1 4776 126 NUTRACEUTICAL ACTIVITY IN OSTEOARTHRITIS BIOLOGY: A FOCUS ON THE NUTRIGENOMIC ROLE. OSTEOARTHRITIS (OA) IS A DISEASE ASSOCIATED TO AGE OR CONDITIONS THAT PRECIPITATE AGING OF ARTICULAR CARTILAGE, A POST-MITOTIC TISSUE THAT REMAINS FUNCTIONAL UNTIL THE FAILURE OF MAJOR HOMEOSTATIC MECHANISMS. OA SEVERELY IMPACTS THE NATIONAL HEALTH SYSTEM COSTS AND PATIENTS' QUALITY OF LIFE BECAUSE OF PAIN AND DISABILITY. IT IS A WHOLE-JOINT DISEASE SUSTAINED BY INFLAMMATORY AND OXIDATIVE SIGNALING PATHWAYS AND MARKED EPIGENETIC CHANGES RESPONSIBLE FOR CATABOLISM OF THE CARTILAGE EXTRACELLULAR MATRIX. OA USUALLY PROGRESSES UNTIL ITS SEVERITY REQUIRES JOINT ARTHROPLASTY. TO DELAY THIS PROGRESSION AND TO IMPROVE SYMPTOMS, A WIDE RANGE OF NATURALLY DERIVED COMPOUNDS HAVE BEEN PROPOSED AND ARE SUMMARIZED IN THIS REVIEW. PRECLINICAL IN VITRO AND IN VIVO STUDIES HAVE PROVIDED PROOF OF PRINCIPLE THAT MANY OF THESE NUTRACEUTICALS ARE ABLE TO EXERT PLEIOTROPIC AND SYNERGISTIC EFFECTS AND EFFECTIVELY COUNTERACT OA PATHOGENESIS BY EXERTING BOTH ANTI-INFLAMMATORY AND ANTIOXIDANT ACTIVITIES AND BY TUNING MAJOR OA-RELATED SIGNALING PATHWAYS. THE LATTER ARE THE BASIS FOR THE NUTRIGENOMIC ROLE PLAYED BY SOME OF THESE COMPOUNDS, GIVEN THE MARKED CHANGES IN THE TRANSCRIPTOME, MIRNOME, AND METHYLOME. ONGOING AND FUTURE CLINICAL TRIALS WILL HOPEFULLY CONFIRM THE DISEASE-MODIFYING ABILITY OF THESE BIOACTIVE MOLECULES IN OA PATIENTS. 2020 2 2309 28 EPIGENETIC REGULATION OF CHONDROCYTES AND SUBCHONDRAL BONE IN OSTEOARTHRITIS. THE AIM OF THIS REVIEW IS TO PROVIDE AN UPDATED REVIEW OF THE EPIGENETIC FACTORS INVOLVED IN THE ONSET AND DEVELOPMENT OF OSTEOARTHRITIS (OA). OA IS A PREVALENT DEGENERATIVE JOINT DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION, ECTOPIC BONE FORMATION WITHIN THE JOINT, AND PHYSICAL AND PROTEOLYTIC CARTILAGE DEGRADATION WHICH RESULT IN CHRONIC PAIN AND LOSS OF MOBILITY. AT PRESENT, NO DISEASE-MODIFYING THERAPEUTICS EXIST FOR THE PREVENTION OR TREATMENT OF THE DISEASE. RESEARCH HAS IDENTIFIED SEVERAL OA RISK FACTORS INCLUDING MECHANICAL STRESSORS, PHYSICAL ACTIVITY, OBESITY, TRAUMATIC JOINT INJURY, GENETIC PREDISPOSITION, AND AGE. RECENTLY, THERE HAS BEEN INCREASED INTEREST IN IDENTIFYING EPIGENETIC FACTORS INVOLVED IN THE PATHOGENESIS OF OA. IN THIS REVIEW, WE DETAIL SEVERAL OF THESE EPIGENETIC MODIFICATIONS WITH KNOWN FUNCTIONS IN THE ONSET AND PROGRESSION OF THE DISEASE. WE ALSO REVIEW CURRENT THERAPEUTICS TARGETING ABERRANT EPIGENETIC REGULATION AS POTENTIAL OPTIONS FOR PREVENTIVE OR THERAPEUTIC TREATMENT. 2022 3 4679 36 NEW MOLECULAR TARGETS FOR THE TREATMENT OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A CHRONIC DEGENERATIVE JOINT DISORDER CHARACTERIZED BY DESTRUCTION OF THE ARTICULAR CARTILAGE, SUBCHONDRAL BONE ALTERATIONS AND SYNOVITIS. CURRENT TREATMENTS ARE FOCUSED ON SYMPTOMATIC RELIEF BUT THEY LACK EFFICACY TO CONTROL THE PROGRESSION OF THIS DISEASE WHICH IS A LEADING CAUSE OF DISABILITY. THEREFORE, THE DEVELOPMENT OF EFFECTIVE DISEASE-MODIFYING DRUGS IS URGENTLY NEEDED. DIFFERENT INITIATIVES ARE IN PROGRESS TO DEFINE THE MOLECULAR MECHANISMS INVOLVED IN THE INITIATION AND PROGRESSION OF OA. THESE STUDIES SUPPORT THE THERAPEUTIC POTENTIAL OF PATHWAYS RELEVANT IN JOINT METABOLISM SUCH AS WNT/BETA-CATENIN, DISCOIDIN DOMAIN RECEPTOR 2 OR PROTEINASE-ACTIVATED RECEPTOR 2. THE DYSREGULATION IN CARTILAGE CATABOLISM AND SUBCHONDRAL BONE REMODELING COULD BE IMPROVED BY SELECTIVE INHIBITORS OF MATRIX METALLOPROTEINASES, AGGRECANASES AND OTHER PROTEASES. ANOTHER APPROACH WOULD FAVOR THE ACTIVITY OF ANABOLIC PROCESSES BY USING GROWTH FACTORS OR REGULATORY MOLECULES. RECENT STUDIES HAVE ALSO REVEALED THE ROLE OF OXIDATIVE STRESS AND SYNOVITIS IN THE PROGRESSION OF THIS DISEASE, SUPPORTING THE DEVELOPMENT OF A NUMBER OF INHIBITORY STRATEGIES. NOVEL TARGETS IN OA ARE REPRESENTED BY GENES INVOLVED IN OA PATHOPHYSIOLOGY DISCOVERED USING GENE NETWORK, EPIGENETIC AND MICRORNA APPROACHES. FURTHER INSIGHTS INTO THE MOLECULAR MECHANISMS INVOLVED IN OA INITIATION AND PROGRESSION MAY LEAD TO THE DEVELOPMENT OF NEW THERAPIES ABLE TO CONTROL JOINT DESTRUCTION AND REPAIR. 2010 4 5109 41 POLYPHENOL-RELATED EPIGENETIC MODIFICATIONS IN OSTEOARTHRITIS: CURRENT THERAPEUTIC PERSPECTIVES. THE HYALINE CARTILAGE IS AN AVASCULAR, ANEURAL AND ALYMPHATIC TISSUE WITH A LIMITED ABILITY TO REPAIR ITSELF. WHEN THE CARTILAGE IS EXPOSED TO SOME KIND OF INJURY, IT USUALLY TRIGGERS OSTEOARTHRITIS (OA), A PREVALENT AND DEGENERATIVE JOINT DISEASE CLOSELY RELATED TO AGING. OA IS BOTH COMPLEX AND MULTIFACTORIAL, AND IS THE MOST COMMON FORM OF ARTHRITIS, BEING POSITIONED AS A MAJOR CAUSE OF PAIN AND DYSFUNCTION IN THE WORLD. IN ADDITION, HIGH OA PREVALENCE CAN GREATLY AFFECT WORK CAPACITY, MAKING THIS DISEASE A SIGNIFICANT SOCIAL PROBLEM, THEREFORE, ITS PREVENTION AND TREATMENT BECOMES A PRIORITY. AT THIS TIME, THERE ARE NUMEROUS THERAPEUTIC STRATEGIES AVAILABLE TO IMPROVE HYALINE CARTILAGE REPAIR BY USING CHONDROCYTES OR MESENCHYMAL CELLS, BUT NEITHER IS EFFECTIVE ENOUGH TO GENERATE FUNCTIONAL AND DURABLE TISSUE REPARATION OVER TIME. IN OA, CHONDROCYTES HAVE AN ABERRANT GENE EXPRESSION AND PHENOTYPE, RESULTING IN A LOSS OF BALANCE BETWEEN ANABOLIC AND CATABOLIC PROCESSES. ENVIRONMENTAL INFLUENCES SUCH AS RADIATION, INFECTION, SMOKING, NUTRIENTS, TOXINS AND STRESS CAN AFFECT GENE EXPRESSION PATTERNS, WHICH MAY CONSTITUTE RISK FACTORS FOR VARIOUS CHRONIC AND DEGENERATIVE DISEASES, SUCH AS OA. IN ADDITION, CONSIDERABLE EVIDENCE SHOWS THAT EPIGENETIC MECHANISMS PLAY AN IMPORTANT ROLE IN OA CHONDROGENESIS AND PATHOGENESIS. NATURAL PLANT-DERIVED PRODUCTS SUCH AS POLYPHENOLS, WHICH ARE SECONDARY METABOLITES CONSIDERED TO HAVE POTENTIAL ACTIVITY TO BLOCK INFLAMMATION IN SEVERAL DEGENERATIVE DISEASES, CAN STIMULATE EPIGENETIC MODIFICATIONS, AND MAY PROVIDE NEW THERAPEUTIC TARGETS AND COST-EFFECTIVE TREATMENTS. THIS REVIEW AIMS TO PRESENT VARIOUS POLYPHENOLBASED THERAPIES CURRENTLY USED FOR THE TREATMENT OF SEVERAL PROGRESSIVE DISEASES, INCLUDING OA. 2016 5 2232 32 EPIGENETIC MODIFICATIONS OF MIRNAS IN OSTEOARTHRITIS: A SYSTEMATIC REVIEW ON THEIR METHYLATION LEVELS AND EFFECTS ON CHONDROCYTES, EXTRACELLULAR MATRIX AND JOINT INFLAMMATION. OSTEOARTHRITIS (OA) IS A JOINT DISORDER CHARACTERIZED BY PROGRESSIVE DEGENERATION OF CARTILAGE EXTRACELLULAR MATRIX (ECM), CHONDROCYTE HYPERTROPHY AND APOPTOSIS AND INFLAMMATION. THE CURRENT TREATMENTS MAINLY CONCERN PAIN CONTROL AND REDUCTION OF INFLAMMATION, BUT NO THERAPEUTIC STRATEGY HAS BEEN IDENTIFIED AS A DISEASE-MODIFYING TREATMENT. THEREFORE, IDENTIFYING SPECIFIC BIOMARKERS USEFUL TO PREVENT, TREAT OR DISTINGUISH THE STAGES OF OA DISEASE HAS BECOME AN IMMEDIATE NEED OF CLINICAL PRACTICE. THE ROLE OF MICRORNAS (MIRNAS) IN OA HAS BEEN INVESTIGATED IN THE LAST DECADE, AND INCREASING EVIDENCE HAS EMERGED THAT THE INFLUENCE OF THE ENVIRONMENT ON GENE EXPRESSION THROUGH EPIGENETIC PROCESSES CONTRIBUTES TO THE DEVELOPMENT, PROGRESSION AND AGGRESSIVENESS OF OA, IN PARTICULAR ACTING ON THE MICROENVIRONMENT MODULATIONS. THE EFFECTS OF EPIGENETIC REGULATION, PARTICULARLY DIFFERENT MIRNA METHYLATION DURING OA DISEASE, WERE HIGHLIGHTED IN THE PRESENT SYSTEMATIC REVIEW. THE EVIDENCE ARISING FROM THIS STUDY OF THE LITERATURE CONDUCTED IN THREE DATABASES (PUBMED, SCOPUS, WEB OF SCIENCE) SUGGESTED THAT MIRNA METHYLATION STATE ALREADY STRONGLY IMPACTS OA PROGRESSION, DRIVING CHONDROCYTES AND SYNOVIOCYTE PROLIFERATION, APOPTOSIS, INFLAMMATION AND ECM DEPOSITION. HOWEVER, THE POSSIBILITY OF UNDERSTANDING THE MECHANISM BY WHICH DIFFERENT EPIGENETIC MODIFICATIONS OF MIRNA OR PRE-MIRNA SEQUENCES DRIVE THE AGGRESSIVENESS OF OA COULD BE THE NEW FOCUS OF FUTURE INVESTIGATIONS. 2023 6 3038 32 GENOME ENGINEERING FOR OSTEOARTHRITIS: FROM DESIGNER CELLS TO DISEASE-MODIFYING DRUGS. BACKGROUND: OSTEOARTHRITIS (OA) IS A HIGHLY PREVALENT DEGENERATIVE JOINT DISEASE INVOLVING JOINT CARTILAGE AND ITS SURROUNDING TISSUES. OA IS THE LEADING CAUSE OF PAIN AND DISABILITY WORLDWIDE. AT PRESENT, THERE ARE NO DISEASE-MODIFYING OA DRUGS, AND THE PRIMARY THERAPIES INCLUDE EXERCISE AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS UNTIL TOTAL JOINT REPLACEMENT AT THE END-STAGE OF THE DISEASE. METHODS: IN THIS REVIEW, WE SUMMARIZED THE CURRENT STATE OF KNOWLEDGE IN GENETIC AND EPIGENETIC ASSOCIATIONS AND RISK FACTORS FOR OA AND THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. RESULTS: GENOME-WIDE ASSOCIATION STUDIES AND ANALYSIS OF EPIGENETIC MODIFICATIONS (SUCH AS MIRNA EXPRESSION, DNA METHYLATION AND HISTONE MODIFICATIONS) CONDUCTED ACROSS VARIOUS POPULATIONS SUPPORT THE NOTION THAT THERE IS A GENETIC BASIS FOR CERTAIN SUBSETS OF OA PATHOGENESIS. CONCLUSION: WITH RECENT ADVANCES IN THE DEVELOPMENT OF GENOME EDITING TECHNOLOGIES SUCH AS THE CRISPR-CAS9 SYSTEM, THESE GENETIC AND EPIGENETIC ALTERNATIONS IN OA CAN BE USED AS PLATFORMS FROM WHICH POTENTIAL BIOMARKERS FOR THE DIAGNOSIS, PROGNOSIS, DRUG RESPONSE, AND DEVELOPMENT OF POTENTIAL PERSONALIZED THERAPEUTIC TARGETS FOR OA CAN BE APPROACHED. FURTHERMORE, GENOME EDITING HAS ALLOWED THE DEVELOPMENT OF "DESIGNER" CELLS, WHEREBY THE RECEPTORS, GENE REGULATORY NETWORKS, OR TRANSGENES CAN BE MODIFIED AS A BASIS FOR NEW CELL-BASED THERAPIES. 2019 7 2460 33 EPIGENETIC THERAPIES FOR OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS AN AGE-ASSOCIATED DISEASE CHARACTERIZED BY CHRONIC JOINT PAIN RESULTING FROM DEGRADATION OF ARTICULAR CARTILAGE, INFLAMMATION OF THE SYNOVIAL LINING, AND CHANGES TO THE SUBCHONDRAL BONE. DESPITE THE WIDE PREVALENCE, NO FDA-APPROVED DISEASE-MODIFYING DRUGS EXIST. RECENT EVIDENCE HAS DEMONSTRATED THAT EPIGENETIC DYSREGULATION OF MULTIPLE MOLECULAR PATHWAYS UNDERLIES OA PATHOGENESIS, PROVIDING A NEW MECHANISTIC AND THERAPEUTIC AXIS WITH THE ADVANTAGE OF TARGETING MULTIPLE DEREGULATED PATHWAYS SIMULTANEOUSLY. IN THIS REVIEW, WE FOCUS ON THE EPIGENETIC REGULATORS THAT HAVE BEEN IMPLICATED IN OA, THEIR INDIVIDUAL ROLES, AND POTENTIAL CROSSTALK. FINALLY, WE DISCUSS THE PHARMACOLOGICAL MOLECULES THAT CAN MODULATE THEIR ACTIVITIES AND DISCUSS THE POTENTIAL ADVANTAGES AND CHALLENGES ASSOCIATED WITH EPIGENOME-BASED THERAPEUTICS FOR OA. 2020 8 554 41 AUTOPHAGY IN HUMAN HEALTH AND DISEASE: NOVEL THERAPEUTIC OPPORTUNITIES. SIGNIFICANCE: IN EUKARYOTES, AUTOPHAGY REPRESENTS A HIGHLY EVOLUTIONARY CONSERVED PROCESS, THROUGH WHICH MACROMOLECULES AND CYTOPLASMIC MATERIAL ARE DEGRADED INTO LYSOSOMES AND RECYCLED FOR BIOSYNTHETIC OR ENERGETIC PURPOSES. DYSFUNCTION OF THE AUTOPHAGIC PROCESS HAS BEEN ASSOCIATED WITH THE ONSET AND DEVELOPMENT OF MANY HUMAN CHRONIC PATHOLOGIES, SUCH AS CARDIOVASCULAR, METABOLIC, AND NEURODEGENERATIVE DISEASES AS WELL AS CANCER. RECENT ADVANCES: CURRENTLY, COMPREHENSIVE RESEARCH IS BEING CARRIED OUT TO DISCOVER NEW THERAPEUTIC AGENTS THAT ARE ABLE TO MODULATE THE AUTOPHAGIC PROCESS IN VIVO. RECENT EVIDENCE HAS SHOWN THAT A LARGE NUMBER OF NATURAL BIOACTIVE COMPOUNDS ARE INVOLVED IN THE REGULATION OF AUTOPHAGY BY MODULATING SEVERAL TRANSCRIPTIONAL FACTORS AND SIGNALING PATHWAYS. CRITICAL ISSUES: CRITICAL ISSUES THAT DESERVE PARTICULAR ATTENTION ARE THE INADEQUATE UNDERSTANDING OF THE COMPLEX ROLE OF AUTOPHAGY IN DISEASE PATHOGENESIS, THE LIMITED AVAILABILITY OF THERAPEUTIC DRUGS, AND THE LACK OF CLINICAL TRIALS. IN THIS CONTEXT, THE EFFECTS THAT NATURAL BIOACTIVE COMPOUNDS EXERT ON AUTOPHAGIC MODULATION SHOULD BE CLEARLY HIGHLIGHTED, SINCE THEY DEPEND ON THE TYPE AND STAGE OF THE PATHOLOGICAL CONDITIONS OF DISEASES. FUTURE DIRECTIONS: RESEARCH EFFORTS SHOULD NOW FOCUS ON UNDERSTANDING THE SURVIVAL-SUPPORTING AND DEATH-PROMOTING ROLES OF AUTOPHAGY, HOW NATURAL COMPOUNDS INTERACT EXACTLY WITH THE AUTOPHAGIC TARGETS SO AS TO INDUCE OR INHIBIT AUTOPHAGY AND ON THE EVALUATION OF THEIR PHARMACOLOGICAL EFFECTS IN A MORE IN-DEPTH AND MECHANISTIC WAY. IN ADDITION, CLINICAL STUDIES ON AUTOPHAGY-INDUCING NATURAL PRODUCTS ARE STRONGLY ENCOURAGED, ALSO TO HIGHLIGHT SOME FUNDAMENTAL ASPECTS, SUCH AS THE DOSE, THE DURATION, AND THE POSSIBLE SYNERGISTIC ACTION OF THESE COMPOUNDS WITH CONVENTIONAL THERAPY. 2019 9 3108 27 GENOMICS OF PAIN IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) ACCOUNTS FOR THE MAJORITY OF THE DISEASE BURDEN FOR MUSCULOSKELETAL DISORDERS AND IS ONE OF THE LEADING CAUSES OF DISABILITY WORLDWIDE. THIS DISABILITY IS THE RESULT NOT OF THE CARTILAGE LOSS THAT DEFINES OA RADIOGRAPHICALLY, BUT OF THE CHRONIC PAIN WHOSE PRESENCE DEFINES SYMPTOMATIC OA. IT IS BECOMING CLEAR THAT MANY GENES, EACH WITH A SMALL EFFECT SIZE, CONTRIBUTE TO THE RISK OF DEVELOPING OA. HOWEVER, THE GENETICS OF OA PAIN ARE ONLY JUST STARTING TO BE EXPLORED. THIS REVIEW WILL DESCRIBE THE FIRST GENES TO HAVE BEEN IDENTIFIED IN GENOMIC STUDIES OF OA PAIN, AS WELL AS THE POSSIBLE DUAL ROLES OF GENES PREVIOUSLY IDENTIFIED IN GENOMIC STUDIES OF OA IN THE CONTEXT OF PAIN. DIFFICULTIES ASSOCIATED WITH ATTEMPTING TO CHARACTERISE THE GENETICS OF OA PAIN WILL BE DISCUSSED AND PROMISING FUTURE AVENUES OF RESEARCH INTO GENETIC AND EPIGENETIC FACTORS AFFECTING OA PAIN DESCRIBED. 2013 10 4273 31 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 11 2333 29 EPIGENETIC REGULATION OF INFLAMMATION: THE METABOLOMICS CONNECTION. EPIGENETIC FACTORS ARE CONSIDERED THE REGULATOR OF COMPLEX MACHINERY BEHIND INFLAMMATORY DISORDERS AND SIGNIFICANTLY CONTRIBUTED TO THE EXPRESSION OF INFLAMMATION-ASSOCIATED GENES. EPIGENETIC MODIFICATIONS MODULATE VARIATION IN THE EXPRESSION PATTERN OF TARGET GENES WITHOUT AFFECTING THE DNA SEQUENCE. THE CURRENT KNOWLEDGE OF EPIGENETIC RESEARCH FOCUSED ON THEIR ROLE IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES THAT CAUSES MORBIDITY AND MORTALITY WORLDWIDE. INFLAMMATORY DISEASES ARE CATEGORIZED AS ACUTE AND CHRONIC BASED ON THE DISEASE SEVERITY AND ARE REGULATED BY THE EXPRESSION PATTERN OF VARIOUS GENES. HENCE, UNDERSTANDING THE ROLE OF EPIGENETIC MODIFICATIONS DURING INFLAMMATION PROGRESSION WILL CONTRIBUTE TO THE DISEASE OUTCOMES AND THERAPEUTIC APPROACHES. THIS REVIEW ALSO FOCUSES ON THE METABOLOMICS APPROACH ASSOCIATED WITH THE STUDY OF INFLAMMATORY DISORDERS. INFLAMMATORY RESPONSES AND METABOLIC REGULATION ARE HIGHLY INTEGRATED AND VARIOUS ADVANCED TECHNIQUES ARE ADOPTED TO STUDY THE METABOLIC SIGNATURE MOLECULES. HERE WE DISCUSS SEVERAL METABOLOMICS APPROACHES USED TO LINK INFLAMMATORY DISORDERS AND EPIGENETIC CHANGES. WE PROPOSED THAT DECIPHERING THE MECHANISM BEHIND THE INFLAMMATION-METABOLISM LOOP MAY HAVE IMMENSE IMPORTANCE IN BIOMARKERS RESEARCH AND MAY ACT AS A PRINCIPAL COMPONENT IN DRUG DISCOVERY AS WELL AS THERAPEUTIC APPLICATIONS. 2022 12 4783 33 NUTRIGENOMICS IN PARKINSON'S DISEASE: DIVERSITY OF MODULATORY ACTIONS OF POLYPHENOLS ON EPIGENETIC EFFECTS INDUCED BY TOXINS. ALTHOUGH THE PATHOGENESIS OF PARKINSON'S DISEASE (PD) IS NOT COMPLETELY UNDERSTOOD, THERE IS A CONSENSUS THAT IT CAN BE CAUSED BY MULTIFACTORIAL MECHANISMS INVOLVING GENETIC SUSCEPTIBILITY, EPIGENETIC MODIFICATIONS INDUCED BY TOXINS AND MITOCHONDRIAL DYSFUNCTION. IN THE PAST 20 YEARS, GREAT EFFORTS HAVE BEEN MADE IN ORDER TO CLARIFY MOLECULAR MECHANISMS THAT ARE RISK FACTORS FOR THIS DISEASE, AS WELL AS TO IDENTIFY BIOACTIVE AGENTS FOR PREVENTION AND SLOWING DOWN OF ITS PROGRESSION. NUTRACEUTICAL PRODUCTS HAVE RECEIVED SUBSTANTIAL INTEREST DUE TO THEIR NUTRITIONAL, SAFE AND THERAPEUTIC EFFECTS ON SEVERAL CHRONIC DISEASES. THE AIM OF THIS REVIEW WAS TO GATHER THE MAIN EVIDENCE OF THE EPIGENETIC MECHANISMS INVOLVED IN THE NEUROPROTECTIVE EFFECTS OF PHENOLIC COMPOUNDS CURRENTLY UNDER INVESTIGATION FOR THE TREATMENT OF TOXIN-INDUCED PD. THESE STUDIES CONFIRM THAT THE NEUROPROTECTIVE ACTIONS OF POLYPHENOLS INVOLVE COMPLEX EPIGENETIC MODULATIONS, DEMONSTRATING THAT THE INTAKE OF THESE NATURAL COMPOUNDS CAN BE A PROMISING, LOW-COST, PHARMACOGENOMIC STRATEGY AGAINST THE DEVELOPMENT OF PD. 2023 13 3404 31 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 14 3547 44 IMMUNOMODULATORY ROLE OF NUTRIENTS: HOW CAN PULMONARY DYSFUNCTIONS IMPROVE? NUTRITION IS AN IMPORTANT TOOL THAT CAN BE USED TO MODULATE THE IMMUNE RESPONSE DURING INFECTIOUS DISEASES. IN ADDITION, THROUGH DIET, IMPORTANT SUBSTRATES ARE ACQUIRED FOR THE BIOSYNTHESIS OF REGULATORY MOLECULES IN THE IMMUNE RESPONSE, INFLUENCING THE PROGRESSION AND TREATMENT OF CHRONIC LUNG DISEASES, SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). IN THIS WAY, NUTRITION CAN PROMOTE LUNG HEALTH STATUS. A RANGE OF NUTRIENTS, SUCH AS VITAMINS (A, C, D, AND E), MINERALS (ZINC, SELENIUM, IRON, AND MAGNESIUM), FLAVONOIDS AND FATTY ACIDS, PLAY IMPORTANT ROLES IN REDUCING THE RISK OF PULMONARY CHRONIC DISEASES AND VIRAL INFECTIONS. THROUGH THEIR ANTIOXIDANT AND ANTI-INFLAMMATORY EFFECTS, NUTRIENTS ARE ASSOCIATED WITH BETTER LUNG FUNCTION AND A LOWER RISK OF COMPLICATIONS SINCE THEY CAN DECREASE THE HARMFUL EFFECTS FROM THE IMMUNE SYSTEM DURING THE INFLAMMATORY RESPONSE. IN ADDITION, BIOACTIVE COMPOUNDS CAN EVEN CONTRIBUTE TO EPIGENETIC CHANGES, INCLUDING HISTONE DEACETYLASE (HDAC) MODIFICATIONS THAT INHIBIT THE TRANSCRIPTION OF PROINFLAMMATORY CYTOKINES, WHICH CAN CONTRIBUTE TO THE MAINTENANCE OF HOMEOSTASIS IN THE CONTEXT OF INFECTIONS AND CHRONIC INFLAMMATORY DISEASES. THESE NUTRIENTS ALSO PLAY AN IMPORTANT ROLE IN ACTIVATING IMMUNE RESPONSES AGAINST PATHOGENS, WHICH CAN HELP THE IMMUNE SYSTEM DURING INFECTIONS. HERE, WE PROVIDE AN UPDATED OVERVIEW OF THE ROLES PLAYED BY DIETARY FACTORS AND HOW THEY CAN AFFECT RESPIRATORY HEALTH. THEREFORE, WE WILL SHOW THE ANTI-INFLAMMATORY ROLE OF FLAVONOIDS, FATTY ACIDS, VITAMINS AND MICROBIOTA, IMPORTANT FOR THE CONTROL OF CHRONIC INFLAMMATORY DISEASES AND ALLERGIES, IN ADDITION TO THE ANTIVIRAL ROLE OF VITAMINS, FLAVONOIDS, AND MINERALS DURING PULMONARY VIRAL INFECTIONS, ADDRESSING THE MECHANISMS INVOLVED IN EACH FUNCTION. THESE MECHANISMS ARE INTERESTING IN THE DISCUSSION OF PERSPECTIVES ASSOCIATED WITH SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2) INFECTION AND ITS PULMONARY COMPLICATIONS SINCE PATIENTS WITH SEVERE DISEASE HAVE VITAMINS DEFICIENCY, ESPECIALLY VITAMIN D. IN ADDITION, RESEARCHES WITH THE USE OF FLAVONOIDS HAVE BEEN SHOWN TO DECREASE VIRAL REPLICATION IN VITRO. THIS WAY, A FULL UNDERSTANDING OF DIETARY INFLUENCES CAN IMPROVE THE LUNG HEALTH OF PATIENTS. 2021 15 3829 26 INVOLVEMENT OF EPIGENETICS IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS THE MOST PREVALENT CHRONIC AGE-RELATED ARTHRITIC DISEASE THAT MAINLY AFFECTS THE DIARTHRODIAL JOINTS. NEVERTHELESS, THERE IS NO TREATMENT CURRENTLY AVAILABLE THAT CAN EFFECTIVELY REDUCE SYMPTOMS OR SLOW DOWN OR STOP DISEASE PROGRESSION. THE LACK OF DISEASE-MODIFYING THERAPIES COULD BE EXPLAINED BY THE COMPLEX PATHOGENESIS OF OA, WHICH IS STILL NOT COMPLETELY UNDERSTOOD. INTERTWINED EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, AND NONCODING RNAS (NCRNAS) HAVE BEEN INDICATED AS IMPORTANT CELLULAR TOOLS TO MAINTAIN TISSUE HOMEOSTASIS UPON ENVIRONMENTAL CHALLENGES. THE CURRENT REVIEW ILLUSTRATES THAT DYSFUNCTIONAL EPIGENETIC CONTROL MECHANISMS IN THE ARTICULAR CARTILAGE LIKELY PLAY AN IMPORTANT ROLE IN DRIVING OA PATHOPHYSIOLOGY. 2017 16 3800 32 INTERPLAY OF INFLAMMATORY MEDIATORS WITH EPIGENETICS AND CARTILAGE MODIFICATIONS IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA), A DEGENERATIVE DISEASE OF DIARTHRODIAL JOINTS, IS INFLUENCED BY MECHANICAL AND INFLAMMATORY FACTORS WITH AGING, OBESITY, CHRONIC INJURIES, AND SECONDARY DISEASES THOUGHT TO BE MAJOR FACTORS DRIVING THE PROCESS OF ARTICULAR CARTILAGE DEGENERATION. CHONDROCYTES, THE CELLULAR COMPONENT OF CARTILAGE, RESIDE IN AN AVASCULAR ENVIRONMENT AND NORMALLY HAVE LIMITED POTENTIAL TO REPLICATE. HOWEVER, EXTRINSIC FACTORS SUCH AS INJURY TO THE JOINT OR INTRINSIC ALTERATIONS TO THE CHONDROCYTES THEMSELVES CAN LEAD TO AN ALTERED PHENOTYPE AND DEVELOPMENT OF OA. SYNOVIAL INFLAMMATION IS ALSO A PIVOTAL ELEMENT OF THE OSTEOARTHRITIC, DEGENERATIVE PROCESS: INFLUX OF PRO-INFLAMMATORY CYTOKINES AND PRODUCTION OF MATRIX METALLOPROTEINASES ACCELERATE ADVANCED CELLULAR PROCESSES SUCH AS SYNOVITIS AND CARTILAGE DAMAGE. AS WELL AS A GENETIC INPUT, RECENT DATA HAVE HIGHLIGHTED EPIGENETIC FACTORS AS CONTRIBUTING TO DISEASE. STUDIES CONDUCTED OVER THE LAST DECADE HAVE FOCUSED ON THREE KEY ASPECTS IN OA; INFLAMMATION AND THE IMMUNE RESPONSE, GENOME-WIDE ASSOCIATION STUDIES THAT HAVE IDENTIFIED IMPORTANT GENES UNDERGOING EPIGENETIC MODIFICATIONS, AND FINALLY HOW CHONDROCYTES TRANSFORM IN THEIR FUNCTION DURING DEVELOPMENT AND DISEASE. DATA HIGHLIGHTED HERE HAVE IDENTIFIED CRITICAL INFLAMMATORY GENES INVOLVED IN OA AND HOW THESE FACTORS IMPACT CHONDROCYTE HYPERTROPHY IN THE DISEASE. THIS REVIEW ALSO ADDRESSES KEY INFLAMMATORY FACTORS IN SYNOVIAL INFLAMMATION, EPIGENETICS, AND CHONDROCYTE FATE, AND HOW AGENTS THAT INHIBIT EPIGENETIC MECHANISMS LIKE DNA METHYLATION AND HISTONE MODIFICATIONS COULD AID IN DEVELOPMENT OF LONG-TERM TREATMENT STRATEGIES FOR THE DISEASE. 2018 17 5110 32 POLYPHENOLS AND THE MODULATION OF GENE EXPRESSION PATHWAYS: CAN WE EAT OUR WAY OUT OF THE DANGER OF CHRONIC DISEASE? PLANT-DERIVED DIETARY POLYPHENOLS MAY IMPROVE SOME DISEASE STATES AND PROMOTE HEALTH. EXPERIMENTAL EVIDENCE SUGGESTS THAT THIS IS PARTIALLY ATTRIBUTABLE TO CHANGES IN GENE EXPRESSION. THE RATIONAL USE OF BIOACTIVE FOOD COMPONENTS MAY THEREFORE PRESENT AN OPPORTUNITY TO ACTIVATE OR REPRESS SELECTED GENE EXPRESSION PATHWAYS AND, CONSEQUENTLY, TO MANAGE OR PREVENT DISEASE. IT REMAINS TO BE DETERMINED WHETHER THIS USE OF BIOACTIVE FOOD COMPONENTS CAN BE DONE SAFELY. THIS ARTICLE REVIEWS THE ASSOCIATED CONTROVERSIES AND LIMITATIONS OF POLYPHENOL THERAPY. THERE IS A PAUCITY OF CLINICAL DATA ON THE RATIONAL USE OF POLYPHENOLS, INCLUDING A LACK OF KNOWLEDGE ON EFFECTIVE DOSAGE, ACTUAL CHEMICAL FORMULATIONS, BIOAVAILABILITY, DISTRIBUTION IN TISSUES, THE EFFECT OF GENETIC VARIATIONS, DIFFERENCES IN GUT MICROFLORA, THE SYNERGISTIC (OR ANTAGONISTIC) EFFECTS OBSERVED IN EXTRACTS, AND THE POSSIBLE INTERACTION BETWEEN POLYPHENOLS AND LIPID DOMAINS OF CELL MEMBRANES THAT MAY ALTER THE FUNCTION OF RELEVANT RECEPTORS. THE SEMINAL QUESTION OF WHY PLANTS MAKE SUBSTANCES THAT BENEFIT HUMANS REMAINS UNANSWERED, AND THERE IS STILL MUCH TO LEARN IN TERMS OF CORRELATIVE VERSUS CAUSAL EFFECTS OF HUMAN EXPOSURE TO VARIOUS NUTRIENTS. THE AVAILABLE DATA STRONGLY SUGGEST SIGNIFICANT EFFECTS AT THE MOLECULAR LEVEL THAT REPRESENT INTERACTIONS WITH THE EPIGENOME. THE ADVENT OF RELATIVELY SIMPLE TECHNOLOGIES IS HELPING THE FIELD OF EPIGENETICS PROGRESS AND FACILITATING THE ACQUISITION OF MULTIPLE TYPES OF DATA THAT WERE PREVIOUSLY DIFFICULT TO OBTAIN. IN THIS REVIEW, WE SUMMARIZE THE MOLECULAR BASIS OF THE EPIGENETIC REGULATION OF GENE EXPRESSION AND THE EPIGENETIC CHANGES ASSOCIATED WITH THE CONSUMPTION OF POLYPHENOLS THAT ILLUSTRATE HOW MODIFICATIONS IN HUMAN NUTRITION MAY BECOME RELEVANT TO HEALTH AND DISEASE. 2014 18 5724 30 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 19 3355 30 HISTONE EXTRACTION FROM HUMAN ARTICULAR CARTILAGE FOR THE STUDY OF EPIGENETIC REGULATION IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A CHRONIC DISEASE THAT AFFECTS ARTICULAR CARTILAGE, CAUSING ITS DEGENERATION. ALTHOUGH OA IS ONE OF THE MOST PREVALENT PATHOLOGIES GLOBALLY, THERE ARE NO DEFINITIVE TREATMENTS AVAILABLE. RECENTLY, RESEARCH HAS FOCUSED ON ELUCIDATING THE COMPLEX INTERPLAY THAT TAKES PLACE BETWEEN INFLAMMATORY PROCESSES AND EPIGENETIC REGULATION, SHOWING THAT HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS) CAN EXERT A PRONOUNCED EFFECT ON THE EXPRESSION OF OA-RELATED GENES. OA CHONDROCYTES ENHANCE THE PRODUCTION OF INTERLEUKIN 1BETA (IL-1BETA) AND INTERLEUKIN 8 (IL-8), WHICH ARE EPIGENETICALLY REGULATED. THESE CYTOKINES UPREGULATE THE SYNTHESIS OF MATRIX METALLOPROTEINASES (MMPS) AND AGGRECANASES, WHICH PROMOTE THE EXTRACELLULAR MATRIX (ECM) DESTRUCTION. THIS MOTIVATES THE STUDY OF HISTONE PTMS TO INVESTIGATE THE EPIGENETIC REGULATION OF PROINFLAMMATORY MOLECULES, BUT THE ABSENCE OF SPECIFIC PROTOCOLS TO EXTRACT HISTONES FROM HUMAN ARTICULAR CARTILAGE HAS COMPLICATED THIS TASK. THE LACK OF EFFECTIVE METHODS CAN BE EXPLAINED BY THE STRUCTURAL COMPLEXITY AND LOW CELLULARITY OF THIS TISSUE, WHICH ARE RESPONSIBLE FOR THE BIOMECHANICAL PROPERTIES THAT ALLOW THE MOVEMENT OF THE JOINT BUT ALSO COMPLICATE HISTONE ISOLATION. HERE, WE PROVIDE A HISTONE EXTRACTION PROCEDURE SPECIFICALLY ADAPTED FOR CRYOPRESERVED HUMAN ARTICULAR CARTILAGE THAT CAN BE USEFUL TO UNDERSTAND EPIGENETIC REGULATION IN OA AND ACCELERATE THE SEARCH FOR NOVEL STRATEGIES. 2022 20 6447 27 THERAPEUTIC PROSPECTS FOR EPIGENETIC MODULATION. INTRODUCTION: EPIGENETICS DESCRIBES THE PHENOMENON OF HERITABLE CHANGES IN GENE REGULATION GOVERNED BY NON-MENDELIAN PROCESSES, PRIMARILY THROUGH BIOCHEMICAL MODIFICATIONS TO CHROMATIN THAT OCCUR DURING CELL DIFFERENTIATION AND DEVELOPMENT. ABNORMAL LEVELS OF DNA AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. DRUGS THAT TARGET THE PROTEINS CONTROLLING THESE CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS WITH SINGLE TARGET PHARMACOLOGIES THAT ARE SUSCEPTIBLE TO BIOCHEMICAL PATHWAY DEGENERACY. AREAS COVERED: THIS ARTICLE REVIEWS RESEARCH CHARACTERIZING DYSREGULATION OF EPIGENETIC PROCESSES IN CANCER, IMMUNO-INFLAMMATORY, PSYCHIATRIC, NEUROLOGICAL, METABOLIC AND VIROLOGY DISEASE AREAS, AND SUMMARIZES RECENT DEVELOPMENTS IN IDENTIFYING SMALL MOLECULE MODULATORS THAT ARE BEING USED TO INFORM TARGET DISCOVERY AND INITIATE DRUG DISCOVERY PROJECTS. EXPERT OPINION: THERE ARE NUMEROUS POTENTIAL OPPORTUNITIES FOR EPIGENETIC MODULATORS IN TREATING A WIDE RANGE OF CHRONIC DISEASES; HOWEVER, THE FIELD IS COMPLEX, INVOLVING > 300 PROTEINS, AND MUCH WORK IS STILL REQUIRED TO PROVIDE TOOLS TO UNRAVEL THE FUNCTIONS OF INDIVIDUAL PROTEINS, PARTICULARLY IN VIVO. THIS GROUNDWORK IS ESSENTIAL TO ALLOW THE DRUG DISCOVERY COMMUNITY TO FOCUS ON THOSE EPIGENETIC PROTEINS MOST LIKELY TO BE SUITABLE TARGETS FOR SAFE, EFFICACIOUS NEW THERAPIES. 2011