1 3197 90 HDAC INHIBITORS: TARGETS FOR TUMOR THERAPY, IMMUNE MODULATION AND LUNG DISEASES. HISTONE DEACETYLASES (HDACS) ARE ENZYMES THAT PLAY A KEY ROLE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION BY REMODELING CHROMATIN. INHIBITION OF HDACS IS A PROSPECTIVE THERAPEUTIC APPROACH FOR REVERSING EPIGENETIC ALTERATION IN SEVERAL DISEASES. IN PRECLINICAL RESEARCH, NUMEROUS TYPES OF HDAC INHIBITORS WERE DISCOVERED TO EXHIBIT POWERFUL AND SELECTIVE ANTICANCER PROPERTIES. HOWEVER, SUCH RESEARCH HAS REVEALED THAT THE EFFECTS OF HDAC INHIBITORS MAY BE FAR BROADER AND MORE INTRICATE THAN PREVIOUSLY THOUGHT. THIS REVIEW WILL PROVIDE INSIGHT INTO THE HDAC INHIBITORS AND THEIR MECHANISM OF ACTION WITH SPECIAL EMPHASIS ON THE SIGNIFICANCE OF HDAC INHIBITORS IN THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CANCER. NANOCARRIER-MEDIATED HDAC INHIBITOR DELIVERY AND NEW APPROACHES FOR TARGETING HDACS ARE ALSO DISCUSSED. 2022 2 4693 22 NEXT GENERATION OF TARGETED MOLECULES FOR NON-HODGKIN LYMPHOMAS: SMALL-MOLECULE INHIBITORS OF INTRACELLULAR TARGETS AND SIGNALING PATHWAYS. ADVANCES IN OUR UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF B-CELL LYMPHOMA HAVE GUIDED THE DEVELOPMENT OF TARGETED THERAPIES THAT DISRUPT ABERRANT SIGNALING PATHWAYS IMPORTANT FOR COMMUNICATION WITHIN LYMPHOMA CELLS AND FOR THEIR INTERACTIONS WITH THE TUMOR MICROENVIRONMENT. THIS HAS LED TO UNPRECEDENTED THERAPEUTIC PROGRESS, WITH BIOLOGIC AGENTS THAT HAVE BEGUN TO TRANSFORM THE CARE OF PATIENTS WITH LYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA. THIS REVIEW DISCUSSES THE MECHANISMS OF ACTION, CLINICAL DEVELOPMENT, AND EMERGING APPLICATIONS OF SMALL-MOLECULE INHIBITORS THAT TARGET B-CELL RECEPTOR SIGNALING PATHWAYS, B-CELL LYMPHOMA-2 INHIBITORS, SELECTIVE INHIBITORS OF NUCLEAR EXPORT, AND EPIGENETIC MODIFIERS. 2016 3 6687 19 VALIDATION OF THE EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A THERAPEUTIC TARGET FOR TREATMENT OF AIRWAY REMODELING. STRUCTURAL REMODELING IS CENTRAL TO THE INITIATION AND PROGRESSION OF MANY CHRONIC LUNG DISEASES, REPRESENTING AN IMPORTANT UNMET NEED. WE EXAMINE THE EVIDENCE SUPPORTING BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A VALIDATED BIOLOGICAL TARGET FOR TREATMENT OF AIRWAY REMODELING. IN EPITHELIAL CELLS AND FIBROBLASTS, BRD4 SERVES AS A SCAFFOLD FOR CHROMATIN REMODELING COMPLEXES IN ACTIVE SUPER-ENHANCERS. IN RESPONSE TO INFLAMMATORY STIMULI, BRD4 IS REPOSITIONED TO INNATE AND MESENCHYMAL GENES ACTIVATING THEIR PRODUCTION. PROOF-OF-CONCEPT STUDIES SHOW PROMISING BENEFIT OF SELECTIVE BRD4 INHIBITORS IN DISRUPTING EPITHELIAL MESENCHYMAL TRANSITION AND MYOFIBROBLAST TRANSITION IN DIVERSE MODELS OF LUNG INJURY. RECENT IDENTIFICATION OF BIOMARKERS OF BRD4 PROVIDES A BASIS FOR FURTHER DRUG DEVELOPMENT FOR APPLICATION IN VIRAL-INDUCED AIRWAY INFLAMMATION, COPD AND INTERSTITIAL LUNG DISEASES. 2020 4 700 32 BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4): A KEY PLAYER IN INFLAMMATORY BOWEL DISEASE AND POTENTIAL TO INSPIRE EPIGENETIC THERAPEUTICS. INTRODUCTION: INFLAMMATORY BOWEL DISEASES (IBDS) ARE DEBILITATING CHRONIC INFLAMMATORY DISORDERS WITH INCREASING PREVALENCE WORLDWIDE. EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) IS CRITICAL IN CONTROLLING GENE EXPRESSION OF IBD-ASSOCIATED INFLAMMATORY CYTOKINE NETWORKS. BRD4 AS A PROMISING THERAPEUTIC TARGET IS ALSO TIGHTLY ASSOCIATED WITH MANY OTHER DISEASES, SUCH AS AIRWAY INFLAMMATION AND FIBROSIS, CANCERS, INFECTIOUS DISEASES AND CENTRAL NERVOUS SYSTEM DISORDERS. AREAS COVERED: THIS REVIEW BRIEFLY SUMMARIZED THE CRITICAL ROLE OF BRD4 IN THE PATHOGENESIS OF IBDS AND THE CURRENT CLINICAL LANDSCAPE OF DEVELOPING BROMODOMAIN AND EXTRA TERMINAL DOMAIN (BET) INHIBITORS. THE CHALLENGES AND OPPORTUNITIES AS WELL AS FUTURE DIRECTIONS OF TARGETING BRD4 INHIBITION FOR POTENTIAL IBD MEDICATIONS WERE ALSO DISCUSSED. EXPERT OPINION: TARGETING BRD4 WITH POTENT AND SPECIFIC INHIBITORS MAY OFFER NOVEL EFFECTIVE THERAPEUTICS FOR IBD PATIENTS, PARTICULARLY THOSE WHO ARE REFRACTORY TO ANTI-TNFALPHA THERAPY AND IBD-RELATED PROFIBROTIC. DEVELOPING HIGHLY SPECIFIC BRD4 INHIBITORS FOR IBD MEDICATIONS MAY HELP ERASE THE DRAWBACKS OF MOST CURRENT PAN-BET/BRD4 INHIBITORS, SUCH AS OFF-TARGET EFFECTS, POOR ORAL BIOAVAILABILITY, AND LOW GUT MUCOSAL ABSORBANCE. NOVEL STRATEGIES SUCH AS COMBINATORIAL THERAPY, BRD4-BASED DUAL INHIBITORS AND PROTEOLYSIS TARGETING CHIMERAS (PROTACS) MAY ALSO HAVE GREAT POTENTIAL TO MITIGATE SIDE EFFECTS AND OVERCOME DRUG RESISTANCE DURING IBD TREATMENT. 2023 5 5939 36 TARGETING MECHANOTRANSDUCTION AT THE TRANSCRIPTIONAL LEVEL: YAP AND BRD4 ARE NOVEL THERAPEUTIC TARGETS FOR THE REVERSAL OF LIVER FIBROSIS. LIVER FIBROSIS IS THE RESULT OF A DEREGULATED WOUND HEALING PROCESS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX. HEPATIC STELLATE CELLS (HSCS), WHICH ARE ACTIVATED IN RESPONSE TO LIVER INJURY, ARE THE MAJOR SOURCE OF EXTRACELLULAR MATRIX AND DRIVE THE WOUND HEALING PROCESS. HOWEVER, CHRONIC LIVER DAMAGE LEADS TO PERPETUAL HSC ACTIVATION, PROGRESSIVE FORMATION OF PATHOLOGICAL SCAR TISSUE AND ULTIMATELY, CIRRHOSIS AND ORGAN FAILURE. HSC ACTIVATION IS TRIGGERED LARGELY IN RESPONSE TO MECHANOSIGNALING FROM THE MICROENVIRONMENT, WHICH INDUCES A PROFIBROTIC NUCLEAR TRANSCRIPTION PROGRAM THAT PROMOTES HSC PROLIFERATION AND EXTRACELLULAR MATRIX SECRETION THEREBY SETTING UP A POSITIVE FEEDBACK LOOP LEADING TO MATRIX STIFFENING AND SELF-SUSTAINED, PATHOLOGICAL, HSC ACTIVATION. DESPITE THE SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF LIVER FIBROSIS, THE MOLECULAR MECHANISMS THROUGH WHICH THE EXTRACELLULAR MATRIX PROMOTES HSC ACTIVATION ARE NOT WELL UNDERSTOOD AND NO EFFECTIVE THERAPIES HAVE BEEN APPROVED TO DATE THAT CAN TARGET THIS EARLY, REVERSIBLE, STAGE IN LIVER FIBROSIS. SEVERAL NEW LINES OF INVESTIGATION NOW PROVIDE IMPORTANT INSIGHT INTO THIS AREA OF STUDY AND IDENTIFY TWO NUCLEAR TARGETS WHOSE INHIBITION HAS THE POTENTIAL OF REVERSING LIVER FIBROSIS BY INTERFERING WITH HSC ACTIVATION: YES-ASSOCIATED PROTEIN (YAP), A TRANSCRIPTIONAL CO-ACTIVATOR AND EFFECTOR OF THE MECHANOSENSITIVE HIPPO PATHWAY, AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC REGULATOR OF GENE EXPRESSION. YAP AND BRD4 ACTIVITY IS INDUCED IN RESPONSE TO MECHANICAL STIMULATION OF HSCS AND EACH PROTEIN INDEPENDENTLY CONTROLS WAVES OF EARLY GENE EXPRESSION NECESSARY FOR HSC ACTIVATION. SIGNIFICANTLY, INHIBITION OF EITHER PROTEIN CAN REVERT THE CHRONIC ACTIVATION OF HSCS AND IMPEDE PATHOLOGICAL PROGRESSION OF LIVER FIBROSIS IN CLINICALLY RELEVANT MODEL SYSTEMS. IN THIS REVIEW WE WILL DISCUSS THE ROLES OF THESE NUCLEAR CO-ACTIVATORS IN HSC ACTIVATION, THEIR MECHANISM OF ACTION IN THE FIBROTIC PROCESS IN THE LIVER AND OTHER ORGANS, AND THE POTENTIAL OF TARGETING THEIR ACTIVITY WITH SMALL MOLECULE DRUGS FOR FIBROSIS REVERSAL. 2016 6 3374 23 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 7 697 31 BROMODOMAIN AND EXTRATERMINAL PROTEINS AS NOVEL EPIGENETIC TARGETS FOR RENAL DISEASES. EPIGENETIC MECHANISMS, ESPECIALLY DNA METHYLATION AND HISTONE MODIFICATIONS, ARE DYNAMIC PROCESSES THAT REGULATE THE GENE EXPRESSION TRANSCRIPTIONAL PROGRAM IN NORMAL AND DISEASED STATES. THE BROMODOMAIN AND EXTRATERMINAL (BET) PROTEIN FAMILY (BRD2, BRD3, BRD4, AND BRDT) ARE EPIGENETIC READERS THAT, VIA BROMODOMAINS, REGULATE GENE TRANSCRIPTION BY BINDING TO ACETYLATED LYSINE RESIDUES ON HISTONES AND MASTER TRANSCRIPTIONAL FACTORS. EXPERIMENTAL DATA HAVE DEMONSTRATED THE INVOLVEMENT OF SOME BET PROTEINS IN MANY PATHOLOGICAL CONDITIONS, INCLUDING TUMOR DEVELOPMENT, INFECTIONS, AUTOIMMUNITY, AND INFLAMMATION. SELECTIVE BROMODOMAIN INHIBITORS ARE EPIGENETIC DRUGS THAT BLOCK THE INTERACTION BETWEEN BET PROTEINS AND ACETYLATED PROTEINS, THUS EXERTING BENEFICIAL EFFECTS. RECENT DATA HAVE DESCRIBED THE BENEFICIAL EFFECT OF BET INHIBITION ON EXPERIMENTAL RENAL DISEASES. EMERGING EVIDENCE UNDERSCORES THE IMPORTANCE OF ENVIRONMENTAL MODIFICATIONS IN THE ORIGIN OF PATHOLOGICAL FEATURES IN CHRONIC KIDNEY DISEASES (CKD). SEVERAL CELLULAR PROCESSES SUCH AS OXIDATION, METABOLIC DISORDERS, CYTOKINES, INFLAMMATION, OR ACCUMULATED UREMIC TOXINS MAY INDUCE EPIGENETIC MODIFICATIONS THAT REGULATE KEY PROCESSES INVOLVED IN RENAL DAMAGE AND IN OTHER PATHOLOGICAL CONDITIONS OBSERVED IN CKD PATIENTS. HERE, WE REVIEW HOW TARGETING BROMODOMAINS IN BET PROTEINS MAY REGULATE ESSENTIAL PROCESSES INVOLVED IN RENAL DISEASES AND IN ASSOCIATED COMPLICATIONS FOUND IN CKD PATIENTS, SUCH AS CARDIOVASCULAR DAMAGE, HIGHLIGHTING THE POTENTIAL OF EPIGENETIC THERAPEUTIC STRATEGIES AGAINST BET PROTEINS FOR CKD TREATMENT AND ASSOCIATED RISKS. 2019 8 3275 27 HEPATOCELLULAR CARCINOMA: THERAPEUTIC ADVANCES IN SIGNALING, EPIGENETIC AND IMMUNE TARGETS. HEPATOCELLULAR CARCINOMA (HCC) REMAINS A GLOBAL MEDICAL BURDEN WITH RISING INCIDENCE DUE TO CHRONIC VIRAL HEPATITIS AND NON-ALCOHOLIC FATTY LIVER DISEASES. TREATMENT OF ADVANCED DISEASE STAGES IS STILL UNSATISFYING. BESIDES FIRST AND SECOND GENERATION TYROSINE KINASE INHIBITORS, IMMUNE CHECKPOINT INHIBITORS HAVE BECOME CENTRAL FOR THE TREATMENT OF HCC. NEW MODALITIES LIKE EPIGENETIC THERAPY USING HISTONE DEACETYLASE INHIBITORS (HDACI) AND CELL THERAPY APPROACHES WITH CHIMERIC ANTIGEN RECEPTOR T CELLS (CAR-T CELLS) ARE CURRENTLY UNDER INVESTIGATION IN CLINICAL TRIALS. DEVELOPMENT OF SUCH NOVEL DRUGS IS CLOSELY LINKED TO THE AVAILABILITY AND IMPROVEMENT OF NOVEL PRECLINICAL AND ANIMAL MODELS AND THE IDENTIFICATION OF PREDICTIVE BIOMARKERS. THE CURRENT STATUS OF TREATMENT OPTIONS FOR ADVANCED HCC, EMERGING NOVEL THERAPEUTIC APPROACHES AND DIFFERENT PRECLINICAL MODELS FOR HCC DRUG DISCOVERY AND DEVELOPMENT ARE REVIEWED HERE. 2019 9 6910 22 [TRANSFORMING GROWTH FACTOR-BETA AND RENAL FIBROSIS]. TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) IS A DRIVING FORCE OF RENAL FIBROSIS, WHICH MAY LEAD TO CHRONIC KIDNEY DISEASES AND EVEN END STAGE RENAL DISEASES. BY ACTIVATING CANONICAL AND NON-CANONICAL SIGNALING PATHWAYS, TGF-BETA PROMOTES THE SYNTHESIS OF EXTRACELLULAR MATRIX WHILE PREVENTING THEIR DEGRADATION. IN THE INJURED KIDNEY, TGF-BETA INDUCES APOPTOSIS, PROLIFERATION AND FIBROTIC RESPONSE OF RENAL CELLS INCLUDING EPITHELIAL CELLS, ENDOTHELIAL CELLS, PODOCYTES, FIBROBLASTS, PERICYTES AND MACROPHAGES, AND IT ALSO PROMOTES TRANSDIFFERENTIATION, ACTIVATION AND PROLIFERATION OF MYOFIBROBLASTS. ADDITIONALLY, TGF-BETA EXERTS PROFIBROTIC EFFECTS BY INTERPLAYING WITH OTHER SIGNALING PATHWAYS LIKE BMP-7, WNT/BETA-CATENIN AND MAP KINASE. SMAD3 IS THE CENTRAL PATHOLOGICAL GENE IN RENAL FIBROSIS, AND EPIGENETIC REGULATION OF TGF-BETA/SMAD3 IS A HOT TOPIC IN KIDNEY FIELD. ALTHOUGH DIRECT TARGETING TGF-BETA MAY CAUSE SIDE EFFECTS INCLUDING TUMORIGENESIS AND IMMUNE DISEASES, THE THERAPEUTIC STRATEGIES TARGETING THE BALANCE OF DOWNSTREAM SMAD3 AND SMAD7 MAY PREVENT OR DELAY THE PROGRESSION OF FIBROTIC KIDNEY DISEASE. 2018 10 2189 33 EPIGENETIC MECHANISMS UNDERLYING THE THERAPEUTIC EFFECTS OF HDAC INHIBITORS IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A HEMATOLOGICAL DISORDER CAUSED BY THE ONCOGENIC BCR-ABL FUSION PROTEIN IN MORE THAN 90% OF PATIENTS. DESPITE THE STRIKING IMPROVEMENTS IN THE MANAGEMENT OF CML PATIENTS SINCE THE INTRODUCTION OF TYROSINE KINASE INHIBITORS (TKIS), THE APPEARANCE OF TKI RESISTANCE AND SIDE EFFECTS LEAD TO TREATMENT FAILURE, JUSTIFYING THE NEED OF NOVEL THERAPEUTIC APPROACHES. HISTONE DEACETYLASE INHIBITORS (HDACIS), ABLE TO MODULATE GENE EXPRESSION PATTERNS AND IMPORTANT CELLULAR SIGNALING PATHWAYS THROUGH THE REGULATION OF THE ACETYLATION STATUS OF BOTH HISTONE AND NON-HISTONE PROTEIN TARGETS, HAVE BEEN REPORTED TO DISPLAY PROMISING ANTI-LEUKEMIC PROPERTIES ALONE OR IN COMBINATION WITH TKIS. THIS REVIEW SUMMARIZES PRE-CLINICAL AND CLINICAL STUDIES THAT INVESTIGATED THE MECHANISMS UNDERLYING THE ANTICANCER POTENTIAL OF HDACIS AND DISCUSSES THE RATIONALE FOR A COMBINATION OF HDACIS WITH TKIS AS A THERAPEUTIC OPTION IN CML. 2020 11 5917 33 TARGETING BCL-2 IN B-CELL MALIGNANCIES AND OVERCOMING THERAPEUTIC RESISTANCE. DEFECTS IN APOPTOSIS CAN PROMOTE TUMORIGENESIS AND IMPAIR RESPONSES OF MALIGNANT B CELLS TO CHEMOTHERAPEUTICS. MEMBERS OF THE B-CELL LEUKEMIA/LYMPHOMA-2 (BCL-2) FAMILY OF PROTEINS ARE KEY REGULATORS OF THE INTRINSIC, MITOCHONDRIAL APOPTOTIC PATHWAY. OVEREXPRESSION OF ANTIAPOPTOTIC BCL-2 FAMILY PROTEINS IS ASSOCIATED WITH TREATMENT RESISTANCE AND POOR PROGNOSIS. THUS, INHIBITION OF BCL-2 FAMILY PROTEINS IS A RATIONAL THERAPEUTIC OPTION FOR MALIGNANCIES THAT ARE DEPENDENT ON ANTIAPOPTOTIC BCL-2 FAMILY PROTEINS. VENETOCLAX (ABT-199, GDC-0199) IS A HIGHLY SELECTIVE BCL-2 INHIBITOR THAT REPRESENTS THE FIRST APPROVED AGENT OF THIS CLASS AND IS CURRENTLY WIDELY USED IN THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AS WELL AS ACUTE MYELOID LEUKEMIA (AML). DESPITE IMPRESSIVE CLINICAL ACTIVITY, VENETOCLAX MONOTHERAPY FOR A PROLONGED DURATION CAN LEAD TO DRUG RESISTANCE OR LOSS OF DEPENDENCE ON THE TARGETED PROTEIN. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE MECHANISM OF ACTION OF BCL-2 INHIBITION AND THE ROLE OF THIS APPROACH IN THE CURRENT TREATMENT PARADIGM OF B-CELL MALIGNANCIES. WE SUMMARIZE THE DRIVERS OF DE NOVO AND ACQUIRED RESISTANCE TO VENETOCLAX THAT ARE CLOSELY ASSOCIATED WITH COMPLEX CLONAL SHIFTS, INTERPLAY OF EXPRESSION AND INTERACTIONS OF BCL-2 FAMILY MEMBERS, TRANSCRIPTIONAL REGULATORS, AND METABOLIC MODULATORS. WE ALSO EXAMINE HOW TUMORS INITIALLY RESISTANT TO VENETOCLAX BECOME RESPONSIVE TO IT FOLLOWING PRIOR THERAPIES. HERE, WE SUMMARIZE PRECLINICAL DATA PROVIDING A RATIONALE FOR EFFICACIOUS COMBINATION STRATEGIES OF VENETOCLAX TO OVERCOME THERAPEUTIC RESISTANCE BY A TARGETED APPROACH DIRECTED AGAINST ALTERNATIVE ANTIAPOPTOTIC BCL-2 FAMILY PROTEINS (MCL-1, BCL-XL), COMPENSATORY PROSURVIVAL PATHWAYS, EPIGENETIC MODIFIERS, AND DYSREGULATED CELLULAR METABOLISM/ENERGETICS FOR DURABLE CLINICAL REMISSIONS. 2020 12 689 41 BRD4 AS A THERAPEUTIC TARGET IN PULMONARY DISEASES. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC MODULATORS THAT REGULATE GENE TRANSCRIPTION THROUGH INTERACTING WITH ACETYLATED LYSINE RESIDUES OF HISTONE PROTEINS. BET PROTEINS HAVE MULTIPLE ROLES IN REGULATING KEY CELLULAR FUNCTIONS SUCH AS CELL PROLIFERATION, DIFFERENTIATION, INFLAMMATION, OXIDATIVE AND REDOX BALANCE, AND IMMUNE RESPONSES. AS A RESULT, BET PROTEINS HAVE BEEN FOUND TO BE ACTIVELY INVOLVED IN A BROAD RANGE OF HUMAN LUNG DISEASES INCLUDING ACUTE LUNG INFLAMMATION, ASTHMA, PULMONARY ARTERIAL HYPERTENSION, PULMONARY FIBROSIS, AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). DUE TO THE IDENTIFICATION OF SPECIFIC SMALL MOLECULAR INHIBITORS OF BET PROTEINS, TARGETING BET IN THESE LUNG DISEASES HAS BECOME AN AREA OF INCREASING INTEREST. EMERGING EVIDENCE HAS DEMONSTRATED THE BENEFICIAL EFFECTS OF BET INHIBITORS IN PRECLINICAL MODELS OF VARIOUS HUMAN LUNG DISEASES. THIS IS, IN GENERAL, LARGELY RELATED TO THE ABILITY OF BET PROTEINS TO BIND TO PROMOTERS OF GENES THAT ARE CRITICAL FOR INFLAMMATION, DIFFERENTIATION, AND BEYOND. BY MODULATING THESE CRITICAL GENES, BET PROTEINS ARE INTEGRATED INTO THE PATHOGENESIS OF DISEASE PROGRESSION. THE INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY OF BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) IS OF PARTICULAR INTEREST, SEEMS TO ACT INDEPENDENTLY OF ITS BROMODOMAIN BINDING ACTIVITY, AND HAS IMPLICATION IN SOME CONTEXTS. IN THIS REVIEW, WE PROVIDE A BRIEF OVERVIEW OF THE RESEARCH ON BET PROTEINS WITH A FOCUS ON BRD4 IN SEVERAL MAJOR HUMAN LUNG DISEASES, THE UNDERLYING MOLECULAR MECHANISMS, AS WELL AS FINDINGS OF TARGETING BET PROTEINS USING PHARMACEUTICAL INHIBITORS IN DIFFERENT LUNG DISEASES PRECLINICALLY. 2023 13 3245 18 HEPATIC STELLATE CELLS AS KEY TARGET IN LIVER FIBROSIS. PROGRESSIVE LIVER FIBROSIS, INDUCED BY CHRONIC VIRAL AND METABOLIC DISORDERS, LEADS TO MORE THAN ONE MILLION DEATHS ANNUALLY VIA DEVELOPMENT OF CIRRHOSIS, ALTHOUGH NO ANTIFIBROTIC THERAPY HAS BEEN APPROVED TO DATE. TRANSDIFFERENTIATION (OR "ACTIVATION") OF HEPATIC STELLATE CELLS IS THE MAJOR CELLULAR SOURCE OF MATRIX PROTEIN-SECRETING MYOFIBROBLASTS, THE MAJOR DRIVER OF LIVER FIBROGENESIS. PARACRINE SIGNALS FROM INJURED EPITHELIAL CELLS, FIBROTIC TISSUE MICROENVIRONMENT, IMMUNE AND SYSTEMIC METABOLIC DYSREGULATION, ENTERIC DYSBIOSIS, AND HEPATITIS VIRAL PRODUCTS CAN DIRECTLY OR INDIRECTLY INDUCE STELLATE CELL ACTIVATION. DYSREGULATED INTRACELLULAR SIGNALING, EPIGENETIC CHANGES, AND CELLULAR STRESS RESPONSE REPRESENT CANDIDATE TARGETS TO DEACTIVATE STELLATE CELLS BY INDUCING REVERSION TO INACTIVATED STATE, CELLULAR SENESCENCE, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS. CELL TYPE- AND TARGET-SPECIFIC PHARMACOLOGICAL INTERVENTION TO THERAPEUTICALLY INDUCE THE DEACTIVATION WILL ENABLE MORE EFFECTIVE AND LESS TOXIC PRECISION ANTIFIBROTIC THERAPIES. 2017 14 4463 30 MOLECULAR MECHANISMS OF HISTONE DEACETYLASES AND INHIBITORS IN RENAL FIBROSIS PROGRESSION. RENAL FIBROSIS IS A COMMON PROGRESSIVE MANIFESTATION OF CHRONIC KIDNEY DISEASE. THIS PHENOMENON OF SELF-REPAIR IN RESPONSE TO KIDNEY DAMAGE SERIOUSLY AFFECTS THE NORMAL FILTRATION FUNCTION OF THE KIDNEY. YET, THERE ARE NO SPECIFIC TREATMENTS FOR THE CONDITION, WHICH MARKS FIBROSIS AS AN IRREVERSIBLE PATHOLOGICAL SEQUELA. AS SUCH, THERE IS A PRESSING NEED TO IMPROVE OUR UNDERSTANDING OF HOW FIBROSIS DEVELOPS AT THE CELLULAR AND MOLECULAR LEVELS AND EXPLORE SPECIFIC TARGETED THERAPIES FOR THESE PATHOGENIC MECHANISMS. IT IS NOW GENERALLY ACCEPTED THAT RENAL FIBROSIS IS A PATHOLOGICAL TRANSITION MEDIATED BY EXTRACELLULAR MATRIX (ECM) DEPOSITION, ABNORMAL ACTIVATION OF MYOFIBROBLASTS, AND EPITHELIAL-MESENCHYMAL TRANSITION (EMT) OF RENAL TUBULAR EPITHELIAL CELLS UNDER THE REGULATION OF TGF-BETA. HISTONE DEACETYLASES (HDACS) APPEAR TO PLAY AN ESSENTIAL ROLE IN PROMOTING RENAL FIBROSIS THROUGH NON-HISTONE EPIGENETIC MODIFICATIONS. IN THIS REVIEW, WE SUMMARIZE THE MECHANISMS OF RENAL FIBROSIS AND THE SIGNALING PATHWAYS THAT MIGHT BE INVOLVED IN HDACS IN RENAL FIBROSIS, AND THE SPECIFIC MECHANISMS OF ACTION OF VARIOUS HDAC INHIBITORS (HDACI) IN THE ANTI-FIBROTIC PROCESS TO ELUCIDATE HDACI AS A NOVEL THERAPEUTIC TOOL TO SLOW DOWN THE PROGRESSION OF RENAL FIBROSIS. 2022 15 1650 26 DOMAIN-SELECTIVE TARGETING OF BET PROTEINS IN CANCER AND IMMUNOLOGICAL DISEASES. CANCER AND INFLAMMATION ARE STRONGLY INTERCONNECTED PROCESSES. CHRONIC INFLAMMATORY PATHOLOGIES CAN BE AT THE HEART OF TUMOR DEVELOPMENT; SIMILARLY, TUMOR-ELICITED INFLAMMATION IS A CONSEQUENCE OF MANY CANCERS. THE MECHANISTIC INTERDEPENDENCE BETWEEN CANCER AND INFLAMMATORY PATHOLOGIES POINTS TOWARD COMMON PROTEIN EFFECTORS WHICH REPRESENT POTENTIAL SHARED TARGETS FOR PHARMACOLOGICAL INTERVENTION. EPIGENETIC MECHANISMS OFTEN DRIVE RESISTANCE TO CANCER THERAPY AND IMMUNOMODULATORY STRATEGIES. THE BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC ADAPTERS WHICH PLAY A MAJOR ROLE IN CONTROLLING CELL PROLIFERATION AND THE PRODUCTION OF INFLAMMATORY MEDIATORS. A PLETHORA OF SMALL MOLECULES AIMED AT INHIBITING BET PROTEIN FUNCTION TO TREAT CANCER AND INFLAMMATORY DISEASES HAVE POPULATED ACADEMIC AND INDUSTRY EFFORTS IN THE LAST 10 YEARS. IN THIS REVIEW, WE WILL DISCUSS RECENT PHARMACOLOGICAL APPROACHES AIMED AT TARGETING A SINGLE OR A SUBSET OF THE EIGHT BROMODOMAINS WITHIN THE BET FAMILY WHICH HAVE THE POTENTIAL TO TEASE APART CLINICAL EFFICACY AND SAFETY SIGNALS OF BET INHIBITORS. 2020 16 5992 26 TGF-BETA: THE MASTER REGULATOR OF FIBROSIS. TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) IS THE PRIMARY FACTOR THAT DRIVES FIBROSIS IN MOST, IF NOT ALL, FORMS OF CHRONIC KIDNEY DISEASE (CKD). INHIBITION OF THE TGF-BETA ISOFORM, TGF-BETA1, OR ITS DOWNSTREAM SIGNALLING PATHWAYS SUBSTANTIALLY LIMITS RENAL FIBROSIS IN A WIDE RANGE OF DISEASE MODELS WHEREAS OVEREXPRESSION OF TGF-BETA1 INDUCES RENAL FIBROSIS. TGF-BETA1 CAN INDUCE RENAL FIBROSIS VIA ACTIVATION OF BOTH CANONICAL (SMAD-BASED) AND NON-CANONICAL (NON-SMAD-BASED) SIGNALLING PATHWAYS, WHICH RESULT IN ACTIVATION OF MYOFIBROBLASTS, EXCESSIVE PRODUCTION OF EXTRACELLULAR MATRIX (ECM) AND INHIBITION OF ECM DEGRADATION. THE ROLE OF SMAD PROTEINS IN THE REGULATION OF FIBROSIS IS COMPLEX, WITH COMPETING PROFIBROTIC AND ANTIFIBROTIC ACTIONS (INCLUDING IN THE REGULATION OF MESENCHYMAL TRANSITIONING), AND WITH COMPLEX INTERPLAY BETWEEN TGF-BETA/SMADS AND OTHER SIGNALLING PATHWAYS. STUDIES OVER THE PAST 5 YEARS HAVE IDENTIFIED ADDITIONAL MECHANISMS THAT REGULATE THE ACTION OF TGF-BETA1/SMAD SIGNALLING IN FIBROSIS, INCLUDING SHORT AND LONG NONCODING RNA MOLECULES AND EPIGENETIC MODIFICATIONS OF DNA AND HISTONE PROTEINS. ALTHOUGH DIRECT TARGETING OF TGF-BETA1 IS UNLIKELY TO YIELD A VIABLE ANTIFIBROTIC THERAPY DUE TO THE INVOLVEMENT OF TGF-BETA1 IN OTHER PROCESSES, GREATER UNDERSTANDING OF THE VARIOUS PATHWAYS BY WHICH TGF-BETA1 CONTROLS FIBROSIS HAS IDENTIFIED ALTERNATIVE TARGETS FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS TO HALT THIS MOST DAMAGING PROCESS IN CKD. 2016 17 3338 35 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 18 3273 28 HEPATOCELLULAR CARCINOMA: MOLECULAR PATHWAYS AND NEW THERAPEUTIC TARGETS. HEPATOCELLULAR CARCINOMA IS OFTEN DIAGNOSED AT AN ADVANCED STAGE, WHEN IT IS NOT AMENABLE TO CURATIVE THERAPIES. THERE IS NO EFFECTIVE CHEMOTHERAPY. ADVANCES IN CANCER BIOLOGY SUGGEST THAT A LIMITED NUMBER OF PATHWAYS ARE RESPONSIBLE FOR INITIATING AND MAINTAINING DYSREGULATED CELL PROLIFERATION, WHICH IS THE MAJOR CELLULAR ALTERATION RESPONSIBLE FOR THE CANCER PHENOTYPE. NEW TREATMENTS IN DEVELOPMENT TARGET SEVERAL OF THESE CRITICAL PATHWAYS, INCLUDING AGENTS TARGETING THE RECEPTOR TYROSINE KINASE PATHWAYS, THE WNT/BETA-CATENIN SIGNALING PATHWAY, THE UBIQUITIN/PROTEASOME DEGRADATION PATHWAY, THE EPIGENETIC DNA METHYLATION AND HISTONE DEACETYLATION PATHWAYS, THE PI3 KINASE/AKT/MTOR PATHWAY, ANGIOGENIC PATHWAYS, AND TELOMERASE. SEVERAL OF THESE APPROACHES HOLD SIGNIFICANT PROMISE FOR IMPROVING THE LONG-TERM OUTCOME OF PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA. BECAUSE OF THE HIGH PREVALENCE OF LIVER CIRRHOSIS IN HEPATOCELLULAR CARCINOMA PATIENTS, THESE APPROACHES MUST BE COUPLED WITH NEW STRATEGIES FOR HALTING OR REVERSING THE PROGRESSION OF CHRONIC LIVER DISEASE. 2005 19 5803 25 STING SIGNALING ACTIVATION INHIBITS HBV REPLICATION AND ATTENUATES THE SEVERITY OF LIVER INJURY AND HBV-INDUCED FIBROSIS. THE COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) OF HBV PLAYS A CRUCIAL ROLE IN VIRAL PERSISTENCE AND IS ALSO A RISK FACTOR FOR DEVELOPING HBV-INDUCED DISEASES, INCLUDING LIVER FIBROSIS. STIMULATOR OF INTERFERON GENES (STING), A MASTER REGULATOR OF DNA-MEDIATED INNATE IMMUNE ACTIVATION, IS A POTENTIAL THERAPEUTIC TARGET FOR VIRAL INFECTION AND VIRUS-RELATED DISEASES. IN THIS STUDY, AGONIST-INDUCED STING SIGNALING ACTIVATION IN MACROPHAGES WAS REVEALED TO INHIBIT CCCDNA-MEDIATED TRANSCRIPTION AND HBV REPLICATION VIA EPIGENETIC MODIFICATION IN HEPATOCYTES. NOTABLY, STING ACTIVATION COULD EFFICIENTLY ATTENUATE THE SEVERITY OF LIVER INJURY AND FIBROSIS IN A CHRONIC RECOMBINANT CCCDNA (RCCCDNA) MOUSE MODEL, WHICH IS A PROVEN SUITABLE RESEARCH PLATFORM FOR HBV-INDUCED FIBROSIS. MECHANISTICALLY, STING-ACTIVATED AUTOPHAGIC FLUX COULD SUPPRESS MACROPHAGE INFLAMMASOME ACTIVATION, LEADING TO THE AMELIORATION OF LIVER INJURY AND HBV-INDUCED FIBROSIS. OVERALL, THE ACTIVATION OF STING SIGNALING COULD INHIBIT HBV REPLICATION THROUGH EPIGENETIC SUPPRESSION OF CCCDNA AND ALLEVIATE HBV-INDUCED LIVER FIBROSIS THROUGH THE SUPPRESSION OF MACROPHAGE INFLAMMASOME ACTIVATION BY ACTIVATING AUTOPHAGIC FLUX IN A CHRONIC HBV MOUSE MODEL. THIS STUDY SUGGESTS THAT TARGETING THE STING SIGNALING PATHWAY MAY BE AN IMPORTANT THERAPEUTIC STRATEGY TO PROTECT AGAINST PERSISTENT HBV REPLICATION AND HBV-INDUCED FIBROSIS. 2022 20 596 33 BET PROTEINS: AN APPROACH TO FUTURE THERAPIES IN TRANSPLANTATION. IN ORDER TO DEVELOP NEW EFFICIENT THERAPIES FOR ORGAN TRANSPLANTATION, IT IS ESSENTIAL TO ACQUIRE A COMPREHENSIVE KNOWLEDGE OF THE MOLECULAR MECHANISMS AND PROCESSES, SUCH AS IMMUNE ACTIVATION, CHRONIC INFLAMMATION, AND FIBROSIS, WHICH LEAD TO REJECTION AND LONG-TERM GRAFT LOSS. RECENT EFFORTS HAVE SHED SOME LIGHT ON THE EPIGENETIC REGULATION ASSOCIATED WITH THESE PROCESSES. IN THIS CONTEXT, THE BROMO AND EXTRATERMINAL (BET) FAMILY OF BROMODOMAIN PROTEINS (BRD2, BRD3, BRD4, AND BRDT) HAVE EMERGED AS MAJOR EPIGENETIC PLAYERS, CONNECTING CHROMATIN STRUCTURE WITH GENE EXPRESSION CHANGES. THESE PROTEINS RECOGNIZE ACETYLATED LYSINES IN HISTONES AND MASTER TRANSCRIPTION FACTORS TO RECRUIT REGULATORY COMPLEX AND, FINALLY, MODIFY THE TRANSCRIPTIONAL PROGRAM. RECENT STUDIES INDICATE THAT BET PROTEINS ARE ESSENTIAL IN THE NF-KB-MEDIATED INFLAMMATORY RESPONSE, DURING THE ACTIVATION AND DIFFERENTIATION OF TH17-IMMUNE CELLS, AND IN PROFIBROTIC PROCESSES. HERE, WE REVIEW THIS NEW BODY OF DATA AND HIGHLIGHT THE EFFICIENCY OF BET INHIBITORS IN SEVERAL MODELS OF DISEASES. THE PROMISING RESULTS OBTAINED FROM THESE PRECLINICAL MODELS INDICATE THAT IT MAY BE TIME TO TRANSLATE THESE OUTCOMES TO THE TRANSPLANTATION FIELD, WHERE EPIGENETICS WILL BE OF INCREASING VALUE IN THE COMING YEARS. 2017