1 6658 138 UPREGULATED LNCRNA H19 SPONGES MIR-106A-5P AND CONTRIBUTES TO ALDOSTERONE-INDUCED VASCULAR CALCIFICATION VIA ACTIVATING THE RUNX2-DEPENDENT PATHWAY. BACKGROUND: EXCESS ALDOSTERONE IS IMPLICATED IN VASCULAR CALCIFICATION (VC), BUT THE MECHANISM BY WHICH ALDOSTERONE-MR (MINERALOCORTICOID RECEPTOR) COMPLEX PROMOTES VC IS UNCLEAR. EMERGING EVIDENCE INDICATES THAT LONG-NONCODING RNA H19 (H19) PLAYS A CRITICAL ROLE IN VC. WE EXAMINED WHETHER ALDOSTERONE-INDUCED OSTEOGENIC DIFFERENTIATION OF VASCULAR SMOOTH MUSCLE CELLS (VSMCS) THROUGH H19 EPIGENETIC MODIFICATION OF RUNX2 (RUNT-RELATED TRANSCRIPTION FACTOR-2) IN A MR-DEPENDENT MANNER. METHODS: WE INDUCED IN VIVO RAT MODEL OF CHRONIC KIDNEY DISEASE USING A HIGH ADENINE AND PHOSPHATE DIET TO EXPLORE THE RELATIONSHIP AMONG ALDOSTERONE, MR, H19, AND VC. WE ALSO CULTURED HUMAN AORTIC VSMCS TO EXPLORE THE ROLES OF H19 IN ALDOSTERONE-MR COMPLEX-INDUCED OSTEOGENIC DIFFERENTIATION AND CALCIFICATION OF VSMCS. RESULTS: H19 AND RUNX2 WERE SIGNIFICANTLY INCREASED IN ALDOSTERONE-INDUCED VSMC OSTEOGENIC DIFFERENTIATION AND VC, BOTH IN VITRO AND IN VIVO, WHICH WERE SIGNIFICANTLY BLOCKED BY THE MR ANTAGONIST SPIRONOLACTONE. MECHANISTICALLY, OUR FINDINGS REVEAL THAT THE ALDOSTERONE-ACTIVATED MR BOUND TO H19 PROMOTER AND INCREASED ITS TRANSCRIPTIONAL ACTIVITY, AS DETERMINED BY CHROMATIN IMMUNOPRECIPITATION, ELECTROPHORETIC MOBILITY SHIFT ASSAY, AND LUCIFERASE REPORTER ASSAY. SILENCING H19 INCREASED MICRORNA-106A-5P (MIR-106A-5P) EXPRESSION, WHICH SUBSEQUENTLY INHIBITED ALDOSTERONE-INDUCED RUNX2 EXPRESSION AT THE POSTTRANSCRIPTIONAL LEVEL. IMPORTANTLY, WE OBSERVED A DIRECT INTERACTION BETWEEN H19 AND MIR-106A-5P, AND DOWNREGULATION OF MIR-106A-5P EFFICIENTLY REVERSED THE SUPPRESSION OF RUNX2 INDUCED BY H19 SILENCING. CONCLUSIONS: OUR STUDY CLARIFIES A NOVEL MECHANISM BY WHICH UPREGULATION OF H19 CONTRIBUTES TO ALDOSTERONE-MR COMPLEX-PROMOTED RUNX2-DEPENDENT VSMC OSTEOGENIC DIFFERENTIATION AND VC THROUGH SPONGING MIR-106A-5P. THESE FINDINGS HIGHLIGHT A POTENTIAL THERAPEUTIC TARGET FOR ALDOSTERONE-INDUCED VC. 2023 2 6435 45 THE XPB SUBUNIT OF THE TFIIH COMPLEX PLAYS A CRITICAL ROLE IN HIV-1 TRANSCRIPTION AND XPB INHIBITION BY SPIRONOLACTONE PREVENTS HIV-1 REACTIVATION FROM LATENCY. HIV TRANSCRIPTION REQUIRES ASSEMBLY OF CELLULAR TRANSCRIPTION FACTORS AT THE HIV-1PROMOTER. THE TFIIH GENERAL TRANSCRIPTION FACTOR FACILITATES TRANSCRIPTION INITIATION BY OPENING THE DNA STRANDS AROUND THE TRANSCRIPTION START SITE AND PHOSPHORYLATING THE C-TERMINAL DOMAIN FOR RNA POLYMERASE II (RNAPII) FOR ACTIVATION. SPIRONOLACTONE (SP), AN FDA APPROVED ALDOSTERONE ANTAGONIST, TRIGGERS THE PROTEASOMAL DEGRADATION OF THE XPB SUBUNIT OF TFIIH, AND CONCURRENTLY SUPPRESSES ACUTE HIV INFECTION IN VITRO HERE WE INVESTIGATED SP AS A POSSIBLE BLOCK-AND-LOCK AGENT FOR A FUNCTIONAL CURE AIMED AT THE TRANSCRIPTIONAL SILENCING OF THE VIRAL RESERVOIR. THE LONG-TERM ACTIVITY OF SP WAS INVESTIGATED IN PRIMARY AND CELL LINE MODELS OF HIV-1 LATENCY AND REACTIVATION. WE SHOW THAT SP RAPIDLY INHIBITS HIV-1 TRANSCRIPTION BY REDUCING RNAPII RECRUITMENT TO THE HIV-1 GENOME. SHRNA KNOCKDOWN OF XPB CONFIRMED XPB DEGRADATION AS THE MECHANISM OF ACTION. UNFORTUNATELY, LONG-TERM PRE-TREATMENT WITH SP DOES NOT RESULT IN EPIGENETIC SUPPRESSION OF HIV UPON SP TREATMENT INTERRUPTION, SINCE VIRUS RAPIDLY REBOUNDS WHEN XPB REEMERGES; HOWEVER, SP ALONE WITHOUT ART MAINTAINS THE TRANSCRIPTIONAL SUPPRESSION. IMPORTANTLY, SP INHIBITS HIV REACTIVATION FROM LATENCY IN BOTH CELL LINE MODELS AND RESTING CD4(+)T CELLS ISOLATED FROM AVIREMIC INFECTED INDIVIDUALS UPON CELL STIMULATION WITH LATENCY REVERSING AGENTS. FURTHERMORE, LONG-TERM TREATMENT WITH CONCENTRATIONS OF SP THAT POTENTLY DEGRADE XPB DOES NOT LEAD TO GLOBAL DYSREGULATION OF CELLULAR MRNA EXPRESSION. OVERALL, THESE RESULTS SUGGEST THAT XPB PLAYS A KEY ROLE IN HIV TRANSCRIPTIONAL REGULATION AND XPB DEGRADATION BY SP STRENGTHENS THE POTENTIAL OF HIV TRANSCRIPTIONAL INHIBITORS IN BLOCK-AND-LOCK HIV CURE APPROACHES.IMPORTANCE ANTIRETROVIRAL THERAPY (ART) EFFECTIVELY REDUCES AN INDIVIDUAL'S HIV LOADS TO BELOW THE DETECTION LIMIT, NEVERTHELESS RAPID VIRAL REBOUND IMMEDIATELY ENSUES UPON TREATMENT INTERRUPTION. FURTHERMORE, VIRALLY SUPPRESSED INDIVIDUALS EXPERIENCE CHRONIC IMMUNE ACTIVATION FROM ONGOING LOW-LEVEL VIRUS EXPRESSION. THUS, THE IMPORTANCE OF IDENTIFYING NOVEL THERAPEUTICS TO EXPLORE IN BLOCK-AND-LOCK HIV FUNCTIONAL CURE APPROACHES, AIMED AT THE TRANSCRIPTIONAL AND EPIGENETIC SILENCING OF THE VIRAL RESERVOIR TO BLOCK REACTIVATION FROM LATENCY. WE INVESTIGATED THE POTENTIAL OF REPURPOSING THE FDA-APPROVED SPIRONOLACTONE (SP), AS ONE SUCH DRUG. SP TREATMENT RAPIDLY DEGRADES A HOST TRANSCRIPTION FACTOR SUBUNIT, XPB, INHIBITING HIV TRANSCRIPTION AND BLOCKING REACTIVATION FROM LATENCY. LONG-TERM SP TREATMENT DOES NOT AFFECT CELLULAR VIABILITY, CELL CYCLE PROGRESSION OR GLOBAL CELLULAR TRANSCRIPTION. SP ALONE BLOCKS HIV TRANSCRIPTION IN THE ABSENCE OF ART BUT DOES NOT DELAY REBOUND UPON DRUG REMOVAL AS XPB RAPIDLY REEMERGES. THIS STUDY HIGHLIGHTS XPB AS A NOVEL DRUG TARGET IN BLOCK-AND-LOCK THERAPEUTIC APPROACHES. 2021 3 4971 26 PATHOPHYSIOLOGIC MECHANISMS IN DIABETIC KIDNEY DISEASE: A FOCUS ON CURRENT AND FUTURE THERAPEUTIC TARGETS. DIABETIC KIDNEY DISEASE (DKD) IS THE PRIMARY CAUSE OF CHRONIC KIDNEY DISEASE AROUND THE GLOBE AND IS ONE OF THE MAIN COMPLICATIONS IN PATIENTS WITH TYPE 1 AND 2 DIABETES. THE STANDARD TREATMENT FOR DKD IS DRUGS CONTROLLING HYPERGLYCEMIA AND HIGH BLOOD PRESSURE. RENIN ANGIOTENSIN ALDOSTERONE SYSTEM BLOCKADE AND SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITION HAVE YIELDED PROMISING RESULTS IN DKD, BUT MANY DIABETIC PATIENTS ON SUCH TREATMENTS NEVERTHELESS CONTINUE TO DEVELOP DKD, LEADING TO KIDNEY FAILURE AND CARDIOVASCULAR COMORBIDITIES. NEW THERAPEUTIC OPTIONS ARE URGENTLY REQUIRED. WE REVIEW HERE THE PROMISING THERAPEUTIC AVENUES BASED ON INSIGHTS INTO THE MECHANISMS OF DKD THAT HAVE RECENTLY EMERGED, INCLUDING MINERALOCORTICOID RECEPTOR ANTAGONISTS, SGLT2 INHIBITORS, GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST, ENDOTHELIN RECEPTOR A INHIBITION, ANTI-INFLAMMATORY AGENTS, AUTOPHAGY ACTIVATORS AND EPIGENETIC REMODELLING. THE INVOLVEMENT OF SEVERAL MOLECULAR MECHANISMS IN DKD PATHOGENESIS, TOGETHER WITH THE GENETIC AND EPIGENETIC VARIABILITY OF THIS CONDITION, MAKES IT DIFFICULT TO TARGET THIS HETEROGENEOUS PATIENT POPULATION WITH A SINGLE DRUG. PERSONALIZED MEDICINE, TAKING INTO ACCOUNT THE GENETIC AND MECHANISTIC VARIABILITY, MAY THEREFORE IMPROVE RENAL AND CARDIOVASCULAR PROTECTION IN DIABETIC PATIENTS WITH DKD. 2020 4 5716 44 SIRT6 PROTECTS VASCULAR SMOOTH MUSCLE CELLS FROM OSTEOGENIC TRANSDIFFERENTIATION VIA RUNX2 IN CHRONIC KIDNEY DISEASE. VASCULAR CALCIFICATION (VC) IS REGARDED AS AN IMPORTANT PATHOLOGICAL CHANGE LACKING EFFECTIVE TREATMENT AND ASSOCIATED WITH HIGH MORTALITY. SIRTUIN 6 (SIRT6) IS A MEMBER OF THE SIRTUIN FAMILY, A CLASS III HISTONE DEACETYLASE AND A KEY EPIGENETIC REGULATOR. SIRT6 HAS A PROTECTIVE ROLE IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD). HOWEVER, THE EXACT ROLE AND MOLECULAR MECHANISM OF SIRT6 IN VC IN PATIENTS WITH CKD REMAIN UNCLEAR. HERE, WE DEMONSTRATED THAT SIRT6 WAS MARKEDLY DOWNREGULATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND IN THE RADIAL ARTERY TISSUE OF PATIENTS WITH CKD WITH VC. SIRT6-TRANSGENIC (SIRT6-TG) MICE SHOWED ALLEVIATED VC, WHILE VASCULAR SMOOTH MUSCLE CELL-SPECIFIC (VSMC-SPECIFIC) SIRT6 KNOCKED-DOWN MICE SHOWED SEVERE VC IN CKD. SIRT6 SUPPRESSED THE OSTEOGENIC TRANSDIFFERENTIATION OF VSMCS VIA REGULATION OF RUNT-RELATED TRANSCRIPTION FACTOR 2 (RUNX2). COIMMUNOPRECIPITATION (CO-IP) AND IMMUNOPRECIPITATION (IP) ASSAYS CONFIRMED THAT SIRT6 BOUND TO RUNX2. MOREOVER, RUNX2 WAS DEACETYLATED BY SIRT6 AND FURTHER PROMOTED NUCLEAR EXPORT VIA EXPORTIN 1 (XPO1), WHICH IN TURN CAUSED DEGRADATION OF RUNX2 THROUGH THE UBIQUITIN-PROTEASOME SYSTEM. THESE RESULTS DEMONSTRATED THAT SIRT6 PREVENTED VC BY SUPPRESSING THE OSTEOGENIC TRANSDIFFERENTIATION OF VSMCS, AND AS SUCH TARGETING SIRT6 MAY BE AN APPEALING THERAPEUTIC TARGET FOR VC IN CKD. 2022 5 3295 46 HIGH PHOSPHATE-INDUCED DOWNREGULATION OF PPARGAMMA CONTRIBUTES TO CKD-ASSOCIATED VASCULAR CALCIFICATION. MEDIAL ARTERIAL CALCIFICATION ASSOCIATED WITH HYPERPHOSPHATEMIA IS A MAIN CAUSE OF CARDIOVASCULAR MORTALITY IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD), BUT THE MECHANISMS UNDERLYING HIGH PHOSPHATE-INDUCED VASCULAR CALCIFICATION REMAIN LARGELY UNKNOWN. HERE, WE OBSERVED A SIGNIFICANT DECREASE IN THE EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA) IN CALCIFIED ARTERIES BOTH IN CKD PATIENTS AND IN A MOUSE MODEL OF CKD WITH HYPERPHOSPHATEMIA. IN VITRO, HIGH PHOSPHATE TREATMENT LED TO A DECREASED EXPRESSION OF PPARGAMMA IN MOUSE VASCULAR SMOOTH MUSCLE CELLS (VMSCS), ACCOMPANIED BY APPARENT OSTEOGENIC DIFFERENTIATION AND CALCIFICATION. PRETREATMENT WITH PPARGAMMA AGONIST ROSIGLITAZONE SIGNIFICANTLY REVERSED HIGH PHOSPHATE-INDUCED VSMCS CALCIFICATION. FURTHER INVESTIGATION SHOWED THAT METHYL-CPG BINDING PROTEIN 2 (MECP2)-MEDIATED EPIGENETIC REPRESSION WAS INVOLVED IN HIGH PHOSPHATE-INDUCED PPARGAMMA DOWNREGULATION. MOREOVER, THE EXPRESSION OF KLOTHO THAT HAS THE ABILITY TO INHIBIT VASCULAR CALCIFICATION BY REGULATING PHOSPHATE UPTAKE DECREASED WITH THE PPARGAMMA REDUCTION IN VSMCS AFTER HIGH PHOSPHATE TREATMENT, AND ROSIGLITAZONE FAILED TO INHIBIT HIGH PHOSPHATE-INDUCED CALCIFICATION IN VSMCS WITH KNOCKDOWN OF KLOTHO OR IN AORTIC RINGS FROM KLOTHO-DEFICIENT (KL/KL) MICE. FINALLY, AN IN VIVO STUDY DEMONSTRATED THAT ORAL ADMINISTRATION OF ROSIGLITAZONE COULD INCREASE KLOTHO EXPRESSION AND PROTECT AGAINST HIGH PHOSPHATE-INDUCED VASCULAR CALCIFICATION IN CKD MICE. THESE FINDINGS SUGGEST THAT THE INHIBITION OF PPARGAMMA EXPRESSION MAY CONTRIBUTE TO THE PATHOGENESIS OF HIGH PHOSPHATE-INDUCED VASCULAR CALCIFICATION, WHICH MAY PROVIDE A NEW THERAPEUTIC TARGET FOR VASCULAR CALCIFICATION IN CKD PATIENTS. 2018 6 6648 26 UPDATE ON DIAGNOSIS, PATHOPHYSIOLOGY, AND MANAGEMENT OF DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD) IS A CHRONIC COMPLICATION OF DIABETES MELLITUS WHICH MAY EVENTUALLY LEAD TO END-STAGE KIDNEY DISEASE (ESKD). DESPITE IMPROVEMENTS IN GLYCAEMIC CONTROL AND BLOOD PRESSURE MANAGEMENT WITH RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) BLOCKADE, THE CURRENT THERAPY CANNOT COMPLETELY HALT DKD PROGRESSION TO ESKD IN SOME PATIENTS. DKD IS A HETEROGENEOUS DISEASE ENTITY IN TERMS OF ITS CLINICAL MANIFESTATIONS, HISTOPATHOLOGY AND THE RATE OF PROGRESSION, WHICH MAKES IT DIFFICULT TO DEVELOP EFFECTIVE THERAPEUTICS. IT WAS FORMERLY CONSIDERED THAT ALBUMINURIA PRECEDED KIDNEY FUNCTION DECLINE IN DKD, BUT RECENT EPIDEMIOLOGICAL STUDIES REVEALED THAT A DISTINCT GROUP OF PATIENTS PRESENTED KIDNEY DYSFUNCTION WITHOUT DEVELOPING ALBUMINURIA. OTHER COMORBIDITIES, SUCH AS HYPERTENSION, OBESITY AND GOUT, ALSO AFFECT THE CLINICAL COURSE OF DKD. THE PATHOPHYSIOLOGY OF DKD IS COMPLEX AND MULTIFACTORIAL, INVOLVING BOTH METABOLIC AND HAEMODYNAMIC FACTORS. THESE INDUCE ACTIVATION OF INTRACELLULAR SIGNALLING PATHWAYS, OXIDATIVE STRESS, HYPOXIA, DYSREGULATED AUTOPHAGY AND EPIGENETIC CHANGES, WHICH RESULT IN KIDNEY INFLAMMATION AND FIBROSIS. RECENTLY, TWO GROUPS OF ANTIDIABETIC DRUGS, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS AND GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS, WERE DEMONSTRATED TO PROVIDE RENOPROTECTION ON TOP OF THEIR GLUCOSE-LOWERING EFFECTS. SEVERAL OTHER THERAPEUTIC AGENTS ARE ALSO BEING DEVELOPED AND EVALUATED IN CLINICAL TRIALS. 2021 7 5596 31 ROLES OF HISTONE ACETYLATION MODIFIERS AND OTHER EPIGENETIC REGULATORS IN VASCULAR CALCIFICATION. VASCULAR CALCIFICATION (VC) IS CHARACTERIZED BY CALCIUM DEPOSITION INSIDE ARTERIES AND IS CLOSELY ASSOCIATED WITH THE MORBIDITY AND MORTALITY OF ATHEROSCLEROSIS, CHRONIC KIDNEY DISEASE, DIABETES, AND OTHER CARDIOVASCULAR DISEASES (CVDS). VC IS NOW WIDELY KNOWN TO BE AN ACTIVE PROCESS OCCURRING IN VASCULAR SMOOTH MUSCLE CELLS (VSMCS) INVOLVING MULTIPLE MECHANISMS AND FACTORS. THESE MECHANISMS SHARE FEATURES WITH THE PROCESS OF BONE FORMATION, SINCE THE PHENOTYPE SWITCHING FROM THE CONTRACTILE TO THE OSTEOCHONDROGENIC PHENOTYPE ALSO OCCURS IN VSMCS DURING VC. IN ADDITION, VC CAN BE REGULATED BY EPIGENETIC FACTORS, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, AND NONCODING RNAS. ALTHOUGH VC IS COMMONLY OBSERVED IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND CVD, SPECIFIC DRUGS FOR VC HAVE NOT BEEN DEVELOPED. THUS, DISCOVERING NOVEL THERAPEUTIC TARGETS MAY BE NECESSARY. IN THIS REVIEW, WE SUMMARIZE THE CURRENT EXPERIMENTAL EVIDENCE REGARDING THE ROLE OF EPIGENETIC REGULATORS INCLUDING HISTONE DEACETYLASES AND PROPOSE THE THERAPEUTIC IMPLICATION OF THESE REGULATORS IN THE TREATMENT OF VC. 2020 8 6575 21 TREATMENT OF DIABETIC KIDNEY DISEASE: CURRENT AND FUTURE. DIABETIC KIDNEY DISEASE (DKD) IS THE MAJOR CAUSE OF END-STAGE KIDNEY DISEASE. HOWEVER, ONLY RENIN-ANGIOTENSIN SYSTEM INHIBITOR WITH MULTIDISCIPLINARY TREATMENTS IS EFFECTIVE FOR DKD. IN 2019, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR SHOWED EFFICACY AGAINST DKD IN CANAGLIFLOZIN AND RENAL EVENTS IN DIABETES WITH ESTABLISHED NEPHROPATHY CLINICAL EVALUATION (CREDENCE) TRIAL, ADDING A NEW TREATMENT OPTION. HOWEVER, THE PROGRESSION OF DKD HAS NOT BEEN COMPLETELY CONTROLLED. THE PATIENTS WITH TRANSIENT EXPOSURE TO HYPERGLYCEMIA DEVELOP DIABETIC COMPLICATIONS, INCLUDING DKD, EVEN AFTER NORMALIZATION OF THEIR BLOOD GLUCOSE. TEMPORARY HYPERGLYCEMIA CAUSES ADVANCED GLYCATION END PRODUCT (AGE) ACCUMULATIONS AND EPIGENETIC CHANGES AS METABOLIC MEMORY. THE DRUGS THAT IMPROVE METABOLIC MEMORY ARE AWAITED, AND AGE INHIBITORS AND HISTONE MODIFICATION INHIBITORS ARE THE FOCUS OF CLINICAL AND BASIC RESEARCH. IN ADDITION, INCRETIN-RELATED DRUGS SHOWED A RENOPROTECTIVE ABILITY IN MANY CLINICAL TRIALS, AND THESE TRIALS WITH RENAL OUTCOME AS THEIR PRIMARY ENDPOINT ARE CURRENTLY ONGOING. HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITORS RECENTLY APPROVED FOR RENAL ANEMIA MAY BE RENOPROTECTIVE SINCE THEY IMPROVE TUBULOINTERSTITIAL HYPOXIA. FURTHERMORE, NF-E2-RELATED FACTOR 2 ACTIVATORS IMPROVED THE GLOMERULAR FILTRATION RATE OF DKD PATIENTS IN BARDOXOLONE METHYL TREATMENT: RENAL FUNCTION IN CHRONIC KIDNEY DISEASE/TYPE 2 DIABETES (BEAM) TRIAL AND PHASE II STUDY OF BARDOXOLONE METHYL IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES (TSUBAKI) TRIAL. THUS, FOLLOWING SGLT2 INHIBITOR, NUMEROUS NOVEL DRUGS COULD BE UTILIZED IN TREATING DKD. FUTURE STUDIES ARE EXPECTED TO PROVIDE NEW INSIGHTS. 2021 9 1239 20 CURE AND LONG-TERM REMISSION STRATEGIES. THE MAJORITY OF VIRALLY SUPPRESSED INDIVIDUALS WILL EXPERIENCE RAPID VIRAL REBOUND UPON ANTIRETROVIRAL THERAPY (ART) INTERRUPTION, PROVIDING A STRONG RATIONALE FOR THE DEVELOPMENT OF CURE STRATEGIES. MOREOVER, DESPITE ART VIROLOGICAL CONTROL, HIV INFECTION IS STILL ASSOCIATED WITH CHRONIC IMMUNE ACTIVATION, INFLAMMATION, COMORBIDITIES, AND ACCELERATED AGING. THESE EFFECTS ARE BELIEVED TO BE DUE, IN PART, TO LOW-GRADE PERSISTENT TRANSCRIPTION AND TRICKLING PRODUCTION OF VIRAL PROTEINS FROM THE POOL OF LATENT PROVIRUSES CONSTITUTING THE VIRAL RESERVOIR. IN RECENT YEARS THERE HAS BEEN AN INCREASING INTEREST IN DEVELOPING WHAT HAS BEEN TERMED A FUNCTIONAL CURE FOR HIV. THIS APPROACH ENTAILS THE LONG-TERM, DURABLE CONTROL OF VIRAL EXPRESSION IN THE ABSENCE OF THERAPY, PREVENTING DISEASE PROGRESSION AND TRANSMISSION, DESPITE THE PRESENCE OF DETECTABLE INTEGRATED PROVIRUSES. ONE SUCH STRATEGY, THE BLOCK-AND-LOCK APPROACH FOR A FUNCTIONAL CURE, PROPOSES THE EPIGENETIC SILENCING OF PROVIRAL EXPRESSION, LOCKING THE VIRUS IN A PROFOUND LATENT STATE, FROM WHICH REACTIVATION IS VERY UNLIKELY. THE PROOF-OF-CONCEPT FOR THIS APPROACH WAS DEMONSTRATED WITH THE USE OF A SPECIFIC SMALL MOLECULE TARGETING HIV TRANSCRIPTION. HERE WE REVIEW THE PRINCIPLES BEHIND THE BLOCK-AND-LOCK APPROACH AND SOME OF THE ADDITIONAL STRATEGIES PROPOSED TO SILENCE HIV EXPRESSION. 2022 10 5715 38 SIRT3 RESTRICTS HEPATITIS B VIRUS TRANSCRIPTION AND REPLICATION THROUGH EPIGENETIC REGULATION OF COVALENTLY CLOSED CIRCULAR DNA INVOLVING SUPPRESSOR OF VARIEGATION 3-9 HOMOLOG 1 AND SET DOMAIN CONTAINING 1A HISTONE METHYLTRANSFERASES. HEPATITIS B VIRUS (HBV) INFECTION REMAINS A MAJOR HEALTH PROBLEM WORLDWIDE. MAINTENANCE OF THE COVALENTLY CLOSED CIRCULAR DNA (CCCDNA), WHICH SERVES AS A TEMPLATE FOR HBV RNA TRANSCRIPTION, IS RESPONSIBLE FOR THE FAILURE OF ERADICATING CHRONIC HBV DURING CURRENT ANTIVIRAL THERAPY. CCCDNA IS ASSEMBLED WITH CELLULAR HISTONE PROTEINS INTO CHROMATIN, BUT LITTLE IS KNOWN ABOUT THE REGULATION OF HBV CHROMATIN BY HISTONE POSTTRANSLATIONAL MODIFICATIONS. IN THIS STUDY, WE IDENTIFIED SILENT MATING TYPE INFORMATION REGULATION 2 HOMOLOG 3 (SIRT3) AS A HOST FACTOR RESTRICTING HBV TRANSCRIPTION AND REPLICATION BY SCREENING SEVEN MEMBERS OF THE SIRTUIN FAMILY, WHICH IS THE CLASS III HISTONE DEACETYLASE. ECTOPIC SIRT3 EXPRESSION SIGNIFICANTLY REDUCED TOTAL HBV RNAS, 3.5-KB RNA, AS WELL AS REPLICATIVE INTERMEDIATE DNA IN HBV-INFECTED HEPG2-NA(+) /TAUROCHOLATE COTRANSPORTING POLYPEPTIDE CELLS AND PRIMARY HUMAN HEPATOCYTES. IN CONTRAST, GENE SILENCING OF SIRT3 PROMOTED HBV TRANSCRIPTION AND REPLICATION. A MECHANISTIC STUDY FOUND THAT NUCLEAR SIRT3 WAS RECRUITED TO THE HBV CCCDNA, WHERE IT DEACETYLATED HISTONE 3 LYSINE 9. IMPORTANTLY, OCCUPANCY OF SIRT3 ON CCCDNA COULD INCREASE THE RECRUITMENT OF HISTONE METHYLTRANSFERASE SUPPRESSOR OF VARIEGATION 3-9 HOMOLOG 1 TO CCCDNA AND DECREASE RECRUITMENT OF SET DOMAIN CONTAINING 1A, LEADING TO A MARKED INCREASE OF TRIMETHYL-HISTONE H3 (LYS9) AND A DECREASE OF TRIMETHYL-HISTONE H3 (LYS4) ON CCCDNA. MOREOVER, SIRT3-MEDIATED HBV CCCDNA TRANSCRIPTIONAL REPRESSION INVOLVED DECREASED BINDING OF HOST RNA POLYMERASE II AND TRANSCRIPTION FACTOR YIN YANG 1 TO CCCDNA. FINALLY, HEPATITIS B VIRAL X PROTEIN COULD RELIEVE SIRT3-MEDIATED CCCDNA TRANSCRIPTIONAL REPRESSION BY INHIBITING BOTH SIRT3 EXPRESSION AND ITS RECRUITMENT TO CCCDNA. CONCLUSION: SIRT3 IS A HOST FACTOR EPIGENETICALLY RESTRICTING HBV CCCDNA TRANSCRIPTION BY ACTING COOPERATIVELY WITH HISTONE METHYLTRANSFERASE; THESE DATA PROVIDE A RATIONALE FOR THE USE OF SIRT3 ACTIVATORS IN THE PREVENTION OR TREATMENT OF HBV INFECTION. (HEPATOLOGY 2018). 2018 11 6700 38 VASCULAR CALCIFICATION MECHANISMS: UPDATES AND RENEWED INSIGHT INTO SIGNALING PATHWAYS INVOLVED IN HIGH PHOSPHATE-MEDIATED VASCULAR SMOOTH MUSCLE CELL CALCIFICATION. VASCULAR CALCIFICATION (VC) IS ASSOCIATED WITH AGING, CARDIOVASCULAR AND RENAL DISEASES AND RESULTS IN POOR MORBIDITY AND INCREASED MORTALITY. VC OCCURS IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD), A CONDITION THAT IS ASSOCIATED WITH HIGH SERUM PHOSPHATE (PI) AND SEVERE CARDIOVASCULAR CONSEQUENCES. HIGH SERUM PI LEVEL IS RELATED TO SOME PATHOLOGIES WHICH AFFECT THE BEHAVIOUR OF VASCULAR CELLS, INCLUDING PLATELETS, ENDOTHELIAL CELLS (ECS) AND SMOOTH MUSCLE CELLS (SMCS), AND PLAYS A CENTRAL ROLE IN PROMOTING VC. VC IS A COMPLEX, ACTIVE AND CELL-MEDIATED PROCESS INVOLVING THE TRANSDIFFERENTIATION OF VASCULAR SMCS TO A BONE-LIKE PHENOTYPE, SYSTEMIC INFLAMMATION, DECREASED ANTI-CALCIFIC EVENTS (LOSS OF CALCIFICATION INHIBITORS), LOSS IN SMC LINEAGE MARKERS AND ENHANCED PRO-CALCIFIC MICRORNAS (MIRS), AN INCREASED INTRACELLULAR CALCIUM LEVEL, APOPTOSIS, ABERRANT DNA DAMAGE RESPONSE (DDR) AND SENESCENCE OF VASCULAR SMCS. THIS REVIEW GIVES A BRIEF OVERVIEW OF THE CURRENT KNOWLEDGE OF VC MECHANISMS WITH A PARTICULAR FOCUS ON PI-INDUCED CHANGES IN THE VASCULAR WALL IMPORTANT IN PROMOTING CALCIFICATION. IN ADDITION TO REVIEWING THE MAIN FINDINGS, THIS REVIEW ALSO SHEDS LIGHT ON DIRECTIONS FOR FUTURE RESEARCH IN THIS AREA AND DISCUSSES EMERGING PATHWAYS SUCH AS PI-REGULATED INTRACELLULAR CALCIUM SIGNALING, EPIGENETICS, OXIDATIVE DNA DAMAGE AND SENESCENCE-MEDIATED MECHANISMS THAT MAY PLAY CRITICAL, YET TO BE EXPLORED, REGULATORY AND DRUGGABLE ROLES IN LIMITING VC. 2021 12 3656 42 INDUCIBLE PRMT1 ABLATION IN ADULT VASCULAR SMOOTH MUSCLE LEADS TO CONTRACTILE DYSFUNCTION AND AORTIC DISSECTION. VASCULAR SMOOTH MUSCLE CELLS (VSMCS) HAVE REMARKABLE PLASTICITY IN RESPONSE TO DIVERSE ENVIRONMENTAL CUES. ALTHOUGH THESE CELLS ARE VERSATILE, CHRONIC STRESS CAN TRIGGER VSMC DYSFUNCTION, WHICH ULTIMATELY LEADS TO VASCULAR DISEASES SUCH AS AORTIC ANEURYSM AND ATHEROSCLEROSIS. PROTEIN ARGININE METHYLTRANSFERASE 1 (PRMT1) IS A MAJOR ENZYME CATALYZING ASYMMETRIC ARGININE DIMETHYLATION OF PROTEINS THAT ARE SOURCES OF ASYMMETRIC DIMETHYLARGININE (ADMA), AN ENDOGENOUS INHIBITOR OF NITRIC OXIDE SYNTHASE. ALTHOUGH A POTENTIAL ROLE OF PRMT1 IN VASCULAR PATHOGENESIS HAS BEEN PROPOSED, ITS ROLE IN VASCULAR FUNCTION HAS YET TO BE CLARIFIED. HERE, WE INVESTIGATED THE ROLE AND UNDERLYING MECHANISM OF PRMT1 IN VASCULAR SMOOTH MUSCLE CONTRACTILITY AND FUNCTION. THE EXPRESSION OF PRMT1 AND CONTRACTILE-RELATED GENES WAS SIGNIFICANTLY DECREASED IN THE AORTAS OF ELDERLY HUMANS AND PATIENTS WITH AORTIC ANEURYSMS. MICE WITH VSMC-SPECIFIC PRMT1 ABLATION (SMKO) EXHIBITED PARTIAL LETHALITY, LOW BLOOD PRESSURE AND AORTIC DILATION. THE PRMT1-ABLATED AORTAS SHOWED AORTIC DISSECTION WITH ELASTIC FIBER DEGENERATION AND CELL DEATH. EX VIVO AND IN VITRO ANALYSES INDICATED THAT PRMT1 ABLATION SIGNIFICANTLY DECREASED THE CONTRACTILITY OF THE AORTA AND TRACTION FORCES OF VSMCS. PRMT1 ABLATION DOWNREGULATED THE EXPRESSION OF CONTRACTILE GENES SUCH AS MYOCARDIN WHILE UPREGULATING THE EXPRESSION OF SYNTHETIC GENES, THUS CAUSING THE CONTRACTILE TO SYNTHETIC PHENOTYPIC SWITCH OF VSMCS. IN ADDITION, MECHANISTIC STUDIES DEMONSTRATED THAT PRMT1 DIRECTLY REGULATES MYOCARDIN GENE ACTIVATION BY MODULATING EPIGENETIC HISTONE MODIFICATIONS IN THE MYOCARDIN PROMOTER REGION. THUS, OUR STUDY DEMONSTRATES THAT VSMC PRMT1 IS ESSENTIAL FOR VASCULAR HOMEOSTASIS AND THAT ITS ABLATION CAUSES AORTIC DILATION/DISSECTION THROUGH IMPAIRED MYOCARDIN EXPRESSION. 2021 13 6699 29 VASCULAR CALCIFICATION IN CKD: NEW INSIGHTS INTO ITS MECHANISMS. VASCULAR CALCIFICATION (VC) IS A COMMON COMPLICATION OF CHRONIC KIDNEY DISEASE (CKD) AND CONTRIBUTES TO AN INCREASED RISK OF CARDIOVASCULAR MORBIDITY AND MORTALITY. HOWEVER, EFFECTIVE THERAPIES ARE STILL UNAVAILABLE AT PRESENT. IT HAS BEEN WELL ESTABLISHED THAT VC ASSOCIATED WITH CKD IS NOT A PASSIVE PROCESS OF CALCIUM PHOSPHATE DEPOSITION, BUT AN ACTIVELY REGULATED AND CELL-MEDIATED PROCESS THAT SHARES MANY SIMILARITIES WITH BONE FORMATION. ADDITIONALLY, NUMEROUS STUDIES HAVE SUGGESTED THAT CKD PATIENTS HAVE SPECIFIC RISK FACTORS AND CONTRIBUTORS TO THE DEVELOPMENT OF VC, SUCH AS HYPERPHOSPHATEMIA, UREMIC TOXINS, OXIDATIVE STRESS AND INFLAMMATION. ALTHOUGH RESEARCH EFFORTS IN THE PAST DECADE HAVE GREATLY IMPROVED OUR KNOWLEDGE OF THE MULTIPLE FACTORS AND MECHANISMS INVOLVED IN CKD-RELATED VC, MANY QUESTIONS REMAIN UNANSWERED. MOREOVER, STUDIES FROM THE PAST DECADE HAVE DEMONSTRATED THAT EPIGENETIC MODIFICATIONS ABNORMALITIES, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND NONCODING RNAS, PLAY AN IMPORTANT ROLE IN THE REGULATION OF VC. THIS REVIEW SEEKS TO PROVIDE AN OVERVIEW OF THE PATHOPHYSIOLOGICAL AND MOLECULAR MECHANISMS OF VC ASSOCIATED WITH CKD, MAINLY FOCUSING ON THE INVOLVEMENT OF EPIGENETIC MODIFICATIONS IN THE INITIATION AND PROGRESSION OF UREMIC VC, WITH THE AIM TO DEVELOP PROMISING THERAPIES FOR CKD-RELATED CARDIOVASCULAR EVENTS IN THE FUTURE. 2023 14 4137 24 MECHANISMS OF METABOLIC MEMORY AND RENAL HYPOXIA AS A THERAPEUTIC TARGET IN DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD) IS A WORLDWIDE PUBLIC HEALTH PROBLEM. THE DEFINITION OF DKD IS UNDER DISCUSSION. ALTHOUGH THE TERM DKD WAS ORIGINALLY DEFINED AS 'KIDNEY DISEASE SPECIFIC TO DIABETES,' DKD FREQUENTLY MEANS CHRONIC KIDNEY DISEASE WITH DIABETES MELLITUS AND INCLUDES NOT ONLY CLASSICAL DIABETIC NEPHROPATHY, BUT ALSO KIDNEY DYSFUNCTION AS A RESULT OF NEPHROSCLEROSIS AND OTHER CAUSES. METABOLIC MEMORY PLAYS A CRUCIAL ROLE IN THE PROGRESSION OF VARIOUS COMPLICATIONS OF DIABETES, INCLUDING DKD. THE MECHANISMS OF METABOLIC MEMORY IN DKD ARE SUPPOSED TO INCLUDE ADVANCED GLYCATION END-PRODUCTS, DEOXYRIBONUCLEIC ACID METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RIBONUCLEIC ACID INCLUDING MICRO RIBONUCLEIC ACID. REGARDLESS OF THE PRESENCE OF DIABETES MELLITUS, THE FINAL COMMON PATHWAY IN CHRONIC KIDNEY DISEASE IS CHRONIC KIDNEY HYPOXIA, WHICH INFLUENCES EPIGENETIC PROCESSES, INCLUDING DEOXYRIBONUCLEIC ACID METHYLATION, HISTONE MODIFICATION, AND CONFORMATIONAL CHANGES IN MICRO RIBONUCLEIC ACID AND CHROMATIN. THEREFORE, HYPOXIA AND OXIDATIVE STRESS ARE APPROPRIATE TARGETS OF THERAPIES AGAINST DKD. PROLYL HYDROXYLASE DOMAIN INHIBITOR ENHANCES THE DEFENSIVE MECHANISMS AGAINST HYPOXIA. BARDOXOLONE METHYL PROTECTS AGAINST OXIDATIVE STRESS, AND CAN EVEN REVERSE IMPAIRED RENAL FUNCTION; A PHASE 2 TRIAL WITH CONSIDERABLE ATTENTION TO HEART COMPLICATIONS IS CURRENTLY ONGOING IN JAPAN. 2017 15 5363 16 RECENT ADVANCES IN DIABETIC KIDNEY DISEASES: FROM KIDNEY INJURY TO KIDNEY FIBROSIS. DIABETIC KIDNEY DISEASE (DKD) IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE. THE NATURAL HISTORY OF DKD INCLUDES GLOMERULAR HYPERFILTRATION, PROGRESSIVE ALBUMINURIA, DECLINING ESTIMATED GLOMERULAR FILTRATION RATE, AND, ULTIMATELY, KIDNEY FAILURE. IT IS KNOWN THAT DKD IS ASSOCIATED WITH METABOLIC CHANGES CAUSED BY HYPERGLYCEMIA, RESULTING IN GLOMERULAR HYPERTROPHY, GLOMERULOSCLEROSIS, AND TUBULOINTERSTITIAL INFLAMMATION AND FIBROSIS. HYPERGLYCEMIA IS ALSO KNOWN TO CAUSE PROGRAMMED EPIGENETIC MODIFICATION. HOWEVER, THE DETAILED MECHANISMS INVOLVED IN THE ONSET AND PROGRESSION OF DKD REMAIN ELUSIVE. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES REGARDING THE PATHOGENIC MECHANISMS INVOLVED IN DKD. 2021 16 5226 37 PRMT5 RESTRICTS HEPATITIS B VIRUS REPLICATION THROUGH EPIGENETIC REPRESSION OF COVALENTLY CLOSED CIRCULAR DNA TRANSCRIPTION AND INTERFERENCE WITH PREGENOMIC RNA ENCAPSIDATION. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION REMAINS A MAJOR HEALTH PROBLEM WORLDWIDE. THE COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) MINICHROMOSOME, WHICH SERVES AS THE TEMPLATE FOR THE TRANSCRIPTION OF VIRAL RNAS, PLAYS A KEY ROLE IN VIRAL PERSISTENCE. WHILE ACCUMULATING EVIDENCE SUGGESTS THAT CCCDNA TRANSCRIPTION IS REGULATED BY EPIGENETIC MACHINERY, PARTICULARLY THE ACETYLATION OF CCCDNA-BOUND HISTONE 3 (H3) AND H4, THE POTENTIAL CONTRIBUTIONS OF HISTONE METHYLATION AND RELATED HOST FACTORS REMAIN OBSCURE. HERE, BY SCREENING A SERIES OF METHYLTRANSFERASES AND DEMETHYLASES, WE IDENTIFIED PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT5) AS AN EFFECTIVE RESTRICTOR OF HBV TRANSCRIPTION AND REPLICATION. IN CELL CULTURE-BASED MODELS FOR HBV INFECTION AND IN LIVER TISSUES OF PATIENTS WITH CHRONIC HBV INFECTION, WE FOUND THAT SYMMETRIC DIMETHYLATION OF ARGININE 3 ON H4 ON CCCDNA WAS A REPRESSIVE MARKER OF CCCDNA TRANSCRIPTION AND WAS REGULATED BY PRMT5 DEPENDING ON ITS METHYLTRANSFERASE DOMAIN. MOREOVER, PRMT5-TRIGGERED SYMMETRIC DIMETHYLATION OF ARGININE 3 ON H4 ON THE CCCDNA MINICHROMOSOME INVOLVED AN INTERACTION WITH THE HBV CORE PROTEIN AND THE BRG1-BASED HUMAN SWI/SNF CHROMATIN REMODELER, WHICH RESULTED IN DOWN-REGULATION OF THE BINDING OF RNA POLYMERASE II TO CCCDNA. IN ADDITION TO THE INHIBITORY EFFECT ON CCCDNA TRANSCRIPTION, PRMT5 INHIBITED HBV CORE PARTICLE DNA PRODUCTION INDEPENDENTLY OF ITS METHYLTRANSFERASE ACTIVITY. FURTHER STUDY REVEALED THAT PRMT5 INTERFERED WITH PREGENOMIC RNA ENCAPSIDATION BY PREVENTING ITS INTERACTION WITH VIRAL POLYMERASE PROTEIN THROUGH BINDING TO THE REVERSE TRANSCRIPTASE-RIBONUCLEASE H REGION OF POLYMERASE, WHICH IS CRUCIAL FOR THE POLYMERASE-PREGENOMIC RNA INTERACTION. CONCLUSION: PRMT5 RESTRICTS HBV REPLICATION THROUGH A TWO-PART MECHANISM INCLUDING EPIGENETIC SUPPRESSION OF CCCDNA TRANSCRIPTION AND INTERFERENCE WITH PREGENOMIC RNA ENCAPSIDATION; THESE FINDINGS IMPROVE THE UNDERSTANDING OF EPIGENETIC REGULATION OF HBV TRANSCRIPTION AND HOST-HBV INTERACTION, THUS PROVIDING NEW INSIGHTS INTO TARGETED THERAPEUTIC INTERVENTION. (HEPATOLOGY 2017;66:398-415). 2017 17 6473 32 TO DO ONE AND TO GET MORE: PART II. DIABETES AND METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASES. TYPE 2 DIABETES MELLITUS (DM) IS CHARACTERIZED BY INABILITY OF FAULTY PANCREATIC BETA-CELLS TO SECRET A NORMAL AMOUNT OF INSULIN TO MAINTAIN NORMAL BODY CONSUMPTION, AND/OR PERIPHERAL TISSUE HAS A DECREASED SUSCEPTIBILITY TO INSULIN, RESULTING IN HYPERGLYCEMIA AND INSULIN RESISTANCE. SIMILAR TO OTHER CHRONIC SYSTEMIC INFLAMMATORY DISEASES, DM IS A RESULT FROM DYSREGULATED INTERACTIONS BETWEEN ETHNIC, GENETIC, EPIGENETIC, IMMUNOREGULATORY, HORMONAL, AND ENVIRONMENTAL FACTORS. THEREFORE, IT IS RATIONAL TO SUPPOSE THE CONCEPT AS "TO DO ONE AND TO GET MORE", WHILE USING ANTIDIABETIC AGENTS (ADA), A MAIN PHARMACOLOGIC AGENT FOR THE TREATMENT OF DM, CAN PROVIDE AN EXTRAGLYCEMIA EFFECT ON COMORBIDITIES OR CONCOMITTENT COMORBIDITIES TO DM. IN THIS REVIEW, BASED ON THE MUCH STRONG CORRELATION BETWEEN DM AND METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASES (MAFLD) SHOWN BY SIMILAR PATHOPHYSIOLOGICAL MECHANISMS AND A HIGH PREVALENCE OF DM IN MAFLD AND ITS VICE VERSA (A HIGH PREVALENCE OF MAFLD IN DM), IT IS POSSIBLE TO USE THE STRATEGY TO TARGET BOTH DISEASES SIMULTANEOUSLY. WE FOCUS ON A NEW CLASSIFICATION OF ADA, SUCH AS GLUCAGON-LIKE PEPTIDE-1 RECEPTOR (GLP1R) AGONIST AND SODIUM-GLUCOSE COTRANSPORTER-2 (SGLT-2) INHIBITORS TO SHOW THE POTENTIAL BENEFITS OF EXTRAGLYCEMIC EFFECT ON MAFLD. WE CONCLUDE THAT THE MANAGEMENT OF DM PATIENTS, ESPECIALLY FOR THOSE WHO NEED ADA AS ADJUVANT THERAPY SHOULD INCLUDE HEALTHY LIFESTYLE MODIFICATION TO OVERCOME THE METABOLIC SYNDROME, CONTRIBUTING TO THE URGENT NEED OF AN EFFECTIVE WEIGHT-REDUCTION STRATEGY. GLP1R AGONIST IS ONE OF EFFECTIVE BODY WEIGHT-LOWERING MEDICATIONS, WHICH MAY BE A BETTER CHOICE FOR DM COMPLICATED WITH MAFLD OR ITS-ASSOCIATED SEVERE FORM AS METABOLIC ASSOCIATED STEATOHEPATITIS (MASH), ALTHOUGH THE ROLE OF SGLT-2 INHIBITORS IS ALSO IMPRESSIVE. THE PRESCRIPTION OF THESE TWO CLASSES OF ADA MAY SATISFY THE CONCEPT "TO DO ONE AND TO GET MORE", BASED ON SUCCESSFUL SUGAR-LOWERING EFFECT FOR CONTROLLING DM AND EXTRAGLYCEMIA BENEFITS OF HEPATOPROTECTIVE ACTIVITY IN DM PATIENTS. 2022 18 4055 30 MAPPING OF HISTONE MODIFICATIONS IN EPISOMAL HBV CCCDNA UNCOVERS AN UNUSUAL CHROMATIN ORGANIZATION AMENABLE TO EPIGENETIC MANIPULATION. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AFFECTS 240 MILLION PEOPLE WORLDWIDE AND IS A MAJOR RISK FACTOR FOR LIVER FAILURE AND HEPATOCELLULAR CARCINOMA. CURRENT ANTIVIRAL THERAPY INHIBITS CYTOPLASMIC HBV GENOMIC REPLICATION, BUT IS NOT CURATIVE BECAUSE IT DOES NOT DIRECTLY AFFECT NUCLEAR HBV CLOSED CIRCULAR DNA (CCCDNA), THE GENOMIC FORM THAT TEMPLATES VIRAL TRANSCRIPTION AND SUSTAINS VIRAL PERSISTENCE. NOVEL APPROACHES THAT DIRECTLY TARGET CCCDNA REGULATION WOULD THEREFORE BE HIGHLY DESIRABLE. CCCDNA IS ASSEMBLED WITH CELLULAR HISTONE PROTEINS INTO CHROMATIN, BUT LITTLE IS KNOWN ABOUT THE REGULATION OF HBV CHROMATIN BY HISTONE POSTTRANSLATIONAL MODIFICATIONS (PTMS). HERE, USING A NEW CCCDNA CHIP-SEQ APPROACH, WE REPORT, TO OUR KNOWLEDGE, THE FIRST GENOME-WIDE MAPS OF PTMS IN CCCDNA-CONTAINING CHROMATIN FROM DE NOVO INFECTED HEPG2 CELLS, PRIMARY HUMAN HEPATOCYTES, AND FROM HBV-INFECTED LIVER TISSUE. WE FIND HIGH LEVELS OF PTMS ASSOCIATED WITH ACTIVE TRANSCRIPTION ENRICHED AT SPECIFIC SITES WITHIN THE HBV GENOME AND, SURPRISINGLY, VERY LOW LEVELS OF PTMS LINKED TO TRANSCRIPTIONAL REPRESSION EVEN AT SILENT HBV PROMOTERS. WE SHOW THAT TRANSCRIPTION AND ACTIVE PTMS IN HBV CHROMATIN ARE REDUCED BY THE ACTIVATION OF AN INNATE IMMUNITY PATHWAY, AND THAT THIS EFFECT CAN BE RECAPITULATED WITH A SMALL MOLECULE EPIGENETIC MODIFYING AGENT, OPENING THE POSSIBILITY THAT CHROMATIN-BASED REGULATION OF CCCDNA TRANSCRIPTION COULD BE A NEW THERAPEUTIC APPROACH TO CHRONIC HBV INFECTION. 2015 19 3654 43 INDOXYL SULFATE ACCELERATES VASCULAR SMOOTH MUSCLE CELL CALCIFICATION VIA MICRORNA-29B DEPENDENT REGULATION OF WNT/BETA-CATENIN SIGNALING. VASCULAR CALCIFICATION (VC) IS A VERY COMMON PHENOMENON IN PATIENTS WITH CHRONIC KIDNEY DISEASE(CKD) AND IT INCREASES THE INCIDENCE OF CARDIOVASCULAR DISEASE AND LEADS TO HIGH MORTALITY IN CKD PATIENTS. IT HAS BEEN REPORTED THAT SOME MICRORNAS (MIRS) PLAY ROLES IN VASCULAR CALCIFICATION AS AN EPIGENETIC REGULATOR. INDOXYL SULFATE (IS) IS A PROTEIN-BOUND UREMIC TOXIN WHICH HAS BEEN PROVEN AS ONE OF THE MAJOR RISK FACTORS OF CARDIOVASCULAR DISEASE IN CKD. HERE WE INVESTIGATED WHETHER MICRORNA-29B (MIR-29B) IS INVOLVED IN IS-INDUCED VASCULAR CALCIFICATION. WE FOUND THAT VASCULAR MIR-29B WAS DOWN-REGULATED IN RADIAL ARTERIES OF PATIENTS WITH END-STAGE RENAL DISEASE. CONSISTENTLY, IS ALSO DECREASED MIR-29B EXPRESSION IN HUMAN AORTIC SMOOTH MUSCLE CELLS (HASMCS) AND POTENTIATED THEIR CALCIFICATION. MIR-29B MIMICS SIGNIFICANTLY SUPPRESSED, WHILE MIR-29B ANTI-MIR MARKEDLY ENHANCED, IS-INDUCED RUNT-RELATED TRANSCRIPTION FACTOR 2 AND OSTEOPONTIN EXPRESSION. THE EXPRESSION OF WNT7B/BETA-CATENIN IN RADIAL ARTERIES WAS HIGHER IN END STAGE RENAL DISEASE THAN IN CONTROL GROUP, AND IS INCREASED WNT7B/BETA-CATENIN EXPRESSION IN HASMCS AS EARLY AS 3DAYS AFTER STIMULATION. FURTHERMORE, MIR-29B MIMICS POTENTLY REPRESSED WNT7B/BETA-CATENIN PROTEIN EXPRESSION IN HASMCS, WHEREAS MIR-29B ANTI-MIR INCREASED THEIR EXPRESSION, INDICATING MIR-29B INDEED NEGATIVELY REGULATES WNT7B/BETA-CATENIN SIGNALING. DICKKOPF-1 PROTEIN, THE WNT/BETA-CATENIN SIGNALING INHIBITOR, SUPPRESSED ANTI-MIR-29B-ENHANCED HASMCS CALCIFICATION. OUR DATA THUS INDICATE THAT MIR-29B DOWNREGULATION AND WNT/BETA-CATENIN SIGNALING ACTIVATION MAY BE THE KEY MECHANISM OF IS INDUCED VASCULAR CALCIFICATION IN CHRONIC KIDNEY DISEASE. 2018 20 3467 25 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