1 3188 132 HBV-SPECIFIC CD8+ T-CELL TOLERANCE IN THE LIVER. HEPATITIS B VIRUS (HBV) REMAINS A LEADING CAUSE OF LIVER-RELATED MORBIDITY AND MORTALITY THROUGH CHRONIC HEPATITIS THAT MAY PROGRESS TO LIVER CIRRHOSIS AND CANCER. THE CENTRAL ROLE PLAYED BY HBV-SPECIFIC CD8+ T CELLS IN THE CLEARANCE OF ACUTE HBV INFECTION, AND HBV-RELATED LIVER INJURY IS NOW WELL ESTABLISHED. VIGOROUS, MULTIFUNCTIONAL CD8+ T CELL RESPONSES ARE USUALLY INDUCED IN MOST ADULT-ONSET HBV INFECTIONS, WHILE CHRONIC HEPATITIS B (CHB) IS CHARACTERIZED BY QUANTITATIVELY AND QUALITATIVELY WEAK HBV-SPECIFIC CD8+ T CELL RESPONSES. THE MOLECULAR BASIS OF THIS DICHOTOMY IS POORLY UNDERSTOOD. GENOMIC ANALYSIS OF DYSFUNCTIONAL HBV-SPECIFIC CD8+ T CELLS IN CHB PATIENTS AND VARIOUS MOUSE MODELS SUGGEST THAT MULTIFACETED MECHANISMS INCLUDING NEGATIVE SIGNALING AND METABOLIC ABNORMALITIES COOPERATIVELY ESTABLISH CD8+ T CELL DYSFUNCTION. IMMUNOREGULATORY CELL POPULATIONS IN THE LIVER, INCLUDING LIVER RESIDENT DENDRITIC CELLS (DCS), HEPATIC STELLATE CELLS (HSCS), MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS), MAY CONTRIBUTE TO INTRAHEPATIC CD8+ T CELL DYSFUNCTION THROUGH THE PRODUCTION OF SOLUBLE MEDIATORS, SUCH AS ARGINASE, INDOLEAMINE 2,3-DIOXYGENASE (IDO) AND SUPPRESSIVE CYTOKINES AND THE EXPRESSION OF CO-INHIBITORY MOLECULES. A SERIES OF RECENT STUDIES WITH MOUSE MODELS OF HBV INFECTION SUGGEST THAT GENETIC AND EPIGENETIC CHANGES IN DYSFUNCTIONAL CD8+ T CELLS ARE THE MANIFESTATION OF PROLONGED ANTIGENIC STIMULATION, AS WELL AS THE ABSENCE OF CO-STIMULATORY OR CYTOKINE SIGNALING. THESE NEW FINDINGS MAY PROVIDE POTENTIAL NEW TARGETS FOR IMMUNOTHERAPY AIMING AT INVIGORATING HBV-SPECIFIC CD8+ T CELLS, WHICH HOPEFULLY CURES CHB. 2021 2 3515 37 IDO AND KYNURENINE METABOLITES IN PERIPHERAL AND CNS DISORDERS. THE IMPORTANCE OF THE KYNURENINE PATHWAY IN NORMAL IMMUNE SYSTEM FUNCTION HAS LED TO AN APPRECIATION OF ITS POSSIBLE CONTRIBUTION TO AUTOIMMUNE DISORDERS SUCH AS RHEUMATOID ARTHRITIS. INDOLEAMINE-2,3-DIOXYGENASE (IDO) ACTIVITY EXERTS A PROTECTIVE FUNCTION, LIMITING THE SEVERITY OF EXPERIMENTAL ARTHRITIS, WHEREAS DELETION OR INHIBITION EXACERBATES THE SYMPTOMS. OTHER CHRONIC DISORDER WITH AN INFLAMMATORY COMPONENT, SUCH AS ATHEROSCLEROSIS, ARE ALSO SUPPRESSED BY IDO ACTIVITY. IT IS SUGGESTED THAT THIS OVERALL ANTI-INFLAMMATORY ACTIVITY IS MEDIATED BY A CHANGE IN THE RELATIVE PRODUCTION OR ACTIVITY OF TH17 AND REGULATORY T CELL POPULATIONS. KYNURENINES MAY PLAY AN ANTI-INFLAMMATORY ROLE ALSO IN CNS DISORDERS SUCH AS HUNTINGTON'S DISEASE, ALZHEIMER'S DISEASE AND MULTIPLE SCLEROSIS, IN WHICH SIGNS OF INFLAMMATION AND NEURODEGENERATION ARE INVOLVED. THE POSSIBILITY IS DISCUSSED THAT IN HUNTINGTON'S DISEASE KYNURENINES INTERACT WITH OTHER ANTI-INFLAMMATORY MOLECULES SUCH AS HUMAN LYMPHOCYTE ANTIGEN-G WHICH MAY BE RELEVANT IN OTHER DISORDERS. KYNURENINE INVOLVEMENT MAY ACCOUNT FOR THE PROTECTION AFFORDED TO ANIMALS WITH CEREBRAL MALARIA AND TRYPANOSOMIASIS WHEN THEY ARE TREATED WITH AN INHIBITOR OF KYNURENINE-3-MONOXYGENASE (KMO). THERE IS SOME EVIDENCE THAT CHANGES IN IL-10 MAY CONTRIBUTE TO THIS PROTECTION AND THE RELATIONSHIP BETWEEN KYNURENINES AND IL-10 IN ARTHRITIS AND OTHER INFLAMMATORY CONDITIONS SHOULD BE EXPLORED. IN ADDITION, METABOLITES OF KYNURENINE DOWNSTREAM OF KMO, SUCH AS ANTHRANILIC ACID AND 3-HYDROXY-ANTHRANILIC ACID CAN INFLUENCE INFLAMMATION, AND THE RATIO OF THESE COMPOUNDS IS A VALUABLE BIOMARKER OF INFLAMMATORY STATUS ALTHOUGH THE UNDERLYING MOLECULAR MECHANISMS OF THE CHANGES REQUIRE CLARIFICATION. HENCE IT IS ESSENTIAL THAT MORE EFFORT BE EXPENDED TO IDENTIFY THEIR SITES OF ACTION AS POTENTIAL TARGETS FOR DRUG DEVELOPMENT. FINALLY, WE DISCUSS INCREASING AWARENESS OF THE EPIGENETIC REGULATION OF IDO, FOR EXAMPLE BY DNA METHYLATION, A PHENOMENON WHICH MAY EXPLAIN DIFFERENCES BETWEEN INDIVIDUALS IN THEIR SUSCEPTIBILITY TO ARTHRITIS AND OTHER INFLAMMATORY DISORDERS. 2020 3 4567 40 MYELOID-DERIVED SUPPRESSOR CELL FUNCTION AND EPIGENETIC EXPRESSION EVOLVES OVER TIME AFTER SURGICAL SEPSIS. BACKGROUND: SEPSIS IS AN INCREASINGLY SIGNIFICANT CHALLENGE THROUGHOUT THE WORLD AS ONE OF THE MAJOR CAUSES OF PATIENT MORBIDITY AND MORTALITY. CENTRAL TO THE HOST IMMUNOLOGIC RESPONSE TO SEPSIS IS THE INCREASE IN CIRCULATING MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS), WHICH HAVE BEEN DEMONSTRATED TO BE PRESENT AND INDEPENDENTLY ASSOCIATED WITH POOR LONG-TERM CLINICAL OUTCOMES. MDSCS ARE PLASTIC CELLS AND POTENTIALLY MODIFIABLE, PARTICULARLY THROUGH EPIGENETIC INTERVENTIONS. THE OBJECTIVE OF THIS STUDY WAS TO DETERMINE HOW THE SUPPRESSIVE PHENOTYPE OF MDSCS EVOLVES AFTER SEPSIS IN SURGICAL ICU PATIENTS, AS WELL AS TO IDENTIFY EPIGENETIC DIFFERENCES IN MDSCS THAT MAY EXPLAIN THESE CHANGES. METHODS: CIRCULATING MDSCS FROM 267 SURVIVORS OF SURGICAL SEPSIS WERE PHENOTYPED AT VARIOUS INTERVALS OVER 6 WEEKS, AND HIGHLY ENRICHED MDSCS FROM 23 OF THESE SAMPLES WERE CO-CULTURED WITH CD3/CD28-STIMULATED AUTOLOGOUS T CELLS. MICRORNA EXPRESSION FROM ENRICHED MDSCS WAS ALSO IDENTIFIED. RESULTS: WE OBSERVED THAT MDSC NUMBERS REMAIN SIGNIFICANTLY ELEVATED IN HOSPITALIZED SEPSIS SURVIVORS FOR AT LEAST 6 WEEKS AFTER THEIR INFECTION. HOWEVER, ONLY MDSCS OBTAINED AT AND BEYOND 14 DAYS POST-SEPSIS SIGNIFICANTLY SUPPRESSED T LYMPHOCYTE PROLIFERATION AND IL-2 PRODUCTION. THESE SAME MDSCS DISPLAYED UNIQUE EPIGENETIC (MIRNA) EXPRESSION PATTERNS COMPARED TO EARLIER TIME POINTS. CONCLUSIONS: WE CONCLUDE THAT IN SEPSIS SURVIVORS, IMMATURE MYELOID CELL NUMBERS ARE INCREASED BUT THE IMMUNE SUPPRESSIVE FUNCTION SPECIFIC TO MDSCS DEVELOPS OVER TIME, AND THIS IS ASSOCIATED WITH A SPECIFIC EPIGENOME. THESE FINDINGS MAY EXPLAIN THE CHRONIC AND PERSISTENT IMMUNE SUPPRESSION SEEN IN THESE SUBJECTS. 2019 4 2662 38 EPSTEIN-BARR VIRUS AND MULTIPLE SCLEROSIS: A CONVOLUTED INTERACTION AND THE OPPORTUNITY TO UNRAVEL PREDICTIVE BIOMARKERS. SINCE THE EARLY 1980S, EPSTEIN-BARR VIRUS (EBV) INFECTION HAS BEEN DESCRIBED AS ONE OF THE MAIN RISK FACTORS FOR DEVELOPING MULTIPLE SCLEROSIS (MS), AND RECENTLY, NEW EPIDEMIOLOGICAL EVIDENCE HAS REINFORCED THIS PREMISE. EBV SEROCONVERSION PRECEDES ALMOST 99% OF THE NEW CASES OF MS AND LIKELY PREDATES THE FIRST CLINICAL SYMPTOMS. THE MOLECULAR MECHANISMS OF THIS ASSOCIATION ARE COMPLEX AND MAY INVOLVE DIFFERENT IMMUNOLOGICAL ROUTES, PERHAPS ALL RUNNING IN PARALLEL (I.E., MOLECULAR MIMICRY, THE BYSTANDER DAMAGE THEORY, ABNORMAL CYTOKINE NETWORKS, AND COINFECTION OF EBV WITH RETROVIRUSES, AMONG OTHERS). HOWEVER, DESPITE THE LARGE AMOUNT OF EVIDENCE AVAILABLE ON THESE TOPICS, THE ULTIMATE ROLE OF EBV IN THE PATHOGENESIS OF MS IS NOT FULLY UNDERSTOOD. FOR INSTANCE, IT IS UNCLEAR WHY AFTER EBV INFECTION SOME INDIVIDUALS DEVELOP MS WHILE OTHERS EVOLVE TO LYMPHOPROLIFERATIVE DISORDERS OR SYSTEMIC AUTOIMMUNE DISEASES. IN THIS REGARD, RECENT STUDIES SUGGEST THAT THE VIRUS MAY EXERT EPIGENETIC CONTROL OVER MS SUSCEPTIBILITY GENES BY MEANS OF SPECIFIC VIRULENCE FACTORS. SUCH GENETIC MANIPULATION HAS BEEN DESCRIBED IN VIRALLY-INFECTED MEMORY B CELLS FROM PATIENTS WITH MS AND ARE THOUGHT TO BE THE MAIN SOURCE OF AUTOREACTIVE IMMUNE RESPONSES. YET, THE ROLE OF EBV INFECTION IN THE NATURAL HISTORY OF MS AND IN THE INITIATION OF NEURODEGENERATION IS EVEN LESS CLEAR. IN THIS NARRATIVE REVIEW, WE WILL DISCUSS THE AVAILABLE EVIDENCE ON THESE TOPICS AND THE POSSIBILITY OF HARNESSING SUCH IMMUNOLOGICAL ALTERATIONS TO UNCOVER PREDICTIVE BIOMARKERS FOR THE ONSET OF MS AND PERHAPS FACILITATE PROGNOSTICATION OF THE CLINICAL COURSE. 2023 5 4489 27 MONOCYTE AND MACROPHAGE IMMUNOMETABOLISM IN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS CHARACTERIZED BY CHRONIC LOW GRADE INFLAMMATION OF ARTERIES THAT RESULTS IN THE DEVELOPMENT OF LIPID DENSE PLAQUES. CHRONIC INFLAMMATION INDUCED BY WESTERN-TYPE DIET IS ASSOCIATED WITH THE RISK OF DEVELOPING ATHEROSCLEROSIS, AND NEW INSIGHTS SHED LIGHT ON THE IMPORTANCE OF METABOLIC AND FUNCTIONAL REPROGRAMMING IN MONOCYTES AND MACROPHAGES FOR PROGRESSION OF ATHEROSCLEROSIS. THIS REVIEW AIMS TO PROVIDE AN OVERVIEW OF OUR CURRENT UNDERSTANDING INTO HOW THE METABOLIC REPROGRAMMING OF GLUCOSE, CHOLESTEROL, FATTY ACID, AND AMINO ACID METABOLISM IN MACROPHAGES CONTRIBUTES TO INFLAMMATION DURING ATHEROSCLEROSIS. RECENT INSIGHTS SUGGEST THAT TRANSCRIPTIONAL AND EPIGENETIC ADAPTATION WITHIN INNATE IMMUNE CELLS (TERMED TRAINED IMMUNITY) PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF ATHEROSCLEROSIS. WE PROPOSE THAT METABOLIC CHANGES INDUCED BY PRO-ATHEROGENIC LIPOPROTEINS PARTLY MEDIATE THESE CHANGES IN TRAINED MACROPHAGES. FINALLY, WE DISCUSS THE POSSIBILITY OF MANIPULATING CELLULAR METABOLISM OF IMMUNE CELLS FOR TARGETED THERAPEUTIC INTERVENTION AGAINST ATHEROSCLEROSIS. 2018 6 6214 26 THE INTRACELLULAR SIGNALING PATHWAYS GOVERNING MACROPHAGE ACTIVATION AND FUNCTION IN HUMAN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY LIPID ACCUMULATION AND PLAQUE FORMATION IN ARTERIAL VESSEL WALLS. ATHEROSCLEROTIC PLAQUES NARROW THE ARTERIAL LUMEN TO INCREASE THE RISK OF HEART ATTACKS, ISCHEMIC STROKE AND PERIPHERAL VASCULAR DISEASE, WHICH ARE MAJOR AND WORLDWIDE HEALTH AND ECONOMIC BURDENS. MACROPHAGE ACCUMULATION WITHIN PLAQUES IS CHARACTERISTIC OF ALL STAGES OF ATHEROSCLEROSIS AND THEIR PRESENCE IS A POTENTIAL MARKER OF DISEASE ACTIVITY AND PLAQUE STABILITY. MACROPHAGES ENGULF LIPIDS AND MODIFIED LIPOPROTEINS TO FORM FOAM CELLS THAT EXPRESS PRO-INFLAMMATORY AND CHEMOTACTIC EFFECTOR MOLECULES, STRESS INDUCING FACTORS AND REACTIVE OXYGEN SPECIES. THEY CONTROL PLAQUE STABILITY AND RUPTURE THROUGH SECRETION OF METALLOPROTEINASES AND EXTRACELLULAR MATRIX DEGRADATION. ALTHOUGH MACROPHAGES CAN WORSEN DISEASE BY PROPAGATING INFLAMMATION, THEY CAN STABILIZE ATHEROSCLEROTIC PLAQUES THROUGH TISSUE REMODELING, PROMOTING THE FORMATION OF A FIBROUS CAP, CLEARING APOPTOTIC CELLS TO PREVENT NECROTIC CORE FORMATION AND THROUGH VASCULAR REPAIR. IN ATHEROSCLEROSIS, MACROPHAGES RESPOND TO DYSLIPIDAEMIA, CYTOKINES, DYING CELLS, METABOLIC FACTORS, LIPIDS, PHYSICAL STIMULI AND EPIGENETIC FACTORS AND EXHIBIT HETEROGENEITY IN THEIR ACTIVATION DEPENDING ON THE STIMULI THEY RECEIVE. UNDERSTANDING THESE SIGNALS AND THE PATHWAYS DRIVING MACROPHAGE FUNCTION WITHIN DEVELOPING AND ESTABLISHED PLAQUES AND HOW THEY CAN BE PHARMACOLOGICALLY MODULATED, REPRESENTS A STRATEGY FOR THE PREVENTION AND TREATMENT OF ATHEROSCLEROSIS. THIS REVIEW FOCUSSES ON THE CURRENT UNDERSTANDING OF FACTORS CONTROLLING MACROPHAGE HETEROGENEITY AND FUNCTION IN ATHEROSCLEROSIS. PARTICULAR ATTENTION IS GIVEN TO THE MACROPHAGE INTRACELLULAR SIGNALING PATHWAYS AND TRANSCRIPTION FACTORS ACTIVATED BY BIOCHEMICAL AND BIOPHYSICAL STIMULI WITHIN PLAQUES, AND HOW THEY ARE INTEGRATED TO REGULATE PLAQUE FORMATION AND STABILITY. 2022 7 6498 28 TRAINED IMMUNITY IN MONOCYTE/MACROPHAGE: NOVEL MECHANISM OF PHYTOCHEMICALS IN THE TREATMENT OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. ATHEROSCLEROSIS (AS) IS THE PATHOLOGY OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASES (ASCVD), CHARACTERIZED BY PERSISTENT CHRONIC INFLAMMATION IN THE VESSEL WALL, IN WHICH MONOCYTES/MACROPHAGES PLAY A KEY ROLE. IT HAS BEEN REPORTED THAT INNATE IMMUNE SYSTEM CELLS CAN ASSUME A PERSISTENT PROINFLAMMATORY STATE AFTER SHORT STIMULATION WITH ENDOGENOUS ATHEROGENIC STIMULI. THE PATHOGENESIS OF AS CAN BE INFLUENCED BY THIS PERSISTENT HYPERACTIVATION OF THE INNATE IMMUNE SYSTEM, WHICH IS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY HAS ALSO BEEN IMPLICATED AS A KEY PATHOLOGICAL MECHANISM, LEADING TO PERSISTENT CHRONIC INFLAMMATION IN AS. TRAINED IMMUNITY IS MEDIATED VIA EPIGENETIC AND METABOLIC REPROGRAMMING AND OCCURS IN MATURE INNATE IMMUNE CELLS AND THEIR BONE MARROW PROGENITORS. NATURAL PRODUCTS ARE PROMISING CANDIDATES FOR NOVEL PHARMACOLOGICAL AGENTS THAT CAN BE USED TO PREVENT OR TREAT CARDIOVASCULAR DISEASES (CVD). A VARIETY OF NATURAL PRODUCTS AND AGENTS EXHIBITING ANTIATHEROSCLEROTIC ABILITIES HAVE BEEN REPORTED TO POTENTIALLY INTERFERE WITH THE PHARMACOLOGICAL TARGETS OF TRAINED IMMUNITY. THIS REVIEW DESCRIBES IN AS MUCH DETAIL AS POSSIBLE THE MECHANISMS INVOLVED IN TRAINED IMMUNITY AND HOW PHYTOCHEMICALS OF THIS PROCESS INHIBIT AS BY AFFECTING TRAINED MONOCYTES/MACROPHAGES. 2023 8 4147 34 MECHANISMS UNDERLYING BIOLOGICAL EFFECTS OF CRUCIFEROUS GLUCOSINOLATE-DERIVED ISOTHIOCYANATES/INDOLES: A FOCUS ON METABOLIC SYNDROME. AN INVERSE CORRELATION BETWEEN VEGETABLE CONSUMPTION AND THE INCIDENCE OF CANCER HAS LONG BEEN DESCRIBED. THIS PROTECTIVE EFFECT IS STRONGER WHEN CRUCIFEROUS VEGETABLES ARE SPECIFICALLY CONSUMED. THE BENEFICIAL PROPERTIES OF VEGETABLES ARE ATTRIBUTED TO THEIR BIOACTIVE COMPONENTS LIKE FIBER, ANTIOXIDANTS VITAMINS, ANTIOXIDANTS, MINERALS, AND PHENOLIC COMPOUNDS. CRUCIFEROUS VEGETABLES CONTAIN ALL THESE MOLECULES; HOWEVER, WHAT MAKES THEM DIFFERENT ARE THEIR SULFUROUS COMPONENTS, CALLED GLUCOSINOLATES, RESPONSIBLE FOR THEIR SPECIAL SMELL AND TASTE. GLUCOSINOLATES ARE INACTIVE BIOLOGICALLY IN THE ORGANISM BUT ARE HYDROLYZED BY THE ENZYME MYROSINASE RELEASED AS A RESULT OF CHEWING, LEADING TO THE FORMATION OF ACTIVE DERIVATIVES SUCH AS ISOTHIOCYANATES AND INDOLES. A CONSIDERABLE NUMBER OF IN VITRO AND IN VIVO STUDIES HAVE REPORTED THAT ISOTHIOCYANATES AND INDOLES ELICIT CHEMOPREVENTIVE POTENCY THROUGH MULTIPLE MECHANISMS THAT INCLUDE MODULATION OF PHASES I AND II DETOXIFICATION PATHWAY ENZYMES, REGULATION OF CELL CYCLE ARREST, AND CONTROL OF CELL GROWTH, INDUCTION OF APOPTOSIS, ANTIOXIDANT ACTIVITY, ANTI-ANGIOGENIC EFFECTS, AND EPIGENETIC REGULATION. NUCLEAR ERYTHROID 2-RELATED FACTOR 2 (NRF2) AND NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) ARE KEY AND CENTRAL REGULATORS IN ALL THESE PROCESSES WITH A MAIN ROLE IN OXIDATIVE STRESS AND INFLAMMATION CONTROL. IT HAS BEEN DESCRIBED THAT ISOTHIOCYANATES AND INDOLES REGULATE THEIR ACTIVITY DIRECTLY AND INDIRECTLY. TODAY, THE METABOLIC SYNDROME (CENTRAL OBESITY, INSULIN RESISTANCE, HYPERLIPIDEMIA, AND HYPERTENSION) IS RESPONSIBLE FOR A MAJORITY OF DEATHS WORLDWIDE. ALL COMPONENTS OF METABOLIC SYNDROME ARE CHARACTERIZED BY CHRONIC INFLAMMATION WITH DEREGULATION OF THE PI3K/AKT/MTOR, MAPK/EKR/JNK, NRF2, AND NF-KAPPAB SIGNALING PATHWAYS. THE EFFECTS OF GLSS DERIVATIVES CONTROLLING THESE PATHWAYS HAVE BEEN WIDELY DESCRIBED IN RELATION TO CANCER. CHANGES IN FOOD CONSUMPTION PATTERNS OBSERVED IN THE LAST DECADES TO HIGHER CONSUMPTION OF ULTRA-PROCESSED FOODS, WITH ELEVATION IN SIMPLE SUGAR AND SATURATED FAT CONTENTS AND LOWER CONSUMPTION OF VEGETABLES AND FRUITS HAVE BEEN DIRECTLY CORRELATED WITH METABOLIC SYNDROME PREVALENCE. IN THIS REVIEW, IT IS SUMMARIZED THE KNOWLEDGE REGARDING THE MECHANISMS BY WHICH CRUCIFEROUS GLUCOSINOLATE DERIVATIVES (ISOTHIOCYANATES AND INDOLES) DIRECTLY AND INDIRECTLY REGULATE THESE PATHWAYS. HOWEVER, THE REVIEW PLACES A SPECIAL FOCUS ON THE KNOWLEDGE OF THE EFFECTS OF GLUCOSINOLATES DERIVATIVES IN METABOLIC SYNDROME, SINCE THIS HAS NOT BEEN REVIEWED BEFORE. 2020 9 5580 36 ROLE OF NEUROTOXICANTS IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE: A MECHANISTIC INSIGHT. ALZHEIMER'S DISEASE (AD) IS THE MOST CONSPICUOUS CHRONIC NEURODEGENERATIVE SYNDROME, WHICH HAS BECOME A SIGNIFICANT CHALLENGE FOR THE GLOBAL HEALTHCARE SYSTEM. MULTIPLE STUDIES HAVE CORROBORATED A CLEAR ASSOCIATION OF NEUROTOXICANTS WITH AD PATHOGENICITY, SUCH AS AMYLOID BETA (ABETA) PROTEINS AND NEUROFIBRILLARY TANGLES (NFTS), SIGNALLING PATHWAY MODIFICATIONS, CELLULAR STRESS, COGNITIVE DYSFUNCTIONS, NEURONAL APOPTOSIS, NEUROINFLAMMATION, EPIGENETIC MODIFICATION, AND SO ON. THIS REVIEW, THEREFORE, AIMED TO ADDRESS SEVERAL ESSENTIAL MECHANISMS AND SIGNALLING CASCADES, INCLUDING WNT (WINGLESS AND INT.) SIGNALLING PATHWAY, AUTOPHAGY, MAMMALIAN TARGET OF RAPAMYCIN (MTOR), PROTEIN KINASE C (PKC) SIGNALLING CASCADES, CELLULAR REDOX STATUS, ENERGY METABOLISM, GLUTAMATERGIC NEUROTRANSMISSIONS, IMMUNE CELL STIMULATIONS (E.G. MICROGLIA, ASTROCYTES) AS WELL AS AN AMYLOID PRECURSOR PROTEIN (APP), PRESENILIN-1 (PSEN1), PRESENILIN-2 (PSEN2) AND OTHER AD-RELATED GENE EXPRESSIONS THAT HAVE BEEN PRETENTIOUS AND MODULATED BY THE VARIOUS NEUROTOXICANTS. THIS REVIEW CONCLUDED THAT NEUROTOXICANTS PLAY A MOMENTOUS ROLE IN DEVELOPING AD THROUGH MODULATING VARIOUS SIGNALLING CASCADES. NEVERTHELESS, COMPREHENSION OF THIS RISK AGENT-INDUCED NEUROTOXICITY IS FAR TOO LITTLE. MORE IN-DEPTH EPIDEMIOLOGICAL AND SYSTEMATIC INVESTIGATIONS ARE NEEDED TO UNDERSTAND THE POTENTIAL MECHANISMS BETTER TO ADDRESS THESE NEUROTOXICANTS AND IMPROVE APPROACHES TO THEIR RISK EXPOSURE THAT AID IN AD PATHOGENESIS.KEY MESSAGESINEVITABLE CASCADE MECHANISMS OF HOW ALZHEIMER'S DISEASE-RELATED (AD-RELATED) GENE EXPRESSIONS ARE MODULATED BY NEUROTOXICANTS HAVE BEEN DISCUSSED.INVOLVEMENT OF THE NEUROTOXICANTS-INDUCED PATHWAYS CAUSED AN EXTENDED RISK OF AD IS EXPLICITED.INTEGRATION OF CELL CULTURE, ANIMALS AND POPULATION-BASED ANALYSIS ON THE CLINICAL SEVERITY OF AD IS ADDRESSED. 2021 10 3734 37 INNATE IMMUNE MEMORY IN MONOCYTES AND MACROPHAGES: THE POTENTIAL THERAPEUTIC STRATEGIES FOR ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A COMPLEX METABOLIC DISEASE CHARACTERIZED BY THE DYSFUNCTION OF LIPID METABOLISM AND CHRONIC INFLAMMATION IN THE INTIMAL SPACE OF THE VESSEL. AS THE MOST ABUNDANT INNATE IMMUNE CELLS, MONOCYTE-DERIVED MACROPHAGES PLAY A PIVOTAL ROLE IN THE INFLAMMATORY RESPONSE, CHOLESTEROL METABOLISM, AND FOAM CELL FORMATION. IN RECENT DECADES, IT HAS BEEN DEMONSTRATED THAT MONOCYTES AND MACROPHAGES CAN ESTABLISH INNATE IMMUNE MEMORY (ALSO TERMED TRAINED IMMUNITY) VIA ENDOGENOUS AND EXOGENOUS ATHEROGENIC STIMULI AND EXHIBIT A LONG-LASTING PROINFLAMMATORY PHENOTYPE. THE IMPORTANT CELLULAR METABOLISM PROCESSES, INCLUDING GLYCOLYSIS, OXIDATIVE PHOSPHORYLATION (OXPHOS), THE TRICARBOXYLIC ACID (TCA) CYCLE, FATTY ACID SYNTHESIS, AND CHOLESTEROL SYNTHESIS, ARE REPROGRAMMED. TRAINED MONOCYTES/MACROPHAGES WITH INNATE IMMUNE MEMORY CAN BE PERSISTENTLY HYPERACTIVATED AND CAN UNDERGO EXTENSIVE EPIGENETIC REWIRING, WHICH CONTRIBUTES TO THE PATHOPHYSIOLOGICAL DEVELOPMENT OF ATHEROSCLEROSIS VIA INCREASED PROINFLAMMATORY CYTOKINE PRODUCTION AND LIPID ACCUMULATION. HERE, WE PROVIDE AN OVERVIEW OF THE REGULATION OF CELLULAR METABOLIC PROCESSES AND EPIGENETIC MODIFICATIONS OF INNATE IMMUNE MEMORY IN MONOCYTES/MACROPHAGES AS WELL AS THE POTENTIAL ENDOGENOUS AND EXOGENOUS STIMULATIONS INVOLVED IN THE PROGRESSION OF ATHEROSCLEROSIS THAT HAVE BEEN REPORTED RECENTLY. THESE ELUCIDATIONS MIGHT BE BENEFICIAL FOR FURTHER UNDERSTANDING INNATE IMMUNE MEMORY AND THE DEVELOPMENT OF THERAPEUTIC STRATEGIES FOR INFLAMMATORY DISEASES AND ATHEROSCLEROSIS. 2022 11 5280 21 PROMOTING SYMPATHOVAGAL BALANCE IN MULTIPLE SCLEROSIS; PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES. ACCUMULATED EVIDENCE SUGGESTS THAT CARDIOVASCULAR AUTONOMIC NERVOUS SYSTEM (ANS) DYSFUNCTION MAY BE THE UNDERLYING CAUSE OF MANY MS CLINICAL PRESENTATIONS, INCLUDING NEURODEGENERATION AND REDUCED RESPONSE TO IMMUNOMODULATORY THERAPIES, DEPRESSION, FATIGUE AND SLEEP DISORDERS, MIGRAINE, OSTEOPOROSIS, AND CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY, THE NEWER MS VASCULAR ETIOLOGY. WE HAVE RECENTLY DESCRIBED THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS WITH THE POTENTIAL INFLUENCING ANS ACTIVITY, AND THE INTERACTIONS AMONG THESE FACTORS. THIS REVIEW EXPANDS UPON PREVIOUS ONES, DESCRIBING THE PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES THAT COULD BE ADOPTED TO PREVENT AND MINIMIZE THE DETERIORATION IN ANS FUNCTION, PROMOTING A STATE OF SYMPATHOVAGAL BALANCE. HOWEVER, THESE STRATEGIES SHOULD NOT BE APPLIED AS "ONE SIZE FITS ALL", BUT SHOULD TAKE INTO ACCOUNT THE NATURE AND THE DEGREE OF ANS DYSFUNCTION. THESE STRATEGIES WOULD BE EFFECTIVE IN IMPROVING ANS FUNCTION NOT ONLY IN MS, BUT ALSO IN OTHER AUTOIMMUNE AND NEURODEGENERATIVE DISEASES, WHERE THE DYSFUNCTION OF THIS SYSTEM PLAYS A ROLE. 2016 12 6502 28 TRAINED IMMUNITY: LONG-TERM ADAPTATION IN INNATE IMMUNE RESPONSES. ADAPTIVE IMMUNE RESPONSES ARE CHARACTERIZED BY ANTIGEN SPECIFICITY AND INDUCTION OF LIFELONG IMMUNOLOGIC MEMORY. RECENTLY, IT HAS BEEN REPORTED THAT INNATE IMMUNE CELLS CAN ALSO BUILD IMMUNE MEMORY CHARACTERISTICS-A PROCESS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY DESCRIBES THE PERSISTENT HYPERRESPONSIVE PHENOTYPE THAT INNATE IMMUNE CELLS CAN DEVELOP AFTER BRIEF STIMULATION. PATHOGENIC STIMULI SUCH AS MICROORGANISMS, AND ALSO ENDOGENOUS MOLECULES INCLUDING URIC ACID, OXIDIZED LDL (LOW-DENSITY LIPOPROTEIN), AND CATECHOLAMINES, ARE CAPABLE OF INDUCING MEMORY IN MONOCYTES AND MACROPHAGES. WHILE TRAINED IMMUNITY PROVIDES FAVORABLE CROSS-PROTECTION IN THE CONTEXT OF INFECTIOUS DISEASES, THE HEIGHTENED IMMUNE RESPONSE CAN BE MALADAPTIVE IN DISEASES DRIVEN BY CHRONIC SYSTEMIC INFLAMMATION, SUCH AS ATHEROSCLEROSIS. TRAINED IMMUNITY IS MAINTAINED BY DISTINCT EPIGENETIC AND METABOLIC MECHANISMS AND PERSISTS FOR AT LEAST SEVERAL MONTHS IN VIVO DUE TO REPROGRAMMING OF MYELOID PROGENITOR CELLS. ADDITIONALLY, CERTAIN NONIMMUNE CELLS ARE ALSO FOUND TO EXHIBIT TRAINED IMMUNITY CHARACTERISTICS. THUS, TRAINED IMMUNITY PRESENTS AN EXCITING FRAMEWORK TO DEVELOP NEW APPROACHES TO VACCINATION AND ALSO NOVEL PHARMACOLOGICAL TARGETS IN THE TREATMENT OF INFLAMMATORY DISEASES. 2021 13 6505 33 TRAINED INNATE IMMUNITY AS A NOVEL MECHANISM LINKING INFECTION AND THE DEVELOPMENT OF ATHEROSCLEROSIS. RATIONALE: THERE IS STRONG EPIDEMIOLOGICAL EVIDENCE FOR AN ASSOCIATION BETWEEN ACUTE AND CHRONIC INFECTIONS AND THE OCCURRENCE OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. THE UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS REMAIN UNCLEAR. MONOCYTE-DERIVED MACROPHAGES ARE THE MOST ABUNDANT IMMUNE CELLS IN ATHEROSCLEROTIC PLAQUES. IT HAS RECENTLY BEEN ESTABLISHED THAT MONOCYTES/MACROPHAGES CAN DEVELOP A LONG-LASTING PROINFLAMMATORY PHENOTYPE AFTER BRIEF STIMULATION WITH MICRO-ORGANISMS OR MICROBIAL PRODUCTS, WHICH HAS BEEN TERMED TRAINED IMMUNITY. OBJECTIVE: THE AIM OF THIS STUDY IS TO ASSESS WHETHER TRAINED IMMUNITY MEDIATES THE LINK BETWEEN INFECTIONS AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. METHODS AND RESULTS: BRIEF EXPOSURE OF MONOCYTES TO VARIOUS MICRO-ORGANISMS RESULTS IN THE DEVELOPMENT OF MACROPHAGES WITH A PERSISTENT PROINFLAMMATORY PHENOTYPE: THIS REPRESENTS A DE FACTO NONSPECIFIC INNATE IMMUNE MEMORY, WHICH HAS BEEN TERMED TRAINED IMMUNITY. THIS IS MEDIATED BY EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION AND A PROFOUND REWIRING OF INTRACELLULAR METABOLISM. ALTHOUGH THIS MECHANISM OFFERS POWERFUL PROTECTION AGAINST REINFECTION, TRAINED MACROPHAGES DISPLAY AN ATHEROGENIC PHENOTYPE IN TERMS OF CYTOKINE PRODUCTION AND FOAM CELL FORMATION. TRAINED MONOCYTES ARE PRESENT UP TO 3 MONTHS AFTER EXPERIMENTAL INFECTION IN HUMANS. MOREOVER, A TRAINED IMMUNITY PHENOTYPE IS PRESENT IN PATIENTS WITH ESTABLISHED ATHEROSCLEROSIS. CONCLUSIONS: WE PROPOSE THAT TRAINED IMMUNITY PROVIDES THE MISSING MECHANISTIC LINK THAT EXPLAINS THE ASSOCIATION BETWEEN INFECTIONS AND ATHEROSCLEROSIS. THEREFORE, PHARMACOLOGICAL MODULATION OF TRAINED IMMUNITY HAS THE POTENTIAL TO PREVENT INFECTION-RELATED ATHEROSCLEROTIC CARDIOVASCULAR DISEASE IN THE FUTURE. 2018 14 4332 32 MICRORNAS: IMPORTANT MODULATORS OF OXLDL-MEDIATED SIGNALING IN ATHEROSCLEROSIS. OXIDIZED LOW-DENSITY LIPOPROTEIN (OXLDL) IS KNOWN TO BE A MAJOR RISK FACTOR FOR THE INITIATION AND DEVELOPMENT OF ATHEROSCLEROSIS. IT CAN ELICIT AN ARRAY OF ATHEROGENIC RESPONSES IN MULTIPLE TYPES OF CELLS RESIDING IN THE ARTERIAL WALL, SUCH AS ENDOTHELIAL CELLS (ECS), MACROPHAGES, DENDRITIC CELLS (DCS), AND VASCULAR SMOOTH MUSCLE CELLS (VSMCS). ALTHOUGH THEY HAVE BEEN STUDIED FOR MANY YEARS, THE DETAILED MECHANISMS MODULATING OXLDL-INDUCED INFLAMMATION HAVE NOT BEEN FULLY ELUCIDATED. EPIGENETIC MECHANISMS CONSIST OF DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS), AND MICRORNA (MIRNA) ALTERATIONS. RECENTLY, EPIGENETIC FACTORS, ESPECIALLY MIRNAS, HAVE EMERGED AS NOVEL COMPONENTS OF THE GENE EXPRESSION REGULATING OXLDL-TRIGGERED SIGNAL TRANSDUCTION. IN ADDITION TO THEIR REGULATORY ROLES IN SIGNALING MOLECULES, INCREASING EVIDENCE SUGGESTS THAT THE DIFFERENT GENETIC STABILITY AND CROSS-TALK REGULATION AMONG THESE EPIGENETIC FACTORS MAY BE PARTICULARLY IMPORTANT TO THE SUSTAINED INFLAMMATION INITIATED BY TEMPORAL OXLDL STIMULATION. THEREFORE, IN THIS REVIEW, WE PRIMARILY FOCUSED ON THE FUNCTIONAL ROLE OF MIRNAS, AS WELL AS OTHER EPIGENETIC FACTORS, ON MODULATING OXLDL-INDUCED SIGNAL TRANSDUCTION IN DIFFERENT VASCULAR CELLS, WITH A SPECIAL EMPHASIS ON THE CROSSTALK INTERACTIONS BETWEEN MIRNAS AND OTHER EPIGENETIC PLAYERS THAT HELP TRANSLATE TRANSIENT ENVIRONMENT INSULTS INTO CHRONIC INFLAMMATION. MOREOVER, WE EXTENSIVELY DISCUSSED THE POTENTIAL APPLICABILITY OF MIRNAS AS DISEASE BIOMARKERS AND THERAPEUTIC TARGETS IN DIAGNOSING AND TREATING ATHEROSCLEROSIS. 2013 15 1712 40 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 16 3540 25 IMMUNE-DERIVED CYTOKINES IN THE NERVOUS SYSTEM: EPIGENETIC INSTRUCTIVE SIGNALS OR NEUROPATHOGENIC MEDIATORS? THE INVESTIGATION OF THE EFFECTS OF INFLAMMATORY CYTOKINES (IC) ON THE GROWTH AND DIFFERENTIATION OF NEURAL CELLS HAS PROVIDED NEW INSIGHTS ON THE ROLE OF SUCH SOLUBLE MEDIATORS IN NERVOUS SYSTEM DEVELOPMENT AND/OR PLASTIC REMODELING AS WELL AS IN THE PATHOGENESIS OF INFLAMMATORY NEURODEGENERATIVE DISORDERS, WHICH ARE CHARACTERIZED BY CHRONIC IC DYSREGULATION IN THE CENTRAL NERVOUS SYSTEM (CNS). THUS, THE STUDY OF THE INTERACTION BETWEEN CNS AND IMMUNE-DERIVED SOLUBLE SIGNALS IN PHYSIOLOGICAL OR PATHOLOGICAL CONDITIONS IS OF INCREASING INTEREST. THIS REVIEW FIRST DISCUSSES EXPERIMENTAL EVIDENCE SUPPORTING THE INSTRUCTIVE/PERMISSIVE ROLE OF IMMUNE-DERIVED CYTOKINES ON CNS DEVELOPMENT AND PLASTICITY. NEXT, WE FOCUS ON HUMAN NEUROLOGICAL DISEASE STATES SUCH AS MULTIPLE SCLEROSIS AND THE NEURODEGENERATION ASSOCIATED TO THE ACQUIRED IMMUNE DEFICIENCY SYNDROME IN WHICH DIFFERENT INFLAMMATORY CYTOKINES HAVE BEEN PROPOSED AS POTENTIAL NEUROPATHOGENIC MEDIATORS. 1999 17 5351 22 RATIONALE FOR DIETARY ANTIOXIDANT TREATMENT OF ADHD. INCREASING UNDERSTANDING ARISES REGARDING DISADVANTAGES OF STIMULANT MEDICATION IN CHILDREN WITH ADHD (ATTENTION-DEFICIT HYPERACTIVITY DISORDER). THIS REVIEW PRESENTS SCIENTIFIC FINDINGS SUPPORTING DIETARY ANTIOXIDANT TREATMENT OF ADHD AND DESCRIBES SUBSTANTIAL ALTERATIONS IN THE IMMUNE SYSTEM, EPIGENETIC REGULATION OF GENE EXPRESSION, AND OXIDATIVE STRESS REGULATION IN ADHD. AS A RESULT, CHRONIC INFLAMMATION AND OXIDATIVE STRESS COULD DEVELOP, WHICH CAN LEAD TO ADHD SYMPTOMS, FOR EXAMPLE BY CHRONIC T-CELL-MEDIATED NEUROINFLAMMATION, AS WELL AS BY NEURONAL OXIDATIVE DAMAGE AND LOSS OF NORMAL CEREBRAL FUNCTIONS. THEREFORE, MODULATION OF IMMUNE SYSTEM ACTIVITY AND OXIDANT-ANTIOXIDANT BALANCE USING NUTRITIONAL APPROACHES MIGHT HAVE POTENTIAL IN ADHD TREATMENT. THE USE OF NATURAL ANTIOXIDANTS AGAINST OXIDATIVE CONDITIONS IS AN EMERGING FIELD IN THE MANAGEMENT OF NEURODEGENERATIVE DISEASES. DIETARY POLYPHENOLS, FOR EXAMPLE, HAVE ANTIOXIDANT CAPACITIES AS WELL AS IMMUNOREGULATORY EFFECTS AND, THEREFORE, APPEAR APPROPRIATE IN ADHD THERAPY. THIS REVIEW CAN STIMULATE THE DEVELOPMENT AND INVESTIGATION OF DIETARY ANTIOXIDANT TREATMENT IN ADHD, WHICH IS HIGHLY DESIRED. 2018 18 4097 24 MATRIX STIFFNESS REGULATES MACROPHAGE POLARIZATION IN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE AND THE PATHOLOGICAL BASIS OF MANY FATAL CARDIOVASCULAR DISEASES. MACROPHAGES, THE MAIN INFLAMMATORY CELLS IN ATHEROSCLEROTIC PLAQUE, HAVE A PARADOX ROLE IN DISEASE PROGRESSION. IN RESPONSE TO DIFFERENT MICROENVIRONMENTS, MACROPHAGES MAINLY HAVE TWO POLARIZED DIRECTIONS: PRO-INFLAMMATORY MACROPHAGES AND ANTI-INFLAMMATORY MACROPHAGES. MORE AND MORE EVIDENCE SHOWS THAT MACROPHAGE IS MECHANOSENSITIVE AND MATRIX STIFFNESS REGULATE MACROPHAGE PHENOTYPES IN ATHEROSCLEROSIS. HOWEVER, THE MOLECULAR MECHANISM OF MATRIX STIFFNESS REGULATING MACROPHAGE POLARIZATION STILL LACKS IN-DEPTH RESEARCH, WHICH HINDERS THE DEVELOPMENT OF NEW ANTI-ATHEROSCLEROTIC THERAPIES. IN THIS REVIEW, WE DISCUSS THE IMPORTANT ROLE OF MATRIX STIFFNESS IN REGULATING MACROPHAGE POLARIZATION THROUGH MECHANICAL SIGNAL TRANSDUCTION (HIPPO, PIEZO, CYTOSKELETON, AND INTEGRIN) AND EPIGENETIC MECHANISMS (MIRNA, DNA METHYLATION, AND HISTONE). WE HOPE TO PROVIDE A NEW PERSPECTIVE FOR ATHEROSCLEROSIS THERAPY BY TARGETING MATRIX STIFFNESS AND MACROPHAGE POLARIZATION. 2022 19 5409 33 REGULATION OF ACETYLATION STATES BY NUTRIENTS IN THE INHIBITION OF VASCULAR INFLAMMATION AND ATHEROSCLEROSIS. ATHEROSCLEROSIS (AS) IS A CHRONIC METABOLIC DISORDER AND PRIMARY CAUSE OF CARDIOVASCULAR DISEASES, RESULTING IN SUBSTANTIAL MORBIDITY AND MORTALITY WORLDWIDE. INITIATED BY ENDOTHELIAL CELL STIMULATION, AS IS CHARACTERIZED BY ARTERIAL INFLAMMATION, LIPID DEPOSITION, FOAM CELL FORMATION, AND PLAQUE DEVELOPMENT. NUTRIENTS SUCH AS CAROTENOIDS, POLYPHENOLS, AND VITAMINS CAN PREVENT THE ATHEROSCLEROTIC PROCESS BY MODULATING INFLAMMATION AND METABOLIC DISORDERS THROUGH THE REGULATION OF GENE ACETYLATION STATES MEDIATED WITH HISTONE DEACETYLASES (HDACS). NUTRIENTS CAN REGULATE AS-RELATED EPIGENETIC STATES VIA SIRTUINS (SIRTS) ACTIVATION, SPECIFICALLY SIRT1 AND SIRT3. NUTRIENT-DRIVEN ALTERATIONS IN THE REDOX STATE AND GENE MODULATION IN AS PROGRESSION ARE LINKED TO THEIR PROTEIN DEACETYLATING, ANTI-INFLAMMATORY, AND ANTIOXIDANT PROPERTIES. NUTRIENTS CAN ALSO INHIBIT ADVANCED OXIDATION PROTEIN PRODUCT FORMATION, REDUCING ARTERIAL INTIMA-MEDIA THICKNESS EPIGENETICALLY. NONETHELESS, KNOWLEDGE GAPS REMAIN WHEN IT COMES TO UNDERSTANDING EFFECTIVE AS PREVENTION THROUGH EPIGENETIC REGULATION BY NUTRIENTS. THIS WORK REVIEWS AND CONFIRMS THE UNDERLYING MECHANISMS BY WHICH NUTRIENTS PREVENT ARTERIAL INFLAMMATION AND AS, FOCUSING ON THE EPIGENETIC PATHWAYS THAT MODIFY HISTONES AND NON-HISTONE PROTEINS BY REGULATING REDOX AND ACETYLATION STATES THROUGH HDACS SUCH AS SIRTS. THESE FINDINGS MAY SERVE AS A FOUNDATION FOR DEVELOPING POTENTIAL THERAPEUTIC AGENTS TO PREVENT AS AND CARDIOVASCULAR DISEASES BY EMPLOYING NUTRIENTS BASED ON EPIGENETIC REGULATION. 2023 20 3701 30 INFLAMMATORY RESPONSE TO REGULATED CELL DEATH IN GOUT AND ITS FUNCTIONAL IMPLICATIONS. GOUT, A CHRONIC INFLAMMATORY ARTHRITIS DISEASE, IS CHARACTERIZED BY HYPERURICEMIA AND CAUSED BY INTERACTIONS BETWEEN GENETIC, EPIGENETIC, AND METABOLIC FACTORS. ACUTE GOUT SYMPTOMS ARE TRIGGERED BY THE INFLAMMATORY RESPONSE TO MONOSODIUM URATE CRYSTALS, WHICH IS MEDIATED BY THE INNATE IMMUNE SYSTEM AND IMMUNE CELLS (E.G., MACROPHAGES AND NEUTROPHILS), THE NACHT, LRR, AND PYD DOMAINS-CONTAINING PROTEIN 3 (NLRP3) INFLAMMASOME ACTIVATION, AND PRO-INFLAMMATORY CYTOKINE (E.G., IL-1BETA) RELEASE. RECENT STUDIES HAVE INDICATED THAT THE MULTIPLE PROGRAMMED CELL DEATH PATHWAYS INVOLVED IN THE INFLAMMATORY RESPONSE INCLUDE PYROPTOSIS, NETOSIS, NECROPTOSIS, AND APOPTOSIS, WHICH INITIATE INFLAMMATORY REACTIONS. IN THIS REVIEW, WE EXPLORE THE CORRELATION AND INTERACTIONS AMONG THESE FACTORS AND THEIR ROLES IN THE PATHOGENESIS OF GOUT TO PROVIDE FUTURE RESEARCH DIRECTIONS AND POSSIBILITIES FOR IDENTIFYING POTENTIAL NOVEL THERAPEUTIC TARGETS AND ENHANCING OUR UNDERSTANDING OF GOUT PATHOGENESIS. 2022