1 3345 98 HISTONE DEACETYLASES AS EPIGENETIC TARGETS FOR TREATING PARKINSON'S DISEASE. PARKINSON'S DISEASE (PD) IS A CHRONIC PROGRESSIVE NEURODEGENERATIVE DISEASE THAT IS INCREASINGLY BECOMING A GLOBAL THREAT TO THE HEALTH AND LIFE OF THE ELDERLY WORLDWIDE. ALTHOUGH THERE ARE SOME DRUGS CLINICALLY AVAILABLE FOR TREATING PD, THESE TREATMENTS CAN ONLY ALLEVIATE THE SYMPTOMS OF PD PATIENTS BUT CANNOT COMPLETELY CURE THE DISEASE. THEREFORE, EXPLORING OTHER POTENTIAL MECHANISMS TO DEVELOP MORE EFFECTIVE TREATMENTS THAT CAN MODIFY THE COURSE OF PD IS STILL HIGHLY DESIRABLE. OVER THE LAST TWO DECADES, HISTONE DEACETYLASES, AS AN IMPORTANT GROUP OF EPIGENETIC TARGETS, HAVE ATTRACTED MUCH ATTENTION IN DRUG DISCOVERY. THIS REVIEW FOCUSED ON THE CURRENT KNOWLEDGE ABOUT HISTONE DEACETYLASES INVOLVED IN PD PATHOPHYSIOLOGY AND THEIR INHIBITORS USED IN PD STUDIES. FURTHER PERSPECTIVES RELATED TO SMALL MOLECULES THAT CAN INHIBIT OR DEGRADE HISTONE DEACETYLASES TO TREAT PD WERE ALSO DISCUSSED. 2022 2 2932 33 GENES AND EPIGENETIC PROCESSES AS PROSPECTIVE PAIN TARGETS. CHRONIC PAIN AFFECTS APPROXIMATELY ONE IN FIVE ADULTS, RESULTING IN A GREATLY REDUCED QUALITY OF LIFE AND A HIGHER RISK OF DEVELOPING CO-MORBIDITIES SUCH AS DEPRESSION. AVAILABLE TREATMENTS OFTEN PROVIDE INADEQUATE PAIN RELIEF, BUT IT IS HOPED THAT THROUGH DEEPER UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING CHRONIC PAIN STATES WE CAN DISCOVER NEW AND IMPROVED THERAPIES. ALTHOUGH GENETIC RESEARCH HAS FLOURISHED OVER THE PAST DECADE AND HAS IDENTIFIED MANY KEY GENES IN PAIN PROCESSING, THE BUDDING FIELD OF EPIGENETICS PROMISES TO PROVIDE NEW INSIGHTS AND A MORE DYNAMIC VIEW OF PAIN REGULATION. THIS REVIEW GIVES AN OVERVIEW OF BASIC MECHANISMS AND CURRENT THERAPIES TO TREAT PAIN, AND DISCUSSES THE CLINICAL AND PRECLINICAL EVIDENCE FOR THE CONTRIBUTION OF GENETIC AND EPIGENETIC FACTORS, WITH A FOCUS ON HOW THIS KNOWLEDGE CAN AFFECT DRUG DEVELOPMENT. 2013 3 2140 31 EPIGENETIC INTERACTIONS BETWEEN ALCOHOL AND CANNABINERGIC EFFECTS: FOCUS ON HISTONE MODIFICATION AND DNA METHYLATION. EPIGENETIC STUDIES HAVE LED TO A MORE PROFOUND UNDERSTANDING OF THE MECHANISMS INVOLVED IN CHRONIC CONDITIONS. IN THE CASE OF ALCOHOL ADDICTION, ACCORDING TO THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM, 16 MILLION ADULTS SUFFER FROM ALCOHOL USE DISORDERS (AUDS). EVEN THOUGH THERAPEUTIC INTERVENTIONS LIKE BEHAVIORAL THERAPY AND MEDICATIONS TO PREVENT RELAPSE ARE CURRENTLY AVAILABLE, NO ROBUST CURE EXISTS, WHICH STEMS FROM THE LACK OF UNDERSTANDING THE MECHANISMS OF ACTION OF ALCOHOL AND THE LACK OF DEVELOPMENT OF PRECISION MEDICINE APPROACHES TO TREAT AUDS. ANOTHER COMMON GROUP OF ADDICTIVE SUBSTANCE, CANNABINOIDS, HAVE BEEN STUDIED EXTENSIVELY TO REVEAL THEY WORK THROUGH CANNABINOID RECEPTORS. THERAPEUTIC APPLICATIONS HAVE BEEN FOUND FOR THE CANNABINOIDS AND A DEEPER UNDERSTANDING OF THE ENDOCANNABINOID SYSTEM HAS BEEN GAINED OVER THE YEARS. RECENT REPORTS OF CANNABINERGIC MECHANISMS IN AUDS HAS OPENED AN EXCITING REALM OF RESEARCH THAT SEEKS TO ELUCIDATE THE MOLECULAR MECHANISMS OF ALCOHOL-INDUCED END ORGAN DISEASES AND HOPEFULLY PROVIDE INSIGHT INTO NEW THERAPEUTIC STRATEGIES FOR THE TREATMENT OF AUDS. TO DATE, SEVERAL EPIGENETIC MECHANISMS HAVE BEEN ASSOCIATED WITH ALCOHOL AND CANNABINOIDS INDEPENDENTLY. THEREFORE, THE SCOPE OF THIS REVIEW IS TO COMPILE THE MOST RECENT LITERATURE REGARDING ALCOHOL AND CANNABINOIDS IN TERMS OF A POSSIBLE EPIGENETIC CONNECTION BETWEEN THE ENDOCANNABINOID SYSTEM AND ALCOHOL EFFECTS. FIRST, WE WILL PROVIDE AN OVERVIEW OF EPIGENETICS, FOLLOWED BY AN OVERVIEW OF ALCOHOL AND EPIGENETIC MECHANISMS WITH AN EMPHASIS ON HISTONE MODIFICATIONS AND DNA METHYLATIONS. THEN, WE WILL PROVIDE AN OVERVIEW OF CANNABINOIDS AND EPIGENETIC MECHANISMS. LASTLY, WE WILL DISCUSS EVIDENCE OF INTERACTIONS BETWEEN ALCOHOL AND CANNABINERGIC PATHWAYS AND POSSIBLE INSIGHTS INTO THE NOVEL EPIGENETIC MECHANISMS UNDERLYING ALCOHOL-CANNABINERGIC PATHWAY ACTIVITY. FINALIZING THE REVIEW WILL BE A DISCUSSION OF FUTURE DIRECTIONS AND THERAPEUTIC APPLICATIONS. 2017 4 3606 33 IMPROVING TREATMENT OF NEURODEVELOPMENTAL DISORDERS: RECOMMENDATIONS BASED ON PRECLINICAL STUDIES. INTRODUCTION: NEURODEVELOPMENTAL DISORDERS (NDDS) ARE COMMON AND SEVERELY DEBILITATING. THEIR CHRONIC NATURE AND RELIANCE ON BOTH GENETIC AND ENVIRONMENTAL FACTORS MAKES STUDYING NDDS AND THEIR TREATMENT A CHALLENGING TASK. AREAS COVERED: HEREIN, THE AUTHORS DISCUSS THE NEUROBIOLOGICAL MECHANISMS OF NDDS, AND PRESENT RECOMMENDATIONS ON THEIR TRANSLATIONAL RESEARCH AND THERAPY, OUTLINED BY THE INTERNATIONAL STRESS AND BEHAVIOR SOCIETY. VARIOUS DRUGS CURRENTLY PRESCRIBED TO TREAT NDDS ALSO REPRESENT A HIGHLY DIVERSE GROUP. ACTING ON VARIOUS NEUROTRANSMITTER AND PHYSIOLOGICAL SYSTEMS, THESE DRUGS OFTEN LACK SPECIFICITY OF ACTION, AND ARE COMMONLY USED TO TREAT MULTIPLE OTHER PSYCHIATRIC CONDITIONS. THERE HAS ALSO BEEN RELATIVELY LITTLE PROGRESS IN THE DEVELOPMENT OF NOVEL MEDICATIONS TO TREAT NDDS. BASED ON CLINICAL, PRECLINICAL AND TRANSLATIONAL MODELS OF NDDS, OUR RECOMMENDATIONS COVER A WIDE RANGE OF METHODOLOGICAL APPROACHES AND CONCEPTUAL STRATEGIES. EXPERT OPINION: TO IMPROVE PHARMACOTHERAPY AND DRUG DISCOVERY FOR NDDS, WE NEED A STRONGER EMPHASIS ON TARGETING MULTIPLE ENDOPHENOTYPES, A BETTER DISSECTION OF GENETIC/EPIGENETIC FACTORS OR "HIDDEN HERITABILITY," AND A CAREFUL CONSIDERATION OF POTENTIAL DEVELOPMENTAL/TROPHIC ROLES OF BRAIN NEUROTRANSMITTERS. THE VALIDITY OF ANIMAL NDD MODELS CAN BE IMPROVED THROUGH DISCOVERY OF NOVEL (BEHAVIORAL, PHYSIOLOGICAL AND NEUROIMAGING) BIOMARKERS, APPLYING PROPER ENVIRONMENTAL ENRICHMENT, WIDENING THE SPECTRUM OF MODEL ORGANISMS, TARGETING DEVELOPMENTAL TRAJECTORIES OF NDD-RELATED BEHAVIORS AND COMORBID CONDITIONS BEYOND TRADITIONAL NDDS. WHILE THESE RECOMMENDATIONS CANNOT BE ADDRESSED ALL IN ONCE, OUR INCREASED UNDERSTANDING OF NDD PATHOBIOLOGY MAY TRIGGER INNOVATIVE CROSS-DISCIPLINARY RESEARCH EXPANDING BEYOND TRADITIONAL METHODS AND CONCEPTS. 2016 5 1091 30 COGNITIVE ENHANCERS AS A TREATMENT FOR HEROIN RELAPSE AND ADDICTION. HEROIN ADDICTION IS A DISORDER THAT STEMS FROM MALADAPTIVE PLASTICITY WITHIN NEURAL CIRCUITS AND PRODUCES BROAD COGNITIVE DEFICITS. DESPITE CONSIDERABLE ADVANCES IN PSYCHOTHERAPY AND PHARMACOTHERAPY FOR HEROIN RELAPSE AND ADDICTION, EFFECTIVE TREATMENTS FOR HEROIN USE DISORDER ARE STILL LACKING. INCREASING PRECLINICAL EVIDENCE INDICATES THAT HEROIN SEEKING BEHAVIOR IS PERSISTENT AFTER WITHDRAWAL, WHILE COGNITIVE DYSFUNCTIONS ASSOCIATED WITH CHRONIC HEROIN USE ARE AN IMPORTANT CONTRIBUTING FACTOR TO RISK OF HEROIN RELAPSE AND ADDICTION. COGNITIVE ENHANCERS MAY BE USED TO STIMULATE TREATMENT SUCCESS AND ENHANCE TREATMENT EFFICACY. THE PURPOSE OF THIS REVIEW IS TO OUTLINE THE LITERATURE THAT DEMONSTRATES THE COGNITIVE DEFICITS DURING THE DEVELOPMENT OF HEROIN ADDICTION AND WITHDRAWAL PROCESS, AND SEVERAL FACTORS THAT UNDERLINE THE EFFICACY OF COGNITIVE ENHANCERS FOR HEROIN USE DISORDERS. THE REVIEW, THEN, EXAMINES THE POTENTIAL USE AND PHARMACOLOGICAL MECHANISMS OF COGNITIVE ENHANCERS THAT ACT ON CHOLINERGIC, GLUTAMATERGIC, DOPAMINERGIC OR ADRENERGIC PATHWAYS. IT ALSO EXAMINES THE EFFECTS OF COMPOUNDS THAT ALTER CREB SIGNALING AND EPIGENETIC MECHANISMS IN ANIMAL MODEL OF HEROIN RELAPSE. THE CURRENT BODY OF RESEARCH REVEALS THE NEW INSIGHTS INTO THE PHARMACOLOGICAL MECHANISMS UNDERLYING HEROIN ADDICTION AND HOLDS A SIGNIFICANT PROMISE FOR COGNITIVE ENHANCERS AS AN IMPROVED APPROACH TO TREAT HEROIN USE DISORDER IN A MORE EFFICIENT AND PERSISTENT WAY. 2019 6 789 32 CELLULAR AND MOLECULAR MECHANISMS DRIVING NEUROPATHIC PAIN: RECENT ADVANCEMENTS AND CHALLENGES. CURRENT PHARMACOTHERAPEUTICS FOR NEUROPATHIC PAIN OFFER ONLY SYMPTOMATIC RELIEF WITHOUT TREATING THE UNDERLYING PATHOPHYSIOLOGY. ADDITIONALLY, THEY ARE ASSOCIATED WITH VARIOUS DOSE-LIMITING SIDE EFFECTS. PAIN RESEARCH IN THE PAST FEW DECADES HAS REVOLVED AROUND THE ROLE OF OXIDATIVE-NITROSATIVE STRESS, PROTEIN KINASES, GLIAL CELL ACTIVATION, AND INFLAMMATORY SIGNALING CASCADES BUT HAS FAILED TO PRODUCE SPECIFIC AND EFFECTIVE THERAPIES. AREAS COVERED: THIS REVIEW FOCUSES ON RECENT ADVANCES IN CELLULAR AND MOLECULAR MECHANISMS OF NEUROPATHIC PAIN THAT MAY BE TRANSLATED INTO FUTURE THERAPIES. WE DISCUSS EMERGING TARGETS SUCH AS WNT SIGNALING MECHANISMS, THE TETRAHYDROBIOPTERIN PATHWAY, MRG RECEPTORS, ENDOGENOUS LIPID MEDIATORS, MICRO-RNAS AND THEIR ROLES IN PAIN REGULATION. RECENT EVIDENCE IS ALSO PRESENTED REGARDING GENETIC AND EPIGENETIC MECHANISMS OF PAIN MODULATION. EXPERT OPINION: DURING CHRONIC NEUROPATHIC PAIN, MALADAPTATION OCCURS IN THE PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, INCLUDING A SHIFT IN MICROGLIAL PHENOTYPE FROM A SURVEILLANCE STATE TO AN ACTIVATED STATE. MICROGLIAL ACTIVATION LEADS TO AN ALTERED EXPRESSION OF CELL SURFACE PROTEINS, GROWTH FACTORS, AND INTRACELLULAR SIGNALING MOLECULES THAT CONTRIBUTE TO DEVELOPMENT OF A NEUROINFLAMMATORY CASCADE AND CHRONIC PAIN SENSITIZATION. SPECIFIC TARGETING OF THESE CELLULAR AND MOLECULAR MECHANISMS MAY PROVIDE THE KEY TO DEVELOPMENT OF EFFECTIVE NEUROPATHIC PAIN THERAPIES THAT HAVE MINIMAL SIDE EFFECTS. 2018 7 1688 35 DUAL BET/HDAC INHIBITION TO RELIEVE NEUROPATHIC PAIN: RECENT ADVANCES, PERSPECTIVES, AND FUTURE OPPORTUNITIES. DESPITE THE INTENSE RESEARCH ON DEVELOPING NEW THERAPIES FOR NEUROPATHIC PAIN STATES, AVAILABLE TREATMENTS HAVE LIMITED EFFICACY AND UNFAVORABLE SAFETY PROFILES. EPIGENETIC ALTERATIONS HAVE A GREAT INFLUENCE ON THE DEVELOPMENT OF CANCER AND NEUROLOGICAL DISEASES, AS WELL AS NEUROPATHIC PAIN. HISTONE ACETYLATION HAS PREVAILED AS ONE OF THE WELL INVESTIGATED EPIGENETIC MODIFICATIONS IN THESE DISEASES. ALTERED SPINAL ACTIVITY OF HISTONE DEACETYLASE (HDAC) AND BROMO AND EXTRA TERMINAL DOMAIN (BET) HAVE BEEN DESCRIBED IN NEUROPATHIC PAIN MODELS AND RESTORATION OF THESE ABERRANT EPIGENETIC MODIFICATIONS SHOWED PAIN-RELIEVING ACTIVITY. OVER THE LAST DECADES HDACS AND BETS HAVE BEEN THE FOCUS OF DRUG DISCOVERY STUDIES, LEADING TO THE DEVELOPMENT OF NUMEROUS SMALL-MOLECULE INHIBITORS. CLINICAL TRIALS TO EVALUATE THEIR ANTICANCER ACTIVITY SHOWED GOOD EFFICACY BUT RAISED TOXICITY CONCERNS THAT LIMITED TRANSLATION TO THE CLINIC. TO MAXIMIZE ACTIVITY AND MINIMIZE TOXICITY, THESE COMPOUNDS CAN BE APPLIED IN COMBINATION OF SUB-MAXIMAL DOSES TO PRODUCE ADDITIVE OR SYNERGISTIC INTERACTIONS (COMBINATION THERAPY). RECENTLY, OF PARTICULAR INTEREST, DUAL BET/HDAC INHIBITORS (MULTI-TARGET DRUGS) HAVE BEEN DEVELOPED TO ASSURE SIMULTANEOUS MODULATION OF BET AND HDAC ACTIVITY BY A SINGLE MOLECULE. THIS REVIEW WILL SUMMARIZE THE MOST RECENT ADVANCES WITH THESE STRATEGIES, DESCRIBING ADVANTAGES AND LIMITATIONS OF SINGLE DRUG TREATMENT VS COMBINATION REGIMENS. THIS REVIEW WILL ALSO PROVIDE A FOCUS ON DUAL BET/HDAC DRUG DISCOVERY INVESTIGATIONS AS FUTURE THERAPEUTIC OPPORTUNITY FOR HUMAN THERAPY OF NEUROPATHIC PAIN. 2021 8 6061 33 THE DEVELOPMENT PROSPECTION OF HDAC INHIBITORS AS A POTENTIAL THERAPEUTIC DIRECTION IN ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISEASE, WHICH IS ASSOCIATED WITH LEARNING AND MEMORY IMPAIRMENT IN THE ELDERLY. RECENT STUDIES HAVE FOUND THAT TREATING AD IN THE WAY OF CHROMATIN REMODELING VIA HISTONE ACETYLATION IS A PROMISING THERAPEUTIC REGIMEN. IN A NUMBER OF RECENT STUDIES, INHIBITORS OF HISTONE DEACETYLASE (HDACS) HAVE BEEN FOUND TO BE A NOVEL PROMISING THERAPEUTIC AGENTS FOR NEUROLOGICAL DISORDERS, PARTICULARLY FOR AD AND OTHER NEURODEGENERATIVE DISEASES. ALTHOUGH HDAC INHIBITORS HAVE THE ABILITY TO AMELIORATE COGNITIVE IMPAIRMENT, SUCCESSFUL TREATMENTS IN THE CLASSIC AD ANIMAL MODEL ARE RARELY TRANSLATED INTO CLINICAL TRIALS. AS FOR THE REDUCTION OF UNWANTED SIDE EFFECTS, THE DEVELOPMENT OF HDAC INHIBITORS WITH INCREASED ISOFORM SELECTIVITY OR SEEKING OTHER DIRECTIONS IS A KEY ISSUE THAT NEEDS TO BE ADDRESSED. THE REVIEW FOCUSED ON LITERATURES ON EPIGENETIC MECHANISMS IN RECENT YEARS, ESPECIALLY ON HISTONE ACETYLATION IN TERMS OF THE ENHANCEMENT OF SPECIFICITY, EFFICACY AND AVOIDING SIDE EFFECTS FOR TREATING AD. 2017 9 1204 33 COULD TARGETING EPIGENETIC PROCESSES RELIEVE CHRONIC PAIN STATES? PURPOSE OF REVIEW: ABERRATIONS IN THE EPIGENETIC LANDSCAPE HAVE PREVIOUSLY BEEN ASSOCIATED WITH HUMAN DISEASES SUCH AS CANCER AND SCHIZOPHRENIA, AND DRUGS THAT TARGET EPIGENETIC PROCESSES ARE CURRENTLY USED AS THERAPEUTIC AGENTS. THIS ARTICLE WILL REVIEW THE EVIDENCE OBTAINED FROM ANIMAL STUDIES INDICATING THAT EPIGENETIC PROCESSES MIGHT REGULATE LONG-TERM PAIN STATES AND THEN DISCUSS THE POSSIBILITY THAT TARGETING EPIGENETIC MECHANISMS MIGHT BE USEFUL FOR THE MANAGEMENT OF CHRONIC PAIN. RECENT FINDINGS: RECENT ANIMAL STUDIES HAVE REPORTED INJURY-INDUCED CHANGES IN EPIGENETIC PROCESSES IN THE CENTRAL NERVOUS SYSTEM. THE PICTURE THAT HAS EMERGED IS THAT OF VERY COMPLEX EPIGENETIC PROGRAMS THAT DEPEND ON THE INJURY. HOWEVER, SOME STUDIES HAVE REPORTED THE SUCCESSFUL USE OF NONSPECIFIC EPIGENETIC TOOLS TO IMPROVE THE HYPERSENSITIVITY THAT DEVELOPS IN ANIMAL MODELS OF LONG-TERM PAIN STATES. SUMMARY: THE FIELD OF EPIGENETICS AND PAIN IS RAPIDLY EMERGING BUT FURTHER INVESTIGATION IS NEEDED TO FULLY COMPREHEND THE CONTRIBUTION OF EPIGENETIC PROCESSES TO CHRONIC PAIN STATES. ALTHOUGH THERAPEUTIC APPROACHES TARGETING THESE MECHANISMS MIGHT SEEM WORTHWHILE, WE CANNOT ASSERT THAT CURRENTLY AVAILABLE GLOBAL TOOLS SUCH AS HISTONE DEACETYLASE INHIBITORS CAN BE USED SUCCESSFULLY FOR THE LONG-TERM TREATMENT OF CHRONIC PAIN STATES. 2015 10 2459 25 EPIGENETIC THERAPIES FOR NON-ONCOLOGY INDICATIONS. CHRONIC AND DEGENERATIVE DISORDERS ARE A MAJOR, AND GROWING, HUMAN HEALTH BURDEN, AND CURRENT TREATMENTS ARE IN MANY CASES INADEQUATE OR VERY EXPENSIVE. EPIGENETIC THERAPIES ARE ATTRACTIVE OPTIONS FOR TREATING SUCH DISORDERS BECAUSE THEY MANIPULATE THE PROCESSES THAT MAINTAIN CELLS IN AN ABNORMAL TRANSCRIPTIONAL STATE. THE CHALLENGES LIE IN IDENTIFYING THE MOST APPROPRIATE DISEASES AND THE ENZYMES THAT SHOULD BE TARGETED. THIS REVIEW DESCRIBES THE DIFFERENT APPROACHES THAT CAN BE USED TO ADDRESS THIS PROBLEM, FOCUSING PARTICULARLY ON CNS DISORDERS (ESPECIALLY MENTAL RETARDATION, NEURODEGENERATIVE DISEASE, PSYCHIATRIC DISORDERS AND DRUG ADDICTION), DIABETES AND DIABETIC COMPLICATIONS, AND AUTOIMMUNITY AND INFLAMMATORY DISEASES. 2010 11 2454 32 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 12 5778 28 SPINAL CORD INJURY INDUCED NEUROPATHIC PAIN: MOLECULAR TARGETS AND THERAPEUTIC APPROACHES. NEUROPATHIC PAIN, ESPECIALLY THAT RESULTING FROM SPINAL CORD INJURY, IS A TREMENDOUS CLINICAL CHALLENGE. A MYRIAD OF BIOLOGICAL CHANGES HAVE BEEN IMPLICATED IN PRODUCING THESE PAIN STATES INCLUDING CELLULAR INTERACTIONS, EXTRACELLULAR PROTEINS, ION CHANNEL EXPRESSION, AND EPIGENETIC INFLUENCES. PHYSIOLOGICAL CONSEQUENCES OF THESE CHANGES ARE VARIED AND INCLUDE FUNCTIONAL DEFICITS AND PAIN RESPONSES. DEVELOPING THERAPIES THAT EFFECTIVELY ADDRESS THE CAUSE OF THESE SYMPTOMS REQUIRE A DEEPER KNOWLEDGE OF ALTERATIONS IN THE MOLECULAR PATHWAYS. MATRIX METALLOPROTEINASES AND TISSUE INHIBITORS OF METALLOPROTEINASES ARE TWO PROMISING THERAPEUTIC TARGETS. MATRIX METALLOPROTEINASES INTERACT WITH AND INFLUENCE MANY OF THE STUDIED PAIN PATHWAYS. GENE EXPRESSION OF ION CHANNELS AND INFLAMMATORY MEDIATORS CLEARLY CONTRIBUTES TO NEUROPATHIC PAIN. LOCALIZED AND TIME DEPENDENT TARGETING OF THESE PROTEINS COULD ALLEVIATE AND EVEN PREVENT NEUROPATHIC PAIN FROM DEVELOPING. CURRENT THERAPEUTIC OPTIONS FOR NEUROPATHIC PAIN ARE LIMITED PRIMARILY TO ANALGESICS TARGETING THE OPIOID PATHWAY. THERAPIES DIRECTED AT MOLECULAR TARGETS ARE HIGHLY DESIRABLE AND IN EARLY STAGES OF DEVELOPMENT. THESE INCLUDE TRANSPLANTATION OF EXOGENOUSLY ENGINEERED CELL POPULATIONS AND TARGETED GENE MANIPULATION. THIS REVIEW DESCRIBES SPECIFIC MOLECULAR TARGETS AMENABLE TO THERAPEUTIC INTERVENTION USING CURRENTLY AVAILABLE DELIVERY SYSTEMS. 2015 13 2238 31 EPIGENETIC MODULATION AS A THERAPEUTIC PROSPECT FOR TREATMENT OF AUTOIMMUNE RHEUMATIC DISEASES. SYSTEMIC INFLAMMATORY RHEUMATIC DISEASES ARE CONSIDERED AS AUTOIMMUNE DISEASES, MEANING THAT THE BALANCE BETWEEN RECOGNITION OF PATHOGENS AND AVOIDANCE OF SELF-ATTACK IS IMPAIRED AND THE IMMUNE SYSTEM ATTACKS AND DESTROYS ITS OWN HEALTHY TISSUE. TREATMENT WITH CONVENTIONAL DISEASE MODIFYING ANTIRHEUMATIC DRUGS (DMARDS) AND/OR NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) IS OFTEN ASSOCIATED WITH VARIOUS ADVERSE REACTIONS DUE TO UNSPECIFIC AND TOXIC PROPERTIES OF THOSE DRUGS. ALTHOUGH BIOLOGIC DRUGS HAVE LARGELY IMPROVED THE OUTCOME IN MANY PATIENTS, SUCH DRUGS STILL POSE SIGNIFICANT PROBLEMS AND FAIL TO PROVIDE A SOLUTION TO ALL PATIENTS. THEREFORE, DEVELOPMENT OF MORE EFFECTIVE TREATMENTS AND IMPROVEMENTS IN EARLY DIAGNOSIS OF RHEUMATIC DISEASES ARE BADLY NEEDED IN ORDER TO INCREASE PATIENT'S FUNCTIONING AND QUALITY OF LIFE. THE REVERSIBLE NATURE OF EPIGENETIC MECHANISMS OFFERS A NEW CLASS OF DRUGS THAT MODULATE THE IMMUNE SYSTEM AND INFLAMMATION. IN FACT, EPIGENETIC DRUGS ARE ALREADY IN USE IN SOME TYPES OF CANCER OR CARDIOVASCULAR DISEASES. THEREFORE, EPIGENETIC-BASED THERAPEUTICS THAT CONTROL AUTOIMMUNITY AND CHRONIC INFLAMMATORY PROCESS HAVE BROAD IMPLICATIONS FOR THE PATHOGENESIS, DIAGNOSIS, AND MANAGEMENT OF RHEUMATIC DISEASES. THIS REVIEW SUMMARISES THE LATEST INFORMATION ABOUT POTENTIAL THERAPEUTIC APPLICATION OF EPIGENETIC MODIFICATION IN TARGETING IMMUNE ABNORMALITIES AND INFLAMMATION OF RHEUMATIC DISEASES. 2016 14 6807 24 [EPIGENETICS AND PAIN]. CHRONIC PAIN AFFECTS APPROXIMATELY 20 % OF ADULTS WORLDWIDE AND IS OFTEN ASSOCIATED WITH A DECREASE IN THE QUALITY OF LIFE AND VARIOUS COMORBIDITIES. CONVENTIONAL ANALGESIC THERAPIES ARE FREQUENTLY INSUFFICIENT AND SOMETIMES LEAD TO SEVERE SIDE EFFECTS. THEREFORE, GREAT EFFORTS ARE STILL BEING MADE TO ELUCIDATE THE SIGNALLING PATHWAYS IN PAIN AND TO DEVELOP NEW, SAFE AND EFFECTIVE THERAPIES. EPIGENETIC MECHANISMS WHICH INTERFERE WITH THE REGULATION OF GENE EXPRESSION ARE INVOLVED IN THE PATHOGENESIS OF SEVERAL DISEASES AND ARE GAINING INCREASING IMPETUS IN MEDICAL RESEARCH. AS THEY ARE ALSO INVOLVED IN PAIN PROCESSING, A MODULATION OF THESE MECHANISMS MIGHT REPRESENT A NOVEL OPTION FOR THE THERAPY OF PAIN PATIENTS. 2014 15 3333 32 HISTONE DEACETYLASE INHIBITORS AND DIABETIC KIDNEY DISEASE. DESPITE RECENT CLINICAL TRIAL ADVANCES AND IMPROVEMENTS IN CLINICAL CARE, KIDNEY DISEASE DUE TO DIABETES REMAINS THE MOST COMMON CAUSE OF CHRONIC KIDNEY FAILURE WORLDWIDE. IN THE SEARCH FOR NEW TREATMENTS, RECENT ATTENTIONS HAVE TURNED TO DRUG REPURPOSING OPPORTUNITIES, INCLUDING STUDY OF THE HISTONE DEACETYLASE (HDAC) INHIBITOR CLASS OF AGENTS. HDACS ARE A GROUP OF ENZYMES THAT REMOVE FUNCTIONAL ACETYL GROUPS FROM HISTONE AND NON-HISTONE PROTEINS AND THEY CAN AFFECT CELLULAR FUNCTION THROUGH BOTH EPIGENETIC AND NON-EPIGENETIC MEANS. OVER THE PAST DECADE, SEVERAL HDAC INHIBITORS HAVE BEEN ADOPTED INTO CLINICAL PRACTICE, PRIMARILY FOR THE TREATMENT OF HEMATOLOGICAL MALIGNANCY, WHEREAS OTHER EXISTING THERAPIES (FOR INSTANCE VALPROATE) HAVE BEEN FOUND TO HAVE HDAC INHIBITORY EFFECTS. HERE WE REVIEW THE CURRENT HDAC INHIBITORS IN THE CLINIC AND UNDER DEVELOPMENT; THE LITERATURE EVIDENCE SUPPORTING THE RENOPROTECTIVE EFFECTS OF HDAC INHIBITORS IN EXPERIMENTAL DIABETIC KIDNEY DISEASE; AND THE ADVERSE EFFECT PROFILES THAT MAY PREVENT EXISTING THERAPIES FROM ENTERING THE CLINIC FOR THIS INDICATION. WHEREAS RECENT RESEARCH EFFORTS HAVE SHED LIGHT ON THE FUNDAMENTAL ACTIONS OF HDACS IN THE DIABETIC KIDNEY, WHETHER THESE EFFORTS WILL TRANSLATE INTO NOVEL THERAPIES FOR PATIENTS WILL REQUIRE MORE SPECIFIC AND BETTER-TOLERATED THERAPIES. 2018 16 1687 31 DRUGS OF ABUSE: EPIGENETIC MECHANISMS IN TOXICITY AND ADDICTION. THE ABUSE OF SUBSTANCES SUCH AS ETHANOL, COCAINE, AMPHETAMINES AND HEROIN IS ASSOCIATED WITH TOXIC EFFECTS ON ALMOST EVERY SYSTEM OF THE ORGANISM. FURTHERMORE, THE TRANSITION FROM OCCASIONAL-RECREATIONAL USE TO CHRONIC ABUSE AND ADDICTION IS A SERIOUS PSYCHIATRIC DISORDER WITH ONLY FEW CHANCES FOR EFFECTIVE AND DEFINITIVE TREATMENT SINCE MOST INDIVIDUALS RELAPSE, EVEN AFTER LONG PERIODS OF ABSTINENCE. IT IS THEREFORE OF UTMOST IMPORTANCE TO ELUCIDATE THE MECHANISMS BY WHICH THESE SUBSTANCES EXERT THEIR TOXICITY AND MEDIATE ADDICTION, IN ORDER TO DEVELOP NEW, EFFICIENT THERAPEUTIC STRATEGIES WITH A LONG-TERM OUTCOME, WHICH ARE CURRENTLY LACKING. WE ALREADY KNOW THAT IN A GREAT NUMBER OF THESE MECHANISMS, ALTERED GENE FUNCTION IS INVOLVED. BUT, WITH THE NEW FIELD OF EPIGENETICS, THERE IS INCREASING EVIDENCE THAT CHANGES IN THE EPIGENOME ARE RESPONSIBLE FOR THE ALTERED GENE FUNCTION. THE ADVANCES IN THE FIELD OF EPIGENETICS TOWARDS ELUCIDATION OF THE MECHANISMS UNDERLYING TOXICITY AND ADDICTION FOR ETHANOL, COCAINE, AMPHETAMINES AND HEROIN ARE CURRENTLY PRESENTED AND DISCUSSED IN THIS REVIEW. 2011 17 5926 30 TARGETING EPIGENETIC MECHANISMS FOR CHRONIC PAIN: A VALID APPROACH FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. CHRONIC PAIN IS A MULTIFACETED AND COMPLEX CONDITION. BROADLY CLASSIFIED INTO SOMATIC, VISCERAL, OR NEUROPATHIC PAIN, IT IS POORLY MANAGED DESPITE ITS PREVALENCE. CURRENT DRUGS USED FOR THE TREATMENT OF CHRONIC PAIN ARE LIMITED BY TOLERANCE WITH LONG-TERM USE, ABUSE POTENTIAL, AND MULTIPLE ADVERSE SIDE EFFECTS. THE PERSISTENT NATURE OF PAIN SUGGESTS THAT EPIGENETIC MACHINERY MAY BE A CRITICAL FACTOR DRIVING CHRONIC PAIN. IN THIS REVIEW, WE DISCUSS THE LATEST INSIGHTS INTO EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS, AND WE DESCRIBE THEIR INVOLVEMENT IN THE PATHOPHYSIOLOGY OF CHRONIC PAIN AND WHETHER EPIGENETIC MODIFICATIONS COULD BE APPLIED AS FUTURE THERAPEUTIC TARGETS FOR CHRONIC PAIN. WE PROVIDE EVIDENCE FROM EXPERIMENTAL MODELS AND TRANSLATIONAL RESEARCH IN HUMAN TISSUE THAT HAVE ENHANCED OUR UNDERSTANDING OF EPIGENETIC PROCESSES MEDIATING NOCICEPTION, AND WE THEN SPECULATE ON THE POTENTIAL FUTURE USE OF MORE SPECIFIC AND SELECTIVE AGENTS THAT TARGET EPIGENETIC MECHANISMS TO ATTENUATE PAIN. 2016 18 5835 28 STRESS-INDUCED VISCERAL PAIN: TOWARD ANIMAL MODELS OF IRRITABLE-BOWEL SYNDROME AND ASSOCIATED COMORBIDITIES. VISCERAL PAIN IS A GLOBAL TERM USED TO DESCRIBE PAIN ORIGINATING FROM THE INTERNAL ORGANS, WHICH IS DISTINCT FROM SOMATIC PAIN. IT IS A HALLMARK OF FUNCTIONAL GASTROINTESTINAL DISORDERS SUCH AS IRRITABLE-BOWEL SYNDROME (IBS). CURRENTLY, THE TREATMENT STRATEGIES TARGETING VISCERAL PAIN ARE UNSATISFACTORY, WITH DEVELOPMENT OF NOVEL THERAPEUTICS HINDERED BY A LACK OF DETAILED KNOWLEDGE OF THE UNDERLYING MECHANISMS. STRESS HAS LONG BEEN IMPLICATED IN THE PATHOPHYSIOLOGY OF VISCERAL PAIN IN BOTH PRECLINICAL AND CLINICAL STUDIES. HERE, WE DISCUSS THE COMPLEX ETIOLOGY OF VISCERAL PAIN REVIEWING OUR CURRENT UNDERSTANDING IN THE CONTEXT OF THE ROLE OF STRESS, GENDER, GUT MICROBIOTA ALTERATIONS, AND IMMUNE FUNCTIONING. FURTHERMORE, WE REVIEW THE ROLE OF GLUTAMATE, GABA, AND EPIGENETIC MECHANISMS AS POSSIBLE THERAPEUTIC STRATEGIES FOR THE TREATMENT OF VISCERAL PAIN FOR WHICH THERE IS AN UNMET MEDICAL NEED. MOREOVER, WE DISCUSS THE MOST WIDELY DESCRIBED RODENT MODELS USED TO MODEL VISCERAL PAIN IN THE PRECLINICAL SETTING. THE THEORY BEHIND, AND APPLICATION OF, ANIMAL MODELS IS KEY FOR BOTH THE UNDERSTANDING OF UNDERLYING MECHANISMS AND DESIGN OF FUTURE THERAPEUTIC INTERVENTIONS. TAKEN TOGETHER, IT IS APPARENT THAT STRESS-INDUCED VISCERAL PAIN AND ITS PSYCHIATRIC COMORBIDITIES, AS TYPIFIED BY IBS, HAS A MULTIFACETED ETIOLOGY. MOREOVER, TREATMENT STRATEGIES STILL LAG FAR BEHIND WHEN COMPARED TO OTHER PAIN MODALITIES. THE DEVELOPMENT OF NOVEL, EFFECTIVE, AND SPECIFIC THERAPEUTICS FOR THE TREATMENT OF VISCERAL PAIN HAS NEVER BEEN MORE PERTINENT. 2015 19 2259 25 EPIGENETIC PRIMING IN DRUG ADDICTION. DRUG ADDICTION IS A CHRONIC RELAPSING BRAIN DISORDER THAT IS CHARACTERIZED BY COMPULSIVE DRUG SEEKING AND CONTINUED USE DESPITE NEGATIVE OUTCOMES. CURRENT PHARMACOLOGICAL THERAPIES TARGET NEURONAL RECEPTORS OR TRANSPORTERS UPON WHICH DRUGS OF ABUSE ACT INITIALLY, YET THESE TREATMENTS REMAIN INEFFECTIVE FOR MOST INDIVIDUALS AND DO NOT PREVENT DISEASE RELAPSE AFTER ABSTINENCE. DRUGS OF ABUSE, IN ADDITION TO THEIR ACUTE EFFECTS, CAUSE PERSISTENT PLASTICITY AFTER REPEATED USE, INVOLVING DYSREGULATED GENE EXPRESSION IN THE BRAIN'S REWARD REGIONS, WHICH ARE THOUGHT TO MEDIATE THE PERSISTENT BEHAVIORAL ABNORMALITIES THAT CHARACTERIZE ADDICTION. EMERGING EVIDENCE IMPLICATES EPIGENETIC PRIMING AS A KEY MECHANISM THAT UNDERLIES THE LONG-LASTING ALTERATIONS IN NEURONAL GENE REGULATION, WHICH CAN REMAIN LATENT UNTIL TRIGGERED BY RE-EXPOSURE TO DRUG-ASSOCIATED STIMULI OR THE DRUG ITSELF. THUS, TO EFFECTIVELY TREAT DRUG ADDICTION, WE MUST IDENTIFY THE PRECISE EPIGENETIC MECHANISMS THAT ESTABLISH AND PRESERVE THE DRUG-INDUCED PATHOLOGY OF THE BRAIN REWARD CIRCUITRY. 2018 20 1127 25 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