1 4928 107 PARP-1 AND PARP-2 ACTIVITY IN CANCER-INDUCED CACHEXIA: POTENTIAL THERAPEUTIC IMPLICATIONS. SKELETAL MUSCLE DYSFUNCTION AND MASS LOSS IS A CHARACTERISTIC FEATURE IN PATIENTS WITH CHRONIC DISEASES INCLUDING CANCER AND ACUTE CONDITIONS SUCH AS CRITICAL ILLNESS. MAINTENANCE OF AN ADEQUATE MUSCLE MASS IS CRUCIAL FOR THE PATIENTS' PROGNOSIS IRRESPECTIVE OF THE UNDERLYING CONDITION. MOREOVER, AGING-RELATED SARCOPENIA MAY FURTHER AGGRAVATE THE MUSCLE WASTING PROCESS ASSOCIATED WITH CHRONIC DISEASES AND CANCER. POLY(ADENOSINE DIPHOSPHATE-RIBOSE) POLYMERASE (PARP) ACTIVATION HAS BEEN DEMONSTRATED TO CONTRIBUTE TO THE PATHOPHYSIOLOGY OF MUSCLE MASS LOSS AND DYSFUNCTION IN ANIMAL MODELS OF CANCER-INDUCED CACHEXIA. GENETIC INHIBITION OF PARP ACTIVITY ATTENUATED THE DELETERIOUS EFFECTS SEEN ON DEPLETED MUSCLES IN MOUSE MODELS OF ONCOLOGIC CACHEXIA. IN THE PRESENT MINIREVIEW THE MECHANISMS WHEREBY PARP ACTIVITY INHIBITION MAY IMPROVE MUSCLE MASS AND PERFORMANCE IN MODELS OF CANCER-INDUCED CACHEXIA ARE DISCUSSED. SPECIFICALLY, THE BENEFICIAL EFFECTS OF INHIBITION OF PARP ACTIVITY ON ATTENUATION OF INCREASED OXIDATIVE STRESS, PROTEIN CATABOLISM, POOR MUSCLE ANABOLISM AND MITOCHONDRIAL CONTENT AND EPIGENETIC MODULATION OF MUSCLE PHENOTYPE ARE REVIEWED IN THIS ARTICLE. FINALLY, THE POTENTIAL THERAPEUTIC STRATEGIES OF PHARMACOLOGICAL PARP ACTIVITY INHIBITION FOR THE TREATMENT OF CANCER-INDUCED CACHEXIA ARE ALSO BEING DESCRIBED IN THIS REVIEW. 2018 2 6360 29 THE ROLE OF INFLAMMATORY PATHWAYS IN CANCER-ASSOCIATED CACHEXIA AND RADIATION RESISTANCE. DYSREGULATED INFLAMMATORY RESPONSES ARE KEY CONTRIBUTORS TO A MULTITUDE OF CHRONIC AILMENTS, INCLUDING CANCER. EVIDENCE INDICATES THAT DISEASE PROGRESSION IN CANCER IS DEPENDENT ON THE COMPLEX INTERACTION BETWEEN THE TUMOR AND THE HOST MICROENVIRONMENT. MOST RECENTLY, THE INFLAMMATORY RESPONSE HAS BEEN SUGGESTED TO BE CRITICAL, AS BOTH THE TUMOR AND MICROENVIRONMENT COMPARTMENTS PRODUCE CYTOKINES THAT ACT ON NUMEROUS TARGET SITES, WHERE THEY FOSTER A COMPLEX CASCADE OF BIOLOGIC OUTCOMES. PATIENTS WITH CANCER-ASSOCIATED CACHEXIA (CAC) SUFFER FROM A DRAMATIC LOSS OF SKELETAL MUSCLE AND ADIPOSE TISSUE, ULTIMATELY PRECLUDING THEM FROM MANY FORMS OF THERAPEUTIC INTERVENTION, INCLUDING RADIOTHERAPY. THE CYTOKINES THAT HAVE BEEN LINKED TO THE PROMOTION OF THE CACHECTIC RESPONSE MAY ALSO PARTICIPATE IN RADIATION RESISTANCE. THE MAJOR CHANGES AT THE CYTOKINE LEVEL ARE, IN PART, DUE TO TRANSCRIPTIONAL REGULATORY ALTERATIONS POSSIBLY DUE TO EPIGENETIC MODIFICATIONS. HEREIN WE DISCUSS THE ROLE OF INFLAMMATORY PATHWAYS IN CAC AND EXAMINE THE POTENTIAL LINK BETWEEN CACHEXIA INDUCTION AND RADIATION RESISTANCE. 2013 3 5672 35 SHARED AND DIVERGENT EPIGENETIC MECHANISMS IN CACHEXIA AND SARCOPENIA. SIGNIFICANT LOSS OF MUSCLE MASS MAY OCCUR IN CACHEXIA AND SARCOPENIA, WHICH ARE MAJOR CAUSES OF MORTALITY AND DISABILITY. CACHEXIA REPRESENTS A COMPLEX MULTI-ORGAN SYNDROME ASSOCIATED WITH CANCER AND CHRONIC DISEASES. IT IS OFTEN CHARACTERIZED BY BODY WEIGHT LOSS, INFLAMMATION, AND MUSCLE AND ADIPOSE WASTING. PROGRESSIVE MUSCLE LOSS IS ALSO A HALLMARK OF HEALTHY AGING, WHICH IS EMERGING WORLDWIDE AS A MAIN DEMOGRAPHIC TREND. A GREAT CHALLENGE FOR THE HEALTH CARE SYSTEMS IS THE AGE-RELATED DECLINE IN FUNCTIONALITY WHICH THREATENS THE INDEPENDENCE AND QUALITY OF LIFE OF ELDERLY PEOPLE. THIS BIOLOGICAL DECLINE CAN ALSO BE ASSOCIATED WITH FUNCTIONAL MUSCLE LOSS, KNOWN AS SARCOPENIA. PREVIOUS STUDIES HAVE SHOWN THAT MICRORNAS (MIRNAS) PLAY PIVOTAL ROLES IN THE DEVELOPMENT AND PROGRESSION OF MUSCLE WASTING IN BOTH CACHEXIA AND SARCOPENIA. THESE SMALL NON-CODING RNAS, OFTEN CARRIED IN EXTRACELLULAR VESICLES, INHIBIT TRANSLATION BY TARGETING MESSENGER RNAS, THEREFORE REPRESENTING POTENT EPIGENETIC MODULATORS. THE MOLECULAR MECHANISMS BEHIND CACHEXIA AND SARCOPENIA, INCLUDING THE EXPRESSION OF SPECIFIC MIRNAS, SHARE COMMON AND DISTINCTIVE TRENDS. THE AIM OF THE PRESENT REVIEW IS TO COMPILE RECENT EVIDENCE ABOUT SHARED AND DIVERGENT EPIGENETIC MECHANISMS, PARTICULARLY FOCUSING ON MIRNAS, BETWEEN CACHEXIA AND SARCOPENIA TO UNDERSTAND A FACET IN THE UNDERLYING MUSCLE WASTING ASSOCIATED WITH THESE MORBIDITIES AND DISCLOSE POTENTIAL THERAPEUTIC INTERVENTIONS. 2022 4 4974 29 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 5 5724 29 SKELETAL MUSCLE WASTING AND ITS RELATIONSHIP WITH OSTEOARTHRITIS: A MINI-REVIEW OF MECHANISMS AND CURRENT INTERVENTIONS. PURPOSE OF REVIEW: OSTEOARTHRITIS (OA) IS A SUBSET OF JOINT DISORDERS RESULTING IN DEGENERATION OF SYNOVIAL JOINTS. THIS LEADS TO PAIN, DISABILITY AND LOSS OF INDEPENDENCE. KNEE AND HIP OA ARE EXTREMELY PREVALENT, AND THEIR OCCURRENCE INCREASES WITH AGEING. SIMILARLY, LOSS OF MUSCLE MASS AND FUNCTION, SARCOPENIA, OCCURS DURING AGEING. RECENT FINDINGS: LITTLE IS KNOWN ABOUT THE IMPACT OF MUSCLE WASTING ON OA PROGRESSION; NEVERTHELESS, IT HAS BEEN SUGGESTED THAT MUSCLE WASTING DIRECTLY AFFECTS THE STABILITY OF THE JOINTS AND LOSS OF MOBILITY LEADS TO GRADUAL DEGENERATION OF ARTICULAR CARTILAGE. THE MOLECULAR MECHANISMS UNDERLYING MUSCLE WASTING IN OA ARE NOT WELL UNDERSTOOD; HOWEVER, THESE ARE PROBABLY RELATED TO CHANGES IN GENE EXPRESSION, AS WELL AS EPIGENETIC MODIFICATIONS. IT IS BECOMING CLEAR THAT SKELETAL MUSCLE WASTING PLAYS AN IMPORTANT ROLE IN OA DEVELOPMENT AND/OR PROGRESSION. HERE, WE DISCUSS MECHANISMS, CURRENT INTERVENTIONS, SUCH AS EXERCISE, AND POTENTIALLY NOVEL APPROACHES, SUCH AS MODULATION OF MICRORNAS, AIMING AT AMELIORATING OA SYMPTOMS THROUGH MAINTAINING MUSCLE MASS AND FUNCTION. 2019 6 5471 32 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 7 2704 28 EXERCISE AND COLORECTAL CANCER: PREVENTION AND MOLECULAR MECHANISMS. EXERCISE AND PHYSICAL ACTIVITY HAVE BEEN SHOWN TO BE STRONGLY ASSOCIATED WITH A DECREASED INCIDENCE RATE OF VARIOUS CHRONIC DISEASES ESPECIALLY NUMEROUS HUMAN MALIGNANCIES. A HUGE NUMBER OF CLINICAL TRIALS AND META-ANALYSIS HAVE DEMONSTRATED THAT EXERCISE IS SIGNIFICANTLY EFFECTIVE IN LOWERING THE RISK OF COLORECTAL CANCER. IN ADDITION, IT IS SUGGESTED AS AN EFFECTIVE THERAPEUTIC MODALITY AGAINST THIS CANCER TYPE. THEREFORE, IN THIS REVIEW, WE WILL REVIEW COMPREHENSIBLY THE EFFECTS OF EXERCISE IN PREVENTING, TREATING, AND ALLEVIATING THE ADVERSE EFFECTS OF CONVENTIONAL THERAPEUTIC OPTIONS IN COLORECTAL CANCER. MOREOVER, THE POSSIBLE MECHANISMS UNDERLYING THE POSITIVE EFFECTS OF EXERCISE AND PHYSICAL ACTIVITY IN COLORECTAL CANCER, INCLUDING REGULATION OF INFLAMMATION, APOPTOSIS, GROWTH FACTOR AXIS, IMMUNITY, EPIGENETIC, ETC. WILL BE ALSO DISCUSSED. 2022 8 2360 26 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 9 2505 41 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 10 5581 32 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 11 5943 27 TARGETING OXIDATIVE STRESS IN CANCER. IMPORTANCE OF THE FIELD: REACTIVE OXYGEN SPECIES (ROS) OCCUR AS NATURAL BY-PRODUCTS OF OXYGEN METABOLISM AND HAVE IMPORTANT CELLULAR FUNCTIONS. NORMALLY, THE CELL IS ABLE TO MAINTAIN AN ADEQUATE BALANCE BETWEEN THE FORMATION AND REMOVAL OF ROS EITHER VIA ANTI-OXIDANTS OR THROUGH THE USE SPECIFIC ENZYMATIC PATHWAYS. HOWEVER, IF THIS BALANCE IS DISTURBED, OXIDATIVE STRESS MAY OCCUR IN THE CELL, A SITUATION LINKED TO THE PATHOGENESIS OF MANY DISEASES, INCLUDING CANCER. AREAS COVERED IN THIS REVIEW: HDACS ARE IMPORTANT REGULATORS OF MANY OXIDATIVE STRESS PATHWAYS INCLUDING THOSE INVOLVED WITH BOTH SENSING AND COORDINATING THE CELLULAR RESPONSE TO OXIDATIVE STRESS. IN PARTICULAR ABERRANT REGULATION OF THESE PATHWAYS BY HISTONE DEACETYLASES MAY PLAY CRITICAL ROLES IN CANCER PROGRESSION. WHAT THE READER WILL GAIN: IN THIS REVIEW WE DISCUSS THE NOTION THAT TARGETING HDACS MAY BE A USEFUL THERAPEUTIC AVENUE IN THE TREATMENT OF OXIDATIVE STRESS IN CANCER, USING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), NSCLC AND HEPATOCELLULAR CARCINOMA (HCC) AS EXAMPLES TO ILLUSTRATE THIS POSSIBILITY. TAKE HOME MESSAGE: EPIGENETIC MECHANISMS MAY BE AN IMPORTANT NEW THERAPEUTIC AVENUE FOR TARGETING OXIDATIVE STRESS IN CANCER. 2010 12 4543 40 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 13 2348 34 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 14 4898 28 OXIDATIVE STRESS INDUCED LUNG CANCER AND COPD: OPPORTUNITIES FOR EPIGENETIC THERAPY. REACTIVE OXYGEN SPECIES (ROS) FORM AS A NATURAL BY-PRODUCT OF THE NORMAL METABOLISM OF OXYGEN AND PLAY IMPORTANT ROLES WITHIN THE CELL. UNDER NORMAL CIRCUMSTANCES THE CELL IS ABLE TO MAINTAIN AN ADEQUATE HOMEOSTASIS BETWEEN THE FORMATION OF ROS AND ITS REMOVAL THROUGH PARTICULAR ENZYMATIC PATHWAYS OR VIA ANTIOXIDANTS. IF HOWEVER, THIS BALANCE IS DISTURBED A SITUATION CALLED OXIDATIVE STRESS OCCURS. CRITICALLY, OXIDATIVE STRESS PLAYS IMPORTANT ROLES IN THE PATHOGENESIS OF MANY DISEASES, INCLUDING CANCER. EPIGENETICS IS A PROCESS WHERE GENE EXPRESSION IS REGULATED BY HERITABLE MECHANISMS THAT DO NOT CAUSE ANY DIRECT CHANGES TO THE DNA SEQUENCE ITSELF, AND DISRUPTION OF EPIGENETIC MECHANISMS HAS IMPORTANT IMPLICATIONS IN DISEASE. EVIDENCE IS EMERGING THAT HISTONE DEACETYLASES (HDACS) PLAY DECISIVE ROLES IN REGULATING IMPORTANT CELLULAR OXIDATIVE STRESS PATHWAYS INCLUDING THOSE INVOLVED WITH SENSING OXIDATIVE STRESS AND THOSE INVOLVED WITH REGULATING THE CELLULAR RESPONSE TO OXIDATIVE STRESS. IN PARTICULAR ABERRANT REGULATION OF THESE PATHWAYS BY HDACS MAY PLAY CRITICAL ROLES IN CANCER PROGRESSION. IN THIS REVIEW WE DISCUSS THE CURRENT EVIDENCE LINKING EPIGENETICS AND OXIDATIVE STRESS AND CANCER, USING CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND NON-SMALL CELL LUNG CANCER TO ILLUSTRATE THE IMPORTANCE OF EPIGENETICS ON THESE PATHWAYS WITHIN THESE DISEASE SETTINGS. 2009 15 1254 26 CURRENT PROGRESS ON THE MECHANISMS OF HYPERHOMOCYSTEINEMIA-INDUCED VASCULAR INJURY AND USE OF NATURAL POLYPHENOL COMPOUNDS. CARDIOVASCULAR DISEASE IS ONE OF THE MOST COMMON DISEASES IN THE ELDERLY POPULATION, AND ITS INCIDENCE HAS RAPIDLY INCREASED WITH THE PROLONGATION OF LIFE EXPECTANCY. HYPERHOMOCYSTEINEMIA IS AN INDEPENDENT RISK FACTOR FOR VARIOUS CARDIOVASCULAR DISEASES, INCLUDING ATHEROSCLEROSIS, AND DAMAGE TO VASCULAR FUNCTION PLAYS AN INITIAL ROLE IN ITS PATHOGENESIS. THIS REVIEW PRESENTS THE LATEST KNOWLEDGE ON THE MECHANISMS OF VASCULAR INJURY CAUSED BY HYPERHOMOCYSTEINEMIA, INCLUDING OXIDATIVE STRESS, ENDOPLASMIC RETICULUM STRESS, PROTEIN N-HOMOCYSTEINIZATION, AND EPIGENETIC MODIFICATION, AND DISCUSSES THE THERAPEUTIC TARGETS OF NATURAL POLYPHENOLS. STUDIES HAVE SHOWN THAT NATURAL POLYPHENOLS IN PLANTS CAN REDUCE HOMOCYSTEINE LEVELS AND REGULATE DNA METHYLATION BY ACTING ON OXIDATIVE STRESS AND ENDOPLASMIC RETICULUM STRESS-RELATED SIGNALING PATHWAYS, THUS IMPROVING HYPERHOMOCYSTEINEMIA-INDUCED VASCULAR INJURY. NATURAL POLYPHENOLS OBTAINED VIA DAILY DIET ARE SAFER AND HAVE MORE PRACTICAL SIGNIFICANCE IN THE PREVENTION AND TREATMENT OF CHRONIC DISEASES THAN TRADITIONAL DRUGS. 2021 16 4902 31 OXIDATIVE-STRESS-INDUCED EPIGENETIC CHANGES IN CHRONIC DIABETIC COMPLICATIONS. OXIDATIVE STRESS PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC DIABETIC COMPLICATIONS. DIABETES CAUSES MITOCHONDRIAL SUPEROXIDE OVERPRODUCTION IN THE ENDOTHELIAL CELLS OF BOTH LARGE AND SMALL VESSELS. THIS INCREASED SUPEROXIDE PRODUCTION CAUSES THE ACTIVATION OF SEVERAL SIGNAL PATHWAYS INVOLVED IN THE PATHOGENESIS OF CHRONIC COMPLICATIONS. IN PARTICULAR, ENDOTHELIAL CELLS ARE MAJOR TARGETS OF GLUCOSE-INDUCED OXIDATIVE DAMAGE IN THE TARGET ORGANS. OXIDATIVE STRESS ACTIVATES CELLULAR SIGNALING PATHWAYS AND TRANSCRIPTION FACTORS IN ENDOTHELIAL CELLS INCLUDING PROTEIN KINASE C (PKC), C-JUN-N-TERMINAL KINASE (JNK), P38 MITOGEN-ACTIVATED PROTEIN KINASE (MAPK), FORKHEAD BOX O (FOXO), AND NUCLEAR FACTOR KAPPA-B (NF-KAPPAB). OXIDATIVE STRESS ALSO CAUSES DNA DAMAGE AND ACTIVATES DNA NUCLEOTIDE EXCISION REPAIR ENZYMES INCLUDING THE EXCISION REPAIR CROSS COMPLIMENTING 1(ERCC1), ERCC4, AND POLY(ADP-RIBOSE) POLYMERASE (PARP). AUGMENTED PRODUCTION OF HISTONE ACETYLTRANSFERASE P300, AND ALTERATIONS OF HISTONE DEACETYLASES, INCLUDING CLASS III DEACETYLASES SIRTUINS, ARE ALSO INVOLVED IN THIS PROCESS. RECENT RESEARCH HAS FOUND THAT SMALL NONCODING RNAS, LIKE MICRORNA, ARE A NEW KIND OF REGULATOR ASSOCIATED WITH CHRONIC DIABETIC COMPLICATIONS. THERE ARE EXTENSIVE AND COMPLICATED INTERACTIONS AND AMONG THESE MOLECULES. THE PURPOSE OF THIS REVIEW IS TO DEMONSTRATE THE ROLE OF OXIDATIVE STRESS IN THE DEVELOPMENT OF DIABETIC COMPLICATIONS IN RELATION TO EPIGENETIC CHANGES SUCH AS ACETYLATION AND MICRORNA ALTERATIONS. 2013 17 3921 33 LINKING INFLAMMATION TO CELL CYCLE PROGRESSION. RISK OF GASTROINTESTINAL CANCERS IS CLOSELY RELATED TO INCREASED LEVELS OF OXIDANTS IN THE BALANCE BETWEEN OXIDANT AND ANTI-OXIDANT AGENTS. A POSSIBLE EXPLANATION OF THIS EPIDEMIOLOGICAL OBSERVATION IS THE LOCAL LOSS OF THE EPITHELIAL BARRIER FUNCTION WITH A FOCAL INFLAMMATORY RESPONSE. ACCORDINGLY, CHRONIC INFLAMMATORY DISEASES REPRESENT WELL-KNOWN RISK FACTORS FOR CANCER AND, ON THE OTHER HAND, IT IS KNOWN THAT ANTI-INFLAMMATORY AGENTS, DEMULCENTS AND ANTIOXIDANTS MARKEDLY INHIBIT THE DEVELOPMENT OF COLON CANCER IN ANIMAL MODELS AS WELL IN HUMANS. AT MOLECULAR LEVEL A KEY ROLE IN THE PROCESS THAT LINK INFLAMMATION TO CELLULAR TRANSFORMATION SEEMS TO BE PLAYED BY ACTIVATION OF CYCLOOXYGENASE-2 (COX-2) TOGETHER WITH PRODUCTION OF REACTIVE OXYGEN INTERMEDIATE (ROI). BOTH THESE EVENTS HAVE BEEN STRICTLY LINKED WITH CELL PROLIFERATION AND TRANSFORMATION, ALTHOUGH THE INTRACELLULAR PATHWAYS INVOLVED IN THESE PROCESSES ARE STILL NOT COMPLETELY UNDERSTOOD. THE UNCONTROLLED PROLIFERATION, WHICH IS A LANDMARK OF CELLULAR TRANSFORMATION, IS ACCOMPANIED BY THE DEREGULATION OF PROTEINS INVOLVED IN THE CONTROL OF CELL CYCLE CHECKPOINTS. ALTERED EXPRESSION AND FUNCTION OF CYCLOOXYGENASE AND NITRIC OXIDE SYNTHASE SEEM TO INFLUENCE, AMONG OTHERS, THE EXPRESSION OF PROTEINS INVOLVED IN THE REGULATION OF CELL CYCLE PROGRESSION. SIMILARLY, ANTI-INFLAMMATORY AND ANTIOXIDANT AGENTS MAY ALSO ACT ON THE EXPRESSION AND FUNCTION OF SEVERAL CELL CYCLE REGULATING PROTEINS. UNDERSTANDING THE MECHANISMS BY WHICH CHRONIC INFLAMMATION CONTRIBUTES TO GENETIC AND EPIGENETIC CHANGES INVOLVED IN THE REGULATION OF CRITICAL CELL CYCLE CHECKPOINTS MAY HELP TO DEVELOP MORE AND MORE SPECIFIC TREATMENT STRATEGIES FOR REDUCING MALIGNANT TRANSFORMATION OF THESE INFLAMMATORY DISEASES. 2004 18 3581 25 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 19 5560 32 ROLE OF HISTONE DEACETYLASE 2 IN EPIGENETICS AND CELLULAR SENESCENCE: IMPLICATIONS IN LUNG INFLAMMAGING AND COPD. HISTONE DEACETYLASE 2 (HDAC2) IS A CLASS I HISTONE DEACETYLASE THAT REGULATES VARIOUS CELLULAR PROCESSES, SUCH AS CELL CYCLE, SENESCENCE, PROLIFERATION, DIFFERENTIATION, DEVELOPMENT, APOPTOSIS, AND GLUCOCORTICOID FUNCTION IN INHIBITING INFLAMMATORY RESPONSE. HDAC2 HAS BEEN SHOWN TO PROTECT AGAINST DNA DAMAGE RESPONSE AND CELLULAR SENESCENCE/PREMATURE AGING VIA AN EPIGENETIC MECHANISM IN RESPONSE TO OXIDATIVE STRESS. THESE PHENOMENA ARE OBSERVED IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). HDAC2 IS POSTTRANSLATIONALLY MODIFIED BY OXIDATIVE/CARBONYL STRESS IMPOSED BY CIGARETTE SMOKE AND OXIDANTS, LEADING TO ITS REDUCTION VIA AN UBIQUITINATION-PROTEASOME DEPENDENT DEGRADATION IN LUNGS OF PATIENTS WITH COPD. IN THIS PERSPECTIVE, WE HAVE DISCUSSED THE ROLE OF HDAC2 POSTTRANSLATIONAL MODIFICATIONS AND ITS ROLE IN REGULATION OF INFLAMMATION, HISTONE/DNA EPIGENETIC MODIFICATIONS, DNA DAMAGE RESPONSE, AND CELLULAR SENESCENCE, PARTICULARLY IN INFLAMMAGING, AND DURING THE DEVELOPMENT OF COPD. WE HAVE ALSO DISCUSSED THE POTENTIAL DIRECTIONS FOR FUTURE TRANSLATIONAL RESEARCH AVENUES IN MODULATING LUNG INFLAMMAGING AND CELLULAR SENESCENCE BASED ON EPIGENETIC CHROMATIN MODIFICATIONS IN DISEASES ASSOCIATED WITH INCREASED OXIDATIVE STRESS. 2012 20 1487 27 DNA DAMAGE AND EPIGENETIC CHANGES IN KIDNEY DISEASES - FOCUSED ON TRANSCRIPTION FACTORS IN PODOCYTES. RECENTLY IT HAS BEEN SHOWN THAT EPIGENETIC MECHANISMS ARE INVOLVED IN INITIATION AND PROGRESSION OF CARIDIOVASCULAR AND METABOLIC DISEASES, INCLUDING DIABETES, OBESITY, ATHEROSCLEROSIS, HEART FAILURE, HYPERTENSION AND KIDNEY DISEASES. IN THESE CHRONIC DISEASES, VARIOUS EXOGENOUS AND ENDOGENOUS STRESSES CAUSE DNA DAMAGE, FOLLOWED BY DNA REPAIR PROCESS. ACCUMULATION OF DNA DAMAGES AND IMPAIRED REPAIR PROCESS CAN LEAD TO EPIGENETIC CHANGES, WHICH MAY CONTRIBUTE TO ONSET AND PROGRESSION OF DISEASES. RECENTLY WE HAVE SHOWN THAT THERAPEUTIC EFFECT OF TRANSCRIPTION FACTOR KLF4 (KRUPPEL-LIKE FACTOR 4) IN KIDNEY GLOMERULAR EPITHELIAL CELLS (PODOCYTES) ON PROTEINURIC KIDNEY DISEASES THROUGH EPIGENETIC MECHANISMS. OUR RESULT SUGGESTS THE POSSIBILITY OF TRANSCRIPTION FACTORS AS A TARGET OF SELECTIVE EPIGENETIC THERAPY. MOREOVER, WE HAVE REPORTED THAT RENIN-ANGIOTENSIN SYSTEM (RAS) BLOCKERS, WHICH ARE WIDELY PRESCRIBED FOR THE TREATMENT OF CARDIOVASCULAR DISEASES, CAN RESTORE EPIGENETIC CHANGES THROUGH KLF4 IN PART. THESE RESULTS SUGGEST THAT ACTIVATION OF RAS CAUSES EPIGENETIC CHANGES IN DISEASE STATES, AND ELUCIDATION OF THE PRECISE MECHANISM MAY LEAD TO ESTABLISHMENT OF NOVEL THERAPEUTIC TARGET OF KIDNEY DISEASES. IN THIS REVIEW WE FOCUS ON DNA DAMAGE REPAIR SYSTEM AND EPIGENETIC MODULATORS IN DISEASE STATES, AND SPECULATE A CANDIDATE FOR EPIGENETIC THERAPY OF KIDNEY DISEASES. 2016