1 2800 131 FEEDBACK REGULATORS OF HYPOXIA-INDUCIBLE FACTORS AND THEIR ROLE IN CANCER BIOLOGY. MALIGNANT TUMORS ARE CHARACTERIZED BY REGIONS OF LOW OXYGEN CONCENTRATION (HYPOXIA). THE HYPOXIC TUMOR MICROENVIRONMENT CONTRIBUTES TO TUMOR PROGRESSION BY ACTIVATING A SET OF ADAPTIVE RESPONSES VIA THE KEY TRANSCRIPTIONAL REGULATORS HIF-1ALPHA AND HIF-2ALPHA. THESE FACTORS HAVE BEEN TRADITIONALLY LINKED TO AN AGGRESSIVE TUMOR PHENOTYPE BY PROMOTING PROCESSES ESSENTIAL FOR TUMOR GROWTH, SUCH AS ANGIOGENESIS, GLYCOLYSIS, METASTASIS AND INVASION, AS WELL AS DIFFERENTIATION AND SELF RENEWAL. NOTABLY, THE COMPLEX HIF PATHWAY ALSO INITIATES ANTI-TUMORIGENIC MECHANISMS THAT LEAD TO CELL CYCLE ARREST OR CELL DEATH, INDICATING THE NEED FOR A STRINGENT CONTROL OF THE EXTENT AND THE DIRECTION OF THE HYPOXIA RESPONSE. THE IMPORTANCE OF THIS CONTROL FOR TUMOR CELL SURVIVAL IS ILLUSTRATED BY THE INTRICATE REGULATION OF HIF ACTIVITY AT THE MRNA, PROTEIN AND EPIGENETIC LEVEL BY A COMPLEX NETWORK OF POSITIVE AND NEGATIVE FEEDBACK REGULATORS. WE PROPOSE THAT THESE FEEDBACK REGULATORS HELP TO FLEXIBLY ADJUST AND ADAPT HIF ACTIVATED RESPONSES TO THE FLUCTUATING OXYGEN CONCENTRATIONS WITHIN TUMORS DURING ACUTE AND CHRONIC HYPOXIA AND TO CURTAIL THE TUMOR-SUPPRESSING COMPONENTS OF THE HIF PATHWAY. MOREOVER, FEEDBACK REGULATION OF HIF INDUCES A SWITCH FROM HIF-1ALPHA TO HIF-2ALPHA DRIVEN RESPONSES UNDER CHRONIC HYPOXIA WHICH MAY HAVE ESSENTIAL FUNCTIONS IN THE REGULATION OF TUMOR CELL DIFFERENTIATION AND TUMOR STEM CELL MAINTENANCE. GIVEN THEIR CENTRAL ROLE IN CANCER BIOLOGY, HIF FEEDBACK REGULATORS MAY REPRESENT AN ATTRACTIVE AND NOVEL ANTI-TUMOR THERAPY TARGET TO OVERCOME CELL DEATH RESISTANCE IN TUMORS. 2010 2 1291 27 DECODING THE ROLE OF EPIGENETICS AND GENOMICS IN PAIN MANAGEMENT. PERSISTENT PAIN IS A COSTLY EPIDEMIC, AFFECTING >50 MILLION AMERICANS WITH ESTIMATED EXPENDITURES OF >$200 BILLION ANNUALLY FOR DIRECT CARE AND LOST PRODUCTIVITY. RECENT ADVANCES IN EPIGENETIC/GENOMIC UNDERSTANDING OF PAIN AND ANALGESIC RESPONSE MAY LEAD TO IMPROVEMENTS IN PAIN MANAGEMENT AND HELP CURTAIL COSTS BY PROVIDING MORE PRECISE DETECTION OF THE PAIN MECHANISMS INVOLVED AND THEREBY MORE PERSONALIZED AND EFFECTIVE TREATMENTS. HOWEVER, THE TRANSLATION OF EPIGENETIC AND GENOMIC STRATEGIES FOR PAIN MANAGEMENT INTO CLINICAL PRACTICE WILL DEPEND ON UNDERSTANDING THEIR POTENTIAL APPLICATIONS. THE PURPOSE OF THIS ARTICLE IS TO EXAMINE CURRENT KNOWLEDGE ABOUT EPIGENETIC AND GENOMIC MECHANISMS OF PERSISTENT PAIN AND POTENTIAL OPPORTUNITIES FOR IMPROVING PAIN MANAGEMENT. THE INITIAL DISCUSSION FOCUSES ON PRESENT UNDERSTANDING OF NOCICEPTIVE PATHWAYS AND ALTERATIONS THAT LEAD TO PATHOLOGIC PAIN. THE DISCUSSION THEN MOVES TO A REVIEW OF EPIGENETIC MECHANISMS THAT HAVE BEEN IDENTIFIED IN THE TRANSITION TO AND MAINTENANCE OF PERSISTENT PAIN AS WELL AS IN THE INDIVIDUAL'S RESPONSE TO ANALGESICS. POTENTIAL APPLICATIONS OF EPIGENETICS/GENOMICS TO IDENTIFY PEOPLE AT RISK AND POSSIBLY PREVENT PERSISTENT PAIN AND GUIDE DIAGNOSIS AND THE SELECTION OF THERAPEUTIC MODALITIES ARE PRESENTED. 2013 3 5420 43 REGULATION OF HYPOXIA-INDUCIBLE FACTOR IN KIDNEY DISEASE. HYPOXIA PLAYS A CRUCIAL ROLE IN THE PATHOPHYSIOLOGY OF ACUTE KIDNEY INJURY (AKI) AND PRESUMABLY ALSO CHRONIC KIDNEY DISEASE (CKD). HYPOXIA-INDUCIBLE FACTOR (HIF) IS THE MASTER TRANSCRIPTION FACTOR THAT REGULATES ADAPTIVE RESPONSES AGAINST HYPOXIA. UNDER HYPOXIC CONDITIONS, HIF ACTIVATES TARGET GENES WITH HYPOXIA-RESPONSIVE ELEMENTS IN THEIR REGULATORY REGIONS. THE HIF ISOFORMS AND REGULATORS OF HIF (I.E. PROLYL HYDROXYLASES) SHOW CELL TYPE-SPECIFIC DISTRIBUTIONS. HYPOXIA IS OBSERVED IN BOTH ISCHAEMIC AND SO-CALLED NON-ISCHAEMIC FORMS OF AKI. IN ADDITION TO THE ACUTE PHASE, HYPOXIA MAY ENSUE DURING THE RECOVERY PHASE OF AKI, POSSIBLY DUE TO THE OXYGEN-CONSUMING PROCESSES OF CELL GROWTH AND PROLIFERATION FOR REPAIR. ALTHOUGH HIF PROTECTS THE KIDNEY AGAINST AKI, INTRINSIC HIF ACTIVATION IS SUBMAXIMAL IN AKI AND FURTHER AUGMENTATION OF HIF AMELIORATES DISEASE MANIFESTATIONS. THE KIDNEY IN CKD ALSO SUFFERS FROM HYPOXIA CAUSED BY MULTIPLE MECHANISMS, INCLUDING SUSTAINED OXYGEN DEMANDS IN THE REMAINING NEPHRONS DUE TO MALADAPTIVE TUBULOGLOMERULAR FEEDBACK. WHETHER HIF IS CHRONICALLY UPREGULATED IN CKD IS CONTENTIOUS. HYPOXIA-INDUCIBLE FACTOR ACTIVATION IS A PROMISING THERAPEUTIC APPROACH TO CKD, BUT EXCESSIVE ACTIVATION OF HIF MAY BE DELETERIOUS. IT IS LIKELY THAT THERE IS A THERAPEUTIC WINDOW OF HIF ACTIVATION IN CHRONIC CONDITIONS. UNDER CERTAIN CIRCUMSTANCES, ANIMALS WITH CKD ARE PROTECTED AGAINST AKI AND THIS MAY BE EXPLAINED BY NON-PHYSIOLOGICAL HYPOXIA OF THE KIDNEY AND SUBSEQUENT HIF EXPRESSION. IN ADDITION, AN ACUTE HYPOXIC INSULT MAY INDUCE LONG-LASTING CHANGES, POSSIBLY INCLUDING EPIGENETIC MODIFICATIONS INDUCED BY HIF. THESE OBSERVATIONS SUGGEST A COMPLEX INTERACTION BETWEEN AKI AND CKD VIA HYPOXIA AND HIF ACTIVATION. 2013 4 3338 41 HISTONE DEACETYLASE INHIBITORS: THE EPIGENETIC THERAPEUTICS THAT REPRESS HYPOXIA-INDUCIBLE FACTORS. HISTONE DEACETYLASE INHIBITORS (HDACIS) HAVE BEEN ACTIVELY EXPLORED AS A NEW GENERATION OF CHEMOTHERAPEUTICS FOR CANCERS, GENERALLY KNOWN AS EPIGENETIC THERAPEUTICS. RECENT FINDINGS INDICATE THAT SEVERAL TYPES OF HDACIS REPRESS ANGIOGENESIS, A PROCESS ESSENTIAL FOR TUMOR METABOLISM AND PROGRESSION. ACCUMULATING EVIDENCE SUPPORTS THAT THIS REPRESSION IS MEDIATED BY DISRUPTING THE FUNCTION OF HYPOXIA-INDUCIBLE FACTORS (HIF-1, HIF-2, AND COLLECTIVELY, HIF), WHICH ARE THE MASTER REGULATORS OF ANGIOGENESIS AND CELLULAR ADAPTATION TO HYPOXIA. SINCE HIF ALSO REGULATE GLUCOSE METABOLISM, CELL SURVIVAL, MICROENVIRONMENT REMODELING, AND OTHER ALTERATIONS COMMONLY REQUIRED FOR TUMOR PROGRESSION, THEY ARE CONSIDERED AS NOVEL TARGETS FOR CANCER CHEMOTHERAPY. THOUGH THE PRECISE BIOCHEMICAL MECHANISM UNDERLYING THE HDACI-TRIGGERED REPRESSION OF HIF FUNCTION REMAINS UNCLEAR, POTENTIAL CELLULAR FACTORS THAT MAY LINK THE INHIBITION OF DEACETYLASE ACTIVITY TO THE REPRESSION OF HIF FUNCTION HAVE BEEN PROPOSED. HERE WE REVIEW PUBLISHED DATA THAT INHIBITORS OF TYPE I/II HDACS REPRESS HIF FUNCTION BY EITHER REDUCING FUNCTIONAL HIF-1ALPHA LEVELS, OR REPRESSING HIF-ALPHA TRANSACTIVATION ACTIVITY. IN ADDITION, UNDERLYING MECHANISMS AND POTENTIAL PROTEINS INVOLVED IN THE REPRESSION WILL BE DISCUSSED. A THOROUGH UNDERSTANDING OF HDACI-INDUCED REPRESSION OF HIF FUNCTION MAY FACILITATE THE DEVELOPMENT OF FUTURE THERAPIES TO EITHER REPRESS OR PROMOTE ANGIOGENESIS FOR CANCER OR CHRONIC ISCHEMIC DISORDERS, RESPECTIVELY. 2011 5 5565 34 ROLE OF HYPOXIA IN PROGRESSIVE CHRONIC KIDNEY DISEASE AND IMPLICATIONS FOR THERAPY. PURPOSE OF REVIEW: CHRONIC HYPOXIA IN THE TUBULOINTERSTITIUM HAS BEEN RECOGNIZED AS A FINAL COMMON PATHWAY THAT LEADS TO THE DEVELOPMENT OF END-STAGE RENAL DISEASE. HYPOXIA-INDUCIBLE FACTOR (HIF), A MASTER REGULATOR OF THE ADAPTIVE RESPONSE AGAINST HYPOXIA, IS INVOLVED IN THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE (CKD). THIS REVIEW FOCUSES ON HIF AND NOVEL THERAPEUTIC STRATEGIES TARGETING HIF. RECENT FINDINGS: ALTHOUGH HIF UPREGULATION IS BENEFICIAL AGAINST HYPOXIC KIDNEY INJURY, IT MAY BE HARMFUL UNDER CERTAIN PATHOLOGICAL CONDITIONS. RECENT ADVANCES IN EPIGENETIC CHANGES PROVIDE AN ADDITIONAL LAYER OF COMPLEXITY TO OUR UNDERSTANDING OF GENE REGULATION IN RESPONSE TO HYPOXIA, WHICH IS MOST LIKELY INVOLVED IN THE PROGRESSION OF CKD. ON THE BASIS OF THIS NOVEL KNOWLEDGE, THE PHARMACOLOGICAL ACTIVATION AND MODULATION OF HIF IS EMERGING AS A NOVEL THERAPEUTIC TARGET. SUMMARY: HIF PLAYS A CRUCIAL ROLE IN THE PATHOPHYSIOLOGY OF CKD. THE UNDERLYING MOLECULAR MECHANISMS, INCLUDING EPIGENETICS, HAVE BEEN THOROUGHLY INVESTIGATED. ON THE BASIS OF THE EXPERIMENTAL DATA AVAILABLE TO DATE, THE PHARMACOLOGICAL ACTIVATION OF HIF IS LIKELY A NOVEL PROMISING THERAPY FOR CKD. 2014 6 3467 36 HYPOXIA, HIF, AND ASSOCIATED SIGNALING NETWORKS IN CHRONIC KIDNEY DISEASE. THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE (CKD) IS COMPLEX AND APPARENTLY MULTIFACTORIAL. HYPOXIA OR DECREASE IN OXYGEN SUPPLY IN KIDNEY TISSUES HAS BEEN IMPLICATED IN CKD. HYPOXIA INDUCIBLE FACTORS (HIF) ARE A SMALL FAMILY OF TRANSCRIPTION FACTORS THAT ARE MAINLY RESPONSIVE TO HYPOXIA AND MEDIATE HYPOXIC RESPONSE. HIF PLAYS A CRITICAL ROLE IN RENAL FIBROSIS DURING CKD THROUGH THE MODULATION OF GENE TRANSCRIPTION, CROSSTALK WITH MULTIPLE SIGNALING PATHWAYS, EPITHELIAL-MESENCHYMAL TRANSITION, AND EPIGENETIC REGULATION. MOREOVER, HIF ALSO CONTRIBUTES TO THE DEVELOPMENT OF VARIOUS PATHOLOGICAL CONDITIONS ASSOCIATED WITH CKD, SUCH AS ANEMIA, INFLAMMATION, ABERRANT ANGIOGENESIS, AND VASCULAR CALCIFICATION. TREATMENTS TARGETING HIF AND RELATED SIGNALING PATHWAYS FOR CKD THERAPY ARE BEING DEVELOPED WITH PROMISING CLINICAL BENEFITS, ESPECIALLY FOR ANEMIA. THIS REVIEW PRESENTS AN UPDATED ANALYSIS OF HYPOXIA RESPONSE, HIF, AND THEIR ASSOCIATED SIGNALING NETWORK INVOLVED IN THE PATHOGENESIS OF CKD. 2017 7 4666 40 NEW INSIGHTS AND OPTIONS INTO THE MECHANISMS AND EFFECTS OF COMBINED TARGETED THERAPY AND IMMUNOTHERAPY IN PROSTATE CANCER. CHRONIC INFLAMMATION IS BELIEVED TO DRIVE PROSTATE CARCINOGENESIS BY PRODUCING REACTIVE OXYGEN SPECIES OR REACTIVE NITROGEN SPECIES TO INDUCE DNA DAMAGE. THIS EFFECT MIGHT SUBSEQUENTLY CAUSE EPIGENETIC AND GENOMIC ALTERATIONS, LEADING TO MALIGNANT TRANSFORMATION. ALTHOUGH ESTABLISHED THERAPEUTIC ADVANCES HAVE EXTENDED OVERALL SURVIVAL, TUMORS IN PATIENTS WITH ADVANCED PROSTATE CANCER ARE PRONE TO METASTASIS, TRANSFORMATION INTO METASTATIC CASTRATION-RESISTANT PROSTATE CANCER, AND THERAPEUTIC RESISTANCE. THE TUMOR MICROENVIRONMENT (TME) OF PROSTATE CANCER IS INVOLVED IN CARCINOGENESIS, INVASION AND DRUG RESISTANCE. A PLETHORA OF PRECLINICAL STUDIES HAVE FOCUSED ON IMMUNE-BASED THERAPIES. UNDERSTANDING THE INTRICATE TME SYSTEM IN PROSTATE CANCER MAY HOLD MUCH PROMISE FOR DEVELOPING NOVEL THERAPIES, DESIGNING COMBINATIONAL THERAPEUTIC STRATEGIES, AND FURTHER OVERCOMING RESISTANCE TO ESTABLISHED TREATMENTS TO IMPROVE THE LIVES OF PROSTATE CANCER PATIENTS. IN THIS REVIEW, WE DISCUSS NONIMMUNE COMPONENTS AND VARIOUS IMMUNE CELLS WITHIN THE TME AND THEIR PUTATIVE ROLES DURING PROSTATE CANCER INITIATION, PROGRESSION, AND METASTASIS. WE ALSO OUTLINE THE UPDATED FUNDAMENTAL RESEARCH FOCUSING ON THERAPEUTIC ADVANCES OF TARGETED THERAPY AS WELL AS COMBINATIONAL OPTIONS FOR PROSTATE CANCER. 2023 8 3289 42 HIF-1ALPHA MEDIATES TUMOR HYPOXIA TO CONFER A PERPETUAL MESENCHYMAL PHENOTYPE FOR MALIGNANT PROGRESSION. ALTHOUGH TUMOR PROGRESSION INVOLVES GENETIC AND EPIGENETIC ALTERATIONS TO NORMAL CELLULAR BIOLOGY, THE UNDERLYING MECHANISMS OF THESE CHANGES REMAIN OBSCURE. NUMEROUS STUDIES HAVE SHOWN THAT HYPOXIA-INDUCIBLE FACTOR 1ALPHA (HIF-1ALPHA) IS OVEREXPRESSED IN MANY HUMAN CANCERS AND UP-REGULATES A HOST OF HYPOXIA-RESPONSIVE GENES FOR CANCER GROWTH AND SURVIVAL. WE RECENTLY IDENTIFIED AN ALTERNATIVE MECHANISM OF HIF-1ALPHA FUNCTION THAT INDUCES GENETIC ALTERATIONS BY SUPPRESSING DNA REPAIR. HERE, WE SHOW THAT LONG-TERM HYPOXIA, WHICH MIMICS THE TUMOR MICROENVIRONMENT, DRIVES A PERPETUAL EPITHELIAL-MESENCHYMAL TRANSITION (EMT) THROUGH UP-REGULATION OF THE ZINC FINGER E-BOX BINDING HOMEOBOX PROTEIN ZEB2, WHEREAS SHORT-TERM HYPOXIA INDUCES A REVERSIBLE EMT THAT REQUIRES THE TRANSCRIPTION FACTOR TWIST1. MOREOVER, WE SHOW THAT THE PERPETUAL EMT DRIVEN BY CHRONIC HYPOXIA DEPENDS ON HIF-1ALPHA INDUCTION OF GENETIC ALTERATIONS RATHER THAN ITS CANONICAL TRANSCRIPTIONAL ACTIVATOR FUNCTION. THESE MESENCHYMAL TUMOR CELLS NOT ONLY ACQUIRE TUMORIGENICITY BUT ALSO DISPLAY CHARACTERISTICS OF ADVANCED CANCERS, INCLUDING NECROSIS, AGGRESSIVE INVASION, AND METASTASIS. HENCE, THESE RESULTS REVEAL A MECHANISM BY WHICH HIF-1ALPHA PROMOTES A PERPETUAL MESENCHYMAL PHENOTYPE, THEREBY ADVANCING TUMOR PROGRESSION. 2011 9 4754 19 NOVEL THERAPEUTIC STRATEGIES FOR CHRONIC HEPATITIS B. THE LAST FEW YEARS HAVE SEEN A RESURGENCE OF ACTIVITY IN THE HEPATITIS B DRUG PIPELINE, WITH MANY COMPOUNDS IN VARIOUS STAGES OF DEVELOPMENT. THIS REVIEW AIMS TO PROVIDE A COMPREHENSIVE OVERVIEW OF THE LATEST ADVANCES IN THERAPEUTICS FOR CHRONIC HEPATITIS B (CHB). WE WILL DISCUSS THE BROAD SPECTRUM OF DIRECT-ACTING ANTIVIRALS IN CLINICAL DEVELOPMENT, INCLUDING CAPSIDS INHIBITORS, SIRNA, HBSAG AND POLYMERASE INHIBITORS. IN ADDITION, HOST-TARGETED THERAPIES (HTT) WILL BE EXTENSIVELY REVIEWED, FOCUSING ON THE LATEST PROGRESS IN IMMUNOTHERAPEUTICS SUCH AS TOLL-LIKE RECEPTORS AND RIG-1 AGONISTS, THERAPEUTIC VACCINES AND IMMUNE CHECKPOINTS MODULATORS. A GROWING NUMBER OF HTT IN PRE-CLINICAL DEVELOPMENT DIRECTLY TARGET THE KEY TO HBV PERSISTENCE, NAMELY THE COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) AND HOLD GREAT PROMISE FOR HBV CURE. THIS EXCITING AREA OF HBV RESEARCH WILL BE HIGHLIGHTED, AND MOLECULES SUCH AS CYCLOPHILINS INHIBITORS, APOBEC3 DEAMINASES AND EPIGENETIC MODIFIERS WILL BE DISCUSSED. 2022 10 3938 28 LNC(ING)RNAS TO THE "SHOCK AND KILL" STRATEGY FOR HIV-1 CURE. THE ADVENT OF ANTIRETROVIRAL THERAPY ALMOST 25 YEARS AGO HAS TRANSFORMED HIV-1 INFECTION INTO A MANAGEABLE CHRONIC CONDITION, ALBEIT STILL INCURABLE. THE INABILITY OF THE TREATMENT REGIMEN TO ELIMINATE LATENTLY INFECTED CELLS THAT HARBOR THE VIRUS IN AN EPIGENETICALLY SILENT STATE POSES A MAJOR HURDLE. CURRENT CURE APPROACHES ARE FOCUSED ON A "SHOCK AND KILL" STRATEGY THAT USES LATENCY-REVERSING AGENTS TO CHEMICALLY REVERSE THE PROVIRAL QUIESCENCE IN LATENTLY INFECTED CELLS, FOLLOWED BY IMMUNE-MEDIATED CLEARANCE OF REACTIVATED CELLS. TO DATE, HUNDREDS OF COMPOUNDS HAVE BEEN INVESTIGATED FOR VIRAL REACTIVATION, YET NONE HAS RESULTED IN A FUNCTIONAL CURE. THE INSUFFICIENCY OF THESE LATENCY-REVERSING AGENTS (LRAS) ALONE INDICATES A CRITICAL NEED FOR ADDITIONAL, ALTERNATE APPROACHES SUCH AS GENETIC MANIPULATION. LONG NON-CODING RNAS (LNCRNAS) ARE AN EMERGING CLASS OF REGULATORY RNAS WITH FUNCTIONAL ROLES IN MANY CELLULAR PROCESSES, INCLUDING EPIGENETIC MODULATION. A NUMBER OF LNCRNAS HAVE ALREADY BEEN IMPLICATED TO PLAY IMPORTANT ROLES IN HIV-1 LATENCY AND, AS SUCH, PHARMACOLOGICAL MODULATION OF LNCRNAS CONSTITUTES A RATIONAL ALTERNATIVE APPROACH IN HIV-1 CURE RESEARCH. IN THIS REVIEW, WE DISCUSS THE CURRENT STATE OF KNOWLEDGE OF THE ROLE OF LNCRNAS IN HIV-1 INFECTION AND EXPLORE THE SCOPE FOR A LNCRNA-MEDIATED GENETIC APPROACH WITHIN THE SHOCK AND KILL STRATEGY OF HIV-1 CURE. 2021 11 2614 38 EPIGENETICS: NEW QUESTIONS ON THE RESPONSE TO HYPOXIA. REDUCTION IN OXYGEN LEVELS BELOW NORMAL CONCENTRATIONS PLAYS IMPORTANT ROLES IN DIFFERENT NORMAL AND PATHOLOGICAL CONDITIONS, SUCH AS DEVELOPMENT, TUMORIGENESIS, CHRONIC KIDNEY DISEASE AND STROKE. ORGANISMS EXPOSED TO HYPOXIA TRIGGER CHANGES AT BOTH CELLULAR AND SYSTEMIC LEVELS TO RECOVER OXYGEN HOMEOSTASIS. MOST OF THESE PROCESSES ARE MEDIATED BY HYPOXIA INDUCIBLE FACTORS, HIFS, A FAMILY OF TRANSCRIPTION FACTORS THAT DIRECTLY INDUCE THE EXPRESSION OF SEVERAL HUNDRED GENES IN MAMMALIAN CELLS. ALTHOUGH DIFFERENT ASPECTS OF HIF REGULATION ARE WELL KNOWN, IT IS STILL UNCLEAR BY WHICH PRECISE MECHANISM HIFS ACTIVATE TRANSCRIPTION OF THEIR TARGET GENES. CONCOMITANTLY, HYPOXIA PROVOKES A DRAMATIC DECREASE OF GENERAL TRANSCRIPTION THAT SEEMS TO RELY IN PART ON EPIGENETIC CHANGES THROUGH A POORLY UNDERSTOOD MECHANISM. IN THIS REVIEW WE DISCUSS THE CURRENT KNOWLEDGE ON CHROMATIN CHANGES INVOLVED IN HIF DEPENDENT GENE ACTIVATION, AS WELL AS ON OTHER EPIGENETIC CHANGES, NOT NECESSARILY LINKED TO HIF THAT TAKE PLACE UNDER HYPOXIC CONDITIONS. 2011 12 6706 26 VIRAL GENE PRODUCTS ACTIVELY PROMOTE LATENT INFECTION BY EPIGENETIC SILENCING MECHANISMS. MANY VIRUSES UNDERGO AN ACUTE INFECTION IN THE HOST ORGANISM AND THEN ARE CLEARED BY THE ENSUING HOST IMMUNE RESPONSE, BUT OTHER VIRUSES ESTABLISH A PERSISTENT INFECTION INVOLVING A LATENT INFECTION OR A CHRONIC INFECTION. LATENT INFECTION BY THE HERPESVIRUSES OR HUMAN IMMUNODEFICIENCY VIRUS INVOLVES EPIGENETIC SILENCING OF THE DNA GENOME OR PROVIRAL GENOME, RESPECTIVELY. LATENT INFECTION WAS PREVIOUSLY THOUGHT TO BE A DEFAULT PATHWAY RESULTING FROM INFECTION OF A NONPERMISSIVE CELL, BUT RECENT STUDIES HAVE SHOWN THAT VIRAL GENE PRODUCTS CAN PROMOTE EPIGENETIC SILENCING AND LATENT INFECTION. THIS REVIEW WILL SUMMARIZE THE VIRAL GENE PRODUCTS THAT HAVE BEEN SHOWN TO PROMOTE EPIGENETIC SILENCING OF THE GENOMES AND THEIR POTENTIAL FOR THERAPEUTICS TO TARGET THESE VIRAL GENE PRODUCTS AND DISRUPT OR LOCK IN LATENT INFECTION. 2017 13 4532 26 MULTIMODAL ANALGESIA FOR PERIOPERATIVE MANAGEMENT OF PATIENTS PRESENTING FOR SPINAL SURGERY. MULTIMODAL, NON-OPIOID BASED ANALGESIA HAS BECOME THE CORNERSTONE OF ERAS PROTOCOLS FOR EFFECTIVE ANALGESIA AFTER SPINAL SURGERY. OPIOID SIDE EFFECTS, DEPENDENCE AND LEGISLATION RESTRICTING LONG TERM OPIOID USE HAS LED TO A RESURGENCE IN INTEREST IN OPIOID SPARING TECHNIQUES. THE INCREASING ARRAY OF MULTIMODAL OPIOID SPARING ANALGESICS AVAILABLE FOR SPINAL SURGERY TARGETING NOVEL RECEPTORS, TRANSMITTERS, AND ALTERING EPIGENETICS CAN HELP PROVIDE AN OPTIMAL PERIOPERATIVE EXPERIENCE WITH LESS OPIOID SIDE EFFECTS AND LONG-TERM DEPENDENCE. EPIGENETIC MECHANISMS OF PAIN MAY ENHANCE OR SUPPRESS GENE EXPRESSION, WITHOUT ALTERING THE GENOME ITSELF. SUCH MECHANISMS ARE COMPLEX, DYNAMIC AND RESPONSIVE TO ENVIRONMENT. ALTERATIONS THAT OCCUR CAN AFFECT THE PATHOPHYSIOLOGY OF PAIN MANAGEMENT AT A DNA LEVEL, MODIFYING PERCEIVED PAIN RELIEF. IN THIS REVIEW, WE PROVIDE A BRIEF OVERVIEW OF EPIGENETICS OF PAIN, SYSTEMIC LOCAL ANESTHETICS AND NEURAXIAL TECHNIQUES THAT CONTINUE TO REMAIN USEFUL FOR SPINAL SURGERY, NEUROPATHIC AGENTS, AS WELL AS OTHER COMMON AND LESS COMMON TARGET RECEPTORS FOR A TRULY MULTIMODAL APPROACH TO PERIOPERATIVE PAIN MANAGEMENT. 2019 14 5806 36 STRATEGIES TO REINVIGORATE EXHAUSTED CD8(+) T CELLS IN TUMOR MICROENVIRONMENT. CD8(+) T CELL EXHAUSTION IS A STABLE DYSFUNCTIONAL STATE DRIVEN BY CHRONIC ANTIGEN STIMULATION IN THE TUMOR MICROENVIRONMENT (TME). DIFFERENTIATION OF EXHAUSTED CD8(+) T CELLS (CD8(+) TEXS) IS ACCOMPANIED BY EXTENSIVE TRANSCRIPTIONAL, EPIGENETIC AND METABOLIC REPROGRAMMING. CD8(+) TEXS ARE MAINLY CHARACTERIZED BY IMPAIRED PROLIFERATIVE AND CYTOTOXIC CAPACITY AS WELL AS THE INCREASED EXPRESSION OF MULTIPLE CO-INHIBITORY RECEPTORS. PRECLINICAL TUMOR STUDIES AND CLINICAL COHORTS HAVE DEMONSTRATED THAT T CELL EXHAUSTION IS FIRMLY ASSOCIATED WITH POOR CLINICAL OUTCOMES IN A VARIETY OF CANCERS. MORE IMPORTANTLY, CD8(+) TEXS ARE REGARDED AS THE MAIN RESPONDER TO IMMUNE CHECKPOINT BLOCKADE (ICB). HOWEVER, TO DATE, A LARGE NUMBER OF CANCER PATIENTS HAVE FAILED TO ACHIEVE DURABLE RESPONSES AFTER ICB. THEREFORE, IMPROVING CD8(+) TEXS MAY BE A BREAKTHROUGH POINT TO REVERSE THE CURRENT DILEMMA OF CANCER IMMUNOTHERAPY AND ELIMINATE CANCERS. STRATEGIES TO REINVIGORATE CD8(+) TEXS IN TME MAINLY INCLUDE ICB, TRANSCRIPTION FACTOR-BASED THERAPY, EPIGENETIC THERAPY, METABOLISM-BASED THERAPY AND CYTOKINE THERAPY, WHICH TARGET ON DIFFERENT ASPECTS OF EXHAUSTION PROGRESSION. EACH OF THEM HAS ITS ADVANTAGES AND APPLICATION SCOPE. IN THIS REVIEW, WE MAINLY FOCUS ON THE MAJOR ADVANCES OF CURRENT STRATEGIES TO REINVIGORATE CD8(+) TEXS IN TME. WE SUMMARIZE THEIR EFFICACY AND MECHANISMS, IDENTIFY THE PROMISING MONOTHERAPY AND COMBINED THERAPY AND PROPOSE SUGGESTIONS TO ENHANCE THE TREATMENT EFFICACY TO SIGNIFICANTLY BOOST ANTI-TUMOR IMMUNITY AND ACHIEVE BETTER CLINICAL OUTCOMES. 2023 15 5447 40 REPOSITIONING LIDOCAINE AS AN ANTICANCER DRUG: THE ROLE BEYOND ANESTHESIA. WHILE CANCER TREATMENT HAS IMPROVED DRAMATICALLY, IT HAS ALSO ENCOUNTERED MANY CRITICAL CHALLENGES, SUCH AS DISEASE RECURRENCE, METASTASIS, AND DRUG RESISTANCE, MAKING NEW DRUGS WITH NOVEL MECHANISMS AN URGENT CLINICAL NEED. THE TERM "DRUG REPOSITIONING," ALSO KNOWN AS OLD DRUGS FOR NEW USES, HAS EMERGED AS ONE PRACTICAL STRATEGY TO DEVELOP NEW ANTICANCER DRUGS. ANESTHETICS HAVE BEEN WIDELY USED IN SURGICAL PROCEDURES TO REDUCE THE EXCRUCIATING PAIN. LIDOCAINE, ONE OF THE MOST-USED LOCAL ANESTHETICS IN CLINICAL SETTINGS, HAS BEEN FOUND TO SHOW MULTI-ACTIVITIES, INCLUDING POTENTIAL IN CANCER TREATMENT. GROWING EVIDENCE SHOWS THAT LIDOCAINE MAY NOT ONLY WORK AS A CHEMOSENSITIZER THAT SENSITIZES OTHER CONVENTIONAL CHEMOTHERAPEUTICS TO CERTAIN RESISTANT CANCER CELLS, BUT ALSO COULD SUPPRESS CANCER CELLS GROWTH BY SINGLE USE AT DIFFERENT DOSES OR CONCENTRATIONS. LIDOCAINE COULD SUPPRESS CANCER CELL GROWTH IN VITRO AND IN VIVO VIA MULTIPLE MECHANISMS, SUCH AS REGULATING EPIGENETIC CHANGES AND PROMOTING PRO-APOPTOSIS PATHWAYS, AS WELL AS REGULATING ABC TRANSPORTERS, METASTASIS, AND ANGIOGENESIS, ETC., PROVIDING VALUABLE INFORMATION FOR ITS FURTHER APPLICATION IN CANCER TREATMENT AND FOR NEW DRUG DISCOVERY. IN ADDITION, LIDOCAINE IS NOW UNDER CLINICAL TRIALS TO TREAT CERTAIN TYPES OF CANCER. IN THE CURRENT REVIEW, WE SUMMARIZE THE RESEARCH AND ANALYZE THE UNDERLYING MECHANISMS, AND ADDRESS KEY ISSUES IN THIS AREA. 2020 16 6198 41 THE IMPLICATION OF CANCER PROGENITOR CELLS AND THE ROLE OF EPIGENETICS IN THE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES FOR CHRONIC MYELOID LEUKEMIA. SIGNIFICANCE: CHRONIC MYELOID LEUKEMIA (CML) INVOLVES THE MALIGNANT TRANSFORMATION OF HEMATOPOIETIC STEM CELLS, DEFINED LARGELY BY THE PHILADELPHIA CHROMOSOME AND EXPRESSION OF THE BREAKPOINT CLUSTER REGION-ABELSON (BCR-ABL) ONCOPROTEIN. PHARMACOLOGICAL TYROSINE KINASE INHIBITORS (TKIS), INCLUDING IMATINIB MESYLATE, HAVE OVERCOME LIMITATIONS IN CONVENTIONAL TREATMENT FOR THE IMPROVED CLINICAL MANAGEMENT OF CML. RECENT ADVANCES: ACCUMULATED EVIDENCE HAS LED TO THE IDENTIFICATION OF A SUBPOPULATION OF QUIESCENT LEUKEMIA PROGENITOR CELLS WITH STEM-LIKE SELF RENEWAL PROPERTIES THAT MAY INITIATE LEUKEMOGENESIS, WHICH ARE ALSO SHOWN TO BE PRESENT IN RESIDUAL DISEASE DUE TO THEIR INSENSITIVITY TO TYROSINE KINASE INHIBITION. CRITICAL ISSUES: THE CHARACTERIZATION OF QUIESCENT LEUKEMIA PROGENITOR CELLS AS A UNIQUE CELL POPULATION IN CML PATHOGENESIS HAS BECOME CRITICAL WITH THE COMPLETE ELUCIDATION OF MECHANISMS INVOLVED IN THEIR SURVIVAL INDEPENDENT OF BCR-ABL THAT IS IMPORTANT IN THE DEVELOPMENT OF NOVEL ANTICANCER STRATEGIES. UNDERSTANDING OF THESE FUNCTIONAL PATHWAYS IN CML PROGENITOR CELLS WILL ALLOW FOR THEIR SELECTIVE THERAPEUTIC TARGETING. IN ADDITION, DISEASE PATHOGENESIS AND DRUG RESPONSIVENESS IS ALSO THOUGHT TO BE MODULATED BY EPIGENETIC REGULATORY MECHANISMS SUCH AS DNA METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION, WITH A CAPACITY TO CONTROL CML-ASSOCIATED GENE TRANSCRIPTION. FUTURE DIRECTIONS: A NUMBER OF COMPOUNDS IN COMBINATION WITH TKIS ARE UNDER PRECLINICAL AND CLINICAL INVESTIGATION TO ASSESS THEIR SYNERGISTIC POTENTIAL IN TARGETING LEUKEMIC PROGENITOR CELLS AND/OR THE EPIGENOME IN CML. DESPITE THE COLLECTIVE PROMISE, FURTHER RESEARCH IS REQUIRED IN ORDER TO REFINE UNDERSTANDING, AND, ULTIMATELY, ADVANCE ANTILEUKEMIC THERAPEUTIC STRATEGIES. 2015 17 3374 22 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 18 789 37 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 19 6647 36 UPDATE OF PERICYTES FUNCTION AND THEIR ROLES IN KIDNEY DISEASES. STUDIES HAVE HIGHLIGHTED THE SIGNIFICANT INVOLVEMENT OF KIDNEY PERICYTES IN RENAL FIBROSIS. KIDNEY PERICYTES, CLASSIFIED AS INTERSTITIAL MESENCHYMAL CELLS, ARE EXTENSIVELY BRANCHED, COLLAGEN-PRODUCING CELLS THAT CLOSELY INTERACT WITH ENDOTHELIAL CELLS. THIS ARTICLE AIMS TO PROVIDE AN OVERVIEW OF THE RECENT ADVANCEMENTS IN UNDERSTANDING THE PHYSIOLOGICAL FUNCTIONS OF PERICYTES AND THEIR ROLES IN KIDNEY DISEASES. IN A HEALTHY KIDNEY, PERICYTES HAVE ESSENTIAL PHYSIOLOGICAL FUNCTION IN ANGIOGENESIS, ERYTHROPOIETIN (EPO) PRODUCTION, AND THE REGULATION OF RENAL BLOOD FLOW. NEVERTHELESS, PERICYTE-MYOFIBROBLAST TRANSITION HAS BEEN IDENTIFIED AS THE PRIMARY CAUSE OF DISEASE PROGRESSION IN ACUTE KIDNEY INJURY (AKI)-TO-CHRONIC KIDNEY DISEASE (CKD) CONTINUUM. OUR RECENT RESEARCH HAS DEMONSTRATED THAT HYPOXIA-INDUCIBLE FACTOR-2ALPHA (HIF-2ALPHA) REGULATES ERYTHROPOIETIN PRODUCTION IN PERICYTES. HOWEVER, THIS PRODUCTION IS REPRESSED BY EPO GENE HYPERMETHYLATION AND HIF-2ALPHA DOWNREGULATION WHICH WERE INDUCED BY TRANSFORMING GROWTH FACTOR-BETA1-ACTIVATED DNA METHYLTRANSFERASE AND ACTIVIN RECEPTOR-LIKE KINASE-5 SIGNALING PATHWAY DURING RENAL FIBROSIS, RESPECTIVELY. ADDITIONALLY, AKI INDUCES EPIGENETIC MODIFICATIONS IN PERICYTES, RENDERING THEM MORE PRONE TO EXTRACELLULAR MATRIX PRODUCTION, CELL MIGRATION AND PROLIFERATION, THEREBY CONTRIBUTING TO SUBSEQUENT CAPILLARY RAREFACTION AND RENAL FIBROSIS. FURTHER INVESTIGATION INTO THE SPECIFIC FUNCTIONS AND ROLES OF DIFFERENT SUBPOPULATIONS OF PERICYTES MAY CONTRIBUTE FOR THE DEVELOPMENT OF TARGETED THERAPIES AIMED AT ATTENUATING KIDNEY DISEASE AND MITIGATING THEIR ADVERSE EFFECTS. 2023 20 6044 38 THE COMPLEX BIOLOGY OF HUMAN CYTOMEGALOVIRUS LATENCY. WHILE MANY VIRAL INFECTIONS ARE LIMITED AND EVENTUALLY RESOLVED BY THE HOST IMMUNE RESPONSE OR BY DEATH OF THE HOST, OTHER VIRUSES ESTABLISH LONG-TERM RELATIONSHIPS WITH THE HOST BY WAY OF A PERSISTENT INFECTION, THAT RANGE FROM CHRONIC VIRUSES THAT MAY BE EVENTUALLY CLEARED TO THOSE THAT ESTABLISH LIFE-LONG PERSISTENT OR LATENT INFECTION. VIRUSES INFECTING HOSTS FROM BACTERIA TO HUMANS ESTABLISH QUIESCENT INFECTIONS THAT MUST BE REACTIVATED TO PRODUCE PROGENY. FOR MAMMALIAN VIRUSES, MOST NOTABLY HERPESVIRUSES, THIS QUIESCENT MAINTENANCE OF VIRAL GENOMES IN THE ABSENCE OF VIRUS REPLICATION IS REFERRED TO AS LATENCY. THE LATENT STRATEGY ALLOWS THE VIRUS TO PERSIST QUIESCENTLY WITHIN A SINGLE HOST UNTIL CONDITIONS INDICATE A NEED TO REACTIVATE TO REACH A NEW HOST OR, TO RE-SEED A RESERVOIR WITHIN THE HOST. HERE, I REVIEW COMMON THEMES IN VIRAL STRATEGIES TO REGULATE THE LATENT CYCLE AND REACTIVATE FROM IT RANGING FROM BACTERIOPHAGE TO HERPESVIRUSES WITH A FOCUS ON HUMAN CYTOMEGALOVIRUS (HCMV). THEMES CENTRAL TO HERPESVIRUS LATENCY INCLUDE, EPIGENETIC REPRESSION OF VIRAL GENE EXPRESSION AND MECHANISMS TO REGULATE HOST SIGNALING AND SURVIVAL. CRITICAL TO THE SUCCESS OF A LATENT PROGRAM ARE MECHANISMS BY WHICH THE VIRUS CAN "SENSE" FLUCTUATIONS IN HOST BIOLOGY (WITHIN THE HOST) OR ENVIRONMENT (OUTSIDE THE HOST) AND MAKE APPROPRIATE "DECISIONS" TO MAINTAIN LATENCY OR RE-INITIATE THE REPLICATIVE PROGRAM. THE SIGNALS OR ENVIRONMENTS THAT INDICATE THE ESTABLISHMENT OF A LATENT STATE, THE VERY NATURE OF THE LATENT STATE, AS WELL AS THE SIGNALS DRIVING REACTIVATION HAVE BEEN TOPICS OF INTENSE STUDY FROM BACTERIOPHAGE TO HUMAN VIRUSES, AS THESE QUESTIONS ENCOMPASS THE HEIGHT OF COMPLEXITY IN VIRUS-HOST INTERACTIONS-WHERE THE HOST AND THE VIRUS COEXIST. 2022