1 6221 138 THE LANDSCAPE OF HISTONE MODIFICATIONS IN A HIGH-FAT DIET-INDUCED OBESE (DIO) MOUSE MODEL. TYPE 2 DIABETES (T2D) IS A MAJOR CHRONIC HEALTHCARE CONCERN WORLDWIDE. EMERGING EVIDENCE SUGGESTS THAT A HISTONE-MODIFICATION-MEDIATED EPIGENETIC MECHANISM UNDERLIES T2D. NEVERTHELESS, THE DYNAMICS OF HISTONE MARKS IN T2D HAVE NOT YET BEEN CAREFULLY ANALYZED. USING A MASS SPECTROMETRY-BASED LABEL-FREE AND CHEMICAL STABLE ISOTOPE LABELING QUANTITATIVE PROTEOMIC APPROACH, WE SYSTEMATICALLY PROFILED LIVER HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS) IN A PREDIABETIC HIGH-FAT DIET-INDUCED OBESE (DIO) MOUSE MODEL. WE IDENTIFIED 170 HISTONE MARKS, 30 OF WHICH WERE PREVIOUSLY UNKNOWN. INTERESTINGLY, ABOUT 30% OF THE HISTONE MARKS IDENTIFIED IN DIO MOUSE LIVER BELONGED TO A SET OF RECENTLY REPORTED LYSINE ACYLATION MODIFICATIONS, INCLUDING PROPIONYLATION, BUTYRYLATION, MALONYLATION, AND SUCCINYLATION, SUGGESTING POSSIBLE ROLES OF THESE NEWLY IDENTIFIED HISTONE ACYLATIONS IN DIABETES AND OBESITY. THESE HISTONE MARKS WERE DETECTED WITHOUT PRIOR AFFINITY ENRICHMENT WITH AN ANTIBODY, DEMONSTRATING THAT THE HISTONE ACYLATION MARKS ARE PRESENT AT REASONABLY HIGH STOICHIOMETRY. FIFTEEN HISTONE MARKS DIFFERED IN ABUNDANCE IN DIO MOUSE LIVER COMPARED WITH LIVER FROM CHOW-FED MICE IN LABEL-FREE QUANTIFICATION, AND SIX HISTONE MARKS IN STABLE ISOTOPE LABELING QUANTIFICATION. ANALYSIS OF HEPATIC HISTONE MODIFICATIONS FROM METFORMIN-TREATED DIO MICE REVEALED THAT METFORMIN, A DRUG WIDELY USED FOR T2D, COULD REVERSE DIO-STIMULATED HISTONE H3K36ME2 IN PREDIABETES, SUGGESTING THAT THIS MARK IS LIKELY ASSOCIATED WITH T2D DEVELOPMENT. OUR STUDY THUS OFFERS A COMPREHENSIVE LANDSCAPE OF HISTONE MARKS IN A PREDIABETIC MOUSE MODEL, PROVIDES A RESOURCE FOR STUDYING EPIGENETIC FUNCTIONS OF HISTONE MODIFICATIONS IN OBESITY AND T2D, AND SUGGEST A NEW EPIGENETIC MECHANISM FOR THE PHYSIOLOGICAL FUNCTION OF METFORMIN. 2017 2 5125 36 POST-TRANSLATIONAL MODIFICATIONS OF TRYPANOSOMA CRUZI CANONICAL AND VARIANT HISTONES. CHAGAS DISEASE, CAUSED BY TRYPANOSOMA CRUZI, STILL AFFECTS MILLIONS OF PEOPLE AROUND THE WORLD. NO VACCINES NOR TREATMENT FOR CHRONIC CHAGAS DISEASE ARE AVAILABLE, AND CHEMOTHERAPY FOR THE ACUTE PHASE IS HINDERED BY LIMITED EFFICACY AND SEVERE SIDE EFFECTS. THE PROCESSES BY WHICH THE PARASITE ACQUIRES INFECTIVITY AND SURVIVES IN DIFFERENT HOSTS INVOLVE TIGHT REGULATION OF GENE EXPRESSION, MAINLY POST-TRANSCRIPTIONALLY. NEVERTHELESS, CHROMATIN STRUCTURE/ORGANIZATION OF TRYPANOSOMATIDS IS SIMILAR TO OTHER EUKARYOTES, INCLUDING HISTONE VARIANTS AND POST-TRANSLATIONAL MODIFICATIONS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS ALSO PLAY AN IMPORTANT ROLE IN THE BIOLOGY/PATHOGENESIS OF THESE PARASITES, MAKING EPIGENETIC TARGETS SUITABLE CANDIDATES TO DRUG DISCOVERY. HERE, WE PRESENT THE FIRST COMPREHENSIVE MAP OF POST-TRANSLATIONAL MODIFICATIONS OF T. CRUZI CANONICAL AND VARIANT HISTONES AND SHOW THAT ITS HISTONE CODE CAN BE AS SOPHISTICATED AS THAT OF OTHER EUKARYOTES. A TOTAL OF 13 DISTINCT MODIFICATION TYPES WERE IDENTIFIED, INCLUDING RATHER NOVEL AND UNUSUAL ONES SUCH AS ALTERNATIVE LYSINE ACYLATIONS, SERINE/THREONINE ACETYLATION, AND N-TERMINAL METHYLATION. SOME HISTONE MARKS CORRELATE TO THOSE DESCRIBED FOR OTHER ORGANISMS, SUGGESTING THAT SIMILAR REGULATORY MECHANISMS MAY BE IN PLACE. OTHERS, HOWEVER, ARE UNIQUE TO T. CRUZI OR TO TRYPANOSOMATIDS AS A GROUP AND MIGHT REPRESENT GOOD CANDIDATES FOR THE DEVELOPMENT OF ANTIPARASITIC DRUGS. 2017 3 1411 26 DIETARY NATURAL PRODUCTS AS EPIGENETIC MODIFIERS IN AGING-ASSOCIATED INFLAMMATION AND DISEASE. COVERING: UP TO 2020CHRONIC, LOW-GRADE INFLAMMATION IS LINKED TO AGING AND HAS BEEN TERMED "INFLAMMAGING". INFLAMMAGING IS CONSIDERED A KEY CONTRIBUTOR TO THE DEVELOPMENT OF METABOLIC DYSFUNCTION AND A BROAD SPECTRUM OF DISEASES OR DISORDERS INCLUDING DECLINES IN BRAIN AND HEART FUNCTION. GENOME-WIDE ASSOCIATION STUDIES (GWAS) COUPLED WITH EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE SHOWN THE IMPORTANCE OF DIET IN THE DEVELOPMENT OF CHRONIC AND AGE-RELATED DISEASES. MOREOVER, DIETARY INTERVENTIONS E.G. CALORIC RESTRICTION CAN ATTENUATE INFLAMMATION TO DELAY AND/OR PREVENT THESE DISEASES. COMMON THEMES IN THESE STUDIES ENTAIL THE USE OF PHYTOCHEMICALS (PLANT-DERIVED COMPOUNDS) OR THE PRODUCTION OF SHORT CHAIN FATTY ACIDS (SCFAS) AS EPIGENETIC MODIFIERS OF DNA AND HISTONE PROTEINS. EPIGENETIC MODIFICATIONS ARE DYNAMICALLY REGULATED AND AS SUCH, SERVE AS POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OR PREVENTION OF AGE-RELATED DISEASE. IN THIS REVIEW, WE WILL FOCUS ON THE ROLE FOR NATURAL PRODUCTS THAT INCLUDE PHYTOCHEMICALS AND SHORT CHAIN FATTY ACIDS (SCFAS) AS REGULATORS OF THESE EPIGENETIC ADAPTATIONS. SPECIFICALLY, WE DISCUSS REGULATORS OF METHYLATION, ACETYLATION AND ACYLATION, IN THE PROTECTION FROM CHRONIC INFLAMMATION DRIVEN METABOLIC DYSFUNCTION AND DETERIORATION OF NEUROCOGNITIVE AND CARDIAC FUNCTION. 2020 4 281 25 AGEING - OXIDATIVE STRESS, PTMS AND DISEASE. POST-TRANSLATIONAL MODIFICATIONS (PTMS) HAVE BEEN PROPOSED AS A LINK BETWEEN THE OXIDATIVE STRESS-INFLAMMATION-AGEING TRINITY, THEREBY AFFECTING SEVERAL HALLMARKS OF AGEING. PHOSPHORYLATION, ACETYLATION, AND UBIQUITINATION COVER >90% OF ALL THE REPORTED PTMS. SEVERAL OF THE MAIN PTMS ARE INVOLVED IN NORMAL "HEALTHY" AGEING AND IN DIFFERENT AGE-RELATED DISEASES, FOR INSTANCE NEURODEGENERATIVE, METABOLIC, CARDIOVASCULAR, AND BONE DISEASES, AS WELL AS CANCER AND CHRONIC KIDNEY DISEASE. ULTIMATELY, DATA FROM HUMAN RARE PROGEROID SYNDROMES, BUT ALSO FROM LONG-LIVING ANIMAL SPECIES, IMPLY THAT PTMS ARE CRITICAL REGULATORS OF THE AGEING PROCESS. MECHANISTICALLY, PTMS TARGET EPIGENETIC AND NON-EPIGENETIC PATHWAYS DURING AGEING. IN PARTICULAR, EPIGENETIC HISTONE MODIFICATION HAS CRITICAL IMPLICATIONS FOR THE AGEING PROCESS AND CAN MODULATE LIFESPAN. THEREFORE, PTM-BASED THERAPEUTICS APPEAR TO BE ATTRACTIVE PHARMACEUTICAL CANDIDATES TO REDUCE THE BURDEN OF AGEING-RELATED DISEASES. SEVERAL PHOSPHORYLATION AND ACETYLATION INHIBITORS HAVE ALREADY BEEN FDA-APPROVED FOR THE TREATMENT OF OTHER DISEASES AND OFFER A UNIQUE POTENTIAL TO INVESTIGATE BOTH BENEFICIAL EFFECTS AND POSSIBLE SIDE-EFFECTS. AS AN EXAMPLE, THE MOST WELL-STUDIED SENOLYTIC COMPOUNDS DASATINIB AND QUERCETIN, WHICH HAVE ALREADY BEEN TESTED IN PHASE 1 PILOT STUDIES, ALSO ACT AS KINASE INHIBITORS, TARGETING CELLULAR SENESCENCE AND INCREASING LIFESPAN. FUTURE STUDIES NEED TO CAREFULLY DETERMINE THE BEST PTM-BASED CANDIDATES FOR THE TREATMENT OF THE "DISEASOME OF AGEING". 2022 5 3374 21 HISTONE POST-TRANSLATIONAL MODIFICATIONS AS POTENTIAL THERAPEUTIC TARGETS FOR PAIN MANAGEMENT. EFFECTIVE PHARMACOLOGICAL MANAGEMENT OF PAIN ASSOCIATED WITH TISSUE PATHOLOGY IS AN UNMET MEDICAL NEED. TRANSCRIPTIONAL MODIFICATIONS IN NOCICEPTIVE PATHWAYS ARE PIVOTAL FOR THE DEVELOPMENT AND THE MAINTENANCE OF PAIN ASSOCIATED WITH TISSUE DAMAGE. ACCUMULATING EVIDENCE HAS SHOWN THE IMPORTANCE OF THE EPIGENETIC CONTROL OF TRANSCRIPTION IN NOCICEPTIVE PATHWAYS VIA HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS). HENCE, HISTONE PTMS COULD BE TARGETS FOR NOVEL EFFECTIVE ANALGESICS. HERE, WE DISCUSS THE CURRENT UNDERSTANDING OF HISTONE PTMS IN THE MODULATION OF GENE EXPRESSION AFFECTING NOCICEPTION AND PAIN PHENOTYPES FOLLOWING TISSUE INJURY. WE ALSO PROVIDE A CRITICAL VIEW OF THE TRANSLATIONAL IMPLICATIONS OF PRECLINICAL MODELS AND DISCUSS OPPORTUNITIES AND CHALLENGES OF TARGETING HISTONE PTMS TO RELIEVE PAIN IN CLINICALLY RELEVANT TISSUE INJURIES. 2021 6 4891 30 OXIDATIVE STRESS AND INFLAMMATORY MARKERS IN PREDIABETES AND DIABETES. PREDIABETES IS A STATE OF ELEVATED PLASMA GLUCOSE IN WHICH THE THRESHOLD FOR DIABETES HAS NOT YET BEEN REACHED AND CAN PREDISPOSE TO THE DEVELOPMENT OF TYPE 2 DIABETES AND CARDIOVASCULAR DISEASES. INSULIN RESISTANCE AND IMPAIRED BETA-CELL FUNCTION ARE OFTEN ALREADY PRESENT IN PREDIABETES. HYPERGLYCEMIA CAN UPREGULATE MARKERS OF CHRONIC INFLAMMATION AND CONTRIBUTE TO INCREASED REACTIVE OXYGEN SPECIES (ROS) GENERATION, WHICH ULTIMATELY CAUSE VASCULAR DYSFUNCTION. CONVERSELY, INCREASED OXIDATIVE STRESS AND INFLAMMATION CAN LEAD TO INSULIN RESISTANCE AND IMPAIRED INSULIN SECRETION. PROPER TREATMENT OF HYPERGLYCEMIA AND INHIBITION OF ROS OVERPRODUCTION IS CRUCIAL FOR DELAYING ONSET OF DIABETES AND FOR PREVENTION OF CARDIOVASCULAR COMPLICATIONS. THUS, IT IS IMPERATIVE TO DETERMINE THE MECHANISMS INVOLVED IN THE PROGRESSION FROM PREDIABETES TO DIABETES INCLUDING A CLARIFICATION OF HOW OLD AND NEW MEDICATIONS AFFECT OXIDATIVE AND IMMUNE MECHANISMS OF DIABETES. IN THIS REVIEW, WE DISCUSS THE RELATIONSHIP BETWEEN OXIDATIVE STRESS AND HYPERGLYCEMIA ALONG WITH LINKS BETWEEN INFLAMMATION AND PREDIABETES. ADDITIONALLY, THE EFFECTS OF HYPERGLYCEMIC MEMORY, MICROVESICLES, MICRO-RNA, AND EPIGENETIC REGULATION ON INFLAMMATION, OXIDATIVE STATE, AND GLYCEMIC CONTROL ARE HIGHLIGHTED. ADIPOSE TISSUE AND THEIR INFLUENCE ON CHRONIC INFLAMMATION ARE ALSO BRIEFLY REVIEWED. FINALLY, THE ROLE OF IMMUNE-TARGETED THERAPIES AND ANTI-DIABETIC MEDICATION ON GLYCEMIC CONTROL AND OXIDATIVE STRESS ARE DISCUSSED. 2019 7 2498 33 EPIGENETICS AND EPILEPSY PREVENTION: THE THERAPEUTIC POTENTIAL OF ADENOSINE AND METABOLIC THERAPIES. PREVENTION OF EPILEPSY AND ITS PROGRESSION REMAINS THE MOST URGENT NEED FOR EPILEPSY RESEARCH AND THERAPY DEVELOPMENT. NOVEL CONCEPTUAL ADVANCES ARE REQUIRED TO MEANINGFULLY ADDRESS THIS FUNDAMENTAL CHALLENGE. MALADAPTIVE EPIGENETIC CHANGES, WHICH INCLUDE METHYLATION OF DNA AND ACETYLATION OF HISTONES - AMONG OTHER MECHANISMS, ARE NOW WELL RECOGNIZED TO PLAY A FUNCTIONAL ROLE IN THE DEVELOPMENT OF EPILEPSY AND ITS PROGRESSION. THE METHYLATION HYPOTHESIS OF EPILEPTOGENESIS SUGGESTS THAT CHANGES IN DNA METHYLATION ARE IMPLICATED IN THE PROGRESSION OF THE DISEASE. IN THIS CONTEXT, GLOBAL DNA HYPERMETHYLATION IS PARTICULARLY ASSOCIATED WITH CHRONIC EPILEPSY. LIKEWISE, ACETYLATION CHANGES OF HISTONES HAVE BEEN LINKED TO EPILEPSY DEVELOPMENT. CLINICAL AS WELL AS EXPERIMENTAL EVIDENCE DEMONSTRATE THAT EPILEPSY AND ITS PROGRESSION CAN BE PREVENTED BY METABOLIC AND BIOCHEMICAL MANIPULATIONS THAT TARGET PREVIOUSLY UNRECOGNIZED EPIGENETIC FUNCTIONS CONTRIBUTING TO EPILEPSY DEVELOPMENT AND MAINTENANCE OF THE EPILEPTIC STATE. THIS REVIEW WILL DISCUSS EPIGENETIC MECHANISMS IMPLICATED IN EPILEPSY DEVELOPMENT AS WELL AS METABOLIC AND BIOCHEMICAL INTERACTIONS THOUGHT TO DRIVE EPILEPTOGENESIS. THEREFORE, METABOLIC AND BIOCHEMICAL MECHANISMS ARE IDENTIFIED AS NOVEL TARGETS FOR EPILEPSY PREVENTION. WE WILL SPECIFICALLY DISCUSS ADENOSINE BIOCHEMISTRY AS A NOVEL THERAPEUTIC STRATEGY TO RECONSTRUCT THE DNA METHYLOME AS ANTIEPILEPTOGENIC STRATEGY AS WELL AS METABOLIC MEDIATORS, SUCH AS BETA-HYDROXYBUTYRATE, WHICH AFFECT HISTONE ACETYLATION. FINALLY, METABOLIC DIETARY INTERVENTIONS (SUCH AS THE KETOGENIC DIET) WHICH HAVE THE UNIQUE POTENTIAL TO PREVENT EPILEPTOGENESIS THROUGH RECENTLY IDENTIFIED EPIGENETIC MECHANISMS WILL BE REVIEWED. THIS ARTICLE IS PART OF THE SPECIAL ISSUE ENTITLED 'NEW EPILEPSY THERAPIES FOR THE 21ST CENTURY - FROM ANTISEIZURE DRUGS TO PREVENTION, MODIFICATION AND CURE OF EPILEPSY'. 2020 8 5080 25 PHYTOPHARMACOLOGICAL STRATEGIES IN THE MANAGEMENT OF TYPE 2 DIABETES MELLITUS. TYPE 2 DIABETES MELLITUS (T2DM) IS A CHRONIC DISEASE WHICH CORRESPONDS TO 90% OF THE WORLDWIDE CASES OF DIABETES, MAINLY DUE TO EPIGENETIC FACTORS SUCH AS UNHEALTHY LIFESTYLES. FIRST LINE THERAPEUTIC APPROACHES ARE BASED ON LIFESTYLE CHANGES, MOST OF THE TIME COMPLEMENTED WITH MEDICATION MOSTLY ASSOCIATED WITH SEVERAL SIDE EFFECTS AND HIGH COSTS. AS A RESULT, THE SCIENTIFIC COMMUNITY IS CONSTANTLY WORKING FOR THE DISCOVERY AND DEVELOPMENT OF NATURAL THERAPEUTIC STRATEGIES THAT PROVIDE LOWER FINANCIAL IMPACT AND MINIMIZE SIDE EFFECTS. THIS REVIEW FOCUS ON THESE NATURE-BASED THERAPEUTIC STRATEGIES FOR PREVENTION AND CONTROL OF T2DM, WITH A SPECIAL EMPHASIS ON NATURAL COMPOUNDS THAT PRESENT PHARMACOLOGICAL ACTIVITY AS DIPEPTIDYL PEPTIDASE-4 (DPP4), ALPHA-AMYLASE, ALPHA-GLUCOSIDASE, LIPASE, AND PROTEIN TYROSINE PHOSPHATASE 1B (PTP1B) INHIBITORS. 2020 9 615 32 BIOACTIVE COMPONENTS AND POSSIBLE ACTIVITIES OF MEDICINAL MUSHROOMS IN ALLEVIATING THE PATHOGENESIS OF NONALCOHOLIC FATTY LIVER DISEASE (REVIEW). NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A GLOBAL DISEASE THAT IS CLOSELY ASSOCIATED WITH OBESITY, TYPE 2 DIABETES MELLITUS, AND CARDIOVASCULAR DISEASE. EXCESSIVE FAT ACCUMULATION, FATTY DEGENERATION, AND CHRONIC INFLAMMATION OF THE LIVER ACTIVATE THE PROGRESSION OF NAFLD FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS AND FURTHER TO LIVER FIBROSIS, CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. THE UNDERLYING MECHANISM FOR THE DEVELOPMENT AND PROGRESSION OF NAFLD IS COMPLEX AND A MULTIPLE-HIT HYPOTHESIS INCLUDING DIETARY, ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS HAS BEEN RAISED. INCREASED DE NOVO LIPOGENESIS, DECREASED LIPOLYSIS, AND INSULIN RESISTANCE ARE ASSOCIATED WITH THE DEVELOPMENT OF NAFLD. CURRENTLY, NO EFFECTIVE DRUG THERAPIES ARE APPROVED FOR THE TREATMENT OF NAFLD. SEVERAL MEDICINAL MUSHROOMS HAVE BEEN FOUND TO HAVE SIGNIFICANT WEIGHT CONTROL AND GUT MICROBE MODULATION ACTIVITIES AND ANTIHYPERTRIGLYCERIDEMIC, ANTIHYPERGLYCEMIC, ANTIOXIDANT, AND ANTI-INFLAMMATORY EFFECTS, WHICH MAY BE USEFUL TO PREVENT AND ATTENUATE THE DEVELOPMENT AND PROGRESSION OF NAFLD. THESE BENEFICIAL EFFECTS ARE ASSOCIATED WITH MUSHROOMS' BIOACTIVE COMPONENTS, SUCH AS POLYSACCHARIDES, DIETARY FIBERS, ANTIOXIDANTS, AND OTHER COMPOUNDS DERIVED FROM FRUITING BODIES, CULTURED MYCELIUM, AND/OR BROTH OF MEDICINAL MUSHROOMS. THIS ARTICLE PRESENTS AN OVERVIEW OF MULTIPLE ASPECTS OF NAFLD, INCLUDING THE EPIDEMIOLOGY, PATHOGENESIS, MANAGEMENT, AND TREATMENT. THE BIOACTIVE COMPONENTS AND POSSIBLE ACTIVITIES OF MEDICINAL MUSHROOMS IN ALLEVIATING THE PATHOGENESIS OF NAFLD ARE ALSO REVIEWED. 2021 10 5919 16 TARGETING CELLULAR SENESCENCE FOR AGE-RELATED DISEASES: PATH TO CLINICAL TRANSLATION. BEYOND THE PALLIATIVE REACH OF TODAY'S MEDICINES, MEDICAL THERAPIES OF TOMORROW AIM TO TREAT THE ROOT CAUSE OF AGE-RELATED DISEASES BY TARGETING FUNDAMENTAL AGING MECHANISMS. PILLARS OF AGING INCLUDE, AMONG OTHERS, GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DYSREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION. THE UNITARY THEORY OF FUNDAMENTAL AGING PROCESSES POSITS THAT BY TARGETING ONE FUNDAMENTAL AGING PROCESS, IT MAY BE FEASIBLE TO IMPACT SEVERAL OR ALL OTHERS GIVEN ITS INTERDEPENDENCE. INDEED, PATHOLOGIC ACCUMULATION OF SENESCENT CELLS IS IMPLICATED IN CHRONIC DISEASES AND AGE-ASSOCIATED MORBIDITIES, SUGGESTING THAT SENESCENT CELLS ARE A GOOD TARGET FOR WHOLE-BODY AGING INTERVENTION. PRECLINICAL STUDIES USING SENOLYTICS, AGENTS THAT SELECTIVELY ELIMINATE SENESCENT CELLS, AND SENOMORPHICS, AGENTS THAT INHIBIT PRODUCTION OR RELEASE OF SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE FACTORS, SHOW PROMISE IN SEVERAL AGING AND DISEASE PRECLINICAL MODELS. EARLY CLINICAL TRIALS USING A SENOLYTIC COMBINATION (DASATINIB AND QUERCETIN), AND OTHER SENOLYTICS INCLUDING FLAVONOID, FISETIN, AND BCL-XL INHIBITORS, ILLUSTRATE THE POTENTIAL OF SENOLYTICS TO ALLEVIATE AGE-RELATED DYSFUNCTION AND DISEASES INCLUDING WOUND HEALING. TRANSLATION INTO CLINICAL APPLICATIONS REQUIRES PARALLEL CLINICAL TRIALS ACROSS INSTITUTIONS TO VALIDATE SENOTHERAPEUTICS AS A VANGUARD FOR DELAYING, PREVENTING, OR TREATING AGE-RELATED DISORDERS AND AESTHETIC AGING. 2022 11 2549 36 EPIGENETICS IN OBESITY AND DIABETES MELLITUS: NEW INSIGHTS. A LONG-TERM COMPLICATION OF OBESITY IS THE DEVELOPMENT OF TYPE 2 DIABETES (T2D). PATIENTS WITH T2D HAVE BEEN DESCRIBED AS HAVING EPIGENETIC MODIFICATIONS. EPIGENETICS IS THE POST-TRANSCRIPTIONAL MODIFICATION OF DNA OR ASSOCIATED FACTORS CONTAINING GENETIC INFORMATION. THESE ENVIRONMENTALLY-INFLUENCED MODIFICATIONS, MAINTAINED DURING CELL DIVISION, CAUSE STABLE CHANGES IN GENE EXPRESSION. EPIGENETIC MODIFICATIONS OF T2D ARE DNA METHYLATION, ACETYLATION, UBIQUITYLATION, SUMOYLATION, AND PHOSPHORYLATION AT THE LYSINE RESIDUE AT THE AMINO TERMINUS OF HISTONES, AFFECTING DNA, HISTONES, AND NON-CODING RNA. DNA METHYLATION HAS BEEN SHOWN IN PANCREATIC ISLETS, ADIPOSE TISSUE, SKELETAL MUSCLE, AND THE LIVER. FURTHERMORE, EPIGENETIC CHANGES HAVE BEEN OBSERVED IN CHRONIC COMPLICATIONS OF T2D, SUCH AS DIABETIC NEPHROPATHY, DIABETIC RETINOPATHY, AND DIABETIC NEUROPATHY. RECENTLY, A NEW DRUG HAS BEEN DEVELOPED WHICH ACTS ON BROMODOMAINS AND EXTRATERMINAL (BET) DOMAIN PROTEINS, WHICH OPERATE LIKE EPIGENETIC READERS AND COMMUNICATE WITH CHROMATIN TO MAKE DNA ACCESSIBLE FOR TRANSCRIPTION BY INHIBITING THEM. THIS DRUG (APABETALONE) IS BEING STUDIED TO PREVENT MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PEOPLE WITH T2D, LOW HDL CHOLESTEROL, CHRONIC KIDNEY FAILURE, AND RECENT CORONARY EVENTS. THIS REVIEW AIMS TO DESCRIBE THE RELATIONSHIP BETWEEN OBESITY, LONG-TERM COMPLICATIONS SUCH AS T2D, AND EPIGENETIC MODIFICATIONS AND THEIR POSSIBLE TREATMENTS. 2023 12 644 17 BIOPHARMACEUTICAL MONOTARGETING VERSUS 'UNIVERSAL TARGETING' OF LATE-ONSET ALZHEIMER'S DISEASE USING MIXTURES OF PLEIOTROPIC NATURAL COMPOUNDS. A FIVE-YEAR CLOSE READING OF THE SCIENTIFIC LITERATURE ON LATE-ONSET ALZHEIMER'S DISEASE (AD) HAS PROMPTED THE INVENTION OF A NOVEL THERAPEUTIC METHOD THAT BIOMECHANISTICALLY TARGETS THE TARGETABLE DISEASE-PROCESS TARGETS OF AD WITH ONE OR ANOTHER MIXTURE OF NON-TOXIC PLEIOTROPIC NATURAL COMPOUNDS. THE FEATURED MIXTURE HEREIN IS COMPRISED OF CURCUMIN, RESVERATROL, AND EGCG. THE MIXTURE'S TARGETS INCLUDE CENTRAL PATHOLOGICAL ELEMENTS OF AD (INCLUDING AMYLOID, TAU, SYNAPTIC DYSFUNCTION, OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, AND ABERRANT NEUROINFLAMMATION), MODIFIABLE RISK FACTORS, COMORBIDITIES, AND EPIGENETIC ELEMENTS. THE FEATURED MIXTURE AND OTHER SUCH MIXTURES ARE SUITABLE FOR LONG-TERM USE, AND MAY BE APPLIED TO ANY STAGE OF AD, INCLUDING PRIMARY AND SECONDARY PREVENTION. SUCH MIXTURES ALSO WOULD BE AMENABLE FOR USE AS PRE-TREATMENT, CO-TREATMENT, AND POST-TREATMENT APPLICATIONS WITH CERTAIN BIOPHARMACEUTICAL AGENTS. THE TARGETING FOCUS HERE IS THE MAJOR CREDIBLE HYPOTHESES OF AD. THE FOCUS OF FUTURE SUCH ARTICLES WILL INCLUDE OTHER AD-RELATED TARGETS, MODIFIABLE RISK FACTORS AND COMORBIDITIES, APOE4, EPIGENETIC FACTORS, BIOAVAILABILITY, DOSE RESPONSE, AND IMPLICATIONS FOR CLINICAL TESTING. THE "UNIVERSAL TARGETING" METHOD DESCRIBED HEREIN-THAT IS, "TARGETING THE TARGETABLE TARGETS" OF AD USING CERTAIN MIXTURES OF NATURAL COMPOUNDS-IS REPROGRAMMABLE AND THUS IS APPLICABLE TO OTHER CHRONIC NEUROLOGICAL CONDITIONS, INCLUDING PARKINSON'S DISEASE, VASCULAR DEMENTIA, ISCHEMIC-STROKE PREVENTION AND RECOVERY, AND SPORTS-RELATED HEAD INJURIES AND SEQUELAE LEADING TO CHRONIC TRAUMATIC ENCEPHALOPATHY. 2019 13 1683 23 DRUG-RESISTANT EPILEPSY: DRUG TARGET HYPOTHESIS AND BEYOND THE RECEPTORS. EPILEPSY IS A CHRONIC NEUROLOGICAL DISORDER THAT AFFECTS MORE THAN 50 MILLION PEOPLE WORLDWIDE. DESPITE A RECENT INTRODUCTION OF ANTISEIZURE DRUGS FOR THE TREATMENT OF EPILEPTIC SEIZURES, ONE-THIRD OF THESE PATIENTS SUFFER FROM DRUG-RESISTANT EPILEPSY (DRE). THE THERAPEUTIC TARGET HYPOTHESIS IS A CITED THEORY TO EXPLAIN DRE. ACCORDING TO THE TARGET HYPOTHESIS, THE FAILURE TO ACHIEVE SEIZURE FREEDOM LEADS TO ALTERATION OF THE STRUCTURE AND/OR FUNCTION OF THE ANTISEIZURE MEDICATION (ASM) TARGET. HOWEVER, THIS HYPOTHESIS FAILS TO EXPLAIN WHY PATIENTS WITH DRE DO NOT RESPOND TO ANTISEIZURE MEDICATIONS OF DIFFERENT TARGETS. THIS REVIEW PRESENTS DIFFERENT CONDITIONS, SUCH AS EPIGENETIC MECHANISMS AND PROTEIN-PROTEIN INTERACTIONS THAT MAY RESULT IN ALTERATIONS OF DIVERSE DRUG TARGETS USING DIFFERENT MECHANISMS. THESE NOVEL CONDITIONS REPRESENT NEW TARGETS TO CONTROL DRE. 2022 14 4672 23 NEW INSIGHTS INTO THE MECHANISMS OF THE KETOGENIC DIET. PURPOSE OF REVIEW: HIGH-FAT, LOW-CARBOHYDRATE KETOGENIC DIETS HAVE BEEN USED FOR ALMOST A CENTURY FOR THE TREATMENT OF EPILEPSY. USED TRADITIONALLY FOR THE TREATMENT OF REFRACTORY PEDIATRIC EPILEPSIES, IN RECENT YEARS THE USE OF KETOGENIC DIETS HAS EXPERIENCED A REVIVAL TO INCLUDE THE TREATMENT OF ADULTHOOD EPILEPSIES AS WELL AS CONDITIONS RANGING FROM AUTISM TO CHRONIC PAIN AND CANCER. DESPITE THE ABILITY OF KETOGENIC DIET THERAPY TO SUPPRESS SEIZURES REFRACTORY TO ANTIEPILEPTIC DRUGS AND REPORTS OF LASTING SEIZURE FREEDOM, THE UNDERLYING MECHANISMS ARE POORLY UNDERSTOOD. THIS REVIEW EXPLORES NEW INSIGHTS INTO MECHANISMS MOBILIZED BY KETOGENIC DIET THERAPIES. RECENT FINDINGS: KETOGENIC DIETS ACT THROUGH A COMBINATION OF MECHANISMS, WHICH ARE LINKED TO THE EFFECTS OF KETONES AND GLUCOSE RESTRICTION, AND TO INTERACTIONS WITH RECEPTORS, CHANNELS, AND METABOLIC ENZYMES. DECANOIC ACID, A COMPONENT OF MEDIUM-CHAIN TRICLYCERIDES, CONTRIBUTES TO SEIZURE CONTROL THROUGH DIRECT ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID (AMPA) RECEPTOR INHIBITION, WHEREAS DRUGS TARGETING LACTATE DEHYDROGENASE REDUCE SEIZURES THROUGH INHIBITION OF A METABOLIC PATHWAY. KETOGENIC DIET THERAPY ALSO AFFECTS DNA METHYLATION, A NOVEL EPIGENETIC MECHANISM OF THE DIET. SUMMARY: KETOGENIC DIET THERAPY COMBINES SEVERAL BENEFICIAL MECHANISMS THAT PROVIDE BROAD BENEFITS FOR THE TREATMENT OF EPILEPSY WITH THE POTENTIAL TO NOT ONLY SUPPRESS SEIZURES BUT ALSO TO MODIFY THE COURSE OF THE EPILEPSY. 2017 15 2116 29 EPIGENETIC HISTONE DEACETYLATION INHIBITION PREVENTS THE DEVELOPMENT AND PERSISTENCE OF TEMPORAL LOBE EPILEPSY. EPILEPSY IS A CHRONIC BRAIN DISEASE CHARACTERIZED BY REPEATED UNPROVOKED SEIZURES. CURRENTLY, NO DRUG THERAPY EXISTS FOR CURING EPILEPSY OR DISEASE MODIFICATION IN PEOPLE AT RISK. DESPITE SEVERAL EMERGING MECHANISMS, THERE HAVE BEEN FEW STUDIES OF EPIGENETIC SIGNALING IN EPILEPTOGENESIS, THE PROCESS WHEREBY A NORMAL BRAIN BECOMES PROGRESSIVELY EPILEPTIC BECAUSE OF PRECIPITATING FACTORS. HERE, WE REPORT A NOVEL ROLE OF HISTONE DEACETYLATION AS A CRITICAL EPIGENETIC MECHANISM IN EPILEPTOGENESIS. EXPERIMENTS WERE CONDUCTED USING THE HISTONE DEACETYLASE (HDAC) INHIBITOR SODIUM BUTYRATE IN THE HIPPOCAMPUS KINDLING MODEL OF TEMPORAL LOBE EPILEPSY (TLE), A CLASSIC MODEL HEAVILY USED TO APPROVE DRUGS FOR TREATMENT OF EPILEPSY. DAILY TREATMENT WITH BUTYRATE SIGNIFICANTLY INHIBITED HDAC ACTIVITY AND RETARDED THE DEVELOPMENT OF LIMBIC EPILEPTOGENESIS WITHOUT AFFECTING AFTER-DISCHARGE SIGNAL. HDAC INHIBITION MARKEDLY IMPAIRED THE PERSISTENCE OF SEIZURE EXPRESSION MANY WEEKS AFTER EPILEPSY DEVELOPMENT. MOREOVER, SUBCHRONIC HDAC INHIBITION FOR 2 WEEKS RESULTED IN A STRIKING RETARDATION OF EPILEPTOGENESIS. HDAC INHIBITION, UNEXPECTEDLY, ALSO SHOWED ERASURE OF THE EPILEPTOGENIC STATE IN EPILEPTIC ANIMALS. FINALLY, BUTYRATE-TREATED ANIMALS EXHIBITED A POWERFUL REDUCTION IN MOSSY FIBER SPROUTING, A MORPHOLOGIC INDEX OF EPILEPTOGENESIS. TOGETHER THESE RESULTS UNDERSCORE THAT HDAC INHIBITION PREVENTS THE DEVELOPMENT OF TLE, INDICATING HDAC'S CRITICAL SIGNALING ROLE IN EPILEPTOGENESIS. THESE FINDINGS, THEREFORE, ENVISAGE A UNIQUE NOVEL THERAPY FOR PREVENTING OR CURING EPILEPSY BY TARGETING THE EPIGENETIC HDAC PATHWAY. 2018 16 4211 25 METFORMIN FOR CARDIOVASCULAR PROTECTION, INFLAMMATORY BOWEL DISEASE, OSTEOPOROSIS, PERIODONTITIS, POLYCYSTIC OVARIAN SYNDROME, NEURODEGENERATION, CANCER, INFLAMMATION AND SENESCENCE: WHAT IS NEXT? DIABETES IS ACCOMPANIED BY SEVERAL COMPLICATIONS. HIGHER PREVALENCE OF CANCERS, CARDIOVASCULAR DISEASES, CHRONIC KIDNEY DISEASE (CKD), OBESITY, OSTEOPOROSIS, AND NEURODEGENERATIVE DISEASES HAS BEEN REPORTED AMONG PATIENTS WITH DIABETES. METFORMIN IS THE OLDEST ORAL ANTIDIABETIC DRUG AND CAN IMPROVE COEXISTING COMPLICATIONS OF DIABETES. CLINICAL TRIALS AND OBSERVATIONAL STUDIES UNCOVERED THAT METFORMIN CAN REMARKABLY PREVENT OR ALLEVIATE CARDIOVASCULAR DISEASES, OBESITY, POLYCYSTIC OVARIAN SYNDROME (PCOS), OSTEOPOROSIS, CANCER, PERIODONTITIS, NEURONAL DAMAGE AND NEURODEGENERATIVE DISEASES, INFLAMMATION, INFLAMMATORY BOWEL DISEASE (IBD), TUBERCULOSIS, AND COVID-19. IN ADDITION, METFORMIN HAS BEEN PROPOSED AS AN ANTIAGING AGENT. NUMEROUS MECHANISMS WERE SHOWN TO BE INVOLVED IN THE PROTECTIVE EFFECTS OF METFORMIN. METFORMIN ACTIVATES THE LKB1/AMPK PATHWAY TO INTERACT WITH SEVERAL INTRACELLULAR SIGNALING PATHWAYS AND MOLECULAR MECHANISMS. THE DRUG MODIFIES THE BIOLOGIC FUNCTION OF NF-KAPPAB, PI3K/AKT/MTOR, SIRT1/PGC-1ALPHA, NLRP3, ERK, P38 MAPK, WNT/BETA-CATENIN, NRF2, JNK, AND OTHER MAJOR MOLECULES IN THE INTRACELLULAR SIGNALING NETWORK. IT ALSO REGULATES THE EXPRESSION OF NONCODING RNAS. THEREBY, METFORMIN CAN REGULATE METABOLISM, GROWTH, PROLIFERATION, INFLAMMATION, TUMORIGENESIS, AND SENESCENCE. ADDITIONALLY, METFORMIN MODULATES IMMUNE RESPONSE, AUTOPHAGY, MITOPHAGY, ENDOPLASMIC RETICULUM (ER) STRESS, AND APOPTOSIS AND EXERTS EPIGENETIC EFFECTS. FURTHERMORE, METFORMIN PROTECTS AGAINST OXIDATIVE STRESS AND GENOMIC INSTABILITY, PRESERVES TELOMERE LENGTH, AND PREVENTS STEM CELL EXHAUSTION. IN THIS REVIEW, THE PROTECTIVE EFFECTS OF METFORMIN ON EACH DISEASE WILL BE DISCUSSED USING THE RESULTS OF RECENT META-ANALYSES, CLINICAL TRIALS, AND OBSERVATIONAL STUDIES. THEREAFTER, IT WILL BE METICULOUSLY EXPLAINED HOW METFORMIN REPROGRAMS INTRACELLULAR SIGNALING PATHWAYS AND ALTERS MOLECULAR AND CELLULAR INTERACTIONS TO MODIFY THE CLINICAL PRESENTATIONS OF SEVERAL DISEASES. 2021 17 2141 32 EPIGENETIC INTERVENTIONS FOR EPILEPTOGENESIS: A NEW FRONTIER FOR CURING EPILEPSY. THIS ARTICLE HIGHLIGHTS THE EMERGING THERAPEUTIC POTENTIAL OF SPECIFIC EPIGENETIC MODULATORS AS PROMISING ANTIEPILEPTOGENIC OR DISEASE-MODIFYING AGENTS FOR CURING EPILEPSY. CURRENTLY, THERE IS AN UNMET NEED FOR ANTIEPILEPTOGENIC AGENTS THAT TRULY PREVENT THE DEVELOPMENT OF EPILEPSY IN PEOPLE AT RISK. THERE IS STRONG EVIDENCE THAT EPIGENETIC SIGNALING, WHICH EXERTS HIGH FIDELITY REGULATION OF GENE EXPRESSION, PLAYS A CRUCIAL ROLE IN THE PATHOPHYSIOLOGY OF EPILEPTOGENESIS AND CHRONIC EPILEPSY. THESE MODIFICATIONS ARE NOT HARD-WIRED INTO THE GENOME AND ARE CONSTANTLY REPROGRAMMED BY ENVIRONMENTAL INFLUENCES. THE POTENTIAL EPIGENETIC MECHANISMS, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, MICRORNA-BASED TRANSCRIPTIONAL CONTROL, AND BROMODOMAIN READING ACTIVITY, CAN DRASTICALLY ALTER THE NEURONAL GENE EXPRESSION PROFILE BY EXERTING THEIR SUMMATIVE EFFECTS IN A COORDINATED FASHION. SUCH AN EPIGENETIC INTERVENTION APPEARS MORE RATIONAL STRATEGY FOR PREVENTING EPILEPSY BECAUSE IT TARGETS THE PRIMARY PATHWAY THAT INITIALLY TRIGGERS THE NUMEROUS DOWNSTREAM CELLULAR AND MOLECULAR EVENTS MEDIATING EPILEPTOGENESIS. AMONG CURRENTLY APPROVED EPIGENETIC DRUGS, THE MAJORITY ARE ANTICANCER DRUGS WITH WELL-ESTABLISHED PROFILES IN CLINICAL TRIALS AND PRACTICE. EVIDENCE FROM PRECLINICAL STUDIES SUPPORTS THE PREMISE THAT THESE DRUGS MAY BE APPLIED TO A WIDE RANGE OF BRAIN DISORDERS. TARGETING HISTONE DEACETYLATION BY INHIBITING HISTONE DEACETYLASE ENZYMES APPEARS TO BE ONE PROMISING EPIGENETIC THERAPY SINCE CERTAIN INHIBITORS HAVE BEEN SHOWN TO PREVENT EPILEPTOGENESIS IN ANIMAL MODELS. HOWEVER, DEVELOPING NEURONAL SPECIFIC EPIGENETIC MODULATORS REQUIRES RATIONAL, PATHOPHYSIOLOGY-BASED OPTIMIZATION TO EFFICIENTLY INTERCEPT THE UPSTREAM PATHWAYS IN EPILEPTOGENESIS. OVERALL, EPIGENETIC AGENTS HAVE BEEN WELL POSITIONED AS NEW FRONTIER TOOLS TOWARDS THE NATIONAL GOAL OF CURING EPILEPSY. 2017 18 1397 22 DIET PHYTOCHEMICALS AND CUTANEOUS CARCINOMA CHEMOPREVENTION: A REVIEW. CUTANEOUS CARCINOMA, WHICH HAS OCCUPIED A PECULIAR PLACE AMONG WORLDWIDE POPULATIONS, IS COMMONLY RESPONSIBLE FOR THE CONSIDERABLY INCREASING MORBIDITY AND MORTALITY RATES. CURRENTLY AVAILABLE MEDICAL PROCEDURES FAIL TO COMPLETELY AVOID CUTANEOUS CARCINOMA DEVELOPMENT OR TO PREVENT MORTALITY. CANCER CHEMOPREVENTION, AS AN ALTERNATIVE STRATEGY, IS BEING CONSIDERED TO REDUCE THE INCIDENCE AND BURDEN OF CANCERS THROUGH CHEMICAL AGENTS. DERIVED FROM DIETARY FOODS, PHYTOCHEMICALS HAVE BECOME SAFE AND RELIABLE COMPOUNDS FOR THE CHEMOPREVENTION OF CUTANEOUS CARCINOMA BY RELIEVING MULTIPLE PATHOLOGICAL PROCESSES, INCLUDING OXIDATIVE DAMAGE, EPIGENETIC ALTERATION, CHRONIC INFLAMMATION, ANGIOGENESIS, ETC. IN THIS REVIEW, WE PRESENTED COMPREHENSIVE KNOWLEDGES, MAIN MOLECULAR MECHANISMS FOR THE INITIATION AND DEVELOPMENT OF CUTANEOUS CARCINOMA AS WELL AS EFFECTS OF VARIOUS DIET PHYTOCHEMICALS ON CHEMOPREVENTION. 2017 19 1127 19 COMPOUND COMBINATIONS TARGETING LONGEVITY: CHALLENGES AND PERSPECTIVES. AGING IS ONE OF THE WORLD'S GREATEST CONCERNS, REQUIRING URGENT, EFFECTIVE, LARGE-SCALE INTERVENTIONS TO DECREASE THE NUMBER OF LATE-LIFE CHRONIC DISEASES AND IMPROVE HUMAN HEALTHSPAN. ANTI-AGING DRUG THERAPY IS ONE OF THE MOST PROMISING STRATEGIES TO COMBAT THE EFFECTS OF AGING. HOWEVER, MOST GEROPROTECTIVE COMPOUNDS ARE KNOWN TO SUCCESSFULLY AFFECT ONLY A FEW AGING-RELATED TARGETS. GIVEN THIS, THERE IS A GREAT BIOLOGICAL RATIONALE FOR THE USE OF COMBINATIONS OF ANTI-AGING INTERVENTIONS. IN THIS REVIEW, WE CHARACTERIZE THE VARIOUS TYPES OF COMPOUND COMBINATIONS USED TO MODULATE LIFESPAN, DISCUSS THE EXISTING EVIDENCE ON THEIR ROLE IN LIFE EXTENSION, AND PRESENT SOME KEY POINTS ABOUT CURRENT CHALLENGES AND FUTURE PROSPECTS FOR THE DEVELOPMENT OF COMBINATION DRUG ANTI-AGING THERAPY. 2023 20 2454 20 EPIGENETIC TARGETING OF HISTONE DEACETYLASES IN DIAGNOSTICS AND TREATMENT OF DEPRESSION. DEPRESSION IS A HIGHLY PREVALENT, DISABLING, AND OFTEN CHRONIC ILLNESS THAT PLACES SUBSTANTIAL BURDENS ON PATIENTS, FAMILIES, HEALTHCARE SYSTEMS, AND THE ECONOMY. A SUBSTANTIAL MINORITY OF PATIENTS ARE UNRESPONSIVE TO CURRENT THERAPIES, SO THERE IS AN URGENT NEED TO DEVELOP MORE BROADLY EFFECTIVE, ACCESSIBLE, AND TOLERABLE THERAPIES. PHARMACOLOGICAL REGULATION OF HISTONE ACETYLATION LEVEL HAS BEEN INVESTIGATED AS ONE POTENTIAL CLINICAL STRATEGY. HISTONE ACETYLATION STATUS IS CONSIDERED A POTENTIAL DIAGNOSTIC BIOMARKER FOR DEPRESSION, WHILE INHIBITORS OF HISTONE DEACETYLASES (HDACS) HAVE GARNERED INTEREST AS NOVEL THERAPEUTICS. THIS REVIEW DESCRIBES RECENT ADVANCES IN OUR KNOWLEDGE OF HISTONE ACETYLATION STATUS IN DEPRESSION AND THE THERAPEUTIC POTENTIAL OF HDAC INHIBITORS. 2021