIOUS DISEASES. EPIGENETIC CHANGES ARE MOSTLY MODULATED BY ENVIRONMENTAL FACTORS, INCLUDING THE HUMAN MICROBIOTA LIVING IN DIFFERENT PARTS OF OUR BODIES. THE MICROBIAL STRUCTURAL COMPONENTS AND THE MICROBIALLY DERIVED METABOLITES DIRECTLY INTERACT WITH HOST CELLS, THEREBY MAINTAINING HOMEOSTASIS. MICROBIOME DYSBIOSIS, ON THE OTHER HAND, IS KNOWN TO PRODUCE ELEVATED LEVELS OF DISEASE-LINKED METABOLITES, WHICH MAY DIRECTLY AFFECT A HOST METABOLIC PATHWAY OR INDUCE EPIGENETIC CHANGES THAT CAN LEAD TO DISEASE DEVELOPMENT. DESPITE THEIR IMPORTANT ROLE IN HOST PHYSIOLOGY AND SIGNAL TRANSDUCTION, THERE HAS BEEN LITTLE RESEARCH INTO THE MECHANICS AND PATHWAYS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. THIS CHAPTER FOCUSES ON THE RELATIONSHIP BETWEEN MICROBES AND THEIR EPIGENETIC EFFECTS IN DISEASED PATHOLOGY, AS WELL AS ON THE REGULATION AND METABOLISM OF THE DIETARY OPTIONS AVAILABLE TO THE MICROBES. FURTHERMORE, THIS CHAPTER ALSO PROVIDES A PROSPECTIVE LINK BETWEEN THESE TWO IMPORTANT PHENOMENA, TERMED "MICROBIOME AND EPIGENETICS." 2023 19 462 33 ARE ALTERATIONS IN DNA METHYLATION RELATED TO CKD DEVELOPMENT? THE MODIFICATIONS IN GENOMIC DNA METHYLATION ARE INVOLVED IN THE REGULATION OF NORMAL AND PATHOLOGICAL CELLULAR PROCESSES. THE EPIGENETIC REGULATION STIMULATES BIOLOGICAL PLASTICITY AS AN ADAPTIVE RESPONSE TO VARIATIONS IN ENVIRONMENTAL FACTORS. THE ROLE OF EPIGENETIC CHANGES IS VITAL FOR THE DEVELOPMENT OF SOME DISEASES, INCLUDING ATHEROGENESIS, CANCERS, AND CHRONIC KIDNEY DISEASE (CKD). THE RESULTS OF STUDIES PRESENTED IN THIS REVIEW HAVE SUGGESTED THAT ALTERED DNA METHYLATION CAN MODULATE THE EXPRESSION OF PRO-INFLAMMATORY AND PRO-FIBROTIC GENES, AS WELL THOSE ESSENTIAL FOR KIDNEY DEVELOPMENT AND FUNCTION, THUS STIMULATING RENAL DISEASE PROGRESSION. ABNORMALLY INCREASED HOMOCYSTEINE, HYPOXIA, AND INFLAMMATION HAVE BEEN SUGGESTED TO ALTER EPIGENETIC REGULATION OF GENE EXPRESSION IN CKD. STUDIES OF RENAL SAMPLES HAVE DEMONSTRATED THE RELATIONSHIP BETWEEN VARIATIONS IN DNA METHYLATION AND FIBROSIS AND VARIATIONS IN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) IN HUMAN CKD. THE UNRAVELLING OF THE GENETIC-EPIGENETIC PROFILE WOULD ENHANCE OUR UNDERSTANDING OF PROCESSES UNDERLYING THE DEVELOPMENT OF CKD. THE UNDERSTANDING OF MULTIFACETED RELATIONSHIP BETWEEN DNA METHYLATION, GENES EXPRESSION, AND DISEASE DEVELOPMENT AND PROGRESSION COULD IMPROVE THE ABILITY TO IDENTIFY INDIVIDUALS AT RISK OF CKD AND ENABLE THE CHOICE OF APPROPRIATE DISEASE MANAGEMENT. 2022 20 2505 42 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