1 4646 99 NEUROPATHOLOGICAL MECHANISMS ASSOCIATED WITH PESTICIDES IN ALZHEIMER'S DISEASE. ENVIRONMENTAL TOXICANTS HAVE BEEN IMPLICATED IN NEURODEGENERATIVE DISEASES, AND PESTICIDE EXPOSURE IS A SUSPECTED ENVIRONMENTAL RISK FACTOR FOR ALZHEIMER'S DISEASE (AD). SEVERAL EPIDEMIOLOGICAL ANALYSES HAVE AFFIRMED A LINK BETWEEN PESTICIDES AND INCIDENCE OF SPORADIC AD. MEANWHILE, IN VITRO AND ANIMAL MODELS OF AD HAVE SHED LIGHT ON POTENTIAL NEUROPATHOLOGICAL MECHANISMS. IN THIS PAPER, A PERSPECTIVE ON NEUROPATHOLOGICAL MECHANISMS UNDERLYING PESTICIDES' INDUCTION OF AD IS PROVIDED. PROPOSED MECHANISMS RANGE FROM GENERIC OXIDATIVE STRESS INDUCTION IN NEURONS TO MORE AD-SPECIFIC PROCESSES INVOLVING AMYLOID-BETA (ABETA) AND HYPERPHOSPHORYLATED TAU (P-TAU). MECHANISMS THAT ARE MORE SPECULATIVE OR INDIRECT IN NATURE, INCLUDING SOMATIC MUTATION, EPIGENETIC MODULATION, IMPAIRMENT OF ADULT NEUROGENESIS, AND MICROBIOTA DYSBIOSIS, ARE ALSO DISCUSSED. CHRONIC TOXICITY MECHANISMS OF ENVIRONMENTAL PESTICIDE EXPOSURE CROSSTALKS IN COMPLEX WAYS AND COULD POTENTIALLY BE MUTUALLY ENHANCING, THUS MAKING THE DECIPHERING OF SIMPLISTIC CAUSAL RELATIONSHIPS DIFFICULT. 2020 2 2227 25 EPIGENETIC MODIFICATIONS OF CHRONIC HYPOXIA-MEDIATED NEURODEGENERATION IN ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS THE MOST COMMON NEURODEGENERATIVE DISORDER AFFECTING THE ELDERLY PEOPLE. AD IS CHARACTERIZED BY PROGRESSIVE AND GRADUAL DECLINE IN COGNITIVE FUNCTION AND MEMORY LOSS. WHILE FAMILIAL EARLY-ONSET AD IS USUALLY ASSOCIATED WITH GENE MUTATIONS, THE ETIOLOGY OF SPORADIC LATE-ONSET FORM OF AD IS LARGELY UNKNOWN. IT HAS BEEN REPORTED THAT ENVIRONMENTAL FACTORS AND EPIGENETIC ALTERATIONS SIGNIFICANTLY CONTRIBUTE TO THE PROCESS OF AD. OUR PREVIOUS STUDIES HAVE DOCUMENTED THAT CHRONIC HYPOXIA IS ONE OF THE ENVIRONMENTAL FACTORS THAT MAY TRIGGER THE AD DEVELOPMENT AND AGGRAVATE THE DISEASE PROGRESSION. IN THIS REVIEW, WE WILL SUMMARIZE THE PATHOLOGICAL EFFECTS OF CHRONIC HYPOXIA ON THE ONSET AND DEVELOPMENT OF AD AND PUT FORWARD THE POSSIBLE MOLECULE MECHANISMS UNDERLYING THE CHRONIC HYPOXIA MEDIATED AD PATHOGENESIS. FINALLY, WE PROPOSE THAT EPIGENETIC REGULATIONS MAY REPRESENT NEW OPPORTUNITY FOR THE THERAPEUTIC INTERVENTION OF THIS DISEASE. 2014 3 1199 25 CORTICOTROPIN RELEASING FACTOR-BINDING PROTEIN (CRF-BP) AS A POTENTIAL NEW THERAPEUTIC TARGET IN ALZHEIMER'S DISEASE AND STRESS DISORDERS. ALZHEIMER'S DISEASE IS THE MOST COMMON CAUSE OF DEMENTIA AND ONE OF THE MOST COMPLEX HUMAN NEURODEGENERATIVE DISEASES. NUMEROUS STUDIES HAVE DEMONSTRATED A CRITICAL ROLE OF THE ENVIRONMENT IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF THE DISEASE, WHERE DAILY LIFE STRESS PLAYS AN IMPORTANT ROLE. A LOT OF EPIGENETIC STUDIES HAVE LED TO THE CONCLUSION THAT CHRONIC STRESS AND STRESS-RELATED DISORDERS PLAY AN IMPORTANT PART IN THE ONSET OF NEURODEGENERATIVE DISORDERS, AND AN ENORMOUS AMOUNT OF RESEARCH YIELDED VALUABLE DISCOVERIES BUT HAS SO FAR NOT LED TO THE DEVELOPMENT OF EFFECTIVE TREATMENT STRATEGIES FOR ALZHEIMER'S DISEASE. CORTICOTROPIN-RELEASING FACTOR (CRF) IS ONE OF THE MAJOR HORMONES AND AT THE SAME TIME A NEUROPEPTIDE ACTING IN STRESS RESPONSE. DEREGULATION OF PROTEIN LEVELS OF CRF IS INVOLVED IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE, BUT LITTLE IS KNOWN ABOUT THE PRECISE ROLES OF CRF AND ITS BINDING PROTEIN, CRF-BP, IN NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE SUMMARIZE THE KEY EVIDENCE FOR AND AGAINST THE INVOLVEMENT OF STRESS-ASSOCIATED MODULATION OF THE CRF SYSTEM IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE AND DISCUSS HOW RECENT FINDINGS COULD LEAD TO NEW POTENTIAL TREATMENT POSSIBILITIES IN ALZHEIMER'S DISEASE BY USING CRF-BP AS A THERAPEUTIC TARGET. 2019 4 2010 33 EPIGENETIC BASIS OF LEAD-INDUCED NEUROLOGICAL DISORDERS. ENVIRONMENTAL LEAD (PB) EXPOSURE IS CLOSELY ASSOCIATED WITH PATHOGENESIS OF A RANGE OF NEUROLOGICAL DISORDERS, INCLUDING ALZHEIMER'S DISEASE (AD), PARKINSON'S DISEASE (PD), AMYOTROPHIC LATERAL SCLEROSIS (ALS), ATTENTION DEFICIT/HYPERACTIVITY DISORDER (ADHD), ETC. EPIGENETIC MACHINERY MODULATES NEURAL DEVELOPMENT AND ACTIVITIES, WHILE FAULTY EPIGENETIC REGULATION CONTRIBUTES TO THE DIVERSE FORMS OF CNS (CENTRAL NERVOUS SYSTEM) ABNORMALITIES AND DISEASES. AS A POTENT EPIGENETIC MODIFIER, LEAD IS THOUGHT TO CAUSE NEUROLOGICAL DISORDERS THROUGH MODULATING EPIGENETIC MECHANISMS. SPECIFICALLY, INCREASING EVIDENCE LINKED ABERRANT DNA METHYLATIONS, HISTONE MODIFICATIONS AS WELL AS NCRNAS (NON-CODING RNAS) WITH AD CASES, AMONG WHICH CIRCRNA (CIRCULAR RNA) STANDS OUT AS A NEW AND PROMISING FIELD FOR ASSOCIATION STUDIES. IN 23-YEAR-OLD PRIMATES WITH DEVELOPMENTAL LEAD TREATMENT, ZAWIA GROUP DISCOVERED A VARIETY OF EPIGENETIC CHANGES RELATING TO AD PATHOGENESIS. THIS IS A DIRECT EVIDENCE IMPLICATING EPIGENETIC BASIS IN LEAD-INDUCED AD ANIMALS WITH AN ENTIRE LIFESPAN. ADDITIONALLY, SOME EPIGENETIC MOLECULES ASSOCIATED WITH AD ETIOLOGY WERE ALSO KNOWN TO RESPOND TO CHRONIC LEAD EXPOSURE IN COMPARABLE DISEASE MODELS, INDICATING POTENTIALLY INTERLACED MECHANISMS WITH RESPECT TO THE STUDIED NEUROTOXIC AND PATHOLOGICAL EVENTS. OF NOTE, EPIGENETIC MOLECULES ACTED VIA GLOBALLY OR SELECTIVELY INFLUENCING THE EXPRESSION OF DISEASE-RELATED GENES. COMPARED TO AD, THE ASSOCIATION OF LEAD EXPOSURE WITH OTHER NEUROLOGICAL DISORDERS WERE PRIMARILY SUPPORTED BY EPIDEMIOLOGICAL SURVEY, WITH FEWER REPORTS CONNECTING EPIGENETIC REGULATORS WITH LEAD-INDUCED PATHOGENESIS. SOME PHARMACEUTICALS, SUCH AS HDAC (HISTONE DEACETYLASE) INHIBITORS AND DNA METHYLATION INHIBITORS, WERE DEVELOPED TO DEAL WITH CNS DISEASE BY TARGETING EPIGENETIC COMPONENTS. STILL, UNDERSTANDINGS ARE INSUFFICIENT REGARDING THE CAUSE-CONSEQUENCE RELATIONS OF EPIGENETIC FACTORS AND NEUROLOGICAL ILLNESS. THEREFORE, CLEAR EVIDENCE SHOULD BE PROVIDED IN FUTURE INVESTIGATIONS TO ADDRESS DETAILED ROLES OF NOVEL EPIGENETIC FACTORS IN LEAD-INDUCED NEUROLOGICAL DISORDERS, AND EFFORTS OF DEVELOPING SPECIFIC EPIGENETIC THERAPEUTICS SHOULD BE APPRAISED. 2020 5 2447 30 EPIGENETIC STUDIES IN ALZHEIMER'S DISEASE: CURRENT FINDINGS, CAVEATS, AND CONSIDERATIONS FOR FUTURE STUDIES. ALZHEIMER'S DISEASE (AD) IS A SPORADIC, CHRONIC NEURODEGENERATIVE DISEASE, USUALLY OCCURRING LATE IN LIFE. THE LAST DECADE HAS WITNESSED TREMENDOUS ADVANCES IN OUR UNDERSTANDING ABOUT THE GENETIC BASIS OF AD, BUT A LARGE AMOUNT OF THE VARIANCE IN DISEASE RISK REMAINS TO BE EXPLAINED. EPIGENETIC MECHANISMS, WHICH DEVELOPMENTALLY REGULATE GENE EXPRESSION VIA MODIFICATIONS TO DNA, HISTONE PROTEINS, AND CHROMATIN, HAVE BEEN HYPOTHESIZED TO PLAY A ROLE IN OTHER COMPLEX NEUROBIOLOGICAL DISEASES, AND STUDIES TO IDENTIFY GENOME-WIDE EPIGENETIC CHANGES IN AD ARE CURRENTLY UNDER WAY. HOWEVER, THE SIMPLE BRUTE-FORCE APPROACH THAT HAS BEEN SUCCESSFULLY EMPLOYED IN GENOME-WIDE ASSOCIATION STUDIES IS UNLIKELY TO BE SUCCESSFUL IN EPIGENOME-WIDE ASSOCIATION STUDIES OF NEURODEGENERATION. A MORE ACADEMIC APPROACH TO UNDERSTANDING THE ROLE OF EPIGENETIC VARIATION IN AD IS REQUIRED, WITH CAREFUL CONSIDERATION OF STUDY DESIGN, METHODOLOGICAL APPROACHES, TISSUE-SPECIFICITY, AND CAUSAL INFERENCE. IN THIS ARTICLE, WE REVIEW THE EMPIRICAL LITERATURE SUPPORTING A ROLE FOR EPIGENETIC PROCESSES IN AD, AND DISCUSS IMPORTANT CONSIDERATIONS AND FUTURE DIRECTIONS FOR THIS NEW AND EMERGING FIELD OF RESEARCH. 2013 6 4635 36 NEUROINFLAMMATORY MECHANISMS IN PARKINSON'S DISEASE: POTENTIAL ENVIRONMENTAL TRIGGERS, PATHWAYS, AND TARGETS FOR EARLY THERAPEUTIC INTERVENTION. MOST ACUTE AND CHRONIC NEURODEGENERATIVE CONDITIONS ARE ACCOMPANIED BY NEUROINFLAMMATION; YET THE EXACT NATURE OF THE INFLAMMATORY PROCESSES AND WHETHER THEY MODIFY DISEASE PROGRESSION IS NOT WELL UNDERSTOOD. IN THIS REVIEW, WE DISCUSS THE KEY EPIDEMIOLOGICAL, CLINICAL, AND EXPERIMENTAL EVIDENCE IMPLICATING INFLAMMATORY PROCESSES IN THE PROGRESSIVE DEGENERATION OF THE DOPAMINERGIC (DA) NIGROSTRIATAL PATHWAY AND THEIR POTENTIAL CONTRIBUTION TO THE PATHOPHYSIOLOGY OF PARKINSON'S DISEASE (PD). GIVEN THAT INTERPLAY BETWEEN GENETICS AND ENVIRONMENT ARE LIKELY TO CONTRIBUTE TO RISK FOR DEVELOPMENT OF IDIOPATHIC PD, RECENT DATA SHOWING INTERACTIONS BETWEEN PRODUCTS OF GENES LINKED TO HERITABLE PD THAT FUNCTION TO PROTECT DA NEURONS AGAINST OXIDATIVE OR PROTEOLYTIC STRESS AND INFLAMMATION PATHWAYS WILL BE DISCUSSED. CELLULAR MECHANISMS ACTIVATED OR ENHANCED BY INFLAMMATORY PROCESSES THAT MAY CONTRIBUTE TO MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, OR APOPTOSIS OF DOPAMINERGIC (DA) NEURONS WILL BE REVIEWED, WITH SPECIAL EMPHASIS ON TUMOR NECROSIS FACTOR (TNF) AND INTERLEUKIN-1-BETA (IL-1BETA) SIGNALING PATHWAYS. EPIGENETIC FACTORS WHICH HAVE THE POTENTIAL TO TRIGGER NEUROINFLAMMATION, INCLUDING ENVIRONMENTAL EXPOSURES AND AGE-ASSOCIATED CHRONIC INFLAMMATORY CONDITIONS, WILL BE DISCUSSED AS POSSIBLE 'SECOND-HIT' TRIGGERS THAT MAY AFFECT DISEASE ONSET OR PROGRESSION OF IDIOPATHIC PD. IF INFLAMMATORY PROCESSES HAVE AN ACTIVE ROLE IN NIGROSTRIATAL PATHWAY DEGENERATION, THEN EVIDENCE SHOULD EXIST TO INDICATE THAT SUCH PROCESSES BEGIN IN THE EARLY STAGES OF DISEASE AND THAT THEY CONTRIBUTE TO NEURONAL DYSFUNCTION AND/OR HASTEN NEURODEGENERATION OF THE NIGROSTRIATAL PATHWAY. THERAPEUTICALLY, IF ANTI-INFLAMMATORY INTERVENTIONS CAN BE SHOWN TO RESCUE NIGRAL DA NEURONS FROM DEGENERATION AND LOWER PD RISK, THEN TIMELY USE OF ANTI-INFLAMMATORY THERAPIES SHOULD BE INVESTIGATED FURTHER IN WELL-DESIGNED CLINICAL TRIALS FOR THEIR ABILITY TO PREVENT OR DELAY THE PROGRESSIVE LOSS OF NIGRAL DA NEURONS IN GENETICALLY SUSCEPTIBLE POPULATIONS. 2007 7 1459 40 DISORDERED APP METABOLISM AND NEUROVASCULATURE IN TRAUMA AND AGING: COMBINED RISKS FOR CHRONIC NEURODEGENERATIVE DISORDERS. TRAUMATIC BRAIN INJURY (TBI), ADVANCED AGE, AND CEREBRAL VASCULAR DISEASE ARE FACTORS CONFERRING INCREASED RISK FOR LATE ONSET ALZHEIMER'S DISEASE (AD). THESE CONDITIONS ARE ALSO RELATED PATHOLOGICALLY THROUGH MULTIPLE INTERACTING MECHANISMS. THE HALLMARK PATHOLOGY OF AD CONSISTS OF PATHOLOGICAL AGGREGATES OF AMYLOID-BETA (ABETA) PEPTIDES AND TAU PROTEINS. THESE MOLECULES ARE ALSO INVOLVED IN NEUROPATHOLOGY OF SEVERAL OTHER CHRONIC NEURODEGENERATIVE DISEASES, AND ARE UNDER INTENSE INVESTIGATION IN THE AFTERMATH OF TBI AS POTENTIAL CONTRIBUTORS TO THE RISK FOR DEVELOPING AD AND CHRONIC TRAUMATIC ENCEPHALOPATHY (CTE). THE PATHOLOGY OF TBI IS COMPLEX AND DEPENDENT ON INJURY SEVERITY, AGE-AT-INJURY, AND LENGTH OF TIME BETWEEN INJURY AND NEUROPATHOLOGICAL EVALUATION. IN ADDITION, THE MECHANISMS INFLUENCING PATHOLOGY AND RECOVERY AFTER TBI LIKELY INVOLVE GENETIC/EPIGENETIC FACTORS AS WELL AS ADDITIONAL DISORDERS OR COMORBID STATES RELATED TO AGE AND CENTRAL AND PERIPHERAL VASCULAR HEALTH. IN THIS REGARD, DYSFUNCTION OF THE AGING NEUROVASCULAR SYSTEM COULD BE AN IMPORTANT LINK BETWEEN TBI AND CHRONIC NEURODEGENERATIVE DISEASES, EITHER AS A PRECIPITATING EVENT OR RELATED TO ACCUMULATION OF AD-LIKE PATHOLOGY WHICH IS AMPLIFIED IN THE CONTEXT OF AGING. THUS WITH ADVANCED AGE AND VASCULAR DYSFUNCTION, TBI CAN TRIGGER SELF-PROPAGATING CYCLES OF NEURONAL INJURY, PATHOLOGICAL PROTEIN AGGREGATION, AND SYNAPTIC LOSS RESULTING IN CHRONIC NEURODEGENERATIVE DISEASE. IN THIS REVIEW WE DISCUSS EVIDENCE SUPPORTING TBI AND AGING AS DUAL, INTERACTING RISK FACTORS FOR AD, AND THE ROLE OF ABETA AND CEREBRAL VASCULAR DYSFUNCTION IN THIS RELATIONSHIP. EVIDENCE IS DISCUSSED THAT ABETA IS INVOLVED IN CYTO- AND SYNAPTO-TOXICITY AFTER SEVERE TBI, AND THAT ITS CHRONIC EFFECTS ARE POTENTIATED BY AGING AND IMPAIRED CEREBRAL VASCULAR FUNCTION. FROM A THERAPEUTIC PERSPECTIVE, WE EMPHASIZE THAT IN THE FIELDS OF TBI- AND AGING-RELATED NEURODEGENERATION PROTECTIVE STRATEGIES SHOULD INCLUDE PRESERVATION OF NEUROVASCULAR FUNCTION. 2017 8 4682 27 NEW PATHWAYS IDENTIFY NOVEL DRUG TARGETS FOR THE PREVENTION AND TREATMENT OF ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS AN INCURABLE, PROGRESSIVE NEURODEGENERATIVE DISORDER. AD IS A COMPLEX AND MULTIFACTORIAL DISEASE THAT IS RESPONSIBLE FOR 60-80% OF DEMENTIA CASES. AGING, GENETIC FACTORS, AND EPIGENETIC CHANGES ARE THE MAIN RISK FACTORS FOR AD. TWO AGGREGATION-PRONE PROTEINS PLAY A DECISIVE ROLE IN AD PATHOGENESIS: BETA-AMYLOID (ABETA) AND HYPERPHOSPHORYLATED TAU (PTAU). BOTH OF THEM FORM DEPOSITS AND DIFFUSIBLE TOXIC AGGREGATES IN THE BRAIN. THESE PROTEINS ARE THE BIOMARKERS OF AD. DIFFERENT HYPOTHESES HAVE TRIED TO EXPLAIN AD PATHOGENESIS AND SERVED AS PLATFORMS FOR AD DRUG RESEARCH. EXPERIMENTS DEMONSTRATED THAT BOTH ABETA AND PTAU MIGHT START NEURODEGENERATIVE PROCESSES AND ARE NECESSARY FOR COGNITIVE DECLINE. THE TWO PATHOLOGIES ACT IN SYNERGY. INHIBITION OF THE FORMATION OF TOXIC ABETA AND PTAU AGGREGATES HAS BEEN AN OLD DRUG TARGET. RECENTLY, SUCCESSFUL ABETA CLEARANCE BY MONOCLONAL ANTIBODIES HAS RAISED NEW HOPES FOR AD TREATMENTS IF THE DISEASE IS DETECTED AT EARLY STAGES. MORE RECENTLY, NOVEL TARGETS, E.G., IMPROVEMENTS IN AMYLOID CLEARANCE FROM THE BRAIN, APPLICATION OF SMALL HEAT SHOCK PROTEINS (HSPS), MODULATION OF CHRONIC NEUROINFLAMMATION BY DIFFERENT RECEPTOR LIGANDS, MODULATION OF MICROGLIAL PHAGOCYTOSIS, AND INCREASE IN MYELINATION HAVE BEEN REVEALED IN AD RESEARCH. 2023 9 5766 29 SPECIAL ISSUE: ALZHEIMER'S DISEASE. MORE THAN 45 MILLION PEOPLE WORLDWIDE HAVE ALZHEIMER'S DISEASE (AD), A DETERIORATION OF MEMORY AND OTHER COGNITIVE DOMAINS THAT LEADS TO DEATH WITHIN 3 TO 9 YEARS AFTER DIAGNOSIS. THE PRINCIPAL RISK FACTOR FOR AD IS AGE. AS THE AGING POPULATION INCREASES, THE PREVALENCE WILL APPROACH 131 MILLION CASES WORLDWIDE IN 2050. AD IS THEREFORE A GLOBAL PROBLEM CREATING A RAPIDLY GROWING EPIDEMIC AND BECOMING A MAJOR THREAT TO HEALTHCARE IN OUR SOCIETIES. IT HAS BEEN MORE THAN 20 YEARS SINCE IT WAS FIRST PROPOSED THAT THE NEURODEGENERATION IN AD MAY BE CAUSED BY DEPOSITION OF AMYLOID-BETA (ABETA) PEPTIDES IN PLAQUES IN BRAIN TISSUE. ACCORDING TO THE AMYLOID HYPOTHESIS, ACCUMULATION OF ABETA PEPTIDES, RESULTING FROM A CHRONIC IMBALANCE BETWEEN ABETA PRODUCTION AND ABETA CLEARANCE IN THE BRAIN, IS THE PRIMARY INFLUENCE DRIVING AD PATHOGENESIS. CURRENT AVAILABLE MEDICATIONS APPEAR TO BE ABLE TO PRODUCE MODERATE SYMPTOMATIC BENEFITS BUT NOT TO STOP DISEASE PROGRESSION. THE SEARCH FOR BIOMARKERS AS WELL AS NOVEL THERAPEUTIC APPROACHES FOR AD HAS BEEN A MAJOR FOCUS OF RESEARCH. RECENT FINDINGS, HOWEVER, SHOW THAT NEURONAL-INJURY BIOMARKERS ARE INDEPENDENT OF ABETA SUGGESTING EPIGENETIC MODIFICATIONS, GENE-GENE AND/OR GENE-ENVIRONMENT INTERACTIONS IN THE DISEASE ETIOLOGY, AND CALLING FOR RECONSIDERATION OF THE PATHOLOGICAL CASCADE AND ASSESSMENT OF ALTERNATIVE THERAPEUTIC STRATEGIES. IN ADDITION, RECENT RESEARCH RESULTS REGARDING THE EXPRESSION OF THE BETA-AMYLOID PRECURSOR PROTEIN (APP) GENE RESULTING IN THE PRESENCE OF VARIOUS APP-MRNA ISOFORMS AND THEIR QUANTIFICATION, ESPECIALLY FOR IDENTIFYING THE MOST ABUNDANT ONE THAT MAY DECISIVE FOR THE NORMAL STATUS OR DISEASE RISK, HAVE BEEN REPORTED. AS SUCH, A MORE COMPLETE UNDERSTANDING OF AD PATHOGENESIS WILL LIKELY REQUIRE GREATER INSIGHTS INTO THE PHYSIOLOGICAL FUNCTION OF THE BETA-AMYLOID PRECURSOR PROTEIN (APP). 2018 10 5033 31 PESTICIDES AND HUMAN CHRONIC DISEASES: EVIDENCES, MECHANISMS, AND PERSPECTIVES. ALONG WITH THE WIDE USE OF PESTICIDES IN THE WORLD, THE CONCERNS OVER THEIR HEALTH IMPACTS ARE RAPIDLY GROWING. THERE IS A HUGE BODY OF EVIDENCE ON THE RELATION BETWEEN EXPOSURE TO PESTICIDES AND ELEVATED RATE OF CHRONIC DISEASES SUCH AS DIFFERENT TYPES OF CANCERS, DIABETES, NEURODEGENERATIVE DISORDERS LIKE PARKINSON, ALZHEIMER, AND AMYOTROPHIC LATERAL SCLEROSIS (ALS), BIRTH DEFECTS, AND REPRODUCTIVE DISORDERS. THERE IS ALSO CIRCUMSTANTIAL EVIDENCE ON THE ASSOCIATION OF EXPOSURE TO PESTICIDES WITH SOME OTHER CHRONIC DISEASES LIKE RESPIRATORY PROBLEMS, PARTICULARLY ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), CARDIOVASCULAR DISEASE SUCH AS ATHEROSCLEROSIS AND CORONARY ARTERY DISEASE, CHRONIC NEPHROPATHIES, AUTOIMMUNE DISEASES LIKE SYSTEMIC LUPUS ERYTHEMATOUS AND RHEUMATOID ARTHRITIS, CHRONIC FATIGUE SYNDROME, AND AGING. THE COMMON FEATURE OF CHRONIC DISORDERS IS A DISTURBANCE IN CELLULAR HOMEOSTASIS, WHICH CAN BE INDUCED VIA PESTICIDES' PRIMARY ACTION LIKE PERTURBATION OF ION CHANNELS, ENZYMES, RECEPTORS, ETC., OR CAN AS WELL BE MEDIATED VIA PATHWAYS OTHER THAN THE MAIN MECHANISM. IN THIS REVIEW, WE PRESENT THE HIGHLIGHTED EVIDENCE ON THE ASSOCIATION OF PESTICIDE'S EXPOSURE WITH THE INCIDENCE OF CHRONIC DISEASES AND INTRODUCE GENETIC DAMAGES, EPIGENETIC MODIFICATIONS, ENDOCRINE DISRUPTION, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, ENDOPLASMIC RETICULUM STRESS AND UNFOLDED PROTEIN RESPONSE (UPR), IMPAIRMENT OF UBIQUITIN PROTEASOME SYSTEM, AND DEFECTIVE AUTOPHAGY AS THE EFFECTIVE MECHANISMS OF ACTION. 2013 11 627 27 BIOLOGICAL AGING PROCESSES UNDERLYING COGNITIVE DECLINE AND NEURODEGENERATIVE DISEASE. ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (ADRD) ARE AMONG THE TOP CONTRIBUTORS TO DISABILITY AND MORTALITY IN LATER LIFE. AS WITH MANY CHRONIC CONDITIONS, AGING IS THE SINGLE MOST INFLUENTIAL FACTOR IN THE DEVELOPMENT OF ADRD. EVEN AMONG OLDER ADULTS WHO REMAIN FREE OF DEMENTIA THROUGHOUT THEIR LIVES, COGNITIVE DECLINE AND NEURODEGENERATIVE CHANGES ARE APPRECIABLE WITH ADVANCING AGE, SUGGESTING SHARED PATHOPHYSIOLOGICAL MECHANISMS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF CHANGES IN COGNITION, BRAIN MORPHOLOGY, AND NEUROPATHOLOGICAL PROTEIN ACCUMULATION ACROSS THE LIFESPAN IN HUMANS, WITH COMPLEMENTARY AND MECHANISTIC EVIDENCE FROM ANIMAL MODELS. NEXT, WE HIGHLIGHT SELECTED AGING PROCESSES THAT ARE DIFFERENTIALLY REGULATED IN NEURODEGENERATIVE DISEASE, INCLUDING ABERRANT AUTOPHAGY, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, EPIGENETIC CHANGES, CEREBROVASCULAR DYSFUNCTION, INFLAMMATION, AND LIPID DYSREGULATION. WE SUMMARIZE RESEARCH ACROSS CLINICAL AND TRANSLATIONAL STUDIES TO LINK BIOLOGICAL AGING PROCESSES TO UNDERLYING ADRD PATHOGENESIS. TARGETING FUNDAMENTAL PROCESSES UNDERLYING BIOLOGICAL AGING MAY REPRESENT A YET RELATIVELY UNEXPLORED AVENUE TO ATTENUATE BOTH AGE-RELATED COGNITIVE DECLINE AND ADRD. COLLABORATION ACROSS THE FIELDS OF GEROSCIENCE AND NEUROSCIENCE, COUPLED WITH THE DEVELOPMENT OF NEW TRANSLATIONAL ANIMAL MODELS THAT MORE CLOSELY ALIGN WITH HUMAN DISEASE PROCESSES, IS NECESSARY TO ADVANCE NOVEL THERAPEUTIC DISCOVERY IN THIS REALM. 2022 12 5670 28 SHARED (EPI)GENOMIC BACKGROUND CONNECTING NEURODEGENERATIVE DISEASES AND TYPE 2 DIABETES. THE PROGRESSIVE AGING OF POPULATIONS HAS RESULTED IN AN INCREASED PREVALENCE OF CHRONIC PATHOLOGIES, ESPECIALLY OF METABOLIC, NEURODEGENERATIVE AND MOVEMENT DISORDERS. IN PARTICULAR, TYPE 2 DIABETES (T2D), ALZHEIMER'S DISEASE (AD) AND PARKINSON'S DISEASE (PD) ARE AMONG THE MOST PREVALENT AGE-RELATED, MULTIFACTORIAL PATHOLOGIES THAT DESERVE PARTICULAR ATTENTION, GIVEN THEIR DRAMATIC IMPACT ON PATIENT QUALITY OF LIFE, THEIR ECONOMIC AND SOCIAL BURDEN AS WELL THE ETIOPATHOGENETIC MECHANISMS, WHICH MAY OVERLAP IN SOME CASES. INDEED, THE EXISTENCE OF COMMON TRIGGERING FACTORS REFLECTS THE CONTRIBUTION OF MUTUAL GENETIC, EPIGENETIC AND ENVIRONMENTAL FEATURES IN THE ETIOPATHOGENETIC MECHANISMS UNDERLYING T2D AND AD/PD. ON THIS SUBJECT, THIS REVIEW WILL SUMMARIZE THE SHARED (EPI)GENOMIC FEATURES THAT CHARACTERIZE THESE COMPLEX PATHOLOGIES. IN PARTICULAR, GENETIC VARIANTS AND GENE EXPRESSION PROFILES ASSOCIATED WITH T2D AND AD/PD WILL BE DISCUSSED AS POSSIBLE CONTRIBUTORS TO DETERMINE THE SUSCEPTIBILITY AND PROGRESSION TO THESE DISORDERS. MOREOVER, POTENTIAL SHARED EPIGENETIC MODIFICATIONS AND FACTORS AMONG T2D, AD AND PD WILL ALSO BE ILLUSTRATED. OVERALL, THIS REVIEW SHOWS THAT FINDINGS FROM GENOMIC STUDIES STILL DESERVES FURTHER RESEARCH TO EVALUATE AND IDENTIFY GENETIC FACTORS THAT DIRECTLY CONTRIBUTE TO THE SHARED ETIOPATHOGENESIS. MOREOVER, A COMMON EPIGENETIC BACKGROUND STILL NEEDS TO BE INVESTIGATED AND CHARACTERIZED. THE EVIDENCES DISCUSSED IN THIS REVIEW UNDERLINE THE IMPORTANCE OF INTEGRATING LARGE-SCALE (EPI)GENOMIC DATA WITH ADDITIONAL MOLECULAR INFORMATION AND CLINICAL AND SOCIAL BACKGROUND IN ORDER TO FINELY DISSECT THE COMPLEX ETIOPATHOGENIC NETWORKS THAT BUILD UP THE "DISEASE INTERACTOME" CHARACTERIZING T2D, AD AND PD. 2020 13 5377 30 RECENT FINDINGS IN ALZHEIMER DISEASE AND NUTRITION FOCUSING ON EPIGENETICS. ALZHEIMER DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISEASE WITH NO EFFECTIVE CURE SO FAR. THE CURRENT REVIEW FOCUSES ON THE EPIGENETIC MECHANISMS OF AD AND HOW NUTRITION CAN INFLUENCE THE COURSE OF THIS DISEASE THROUGH REGULATION OF GENE EXPRESSION, ACCORDING TO THE LATEST SCIENTIFIC FINDINGS. THE SEARCH STRATEGY WAS THE USE OF SCIENTIFIC DATABASES SUCH AS PUBMED AND SCOPUS IN ORDER TO FIND RELATIVE RESEARCH OR REVIEW ARTICLES PUBLISHED IN THE YEARS 2012-2015. BY SHOWING THE LATEST DATA OF VARIOUS NUTRITIONAL COMPOUNDS, THIS STUDY AIMS TO STIMULATE THE SCIENTIFIC COMMUNITY TO RECOGNIZE THE VALUE OF NUTRITION IN THIS SUBJECT. EPIGENETICS IS BECOMING A VERY ATTRACTIVE SUBJECT FOR RESEARCHERS BECAUSE IT CAN SHED LIGHT ON UNKNOWN ASPECTS OF COMPLEX DISEASES LIKE AD. DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS ARE THE PRINCIPAL EPIGENETIC MECHANISMS INVOLVED IN AD PATHOPHYSIOLOGY. NUTRITION IS AN ENVIRONMENTAL FACTOR THAT IS RELATED TO AD THROUGH EPIGENETIC PATHWAYS. VITAMIN B-12, FOR INSTANCE, CAN ALTER THE ONE-CARBON METABOLISM AND THUS INTERFERE IN THE DNA METHYLATION PROCESS. THE RESEARCH RESULTS MIGHT SEEM AMBIGUOUS ABOUT THE CLINICAL ROLE OF NUTRITION, BUT THERE IS STRENGTHENING EVIDENCE THAT PROPER NUTRITION CAN NOT ONLY CHANGE EPIGENETIC BIOMARKER LEVELS BUT ALSO PREVENT THE DEVELOPMENT OF LATE-ONSET AD AND ATTENUATE COGNITION DEFICIT. NUTRITION MIGHT GROW TO BECOME A PREVENTIVE AND EVEN THERAPEUTIC ALTERNATIVE AGAINST AD, ESPECIALLY IF COMBINED WITH OTHER ANTIDEMENTIA INTERVENTIONS, BRAIN EXERCISE, PHYSICAL TRAINING, ETC. EPIGENETIC BIOMARKERS CAN BE A VERY HELPFUL TOOL TO HELP RESEARCHERS FIND THE EXACT NUTRIENTS NEEDED TO CREATE SPECIFIC REMEDIES, AND PERHAPS THE SAME BIOMARKERS CAN BE USED EVEN IN PATIENT SCREENING IN THE FUTURE. 2016 14 676 28 BRAIN AGING: A IANUS-FACED PLAYER BETWEEN HEALTH AND NEURODEGENERATION. NEURODEGENERATIVE DISEASES ARE INCURABLE DEBILITATING DISORDERS CHARACTERIZED BY STRUCTURAL AND FUNCTIONAL NEURONAL LOSS. APPROXIMATELY 30 MILLION PEOPLE ARE AFFECTED WORLDWIDE, AND THIS NUMBER IS PREDICTED TO REACH MORE THAN 150 MILLION BY 2050. NEURODEGENERATIVE DISORDERS INCLUDE ALZHEIMER'S, PARKINSON'S, AND PRION DISEASES AMONG OTHERS. THESE DISORDERS ARE CHARACTERIZED BY THE ACCUMULATION OF AGGREGATING PROTEINS FORMING AMYLOID, RESPONSIBLE FOR THE DISEASE-ASSOCIATED PATHOLOGICAL LESIONS. THE AGGREGATION OF AMYLOIDOGENIC PROTEINS CAN RESULT EITHER IN GAINING OF TOXIC FUNCTIONS, DERIVED FROM THE DAMAGE PROVOKED BY THESE DEPOSITS IN AFFECTED TISSUE, OR IN A LOSS OF FUNCTIONS, DUE TO THE SEQUESTRATION AND THE CONSEQUENT INABILITY OF THE AGGREGATING PROTEIN TO ENSURE ITS PHYSIOLOGICAL ROLE. WHILE IT IS WIDELY ACCEPTED THAT AGING REPRESENTS THE MAIN RISK FACTOR FOR NEURODEGENERATION, THERE IS STILL NO CLEAR CUT-OFF LINE BETWEEN THE TWO CONDITIONS. INDEED, MANY OF THE PATHWAYS THAT ARE COMMONLY ALTERED IN NEURODEGENERATION-MISFOLDED PROTEIN ACCUMULATION, CHRONIC INFLAMMATION, MITOCHONDRIAL DYSFUNCTION, IMPAIRED IRON HOMEOSTASIS, EPIGENETIC MODIFICATIONS-HAVE BEEN OFTEN CORRELATED ALSO WITH HEALTHY AGING. THIS OVERLAP COULD BE EXPLAINED BY THE FACT THAT THE CONTINUOUS ACCUMULATION OF CELLULAR DAMAGES, TOGETHER WITH A PROGRESSIVE DECLINE IN METABOLIC EFFICIENCY DURING AGING, MAKES THE NEURONS MORE VULNERABLE TO TOXIC INJURIES. WHEN A GIVEN THRESHOLD IS EXCEEDED, ALL THESE ALTERATIONS MIGHT GIVE RISE TO PATHOLOGICAL PHENOTYPES THAT ULTIMATELY LEAD TO NEURODEGENERATION. 2020 15 5829 26 STRESS, PSYCHIATRIC DISORDERS, MOLECULAR TARGETS, AND MORE. MENTAL HEALTH IS CENTRAL TO NORMAL HEALTH OUTCOMES. A WIDELY ACCEPTED THEORY IS THAT CHRONIC PERSISTENT STRESS DURING ADULTHOOD AS WELL AS DURING EARLY LIFE TRIGGERS ONSET OF NEUROPSYCHIATRIC AILMENTS. HOWEVER, QUESTIONS RELATED TO HOW THAT OCCURS, AND WHY ARE SOME INDIVIDUALS RESISTANT TO STRESS WHILE OTHERS ARE NOT, REMAIN UNANSWERED. AN INTEGRATED, MULTISYSTEMIC STRESS RESPONSE INVOLVING NEUROINFLAMMATORY, NEUROENDOCRINE, EPIGENETIC AND METABOLIC CASCADES HAVE BEEN SUGGESTED TO HAVE CAUSATIVE LINKS. SEVERAL THEORIES HAVE BEEN PROPOSED OVER THE YEARS TO CONCEPTUALIZE THIS LINK INCLUDING THE CYTOKINE HYPOTHESIS, THE ENDOCRINE HYPOTHESIS, THE OXIDATIVE STRESS HYPOTHESIS AND THE OXIDO-NEUROINFLAMMATION HYPOTHESIS. THE DATA DISCUSSED IN THIS REVIEW DESCRIBES POTENTIAL BIOCHEMICAL BASIS OF THE LINK BETWEEN STRESS, AND STRESS-INDUCED NEURONAL, BEHAVIORAL AND EMOTIONAL DEFICITS, PROVIDING INSIGHTS INTO POTENTIALLY NOVEL DRUG TARGETS. 2019 16 2528 33 EPIGENETICS AS A KEY LINK BETWEEN PSYCHOSOCIAL STRESS AND AGING: CONCEPTS, EVIDENCE, MECHANISMS . PSYCHOSOCIAL STRESS-ESPECIALLY WHEN CHRONIC, EXCESSIVE, OR OCCURRING EARLY IN LIFE-HAS BEEN ASSOCIATED WITH ACCELERATED AGING AND INCREASED DISEASE RISK. WITH RAPID AGING OF THE WORLD POPULATION, THE NEED TO ELUCIDATE THE UNDERLYING MECHANISMS IS PRESSING, NOW MORE SO THAN EVER. AMONG MOLECULAR MECHANISMS LINKING STRESS AND AGING, THE PRESENT ARTICLE REVIEWS EVIDENCE ON THE ROLE OF EPIGENETICS, BIOCHEMICAL PROCESSES THAT CAN BE SET INTO MOTION BY STRESSORS AND IN TURN INFLUENCE GENOMIC FUNCTION AND COMPLEX PHENOTYPES, INCLUDING AGING-RELATED OUTCOMES. THE ARTICLE FURTHER PROVIDES A CONCEPTUAL MECHANISTIC FRAMEWORK ON HOW STRESS MAY DRIVE EPIGENETIC CHANGES AT SUSCEPTIBLE GENOMIC SITES, THEREBY EXERTING SYSTEMS-LEVEL EFFECTS ON THE AGING EPIGENOME WHILE ALSO REGULATING THE EXPRESSION OF MOLECULES IMPLICATED IN AGING-RELATED PROCESSES. THIS EMERGING EVIDENCE, TOGETHER WITH WORK EXAMINING RELATED BIOLOGICAL PROCESSES, BEGINS TO SHED LIGHT ON THE EPIGENETIC AND, MORE BROADLY, MOLECULAR UNDERPINNINGS OF THE LONG-HYPOTHESIZED CONNECTION BETWEEN STRESS AND AGING. . 2019 17 2049 24 EPIGENETIC CODE AND POTENTIAL EPIGENETIC-BASED THERAPIES AGAINST CHRONIC DISEASES IN DEVELOPMENTAL ORIGINS. ACCUMULATED FINDINGS HAVE DEMONSTRATED THAT THE EPIGENETIC CODE PROVIDES A POTENTIAL LINK BETWEEN PRENATAL STRESS AND CHANGES IN GENE EXPRESSION THAT COULD BE INVOLVED IN THE DEVELOPMENTAL PROGRAMMING OF VARIOUS CHRONIC DISEASES IN LATER LIFE. MEANWHILE, BASED ON THE FACT THAT EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND CAN BE MANIPULATED, THIS PROVIDES A UNIQUE CHANCE TO DEVELOP MULTIPLE NOVEL EPIGENETIC-BASED THERAPEUTIC STRATEGIES AGAINST MANY CHRONIC DISEASES IN EARLY DEVELOPMENTAL PERIODS. THIS ARTICLE WILL GIVE A SHORT REVIEW OF RECENT FINDINGS OF PRENATAL INSULT-INDUCED EPIGENETIC CHANGES IN DEVELOPMENTAL ORIGINS OF SEVERAL CHRONIC DISEASES, AND WILL ATTEMPT TO PROVIDE AN OVERVIEW OF THE CURRENT EPIGENETIC-BASED STRATEGIES APPLIED IN THE EARLY PREVENTION, DIAGNOSIS AND POSSIBLE THERAPIES FOR HUMAN CHRONIC DISEASES. 2014 18 2586 21 EPIGENETICS OF PAIN MEDIATORS. PURPOSE OF REVIEW: THE FIELD OF EPIGENETICS CONTINUES ITS INFLUENTIAL RISE AS A MEANS TO BETTER UNDERSTAND AN ORGANISM'S UNIQUE DEVELOPMENTAL IDENTITY OVER A LIFESPAN. WHEREAS A GENOME IS CONSTANT AND UNCHANGING, AN EPIGENOME IS DYNAMIC AND ALTERABLE. EPIGENETIC CHANGES ARE IN RESPONSE TO INNUMERABLE INTERNAL AND EXTERNAL INFLUENCES INCLUDING ENVIRONMENTAL CHANGES SUCH AS DIET, EXERCISE, DISEASE, TOXINS, AND STRESS. EPIGENETICS IS OF PARTICULAR INTEREST IN THE MEDICAL RESEARCH COMMUNITY BOTH FOR THE POTENTIAL TO CAUSE DISEASE AND AS A TARGET FOR THERAPEUTIC INTERVENTIONS. THIS ARTICLE PROVIDES A SUCCINCT EXPLANATION OF THE POTENTIAL FOR EPIGENETICS TO INFLUENCE THE UNDERSTANDING OF PAIN AS WELL AS A REVIEW OF RELEVANT RESEARCH ON THE TOPIC. RECENT FINDINGS: STUDIES ON EPIGENETICS AND PAIN REMAIN LARGELY PRECLINICAL AND INVESTIGATE THE THEORETICAL ABILITY OF EPIGENETICS TO ALTER THE NOCICEPTIVE PATHWAYS BOTH IN THE PERIPHERY AND CENTRALLY. SIGNIFICANT EVIDENCE NOW EXISTS FOR THE ABILITY OF EPIGENETICS TO MODIFY BROADLY CATEGORIZED PAIN TYPES, INCLUDING INFLAMMATORY, NEUROPATHIC, VISCERAL, AND CANCER RELATED. SUMMARY: BOTH PATIENTS AND PROVIDERS RECOGNIZE THAT NOVEL MEDICATIONS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC PAIN CONDITIONS ARE SORELY NEEDED. THE UNDERSTANDING OF EPIGENETICS AND ITS INFLUENCE ON NOCICEPTION REMAINS IN RELATIVE INFANCY BUT EARLY EVIDENCE IS STRONG FOR POTENTIAL THERAPEUTIC BENEFITS TO TREAT THESE CONDITIONS. 2018 19 5519 32 RISK FACTORS FOR ALZHEIMER'S DISEASE: ROLE OF MULTIPLE ANTIOXIDANTS, NON-STEROIDAL ANTI-INFLAMMATORY AND CHOLINERGIC AGENTS ALONE OR IN COMBINATION IN PREVENTION AND TREATMENT. THE ETIOLOGY OF ALZHEIMER'S DISEASE (AD) IS NOT WELL UNDERSTOOD. ETIOLOGIC FACTORS, CHRONIC INFLAMMATORY REACTIONS, OXIDATIVE AND NITROSYLATIVE STRESSES AND HIGH CHOLESTEROL LEVELS ARE THOUGHT TO BE IMPORTANT FOR INITIATING AND PROMOTING NEURODEGENERATIVE CHANGES COMMONLY FOUND IN AD BRAINS. EVEN IN FAMILIAL AD, OXIDATIVE STRESS PLAYS AN IMPORTANT ROLE IN THE EARLY ONSET OF THE DISEASE. MITOCHONDRIAL DAMAGE AND PROTEASOME INHIBITION REPRESENT EARLY EVENTS IN THE PATHOGENESIS OF AD, WHEREAS INCREASED PROCESSING OF AMYLOID PRECURSOR PROTEIN (APP) TO BETA-AMYLOID (ABETA) FRAGMENTS (ABETA(40) AND ABETA(42)) AND FORMATION OF SENILE PLAQUES AND NEUROFIBRILLARY TANGLES (NFTS) REPRESENT LATE EVENTS. WE PROPOSE A HYPOTHESIS THAT IN IDIOPATHIC AD, EPIGENETIC COMPONENTS OF NEURONS SUCH AS MITOCHONDRIA, PROTEASOMES AND POST-TRANSLATION PROTEIN MODIFICATIONS (PROCESSING OF AMYLOID PRECURSOR PROTEIN TO BETA-AMYLOID AND HYPERPHOSPHORYLATION OF TAU), RATHER THAN NUCLEAR GENES, ARE THE PRIMARY TARGETS FOR THE ACTION OF DIVERSE GROUPS OF NEUROTOXINS. BASED ON EPIDEMIOLOGIC, LABORATORY AND LIMITED CLINICAL STUDIES, WE PROPOSE THAT A COMBINATION OF NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) AND APPROPRIATE LEVELS AND TYPES OF MULTIPLE MICRONUTRIENTS, INCLUDING ANTIOXIDANTS, MAY BE MORE EFFECTIVE THAN THE INDIVIDUAL AGENTS IN THE PREVENTION, AND THEY, IN COMBINATION WITH A CHOLINERGIC AGENT, MAY BE MORE EFFECTIVE IN THE TREATMENT OF AD THAN THE INDIVIDUAL AGENTS ALONE. IN ADDITION, AGENTS, WHICH CAN PREVENT FORMATION OF PLAQUES OR DISSOLVE THESE PLAQUES MAY FURTHER ENHANCE THE EFFICACY OF OUR PROPOSED TREATMENT STRATEGY. 2002 20 1453 23 DISCOVERING HOW ENVIRONMENTAL EXPOSURES ALTER GENES COULD LEAD TO NEW TREATMENTS FOR CHRONIC ILLNESSES. EMERGING RESEARCH DEMONSTRATES THAT DIET, POLLUTION, AND OTHER ENVIRONMENTAL TRIGGERS CAN ALTER BOTH THE FUNCTION AND EXPRESSION OF HUMAN GENES AND LEAD TO A HEIGHTENED DISEASE RISK. THESE ENVIRONMENT-GENE INTERACTIONS CAN CAUSE SO-CALLED EPIGENETIC CHANGES IN GENE EXPRESSION-PATTERNS OF WHICH GENES ARE SWITCHED "ON" OR "OFF"-THAT MAY ACCOUNT FOR THE RISING MORTALITY FROM CHRONIC DISEASES IN INDUSTRIALIZED NATIONS. IN THIS PAPER, WE CALL FOR A NEW TRANSDISCIPLINARY APPROACH TO PUBLIC HEALTH THAT WOULD EXAMINE HOW ENVIRONMENTAL EXPOSURES, BOTH PHYSICAL AND SOCIAL, INFLUENCE GENE EXPRESSION AND A PERSON'S SUSCEPTIBILITY TO CHRONIC DISEASE. THIS INITIATIVE COULD LEAD TO NEW WAYS TO PREVENT AND TREAT SUCH ILLNESSES. 2011