1 238 129 ADENOSINE KINASE: A KEY REGULATOR OF PURINERGIC PHYSIOLOGY. ADENOSINE (ADO) IS AN ESSENTIAL BIOMOLECULE FOR LIFE THAT PROVIDES CRITICAL REGULATION OF ENERGY UTILIZATION AND HOMEOSTASIS. ADENOSINE KINASE (ADK) IS AN EVOLUTIONARY ANCIENT RIBOKINASE DERIVED FROM BACTERIAL SUGAR KINASES THAT IS WIDELY EXPRESSED IN ALL FORMS OF LIFE, TISSUES AND ORGAN SYSTEMS THAT TIGHTLY REGULATES INTRACELLULAR AND EXTRACELLULAR ADO CONCENTRATIONS. THE FACILE ABILITY OF ADK TO ALTER ADO AVAILABILITY PROVIDES A "SITE AND EVENT" SPECIFICITY TO THE ENDOGENOUS PROTECTIVE EFFECTS OF ADO IN SITUATIONS OF CELLULAR STRESS. IN ADDITION TO MODULATING THE ABILITY OF ADO TO ACTIVATE ITS COGNATE RECEPTORS (P1 RECEPTORS), NUCLEAR ADK ISOFORM ACTIVITY HAS BEEN LINKED TO EPIGENETIC MECHANISMS BASED ON TRANSMETHYLATION PATHWAYS. PREVIOUS DRUG DISCOVERY RESEARCH HAS TARGETED ADK INHIBITION AS A THERAPEUTIC APPROACH TO MANAGE EPILEPSY, PAIN, AND INFLAMMATION. THESE EFFORTS GENERATED MULTIPLE CLASSES OF HIGHLY POTENT AND SELECTIVE INHIBITORS. HOWEVER, CLINICAL DEVELOPMENT OF EARLY ADK INHIBITORS WAS STOPPED DUE TO APPARENT MECHANISTIC TOXICITY AND THE LACK OF SUITABLE TRANSLATIONAL MARKERS. NEW INSIGHTS REGARDING THE POTENTIAL ROLE OF THE NUCLEAR ADK ISOFORM (ADK-LONG) IN THE EPIGENETIC MODULATION OF MALADAPTIVE DNA METHYLATION OFFERS THE POSSIBILITY OF IDENTIFYING NOVEL ADK-ISOFORM SELECTIVE INHIBITORS AND NEW INTERVENTIONAL STRATEGIES THAT ARE INDEPENDENT OF ADO RECEPTOR ACTIVATION. 2021 2 5511 20 RIBONUCLEASES IN TUMOR GROWTH. THIS REVIEW SUMMARIZES DATA ON AMBIGUOUS BIOLOGICAL FUNCTIONS OF RIBONUCLEASES (RNASES) AT TUMOR GROWTH. IN SOME CASES THE RAISED LEVEL OF ENZYME ACTIVITY IN BIOLOGICAL FLUIDS CAN BE REGARDED AS AN ADDITIONAL MARKER OF MALIGNANT GROWTH (PANCREAS CANCER, CHRONIC MYELOID LEUKEMIA, ETC.). AT THE SAME TIME THE ACTIVITY OF RNASES IS OFTEN LOWERED IN TUMOR TISSUE. HIGH SUBSTRATE SPECIFICITY OF PARTICULAR RNASES PROVIDES METABOLIC BALANCE BETWEEN VARIOUS KINDS OF RNAS WITH VARIOUS HALF-TIME EXCHANGE TURN. RNASES ARE THE IMPORTANT FACTORS OF EPIGENETIC REGULATION OF GENE ACTIVITY IN CELLS. THE ACTIVITY OF RNASES IS ADJUSTABLE BY INHIBITORS AND OTHER FACTORS, AND DEFINES TIME OF EXISTENCE OF DIFFERENT KINDS OF RNAS. RNASES (THE MODIFIED VARIANTS OF RNASE A, RNASES OF SEMEN FLUID OF THE CATTLE, RNASE OF AMPHIBIA OOCYTES) CAN BE USED AS ANTI-TUMOR THERAPEUTIC AGENTS. ON THE OTHER HAND, SOME INHIBITORS OF RNASES OF NATURAL OR SYNTHETIC ORIGIN WERE DEMONSTRATED TO BE PERSPECTIVE DRUGS THAT INHIBIT TUMOR GROWTH. 2009 3 1679 28 DRUG RESISTANCE IN GIARDIA DUODENALIS. GIARDIA DUODENALIS IS A MICROAEROPHILIC PARASITE OF THE HUMAN GASTROINTESTINAL TRACT AND A MAJOR CONTRIBUTOR TO DIARRHEAL AND POST-INFECTIOUS CHRONIC GASTROINTESTINAL DISEASE WORLD-WIDE. TREATMENT OF G. DUODENALIS INFECTION CURRENTLY RELIES ON A SMALL NUMBER OF DRUG CLASSES. NITROHETEROCYCLICS, IN PARTICULAR METRONIDAZOLE, HAVE REPRESENTED THE FRONT LINE TREATMENT FOR THE LAST 40 YEARS. NITROHETEROCYCLIC-RESISTANT G. DUODENALIS HAVE BEEN ISOLATED FROM PATIENTS AND CREATED IN VITRO, PROMPTING CONSIDERABLE RESEARCH INTO THE BIOMOLECULAR MECHANISMS OF RESISTANCE. THESE COMPOUNDS ARE REDOX-ACTIVE AND ARE BELIEVED TO DAMAGE PROTEINS AND DNA AFTER BEING ACTIVATED BY OXIDOREDUCTASE ENZYMES IN METABOLICALLY ACTIVE CELLS. IN THIS REVIEW, WE EXPLORE THE MOLECULAR PHENOTYPES OF NITROHETEROCYCLIC-RESISTANT G. DUODENALIS DESCRIBED TO DATE IN THE CONTEXT OF THE PROTIST'S UNUSUAL GLYCOLYTIC AND ANTIOXIDANT SYSTEMS. WE PROPOSE THAT RESISTANCE MECHANISMS ARE LIKELY TO EXTEND WELL BEYOND CURRENTLY DESCRIBED RESISTANCE-ASSOCIATED ENZYMES (I.E., PYRUVATE FERREDOXIN OXIDOREDUCTASES AND NITROREDUCTASES), TO INCLUDE NAD(P)H- AND FLAVIN-GENERATING PATHWAYS, AND POSSIBLY REDOX-SENSITIVE EPIGENETIC REGULATION. MECHANISMS THAT ALLOW G. DUODENALIS TO TOLERATE OXIDATIVE STRESS MAY LEAD TO RESISTANCE AGAINST BOTH OXYGEN AND NITROHETEROCYCLICS, WITH IMPLICATIONS FOR CLINICAL CONTROL. THE PRESENT REVIEW HIGHLIGHTS THE POTENTIAL FOR SYSTEMS BIOLOGY TOOLS AND ADVANCED BIOINFORMATICS TO FURTHER INVESTIGATE THE MULTIFACETED MECHANISMS OF NITROHETEROCYCLIC RESISTANCE IN THIS IMPORTANT PATHOGEN. 2015 4 2818 12 FIBROSIS UNDER ARREST. APPROXIMATELY 5% OF PEOPLE THAT ARE HOSPITALIZED FOR ANY REASON DEVELOP ACUTE KIDNEY FAILURE, WHICH, IN SOME CASES, PROGRESSES TO A CHRONIC CONDITION RESULTING IN FIBROSIS OF THE KIDNEY AND PERMANENT CHANGES IN THE ORGAN'S FUNCTION. TWO NEW STUDIES SUGGEST THAT CELL CYCLE ARREST OF EPITHELIAL CELLS AND EPIGENETIC MODIFICATIONS HAVE KEY ROLES IN THE SWITCH TO CHRONIC DISEASE (PAGES 535-543 AND 544-550). 2010 5 760 20 CASZ1: CURRENT IMPLICATIONS IN CARDIOVASCULAR DISEASES AND CANCERS. CASTOR ZINC FINGER 1 (CASZ1) IS A C2H2 ZINC FINGER FAMILY PROTEIN THAT HAS TWO SPLICING VARIANTS, CASZ1A AND CASZ1B. IT IS INVOLVED IN MULTIPLE PHYSIOLOGICAL PROCESSES, SUCH AS TISSUE DIFFERENTIATION AND ALDOSTERONE ANTAGONISM. GENETIC AND EPIGENETIC ALTERNATIONS OF CASZ1 HAVE BEEN CHARACTERIZED IN MULTIPLE CARDIOVASCULAR DISORDERS, SUCH AS CONGENITAL HEART DISEASES, CHRONIC VENOUS DISEASES, AND HYPERTENSION. HOWEVER, LITTLE IS KNOWN ABOUT HOW CASZ1 MECHANICALLY PARTICIPATES IN THE PATHOGENESIS OF THESE DISEASES. OVER THE PAST DECADES, AT FIRST GLANCE, PARADOXICAL INFLUENCES ON CELL BEHAVIORS AND PROGRESSIONS OF DIFFERENT CANCER TYPES HAVE BEEN DISCOVERED FOR CASZ1, WHICH MAY BE EXPLAINED BY A "DOUBLE-AGENT" ROLE FOR CASZ1. IN THIS REVIEW, WE DISCUSS THE PHYSIOLOGICAL FUNCTION OF CASZ1, AND FOCUS ON THE ASSOCIATION OF CASZ1 ABERRATIONS WITH THE PATHOGENESIS OF CARDIOVASCULAR DISEASES AND CANCERS. 2023 6 35 18 A CHROMATIN ACTIVITY-BASED CHEMOPROTEOMIC APPROACH REVEALS A TRANSCRIPTIONAL REPRESSOME FOR GENE-SPECIFIC SILENCING. IMMUNE CELLS DEVELOP ENDOTOXIN TOLERANCE (ET) AFTER PROLONGED STIMULATION. ET INCREASES THE LEVEL OF A REPRESSION MARK H3K9ME2 IN THE TRANSCRIPTIONALLY SILENT CHROMATIN SPECIFICALLY ASSOCIATED WITH PRO-INFLAMMATORY GENES. HOWEVER, IT IS NOT CLEAR WHAT PROTEINS ARE FUNCTIONALLY INVOLVED IN THIS PROCESS. HERE WE SHOW THAT A NOVEL CHROMATIN ACTIVITY-BASED CHEMOPROTEOMIC (CHAC) APPROACH CAN DISSECT THE FUNCTIONAL CHROMATIN PROTEIN COMPLEXES THAT REGULATE ET-ASSOCIATED INFLAMMATION. USING UNC0638 THAT BINDS THE ENZYMATICALLY ACTIVE H3K9-SPECIFIC METHYLTRANSFERASE G9A/GLP, CHAC REVEALS THAT G9A IS CONSTITUTIVELY ACTIVE AT A G9A-DEPENDENT MEGA-DALTON REPRESSOME IN PRIMARY ENDOTOXIN-TOLERANT MACROPHAGES. G9A/GLP BROADLY IMPACTS THE ET-SPECIFIC REPROGRAMMING OF THE HISTONE CODE LANDSCAPE, CHROMATIN REMODELLING AND THE ACTIVITIES OF SELECT TRANSCRIPTION FACTORS. WE DISCOVER THAT THE G9A-DEPENDENT EPIGENETIC ENVIRONMENT PROMOTES THE TRANSCRIPTIONAL REPRESSION ACTIVITY OF C-MYC FOR GENE-SPECIFIC CO-REGULATION OF CHRONIC INFLAMMATION. CHAC MAY ALSO BE APPLICABLE TO DISSECT OTHER FUNCTIONAL PROTEIN COMPLEXES IN THE CONTEXT OF PHENOTYPIC CHROMATIN ARCHITECTURES. 2014 7 3130 25 GLAST BUT NOT LEAST--DISTRIBUTION, FUNCTION, GENETICS AND EPIGENETICS OF L-GLUTAMATE TRANSPORT IN BRAIN--FOCUS ON GLAST/EAAT1. SYNAPTICALLY RELEASED L-GLUTAMATE, THE MOST IMPORTANT EXCITATORY NEUROTRANSMITTER IN THE CNS, IS REMOVED FROM EXTRACELLULAR SPACE BY FAST AND EFFICIENT TRANSPORT MEDIATED BY SEVERAL TRANSPORTERS; THE MOST ABUNDANT ONES ARE EAAT1/GLAST AND EAAT2/GLT1. THE REVIEW FIRST SUMMARIZES THEIR LOCATION, FUNCTIONS AND BASIC CHARACTERISTICS. WE THEN LOOK AT GENETICS AND EPIGENETICS OF EAAT1/GLAST AND EAAT2/GLT1 AND PERFORM IN SILICO ANALYSES OF THEIR PROMOTER REGIONS. THERE IS ONE CPG ISLAND IN SLC1A2 (EAAT2/GLT1) GENE AND NONE IN SLC1A3 (EAAT1/GLAST) SUGGESTING THAT DNA METHYLATION IS NOT THE MOST IMPORTANT EPIGENETIC MECHANISM REGULATING EAAT1/GLAST LEVELS IN BRAIN. THERE ARE TARGETS FOR SPECIFIC MIRNA IN SLC1A2 (EAAT2/GLT1) GENE. WE ALSO NOTE THAT WHILE DEFECTS IN EAAT2/GLT1 HAVE BEEN ASSOCIATED WITH VARIOUS PATHOLOGICAL STATES INCLUDING CHRONIC NEURODEGENERATIVE DISEASES, VERY LITTLE IS KNOWN ON POSSIBLE CONTRIBUTIONS OF DEFECTIVE OR DYSFUNCTIONAL EAAT1/GLAST TO ANY SPECIFIC BRAIN DISEASE. FINALLY, WE REVIEW EVIDENCE OF EAAT1/GLAST INVOLVEMENT IN MECHANISMS OF BRAIN RESPONSE TO ALCOHOLISM AND PRESENT SOME PRELIMINARY DATA SHOWING THAT ETHANOL, AT CONCENTRATIONS WHICH MAY BE REACHED FOLLOWING HEAVY DRINKING, CAN HAVE AN EFFECT ON THE DISTRIBUTION OF EAAT1/GLAST IN CULTURED ASTROCYTES; THE EFFECT IS BLOCKED BY BACLOFEN, A GABA-B RECEPTOR AGONIST AND A DRUG POTENTIALLY USEFUL IN THE TREATMENT OF ALCOHOLISM. WE ARGUE THAT MORE RESEARCH EFFORT SHOULD BE FOCUSED ON EAAT1/GLAST, PARTICULARLY IN RELATION TO ALCOHOLISM AND DRUG ADDICTION. 2015 8 460 31 ARACHIDONIC ACID 15-LIPOXYGENASE: EFFECTS OF ITS EXPRESSION, METABOLITES, AND GENETIC AND EPIGENETIC VARIATIONS ON AIRWAY INFLAMMATION. ARACHIDONIC ACID 15-LIPOXYGENASE (ALOX15) IS AN ENZYME THAT CAN OXIDIZE POLYUNSATURATED FATTY ACIDS. ALOX15 IS STRONGLY EXPRESSED IN AIRWAY EPITHELIAL CELLS, WHERE IT CATALYZES THE CONVERSION OF ARACHIDONIC ACID TO 15-HYDROXYEICOSATETRAENOIC ACID (15-HETE) INVOLVED IN VARIOUS AIRWAY INFLAMMATORY DISEASES. INTERLEUKIN (IL)-4 AND IL-13 INDUCE ALOX15 EXPRESSION BY ACTIVATING JAK2 AND TYK2 KINASES AS WELL AS SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION (STATS) 1/3/5/6. ALOX15 UP-REGULATION AND SUBSEQUENT ASSOCIATION WITH PHOSPHATIDYLETHANOLAMINE-BINDING PROTEIN 1 (PEBP1) ACTIVATE THE MITOGEN-ACTIVATED EXTRACELLULAR SIGNAL-REGULATED KINASE (MEK)-EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) PATHWAY, THUS INDUCING EOSINOPHIL-MEDIATED AIRWAY INFLAMMATION. IN ADDITION, ALOX15 PLAYS A SIGNIFICANT ROLE IN PROMOTING THE MIGRATION OF IMMUNE CELLS, SUCH AS IMMATURE DENDRITIC CELLS, ACTIVATED T CELLS, AND MAST CELLS, AND AIRWAY REMODELING, INCLUDING GOBLET CELL DIFFERENTIATION. GENOME-WIDE ASSOCIATION STUDIES HAVE REVEALED MULTIPLE ALOX15 VARIANTS AND THEIR SIGNIFICANT CORRELATION WITH THE RISK OF DEVELOPING AIRWAY DISEASES. THE EPIGENETIC MODIFICATIONS OF THE ALOX15 GENE, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS, HAVE BEEN SHOWN TO CLOSELY RELATE WITH AIRWAY INFLAMMATION. THIS REVIEW SUMMARIZES THE ROLE OF ALOX15 IN DIFFERENT PHENOTYPES OF ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CHRONIC RHINOSINUSITIS, ASPIRIN-EXACERBATED RESPIRATORY DISEASE, AND NASAL POLYPS, SUGGESTING NEW TREATMENT STRATEGIES FOR THESE AIRWAY INFLAMMATORY DISEASES WITH COMPLEX ETIOLOGY AND POOR TREATMENT RESPONSE. 2021 9 3157 23 GLYCEMIC MEMORY. PURPOSE OF REVIEW: THE MISTAKE OF PREDICTING THE FUTURE IS PERHAPS NOT TENDING TO REPRESSED OR PAST MEMORIES. HAMLET'S 17TH-CENTURY SOLILOQUY 'THE HEARTACHE AND THE THOUSAND NATURAL SHOCKS, THAT FLESH IS HEIR TO', (3.1. 7-8) IS A TALE THAT LOOKS BEYOND THE PRESENT BY LINKING THE PAST WITH THE FUTURE. THE PRESENT ARTICLE EXAMINES THE RESURGENCE IN THE FIELD TO UNDERSTAND GENE-REGULATING EPIGENETIC CHANGES CONFERRING GLYCEMIC MEMORY. RECENT FINDINGS: CHROMATIN MODIFICATIONS ARE CRITICAL IN REGULATING GENOME STRUCTURE AND FUNCTION AND DESPITE THE SIGNIFICANT ADVANCES OF RECENT YEARS IN IDENTIFYING THE ENZYMES-MEDIATING CHEMICAL CHANGES TO HISTONE TAILS AND THE DNA TEMPLATE, THE PRECISE REGULATION OF GENE EXPRESSION REMAINS INCOMPLETE IN MODELS OF HEALTH AND DIABETIC COMPLICATIONS. SUMMARY: DISPELLING THE MYTH THAT ALL GENOMES ARE DRIVEN AND RESPOND EQUALLY, EXPERIMENTAL RESEARCH IS NOW UNCOVERING THE FUNCTION OF ENZYMES CONFERRING CHROMATIN MODIFICATIONS. WHATEVER THE ROLE OF THE EPIGENOME, SHOWING ITS INVOLVEMENT IN GLYCEMIC SIGNALING IS THE FIRST STEP TO NEW STRATEGIES AND TARGETS TO DEVELOP THERAPIES THAT PREVENT, RETARD OR REVERSE THE LONG-TERM DELETERIOUS END-ORGAN EFFECTS OF CHRONIC, INTERMITTENT AND PRIOR HYPERGLYCEMIA. 2012 10 681 33 BRAIN LIPOTOXICITY OF PHYTANIC ACID AND VERY LONG-CHAIN FATTY ACIDS. HARMFUL CELLULAR/MITOCHONDRIAL ACTIVITIES IN REFSUM DISEASE AND X-LINKED ADRENOLEUKODYSTROPHY. IT IS INCREASINGLY UNDERSTOOD THAT IN THE AGING BRAIN, ESPECIALLY IN THE CASE OF PATIENTS SUFFERING FROM NEURODEGENERATIVE DISEASES, SOME FATTY ACIDS AT PATHOLOGICALLY HIGH CONCENTRATIONS EXERT DETRIMENTAL ACTIVITIES. TO STUDY SUCH ACTIVITIES, WE HERE ANALYZE GENETIC DISEASES, WHICH ARE DUE TO COMPROMISED METABOLISM OF SPECIFIC FATTY ACIDS, EITHER THE BRANCHED-CHAIN PHYTANIC ACID OR VERY LONG-CHAIN FATTY ACIDS (VLCFAS). MICROMOLAR CONCENTRATIONS OF PHYTANIC ACID OR OF VLCFAS DISTURB THE INTEGRITY OF NEURAL CELLS BY IMPAIRING CA(2+) HOMEOSTASIS, ENHANCING OXIDATIVE STRESS OR DE-ENERGIZING MITOCHONDRIA. FINALLY, THESE COMBINED HARMFUL ACTIVITIES ACCELERATE CELL DEATH. MITOCHONDRIA ARE MORE SEVERELY TARGETED BY PHYTANIC ACID THAN BY VLCFAS. THE INSERTION OF VLCFAS INTO THE INNER MEMBRANE DISTORTS THE ARRANGEMENT OF MEMBRANE CONSTITUENTS AND THEIR FUNCTIONAL INTERACTIONS. PHYTANIC ACID EXERTS SPECIFIC PROTONOPHORIC ACTIVITY, INDUCES REACTIVE OXYGEN SPECIES (ROS) GENERATION, AND REDUCES ATP GENERATION. A CLEAR INHIBITION OF THE NA(+), K(+)-ATPASE ACTIVITY BY PHYTANIC ACID HAS ALSO BEEN REPORTED. IN ADDITION TO THE INSTANTANEOUS EFFECTS, A CHRONIC EXPOSURE OF BRAIN CELLS TO LOW MICROMOLAR CONCENTRATIONS OF PHYTANIC ACID MAY PRODUCE NEURONAL DAMAGE IN REFSUM DISEASE BY ALTERING EPIGENETIC TRANSCRIPTIONAL REGULATION. MYELIN-PRODUCING OLIGODENDROCYTES RESPOND WITH PARTICULAR SENSITIVITY TO VLCFAS. DELETERIOUS ACTIVITY OF VLCFAS ON ENERGY-DEPENDENT MITOCHONDRIAL FUNCTIONS DECLINES WITH INCREASING THE HYDROCARBON CHAIN LENGTH (C22:0 > C24:0 > C26:0). IN CONTRAST, THE REVERSE SEQUENCE HOLDS TRUE FOR CELL DEATH INDUCTION BY VLCFAS (C22:0 < C24:0 < C26:0). IN ADRENOLEUKODYSTROPHY, THE UPTAKE OF VLCFAS BY PEROXISOMES IS IMPAIRED BY DEFECTS OF THE ABCD1 TRANSPORTER. STUDYING MITOCHONDRIA FROM ABCD1-DEFICIENT AND WILD-TYPE MICE PROVES THAT THE ENERGY-DEPENDENT FUNCTIONS ARE NOT ALTERED IN THE DISEASE MODEL. THUS, A DEFECTIVE ABCD1 APPARENTLY EXERTS NO OBVIOUS ADAPTIVE PRESSURE ON MITOCHONDRIA. FURTHER RESEARCH HAS TO ELUCIDATE THE DETAILED MECHANISTIC BASIS FOR THE FAILURES CAUSING FATTY ACID-MEDIATED NEURODEGENERATION AND SHOULD HELP TO PROVIDE POSSIBLE THERAPEUTIC INTERVENTIONS. 2016 11 1449 19 DIRECT LINEAGE REPROGRAMMING FOR INDUCED KERATINOCYTE STEM CELLS: A POTENTIAL APPROACH FOR SKIN REPAIR. SEVERE TRAUMA OR CHRONIC WOUNDS CAN DEPLETE THE KERATINOCYTE STEM CELLS (KSCS) PRESENT IN THE EPIDERMAL BASAL LAYER OR INHIBIT THEIR MIGRATION LEADING TO COMPROMISED WOUND HEALING. SUPPLEMENTING KSCS IS THE KEY TO SOLUTION WHILE LINEAGE REPROGRAMMING PROVIDES A NEW APPROACH TO ACQUIRING KSCS. THROUGH DIRECT LINEAGE REPROGRAMMING, INDUCED KSCS (IKSCS) CAN BE PRODUCED FROM SOMATIC CELLS, WHICH EXHIBIT GREAT APPLICATION POTENTIAL. TWO STRATEGIES ARE CURRENTLY BEING USED TO DIRECTLY GENERATE IKSCS, LINEAGE TRANSCRIPTION FACTOR (TF)-MEDIATED AND PLURIPOTENCY FACTORS-MEDIATED. THIS REVIEW FOCUSES ON LINEAGE TF-MEDIATED DIRECT REPROGRAMMING AND DESCRIBES THE CONVERSION PROCESS ALONG WITH THE UNDERLYING EPIGENETIC MECHANISMS. IT ALSO DISCUSSES OTHER POTENTIAL INDUCTION STRATEGIES TO GENERATE IKSCS AND CHALLENGES ASSOCIATED WITH IN SITU REPROGRAMMING FOR SKIN REPAIR. 2023 12 3074 18 GENOME-WIDE DNA METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INORGANIC NANOPARTICLES IN HUMAN KIDNEY CELLS AFTER CHRONIC EXPOSURE. THE UNIQUE PHYSICOCHEMICAL PROPERTIES MAKE INORGANIC NANOPARTICLES (INPS) AN EXCITING TOOL IN DIAGNOSIS AND DISEASE MANAGEMENT. HOWEVER, AS INPS ARE RELATIVELY DIFFICULT TO FULLY DEGRADE AND EXCRETE, THEIR UNINTENDED ACCUMULATION IN THE TISSUE MIGHT RESULT IN ADVERSE HEALTH EFFECTS. HEREIN, WE PROVIDE A METHYLOME-TRANSCRIPTOME FRAMEWORK FOR CHRONIC EFFECTS OF INPS, COMMONLY USED IN BIOMEDICAL APPLICATIONS, IN HUMAN KIDNEY TH-1 CELLS. RENAL CLEARANCE IS ONE OF THE MOST IMPORTANT ROUTES OF NANOPARTICLE EXCRETION; THEREFORE, A DETAILED EVALUATION OF NANOPARTICLE-MEDIATED NEPHROTOXICITY IS AN IMPORTANT TASK. INTEGRATED ANALYSIS OF METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INPS (PEG-AUNPS, FE(3)O(4)NPS, SIO(2)NPS, AND TIO(2)NPS) REVEALED SIGNIFICANTLY DEREGULATED GENES WITH FUNCTIONAL CLASSIFICATION IN IMMUNE RESPONSE, DNA DAMAGE, AND CANCER-RELATED PATHWAYS. ALTHOUGH MOST DEREGULATED GENES WERE UNIQUE TO INDIVIDUAL INPS, A RELATIVELY HIGH PROPORTION OF THEM ENCODED THE TRANSCRIPTION FACTORS. INTERESTINGLY, FOS HYPERMETHYLATION INVERSELY CORRELATING WITH GENE EXPRESSION WAS ASSOCIATED WITH ALL INPS EXPOSURES. OUR STUDY EMPHASIZES THE NEED FOR A MORE COMPREHENSIVE INVESTIGATION OF INPS' BIOLOGICAL SAFETY, ESPECIALLY AFTER CHRONIC EXPOSURE. 2022 13 6484 20 TOXICOLOGIC PROFILE OF ACRYLONITRILE. ACRYLONITRILE IS A MONOMER USED EXTENSIVELY AS A RAW MATERIAL IN THE MANUFACTURING OF ACRYLIC FIBERS, PLASTICS, SYNTHETIC RUBBERS, AND ACRYLAMIDE. IT HAS BEEN CLASSIFIED AS A PROBABLE HUMAN CARCINOGEN ACCORDING TO THE RESULTS OF NUMEROUS CHRONIC RAT BIOASSAYS. THE PRESENT REPORT SUMMARIZES THE TOXICITY DATA ON ACRYLONITRILE AND REVIEWS AVAILABLE DATA CONCERNING THE MECHANISM (GENETIC VERSUS EPIGENETIC) BY WHICH ACRYLONITRILE IS CARCINOGENIC IN RATS. FROM THE EVALUATION OF THE RELEVANT TOXICITY DATA, IT CAN BE CONCLUDED THAT ACRYLONITRILE IS INDEED CARCINOGENIC TO RATS AFTER EITHER ORAL OR INHALATIONAL EXPOSURE. HOWEVER, INFORMATION ON OTHER MAMMALIAN SPECIES IS LACKING, AND, MOREOVER, THE EXACT MECHANISM OF THE CARCINOGENIC PROCESS IS UNCLEAR. THEREFORE, IT IS RECOMMENDED TO CONDUCT AN ADDITIONAL LONG-TERM INHALATION CARCINOGENICITY STUDY WITH ACRYLONITRILE IN MICE, AS WELL AS STUDIES INTO THE MECHANISM BY WHICH ACRYLONITRILE INDUCES (BRAIN) TUMORS IN RATS (GENETIC VERSUS EPIGENETIC). 1998 14 1109 21 COMMERCIAL PROCESSED SOY-BASED FOOD PRODUCT CONTAINS GLYCATED AND GLYCOXIDATED LUNASIN PROTEOFORMS. NUTRACEUTICALS HAVE BEEN PROPOSED TO EXERT POSITIVE EFFECTS ON HUMAN HEALTH AND CONFER PROTECTION AGAINST MANY CHRONIC DISEASES. A MAJOR BIOACTIVE COMPONENT OF SOY-BASED FOODS IS LUNASIN PEPTIDE, WHICH HAS POTENTIAL TO EXERT A MAJOR IMPACT ON THE HEALTH OF HUMAN CONSUMERS WORLDWIDE, BUT THE BIOCHEMICAL FEATURES OF DIETARY LUNASIN STILL REMAIN POORLY CHARACTERIZED. IN THIS STUDY, LUNASIN WAS PURIFIED FROM A SOY-BASED FOOD PRODUCT VIA STRONG ANION EXCHANGE SOLID PHASE EXTRACTION AND THEN SUBJECTED TO TOP-DOWN MASS SPECTROMETRY ANALYSIS THAT REVEALED IN DETAIL THE MOLECULAR DIVERSITY OF LUNASIN IN PROCESSED SOYBEAN FOODS. WE DETECTED MULTIPLE GLYCATED PROTEOFORMS TOGETHER WITH POTENTIALLY TOXIC ADVANCED GLYCATION END PRODUCTS (AGES) DERIVED FROM LUNASIN. IN BOTH CASES, MODIFICATION SITES WERE LYS24 AND LYS29 LOCATED AT THE HELICAL REGION THAT SHOWS STRUCTURAL HOMOLOGY WITH A CONSERVED REGION OF CHROMATIN-BINDING PROTEINS. THE IDENTIFIED POST-TRANSLATIONAL MODIFICATIONS MAY HAVE AN IMPORTANT REPERCUSSION ON LUNASIN EPIGENETIC REGULATORY CAPACITY. TAKING TOGETHER, OUR RESULTS DEMONSTRATE THE IMPORTANCE OF PROPER CHEMICAL CHARACTERIZATION OF COMMERCIAL PROCESSED FOOD PRODUCTS TO ASSESS THEIR IMPACT ON CONSUMER'S HEALTH AND RISK OF CHRONIC DISEASES. 2016 15 768 29 CD47 (CLUSTER OF DIFFERENTIATION 47). CD47, ALSO KNOWN AS INTEGRIN-ASSOCIATED PROTEIN, IS A CONSTITUTIVELY AND UBIQUITOUSLY EXPRESSED TRANSMEMBRANE RECEPTOR. CD47 IS CONSERVED ACROSS AMNIOTES INCLUDING MAMMALS, REPTILES, AND BIRDS. EXPRESSION IS INCREASED IN MANY CANCERS AND, IN NON-MALIGNANT CELLS, BY STRESS AND WITH AGING. THE UP-REGULATION OF CD47 EXPRESSION IS GENERALLY EPIGENETIC, WHEREAS GENE AMPLIFICATION OCCURS WITH LOW FREQUENCY IN SOME CANCERS. CD47 IS A HIGH AFFINITY SIGNALING RECEPTOR FOR THE SECRETED PROTEIN THROMBOSPONDIN-1 (THBS1) AND THE COUNTER-RECEPTOR FOR SIGNAL REGULATORY PROTEIN-ALPHA (SIRPA, SIRPALPHA) AND SIRPGAMMA (SIRPG). CD47 INTERACTION WITH SIRPALPHA SERVES AS A MARKER OF SELF TO INNATE IMMUNE CELLS AND THEREBY PROTECTS CANCER CELLS FROM PHAGOCYTIC CLEARANCE. CONSEQUENTLY, HIGHER CD47 CORRELATES WITH A POOR PROGNOSIS IN SOME CANCERS, AND THERAPEUTIC BLOCKADE CAN SUPPRESS TUMOR GROWTH BY ENHANCING INNATE ANTITUMOR IMMUNITY. CD47 EXPRESSED ON CYTOTOXIC T CELLS, DENDRITIC CELLS, AND NK CELLS MEDIATES INHIBITORY THBS1 SIGNALING THAT FURTHER LIMITS ANTITUMOR IMMUNITY. CD47 LATERALLY ASSOCIATES WITH SEVERAL INTEGRINS AND THEREBY REGULATES CELL ADHESION AND MIGRATION. CD47 HAS ADDITIONAL LATERAL BINDING PARTNERS IN SPECIFIC CELL TYPES, AND LIGATION OF CD47 IN SOME CASES MODULATES THEIR FUNCTION. THBS1-CD47 SIGNALING IN NON-MALIGNANT CELLS INHIBITS NITRIC OXIDE/CGMP, CALCIUM, AND VEGF SIGNALING, MITOCHONDRIAL HOMEOSTASIS, STEM CELL MAINTENANCE, PROTECTIVE AUTOPHAGY, AND DNA DAMAGE RESPONSE, AND PROMOTES NADPH OXIDASE ACTIVITY. CD47 SIGNALING IS A PHYSIOLOGICAL REGULATOR OF PLATELET ACTIVATION, ANGIOGENESIS AND BLOOD FLOW. THBS1/CD47 SIGNALING IS FREQUENTLY DYSREGULATED IN CHRONIC DISEASES. 2021 16 2080 22 EPIGENETIC DNA METHYLATION OF EBI3 MODULATES HUMAN INTERLEUKIN-35 FORMATION VIA NFKB SIGNALING: A PROMISING THERAPEUTIC OPTION IN ULCERATIVE COLITIS. ULCERATIVE COLITIS (UC), A SEVERE CHRONIC DISEASE WITH UNCLEAR ETIOLOGY THAT IS ASSOCIATED WITH INCREASED RISK FOR COLORECTAL CANCER, IS ACCOMPANIED BY DYSREGULATION OF CYTOKINES. EPSTEIN-BARR VIRUS-INDUCED GENE 3 (EBI3) ENCODES A SUBUNIT IN THE UNIQUE HETERODIMERIC IL-12 CYTOKINE FAMILY OF EITHER PRO- OR ANTI-INFLAMMATORY FUNCTION. AFTER HAVING RECENTLY DEMONSTRATED THAT UPREGULATION OF EBI3 BY HISTONE ACETYLATION ALLEVIATES DISEASE SYMPTOMS IN A DEXTRAN SULFATE SODIUM (DSS)-TREATED MOUSE MODEL OF CHRONIC COLITIS, WE NOW AIMED TO EXAMINE A POSSIBLE FURTHER EPIGENETIC REGULATION OF EBI3 BY DNA METHYLATION UNDER INFLAMMATORY CONDITIONS. TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR (DNMTI) DECITABINE (DAC) AND TNFALPHA LED TO SYNERGISTIC UPREGULATION OF EBI3 IN HUMAN COLON EPITHELIAL CELLS (HCEC). USE OF DIFFERENT SIGNALING PATHWAY INHIBITORS INDICATED NFKAPPAB SIGNALING WAS NECESSARY AND PROPORTIONAL TO THE SYNERGISTIC EBI3 INDUCTION. MALDI-TOF/MS AND HPLC-ESI-MS/MS ANALYSIS OF DAC/TNFALPHA-TREATED HCEC IDENTIFIED IL-12P35 AS THE MOST PROBABLE BINDING PARTNER TO FORM A FUNCTIONAL PROTEIN. EBI3/IL-12P35 HETERODIMERS (IL-35) INDUCE THEIR OWN GENE UPREGULATION, SOMETHING THAT WAS INDEED OBSERVED IN HCEC CULTURED WITH MEDIA FROM PREVIOUSLY DAC/TNFALPHA-TREATED HCEC. THESE RESULTS SUGGEST THAT UNDER INFLAMMATORY AND DEMETHYLATING CONDITIONS THE UPREGULATION OF EBI3 RESULTS IN THE FORMATION OF ANTI-INFLAMMATORY IL-35, WHICH MIGHT BE CONSIDERED AS A THERAPEUTIC TARGET IN COLITIS. 2021 17 3381 24 HLA AND AUTOIMMUNE DISEASES: TYPE 1 DIABETES (T1D) AS AN EXAMPLE. AUTOIMMUNE DISEASES NEED TO BE CONSIDERED AT A GENETIC AND MECHANISTIC LEVEL. T1D IS AN AUTOIMMUNE, CHRONIC, MULTIFACTORIAL AND POLYGENIC DISEASE CHARACTERIZED BY THE DESTRUCTION OF THE PANCREATIC BETA-CELLS ASSOCIATED WITH LONG TERM DYSFUNCTION OF SEVERAL ORGANS AND TISSUES. MECHANISMS OF SUSCEPTIBILITY INCLUDE EPI-GENETIC AND POST-TRANSCRIPTIONAL EFFECTS THAT REGULATE TRANSMISSION AND EXPRESSION OF THE INHERITED GENES. THE HLA COMPLEX, CONSTITUTES THE MOST RELEVANT REGION CONTRIBUTING 50% OF THE INHERITED RISK FOR T1D. AN ADDITIONAL 17 GENES WITH VARIABLE BUT SMALL EFFECTS HAVE BEEN DESCRIBED. IN NON-CAUCASIANS, THE PRESENCE OF E-DRBETA1-74 AND/OR D-DRBETA1-57 ARE RELEVANT IN PREDISPOSITION. THE "DIABETOGENIC HAPLOTYPES" IN MEXICANS WERE DRB1*0301-DQA1*0501-DQB1*0201 (OR = 21.4); DRB1*0405-DQA1-*0301-DQB1*0302 (OR = 44.5) AND THE SAME DQA1/DQB1 WITH DRB1*0404/*0401 CONFERRING LOWER RISK, INCREASING (OR = 61.3) WITH AN EARLY AGE AT ONSET AND A HETEROZYGOTE DR3/DR4 GENOTYPE. IN MOST POPULATIONS, THE ABSENCE OF D-57 AND THE PRESENCE OF R-52 ARE IMPORTANT TO THE SUSCEPTIBILITY, BUT IN HISPANICS, ALL DR4S (INCLUDING THE PROTECTIVE DRB1*0403/*0407/*0411) ARE IN LINKAGE DISEQUILIBRIUM WITH DQA1/DQB1 SUSCEPTIBILITY ALLELES. THUS, SUSCEPTIBILITY ALLELES IN LATIN AMERICAN MESTIZOS ARE OF MEDITERRANEAN ANCESTRY WHEREAS PROTECTIVE ALLELES ARE OF AMERINDIAN ORIGIN. IN THIS REVIEW, WE DISCUSS THE COMPLEXITY OF T1D AND SOME ASPECTS OF PREVENTION/INTERVENTION BASED ON IMMUNOGENETICS. 2006 18 3626 25 IN-SILICO DISCOVERY OF DUAL ACTIVE MOLECULE TO RESTORE SYNAPTIC WIRING AGAINST AUTISM SPECTRUM DISORDER VIA HDAC2 AND H3R INHIBITION. METAL-DEPENDENT HISTONE DEACETYLASES (HDACS) ARE ESSENTIAL EPIGENETIC REGULATORS; THEIR MOLECULAR AND PHARMACOLOGICAL ROLES IN MEDICALLY CRITICAL DISEASES SUCH AS NEUROPSYCHIATRIC DISORDERS, NEURODEGENERATION, AND CANCER ARE BEING STUDIED GLOBALLY. HDAC2'S DIFFERENTIAL EXPRESSION IN THE CENTRAL NERVOUS SYSTEM MAKES IT AN APPEALING THERAPEUTIC TARGET FOR CHRONIC NEUROLOGICAL DISEASES LIKE AUTISM SPECTRUM DISORDER. IN THIS STUDY, WE IDENTIFIED H3R INHIBITOR MOLECULES THAT ARE COMPUTATIONALLY EFFECTIVE AT BINDING TO THE HDAC2 METAL-COORDINATED BINDING SITE. THE STUDY HIGHLIGHTS THE IMPORTANCE OF PITOLISANT IN SCREENING THE POTENTIAL H3R INHIBITORS BY USING A HYBRID WORKFLOW OF LIGAND AND RECEPTOR-BASED DRUG DISCOVERY. THE SCREENED LEAD COMPOUNDS WITH PUBCHEM SIDS 103179850, 103185945, AND 103362074 SHOW VIABLE BINDING WITH HDAC2 IN SILICO. THE IMPORTANCE OF LIGAND CONTACTS WITH THE ZN2+ ION IN THE HDAC2 CATALYTIC SITE IS ALSO DISCUSSED AND INVESTIGATED FOR A SIGNIFICANT ROLE IN ENZYME INHIBITION. THE PROPOSED H3R INHIBITORS 103179850, 103185945, AND 103362074 ARE ESTIMATED AS DUAL-ACTIVE MOLECULES TO BLOCK THE HDAC2-MEDIATED DEACETYLATION OF THE EAAT2 GENE (SLC1A2) AND H3R-MEDIATED SYNAPTIC TRANSMISSION IRREGULARITY AND ARE, THEREFORE, OPEN FOR EXPERIMENTAL VALIDATION. 2022 19 1282 34 DECIPHERING THE ACTIVE CONSTITUENTS OF DABUSHEN DECOCTION OF AMELIORATING OSTEOARTHRITIS VIA PPARGAMMA PRESERVATION BY TARGETING DNMT1. OSTEOARTHRITIS (OA) IS A MULTIFACTORIAL AND CHRONIC DEGENERATIVE JOINT DISEASE. DUE TO THE ADVERSE EFFECTS OF CURRENTLY USED DRUGS, A SAFER AND MORE EFFECTIVE THERAPY FOR TREATING OA IS NEEDED. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA) IS A KEY PROTEIN PROTECTING CARTILAGE. DNMT1-MEDIATED HYPERMETHYLATION OF PPARGAMMA PROMOTER LEADS TO ITS SUPPRESSION. THEREFORE, DNMT1 MIGHT BE AN EFFECTIVE TARGET FOR EXERTING CARTILAGE PROTECTIVE EFFECTS BY REGULATING THE EPIGENETIC EXPRESSION OF PPARGAMMA. DABUSHEN DECOCTION (DD) IS A REPRESENTATIVE PRESCRIPTION OF DUNHUANG ANCIENT MEDICAL PRESCRIPTION, WHICH HAS A POTENTIAL THERAPEUTIC EFFECT ON OA. SO FAR, THE RESEARCH OF THE EFFICACY AND MATERIAL BASIS OF DD IN THE TREATMENT OF OA REMAINS UNCLEAR. IN THIS STUDY, MICRO-CT, HE STAINING, S-O STAINING, AND IMMUNOHISTOCHEMISTRY ANALYSIS WERE USED TO DEMONSTRATE THAT DD INCREASED THE EXPRESSION OF PPARGAMMA AND COLLAGEN SYNTHESIS IN AN OA RAT MODEL. NEXT, THE STRUCTURE OF DNMT1 WAS USED TO SCREEN THE ACTIVE CONSTITUENTS OF DD BY MOLECULAR DOCKING METHOD FOR TREATMENT OA. SEVEN POTENTIAL ACTIVE CONSTITUENTS, INCLUDING ISOLIQUIRITIGENIN, EMODIN, TAXIFOLIN, CATALPOL, ALISOL A, ZINGERONE, AND SCHISANDRIN C WERE HITED. THE PROTECTIVE EFFECT OF THE POTENTIAL ACTIVE CONSTITUENTS TO CHONDROCYTES WERE EVALUATED BY PROTEIN CAPILLARY ELECTROPHORESIS, IMMUNOFLUORESCENCE ASSAYS, AND EX VIVO CULTURE OF RAT KNEE CARTILAGE. THE FIVE CONSTITUENTS, SUCH AS ALISOL A, EMODIN, TAXIFOLIN, ISOLIQUIRITIGENIN, AND SCHISANDRIN C COULD PROMOTE THE EXPRESSION OF PPARGAMMA AND AMELIORATE IL-1BETA-INDUCED DOWNREGULATION OF COLLAGEN II AND THE PRODUCTION OF MMP-13. ALISOL A AND EMODIN COULD EFFECTIVELY MITIGATE CARTILAGE DAMAGE. AT LAST, MOLECULAR DYNAMICS SIMULATIONS WITH MM-GBSA METHOD WAS APPLIED TO INVESTIGATE THE INTERACTION PATTERN OF THE ACTIVE CONSTITUENTS AND DNMT1 COMPLEXES. THE FIVE CONSTITUENTS, SUCH AS ALISOL A, EMODIN, TAXIFOLIN, ISOLIQUIRITIGENIN, AND SCHISANDRIN C ACHIEVED A STABLE BINDING PATTERN WITH DNMT1, IN WHICH ALISOL A HAS A RELATIVELY HIGH BINDING FREE ENERGY. IN CONCLUSION, THIS STUDY ELUCIDATES THAT THE ACTIVE CONSTITUENTS OF DD (ALISOL A, EMODIN, TAXIFOLIN, ISOLIQUIRITIGENIN, AND SCHISANDRIN C) COULD AMELIORATE OSTEOARTHRITIS VIA PPARGAMMA PRESERVATION BY TARGETING DNMT1.THESE FINDINGS FACILITATED CLINICAL USE OF DD AND PROVIDED A VALUABLE STRATEGY FOR DEVELOPING NATURAL EPIGENETIC MODULATORS FROM CHINESE HERBAL FORMULA. 2022 20 2733 27 EXPLORING THE POTENTIAL OF PHYTOCOMPOUNDS FOR TARGETING EPIGENETIC MECHANISMS IN RHEUMATOID ARTHRITIS: AN IN SILICO STUDY USING SIMILARITY INDEXING. FINDING STRUCTURALLY SIMILAR COMPOUNDS IN COMPOUND DATABASES IS HIGHLY EFFICIENT AND IS WIDELY USED IN PRESENT-DAY DRUG DISCOVERY METHODOLOGY. THE MOST-TRUSTED AND -FOLLOWED SIMILARITY INDEXING METHOD IS TANIMOTO SIMILARITY INDEXING. EPIGENETIC PROTEINS LIKE HISTONE DEACETYLASES (HDACS) INHIBITORS ARE TRADITIONALLY USED TO TARGET CANCER, BUT HAVE ONLY BEEN INVESTIGATED VERY RECENTLY FOR THEIR POSSIBLE EFFECTIVENESS AGAINST RHEUMATOID ARTHRITIS (RA). THE SYNTHETIC DRUGS THAT HAVE BEEN IDENTIFIED AND USED FOR THE INHIBITION OF HDACS INCLUDE SAHA, WHICH IS BEING USED TO INHIBIT THE ACTIVITY OF HDACS OF DIFFERENT CLASSES. SAHA WAS CHOSEN AS A COMPOUND OF HIGH IMPORTANCE AS IT IS REPORTED TO INHIBIT THE ACTIVITY OF MANY HDAC TYPES. SIMILARITY SEARCHING USING THE UNPD DATABASE AS A REFERENCE IDENTIFIED AGLAITHIODULINE FROM THE AGLAIA LEPTANTHA COMPOUND AS HAVING A ~70% SIMILARITY OF MOLECULAR FINGERPRINTS WITH SAHA, BASED ON THE TANIMOTO INDEXING METHOD USING CHEMMINER. AGLAITHIODULINE IS ABUNDANTLY PRESENT IN THE SHELL AND FRUITS OF A. LEPTANTHA. IN SILICO STUDIES WITH AGLAITHIODULINE WERE CARRIED OUT AGAINST THE HDAC8 PROTEIN TARGET AND SHOWED A BINDING AFFINITY OF -8.5 KCAL MOL. THE COMPLEX WAS FURTHER SUBJECTED TO MOLECULAR DYNAMICS SIMULATION USING GROMACS. THE RMSD, RMSF, COMPACTNESS AND SASA PLOTS OF THE TARGET WITH AGLAITHIODULINE, IN COMPARISON WITH THE CO-CRYSTALLIZED LIGAND (SAHA) SYSTEM, SHOWED A VERY STABLE CONFIGURATION. THE RESULTS OF THE STUDY ARE SUPPORTIVE OF THE USAGE OF A. LEPTANTHA AND A. EDULIS IN INDIAN TRADITIONAL MEDICINE FOR THE TREATMENT OF PAIN-RELATED AILMENTS SIMILAR TO RA. OUR STUDY THEREFORE CALLS FOR FURTHER INVESTIGATION OF A. LEPTANTHA AND A. EDULIS FOR THEIR POTENTIAL USE AGAINST RA BY TARGETING EPIGENETIC CHANGES, USING IN VIVO AND IN VITRO STUDIES. 2023