1 4585 117 NAD(+) AND VASCULAR DYSFUNCTION: FROM MECHANISMS TO THERAPEUTIC OPPORTUNITIES. NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)) IS AN ESSENTIAL AND PLEIOTROPIC COENZYME INVOLVED NOT ONLY IN CELLULAR ENERGY METABOLISM, BUT ALSO IN CELL SIGNALING, EPIGENETIC REGULATION, AND POST-TRANSLATIONAL PROTEIN MODIFICATIONS. VASCULAR DISEASE RISK FACTORS ARE ASSOCIATED WITH ABERRANT NAD(+) METABOLISM. CONVERSELY, THE THERAPEUTIC INCREASE OF NAD(+) LEVELS THROUGH THE ADMINISTRATION OF NAD(+) PRECURSORS OR INHIBITORS OF NAD(+)-CONSUMING ENZYMES REDUCES CHRONIC LOW-GRADE INFLAMMATION, REACTIVATES AUTOPHAGY AND MITOCHONDRIAL BIOGENESIS, AND ENHANCES OXIDATIVE METABOLISM IN VASCULAR CELLS OF HUMANS AND RODENTS WITH VASCULAR PATHOLOGIES. AS SUCH, NAD(+) HAS EMERGED AS A POTENTIAL TARGET FOR COMBATTING AGE-RELATED CARDIOVASCULAR AND CEREBROVASCULAR DISORDERS. THIS REVIEW DISCUSSES NAD(+)-REGULATED MECHANISMS CRITICAL FOR VASCULAR HEALTH AND SUMMARIZES NEW ADVANCES IN NAD(+) RESEARCH DIRECTLY RELATED TO VASCULAR AGING AND DISEASE, INCLUDING HYPERTENSION, ATHEROSCLEROSIS, CORONARY ARTERY DISEASE, AND AORTIC ANEURYSMS. FINALLY, WE ENUMERATE CHALLENGES AND OPPORTUNITIES FOR NAD(+) REPLETION THERAPY WHILE ANTICIPATING THE FUTURE OF THIS EXCITING RESEARCH FIELD, WHICH WILL HAVE A MAJOR IMPACT ON VASCULAR MEDICINE. 2022 2 5719 32 SIRTUINS IN NEURODEGENERATIVE DISEASES: AN UPDATE ON POTENTIAL MECHANISMS. SILENT INFORMATION REGULATOR 2 PROTEINS (SIRTUINS OR SIRTS) ARE A GROUP OF DEACETYLASES (OR DEACYLASES) WHOSE ACTIVITIES ARE DEPENDENT ON AND REGULATED BY NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)). COMPELLING EVIDENCE SUPPORTS THAT SIRTUINS PLAY MAJOR ROLES IN MANY ASPECTS OF PHYSIOLOGY, ESPECIALLY IN PATHWAYS RELATED TO AGING - THE PREDOMINANT AND UNIFYING RISK FACTOR FOR NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE HIGHLIGHT THE MOLECULAR MECHANISMS UNDERLYING THE PROTECTIVE EFFECTS OF SIRTUINS IN NEURODEGENERATIVE DISEASES, FOCUSING ON PROTEIN HOMEOSTASIS, NEURAL PLASTICITY, MITOCHONDRIAL FUNCTION, AND SUSTAINED CHRONIC INFLAMMATION. WE WILL ALSO EXAMINE THE POTENTIAL AND CHALLENGES OF TARGETING SIRTUIN PATHWAYS TO BLOCK THESE PATHOGENIC PATHWAYS. 2013 3 6467 48 TISSUE-SPECIFIC EFFECTS OF EXERCISE AS NAD(+) -BOOSTING STRATEGY: CURRENT KNOWLEDGE AND FUTURE PERSPECTIVES. NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+) ) IS AN EVOLUTIONARILY HIGHLY CONSERVED COENZYME WITH MULTI-FACETED CELL FUNCTIONS, INCLUDING ENERGY METABOLISM, MOLECULAR SIGNALING PROCESSES, EPIGENETIC REGULATION, AND DNA REPAIR. SINCE THE DISCOVERY THAT LOWER NAD(+) LEVELS ARE A SHARED CHARACTERISTIC OF VARIOUS DISEASES AND AGING PER SE, SEVERAL NAD(+) -BOOSTING STRATEGIES HAVE EMERGED. OTHER THAN PHARMACOLOGICAL AND NUTRITIONAL APPROACHES, EXERCISE IS THOUGHT TO RESTORE NAD(+) HOMEOSTASIS THROUGH METABOLIC ADAPTION TO CHRONICALLY RECURRING STATES OF INCREASED ENERGY DEMAND. IN THIS REVIEW WE DISCUSS THE IMPACT OF ACUTE EXERCISE AND EXERCISE TRAINING ON TISSUE-SPECIFIC NAD(+) METABOLISM OF RODENTS AND HUMANS TO HIGHLIGHT THE POTENTIAL VALUE AS NAD(+) -BOOSTING STRATEGY. BY INTERCONNECTING RESULTS FROM DIFFERENT INVESTIGATIONS, WE AIM TO DRAW ATTENTION TO TISSUE-SPECIFIC ALTERATIONS IN NAD(+) METABOLISM AND THE ASSOCIATED IMPLICATIONS FOR WHOLE-BODY NAD(+) HOMEOSTASIS. ACUTE EXERCISE LED TO PROFOUND ALTERATIONS OF INTRACELLULAR NAD(+) METABOLISM IN VARIOUS INVESTIGATIONS, WITH THE MAGNITUDE AND DIRECTION OF CHANGES BEING STRONGLY DEPENDENT ON THE APPLIED EXERCISE MODALITY, CELL TYPE, AND INVESTIGATED ANIMAL MODEL OR HUMAN POPULATION. EXERCISE TRAINING ELEVATED NAD(+) LEVELS AND NAD(+) METABOLISM ENZYMES IN VARIOUS TISSUES. BASED ON THESE RESULTS, WE DISCUSS MOLECULAR MECHANISMS THAT MIGHT CONNECT ACUTE EXERCISE-INDUCED DISRUPTIONS OF NAD(+) /NADH HOMEOSTASIS TO CHRONIC EXERCISE ADAPTIONS IN NAD(+) METABOLISM. TAKING THIS HYPOTHESIS-DRIVEN APPROACH, WE HOPE TO INSPIRE FUTURE RESEARCH ON THE MOLECULAR MECHANISMS OF EXERCISE AS NAD(+) -MODIFYING LIFESTYLE INTERVENTION, THEREBY ELUCIDATING THE POTENTIAL THERAPEUTIC VALUE IN NAD(+) -RELATED PATHOLOGIES. 2023 4 4037 30 MACROPHAGE IMMUNOMETABOLISM AND INFLAMMAGING: ROLES OF MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, CD38, AND NAD. AGING IS A COMPLEX PROCESS THAT INVOLVES DYSFUNCTION ON MULTIPLE LEVELS, ALL OF WHICH SEEM TO CONVERGE ON INFLAMMATION. MACROPHAGES ARE INTIMATELY INVOLVED IN INITIATING AND RESOLVING INFLAMMATION, AND THEIR DYSREGULATION WITH AGE IS A PRIMARY CONTRIBUTOR TO INFLAMMAGING-A STATE OF CHRONIC, LOW-GRADE INFLAMMATION THAT DEVELOPS DURING AGING. AMONG THE AGE-RELATED CHANGES THAT OCCUR TO MACROPHAGES ARE A HEIGHTENED STATE OF BASAL INFLAMMATION AND DIMINISHED OR HYPERACTIVE INFLAMMATORY RESPONSES, WHICH SEEM TO BE DRIVEN BY METABOLIC-DEPENDENT EPIGENETIC CHANGES. IN THIS REVIEW ARTICLE WE PROVIDE A BRIEF OVERVIEW OF MITOCHONDRIAL FUNCTIONS AND AGE-RELATED CHANGES THAT OCCUR TO MACROPHAGES, WITH AN EMPHASIS ON HOW THE INFLAMMAGING ENVIRONMENT, SENESCENCE, AND NAD DECLINE CAN AFFECT THEIR METABOLISM, PROMOTE DYSREGULATION, AND CONTRIBUTE TO INFLAMMAGING AND AGE-RELATED PATHOLOGIES. 2020 5 6103 42 THE EMERGING ROLE OF HDACS: PATHOLOGY AND THERAPEUTIC TARGETS IN DIABETES MELLITUS. DIABETES MELLITUS (DM) IS ONE OF THE PRINCIPAL MANIFESTATIONS OF METABOLIC SYNDROME AND ITS PREVALENCE WITH MODERN LIFESTYLE IS INCREASING INCESSANTLY. CHRONIC HYPERGLYCEMIA CAN INDUCE SEVERAL VASCULAR COMPLICATIONS THAT WERE REFERRED TO BE THE MAJOR CAUSE OF MORBIDITY AND MORTALITY IN DM. ALTHOUGH SEVERAL THERAPEUTIC TARGETS HAVE BEEN IDENTIFIED AND ACCESSED CLINICALLY, THE IMMINENT RISK OF DM AND ITS PREVALENCE ARE STILL ASCENDING. SUBSTANTIAL PIECES OF EVIDENCE REVEALED THAT HISTONE DEACETYLASE (HDAC) ISOFORMS CAN REGULATE VARIOUS MOLECULAR ACTIVITIES IN DM VIA EPIGENETIC AND POST-TRANSLATIONAL REGULATION OF SEVERAL TRANSCRIPTION FACTORS. TO DATE, 18 HDAC ISOFORMS HAVE BEEN IDENTIFIED IN MAMMALS THAT WERE CATEGORIZED INTO FOUR DIFFERENT CLASSES. CLASSES I, II, AND IV ARE REGARDED AS CLASSICAL HDACS, WHICH OPERATE THROUGH A ZN-BASED MECHANISM. IN CONTRAST, CLASS III HDACS OR SIRTUINS DEPEND ON NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)) FOR THEIR MOLECULAR ACTIVITY. FUNCTIONALLY, MOST OF THE HDAC ISOFORMS CAN REGULATE BETA CELL FATE, INSULIN RELEASE, INSULIN EXPRESSION AND SIGNALING, AND GLUCOSE METABOLISM. MOREOVER, THE ROLES OF HDAC MEMBERS HAVE BEEN IMPLICATED IN THE REGULATION OF OXIDATIVE STRESS, INFLAMMATION, APOPTOSIS, FIBROSIS, AND OTHER PATHOLOGICAL EVENTS, WHICH SUBSTANTIALLY CONTRIBUTE TO DIABETES-RELATED VASCULAR DYSFUNCTIONS. THEREFORE, HDACS COULD SERVE AS THE POTENTIAL THERAPEUTIC TARGET IN DM TOWARDS DEVELOPING NOVEL INTERVENTION STRATEGIES. THIS REVIEW SHEDS LIGHT ON THE EMERGING ROLE OF HDACS/ISOFORMS IN DIABETIC PATHOPHYSIOLOGY AND EMPHASIZED THE SCOPE OF THEIR TARGETING IN DM FOR CONSTITUTING NOVEL INTERVENTIONAL STRATEGIES FOR METABOLIC DISORDERS/COMPLICATIONS. 2021 6 1254 32 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 7 4145 35 MECHANISMS OF VASCULAR AGING. AGING OF THE VASCULATURE PLAYS A CENTRAL ROLE IN MORBIDITY AND MORTALITY OF OLDER PEOPLE. TO DEVELOP NOVEL TREATMENTS FOR AMELIORATION OF UNSUCCESSFUL VASCULAR AGING AND PREVENTION OF AGE-RELATED VASCULAR PATHOLOGIES, IT IS ESSENTIAL TO UNDERSTAND THE CELLULAR AND FUNCTIONAL CHANGES THAT OCCUR IN THE VASCULATURE DURING AGING. IN THIS REVIEW, THE PATHOPHYSIOLOGICAL ROLES OF FUNDAMENTAL CELLULAR AND MOLECULAR MECHANISMS OF AGING, INCLUDING OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, IMPAIRED RESISTANCE TO MOLECULAR STRESSORS, CHRONIC LOW-GRADE INFLAMMATION, GENOMIC INSTABILITY, CELLULAR SENESCENCE, EPIGENETIC ALTERATIONS, LOSS OF PROTEIN HOMEOSTASIS, DEREGULATED NUTRIENT SENSING, AND STEM CELL DYSFUNCTION IN THE VASCULAR SYSTEM ARE CONSIDERED IN TERMS OF THEIR CONTRIBUTION TO THE PATHOGENESIS OF BOTH MICROVASCULAR AND MACROVASCULAR DISEASES ASSOCIATED WITH OLD AGE. THE IMPORTANCE OF PROGERONIC AND ANTIGERONIC CIRCULATING FACTORS IN RELATION TO DEVELOPMENT OF VASCULAR AGING PHENOTYPES ARE DISCUSSED. FINALLY, FUTURE DIRECTIONS AND OPPORTUNITIES TO DEVELOP NOVEL INTERVENTIONS TO PREVENT/DELAY AGE-RELATED VASCULAR PATHOLOGIES BY TARGETING FUNDAMENTAL CELLULAR AND MOLECULAR AGING PROCESSES ARE PRESENTED. 2018 8 4377 34 MITOCHONDRIAL AGING: FOCUS ON MITOCHONDRIAL DNA DAMAGE IN ATHEROSCLEROSIS - A MINI-REVIEW. ATHEROSCLEROSIS IS A COMPLEX DISEASE WHICH CAN BE DESCRIBED AS AN EXCESSIVE FIBROFATTY, PROLIFERATIVE, INFLAMMATORY RESPONSE TO DAMAGE TO THE ARTERY WALL INVOLVING SEVERAL CELL TYPES SUCH AS SMOOTH MUSCLE CELLS, MONOCYTE-DERIVED MACROPHAGES, LYMPHOCYTES, DENDRITIC CELLS AND PLATELETS. ON THE OTHER HAND, ATHEROSCLEROSIS IS A TYPICAL AGE-RELATED DEGENERATIVE PATHOLOGY, WHICH IS CHARACTERIZED BY SIGNS OF CELL SENESCENCE IN THE ARTERIAL WALL INCLUDING REDUCED CELL PROLIFERATION, IRREVERSIBLE GROWTH ARREST AND APOPTOSIS, INCREASED DNA DAMAGE, THE PRESENCE OF EPIGENETIC MODIFICATIONS, SHORTENING OF TELOMERE LENGTH AND MITOCHONDRIAL DYSFUNCTION. THE MOST PROMINENT CHARACTERISTICS OF MITOCHONDRIAL AGING ARE THEIR STRUCTURAL ALTERATIONS AND MITOCHONDRIAL DNA DAMAGE. THE MECHANISMS OF MITOCHONDRIAL GENOME DAMAGE IN THE DEVELOPMENT OF CHRONIC AGE-RELATED DISEASES SUCH AS ATHEROSCLEROSIS ARE NOT YET WELL UNDERSTOOD. THIS REVIEW FOCUSES ON THE LATEST FINDINGS FROM STUDIES OF THOSE MUTATIONS OF THE MITOCHONDRIAL GENOME WHICH MAY PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF ATHEROSCLEROSIS AND WHICH ARE, AT THE SAME TIME, ALSO MARKERS OF MITOCHONDRIAL AGING AND CELL SENESCENCE. 2015 9 4013 45 LOW-DENSITY LIPOPROTEIN-CHOLESTEROL-INDUCED ENDOTHELIAL DYSFUNCTION AND OXIDATIVE STRESS: THE ROLE OF STATINS. SIGNIFICANCE: CARDIOVASCULAR DISEASES (CVD) REPRESENT A MAJOR PUBLIC HEALTH BURDEN. HIGH LOW-DENSITY LIPOPROTEIN (LDL)-CHOLESTEROL IS A RECOGNIZED PATHOGENIC FACTOR FOR ATHEROSCLEROSIS, AND ITS COMPLICATIONS AND STATINS REPRESENT THE MOST POTENT AND WIDELY USED THERAPEUTIC APPROACH TO PREVENT AND CONTROL THESE DISORDERS. RECENT ADVANCES: A NUMBER OF CLINICAL AND EXPERIMENTAL STUDIES CONCUR TO IDENTIFY ENDOTHELIAL DYSFUNCTION AS A PRIMARY STEP IN THE DEVELOPMENT OF ATHEROSCLEROSIS, AS WELL AS A RISK FACTOR FOR SUBSEQUENT CLINICAL EVENTS. OXIDANT STRESS RESULTING FROM CHRONIC ELEVATION OF PLASMA LDL-CHOLESTEROL (LDL-CHOL) IS A MAJOR CONTRIBUTOR TO BOTH ENDOTHELIAL DYSFUNCTION AND ITS COMPLICATIONS, FOR EXAMPLE, THROUGH ALTERATIONS OF ENDOTHELIAL NITRIC OXIDE SIGNALING. CRITICAL ISSUES: STATIN TREATMENT REDUCES MORBIDITY AND MORTALITY OF CVD, BUT INCREASING EVIDENCE QUESTIONS THAT THIS IS EXCLUSIVELY THROUGH REDUCTION OF PLASMA LDL-CHOL. THE IDENTIFICATION OF ANCILLARY EFFECTS ON (CARDIO)VASCULAR BIOLOGY, FOR EXAMPLE, THROUGH THEIR MODULATION OF OXIDATIVE STRESS, WILL NOT ONLY INCREASE OUR UNDERSTANDING OF THEIR MECHANISMS OF ACTION, WITH A POTENTIAL BROADENING OF THEIR INDICATION(S), BUT ALSO LEAD TO THE IDENTIFICATION OF NEW MOLECULAR TARGETS FOR FUTURE THERAPEUTIC DEVELOPMENTS IN CVD. FUTURE DIRECTIONS: FURTHER CHARACTERIZATION OF MOLECULAR PATHWAYS TARGETED BY STATINS, FOR EXAMPLE, NOT DIRECTLY MEDIATED BY CHANGES IN PLASMA LIPID CONCENTRATIONS, SHOULD ENABLE A MORE COMPREHENSIVE APPROACH TO THE PATHOGENESIS OF (CARDIO)VASCULAR DISEASE, INCLUDING, FOR EXAMPLE, EPIGENETIC REGULATION AND FINE TUNING OF CELL METABOLISM. 2014 10 4597 30 NATURAL PRODUCTS WITH ANTI-AGING POTENTIAL: AFFECTED TARGETS AND MOLECULAR MECHANISMS. IN RECENT YEARS, THERE HAS BEEN A GREAT DEAL OF ATTENTION TOWARD THE MOLECULAR MACHINERY RELEVANT TO AGE-RELATED PROGRESSION CONTROLLED THROUGH THE EXTERNAL INTERVENTION OF POLYPHENOLS- AN EPIGENETIC-MODULATING DIET. NATURAL PRODUCTS MODULATE CELLULAR LONGEVITY THROUGH HISTONE POST-TRANSLATIONAL MODIFICATION AND CAN ALSO INDUCE THE UPREGULATION OF AUTOPHAGY, THUS REDUCING THE LEVEL OF ACETYL COENZYME A (ACCOA). IN ADDITION, THE EFFECT OF CALORIC RESTRICTION (CR) ON CANCER-RELATED CHRONIC INFLAMMATION IS OF GREAT SIGNIFICANCE IN AGING. IN LINE WITH THIS, SIRT1 PROTEIN LEVELS ARE EXPANDED IN RESPONSE TO CALORIE RESTRICTION MIMETICS (CRM), IN THIS WAY ACTING AS AUTOPHAGY INDUCERS RELEVANT TO CANCER PREVENTION. 2018 11 3344 36 HISTONE DEACETYLASES (HDACS) AND ATHEROSCLEROSIS: A MECHANISTIC AND PHARMACOLOGICAL REVIEW. ATHEROSCLEROSIS (AS), THE MOST COMMON UNDERLYING PATHOLOGY FOR CORONARY ARTERY DISEASE, IS A CHRONIC INFLAMMATORY, PROLIFERATIVE DISEASE IN LARGE- AND MEDIUM-SIZED ARTERIES. THE VASCULAR ENDOTHELIUM IS IMPORTANT FOR MAINTAINING VASCULAR HEALTH. ENDOTHELIAL DYSFUNCTION IS A CRITICAL EARLY EVENT LEADING TO AS, WHICH IS A MAJOR RISK FACTOR FOR STROKE AND MYOCARDIAL INFARCTION. ACCUMULATING EVIDENCE HAS SUGGESTED THE CRITICAL ROLES OF HISTONE DEACETYLASES (HDACS) IN REGULATING VASCULAR CELL HOMEOSTASIS AND AS. THE PURPOSE OF THIS REVIEW IS TO PRESENT AN UPDATED VIEW ON THE ROLES OF HDACS (CLASS I, CLASS II, CLASS IV) AND HDAC INHIBITORS IN VASCULAR DYSFUNCTION AND AS. WE ALSO ELABORATE ON THE NOVEL THERAPEUTIC TARGETS AND AGENTS IN ATHEROSCLEROTIC CARDIOVASCULAR DISEASES. 2020 12 2168 32 EPIGENETIC MECHANISMS IN MONOCYTES/MACROPHAGES REGULATE INFLAMMATION IN CARDIOMETABOLIC AND VASCULAR DISEASE. CARDIOMETABOLIC AND VASCULAR DISEASE, WITH THEIR ASSOCIATED SECONDARY COMPLICATIONS, ARE THE LEADING CAUSE OF MORBIDITY AND MORTALITY IN WESTERN SOCIETY. CHRONIC INFLAMMATION IS A COMMON THEME THAT UNDERLIES INITIATION AND PROGRESSION OF CARDIOVASCULAR DISEASE. IN THIS REGARD, MONOCYTES/MACROPHAGES ARE KEY PLAYERS IN THE DEVELOPMENT OF A CHRONIC INFLAMMATORY STATE. OVER THE PAST DECADE, EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION AND POSTTRANSLATIONAL HISTONE PROCESSING, HAVE EMERGED AS IMPORTANT REGULATORS OF IMMUNE CELL PHENOTYPES. ACCUMULATING STUDIES REVEAL THE IMPORTANCE OF EPIGENETIC ENZYMES IN THE DYNAMIC REGULATION OF KEY SIGNALING PATHWAYS THAT ALTER MONOCYTE/MACROPHAGE PHENOTYPES IN RESPONSE TO ENVIRONMENTAL STIMULI. IN THIS REVIEW, WE HIGHLIGHT THE CURRENT PARADIGMS OF MONOCYTE/MACROPHAGE POLARIZATION AND THE EMERGING ROLE OF EPIGENETIC MODIFICATION IN THE REGULATION OF MONOCYTE/MACROPHAGE PHENOTYPE IN OBESITY, DIABETES MELLITUS, ATHEROSCLEROSIS, AND ABDOMINAL AORTIC ANEURYSMS. 2019 13 870 25 CHRONIC ALCOHOL BINGING INJURES THE LIVER AND OTHER ORGANS BY REDUCING NAD(+) LEVELS REQUIRED FOR SIRTUIN'S DEACETYLASE ACTIVITY. NAD(+) LEVELS ARE MARKEDLY REDUCED WHEN BLOOD ALCOHOL LEVELS ARE HIGH DURING BINGE DRINKING. THIS CAUSES LIVER INJURY TO OCCUR BECAUSE THE ENZYMES THAT REQUIRE NAD(+) AS A COFACTOR SUCH AS THE SIRTUIN DE-ACETYLASES CANNOT DE-ACETYLATE ACETYLATED PROTEINS SUCH AS ACETYLATED HISTONES. THIS PREVENTS THE EPIGENETIC CHANGES THAT REGULATE METABOLIC PROCESSES AND WHICH PREVENT ORGAN INJURY SUCH AS FATTY LIVER IN RESPONSE TO ALCOHOL ABUSE. HYPER ACETYLATION OF NUMEROUS REGULATORY PROTEINS DEVELOPS. SYSTEMIC MULTI-ORGAN INJURY OCCURS WHEN NAD(+) IS REDUCED. FOR INSTANCE THE CIRCADIAN CLOCK IS ALTERED IF NAD(+) IS NOT AVAILABLE. CELL CYCLE ARREST OCCURS DUE TO UP REGULATION OF CELL CYCLE INHIBITORS LEADING TO DNA DAMAGE, MUTATIONS, APOPTOSIS AND TUMORIGENESIS. NAD(+) IS LINKED TO AGING IN THE REGULATION OF TELOMERE STABILITY. NAD(+) IS REQUIRED FOR MITOCHONDRIAL RENEWAL. ALCOHOL DEHYDROGENASE IS PRESENT IN EVERY VISCERAL ORGAN IN THE BODY SO THAT THERE IS A SYSTEMIC REDUCTION OF NAD(+) LEVELS IN ALL OF THESE ORGANS DURING BINGE DRINKING. 2016 14 4895 43 OXIDATIVE STRESS DRIVERS AND MODULATORS IN OBESITY AND CARDIOVASCULAR DISEASE: FROM BIOMARKERS TO THERAPEUTIC APPROACH. THIS REVIEW ARTICLE IS INTENDED TO DESCRIBE HOW OXIDATIVE STRESS REGULATES CARDIOVASCULAR DISEASE DEVELOPMENT AND PROGRESSION. EPIGENETIC MECHANISMS RELATED TO OXIDATIVE STRESS, AS WELL AS MORE RELIABLE BIOMARKERS OF OXIDATIVE STRESS, ARE EMERGING OVER THE LAST YEARS AS POTENTIALLY USEFUL TOOLS TO DESIGN THERAPEUTIC APPROACHES AIMED AT MODULATING ENHANCED OXIDATIVE STRESS "IN VIVO", THEREBY MITIGATING THE CONSEQUENT ATHEROSCLEROTIC BURDEN. AS A PARADIGM, WE DESCRIBE THE CASE OF OBESITY, IN WHICH THE INTERTWINING AMONG OXIDATIVE STRESS, DUE TO CALORIC OVERLOAD, CHRONIC LOW-GRADE INFLAMMATION INDUCED BY ADIPOSE TISSUE DYSFUNCTION, AND PLATELET ACTIVATION REPRESENTS A VICIOUS CYCLE FAVORING THE PROGRESSION OF ATHEROTHROMBOSIS. OXIDATIVE STRESS IS A MAJOR PLAYER IN THE PATHOBIOLOGY OF CARDIOVASCULAR DISEASE (CVD). REACTIVE OXYGEN SPECIES (ROS)- DEPENDENT SIGNALING PATHWAYS PROMPT TRANSCRIPTIONAL AND EPIGENETIC DYSREGULATION, INDUCING CHRONIC LOW-GRADE INFLAMMATION, PLATELET ACTIVATION AND ENDOTHELIAL DYSFUNCTION. IN ADDITION, SEVERAL OXIDATIVE BIOMARKERS HAVE BEEN PROPOSED WITH THE POTENTIAL TO IMPROVE CURRENT UNDERSTANDING OF THE MECHANISMS UNDERLYING CVD. THESE INCLUDE ROS-GENERATING AND/OR QUENCHING MOLECULES, AND ROS-MODIFIED COMPOUNDS, SUCH AS F2-ISOPROSTANES. THERE IS ALSO INCREASING EVIDENCE THAT NONCODING MICRO- RNA (MI-RNA) ARE CRITICALLY INVOLVED IN POST- TRANSCRIPTIONAL REGULATION OF CELL FUNCTIONS, INCLUDING ROS GENERATION, INFLAMMATION, REGULATION OF CELL PROLIFERATION, ADIPOCYTE DIFFERENTIATION, ANGIOGENESIS AND APOPTOSIS. THESE MOLECULES HAVE PROMISING TRANSLATIONAL POTENTIAL AS BOTH MARKERS OF DISEASE AND SITE OF TARGETED INTERVENTIONS. FINALLY, OXIDATIVE STRESS IS A CRITICAL TARGET OF SEVERAL CARDIOPROTECTIVE DRUGS AND NUTRACEUTICALS, INCLUDING ANTIDIABETIC AGENTS, STATINS, RENIN-ANGIOTENSIN SYSTEM BLOCKERS, POLYPHENOLS AND OTHER ANTIOXIDANTS. FURTHER UNDERSTANDING OF ROS-GENERATING MECHANISMS, THEIR BIOLOGICAL ROLE AS WELL AS POTENTIAL THERAPEUTIC IMPLICATIONS WOULD TRANSLATE INTO CONSISTENT BENEFITS FOR EFFECTIVE CV PREVENTION. 2015 15 3776 32 INTERACTIONS BETWEEN DYSLIPIDEMIA AND THE IMMUNE SYSTEM AND THEIR RELEVANCE AS PUTATIVE THERAPEUTIC TARGETS IN ATHEROSCLEROSIS. CARDIOVASCULAR DISEASE (CVD) CONTINUES TO BE A LEADING CAUSE OF DEATH WORLDWIDE WITH ATHEROSCLEROSIS BEING THE MAJOR UNDERLYING PATHOLOGY. THE INTERPLAY BETWEEN LIPIDS AND IMMUNE CELLS IS BELIEVED TO BE A DRIVING FORCE IN THE CHRONIC INFLAMMATION OF THE ARTERIAL WALL DURING ATHEROGENESIS. ATHEROSCLEROSIS IS INITIATED AS LIPID PARTICLES ACCUMULATE AND BECOME TRAPPED IN VESSEL WALLS. THE SUBSEQUENT IMMUNE RESPONSE, INVOLVING BOTH ADAPTIVE AND IMMUNE CELLS, PROGRESSES PLAQUE DEVELOPMENT, WHICH MAY BE EXACERBATED UNDER DYSLIPIDEMIC CONDITIONS. BROAD EVIDENCE, ESPECIALLY FROM ANIMAL MODELS, CLEARLY DEMONSTRATES THE EFFECT OF LIPIDS ON IMMUNE CELLS FROM THEIR DEVELOPMENT IN THE BONE MARROW TO THEIR PHENOTYPIC SWITCHING IN CIRCULATION. INTERESTINGLY, RECENT RESEARCH HAS ALSO SHOWN A LONG-LASTING EPIGENETIC SIGNATURE FROM LIPIDS ON IMMUNE CELLS. TRADITIONALLY, CARDIOVASCULAR THERAPIES HAVE APPROACHED ATHEROSCLEROSIS THROUGH LIPID-LOWERING MEDICATIONS BECAUSE, UNTIL RECENTLY, ANTI-INFLAMMATORY THERAPIES HAVE BEEN LARGELY UNSUCCESSFUL IN CLINICAL TRIALS. HOWEVER, THE RECENT CANAKINUMAB ANTIINFLAMMATORY THROMBOSIS OUTCOMES STUDY (CANTOS) PROVIDED PIVOTAL SUPPORT OF THE INFLAMMATORY HYPOTHESIS OF ATHEROSCLEROSIS IN MAN SPURRING ON ANTI-INFLAMMATORY STRATEGIES TO TREAT ATHEROSCLEROSIS. IN THIS REVIEW, WE DESCRIBE THE INTERACTIONS BETWEEN LIPIDS AND IMMUNE CELLS ALONG WITH THEIR SPECIFIC OUTCOMES AS WELL AS DISCUSS THEIR FUTURE PERSPECTIVE AS POTENTIAL CARDIOVASCULAR TARGETS. 2019 16 6258 37 THE MOLECULAR MECHANISM OF POLYPHENOLS IN THE REGULATION OF AGEING HALLMARKS. AGEING IS A COMPLEX PROCESS CHARACTERIZED MAINLY BY A DECLINE IN THE FUNCTION OF CELLS, TISSUES, AND ORGANS, RESULTING IN AN INCREASED RISK OF MORTALITY. THIS PROCESS INVOLVES SEVERAL CHANGES, DESCRIBED AS HALLMARKS OF AGEING, WHICH INCLUDE GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC CHANGES, LOSS OF PROTEOSTASIS, DYSREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL DEPLETION, AND ALTERED INTRACELLULAR COMMUNICATION. THE DETERMINING ROLE THAT ENVIRONMENTAL FACTORS SUCH AS DIET AND LIFESTYLE PLAY ON HEALTH, LIFE EXPECTANCY, AND SUSCEPTIBILITY TO DISEASES, INCLUDING CANCER AND NEURODEGENERATIVE DISEASES, IS WELLESTABLISHED. IN VIEW OF THE GROWING INTEREST IN THE BENEFICIAL EFFECTS OF PHYTOCHEMICALS IN THE PREVENTION OF CHRONIC DISEASES, SEVERAL STUDIES HAVE BEEN CONDUCTED, AND THEY STRONGLY SUGGEST THAT THE INTAKE OF DIETARY POLYPHENOLS MAY BRING NUMEROUS BENEFITS DUE TO THEIR ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES, AND THEIR INTAKE HAS BEEN ASSOCIATED WITH IMPAIRED AGEING IN HUMANS. POLYPHENOL INTAKE HAS BEEN SHOWN TO BE EFFECTIVE IN AMELIORATING SEVERAL AGE-RELATED PHENOTYPES, INCLUDING OXIDATIVE STRESS, INFLAMMATORY PROCESSES, IMPAIRED PROTEOSTASIS, AND CELLULAR SENESCENCE, AMONG OTHER FEATURES, WHICH CONTRIBUTE TO AN INCREASED RISK OF AGEING-ASSOCIATED DISEASES. THIS REVIEW AIMS TO ADDRESS, IN A GENERAL WAY, THE MAIN FINDINGS DESCRIBED IN THE LITERATURE ABOUT THE BENEFITS OF POLYPHENOLS IN EACH OF THE HALLMARKS OF AGEING, AS WELL AS THE MAIN REGULATORY MECHANISMS RESPONSIBLE FOR THE OBSERVED ANTIAGEING EFFECTS. 2023 17 3801 37 INTERPLAY OF VITAMIN D AND SIRT1 IN TISSUE-SPECIFIC METABOLISM-POTENTIAL ROLES IN PREVENTION AND TREATMENT OF NON-COMMUNICABLE DISEASES INCLUDING CANCER. THE IMPORTANCE OF THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES, INCLUDING OBESITY, METABOLIC SYNDROME, TYPE 2 DIABETES, CARDIOVASCULAR DISEASES, AND CANCER, IS INCREASING AS A REQUIREMENT OF THE AGING POPULATION IN DEVELOPED COUNTRIES AND THE SUSTAINABILITY OF HEALTHCARE. SIMILARLY, THE 2013-2030 ACTION PLAN OF THE WHO FOR THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES SEEKS THESE ACHIEVEMENTS. ADEQUATE LIFESTYLE CHANGES, ALONE OR WITH THE NECESSARY TREATMENTS, COULD REDUCE THE RISK OF MORTALITY OR THE DETERIORATION OF QUALITY OF LIFE. IN OUR RECENT WORK, WE SUMMARIZED THE ROLE OF TWO CENTRAL FACTORS, I.E., APPROPRIATE LEVELS OF VITAMIN D AND SIRT1, WHICH ARE CONNECTED TO ADEQUATE LIFESTYLES WITH BENEFICIAL EFFECTS ON THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES. BOTH OF THESE FACTORS HAVE RECEIVED INCREASED ATTENTION IN RELATION TO THE COVID-19 PANDEMIC AS THEY BOTH TAKE PART IN REGULATION OF THE MAIN METABOLIC PROCESSES, I.E., LIPID/GLUCOSE/ENERGY HOMEOSTASIS, OXIDATIVE STRESS, REDOX BALANCE, AND CELL FATE, AS WELL AS IN THE HEALTHY REGULATION OF THE IMMUNE SYSTEM. VITAMIN D AND SIRT1 HAVE DIRECT AND INDIRECT INFLUENCE OF THE REGULATION OF TRANSCRIPTION AND EPIGENETIC CHANGES AND ARE RELATED TO CYTOPLASMIC SIGNALING PATHWAYS SUCH AS PLC/DAG/IP3/PKC/MAPK, MEK/ERK, INSULIN/MTOR/CELL GROWTH, PROLIFERATION; LEPTIN/PI3K-AKT-MTORC1, AKT/NFKB/COX-2, NFKB/TNFALPHA, IL-6, IL-8, IL-1BETA, AND AMPK/PGC-1ALPHA/GLUT4, AMONG OTHERS. THROUGH THEIR PROPER REGULATION, THEY MAINTAIN NORMAL BODY WEIGHT, LIPID PROFILE, INSULIN SECRETION AND SENSITIVITY, BALANCE BETWEEN THE PRO- AND ANTI-INFLAMMATORY PROCESSES UNDER NORMAL CONDITIONS AND INFECTIONS, MAINTAIN ENDOTHELIAL HEALTH; BALANCE CELL DIFFERENTIATION, PROLIFERATION, AND FATE; AND BALANCE THE CIRCADIAN RHYTHM OF THE CELLULAR METABOLISM. THE ROLE OF THESE TWO MOLECULES IS INTERCONNECTED IN THE MOLECULAR NETWORK, AND THEY REGULATE EACH OTHER IN SEVERAL LAYERS OF THE HOMEOSTASIS OF ENERGY AND THE CELLULAR METABOLISM. BOTH HAVE A CENTRAL ROLE IN THE MAINTENANCE OF HEALTHY AND BALANCED IMMUNE REGULATION AND REDOX REACTIONS; THEREFORE, THEY COULD CONSTITUTE PROMISING TARGETS EITHER FOR PREVENTION OR AS COMPLEMENTARY THERAPIES TO ACHIEVE A BETTER QUALITY OF LIFE, AT ANY AGE, FOR HEALTHY PEOPLE AND PATIENTS UNDER CHRONIC CONDITIONS. 2023 18 5933 43 TARGETING EPIGENETICS AND NON-CODING RNAS IN ATHEROSCLEROSIS: FROM MECHANISMS TO THERAPEUTICS. ATHEROSCLEROSIS, THE PRINCIPAL CAUSE OF CARDIOVASCULAR DEATH WORLDWIDE, IS A PATHOLOGICAL DISEASE CHARACTERIZED BY FIBRO-PROLIFERATION, CHRONIC INFLAMMATION, LIPID ACCUMULATION, AND IMMUNE DISORDER IN THE VESSEL WALL. AS THE ATHEROMATOUS PLAQUES DEVELOP INTO ADVANCED STAGE, THE VULNERABLE PLAQUES ARE PRONE TO RUPTURE, WHICH CAUSES ACUTE CARDIOVASCULAR EVENTS, INCLUDING ISCHEMIC STROKE AND MYOCARDIAL INFARCTION. EMERGING EVIDENCE HAS SUGGESTED THAT ATHEROSCLEROSIS IS ALSO AN EPIGENETIC DISEASE WITH THE INTERPLAY OF MULTIPLE EPIGENETIC MECHANISMS. THE EPIGENETIC BASIS OF ATHEROSCLEROSIS HAS TRANSFORMED OUR KNOWLEDGE OF EPIGENETICS FROM AN IMPORTANT BIOLOGICAL PHENOMENON TO A BURGEONING FIELD IN CARDIOVASCULAR RESEARCH. HERE, WE PROVIDE A SYSTEMATIC AND UP-TO-DATE OVERVIEW OF THE CURRENT KNOWLEDGE OF THREE DISTINCT BUT INTERRELATED EPIGENETIC PROCESSES (INCLUDING DNA METHYLATION, HISTONE METHYLATION/ACETYLATION, AND NON-CODING RNAS), IN ATHEROSCLEROTIC PLAQUE DEVELOPMENT AND INSTABILITY. MECHANISTIC AND CONCEPTUAL ADVANCES IN UNDERSTANDING THE BIOLOGICAL ROLES OF VARIOUS EPIGENETIC MODIFIERS IN REGULATING GENE EXPRESSION AND FUNCTIONS OF ENDOTHELIAL CELLS (VASCULAR HOMEOSTASIS, LEUKOCYTE ADHESION, ENDOTHELIAL-MESENCHYMAL TRANSITION, ANGIOGENESIS, AND MECHANOTRANSDUCTION), SMOOTH MUSCLE CELLS (PROLIFERATION, MIGRATION, INFLAMMATION, HYPERTROPHY, AND PHENOTYPIC SWITCH), AND MACROPHAGES (DIFFERENTIATION, INFLAMMATION, FOAM CELL FORMATION, AND POLARIZATION) ARE DISCUSSED. THE INHERENTLY DYNAMIC NATURE AND REVERSIBILITY OF EPIGENETIC REGULATION, ENABLES THE POSSIBILITY OF EPIGENETIC THERAPY BY TARGETING EPIGENETIC "WRITERS", "READERS", AND "ERASERS". SEVERAL FOOD DRUG ADMINISTRATION-APPROVED SMALL-MOLECULE EPIGENETIC DRUGS SHOW PROMISE IN PRE-CLINICAL STUDIES FOR THE TREATMENT OF ATHEROSCLEROSIS. FINALLY, WE DISCUSS POTENTIAL THERAPEUTIC IMPLICATIONS AND CHALLENGES FOR FUTURE RESEARCH INVOLVING CARDIOVASCULAR EPIGENETICS, WITH AN AIM TO PROVIDE A TRANSLATIONAL PERSPECTIVE FOR IDENTIFYING NOVEL BIOMARKERS OF ATHEROSCLEROSIS, AND TRANSFORMING PRECISION CARDIOVASCULAR RESEARCH AND DISEASE THERAPY IN MODERN ERA OF EPIGENETICS. 2019 19 1712 48 DYSFUNCTIONAL VASCULAR ENDOTHELIUM AS A DRIVER OF ATHEROSCLEROSIS: EMERGING INSIGHTS INTO PATHOGENESIS AND TREATMENT. ATHEROSCLEROSIS, THE CHRONIC ACCUMULATION OF CHOLESTEROL-RICH PLAQUE WITHIN ARTERIES, IS ASSOCIATED WITH A BROAD SPECTRUM OF CARDIOVASCULAR DISEASES INCLUDING MYOCARDIAL INFARCTION, AORTIC ANEURYSM, PERIPHERAL VASCULAR DISEASE, AND STROKE. ATHEROSCLEROTIC CARDIOVASCULAR DISEASE REMAINS A LEADING CAUSE OF MORTALITY IN HIGH-INCOME COUNTRIES AND RECENT YEARS HAVE WITNESSED A NOTABLE INCREASE IN PREVALENCE WITHIN LOW- AND MIDDLE-INCOME REGIONS OF THE WORLD. CONSIDERING THIS PROMINENT AND EVOLVING GLOBAL BURDEN, THERE IS A NEED TO IDENTIFY THE CELLULAR MECHANISMS THAT UNDERLIE THE PATHOGENESIS OF ATHEROSCLEROSIS TO DISCOVER NOVEL THERAPEUTIC TARGETS FOR PREVENTING OR MITIGATING ITS CLINICAL SEQUELAE. DESPITE DECADES OF RESEARCH, WE STILL DO NOT FULLY UNDERSTAND THE COMPLEX CELL-CELL INTERACTIONS THAT DRIVE ATHEROSCLEROSIS, BUT NEW INVESTIGATIVE APPROACHES ARE RAPIDLY SHEDDING LIGHT ON THESE ESSENTIAL MECHANISMS. THE VASCULAR ENDOTHELIUM RESIDES AT THE INTERFACE OF SYSTEMIC CIRCULATION AND THE UNDERLYING VESSEL WALL AND PLAYS AN ESSENTIAL ROLE IN GOVERNING PATHOPHYSIOLOGICAL PROCESSES DURING ATHEROGENESIS. IN THIS REVIEW, WE PRESENT EMERGING EVIDENCE THAT IMPLICATES THE ACTIVATED ENDOTHELIUM AS A DRIVER OF ATHEROSCLEROSIS BY DIRECTING SITE-SPECIFICITY OF PLAQUE FORMATION AND BY PROMOTING PLAQUE DEVELOPMENT THROUGH INTRACELLULAR PROCESSES, WHICH REGULATE ENDOTHELIAL CELL PROLIFERATION AND TURNOVER, METABOLISM, PERMEABILITY, AND PLASTICITY. MOREOVER, WE HIGHLIGHT NOVEL MECHANISMS OF INTERCELLULAR COMMUNICATION BY WHICH ENDOTHELIAL CELLS MODULATE THE ACTIVITY OF KEY VASCULAR CELL POPULATIONS INVOLVED IN ATHEROGENESIS, AND DISCUSS HOW ENDOTHELIAL CELLS CONTRIBUTE TO RESOLUTION BIOLOGY - A PROCESS THAT IS DYSREGULATED IN ADVANCED PLAQUES. FINALLY, WE DESCRIBE IMPORTANT FUTURE DIRECTIONS FOR PRECLINICAL ATHEROSCLEROSIS RESEARCH, INCLUDING EPIGENETIC AND TARGETED THERAPIES, TO LIMIT THE PROGRESSION OF ATHEROSCLEROSIS IN AT-RISK OR AFFECTED PATIENTS. 2021 20 1411 37 DIETARY NATURAL PRODUCTS AS EPIGENETIC MODIFIERS IN AGING-ASSOCIATED INFLAMMATION AND DISEASE. COVERING: UP TO 2020CHRONIC, LOW-GRADE INFLAMMATION IS LINKED TO AGING AND HAS BEEN TERMED "INFLAMMAGING". INFLAMMAGING IS CONSIDERED A KEY CONTRIBUTOR TO THE DEVELOPMENT OF METABOLIC DYSFUNCTION AND A BROAD SPECTRUM OF DISEASES OR DISORDERS INCLUDING DECLINES IN BRAIN AND HEART FUNCTION. GENOME-WIDE ASSOCIATION STUDIES (GWAS) COUPLED WITH EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE SHOWN THE IMPORTANCE OF DIET IN THE DEVELOPMENT OF CHRONIC AND AGE-RELATED DISEASES. MOREOVER, DIETARY INTERVENTIONS E.G. CALORIC RESTRICTION CAN ATTENUATE INFLAMMATION TO DELAY AND/OR PREVENT THESE DISEASES. COMMON THEMES IN THESE STUDIES ENTAIL THE USE OF PHYTOCHEMICALS (PLANT-DERIVED COMPOUNDS) OR THE PRODUCTION OF SHORT CHAIN FATTY ACIDS (SCFAS) AS EPIGENETIC MODIFIERS OF DNA AND HISTONE PROTEINS. EPIGENETIC MODIFICATIONS ARE DYNAMICALLY REGULATED AND AS SUCH, SERVE AS POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OR PREVENTION OF AGE-RELATED DISEASE. IN THIS REVIEW, WE WILL FOCUS ON THE ROLE FOR NATURAL PRODUCTS THAT INCLUDE PHYTOCHEMICALS AND SHORT CHAIN FATTY ACIDS (SCFAS) AS REGULATORS OF THESE EPIGENETIC ADAPTATIONS. SPECIFICALLY, WE DISCUSS REGULATORS OF METHYLATION, ACETYLATION AND ACYLATION, IN THE PROTECTION FROM CHRONIC INFLAMMATION DRIVEN METABOLIC DYSFUNCTION AND DETERIORATION OF NEUROCOGNITIVE AND CARDIAC FUNCTION. 2020