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 3830 22 INVOLVEMENT OF HISTONE LYSINE CROTONYLATION IN THE REGULATION OF NERVE-INJURY-INDUCED NEUROPATHIC PAIN. HISTONE LYSINE CROTONYLATION (KCR), A NOVEL EPIGENETIC MODIFICATION, IS IMPORTANT IN REGULATING A BROAD SPECTRUM OF BIOLOGICAL PROCESSES AND VARIOUS DISEASES. HOWEVER, WHETHER KCR IS INVOLVED IN NEUROPATHIC PAIN REMAINS TO BE ELUCIDATED. WE FOUND KCR OCCURS IN MACROPHAGES, SENSORY NEURONS, AND SATELLITE GLIAL CELLS OF TRIGEMINAL GANGLIA (TG), NEURONS, ASTROCYTES, AND MICROGLIA OF THE MEDULLA OBLONGATA. KCR IN TG WAS DETECTED MAINLY IN SMALL AND MEDIUM SENSORY NEURONS, TO A LESSER EXTENT IN LARGE NEURONS. PERIPHERAL NERVE INJURY ELEVATED KCR LEVELS IN MACROPHAGES IN THE TRIGEMINAL AND DORSAL ROOT GANGLIA AND MICROGLIA IN THE MEDULLA OBLONGATA BUT REDUCED KCR LEVELS IN SENSORY NEURONS. INHIBITION OF HISTONE CROTONYLTRANSFERASES (P300) BY INTRA-TG OR INTRATHECAL ADMINISTRATION OF C646 SIGNIFICANTLY ALLEVIATED PARTIAL INFRAORBITAL NERVE TRANSECTION (PIONT)- OR SPINAL NERVE LIGATION (SNL)-INDUCED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA. INTRA-TG OR INTRATHECAL ADMINISTRATION OF CROTONYL COENZYME A TRILITHIUM SALT TO UPREGULATE KCR DOSE-DEPENDENTLY INDUCED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA IN MICE. MECHANISMLY, INHIBITION OF P300 ALLEVIATED PIONT-INDUCED MACROPHAGE ACTIVATION AND REDUCED THE EXPRESSION OF PAIN-RELATED INFLAMMATORY CYTOKINES TNFALPHA, IL1BETA AND CHEMOKINES CCL2 AND CXCL10. CORRESPONDINGLY, EXOGENOUS CROTONYL-COA INDUCED MACROPHAGE ACTIVATION AND THE EXPRESSION OF TNFALPHA, IL1BETA, IL6, CCL2 AND CCL7 IN TG, WHICH C646 CAN REPRESS. THESE FINDINGS SUGGEST THAT HISTONE CROTONYLATION MIGHT BE FUNCTIONALLY INVOLVED IN NEUROPATHIC PAIN AND NEUROINFLAMMATION REGULATION. 2022 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 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 5 870 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 6 1802 33 EFFECT OF PATERNAL DIET ON SPERMATOGENESIS AND OFFSPRING HEALTH: FOCUS ON EPIGENETICS AND INTERVENTIONS WITH FOOD BIOACTIVE COMPOUNDS. INFERTILITY IS A GROWING PUBLIC HEALTH PROBLEM. CONSUMPTION OF ANTIOXIDANT BIOACTIVE FOOD COMPOUNDS (BFCS) THAT INCLUDE MICRONUTRIENTS AND NON-NUTRIENTS HAS BEEN HIGHLIGHTED AS A POTENTIAL STRATEGY TO PROTECT AGAINST OXIDATIVE AND INFLAMMATORY DAMAGE IN THE MALE REPRODUCTIVE SYSTEM INDUCED BY OBESITY, ALCOHOL, AND TOXICANTS AND, THUS, IMPROVE SPERMATOGENESIS AND THE FERTILITY PARAMETERS. PATERNAL CONSUMPTION OF SUCH DIETARY COMPOUNDS COULD NOT ONLY BENEFIT THE FATHERS BUT THEIR OFFSPRING AS WELL. STUDIES IN THE NEW FIELD OF PATERNAL ORIGINS OF HEALTH AND DISEASE SHOW THAT PATERNAL MALNUTRITION CAN ALTER SPERM EPIGENOME, AND THIS CAN ALTER FETAL DEVELOPMENT AND PROGRAM AN INCREASED RISK OF METABOLIC DISEASES AND BREAST CANCER IN ADULTHOOD. BFCS, SUCH AS ASCORBIC ACID, ALPHA-TOCOPHEROL, POLYUNSATURATED FATTY ACIDS, TRACE ELEMENTS, CARNITINES, N-ACETYLCYSTEINE, AND COENZYME Q10, HAVE BEEN SHOWN TO IMPROVE MALE GAMETOGENESIS, MODULATE EPIGENETICS OF GERM CELLS, AND THE EPIGENETIC SIGNATURE OF THE OFFSPRING, RESTORING OFFSPRING METABOLIC HEALTH INDUCED BY STRESSORS DURING EARLY LIFE. THIS INDICATES THAT, FROM A FATHER'S PERSPECTIVE, PRECONCEPTION IS A VALUABLE WINDOW OF OPPORTUNITY TO START POTENTIAL NUTRITIONAL INTERVENTIONS WITH THESE BFCS TO MAXIMIZE SPERM EPIGENETIC INTEGRITY AND PROMOTE ADEQUATE FETAL GROWTH AND DEVELOPMENT, THUS PREVENTING CHRONIC DISEASE IN ADULTHOOD. 2022 7 2597 43 EPIGENETICS OF SUBCELLULAR STRUCTURE FUNCTIONING IN THE ORIGIN OF RISK OR RESILIENCE TO COMORBIDITY OF NEUROPSYCHIATRIC AND CARDIOMETABOLIC DISORDERS. MECHANISMS CONTROLLING MITOCHONDRIAL FUNCTION, PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM (ER) AND NUCLEAR PROCESSES SUCH AS TELOMERE LENGTH AND DNA REPAIR MAY BE SUBJECT TO EPIGENETIC CUES THAT RELATE THE GENOMIC EXPRESSION AND ENVIRONMENTAL EXPOSURES IN EARLY STAGES OF LIFE. THEY MAY ALSO BE INVOLVED IN THE COMORBID APPEARANCE OF CARDIOMETABOLIC (CMD) AND NEUROPSYCHIATRIC DISORDERS (NPD) DURING ADULTHOOD. MITOCHONDRIAL FUNCTION AND PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM ARE ASSOCIATED WITH OXIDATIVE STRESS AND ELEVATED INTRACELLULAR CALCIUM LEVELS AND MAY ALSO UNDERLIE THE VULNERABILITY FOR COMORBID CMD AND NPD. MITOCHONDRIA PROVIDE KEY METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+), ATP, ALPHA-KETOGLUTARATE AND ACETYL COENZYME A THAT ARE REQUIRED FOR MANY TRANSCRIPTIONAL AND EPIGENETIC PROCESSES. THEY ARE ALSO A SOURCE OF FREE RADICALS. ON THE OTHER HAND, EPIGENETIC MARKERS IN NUCLEAR DNA DETERMINE MITOCHONDRIAL BIOGENESIS. THE ER IS THE SUBCELLULAR ORGANELLE IN WHICH SECRETORY PROTEINS ARE FOLDED. MANY ENVIRONMENTAL FACTORS STOP THE ABILITY OF CELLS TO PROPERLY FOLD PROTEINS AND MODIFY POST-TRANSLATIONALLY SECRETORY AND TRANSMEMBRANE PROTEINS LEADING TO ENDOPLASMIC RETICULUM STRESS AND OXIDATIVE STRESS. ER FUNCTIONING MAY BE EPIGENETICALLY DETERMINED. CHRONIC ER STRESS IS EMERGING AS A KEY CONTRIBUTOR TO A GROWING LIST OF HUMAN DISEASES, INCLUDING CMD AND NPD. TELOMERE LOSS CAUSES CHROMOSOMAL FUSION, ACTIVATION OF THE CONTROL OF DNA DAMAGE-RESPONSES, UNSTABLE GENOME AND ALTERED STEM CELL FUNCTION, WHICH MAY UNDERLIE THE COMORBIDITY OF CMD AND NPD. THE LENGTH OF TELOMERES IS RELATED TO OXIDATIVE STRESS AND MAY BE EPIGENETICALLY PROGRAMMED. PATHWAYS INVOLVED IN DNA REPAIR MAY BE EPIGENETICALLY PROGRAMMED AND MAY CONTRIBUTE TO DISEASES. IN THIS PAPER, WE DESCRIBE SUBCELLULAR MECHANISMS THAT ARE DETERMINED BY EPIGENETIC MARKERS AND THEIR POSSIBLE RELATION TO THE DEVELOPMENT OF INCREASED SUSCEPTIBILITY TO DEVELOP CMD AND NPD. 2018 8 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 9 2821 26 FINE-TUNING AUTOPHAGY: FROM TRANSCRIPTIONAL TO POSTTRANSLATIONAL REGULATION. MACROAUTOPHAGY (HEREAFTER CALLED AUTOPHAGY) IS A VACUOLAR LYSOSOMAL PATHWAY FOR DEGRADATION OF INTRACELLULAR MATERIAL IN EUKARYOTIC CELLS. AUTOPHAGY PLAYS CRUCIAL ROLES IN TISSUE HOMEOSTASIS, IN ADAPTATION TO STRESS SITUATIONS, AND IN IMMUNE AND INFLAMMATORY RESPONSES. ALTERATION OF AUTOPHAGY IS ASSOCIATED WITH CANCER, DIABETES AND OBESITY, CARDIOVASCULAR DISEASE, NEURODEGENERATIVE DISEASE, AUTOIMMUNE DISEASE, INFECTION, AND CHRONIC INFLAMMATORY DISEASE. AUTOPHAGY IS CONTROLLED BY AUTOPHAGY-RELATED (ATG) PROTEINS THAT ACT IN A COORDINATED MANNER TO BUILD UP THE INITIAL AUTOPHAGIC VACUOLE NAMED THE AUTOPHAGOSOME. IT IS NOW KNOWN THAT THE ACTIVITIES OF ATG PROTEINS ARE MODULATED BY POSTTRANSLATIONAL MODIFICATIONS SUCH AS PHOSPHORYLATION, UBIQUITINATION, AND ACETYLATION. MOREOVER, TRANSCRIPTIONAL AND EPIGENETIC CONTROLS ARE INVOLVED IN THE REGULATION OF AUTOPHAGY IN STRESS SITUATIONS. HERE WE SUMMARIZE AND DISCUSS HOW POSTTRANSLATIONAL MODIFICATIONS AND TRANSCRIPTIONAL AND EPIGENETIC CONTROLS REGULATE THE INVOLVEMENT OF AUTOPHAGY IN THE PROTEOSTASIS NETWORK. 2016 10 4031 35 LYSINE DEACETYLASE (KDAC) REGULATORY PATHWAYS: AN ALTERNATIVE APPROACH TO SELECTIVE MODULATION. PROTEIN LYSINE DEACETYLASES (KDACS), INCLUDING THE CLASSIC ZN(2+) -DEPENDENT HISTONE DEACETYLASES (HDACS) AND THE NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+) )-REQUIRING SIRTUINS, ARE ENZYMES THAT PLAY CRITICAL ROLES IN NUMEROUS BIOLOGICAL PROCESSES, PARTICULARLY THE EPIGENETIC REGULATION OF GLOBAL GENE EXPRESSION PROGRAMS IN RESPONSE TO INTERNAL AND EXTERNAL CUES. DYSREGULATION OF KDACS IS CHARACTERISTIC OF SEVERAL HUMAN DISEASES, INCLUDING CHRONIC METABOLIC, NEURODEGENERATIVE, AND CARDIOVASCULAR DISEASES AND MANY CANCERS. THIS HAS LED TO THE DEVELOPMENT OF KDAC MODULATORS, TWO OF WHICH (HDAC INHIBITORS VORINOSTAT AND ROMIDEPSIN) HAVE BEEN APPROVED FOR THE TREATMENT OF CUTANEOUS T CELL LYMPHOMA. BY THEIR NATURE, EXISTING KDAC MODULATORS ARE RELATIVELY NONSPECIFIC, LEADING TO PAN-KDAC CHANGES AND UNDESIRED SIDE EFFECTS. GIVEN THAT KDACS ARE REGULATED AT MANY LEVELS, INCLUDING TRANSCRIPTIONAL, POST-TRANSLATIONAL, SUBCELLULAR LOCALIZATION, AND THROUGH THEIR COMPLEXATION WITH OTHER PROTEINS, IT SHOULD BE POSSIBLE TO AFFECT SPECIFIC KDAC ACTIVITY THROUGH MANIPULATION OF ENDOGENOUS SIGNALING PATHWAYS. IN THIS MINIREVIEW, WE DISCUSS OUR PRESENT KNOWLEDGE OF THE CELLULAR CONTROLS OF KDAC ACTIVITY AND EXAMPLES OF THEIR PHARMACOLOGIC REGULATION. 2014 11 313 32 ALCOHOL METABOLISM AND EPIGENETICS CHANGES. METABOLITES, INCLUDING THOSE GENERATED DURING ETHANOL METABOLISM, CAN IMPACT DISEASE STATES BY BINDING TO TRANSCRIPTION FACTORS AND/OR MODIFYING CHROMATIN STRUCTURE, THEREBY ALTERING GENE EXPRESSION PATTERNS. FOR EXAMPLE, THE ACTIVITIES OF ENZYMES INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS DNA AND HISTONE METHYLATION AND HISTONE ACETYLATION, ARE INFLUENCED BY THE LEVELS OF METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD), ADENOSINE TRIPHOSPHATE (ATP), AND S-ADENOSYLMETHIONINE (SAM). CHRONIC ALCOHOL CONSUMPTION LEADS TO SIGNIFICANT REDUCTIONS IN SAM LEVELS, THEREBY CONTRIBUTING TO DNA HYPOMETHYLATION. SIMILARLY, ETHANOL METABOLISM ALTERS THE RATIO OF NAD+ TO REDUCED NAD (NADH) AND PROMOTES THE FORMATION OF REACTIVE OXYGEN SPECIES AND ACETATE, ALL OF WHICH IMPACT EPIGENETIC REGULATORY MECHANISMS. IN ADDITION TO ALTERED CARBOHYDRATE METABOLISM, INDUCTION OF CELL DEATH, AND CHANGES IN MITOCHONDRIAL PERMEABILITY TRANSITION, THESE METABOLISM-RELATED CHANGES CAN LEAD TO MODULATION OF EPIGENETIC REGULATION OF GENE EXPRESSION. UNDERSTANDING THE NATURE OF THESE EPIGENETIC CHANGES WILL HELP RESEARCHERS DESIGN NOVEL MEDICATIONS TO TREAT OR AT LEAST AMELIORATE ALCOHOL-INDUCED ORGAN DAMAGE. 2013 12 4117 39 MECHANISMS OF AUTOPHAGIC RESPONSES TO ALTERED NUTRITIONAL STATUS. AUTOPHAGY IS A DYNAMIC PROCESS AND CRITICAL FOR CELLULAR REMODELING AND ORGANELLE QUALITY CONTROL. IN RESPONSE TO ALTERED NUTRITIONAL STATUS (E.G., FASTING AND FEEDING), AUTOPHAGIC ACTIVITY IS FINELY TUNED BY TRANSCRIPTIONAL, POSTTRANSLATIONAL, AND EPIGENETIC REGULATIONS VIA VARIOUS SIGNALING PATHWAYS, INCLUDING ENERGY SENSORS (E.G., MECHANISTIC TARGET OF RAPAMYCIN (MTOR)/ AMP-ACTIVATED PROTEIN KINASE - UNC-51 LIKE AUTOPHAGY ACTIVATING KINASE 1, MTORC1- WD REPEAT DOMAIN, PHOSPHOINOSITIDE INTERACTING 2, MTORC1- TRANSCRIPTION FACTOR EB, PERILIPIN 5- SIRTUIN 1, AND SIRTUIN 1-MEDIATED DEACETYLATION OF AUTOPHAGY PROTEINS), FASTING OR FEEDING INDUCED HORMONES (E.G., FIBROBLAST GROWTH FACTOR [FGF21]- PROTEIN KINASE A - JUMONJI DOMAIN-CONTAINING PROTEIN D3, FGF21- DOWNSTREAM REGULATORY ELEMENT ANTAGONIST MODULATOR - E3 LIGASE MIDLINE-1- TRANSCRIPTION FACTOR EB, FGF19-SHP- LYSINE-SPECIFIC DEMETHYLASE, INSULIN- INSULIN RECEPTOR SUBSTRATE - PROTEIN KINASE B - FORKHEAD BOX O, GLUCAGON- PROTEIN KINASE A - CAMP RESPONSE BINDING PROTEIN), AND LYSOSOMAL ENZYMES (E.G., CATHEPSIN B AND CATHEPSIN L). IN CONTRAST TO FASTING THAT INDUCES AUTOPHAGY AND HEALTH BENEFITS, NUTRIENT OVERSUPPLY (OVERFEEDING OR FEEDING ON HIGH ENERGY DIETS) DYSREGULATES AUTOPHAGY, WHICH HAS BEEN INCREASINGLY OBSERVED IN ANIMAL MODELS OF HUMAN CHRONIC DISEASES SUCH AS OBESITY, DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, AND CARDIOVASCULAR DISEASE. STUDIES HAVE REVEALED MULTIFACETED EFFECTS OF HIGH ENERGY DIETS ON AUTOPHAGY, BEING EITHER AN INHIBITOR OR ENHANCER OF AUTOPHAGY. THE CONUNDRUM MAY ARISE FROM THE VARIATIONS IN METHODS FOR AUTOPHAGY ANALYSIS, COMPONENTS OF HIGH ENERGY DIETS AND CONTROL DIETS FOR TREATMENTS, TREATMENT DURATIONS, AND THE AGES OF GENETIC BACKGROUNDS OF LABORATORY ANIMALS. IN THIS ARTICLE, WE REVIEWED THE EVIDENCE FROM BOTH HUMAN AND ANIMAL STUDIES, PRESENTING THE MOLECULAR MECHANISM OF AUTOPHAGIC RESPONSE TO ALTERED NUTRITIONAL STATUS AND DISCUSSING THE CONTRIBUTING FACTORS OF AND POSSIBLE SOLUTION TO THE CURRENT CONUNDRUM CONCERNING THE EXACT ROLE OF HIGH ENERGY DIETS IN AUTOPHAGIC REGULATION. 2022 13 4427 34 MOLECULAR BASIS OF ELECTROPHILIC AND OXIDATIVE DEFENSE: PROMISES AND PERILS OF NRF2. INDUCTION OF DRUG-METABOLIZING ENZYMES THROUGH THE ANTIOXIDANT RESPONSE ELEMENT (ARE)-DEPENDENT TRANSCRIPTION WAS INITIALLY IMPLICATED IN CHEMOPREVENTION AGAINST CANCER BY ANTIOXIDANTS. RECENT PROGRESS IN UNDERSTANDING THE BIOLOGY AND MECHANISM OF INDUCTION REVEALED A CRITICAL ROLE OF INDUCTION IN CELLULAR DEFENSE AGAINST ELECTROPHILIC AND OXIDATIVE STRESS. INDUCTION IS MEDIATED THROUGH A NOVEL SIGNALING PATHWAY VIA TWO REGULATORY PROTEINS, THE NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) AND THE KELCH-LIKE ERYTHROID CELL-DERIVED PROTEIN WITH CNC HOMOLOGY-ASSOCIATED PROTEIN 1 (KEAP1). NRF2 BINDS TO KEAP1 AT A TWO SITE-BINDING INTERFACE AND IS UBIQUITINATED BY THE KEAP1/CULLIN 3/RING BOX PROTEIN-1-UBIQUITIN LIGASE, RESULTING IN A RAPID TURNOVER OF NRF2 PROTEIN. ELECTROPHILES AND OXIDANTS MODIFY CRITICAL CYSTEINE THIOLS OF KEAP1 AND NRF2 TO INHIBIT NRF2 UBIQUITINATION, LEADING TO NRF2 ACTIVATION AND INDUCTION. INDUCTION INCREASES STRESS RESISTANCE CRITICAL FOR CELL SURVIVAL, BECAUSE KNOCKOUT OF NRF2 IN MICE INCREASED SUSCEPTIBILITY TO A VARIETY OF TOXICITY AND DISEASE PROCESSES. COLLATERAL TO DIVERSE FUNCTIONS OF NRF2, GENOME-WIDE SEARCH HAS LED TO THE IDENTIFICATION OF A PLETHORA OF ARE-DEPENDENT GENES REGULATED BY NRF2 IN AN INDUCER-, TISSUE-, AND DISEASE-DEPENDENT MANNER TO CONTROL DRUG METABOLISM, ANTIOXIDANT DEFENSE, STRESS RESPONSE, PROTEASOMAL DEGRADATION, AND CELL PROLIFERATION. THE PROTECTIVE NATURE OF NRF2 COULD ALSO BE HIJACKED IN A NUMBER OF PATHOLOGICAL CONDITIONS BY MEANS OF SOMATIC MUTATION, EPIGENETIC ALTERATION, AND ACCUMULATION OF DISRUPTOR PROTEINS, PROMOTING DRUG RESISTANCE IN CANCER AND PATHOLOGIC LIVER FEATURES IN AUTOPHAGY DEFICIENCY. THE REPERTOIRE OF ARE INDUCERS HAS EXPANDED ENORMOUSLY; THE THERAPEUTIC POTENTIAL OF THE INDUCERS HAS BEEN EXAMINED BEYOND CANCER PREVENTION. DEVELOPING POTENT AND SPECIFIC ARE INDUCERS AND NRF2 INHIBITORS HOLDS CERTAIN NEW PROMISE FOR THE PREVENTION AND THERAPY AGAINST CANCER, CHRONIC DISEASE, AND TOXICITY. 2012 14 5720 28 SIRTUINS LINK INFLAMMATION AND METABOLISM. SIRTUINS (SIRT), FIRST DISCOVERED IN YEAST AS NAD+ DEPENDENT EPIGENETIC AND METABOLIC REGULATORS, HAVE COMPARABLE ACTIVITIES IN HUMAN PHYSIOLOGY AND DISEASE. MOUNTING EVIDENCE SUPPORTS THAT THE SEVEN-MEMBER MAMMALIAN SIRTUIN FAMILY (SIRT1-7) GUARD HOMEOSTASIS BY SENSING BIOENERGY NEEDS AND RESPONDING BY MAKING ALTERATIONS IN THE CELL NUTRIENTS. SIRTUINS PLAY A CRITICAL ROLE IN RESTORING HOMEOSTASIS DURING STRESS RESPONSES. INFLAMMATION IS DESIGNED TO "DEFEND AND MEND" AGAINST THE INVADING ORGANISMS. EMERGING EVIDENCE SUPPORTS THAT METABOLISM AND BIOENERGY REPROGRAMMING DIRECT THE SEQUENTIAL COURSE OF INFLAMMATION; FAILURE OF HOMEOSTASIS RETRIEVAL RESULTS IN MANY CHRONIC AND ACUTE INFLAMMATORY DISEASES. ANABOLIC GLYCOLYSIS QUICKLY INDUCED (COMPARED TO OXIDATIVE PHOSPHORYLATION) FOR ROS AND ATP GENERATION IS NEEDED FOR IMMUNE ACTIVATION TO "DEFEND" AGAINST INVADING MICROORGANISMS. LIPOLYSIS/FATTY ACID OXIDATION, ESSENTIAL FOR CELLULAR PROTECTION/HIBERNATION AND CELL SURVIVAL IN ORDER TO "MEND," LEADS TO IMMUNE REPRESSION. ACUTE/CHRONIC INFLAMMATIONS ARE LINKED TO ALTERED GLYCOLYSIS AND FATTY ACID OXIDATION, AT LEAST IN PART, BY NAD+ DEPENDENT FUNCTION OF SIRTUINS. THERAPEUTICALLY TARGETING SIRTUINS MAY PROVIDE A NEW CLASS OF INFLAMMATION AND IMMUNE REGULATORS. THIS REVIEW DISCUSSES HOW SIRTUINS INTEGRATE METABOLISM, BIOENERGETICS, AND IMMUNITY DURING INFLAMMATION AND HOW SIRTUIN-DIRECTED TREATMENT IMPROVES OUTCOME IN CHRONIC INFLAMMATORY DISEASES AND IN THE EXTREME STRESS RESPONSE OF SEPSIS. 2016 15 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 16 4044 23 MACROPHAGES IN OXIDATIVE STRESS AND MODELS TO EVALUATE THE ANTIOXIDANT FUNCTION OF DIETARY NATURAL COMPOUNDS. ANTIOXIDANT TESTING OF NATURAL PRODUCTS HAS ATTRACTED INCREASING INTEREST IN RECENT YEARS, MAINLY DUE TO THE FACT THAT AN ANTIOXIDANT-RICH DIET MIGHT PROVIDE HEALTH BENEFITS. ACTIVATED MACROPHAGES ARE A MAJOR SOURCE OF REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES, AND PEROXYNITRITE GENERATED THROUGH THE SO-CALLED RESPIRATORY BURST. CONSTITUTIVELY RELEASED PROINFLAMMATORY CYTOKINE, ESPECIALLY TUMOR NECROSIS FACTOR-ALPHA, TRIGGERS NUCLEAR FACTOR-KAPPAB, AND ACTIVATOR PROTEIN-1 TRANSLOCATION LEADING TO THE OVER PRODUCTION OF REACTIVE OXYGEN SPECIES AND REACTIVE NITROGEN SPECIES IN MACROPHAGES. ACTIVATION OF TRANSCRIPTION FACTORS IN THE LONG-LIVED TISSUE-RESIDENT MACROPHAGES AND/OR MONOCYTE-DERIVED MACROPHAGES, TRIGGER EPIGENETIC MODIFICATIONS LEADING TO THE PATHOGENESIS OF CHRONIC DISEASES. NUTRACEUTICALS INCLUDING LIPID RAFT STRUCTURE DISRUPTION AGENT, CHOLESTEROL DEPLETION AGENT, FARNESYLTRANSFERASE INHIBITOR, NUCLEAR FACTOR-KAPPAB BLOCKER (ALPHA,BETA-UNSATURATED CARBONYL COMPOUNDS), GLUCOCORTICOID RECEPTOR AGONIST, AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AGONIST HAVE LONG BEEN USED TO INACTIVE MACROPHAGE. THE INHIBITION EFFECTS ON THE FORMATION OF NITRIC OXIDE, SUPEROXIDE, AND NITRITE PEROXIDE MAY BE RESPONSIBLE FOR THE ANTI-INFLAMMATORY FUNCTIONALITIES. ACTIVATED MACROPHAGE MODELS COULD BE USED TO IDENTIFY THE ACTIVE COMPONENTS FOR FUNCTIONAL DIETS DEVELOPMENT THROUGH A MULTIPLE TARGETS STRATEGY. 2017 17 1413 31 DIETARY PHYTOCHEMICALS AND CANCER CHEMOPREVENTION: A PERSPECTIVE ON OXIDATIVE STRESS, INFLAMMATION, AND EPIGENETICS. OXIDATIVE STRESS OCCURS WHEN CELLULAR REACTIVE OXYGEN SPECIES LEVELS EXCEED THE SELF-ANTIOXIDANT CAPACITY OF THE BODY. OXIDATIVE STRESS INDUCES MANY PATHOLOGICAL CHANGES, INCLUDING INFLAMMATION AND CANCER. CHRONIC INFLAMMATION IS BELIEVED TO BE STRONGLY ASSOCIATED WITH THE MAJOR STAGES OF CARCINOGENESIS. THE NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) PATHWAY PLAYS A CRUCIAL ROLE IN REGULATING OXIDATIVE STRESS AND INFLAMMATION BY MANIPULATING KEY ANTIOXIDANT AND DETOXIFICATION ENZYME GENES VIA THE ANTIOXIDANT RESPONSE ELEMENT. MANY DIETARY PHYTOCHEMICALS WITH CANCER CHEMOPREVENTIVE PROPERTIES, SUCH AS POLYPHENOLS, ISOTHIOCYANATES, AND TRITERPENOIDS, EXERT ANTIOXIDANT AND ANTI-INFLAMMATORY FUNCTIONS BY ACTIVATING THE NRF2 PATHWAY. FURTHERMORE, EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS, AND MIRNA-MEDIATED POST-TRANSCRIPTIONAL ALTERATIONS, ALSO LEAD TO VARIOUS CARCINOGENESIS PROCESSES BY SUPPRESSING CANCER REPRESSOR GENE TRANSCRIPTION. USING EPIGENETIC RESEARCH TOOLS, INCLUDING NEXT-GENERATION SEQUENCING TECHNOLOGIES, MANY DIETARY PHYTOCHEMICALS ARE SHOWN TO MODIFY AND REVERSE ABERRANT EPIGENETIC/EPIGENOME CHANGES, POTENTIALLY LEADING TO CANCER PREVENTION/TREATMENT. THUS, THE BENEFICIAL EFFECTS OF DIETARY PHYTOCHEMICALS ON CANCER DEVELOPMENT WARRANT FURTHER INVESTIGATION TO PROVIDE ADDITIONAL IMPETUS FOR CLINICAL TRANSLATIONAL STUDIES. 2016 18 5986 34 TFEB IS A CENTRAL REGULATOR OF THE AGING PROCESS AND AGE-RELATED DISEASES. OLD AGE IS ASSOCIATED WITH A GREATER BURDEN OF DISEASE, INCLUDING NEURODEGENERATIVE DISORDERS SUCH AS ALZHEIMER'S DISEASE AND PARKINSON'S DISEASE, AS WELL AS OTHER CHRONIC DISEASES. COINCIDENTALLY, POPULAR LIFESTYLE INTERVENTIONS, SUCH AS CALORIC RESTRICTION, INTERMITTENT FASTING, AND REGULAR EXERCISE, IN ADDITION TO PHARMACOLOGICAL INTERVENTIONS INTENDED TO PROTECT AGAINST AGE-RELATED DISEASES, INDUCE TRANSCRIPTION FACTOR EB (TFEB) AND AUTOPHAGY. IN THIS REVIEW, WE SUMMARIZE EMERGING DISCOVERIES THAT POINT TO TFEB ACTIVITY AFFECTING THE HALLMARKS OF AGING, INCLUDING INHIBITING DNA DAMAGE AND EPIGENETIC MODIFICATIONS, INDUCING AUTOPHAGY AND CELL CLEARANCE TO PROMOTE PROTEOSTASIS, REGULATING MITOCHONDRIAL QUALITY CONTROL, LINKING NUTRIENT-SENSING TO ENERGY METABOLISM, REGULATING PRO- AND ANTI-INFLAMMATORY PATHWAYS, INHIBITING SENESCENCE AND PROMOTING CELL REGENERATIVE CAPACITY. FURTHERMORE, THE THERAPEUTIC IMPACT OF TFEB ACTIVATION ON NORMAL AGING AND TISSUE-SPECIFIC DISEASE DEVELOPMENT IS ASSESSED IN THE CONTEXTS OF NEURODEGENERATION AND NEUROPLASTICITY, STEM CELL DIFFERENTIATION, IMMUNE RESPONSES, MUSCLE ENERGY ADAPTATION, ADIPOSE TISSUE BROWNING, HEPATIC FUNCTIONS, BONE REMODELING, AND CANCER. SAFE AND EFFECTIVE STRATEGIES OF ACTIVATING TFEB HOLD PROMISE AS A THERAPEUTIC STRATEGY FOR MULTIPLE AGE-ASSOCIATED DISEASES AND FOR EXTENDING LIFESPAN. 2023 19 5052 26 PHARMACOLOGICAL TARGETING OF HEME OXYGENASE-1 IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON AGING-ASSOCIATED DISEASE THAT CLINICALLY MANIFESTS AS JOINT PAIN, MOBILITY LIMITATIONS, AND COMPROMISED QUALITY OF LIFE. TODAY, OA TREATMENT IS LIMITED TO PAIN MANAGEMENT AND JOINT ARTHROPLASTY AT THE LATER STAGES OF DISEASE PROGRESSION. OA PATHOGENESIS IS PREDOMINANTLY MEDIATED BY OXIDATIVE DAMAGE TO JOINT CARTILAGE EXTRACELLULAR MATRIX AND LOCAL CELLS SUCH AS CHONDROCYTES, OSTEOCLASTS, OSTEOBLASTS, AND SYNOVIAL FIBROBLASTS. UNDER NORMAL CONDITIONS, CELLS PREVENT THE ACCUMULATION OF REACTIVE OXYGEN SPECIES (ROS) UNDER OXIDATIVELY STRESSFUL CONDITIONS THROUGH THEIR ADAPTIVE CYTOPROTECTIVE MECHANISMS. HEME OXYGENASE-1 (HO-1) IS AN IRON-DEPENDENT CYTOPROTECTIVE ENZYME THAT FUNCTIONS AS THE INDUCIBLE FORM OF HO. HO-1 AND ITS METABOLITES CARBON MONOXIDE AND BILIVERDIN CONTRIBUTE TOWARDS THE MAINTENANCE OF REDOX HOMEOSTASIS. HO-1 EXPRESSION IS PRIMARILY REGULATED AT THE TRANSCRIPTIONAL LEVEL THROUGH TRANSCRIPTIONAL FACTOR NUCLEAR FACTOR ERYTHROID 2 (NF-E2)-RELATED FACTOR 2 (NRF2), SPECIFICITY PROTEIN 1 (SP1), TRANSCRIPTIONAL REPRESSOR BTB-AND-CNC HOMOLOGY 1 (BACH1), AND EPIGENETIC REGULATION. SEVERAL STUDIES REPORT THAT HO-1 EXPRESSION CAN BE REGULATED USING VARIOUS ANTIOXIDATIVE FACTORS AND CHEMICAL COMPOUNDS, SUGGESTING THERAPEUTIC IMPLICATIONS IN OA PATHOGENESIS AS WELL AS IN THE WIDER CONTEXT OF JOINT DISEASE. HERE, WE REVIEW THE PROTECTIVE ROLE OF HO-1 IN OA WITH A FOCUS ON THE REGULATORY MECHANISMS THAT MEDIATE HO-1 ACTIVITY. 2021 20 1862 31 EMERGENCE OF FIBROBLASTS WITH A PROINFLAMMATORY EPIGENETICALLY ALTERED PHENOTYPE IN SEVERE HYPOXIC PULMONARY HYPERTENSION. PERSISTENT ACCUMULATION OF MONOCYTES/MACROPHAGES IN THE PULMONARY ARTERY ADVENTITIAL/PERIVASCULAR AREAS OF ANIMALS AND HUMANS WITH PULMONARY HYPERTENSION HAS BEEN DOCUMENTED. THE CELLULAR MECHANISMS CONTRIBUTING TO CHRONIC INFLAMMATORY RESPONSES REMAIN UNCLEAR. WE HYPOTHESIZED THAT PERIVASCULAR INFLAMMATION IS PERPETUATED BY ACTIVATED ADVENTITIAL FIBROBLASTS, WHICH, THROUGH SUSTAINED PRODUCTION OF PROINFLAMMATORY CYTOKINES/CHEMOKINES AND ADHESION MOLECULES, INDUCE ACCUMULATION, RETENTION, AND ACTIVATION OF MONOCYTES/MACROPHAGES. WE FURTHER HYPOTHESIZED THAT THIS PROINFLAMMATORY PHENOTYPE IS THE RESULT OF THE ABNORMAL ACTIVITY OF HISTONE-MODIFYING ENZYMES, SPECIFICALLY, CLASS I HISTONE DEACETYLASES (HDACS). PULMONARY ADVENTITIAL FIBROBLASTS FROM CHRONICALLY HYPOXIC HYPERTENSIVE CALVES (TERMED PH-FIBS) EXPRESSED A CONSTITUTIVE AND PERSISTENT PROINFLAMMATORY PHENOTYPE DEFINED BY HIGH EXPRESSION OF IL-1BETA, IL-6, CCL2(MCP-1), CXCL12(SDF-1), CCL5(RANTES), CCR7, CXCR4, GM-CSF, CD40, CD40L, AND VCAM-1. THE PROINFLAMMATORY PHENOTYPE OF PH-FIBS WAS ASSOCIATED WITH EPIGENETIC ALTERATIONS AS DEMONSTRATED BY INCREASED ACTIVITY OF HDACS AND THE FINDINGS THAT CLASS I HDAC INHIBITORS MARKEDLY DECREASED CYTOKINE/CHEMOKINE MRNA EXPRESSION LEVELS IN THESE CELLS. PH-FIBS INDUCED INCREASED ADHESION OF THP-1 MONOCYTES AND PRODUCED SOLUBLE FACTORS THAT INDUCED INCREASED MIGRATION OF THP-1 AND MURINE BONE MARROW-DERIVED MACROPHAGES AS WELL AS ACTIVATED MONOCYTES/MACROPHAGES TO EXPRESS PROINFLAMMATORY CYTOKINES AND PROFIBROGENIC MEDIATORS (TIMP1 AND TYPE I COLLAGEN) AT THE TRANSCRIPTIONAL LEVEL. CLASS I HDAC INHIBITORS MARKEDLY REDUCED THE ABILITY OF PH-FIBS TO INDUCE MONOCYTE MIGRATION AND PROINFLAMMATORY ACTIVATION. THE EMERGENCE OF A DISTINCT ADVENTITIAL FIBROBLAST POPULATION WITH AN EPIGENETICALLY ALTERED PROINFLAMMATORY PHENOTYPE CAPABLE OF RECRUITING, RETAINING, AND ACTIVATING MONOCYTES/MACROPHAGES CHARACTERIZES PULMONARY HYPERTENSION-ASSOCIATED VASCULAR REMODELING AND THUS COULD CONTRIBUTE SIGNIFICANTLY TO CHRONIC INFLAMMATORY PROCESSES IN THE PULMONARY ARTERY WALL. 2011