1 4415 134 MOLECULAR AND CELLULAR MECHANISMS THAT INDUCE ARTERIAL CALCIFICATION BY INDOXYL SULFATE AND P-CRESYL SULFATE. THE PROTEIN-BOUND UREMIC TOXINS, INDOXYL SULFATE (IS) AND P-CRESYL SULFATE (PCS), ARE CONSIDERED TO BE HARMFUL VASCULAR TOXINS. ARTERIAL MEDIA CALCIFICATION, OR THE DEPOSITION OF CALCIUM PHOSPHATE CRYSTALS IN THE ARTERIES, CONTRIBUTES SIGNIFICANTLY TO CARDIOVASCULAR COMPLICATIONS, INCLUDING LEFT VENTRICULAR HYPERTROPHY, HYPERTENSION, AND IMPAIRED CORONARY PERFUSION IN THE ELDERLY AND PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) AND DIABETES. RECENTLY, WE REPORTED THAT BOTH IS AND PCS TRIGGER MODERATE TO SEVERE CALCIFICATION IN THE AORTA AND PERIPHERAL VESSELS OF CKD RATS. THIS REVIEW DESCRIBES THE MOLECULAR AND CELLULAR MECHANISMS BY WHICH THESE UREMIC TOXINS INDUCE ARTERIAL MEDIA CALCIFICATION. A COMPLEX INTERPLAY BETWEEN INFLAMMATION, COAGULATION, AND LIPID METABOLISM PATHWAYS, INFLUENCED BY EPIGENETIC FACTORS, IS CRUCIAL IN IS/PCS-INDUCED ARTERIAL MEDIA CALCIFICATION. HIGH LEVELS OF GLUCOSE ARE LINKED TO THESE EVENTS, SUGGESTING THAT A GOOD BALANCE BETWEEN GLUCOSE AND LIPID LEVELS MIGHT BE IMPORTANT. ON THE CELLULAR LEVEL, EFFECTS ON ENDOTHELIAL CELLS, WHICH ACT AS THE PRIMARY SENSORS OF CIRCULATING PATHOLOGICAL TRIGGERS, MIGHT BE AS IMPORTANT AS THOSE ON VASCULAR SMOOTH MUSCLE CELLS. ENDOTHELIAL DYSFUNCTION, PROVOKED BY IS AND PCS TRIGGERED OXIDATIVE STRESS, MAY BE CONSIDERED A KEY EVENT IN THE ONSET AND DEVELOPMENT OF ARTERIAL MEDIA CALCIFICATION. IN THIS REVIEW A NUMBER OF IMPORTANT OUTSTANDING QUESTIONS SUCH AS THE ROLE OF MIRNA'S, PHENOTYPIC SWITCHING OF BOTH ENDOTHELIAL AND VASCULAR SMOOTH MUSCLE CELLS AND NEW TYPES OF PROGRAMMED CELL DEATH IN ARTERIAL MEDIA CALCIFICATION RELATED TO PROTEIN-BOUND UREMIC TOXINS ARE PUT FORWARD AND DISCUSSED. 2020 2 3901 26 LEAD (PB) AND NEURODEVELOPMENT: A REVIEW ON EXPOSURE AND BIOMARKERS OF EFFECT (BDNF, HDL) AND SUSCEPTIBILITY. LEAD (PB) IS A UBIQUITOUS ENVIRONMENTAL POLLUTANT AND A POTENT TOXIC COMPOUND. HUMANS ARE EXPOSED TO PB THROUGH INHALATION, INGESTION, AND SKIN CONTACT VIA FOOD, WATER, TOBACCO SMOKE, AIR, DUST, AND SOIL. PB ACCUMULATES IN BONES, BRAIN, LIVER AND KIDNEY. FETAL EXPOSURE OCCURS VIA TRANSPLACENTAL TRANSMISSION. THE MOST CRITICAL HEALTH EFFECTS ARE DEVELOPMENTAL NEUROTOXICITY IN INFANTS AND CARDIOVASCULAR EFFECTS AND NEPHROTOXICITY IN ADULTS. PB EXPOSURE HAS BEEN STEADILY DECREASING OVER THE PAST DECADES, BUT THERE ARE FEW RECENT EXPOSURE DATA FROM THE GENERAL EUROPEAN POPULATION; MOREOVER, NO SAFE PB LIMIT HAS BEEN SET. SENSITIVE BIOMARKERS OF EXPOSURE, EFFECT AND SUSCEPTIBILITY, THAT RELIABLY AND TIMELY INDICATE PB-ASSOCIATED TOXICITY ARE REQUIRED TO ASSESS HUMAN EXPOSURE-HEALTH RELATIONSHIPS IN A SITUATION OF LOW TO MODERATE EXPOSURE. THEREFORE, A SYSTEMATIC LITERATURE REVIEW BASED ON PUBMED ENTRIES PUBLISHED BEFORE JULY 2019 THAT ADDRESSED PB EXPOSURE AND BIOMARKERS OF EFFECT AND SUSCEPTIBILITY, NEURODEVELOPMENTAL TOXICITY, EPIGENETIC MODIFICATIONS, AND TRANSCRIPTOMICS WAS CONDUCTED. FINALLY INCLUDED WERE 58 ORIGINAL PAPERS ON PB EXPOSURE AND 17 STUDIES ON BIOMARKERS. THE BIOMARKERS THAT ARE LINKED TO PB EXPOSURE AND NEURODEVELOPMENT WERE GROUPED INTO EFFECT BIOMARKERS (SERUM BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND SERUM/SALIVA CORTISOL), SUSCEPTIBILITY MARKERS (EPIGENETIC MARKERS AND GENE SEQUENCE VARIANTS) AND OTHER BIOMARKERS (SERUM HIGH-DENSITY LIPOPROTEIN (HDL), MATERNAL IRON (FE) AND CALCIUM (CA) STATUS). SERUM BDNF AND PLASMA HDL ARE POTENTIAL CANDIDATES TO BE FURTHER VALIDATED AS EFFECT MARKERS FOR ROUTINE USE IN HBM STUDIES OF PB, COMPLEMENTED BY MARKERS OF FE AND CA STATUS TO ALSO ADDRESS NUTRITIONAL INTERACTIONS RELATED TO NEURODEVELOPMENTAL DISORDERS. FOR SEVERAL MARKERS, A CAUSAL RELATIONSHIP WITH PB-INDUCED NEURODEVELOPMENTAL TOXICITY IS LIKELY. RESULTS ON BDNF ARE DISCUSSED IN RELATION TO ADVERSE OUTCOME PATHWAY (AOP) 13 ("CHRONIC BINDING OF ANTAGONIST TO N-METHYL-D-ASPARTATE RECEPTORS (NMDARS) DURING BRAIN DEVELOPMENT INDUCES IMPAIRMENT OF LEARNING AND MEMORY ABILITIES") OF THE AOP-WIKI. FURTHER STUDIES ARE NEEDED TO VALIDATE SENSITIVE, RELIABLE, AND TIMELY EFFECT BIOMARKERS, ESPECIALLY FOR LOW TO MODERATE PB EXPOSURE SCENARIOS. 2021 3 2066 31 EPIGENETIC CONTROL OF ION CHANNEL EXPRESSION AND CELL-SPECIFIC SPLICING IN NOCICEPTORS: CHRONIC PAIN MECHANISMS AND POTENTIAL THERAPEUTIC TARGETS. ION CHANNELS UNDERLIE ALL FORMS FOR ELECTRICAL SIGNALING INCLUDING THE TRANSMISSION OF INFORMATION ABOUT HARMFUL EVENTS. VOLTAGE-GATED CALCIUM ION CHANNELS HAVE DUAL FUNCTION, THEY SUPPORT ELECTRICAL SIGNALING AS WELL AS INTRACELLULAR CALCIUM SIGNALING THROUGH EXCITATION-DEPENDENT CALCIUM ENTRY ACROSS THE PLASMA MEMBRANE. MECHANISMS THAT REGULATE ION CHANNEL FORMS AND ACTIONS ARE ESSENTIAL FOR MYRIAD CELL FUNCTIONS AND THESE ARE TARGETED BY DRUGS AND THERAPEUTICS. WHEN DISRUPTED, THE CELLULAR MECHANISMS THAT CONTROL ION CHANNEL ACTIVITY CAN CONTRIBUTE TO DISEASE PATHOPHYSIOLOGY. FOR EXAMPLE, ALTERNATIVE PRE-MRNA SPLICING IS A MAJOR STEP IN DEFINING THE PRECISE COMPOSITION OF THE TRANSCRIPTOME ACROSS DIFFERENT CELL TYPES FROM EARLY CELLULAR DIFFERENTIATION TO PROGRAMMED APOPTOSIS. AN ESTIMATED 30% OF DISEASE-CAUSING MUTATIONS ARE ASSOCIATED WITH ALTERED ALTERNATIVE SPLICING, AND MIS-SPLICING IS A FEATURE OF NUMEROUS HIGHLY PREVALENT DISEASES INCLUDING NEURODEGENERATIVE, CANCER, AND CHRONIC PAIN. HERE WE DISCUSS THE IMPORTANT ROLE OF EPIGENETIC REGULATION OF GENE EXPRESSION AND CELL-SPECIFIC ALTERNATIVE SPLICING OF CALCIUM ION CHANNELS IN NOCICEPTORS, WITH EMPHASIS ON HOW THESE PROCESSES ARE DISRUPTED IN CHRONIC PAIN, THE POTENTIAL THERAPEUTIC BENEFIT OF CORRECTING OR COMPENSATING FOR ABERRANT ION CHANNEL SPLICING IN CHRONIC PAIN. 2021 4 4640 31 NEURONAL NUCLEAR CALCIUM SIGNALING SUPPRESSION OF MICROGLIAL REACTIVITY IS MEDIATED BY OSTEOPROTEGERIN AFTER TRAUMATIC BRAIN INJURY. BACKGROUND: TRAUMATIC BRAIN INJURY (TBI) IS CHARACTERIZED BY MASSIVE CHANGES IN NEURONAL EXCITATION, FROM ACUTE EXCITOTOXICITY TO CHRONIC HYPER- OR HYPOEXCITABILITY. NUCLEAR CALCIUM SIGNALING PATHWAYS ARE INVOLVED IN TRANSLATING CHANGES IN SYNAPTIC INPUTS AND NEURONAL ACTIVITY INTO DISCRETE TRANSCRIPTIONAL PROGRAMS WHICH NOT ONLY AFFECT NEURONAL SURVIVAL AND SYNAPTIC INTEGRITY, BUT ALSO THE CROSSTALK BETWEEN NEURONS AND GLIAL CELLS. HERE, WE REPORT THE EFFECTS OF BLUNTING NEURONAL NUCLEAR CALCIUM SIGNALS IN THE CONTEXT OF TBI. METHODS: WE USED AAV VECTORS TO EXPRESS THE GENETICALLY ENCODED AND NUCLEAR-TARGETED CALCIUM BUFFER PARVALBUMIN (PV.NLS.MCHERRY) OR THE CALCIUM/CALMODULIN BUFFER CAMBP4.MCHERRY IN NEURONS ONLY. UPON TBI, THE EXTENT OF NEUROINFLAMMATION, NEURONAL DEATH AND SYNAPTIC LOSS WERE ASSESSED BY IMMUNOHISTOCHEMISTRY AND TARGETED TRANSCRIPTOME ANALYSIS. MODULATION OF THE OVERALL LEVEL OF NEURONAL ACTIVITY WAS ACHIEVED BY PSAM/PSEM CHEMOGENETICS TARGETED TO PARVALBUMIN INTERNEURONS. THE FUNCTIONAL IMPACT OF NEURONAL NUCLEAR CALCIUM BUFFERING IN TBI WAS ASSESSED BY QUANTIFICATION OF SPONTANEOUS WHISKING. RESULTS: BUFFERING NEURONAL NUCLEAR CALCIUM UNEXPECTEDLY RESULTED IN A MASSIVE AND LONG-LASTING INCREASE IN THE RECRUITMENT OF REACTIVE MICROGLIA TO THE INJURY SITE, WHICH WAS CHARACTERIZED BY A DISEASE-ASSOCIATED AND PHAGOCYTIC PHENOTYPE. THIS EFFECT WAS ACCOMPANIED BY A SUBSTANTIAL SURGE IN SYNAPTIC LOSS AND SIGNIFICANTLY REDUCED WHISKING ACTIVITY. TRANSCRIPTOME ANALYSIS REVEALED A COMPLEX EFFECT OF TBI IN THE CONTEXT OF NEURONAL NUCLEAR CALCIUM BUFFERING, WITH UPREGULATION OF COMPLEMENT FACTORS, CHEMOKINES AND INTERFERON-RESPONSE GENES, AS WELL AS THE DOWNREGULATION OF SYNAPTIC GENES AND EPIGENETIC REGULATORS COMPARED TO CONTROL CONDITIONS. NOTABLY, NUCLEAR CALCIUM BUFFERING LED TO A SUBSTANTIAL LOSS IN NEURONAL OSTEOPROTEGERIN (OPG), WHEREAS STIMULATION OF NEURONAL FIRING INDUCED OPG EXPRESSION. VIRAL RE-EXPRESSION OF OPG RESULTED IN DECREASED MICROGLIAL RECRUITMENT AND SYNAPTIC LOSS. OPG UPREGULATION WAS ALSO OBSERVED IN THE CSF OF HUMAN TBI PATIENTS, UNDERSCORING ITS TRANSLATIONAL VALUE. CONCLUSION: NEURONAL NUCLEAR CALCIUM SIGNALS REGULATE THE DEGREE OF MICROGLIAL RECRUITMENT AND REACTIVITY UPON TBI VIA, AMONG OTHERS, OSTEOPROTEGERIN SIGNALS. OUR FINDINGS SUPPORT A MODEL WHEREBY NEURONAL ACTIVITY ALTERED AFTER TBI EXERTS A POWERFUL IMPACT ON THE NEUROINFLAMMATORY CASCADE, WHICH IN TURN CONTRIBUTES TO THE OVERALL LOSS OF SYNAPSES AND FUNCTIONAL IMPAIRMENT. 2022 5 6728 29 VOLTAGE-GATED CALCIUM CHANNELS AND PARKINSON'S DISEASE. A COMPLEX INTERACTION OF ENVIRONMENTAL, GENETIC AND EPIGENETIC FACTORS COMBINE WITH AGEING TO CAUSE THE MOST PREVALENT OF MOVEMENT DISORDERS PARKINSON'S DISEASE. CURRENT PHARMACOLOGICAL TREATMENTS ONLY TACKLE THE SYMPTOMS AND DO NOT STOP PROGRESSION OF THE DISEASE OR REVERSE THE NEURODEGENERATIVE PROCESS. WHILE SOME INCIDENCES OF PARKINSON'S DISEASE ARISE THROUGH HERITABLE GENETIC DEFECTS, THE CAUSE OF THE MAJORITY OF CASES REMAINS UNKNOWN. LIKEWISE, WHY SOME NEURONAL POPULATIONS ARE MORE SUSCEPTIBLE TO NEURODEGENERATION THAN OTHERS IS NOT CLEAR, BUT AS THE MOLECULAR PATHWAYS RESPONSIBLE FOR THE PROCESS OF CELL DEATH ARE UNRAVELLED, IT IS INCREASINGLY APPARENT THAT DISRUPTED CELLULAR ENERGY METABOLISM PLAYS A CENTRAL ROLE. PRECISE CONTROL OF CELLULAR CALCIUM CONCENTRATIONS IS CRUCIAL FOR MAINTENANCE OF ENERGY HOMEOSTASIS. RECENTLY, DIFFERENTIAL CELLULAR EXPRESSION OF NEURONAL VOLTAGE-GATED CALCIUM CHANNEL (CA(V)) ISOFORMS HAS BEEN IMPLICATED IN THE SUSCEPTIBILITY OF VULNERABLE NEURONS TO NEURODEGENERATION IN PARKINSON'S DISEASE. CA(V) CHANNELS ARE ALSO INVOLVED IN THE SYNAPTIC PLASTICITY RESPONSE TO THE DENERVATION THAT OCCURS IN PARKINSON'S DISEASE AND FOLLOWING CHRONIC TREATMENT WITH ANTI-PARKINSONIAN DRUGS. THIS REVIEW WILL EXAMINE THE PUTATIVE ROLE NEURONAL CA(V) CHANNELS HAVE IN THE PATHOGENESIS AND TREATMENT OF PARKINSON'S DISEASE. 2012 6 933 34 CHRONIC KIDNEY DISEASE. THE DEFINITION AND CLASSIFICATION OF CHRONIC KIDNEY DISEASE (CKD) HAVE EVOLVED OVER TIME, BUT CURRENT INTERNATIONAL GUIDELINES DEFINE THIS CONDITION AS DECREASED KIDNEY FUNCTION SHOWN BY GLOMERULAR FILTRATION RATE (GFR) OF LESS THAN 60 ML/MIN PER 1.73 M(2), OR MARKERS OF KIDNEY DAMAGE, OR BOTH, OF AT LEAST 3 MONTHS DURATION, REGARDLESS OF THE UNDERLYING CAUSE. DIABETES AND HYPERTENSION ARE THE MAIN CAUSES OF CKD IN ALL HIGH-INCOME AND MIDDLE-INCOME COUNTRIES, AND ALSO IN MANY LOW-INCOME COUNTRIES. INCIDENCE, PREVALENCE, AND PROGRESSION OF CKD ALSO VARY WITHIN COUNTRIES BY ETHNICITY AND SOCIAL DETERMINANTS OF HEALTH, POSSIBLY THROUGH EPIGENETIC INFLUENCE. MANY PEOPLE ARE ASYMPTOMATIC OR HAVE NON-SPECIFIC SYMPTOMS SUCH AS LETHARGY, ITCH, OR LOSS OF APPETITE. DIAGNOSIS IS COMMONLY MADE AFTER CHANCE FINDINGS FROM SCREENING TESTS (URINARY DIPSTICK OR BLOOD TESTS), OR WHEN SYMPTOMS BECOME SEVERE. THE BEST AVAILABLE INDICATOR OF OVERALL KIDNEY FUNCTION IS GFR, WHICH IS MEASURED EITHER VIA EXOGENOUS MARKERS (EG, DTPA, IOHEXOL), OR ESTIMATED USING EQUATIONS. PRESENCE OF PROTEINURIA IS ASSOCIATED WITH INCREASED RISK OF PROGRESSION OF CKD AND DEATH. KIDNEY BIOPSY SAMPLES CAN SHOW DEFINITIVE EVIDENCE OF CKD, THROUGH COMMON CHANGES SUCH AS GLOMERULAR SCLEROSIS, TUBULAR ATROPHY, AND INTERSTITIAL FIBROSIS. COMPLICATIONS INCLUDE ANAEMIA DUE TO REDUCED PRODUCTION OF ERYTHROPOIETIN BY THE KIDNEY; REDUCED RED BLOOD CELL SURVIVAL AND IRON DEFICIENCY; AND MINERAL BONE DISEASE CAUSED BY DISTURBED VITAMIN D, CALCIUM, AND PHOSPHATE METABOLISM. PEOPLE WITH CKD ARE FIVE TO TEN TIMES MORE LIKELY TO DIE PREMATURELY THAN THEY ARE TO PROGRESS TO END STAGE KIDNEY DISEASE. THIS INCREASED RISK OF DEATH RISES EXPONENTIALLY AS KIDNEY FUNCTION WORSENS AND IS LARGELY ATTRIBUTABLE TO DEATH FROM CARDIOVASCULAR DISEASE, ALTHOUGH CANCER INCIDENCE AND MORTALITY ARE ALSO INCREASED. HEALTH-RELATED QUALITY OF LIFE IS SUBSTANTIALLY LOWER FOR PEOPLE WITH CKD THAN FOR THE GENERAL POPULATION, AND FALLS AS GFR DECLINES. INTERVENTIONS TARGETING SPECIFIC SYMPTOMS, OR AIMED AT SUPPORTING EDUCATIONAL OR LIFESTYLE CONSIDERATIONS, MAKE A POSITIVE DIFFERENCE TO PEOPLE LIVING WITH CKD. INEQUITY IN ACCESS TO SERVICES FOR THIS DISEASE DISPROPORTIONALLY AFFECTS DISADVANTAGED POPULATIONS, AND HEALTH SERVICE PROVISION TO INCENTIVISE EARLY INTERVENTION OVER PROVISION OF CARE ONLY FOR ADVANCED CKD IS STILL EVOLVING IN MANY COUNTRIES. 2017 7 5074 33 PHYSIOLOGIC AND EPIGENETIC EFFECTS OF NUTRIENTS ON DISEASE PATHWAYS. BACKGROUND/OBJECTIVES: EPIGENETIC REGULATION BY NUTRIENTS CAN INFLUENCE THE DEVELOPMENT OF SPECIFIC DISEASES. THIS STUDY SOUGHT TO EXAMINE THE EFFECT OF INDIVIDUAL NUTRIENTS AND NUTRIENT FAMILIES IN THE CONTEXT OF PREVENTING CHRONIC METABOLIC DISEASES VIA EPIGENETIC REGULATION. THE INHIBITION OF LIPID ACCUMULATION AND INFLAMMATION BY NUTRIENTS INCLUDING PROTEINS, LIPIDS, VITAMINS, AND MINERALS WERE OBSERVED, AND HISTONE ACETYLATION BY HISTONE ACETYLTRANSFERASE (HAT) WAS MEASURED. CORRELATIVE ANALYSES WERE ALSO PERFORMED. MATERIALS/METHODS: NUTRIENTS WERE SELECTED ACCORDING TO INFORMATION FROM THE KOREAN MINISTRY OF FOOD AND DRUG SAFETY. SELECTED NUTRIENT FUNCTIONALITIES, INCLUDING THE ATTENUATION OF FATTY ACID-INDUCED LIPID ACCUMULATION AND LIPOPOLYSACCHARIDE-MEDIATED ACUTE INFLAMMATION WERE EVALUATED IN MOUSE MACROPHAGE RAW264.7 AND MOUSE HEPATOCYTE AML-12 CELLS. EFFECTS OF THE SELECTED NUTRIENTS ON IN VITRO HAT INHIBITION WERE ALSO EVALUATED. RESULTS: NITRIC OXIDE (NO) PRODUCTION CORRELATED WITH HAT ACTIVITY, WHICH WAS REGULATED BY THE AMINO ACIDS GROUP, SUGGESTING THAT AMINO ACIDS POTENTIALLY CONTRIBUTE TO THE ATTENUATION OF NO PRODUCTION VIA THE INHIBITION OF HAT ACTIVITY. UNSATURATED FATTY ACIDS TENDED TO ATTENUATE INFLAMMATION BY INHIBITING NO PRODUCTION, WHICH MAY BE ATTRIBUTABLE TO THE INHIBITION OF IN VITRO HAT ACTIVITY. IN CONTRAST TO WATER-SOLUBLE VITAMINS, THE LIPID-SOLUBLE VITAMINS SIGNIFICANTLY DECREASED NO PRODUCTION. WATER- AND LIPID-SOLUBLE VITAMINS BOTH EXHIBITED SIGNIFICANT INHIBITORY ACTIVITIES AGAINST HAT. IN ADDITION, CALCIUM AND MANGANESE SIGNIFICANTLY INHIBITED LIPID ACCUMULATION, NO PRODUCTION, AND HAT ACTIVITY. CONCLUSIONS: SEVERAL CANDIDATE NUTRIENTS AND THEIR FAMILY MEMBERS MAY HAVE ROLES IN THE PREVENTION OF DISEASES, INCLUDING HEPATIC STEATOSIS AND INFLAMMATION-RELATED DISEASES (I.E., NONALCOHOLIC STEATOHEPATITIS) VIA EPIGENETIC REGULATION. FURTHER STUDIES ARE WARRANTED TO DETERMINE WHICH SPECIFIC AMINO ACIDS, UNSATURATED FATTY ACIDS AND LIPID-SOLUBLE VITAMINS OR SPECIFIC MINERALS INFLUENCE THE DEVELOPMENT OF STEATOSIS AND INFLAMMATORY-RELATED DISEASES. 2023 8 126 41 A TOXICOGENOMICS APPROACH TO IDENTIFY NEW PLAUSIBLE EPIGENETIC MECHANISMS OF OCHRATOXIN A CARCINOGENICITY IN RAT. OCHRATOXIN A (OTA) IS A MYCOTOXIN OCCURRING NATURALLY IN A WIDE RANGE OF FOOD COMMODITIES. IN ANIMALS, IT HAS BEEN SHOWN TO CAUSE A VARIETY OF ADVERSE EFFECTS, NEPHROCARCINOGENICITY BEING THE MOST PROMINENT. BECAUSE OF ITS HIGH TOXIC POTENCY AND THE CONTINUOUS EXPOSURE OF THE HUMAN POPULATION, OTA HAS RAISED PUBLIC HEALTH CONCERNS. THERE IS SIGNIFICANT DEBATE ON HOW TO USE THE RAT CARCINOGENICITY DATA TO ASSESS THE POTENTIAL RISK TO HUMANS. IN THIS CONTEXT, THE QUESTION OF THE MECHANISM OF ACTION OF OTA APPEARS OF KEY IMPORTANCE AND WAS STUDIED THROUGH THE APPLICATION OF A TOXICOGENOMICS APPROACH. MALE FISCHER RATS WERE FED OTA FOR UP TO 2 YEARS. RENAL TUMORS WERE DISCOVERED DURING THE LAST 6 MONTHS OF THE STUDY. THE TOTAL TUMOR INCIDENCE REACHED 25% AT THE END OF THE STUDY. GENE EXPRESSION PROFILE WAS ANALYZED IN GROUPS OF ANIMALS TAKEN IN INTERVALS FROM 7 DAYS TO 12 MONTHS. TISSUE-SPECIFIC RESPONSES WERE OBSERVED IN KIDNEY VERSUS LIVER. FOR SELECTED GENES, MICROARRAY DATA WERE CONFIRMED AT BOTH MRNA AND PROTEIN LEVELS. IN KIDNEY, SEVERAL GENES KNOWN AS MARKERS OF KIDNEY INJURY AND CELL REGENERATION WERE SIGNIFICANTLY MODULATED BY OTA. THE EXPRESSION OF GENES KNOWN TO BE INVOLVED IN DNA SYNTHESIS AND REPAIR, OR GENES INDUCED AS A RESULT OF DNA DAMAGE, WAS ONLY MARGINALLY MODULATED. VERY LITTLE OR NO EFFECT WAS FOUND AMONGST GENES ASSOCIATED WITH APOPTOSIS. ALTERATIONS OF GENE EXPRESSION INDICATING EFFECTS ON CALCIUM HOMEOSTASIS AND A DISRUPTION OF PATHWAYS REGULATED BY THE TRANSCRIPTION FACTORS HEPATOCYTE NUCLEAR FACTOR 4 ALPHA (HNF4ALPHA) AND NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (NRF2) WERE OBSERVED IN THE KIDNEY BUT NOT IN THE LIVER. PREVIOUS DATA HAVE SUGGESTED THAT A REDUCTION IN HNF4ALPHA MAY BE ASSOCIATED WITH NEPHROCARCINOGENICITY. MANY NRF2-REGULATED GENES ARE INVOLVED IN CHEMICAL DETOXICATION AND ANTIOXIDANT DEFENSE. THE DEPLETION OF THESE GENES IS LIKELY TO IMPAIR THE DEFENSE POTENTIAL OF THE CELLS, RESULTING IN CHRONIC ELEVATION OF OXIDATIVE STRESS IN THE KIDNEY. THE INHIBITION OF DEFENSE MECHANISM APPEARS AS A HIGHLY PLAUSIBLE NEW MECHANISM, WHICH COULD CONTRIBUTE TO OTA CARCINOGENICITY. 2006 9 6122 39 THE EPIGENETIC LANDSCAPE OF VASCULAR CALCIFICATION: AN INTEGRATIVE PERSPECTIVE. VASCULAR CALCIFICATION (VC) IS AN IMPORTANT COMPLICATION AMONG PATIENTS OF ADVANCED AGE, THOSE WITH CHRONIC KIDNEY DISEASE, AND THOSE WITH DIABETES MELLITUS. THE PATHOPHYSIOLOGY OF VC ENCOMPASSES PASSIVE OCCURRENCE OF PHYSICO-CHEMICAL CALCIUM DEPOSITION, ACTIVE CELLULAR SECRETION OF OSTEOID MATRIX UPON EXPOSURE TO METABOLICALLY NOXIOUS STIMULI, OR A VARIABLE COMBINATION OF BOTH PROCESSES. EPIGENETIC ALTERATIONS HAVE BEEN SHOWN TO PARTICIPATE IN THIS COMPLEX ENVIRONMENT, THROUGH MECHANISMS INCLUDING DNA METHYLATION, NON-CODING RNAS, HISTONE MODIFICATIONS, AND CHROMATIN CHANGES. DESPITE SUCH IMPORTANCE, EXISTING REVIEWS FAIL TO PROVIDE A COMPREHENSIVE VIEW OF ALL RELEVANT REPORTS ADDRESSING EPIGENETIC PROCESSES IN VC, AND CROSS-TALK BETWEEN DIFFERENT EPIGENETIC MACHINERIES IS RARELY EXAMINED. WE CONDUCTED A SYSTEMATIC REVIEW BASED ON PUBMED AND MEDLINE DATABASES UP TO 30 SEPTEMBER 2019, TO IDENTIFY CLINICAL, TRANSLATIONAL, AND EXPERIMENTAL REPORTS ADDRESSING EPIGENETIC PROCESSES IN VC; WE RETRIEVED 66 ORIGINAL STUDIES, AMONG WHICH 60.6% LOOKED INTO THE PATHOGENIC ROLE OF NON-CODING RNA, FOLLOWED BY DNA METHYLATION (12.1%), HISTONE MODIFICATION (9.1%), AND CHROMATIN CHANGES (4.5%). NINE (13.6%) REPORTS EXAMINED THE DISCREPANCY OF EPIGENETIC SIGNATURES BETWEEN SUBJECTS OR TISSUES WITH AND WITHOUT VC, SUPPORTING THEIR APPLICABILITY AS BIOMARKERS. ASSISTED BY BIOINFORMATIC ANALYSES BLENDING IN EACH EPIGENETIC COMPONENT, WE DISCOVERED PROMINENT INTERACTIONS BETWEEN MICRORNAS, DNA METHYLATION, AND HISTONE MODIFICATION REGARDING POTENTIAL INFLUENCES ON VC RISK. 2020 10 6909 36 [TOXIC COMPONENTS OF PM(2.5) AND THEIR TOXICITY MECHANISMS-ON THE TOXICITY OF SULFATE AND CARBON COMPONENTS]. RECENTLY, THE MAIN AIR POLLUTANT HAS BEEN FINE PARTICULATE MATTER (PM(2.5)), WHICH IS TAKEN UP BY THE WHOLE BODY WITH SEVERE ADVERSE HEALTH EFFECTS. THE MAIN CHEMICAL COMPONENTS OF PM(2.5) ARE SALTS OF SULFATE (AND NITRATE) AND CARBONS. HOWEVER, IT REMAINS UNKNOWN WHICH COMPONENTS ARE TOXIC. HERE, THE AUTHOR REVIEWED THE LITERATURES TO DETERMINE WHICH COMPONENTS ARE TOXIC AND THE MAIN MECHANISMS UNDERLYING THEIR TOXICITY. MANY EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT SULFATE CONCENTRATION IS STRONGLY RELATED TO MORTALITY. HOWEVER, THERE IS NO EXPERIMENTAL EVIDENCE SHOWING THAT SULFATE AT ENVIRONMENTAL CONCENTRATIONS OF PM(2.5) CAUSES CARDIOVASCULAR DISEASE OR OTHER DISEASE. ON THE OTHER HAND, CARBON COMPONENTS SUCH AS ELEMENTARY CARBON (EC) PRODUCES HIGH CONCENTRATIONS OF REACTIVE OXYGEN SPECIES (ROS) VIA ITS PHAGOCYTOSIS BY MACROPHAGES, AND ORGANIC CARBON (OC) ALSO PRODUCES HIGH CONCENTRATIONS OF ROS DURING ITS METABOLIC PROCESSES, AND THE ROS CAUSE ACUTE AND CHRONIC INFLAMMATION. THEY CAUSE MANY DISEASES INCLUDING CARDIOVASCULAR DISEASE, ASTHMA AND CANCER. FURTHERMORE, THERE ARE MANY LINES OF EVIDENCE SHOWING THAT EPIGENETIC CHANGES SUCH AS DNA METHYLATION OR MICRORNA EXPRESSION INDUCED BY PARTICULATE MATTERS ALSO INDUCE THE DEVELOPMENT OF MANY DISEASES SUCH AS THOSE MENTIONED ABOVE. IT HAS BEEN REPORTED THAT CARBON COMPONENTS ARE INCORPORATED INTO THE BRAIN AND PRODUCE ROS, AND THAT THE ROS CAUSE DAMAGE TO BRAIN CELLS AND ALZHEIMER'S DISEASE AND COGNITIVE DISORDERS IN THE ELDERLY.FROM THESE LINES OF EVIDENCE, THE AUTHOR WOULD LIKE TO EMPHASIZE THAT THE MAIN TOXICITY OF PM(2.5) IS DUE TO CARBON COMPONENTS, AND IT IS IMPORTANT TO TAKE COUNTERMEASURES TO DECREASE THE CONCENTRATION OF CARBON COMPONENTS IN AMBIENT AIR. 2019 11 2772 39 EXTRACELLULAR ATP AND NEURODEGENERATION. ATP IS A POTENT SIGNALING MOLECULE ABUNDANTLY PRESENT IN THE CNS. IT ELICITS A WIDE ARRAY OF PHYSIOLOGICAL EFFECTS AND IS REGARDED AS THE PHYLOGENETICALLY MOST ANCIENT EPIGENETIC FACTOR PLAYING CRUCIAL BIOLOGICAL ROLES IN SEVERAL DIFFERENT TISSUES. THESE CAN RANGE FROM NEUROTRANSMISSION, SMOOTH MUSCLE CONTRACTION, CHEMOSENSORY SIGNALING, SECRETION AND VASODILATATION, TO MORE COMPLEX PHENOMENA SUCH AS IMMUNE RESPONSES, PAIN, MALE REPRODUCTION, FERTILIZATION AND EMBRYONIC DEVELOPMENT. ATP IS RELEASED INTO THE EXTRACELLULAR SPACE EITHER EXOCYTOTICALLY OR FROM DAMAGED AND DYING CELLS. IT IS OFTEN CO-RELEASED WITH OTHER NEUROTRANSMITTERS AND IT CAN INTERACT WITH GROWTH FACTORS AT BOTH RECEPTOR- AND/OR SIGNAL TRANSDUCTION-LEVEL. ONCE IN THE EXTRACELLULAR ENVIRONMENT, ATP BINDS TO SPECIFIC RECEPTORS TERMED P2. BASED ON PHARMACOLOGICAL PROFILES, ON SELECTIVITY OF COUPLING TO SECOND-MESSENGER PATHWAYS AND ON MOLECULAR CLONING, TWO MAIN SUBCLASSES WITH MULTIPLE SUBTYPES HAVE BEEN DISTINGUISHED. THEY ARE P2X, I.E. FAST CATION-SELECTIVE RECEPTOR CHANNELS (NA+, K+, CA2+), POSSESSING LOW AFFINITY FOR ATP AND RESPONSIBLE FOR FAST EXCITATORY NEUROTRANSMISSION, AND P2Y, I.E. SLOW G PROTEIN-COUPLED METABOTROPIC RECEPTORS, POSSESSING HIGHER AFFINITY FOR THE LIGAND. IN THE NERVOUS SYSTEM, THEY ARE BROADLY EXPRESSED IN BOTH NEURONS AND GLIAL CELLS AND CAN MEDIATE DUAL EFFECTS: SHORT-TERM SUCH AS NEUROTRANSMISSION, AND LONG-TERM SUCH AS TROPHIC ACTIONS. SINCE MASSIVE EXTRACELLULAR RELEASE OF ATP OFTEN OCCURS AFTER METABOLIC STRESS, BRAIN ISCHEMIA AND TRAUMA, PURINERGIC MECHANISMS ARE ALSO CORRELATED TO AND INVOLVED IN THE ETIOPATHOLOGY OF MANY NEURODEGENERATIVE CONDITIONS. FURTHERMORE, EXTRACELLULAR ATP PER SE IS TOXIC FOR PRIMARY NEURONAL DISSOCIATED AND ORGANOTYPIC CNS CULTURES FROM CORTEX, STRIATUM AND CEREBELLUM AND P2 RECEPTORS CAN MEDIATE AND AGGRAVATE HYPOXIC SIGNALING IN MANY CNS NEURONS. CONVERSELY, SEVERAL P2 RECEPTOR ANTAGONISTS ABOLISH THE CELL DEATH FATE OF PRIMARY NEURONAL CULTURES EXPOSED TO EXCESSIVE GLUTAMATE, SERUM/POTASSIUM DEPRIVATION, HYPOGLYCEMIA AND CHEMICAL HYPOXIA. IN PARALLEL WITH THESE DETRIMENTAL EFFECTS, ALSO TROPHIC FUNCTIONS HAVE BEEN EXTENSIVELY DESCRIBED FOR EXTRACELLULAR PURINES (BOTH FOR NEURONAL AND NON-NEURONAL CELLS), BUT THESE MIGHT EITHER AGGRAVATE OR AMELIORATE THE NORMAL CELLULAR CONDITIONS. IN SUMMARY, EXTRACELLULAR ATP PLAYS A VERY COMPLEX ROLE NOT ONLY IN THE REPAIR, REMODELING AND SURVIVAL OCCURRING IN THE NERVOUS SYSTEM, BUT EVEN IN CELL DEATH AND THIS CAN OCCUR EITHER AFTER NORMAL DEVELOPMENTAL CONDITIONS, AFTER INJURY, OR ACUTE AND CHRONIC DISEASES. 2003 12 5381 35 RECONSIDERING THE ROLE OF MITOCHONDRIA IN AGING. BACKGROUND: MITOCHONDRIAL DYSFUNCTION HAS LONG BEEN CONSIDERED A MAJOR CONTRIBUTOR TO AGING AND AGE-RELATED DISEASES. HARMAN'S MITOCHONDRIAL FREE RADICAL THEORY OF AGING POSTULATED THAT SOMATIC MITOCHONDRIAL DNA MUTATIONS THAT ACCUMULATE OVER THE LIFE SPAN CAUSE EXCESSIVE PRODUCTION OF REACTIVE OXYGEN SPECIES THAT DAMAGE MACROMOLECULES AND IMPAIR CELL AND TISSUE FUNCTION. INDEED, STUDIES HAVE SHOWN THAT MAXIMAL OXIDATIVE CAPACITY DECLINES WITH AGE WHILE REACTIVE OXYGEN SPECIES PRODUCTION INCREASES. HARMAN'S HYPOTHESIS HAS BEEN SERIOUSLY CHALLENGED BY RECENT STUDIES SHOWING THAT REACTIVE OXYGEN SPECIES EVOKE METABOLIC HEALTH AND LONGEVITY, PERHAPS THROUGH HORMETIC MECHANISMS THAT INCLUDE AUTOPHAGY. THE PURPOSE OF THIS REVIEW IS TO SCAN THE EVER-GROWING LITERATURE ON MITOCHONDRIA FROM THE PERSPECTIVE OF AGING RESEARCH AND TRY TO IDENTIFY PRIORITY QUESTIONS THAT SHOULD BE ADDRESSED IN FUTURE RESEARCH. METHODS: A SYSTEMATIC SEARCH OF PEER-REVIEWED STUDIES WAS PERFORMED USING PUBMED. SEARCH TERMS INCLUDED (I) MITOCHONDRIA OR MITOCHONDRIAL; (II) AGING, AGEING, OLDER ADULTS OR ELDERLY; AND (III) REACTIVE OXYGEN SPECIES, MITOCHONDRIA DYNAMICS, MITOCHONDRIAL PROTEOSTASIS, CYTOSOL, MITOCHONDRIAL-ASSOCIATED MEMBRANES, REDOX HOMEOSTASIS, ELECTRON TRANSPORT CHAIN, ELECTRON TRANSPORT CHAIN EFFICIENCY, EPIGENETIC REGULATION, DNA HETEROPLASMY. RESULTS: THE IMPORTANCE OF MITOCHONDRIAL BIOLOGY AS A TRAIT D'UNION BETWEEN THE BASIC BIOLOGY OF AGING AND THE PATHOGENESIS OF AGE-RELATED DISEASES IS STRONGER THAN EVER, ALTHOUGH THE EMPHASIS HAS MOVED FROM REACTIVE OXYGEN SPECIES PRODUCTION TO OTHER ASPECTS OF MITOCHONDRIAL PHYSIOLOGY, INCLUDING MITOCHONDRIAL BIOGENESIS AND TURNOVER, ENERGY SENSING, APOPTOSIS, SENESCENCE, AND CALCIUM DYNAMICS. CONCLUSIONS: MITOCHONDRIA COULD PLAY A KEY ROLE IN THE PATHOPHYSIOLOGY OF AGING OR IN THE EARLIER STAGES OF SOME EVENTS THAT LEAD TO THE AGING PHENOTYPE. THEREFORE, MITOCHONDRIA WILL INCREASINGLY BE TARGETED TO PREVENT AND TREAT CHRONIC DISEASES AND TO PROMOTE HEALTHY AGING. 2015 13 6374 38 THE ROLE OF MITOCHONDRIA IN MYOCARDIAL DAMAGE CAUSED BY ENERGY METABOLISM DISORDERS: FROM MECHANISMS TO THERAPEUTICS. MYOCARDIAL DAMAGE IS THE MOST SERIOUS PATHOLOGICAL CONSEQUENCE OF CARDIOVASCULAR DISEASES AND AN IMPORTANT REASON FOR THEIR HIGH MORTALITY. IN RECENT YEARS, BECAUSE OF THE HIGH PREVALENCE OF SYSTEMIC ENERGY METABOLISM DISORDERS (E.G., OBESITY, DIABETES MELLITUS, AND METABOLIC SYNDROME), COMPLICATIONS OF MYOCARDIAL DAMAGE CAUSED BY THESE DISORDERS HAVE ATTRACTED WIDESPREAD ATTENTION. ENERGY METABOLISM DISORDERS ARE INDEPENDENT OF TRADITIONAL INJURY-RELATED RISK FACTORS, SUCH AS ISCHEMIA, HYPOXIA, TRAUMA, AND INFECTION. AN IMBALANCE OF MYOCARDIAL METABOLIC FLEXIBILITY AND MYOCARDIAL ENERGY DEPLETION ARE USUALLY THE INITIAL CHANGES OF MYOCARDIAL INJURY CAUSED BY ENERGY METABOLISM DISORDERS, AND ABNORMAL MORPHOLOGY AND FUNCTIONAL DESTRUCTION OF THE MITOCHONDRIA ARE THEIR IMPORTANT FEATURES. SPECIFICALLY, MITOCHONDRIA ARE THE CENTERS OF ENERGY METABOLISM, AND RECENT EVIDENCE HAS SHOWN THAT DECREASED MITOCHONDRIAL FUNCTION, CAUSED BY AN IMBALANCE IN MITOCHONDRIAL QUALITY CONTROL, MAY PLAY A KEY ROLE IN MYOCARDIAL INJURY CAUSED BY ENERGY METABOLISM DISORDERS. UNDER CHRONIC ENERGY STRESS, MITOCHONDRIA UNDERGO PATHOLOGICAL FISSION, WHILE MITOPHAGY, MITOCHONDRIAL FUSION, AND BIOGENESIS ARE INHIBITED, AND MITOCHONDRIAL PROTEIN BALANCE AND TRANSFER ARE DISTURBED, RESULTING IN THE ACCUMULATION OF NONFUNCTIONAL AND DAMAGED MITOCHONDRIA. CONSEQUENTLY, DAMAGED MITOCHONDRIA LEAD TO MYOCARDIAL ENERGY DEPLETION AND THE ACCUMULATION OF LARGE AMOUNTS OF REACTIVE OXYGEN SPECIES, FURTHER AGGRAVATING THE IMBALANCE IN MITOCHONDRIAL QUALITY CONTROL AND FORMING A VICIOUS CYCLE. IN ADDITION, IMPAIRED MITOCHONDRIA COORDINATE CALCIUM HOMEOSTASIS IMBALANCE, AND EPIGENETIC ALTERATIONS PARTICIPATE IN THE PATHOGENESIS OF MYOCARDIAL DAMAGE. THESE PATHOLOGICAL CHANGES INDUCE RAPID PROGRESSION OF MYOCARDIAL DAMAGE, EVENTUALLY LEADING TO HEART FAILURE OR SUDDEN CARDIAC DEATH. TO INTERVENE MORE SPECIFICALLY IN THE MYOCARDIAL DAMAGE CAUSED BY METABOLIC DISORDERS, WE NEED TO UNDERSTAND THE SPECIFIC ROLE OF MITOCHONDRIA IN THIS CONTEXT IN DETAIL. ACCORDINGLY, PROMISING THERAPEUTIC STRATEGIES HAVE BEEN PROPOSED. WE ALSO SUMMARIZE THE EXISTING THERAPEUTIC STRATEGIES TO PROVIDE A REFERENCE FOR CLINICAL TREATMENT AND DEVELOPING NEW THERAPIES. 2023 14 6700 49 VASCULAR CALCIFICATION MECHANISMS: UPDATES AND RENEWED INSIGHT INTO SIGNALING PATHWAYS INVOLVED IN HIGH PHOSPHATE-MEDIATED VASCULAR SMOOTH MUSCLE CELL CALCIFICATION. VASCULAR CALCIFICATION (VC) IS ASSOCIATED WITH AGING, CARDIOVASCULAR AND RENAL DISEASES AND RESULTS IN POOR MORBIDITY AND INCREASED MORTALITY. VC OCCURS IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD), A CONDITION THAT IS ASSOCIATED WITH HIGH SERUM PHOSPHATE (PI) AND SEVERE CARDIOVASCULAR CONSEQUENCES. HIGH SERUM PI LEVEL IS RELATED TO SOME PATHOLOGIES WHICH AFFECT THE BEHAVIOUR OF VASCULAR CELLS, INCLUDING PLATELETS, ENDOTHELIAL CELLS (ECS) AND SMOOTH MUSCLE CELLS (SMCS), AND PLAYS A CENTRAL ROLE IN PROMOTING VC. VC IS A COMPLEX, ACTIVE AND CELL-MEDIATED PROCESS INVOLVING THE TRANSDIFFERENTIATION OF VASCULAR SMCS TO A BONE-LIKE PHENOTYPE, SYSTEMIC INFLAMMATION, DECREASED ANTI-CALCIFIC EVENTS (LOSS OF CALCIFICATION INHIBITORS), LOSS IN SMC LINEAGE MARKERS AND ENHANCED PRO-CALCIFIC MICRORNAS (MIRS), AN INCREASED INTRACELLULAR CALCIUM LEVEL, APOPTOSIS, ABERRANT DNA DAMAGE RESPONSE (DDR) AND SENESCENCE OF VASCULAR SMCS. THIS REVIEW GIVES A BRIEF OVERVIEW OF THE CURRENT KNOWLEDGE OF VC MECHANISMS WITH A PARTICULAR FOCUS ON PI-INDUCED CHANGES IN THE VASCULAR WALL IMPORTANT IN PROMOTING CALCIFICATION. IN ADDITION TO REVIEWING THE MAIN FINDINGS, THIS REVIEW ALSO SHEDS LIGHT ON DIRECTIONS FOR FUTURE RESEARCH IN THIS AREA AND DISCUSSES EMERGING PATHWAYS SUCH AS PI-REGULATED INTRACELLULAR CALCIUM SIGNALING, EPIGENETICS, OXIDATIVE DNA DAMAGE AND SENESCENCE-MEDIATED MECHANISMS THAT MAY PLAY CRITICAL, YET TO BE EXPLORED, REGULATORY AND DRUGGABLE ROLES IN LIMITING VC. 2021 15 5391 34 REDOX-RELATED BIOMARKERS IN HUMAN CARDIOVASCULAR DISEASE - CLASSICAL FOOTPRINTS AND BEYOND. GLOBAL EPIDEMIOLOGICAL STUDIES SHOW THAT CHRONIC NON-COMMUNICABLE DISEASES SUCH AS ATHEROSCLEROSIS AND METABOLIC DISORDERS REPRESENT THE LEADING CAUSE OF PREMATURE MORTALITY AND MORBIDITY. CARDIOVASCULAR DISEASE SUCH AS ISCHEMIC HEART DISEASE IS A MAJOR CONTRIBUTOR TO THE GLOBAL BURDEN OF DISEASE AND THE SOCIOECONOMIC HEALTH COSTS. CLINICAL AND EPIDEMIOLOGICAL DATA SHOW AN ASSOCIATION OF TYPICAL OXIDATIVE STRESS MARKERS SUCH AS LIPID PEROXIDATION PRODUCTS, 3-NITROTYROSINE OR OXIDIZED DNA/RNA BASES WITH ALL MAJOR CARDIOVASCULAR DISEASES. THIS SUPPORTS THE CONCEPT THAT THE FORMATION OF REACTIVE OXYGEN AND NITROGEN SPECIES BY VARIOUS SOURCES (NADPH OXIDASES, XANTHINE OXIDASE AND MITOCHONDRIAL RESPIRATORY CHAIN) REPRESENTS A HALLMARK OF THE LEADING CARDIOVASCULAR COMORBIDITIES SUCH AS HYPERLIPIDEMIA, HYPERTENSION AND DIABETES. THESE REACTIVE OXYGEN AND NITROGEN SPECIES CAN LEAD TO OXIDATIVE DAMAGE BUT ALSO ADVERSE REDOX SIGNALING AT THE LEVEL OF KINASES, CALCIUM HANDLING, INFLAMMATION, EPIGENETIC CONTROL, CIRCADIAN CLOCK AND PROTEASOMAL SYSTEM. THE IN VIVO FOOTPRINTS OF THESE ADVERSE PROCESSES (REDOX BIOMARKERS) ARE DISCUSSED IN THE PRESENT REVIEW WITH FOCUS ON THEIR CLINICAL RELEVANCE, WHEREAS THE DETAILS OF THEIR MECHANISMS OF FORMATION AND TECHNICAL ASPECTS OF THEIR DETECTION ARE ONLY BRIEFLY MENTIONED. THE MAJOR CATEGORIES OF REDOX BIOMARKERS ARE SUMMARIZED AND EXPLAINED ON THE BASIS OF SUITABLE EXAMPLES. ALSO THE POTENTIAL PROGNOSTIC VALUE OF REDOX BIOMARKERS IS CRITICALLY DISCUSSED TO UNDERSTAND WHAT KIND OF INFORMATION THEY CAN PROVIDE BUT ALSO WHAT THEY CANNOT ACHIEVE. 2021 16 4119 37 MECHANISMS OF CADMIUM CARCINOGENICITY IN THE GASTROINTESTINAL TRACT. CANCER, A SERIOUS PUBLIC HEALTH PROBLEM IN WORLDWIDE, RESULTS FROM AN EXCESSIVE AND UNCONTROLLED PROLIFERATION OF THE BODY CELLS WITHOUT OBVIOUS PHYSIOLOGICAL DEMANDS OF ORGANS. THE GASTROINTESTINAL TRACT, INCLUDING THE ESOPHAGUS, STOMACH AND INTESTINE, IS A UNIQUE ORGAN SYSTEM. IT HAS THE HIGHEST CANCER INCIDENCE AND CANCER- RELATED MORTALITY IN THE BODY AND IS INFLUENCEED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. AMONG THE VARIOUS CHEMICAL ELEMENTS RECOGNIZED IN THE NATURE, SOME OF THEM INCLUDING ZINC, IRON, COBALT, AND COPPER HAVE ESSENTIAL ROLES IN THE VARIOUS BIOCHEMICAL AND PHYSIOLOGICAL PROCESSES, BUT ONLY AT LOW LEVELS AND OTHERS SUCH AS CADMIUM, LEAD, MERCURY, ARSENIC, AND NICKEL ARE CONSIDERED AS THREATS FOR HUMAN HEALTH ESPECIALLY WITH CHRONIC EXPOSURE AT HIGH LEVELS. CADMIUM, AN ENVIRONMENT CONTAMINANT, CANNOT BE DESTROYED IN NATURE. THROUGH IMPAIRMENT OF VITAMIN D METABOLISM IN THE KIDNEY IT CAUSES NEPHROTOXICITY AND SUBSEQUENTLY BONE METABOLISM IMPAIRMENT AND FRAGILITY. THE MAJOR MECHANISMS INVOLVED IN CADMIUM CARCINOGENESIS COULD BE RELATED TO THE SUPPRESSION OF GENE EXPRESSION, INHIBITION OF DNA DAMAGE REPAIR, INHIBITION OF APOPTOSIS, AND INDUCTION OF OXIDATIVE STRESS. IN ADDITION, CADMIUM MAY ACT THROUGH ABERRANT DNA METHYLATION. CADMIUM AFFECTS MULTIPLE CELLULAR PROCESSES, INCLUDING SIGNAL TRANSDUCTION PATHWAYS, CELL PROLIFERATION, DIFFERENTIATION, AND APOPTOSIS. DOWN-REGULATION OF METHYLTRANSFERASES ENZYMES AND REDUCTION OF DNA METHYLATION HAVE BEEN STATED AS EPIGENETIC EFFECTS OF CADMIUM. FURTHERMORE, INCREASING INTRACELLULAR FREE CALCIUM ION LEVELS INDUCES NEURONAL APOPTOSIS IN ADDITION TO OTHER DELETERIOUS INFLUENCE ON THE STABILITY OF THE GENOME. 2015 17 5596 36 ROLES OF HISTONE ACETYLATION MODIFIERS AND OTHER EPIGENETIC REGULATORS IN VASCULAR CALCIFICATION. VASCULAR CALCIFICATION (VC) IS CHARACTERIZED BY CALCIUM DEPOSITION INSIDE ARTERIES AND IS CLOSELY ASSOCIATED WITH THE MORBIDITY AND MORTALITY OF ATHEROSCLEROSIS, CHRONIC KIDNEY DISEASE, DIABETES, AND OTHER CARDIOVASCULAR DISEASES (CVDS). VC IS NOW WIDELY KNOWN TO BE AN ACTIVE PROCESS OCCURRING IN VASCULAR SMOOTH MUSCLE CELLS (VSMCS) INVOLVING MULTIPLE MECHANISMS AND FACTORS. THESE MECHANISMS SHARE FEATURES WITH THE PROCESS OF BONE FORMATION, SINCE THE PHENOTYPE SWITCHING FROM THE CONTRACTILE TO THE OSTEOCHONDROGENIC PHENOTYPE ALSO OCCURS IN VSMCS DURING VC. IN ADDITION, VC CAN BE REGULATED BY EPIGENETIC FACTORS, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, AND NONCODING RNAS. ALTHOUGH VC IS COMMONLY OBSERVED IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND CVD, SPECIFIC DRUGS FOR VC HAVE NOT BEEN DEVELOPED. THUS, DISCOVERING NOVEL THERAPEUTIC TARGETS MAY BE NECESSARY. IN THIS REVIEW, WE SUMMARIZE THE CURRENT EXPERIMENTAL EVIDENCE REGARDING THE ROLE OF EPIGENETIC REGULATORS INCLUDING HISTONE DEACETYLASES AND PROPOSE THE THERAPEUTIC IMPLICATION OF THESE REGULATORS IN THE TREATMENT OF VC. 2020 18 1157 35 CONTAMINANT METALS AS CARDIOVASCULAR RISK FACTORS: A SCIENTIFIC STATEMENT FROM THE AMERICAN HEART ASSOCIATION. EXPOSURE TO ENVIRONMENTAL POLLUTANTS IS LINKED TO INCREASED RISK OF CARDIOVASCULAR DISEASE. BEYOND THE EXTENSIVE EVIDENCE FOR PARTICULATE AIR POLLUTION, ACCUMULATING EVIDENCE SUPPORTS THAT EXPOSURE TO NONESSENTIAL METALS SUCH AS LEAD, CADMIUM, AND ARSENIC IS A SIGNIFICANT CONTRIBUTOR TO CARDIOVASCULAR DISEASE WORLDWIDE. HUMANS ARE EXPOSED TO METALS THROUGH AIR, WATER, SOIL, AND FOOD AND EXTENSIVE INDUSTRIAL AND PUBLIC USE. CONTAMINANT METALS INTERFERE WITH CRITICAL INTRACELLULAR REACTIONS AND FUNCTIONS LEADING TO OXIDATIVE STRESS AND CHRONIC INFLAMMATION THAT RESULT IN ENDOTHELIAL DYSFUNCTION, HYPERTENSION, EPIGENETIC DYSREGULATION, DYSLIPIDEMIA, AND CHANGES IN MYOCARDIAL EXCITATION AND CONTRACTILE FUNCTION. LEAD, CADMIUM, AND ARSENIC HAVE BEEN LINKED TO SUBCLINICAL ATHEROSCLEROSIS, CORONARY ARTERY STENOSIS, AND CALCIFICATION AS WELL AS TO INCREASED RISK OF ISCHEMIC HEART DISEASE AND STROKE, LEFT VENTRICULAR HYPERTROPHY AND HEART FAILURE, AND PERIPHERAL ARTERY DISEASE. EPIDEMIOLOGICAL STUDIES SHOW THAT EXPOSURE TO LEAD, CADMIUM, OR ARSENIC IS ASSOCIATED WITH CARDIOVASCULAR DEATH MOSTLY ATTRIBUTABLE TO ISCHEMIC HEART DISEASE. PUBLIC HEALTH MEASURES REDUCING METAL EXPOSURE ARE ASSOCIATED WITH REDUCTIONS IN CARDIOVASCULAR DISEASE DEATH. POPULATIONS OF COLOR AND LOW SOCIOECONOMIC MEANS ARE MORE COMMONLY EXPOSED TO METALS AND THEREFORE AT GREATER RISK OF METAL-INDUCED CARDIOVASCULAR DISEASE. TOGETHER WITH STRENGTHENING PUBLIC HEALTH MEASURES TO PREVENT METAL EXPOSURES, DEVELOPMENT OF MORE SENSITIVE AND SELECTIVE MEASUREMENT MODALITIES, CLINICAL MONITORING OF METAL EXPOSURES, AND THE DEVELOPMENT OF METAL CHELATION THERAPIES COULD FURTHER DIMINISH THE BURDEN OF CARDIOVASCULAR DISEASE ATTRIBUTABLE TO METAL EXPOSURE. 2023 19 6774 40 [AGE-RELATED VASCULAR CHANGES EXEMPLIFIED BY THE CAROTID ARTERY]. ONE OF THE MAIN RISK FACTORS FOR THE PRESENCE OF CAROTID STENOSIS AND CAROTID-RELATED STROKE IS AGE. THE AIM OF THIS REVIEW ARTICLE IS TO PRESENT THE CURRENT STATE OF KNOWLEDGE ON AGE-RELATED VASCULAR CHANGES USING CAROTID STENOSIS AS AN EXAMPLE.VASCULAR AGING (VASCULAR SENESCENCE) IS A DECREASE OF STRUCTURAL AND FUNCTIONAL PROPERTIES OF THE VESSEL WALL THAT TAKES PLACE ON DIFFERENT LEVELS. AT THE MULTICELLULAR LEVEL AN INCREASE IN VESSEL VOLUME AND DIAMETER AS WELL AS INTIMA MEDIA THICKNESS OCCURS WITH AGE MAINLY DUE TO ATHEROSCLEROTIC CHANGES IN THE VESSEL WALL. AT THE CELLULAR AND EXTRACELLULAR LEVELS THERE IS A DECREASE IN ELASTIN FIBERS, SMOOTH MUSCLE CELLS, AND TOTAL CELLULARITY, AN INCREASE IN LIPID, CHOLESTEROL, AND CALCIUM PHOSPHATE DEPOSITION AS WELL AS NEOVASCULARIZATION. THE CAUSES OF VASCULAR AGING AT THE MOLECULAR LEVEL INCLUDE, IN PARTICULAR OXIDATIVE STRESS, CHRONIC INFLAMMATORY RESPONSE, MITOCHONDRIAL DYSFUNCTION, EPIGENETIC CHANGES, DYSREGULATION OF THE EXPRESSION OF NON-CODING RNAS (NCRNAS), AND THE INCREASE IN SENESCENCE. AGE-RELATED LOSS OF TISSUE HEALING AND REPAIR CAPACITY MAKE PLAQUES MORE VULNERABLE AND, IN THE CASE OF THE CAROTID ARTERY, MORE SUSCEPTIBLE TO ISCHEMIC STROKE.INCREASING KNOWLEDGE OF THE INFLUENCE OF AGING ON THE EPIGENETICS AND NCRNAS IN ATHEROSCLEROTIC PLAQUES CAN IN THE FUTURE MORE ACCURATELY QUANTIFY INDIVIDUAL PATIENT RISK AND CONTRIBUTE TO THE DEVELOPMENT OF TARGETED THERAPEUTIC STRATEGIES; HOWEVER, FURTHER STUDIES ARE NEEDED IN THIS FIELD TO UNDERSTAND THE FULL EXTENT OF VASCULAR AGING AND ITS ASSOCIATED DISEASES SO THAT THESE CAN THEN BE SPECIFICALLY TARGETED. 2022 20 339 31 ALTERATIONS IN HOMOCYSTEINE METABOLISM AMONG ALCOHOL DEPENDENT PATIENTS--CLINICAL, PATHOBIOCHEMICAL AND GENETIC ASPECTS. ADDICTION RESEARCH FOCUSING ON HOMOCYSTEINE METABOLISM AND ITS ASSOCIATION WITH ASPECTS OF ALCOHOL DEPENDENCE HAS REVEALED IMPORTANT FINDINGS. RECENT LITERATURE ON THIS TOPIC HAS BEEN TAKEN INTO ACCOUNT FOR THE REVIEW PROVIDED. METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) IS A KEY ENZYME IN THE HOMOCYSTEINE METABOLISM. PLASMA HOMOCYSTEINE LEVELS ARE INFLUENCED BY THE SINGLE-NUCLEOTIDE POLYMORPHISM (SNP) MTHFR C677T. BESIDES GENETIC FACTORS, ENVIRONMENTAL FACTORS HAVE AN IMPACT ON HOMOCYSTEINE PLASMA LEVELS TOO. THUS, CHRONIC ALCOHOL INTAKE IS ASSOCIATED WITH ELEVATED HOMOCYSTEINE PLASMA CONCENTRATIONS. ELEVATION OF PLASMA HOMOCYSTEINE CONCENTRATION IS CONSIDERED AS A PREDICTOR FOR THE OCCURRENCE OF ALCOHOL WITHDRAWAL SEIZURES AND--AS HOMOCYSTEINE IS A CARDIOVASCULAR RISK FACTOR--MIGHT CONTRIBUTE TO THE HIGHER RISK FOR MYOCARDIAL INFARCTION AMONG ALCOHOL DEPENDENT PATIENTS. HOMOCYSTEINE ACTS AS AN N-METHYL-D-ASPARTATE (NMDA) RECEPTOR AGONIST AND HAS EXCITOTOXIC EFFECTS. FURTHERMORE, IT HAS BEEN DEMONSTRATED THAT HOMOCYSTEINE HAS NEUROTOXIC EFFECTS ESPECIALLY ON DOPAMINERGIC NEURONS. AS THE REWARDING EFFECTS OF ALCOHOL ARE MEDIATED BY THE DOPAMINERGIC SYSTEM, A HOMOCYSTEINE-DEPENDENT IMPAIRMENT OF THE REWARD SYSTEM POSSIBLY LEADS TO AN ALTERED DRINKING BEHAVIOUR ACCORDING TO THE DEFICIT HYPOTHESIS OF ADDICTION. HOMOCYSTEINE IS INVOLVED IN THE METABOLISM OF METHYL GROUPS AND DNA-METHYLATION PLAYS A ROLE IN REGULATION OF GENE EXPRESSION. THEREFORE IT HAS BEEN SUGGESTED THAT HOMOCYSTEINE IS AN IMPORTANT EPIGENETIC FACTOR. IT REMAINS TO BE DETERMINED WHETHER ALCOHOL DEPENDENT PATIENTS BENEFIT FROM HOMOCYSTEINE LOWERING STRATEGIES, E.G., VIA SUPPLEMENTATION OF FOLATE, VITAMIN B6 AND B12. IN THIS RESPECT IT IS NOT CLEAR YET, IF A SUPPLEMENTATION THERAPY CAN REDUCE THE RISK FOR THE OCCURRENCE OF ALCOHOL WITHDRAWAL SEIZURES. 2008