1 4143 87 MECHANISMS OF SCARRING IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS. FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) PRESENTS WITH SCAR IN PARTS OF SOME GLOMERULI AND OFTEN PROGRESSES TO GLOBAL AND DIFFUSE GLOMERULOSCLEROSIS. PODOCYTE INJURY IS THE INITIAL TARGET IN PRIMARY FSGS, INDUCED BY A CIRCULATING FACTOR. SEVERAL GENE VARIANTS, FOR EXAMPLE, APOL1, ARE ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO FSGS. PRIMARY FSGS MAY BE DUE TO GENETIC MUTATION IN KEY PODOCYTE GENES. INCREASED WORK STRESS AFTER LOSS OF NEPHRONS, EPIGENETIC MECHANISMS, AND VARIOUS PROFIBROTIC PATHWAYS CAN CONTRIBUTE TO PROGRESSIVE SCLEROSIS, REGARDLESS OF THE INITIAL INJURY. THE PROGRESSION OF FSGS LESIONS ALSO INVOLVES CROSSTALK BETWEEN PODOCYTES AND OTHER KIDNEY CELLS, SUCH AS PARIETAL EPITHELIAL CELLS, GLOMERULAR ENDOTHELIAL CELLS, AND EVEN TUBULAR EPITHELIAL CELLS. NEW INSIGHTS RELATED TO THESE MECHANISMS COULD POTENTIALLY LEAD TO NEW THERAPEUTIC STRATEGIES TO PREVENT PROGRESSION OF FSGS. 2019 2 2818 16 FIBROSIS UNDER ARREST. APPROXIMATELY 5% OF PEOPLE THAT ARE HOSPITALIZED FOR ANY REASON DEVELOP ACUTE KIDNEY FAILURE, WHICH, IN SOME CASES, PROGRESSES TO A CHRONIC CONDITION RESULTING IN FIBROSIS OF THE KIDNEY AND PERMANENT CHANGES IN THE ORGAN'S FUNCTION. TWO NEW STUDIES SUGGEST THAT CELL CYCLE ARREST OF EPITHELIAL CELLS AND EPIGENETIC MODIFICATIONS HAVE KEY ROLES IN THE SWITCH TO CHRONIC DISEASE (PAGES 535-543 AND 544-550). 2010 3 4968 25 PATHOLOGICAL MECHANISMS AND THERAPEUTIC OUTLOOKS FOR ARTHROFIBROSIS. ARTHROFIBROSIS IS A FIBROTIC JOINT DISORDER THAT BEGINS WITH AN INFLAMMATORY REACTION TO INSULTS SUCH AS INJURY, SURGERY AND INFECTION. EXCESSIVE EXTRACELLULAR MATRIX AND ADHESIONS CONTRACT POUCHES, BURSAE AND TENDONS, CAUSE PAIN AND PREVENT A NORMAL RANGE OF JOINT MOTION, WITH DEVASTATING CONSEQUENCES FOR PATIENT QUALITY OF LIFE. ARTHROFIBROSIS AFFECTS PEOPLE OF ALL AGES, WITH PUBLISHED RATES VARYING. THE RISK FACTORS AND BEST MANAGEMENT STRATEGIES ARE LARGELY UNKNOWN DUE TO A POOR UNDERSTANDING OF THE PATHOLOGY AND LACK OF DIAGNOSTIC BIOMARKERS. HOWEVER, CURRENT RESEARCH INTO THE PATHOGENESIS OF FIBROSIS IN ORGANS NOW INFORMS THE UNDERSTANDING OF ARTHROFIBROSIS. THE PROCESS BEGINS WHEN STRESS SIGNALS STIMULATE IMMUNE CELLS. THE RESULTING CASCADE OF CYTOKINES AND MEDIATORS DRIVES FIBROBLASTS TO DIFFERENTIATE INTO MYOFIBROBLASTS, WHICH SECRETE FIBRILLAR COLLAGENS AND TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA). POSITIVE FEEDBACK NETWORKS THEN DYSREGULATE PROCESSES THAT NORMALLY TERMINATE HEALING PROCESSES. WE PROPOSE TWO SUBTYPES OF ARTHROFIBROSIS OCCUR: ACTIVE ARTHROFIBROSIS AND RESIDUAL ARTHROFIBROSIS. IN THE LATTER THE FIBROGENIC PROCESSES HAVE RESOLVED BUT THE JOINT REMAINS STIFF. THE BEST THERAPEUTIC APPROACH FOR EACH SUBTYPE MAY DIFFER SIGNIFICANTLY. TREATMENT TYPICALLY INVOLVES SURGERY, HOWEVER, A PHARMACOLOGICAL APPROACH TO CORRECT DYSREGULATED CELL SIGNALLING COULD BE MORE EFFECTIVE. RECENT RESEARCH SHOWS THAT MYOFIBROBLASTS ARE CAPABLE OF REVERSING DIFFERENTIATION, AND UNDERSTANDING THE MECHANISMS OF PATHOGENESIS AND RESOLUTION WILL BE ESSENTIAL FOR THE DEVELOPMENT OF CELL-BASED TREATMENTS. THERAPIES WITH SIGNIFICANT PROMISE ARE CURRENTLY AVAILABLE, WITH MORE IN DEVELOPMENT, INCLUDING THOSE THAT INHIBIT TGF-BETA SIGNALLING AND EPIGENETIC MODIFICATIONS. THIS REVIEW FOCUSES ON PATHOGENESIS OF STERILE ARTHROFIBROSIS AND THERAPEUTIC TREATMENTS. 2019 4 4665 26 NEW INSIGHTS AND ADVANCES IN PATHOGENESIS AND TREATMENT OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE. VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE (VEO-IBD) IS CHARACTERIZED BY MULTIFACTORIAL CHRONIC RECURRENT INTESTINAL INFLAMMATION. COMPARED WITH ELDERLY PATIENTS, THOSE WITH VEO-IBD HAVE A MORE SERIOUS CONDITION, NOT RESPONSIVE TO CONVENTIONAL TREATMENTS, WITH A POOR PROGNOSIS. RECENT STUDIES FOUND THAT GENETIC AND IMMUNOLOGIC ABNORMALITIES ARE CLOSELY RELATED TO VEO-IBD. INTESTINAL IMMUNE HOMEOSTASIS MONOGENIC DEFECTS (IIHMDS) ARE CHANGED THROUGH VARIOUS MECHANISMS. RECENT STUDIES HAVE ALSO REVEALED THAT ABNORMALITIES IN GENES AND IMMUNE MOLECULAR MECHANISMS ARE CLOSELY RELATED TO VEO-IBD. IIHMDS CHANGE THROUGH VARIOUS MECHANISMS. EPIGENETIC FACTORS CAN MEDIATE THE INTERACTION BETWEEN THE ENVIRONMENT AND GENOME, AND GENETIC FACTORS AND IMMUNE MOLECULES MAY BE INVOLVED IN THE PATHOGENESIS OF THE ENVIRONMENT AND GUT MICROBIOTA. THESE DISCOVERIES WILL PROVIDE NEW DIRECTIONS AND IDEAS FOR THE TREATMENT OF VEO-IBD. 2022 5 5153 19 PPP2R2B HYPERMETHYLATION CAUSES ACQUIRED APOPTOSIS DEFICIENCY IN SYSTEMIC AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION CAUSES TARGET ORGAN DAMAGE IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES. THE FACTORS THAT ALLOW THIS PROTRACTED RESPONSE ARE POORLY UNDERSTOOD. WE ANALYZED THE TRANSCRIPTIONAL REGULATION OF PPP2R2B (B55SS), A MOLECULE NECESSARY FOR THE TERMINATION OF THE IMMUNE RESPONSE, IN PATIENTS WITH AUTOIMMUNE DISEASES. ALTERED EXPRESSION OF B55SS CONDITIONED RESISTANCE TO CYTOKINE WITHDRAWAL-INDUCED DEATH (CWID) IN PATIENTS WITH AUTOIMMUNE DISEASES. THE IMPAIRED UPREGULATION OF B55SS WAS CAUSED BY INFLAMMATION-DRIVEN HYPERMETHYLATION OF SPECIFIC CYTOSINES LOCATED WITHIN A REGULATORY ELEMENT OF PPP2R2B PREVENTING CTCF BINDING. THIS PHENOTYPE COULD BE INDUCED IN HEALTHY T CELLS BY EXPOSURE TO TNF-ALPHA. OUR RESULTS REVEAL A GENE WHOSE EXPRESSION IS AFFECTED BY AN ACQUIRED DEFECT, THROUGH AN EPIGENETIC MECHANISM, IN THE SETTING OF SYSTEMIC AUTOIMMUNITY. BECAUSE FAILURE TO REMOVE ACTIVATED T CELLS THROUGH CWID COULD CONTRIBUTE TO AUTOIMMUNE PATHOLOGY, THIS MECHANISM ILLUSTRATES A VICIOUS CYCLE THROUGH WHICH AUTOIMMUNE INFLAMMATION CONTRIBUTES TO ITS OWN PERPETUATION. 2019 6 3933 25 LIVER SINUSOIDAL ENDOTHELIAL CELLS ARE IMPLICATED IN MULTIPLE FIBROTIC MECHANISMS. CHRONIC LIVER DISEASES ARE ATTRIBUTED TO LIVER INJURY. DEVELOPMENT OF FIBROSIS FROM CHRONIC LIVER DISEASES IS A DYNAMIC PROCESS THAT INVOLVES MULTIPLE MOLECULAR AND CELLULAR PROCESSES. AS THE FIRST TO BE IMPACTED BY INJURY, LIVER SINUSOIDAL ENDOTHELIAL CELLS (LSECS) ARE INVOLVED IN THE PATHOGENESIS OF LIVER DISEASES CAUSED BY A VARIETY OF ETIOLOGIES. MOREOVER, CAPILLARIZATION OF LSECS HAS BEEN RECOGNIZED AS AN IMPORTANT EVENT IN THE DEVELOPMENT OF CHRONIC LIVER DISEASES AND FIBROSIS. STUDIES HAVE REPORTED THAT VARIOUS CYTOKINES (SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR, TRANSFORMING GROWTH FACTOR-BETA), AND PATHWAYS (SUCH AS HEDGEHOG, AND NOTCH), AS WELL AS EPIGENETIC AND METABOLIC FACTORS ARE INVOLVED IN THE DEVELOPMENT OF LSEC-MEDIATED LIVER FIBROSIS. THIS REVIEW DESCRIBES THE COMPLEXITY AND PLASTICITY OF LSECS IN FIBROTIC LIVER DISEASES FROM SEVERAL PERSPECTIVES, INCLUDING THE CROSS-TALK BETWEEN LSECS AND OTHER INTRA-HEPATIC CELLS. MOREOVER, IT SUMMARIZES THE MECHANISMS OF SEVERAL KINDS OF LSECS-TARGETING ANTI-FIBROSIS CHEMICALS, AND PROVIDES A THEORETICAL BASIS FOR FUTURE STUDIES. 2021 7 669 23 BONE MARROW STROMAL CELL ANTIGEN-1 (CD157) REGULATED BY SPHINGOSINE KINASE 2 MEDIATES KIDNEY FIBROSIS. CHRONIC KIDNEY DISEASE IS A PROGRESSIVE DISEASE THAT MAY LEAD TO END-STAGE RENAL DISEASE. INTERSTITIAL FIBROSIS DEVELOPS AS THE DISEASE PROGRESSES. THERAPIES THAT FOCUS ON FIBROSIS TO DELAY OR REVERSE PROGRESSIVE RENAL FAILURE ARE LIMITED. WE AND OTHERS SHOWED THAT SPHINGOSINE KINASE 2-DEFICIENT MICE (SPHK2 (-/-)) DEVELOP LESS FIBROSIS IN MOUSE MODELS OF KIDNEY FIBROSIS. SPHINGOSINE KINASE2 (SPHK2), ONE OF TWO SPHINGOSINE KINASES THAT PRODUCE SPHINGOSINE 1-PHOSPHATE (S1P), IS PRIMARILY LOCATED IN THE NUCLEUS. S1P PRODUCED BY SPHK2 INHIBITS HISTONE DEACETYLASE (HDAC) AND CHANGES HISTONE ACETYLATION STATUS, WHICH CAN LEAD TO ALTERED TARGET GENE EXPRESSION. WE HYPOTHESIZED THAT SPHK2 EPIGENETICALLY REGULATES DOWNSTREAM GENES TO INDUCE FIBROSIS, AND WE PERFORMED A COMPREHENSIVE ANALYSIS USING THE COMBINATION OF RNA-SEQ AND CHIP-SEQ. BST1/CD157 WAS IDENTIFIED AS A GENE THAT IS REGULATED BY SPHK2 THROUGH A CHANGE IN HISTONE ACETYLATION LEVEL, AND BST1 (-/-) MICE WERE FOUND TO DEVELOP LESS RENAL FIBROSIS AFTER UNILATERAL ISCHEMIA-REPERFUSION INJURY, A MOUSE MODEL OF KIDNEY FIBROSIS. ALTHOUGH BST1 IS A CELL-SURFACE MOLECULE THAT HAS A WIDE VARIETY OF FUNCTIONS THROUGH ITS VARIED ENZYMATIC ACTIVITIES AND DOWNSTREAM INTRACELLULAR SIGNALING PATHWAYS, NO STUDIES ON THE ROLE OF BST1 IN KIDNEY DISEASES HAVE BEEN REPORTED PREVIOUSLY. IN THE CURRENT STUDY, WE DEMONSTRATED THAT BST1 IS A GENE THAT IS REGULATED BY SPHK2 THROUGH EPIGENETIC CHANGE AND IS CRITICAL IN KIDNEY FIBROSIS. 2022 8 5433 24 REL/NF-KAPPA B/I KAPPA B SIGNAL TRANSDUCTION IN THE GENERATION AND TREATMENT OF HUMAN CANCER. THE REL/NF-KAPPA B FAMILY IS A GROUP OF STRUCTURALLY-RELATED, TIGHTLY-REGULATED TRANSCRIPTION FACTORS THAT CONTROL THE EXPRESSION OF A MULTITUDE OF GENES INVOLVED IN KEY CELLULAR AND ORGANISMAL PROCESSES. THE REL/NF-KAPPA B SIGNAL TRANSDUCTION PATHWAY IS MISREGULATED IN A VARIETY OF HUMAN CANCERS, ESPECIALLY ONES OF LYMPHOID CELL ORIGIN, DUE EITHER TO GENETIC CHANGES (SUCH AS CHROMOSOMAL REARRANGEMENTS, AMPLIFICATIONS, AND MUTATIONS) OR TO CHRONIC ACTIVATION OF THE PATHWAY BY EPIGENETIC MECHANISMS. CONSTITUTIVE ACTIVATION OF THE REL/NF-KAPPA B PATHWAY CAN CONTRIBUTE TO THE ONCOGENIC STATE IN SEVERAL WAYS, FOR EXAMPLE, BY DRIVING PROLIFERATION, BY ENHANCING CELL SURVIVAL, OR BY PROMOTING ANGIOGENESIS OR METASTASIS. IN MANY CASES, INHIBITION OF REL/NF-KAPPA B ACTIVITY REVERSES ALL OR PART OF THE MALIGNANT STATE. THUS, THE REL/NF-KAPPA B PATHWAY HAS RECEIVED MUCH ATTENTION AS A FOCAL POINT FOR CLINICAL INTERVENTION. 2002 9 6230 23 THE LONG NONCODING RNA LANDSCAPE IN HYPOXIC AND INFLAMMATORY RENAL EPITHELIAL INJURY. LONG NONCODING RNAS (LNCRNAS) ARE EMERGING AS KEY SPECIES-SPECIFIC REGULATORS OF CELLULAR AND DISEASE PROCESSES. TO IDENTIFY POTENTIAL LNCRNAS RELEVANT TO ACUTE AND CHRONIC RENAL EPITHELIAL INJURY, WE PERFORMED UNBIASED WHOLE TRANSCRIPTOME PROFILING OF HUMAN PROXIMAL TUBULAR EPITHELIAL CELLS (PTECS) IN HYPOXIC AND INFLAMMATORY CONDITIONS. RNA SEQUENCING REVEALED THAT THE PROTEIN-CODING AND NONCODING TRANSCRIPTOMIC LANDSCAPE DIFFERED BETWEEN HYPOXIA-STIMULATED AND CYTOKINE-STIMULATED HUMAN PTECS. HYPOXIA- AND INFLAMMATION-MODULATED LNCRNAS WERE PRIORITIZED FOR FOCUSED FOLLOWUP ACCORDING TO THEIR DEGREE OF INDUCTION BY THESE STRESS STIMULI, THEIR EXPRESSION IN HUMAN KIDNEY TISSUE, AND WHETHER EXPOSURE OF HUMAN PTECS TO PLASMA OF CRITICALLY ILL SEPSIS PATIENTS WITH ACUTE KIDNEY INJURY MODULATED THEIR EXPRESSION. FOR THREE LNCRNAS (MIR210HG, LINC-ATP13A4-8, AND LINC-KIAA1737-2) THAT FULFILLED OUR CRITERIA, WE VALIDATED THEIR EXPRESSION PATTERNS, EXAMINED THEIR LOCI FOR CONSERVATION AND SYNTENY, AND DEFINED THEIR ASSOCIATED EPIGENETIC MARKS. THE LNCRNA LANDSCAPE CHARACTERIZED HERE PROVIDES INSIGHTS INTO NOVEL TRANSCRIPTOMIC VARIATIONS IN THE RENAL EPITHELIAL CELL RESPONSE TO HYPOXIC AND INFLAMMATORY STRESS. 2015 10 3327 21 HISTONE DEACETYLASE 4 PROMOTES CHOLESTATIC LIVER INJURY IN THE ABSENCE OF PROHIBITIN-1. PROHIBITIN-1 (PHB1) IS AN EVOLUTIONARILY CONSERVED PLEIOTROPIC PROTEIN THAT PARTICIPATES IN DIVERSE PROCESSES DEPENDING ON ITS SUBCELLULAR LOCALIZATION AND INTERACTOME. RECENT DATA HAVE INDICATED A DIVERSE ROLE FOR PHB1 IN THE PATHOGENESIS OF OBESITY, CANCER, AND INFLAMMATORY BOWEL DISEASE, AMONG OTHERS. DATA PRESENTED HERE SUGGEST THAT PHB1 IS ALSO LINKED TO CHOLESTATIC LIVER DISEASE. EXPRESSION OF PHB1 IS MARKEDLY REDUCED IN PATIENTS WITH PRIMARY BILIARY CIRRHOSIS AND BILIARY ATRESIA OR WITH ALAGILLE SYNDROME, TWO MAJOR PEDIATRIC CHOLESTATIC CONDITIONS. IN THE EXPERIMENTAL MODEL OF BILE DUCT LIGATION, SILENCING OF PHB1 INDUCED LIVER FIBROSIS, REDUCED ANIMAL SURVIVAL, AND INDUCED BILE DUCT PROLIFERATION. IMPORTANTLY, THE MODULATORY EFFECT OF PHB1 IS NOT DEPENDENT ON ITS KNOWN MITOCHONDRIAL FUNCTION. ALSO, PHB1 INTERACTS WITH HISTONE DEACETYLASE 4 (HDAC4) IN THE PRESENCE OF BILE ACIDS. HENCE, PHB1 DEPLETION LEADS TO INCREASED NUCLEAR HDAC4 CONTENT AND ITS ASSOCIATED EPIGENETIC CHANGES. REMARKABLY, HDAC4 SILENCING AND THE ADMINISTRATION OF THE HDAC INHIBITOR PARTHENOLIDE DURING OBSTRUCTIVE CHOLESTASIS IN VIVO PROMOTE GENOMIC REPROGRAMMING, LEADING TO REGRESSION OF THE FIBROTIC PHENOTYPE IN LIVER-SPECIFIC PHB1 KNOCKOUT MICE. CONCLUSION: PHB1 IS AN IMPORTANT MEDIATOR OF CHOLESTATIC LIVER INJURY THAT REGULATES THE ACTIVITY OF HDAC4, WHICH CONTROLS SPECIFIC EPIGENETIC MARKERS; THESE RESULTS IDENTIFY POTENTIAL NOVEL STRATEGIES TO TREAT LIVER INJURY AND FIBROSIS, PARTICULARLY AS A CONSEQUENCE OF CHRONIC CHOLESTASIS. 2015 11 2568 18 EPIGENETICS OF ALCOHOL-RELATED LIVER DISEASES. ALCOHOL-RELATED LIVER DISEASE (ARLD) IS A PRIMARY CAUSE OF CHRONIC LIVER DISEASE IN THE UNITED STATES. DESPITE ADVANCES IN THE DIAGNOSIS AND MANAGEMENT OF ARLD, IT REMAINS A MAJOR PUBLIC HEALTH PROBLEM ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY, EMPHASISING THE NEED TO ADOPT NOVEL APPROACHES TO THE STUDY OF ARLD AND ITS COMPLICATIONS. EPIGENETIC CHANGES ARE INCREASINGLY BEING RECOGNISED AS CONTRIBUTING TO THE PATHOGENESIS OF MULTIPLE DISEASE STATES. HARNESSING THE POWER OF INNOVATIVE TECHNOLOGIES FOR THE STUDY OF EPIGENETICS (E.G., NEXT-GENERATION SEQUENCING, DNA METHYLATION ASSAYS, HISTONE MODIFICATION PROFILING AND COMPUTATIONAL TECHNIQUES LIKE MACHINE LEARNING) HAS RESULTED IN A SEISMIC SHIFT IN OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF ARLD. KNOWLEDGE OF THESE TECHNIQUES AND ADVANCES IS OF PARAMOUNT IMPORTANCE FOR THE PRACTICING HEPATOLOGIST AND RESEARCHERS ALIKE. ACCORDINGLY, IN THIS REVIEW ARTICLE WE WILL SUMMARISE THE CURRENT KNOWLEDGE ABOUT ALCOHOL-INDUCED EPIGENETIC ALTERATIONS IN THE CONTEXT OF ARLD, INCLUDING BUT NOT LIMITED TO, DNA HYPER/HYPO METHYLATION, HISTONE MODIFICATIONS, CHANGES IN NON-CODING RNA, 3D CHROMATIN ARCHITECTURE AND ENHANCER-PROMOTER INTERACTIONS. ADDITIONALLY, WE WILL DISCUSS THE STATE-OF-THE-ART TECHNIQUES USED IN THE STUDY OF ARLD (E.G. SINGLE-CELL SEQUENCING). WE WILL ALSO HIGHLIGHT THE EPIGENETIC REGULATION OF CHEMOKINES AND THEIR PROINFLAMMATORY ROLE IN THE CONTEXT OF ARLD. LASTLY, WE WILL EXAMINE THE CLINICAL APPLICATIONS OF EPIGENETICS IN THE DIAGNOSIS AND MANAGEMENT OF ARLD. 2022 12 3899 19 LATE NEUROLOGICAL CONSEQUENCES OF ZIKA VIRUS INFECTION: RISK FACTORS AND PHARMACEUTICAL APPROACHES. ZIKA VIRUS (ZIKV) INFECTION WAS HISTORICALLY CONSIDERED A DISEASE WITH MILD SYMPTOMS AND NO MAJOR CONSEQUENCES TO HUMAN HEALTH. HOWEVER, SEVERAL LONG-TERM, LATE ONSET, AND CHRONIC NEUROLOGICAL COMPLICATIONS, BOTH IN CONGENITALLY-EXPOSED BABIES AND IN ADULT PATIENTS, HAVE BEEN REPORTED AFTER ZIKV INFECTION, ESPECIALLY AFTER THE 2015 EPIDEMICS IN THE AMERICAN CONTINENT. THE DEVELOPMENT OR SEVERITY OF THESE CONDITIONS CANNOT BE FULLY PREDICTED, BUT IT IS POSSIBLE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO DETERMINE ZIKV INFECTION OUTCOMES. THIS REINFORCES THE IMPORTANCE THAT INDIVIDUALS EXPOSED TO ZIKV ARE SUBMITTED TO LONG-TERM CLINICAL SURVEILLANCE AND HIGHLIGHTS THE URGENT NEED FOR THE DEVELOPMENT OF THERAPEUTIC APPROACHES TO REDUCE OR ELIMINATE THE NEUROLOGICAL BURDEN OF INFECTION. HERE, WE REVIEW THE EPIDEMIOLOGY OF ZIKV-ASSOCIATED NEUROLOGICAL COMPLICATIONS AND THE ROLE OF FACTORS THAT MAY INFLUENCE DISEASE OUTCOME. MOREOVER, WE DISCUSS EXPERIMENTAL AND CLINICAL EVIDENCE OF DRUGS THAT HAVE SHOWN PROMISING RESULTS IN VITRO OR IN VITRO AGAINST VIRAL REPLICATION AND AND/OR ZIKV-INDUCED NEUROTOXICITY. 2019 13 3152 28 GLUCOSE VARIABILITY: HOW DOES IT WORK? A GROWING BODY OF EVIDENCE POINTS TO THE ROLE OF GLUCOSE VARIABILITY (GV) IN THE DEVELOPMENT OF THE MICROVASCULAR AND MACROVASCULAR COMPLICATIONS OF DIABETES. IN THIS REVIEW, WE SUMMARIZE DATA ON GV-INDUCED BIOCHEMICAL, CELLULAR AND MOLECULAR EVENTS INVOLVED IN THE PATHOGENESIS OF DIABETIC COMPLICATIONS. CURRENT DATA INDICATE THAT THE DETERIORATING EFFECT OF GV ON TARGET ORGANS CAN BE REALIZED THROUGH OXIDATIVE STRESS, GLYCATION, CHRONIC LOW-GRADE INFLAMMATION, ENDOTHELIAL DYSFUNCTION, PLATELET ACTIVATION, IMPAIRED ANGIOGENESIS AND RENAL FIBROSIS. THE EFFECTS OF GV ON OXIDATIVE STRESS, INFLAMMATION, ENDOTHELIAL DYSFUNCTION AND HYPERCOAGULABILITY COULD BE AGGRAVATED BY HYPOGLYCEMIA, ASSOCIATED WITH HIGH GV. OSCILLATING HYPERGLYCEMIA CONTRIBUTES TO BETA CELL DYSFUNCTION, WHICH LEADS TO A FURTHER INCREASE IN GV AND COMPLETES THE VICIOUS CIRCLE. IN CELLS, THE GV-INDUCED CYTOTOXIC EFFECT INCLUDES MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS AND DISTURBANCES IN AUTOPHAGIC FLUX, WHICH ARE ACCOMPANIED BY REDUCED VIABILITY, ACTIVATION OF APOPTOSIS AND ABNORMALITIES IN CELL PROLIFERATION. THESE EFFECTS ARE REALIZED THROUGH THE UP- AND DOWN-REGULATION OF A LARGE NUMBER OF GENES AND THE ACTIVITY OF SIGNALING PATHWAYS SUCH AS PI3K/AKT, NF-KAPPAB, MAPK (ERK), JNK AND TGF-BETA/SMAD. EPIGENETIC MODIFICATIONS MEDIATE THE POSTPONED EFFECTS OF GLUCOSE FLUCTUATIONS. THE MULTIPLE DETERIORATIVE EFFECTS OF GV PROVIDE FURTHER SUPPORT FOR CONSIDERING IT AS A THERAPEUTIC TARGET IN DIABETES. 2021 14 6584 25 TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 : OUR NEW PARTNER IN HUMAN ONCOLOGY? INFLAMMATION IS RECOGNIZED AS ONE OF THE HALLMARKS OF CANCER. INDEED, STRONG EVIDENCE INDICATES THAT CHRONIC INFLAMMATION PLAYS A MAJOR ROLE IN ONCOGENESIS, PROMOTING GENOME INSTABILITY, EPIGENETIC ALTERATIONS, PROLIFERATION AND DISSEMINATION OF CANCER CELLS. MONONUCLEAR PHAGOCYTES (MPS) HAVE BEEN IDENTIFIED AS KEY CONTRIBUTORS OF THE INFLAMMATORY INFILTRATE IN SEVERAL SOLID HUMAN NEOPLASIA, PROMOTING ANGIOGENESIS AND CANCER PROGRESSION. ONE OF THE MOST DESCRIBED AMPLIFIERS OF MPS PRO-INFLAMMATORY INNATE IMMUNE RESPONSE IS THE TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 (TREM-1). GROWING EVIDENCE SUGGESTS TREM-1 INVOLVEMENT IN ONCOGENESIS THROUGH CANCER RELATED INFLAMMATION AND THE SURROUNDING TUMOR MICROENVIRONMENT. IN HUMAN ONCOLOGY, HIGH LEVELS OF TREM-1 AND/OR ITS SOLUBLE FORM HAVE BEEN ASSOCIATED WITH POORER SURVIVAL DATA IN SEVERAL SOLID MALIGNANCIES, ESPECIALLY IN HEPATOCELLULAR CARCINOMA AND LUNG CANCER. TREM-1 SHOULD BE CONSIDERED AS A POTENTIAL BIOMARKER IN HUMAN ONCOLOGY AND COULD BE USED AS A NEW THERAPEUTIC TARGET OF INTEREST IN HUMAN ONCOLOGY (TREM-1 INHIBITORS, TREM-1 AGONISTS). MORE CLINICAL STUDIES ARE URGENTLY NEEDED TO CONFIRM TREM-1 (AND TREM FAMILY) ROLES IN THE PROGNOSIS AND THE TREATMENT OF HUMAN SOLID CANCERS. 2022 15 3762 26 INTEGRATING THE TUMOR-SUPPRESSIVE ACTIVITY OF MASPIN WITH P53 IN RETUNING THE EPITHELIAL HOMEOSTASIS: A WORKING HYPOTHESIS AND APPLICABLE PROSPECTS. EPITHELIAL MALIGNANT TRANSFORMATION AND TUMOROUS DEVELOPMENT WERE BELIEVED TO BE CLOSELY ASSOCIATED WITH THE LOSS OF ITS MICROENVIRONMENT INTEGRITY AND HOMEOSTASIS. THE TUMOR-SUPPRESSIVE MOLECULES MASPIN AND P53 WERE DEMONSTRATED TO PLAY A CRUCIAL ROLE IN BODY EPITHELIAL AND IMMUNE HOMEOSTASIS. DOWNREGULATION OF MASPIN AND MUTATION OF P53 WERE FREQUENTLY ASSOCIATED WITH MALIGNANT TRANSFORMATION AND POOR PROGNOSIS IN VARIOUS HUMAN CANCERS. IN THIS REVIEW, WE FOCUSED ON SUMMARIZING THE PROGRESS OF THE MOLECULAR NETWORK OF MASPIN IN STUDYING EPITHELIAL TUMOROUS DEVELOPMENT AND ITS RESPONSE TO CLINIC TREATMENT AND TRY TO CLARIFY THE UNDERLYING ANTITUMOR MECHANISM. NOTABLY, MASPIN EXPRESSION WAS REPORTED TO BE TRANSCRIPTIONALLY ACTIVATED BY P53, AND THE TRANSCRIPTIONAL ACTIVITY OF P53 WAS DEMONSTRATED TO BE ENHANCED BY ITS ACETYLATION THROUGH INHIBITION OF HDAC1. AS AN ENDOGENOUS INHIBITOR OF HDAC1, MASPIN POSSIBLY POTENTIATES THE TRANSCRIPTIONAL ACTIVITY OF P53 BY ACETYLATING THE P53 PROTEIN. HEREBY, IT COULD FORM A "SELF-PROPELLING" ANTITUMOR MECHANISM. THUS, WE SUMMARIZED THAT, UPON STIMULATION OF CELLULAR STRESS AND BY INTEGRATING WITH P53, THE AROUSED MASPIN PLAYED THE EPIGENETIC SURVEILLANT ROLE TO PREVENT THE EPITHELIAL DIGRESSIONAL PROCESS AND RETUNE THE EPITHELIAL HOMEOSTASIS, WHICH IS INVOLVED IN ACTIVATING HOST IMMUNE SURVEILLANCE, REGULATING THE INFLAMMATORY FACTORS, AND FINE-TUNING ITS ASSOCIATED CELL SIGNALING PATHWAYS. CONSEQUENTIALLY, IN A NORMAL PHYSIOLOGICAL CONDITION, ACTIVATION OF THE ABOVE "SELF-PROPELLING" ANTITUMOR MECHANISM OF MASPIN AND P53 COULD REDUCE CELLULAR STRESS (E.G., CHRONIC INFECTION/INFLAMMATION, OXIDATIVE STRESS, TRANSFORMATION) EFFECTIVELY AND ACHIEVE CANCER PREVENTION. MEANWHILE, DESIGNING A STRATEGY OF MIMICKING MASPIN'S EPIGENETIC REGULATION ACTIVITY WITH INTEGRATING P53 TUMOR-SUPPRESSIVE ACTIVITY COULD ENHANCE THE CHEMOTHERAPY EFFICACY THEORETICALLY IN A PATHOLOGICAL CONDITION OF CANCER. 2022 16 4002 23 LOSS OF P120 CATENIN AND LINKS TO MITOTIC ALTERATIONS, INFLAMMATION, AND SKIN CANCER. TUMOR FORMATION INVOLVES EPIGENETIC MODIFICATIONS AND MICROENVIRONMENTAL CHANGES AS WELL AS CUMULATIVE GENETIC ALTERATIONS ENCOMPASSING SOMATIC MUTATIONS, LOSS OF HETEROZYGOSITY, AND ANEUPLOIDY. HERE, WE SHOW THAT CONDITIONAL TARGETING OF P120 CATENIN IN MICE LEADS TO PROGRESSIVE DEVELOPMENT OF SKIN NEOPLASIAS ASSOCIATED WITH INTRINSIC NF-KAPPAB ACTIVATION. WE FIND THAT, SIMILARLY, SQUAMOUS CELL CARCINOMAS IN HUMANS DISPLAY ALTERED P120 AND ACTIVATED NF-KAPPAB. WE SHOW THAT EPIDERMAL HYPERPROLIFERATION ARISING FROM P120 LOSS CAN BE ABROGATED BY IKAPPAB KINASE 2 INHIBITORS. ALTHOUGH THIS UNDERSCORES THE IMPORTANCE OF THIS PATHWAY, THE ROLE OF NF-KAPPAB IN HYPERPROLIFERATION APPEARS ROOTED IN ITS IMPACT ON EPIDERMAL MICROENVIRONMENT BECAUSE AS P120-NULL KERATINOCYTES DISPLAY A GROWTH-ARRESTED PHENOTYPE IN CULTURE. WE TRACE THIS TO A MITOTIC DEFECT, RESULTING IN UNSTABLE, BINUCLEATED CELLS IN VITRO AND IN VIVO. WE SHOW THAT THE ABNORMAL MITOSES CAN BE AMELIORATED BY INHIBITING RHOA, THE ACTIVITY OF WHICH IS ABNORMALLY HIGH. CONVERSELY, WE CAN ELICIT SUCH MITOTIC DEFECTS IN CONTROL KERATINOCYTES BY ELEVATING RHOA ACTIVITY. THE ABILITY OF P120 DEFICIENCY TO ELICIT MITOTIC ALTERATIONS AND CHRONIC INFLAMMATORY RESPONSES, THAT TOGETHER MAY FACILITATE THE DEVELOPMENT OF GENETIC INSTABILITY IN VIVO, PROVIDES INSIGHTS INTO WHY IT FIGURES SO PROMINENTLY IN SKIN CANCER PROGRESSION. 2008 17 2373 26 EPIGENETIC REGULATION OF THE N-TERMINAL TRUNCATED ISOFORM OF MATRIX METALLOPROTEINASE-2 (NTT-MMP-2) AND ITS PRESENCE IN RENAL AND CARDIAC DISEASES. SEVERAL CLINICAL AND EXPERIMENTAL STUDIES HAVE DOCUMENTED A COMPELLING AND CRITICAL ROLE FOR THE FULL-LENGTH MATRIX METALLOPROTEINASE-2 (FL-MMP-2) IN ISCHEMIC RENAL INJURY, PROGRESSIVE RENAL FIBROSIS, AND DIABETIC NEPHROPATHY. A NOVEL N-TERMINAL TRUNCATED ISOFORM OF MMP-2 (NTT-MMP-2) WAS RECENTLY DISCOVERED, WHICH IS INDUCED BY HYPOXIA AND OXIDATIVE STRESS BY THE ACTIVATION OF A LATENT PROMOTER LOCATED IN THE FIRST INTRON OF THE MMP2 GENE. THIS NTT-MMP-2 ISOFORM IS ENZYMATICALLY ACTIVE BUT REMAINS INTRACELLULAR IN OR NEAR THE MITOCHONDRIA. IN THIS PERSPECTIVE ARTICLE, WE FIRST PRESENT THE FINDINGS ABOUT THE DISCOVERY OF THE NTT-MMP-2 ISOFORM, AND ITS FUNCTIONAL AND STRUCTURAL DIFFERENCES AS COMPARED WITH THE FL-MMP-2 ISOFORM. BASED ON PUBLICLY AVAILABLE EPIGENOMICS DATA FROM THE ENCYCLOPEDIA OF DNA ELEMENTS (ENCODE) PROJECT, WE PROVIDE INSIGHTS INTO THE EPIGENETIC REGULATION OF THE LATENT PROMOTER LOCATED IN THE FIRST INTRON OF THE MMP2 GENE, WHICH SUPPORT THE ACTIVATION OF THE NTT-MMP-2 ISOFORM. WE THEN FOCUS ON ITS FUNCTIONAL ASSESSMENT BY COVERING THE ALTERATIONS FOUND IN THE KIDNEY OF TRANSGENIC MICE EXPRESSING THE NTT-MMP-2 ISOFORM. NEXT, WE HIGHLIGHT RECENT FINDINGS REGARDING THE PRESENCE OF THE NTT-MMP-2 ISOFORM IN RENAL DYSFUNCTION, IN KIDNEY AND CARDIAC DISEASES, INCLUDING DAMAGE OBSERVED IN AGING, ACUTE ISCHEMIA-REPERFUSION INJURY (IRI), CHRONIC KIDNEY DISEASE, DIABETIC NEPHROPATHY, AND HUMAN RENAL TRANSPLANTS WITH DELAYED GRAFT FUNCTION. FINALLY, WE BRIEFLY DISCUSS HOW OUR INSIGHTS MAY GUIDE FURTHER EXPERIMENTAL AND CLINICAL STUDIES THAT ARE NEEDED TO ELUCIDATE THE UNDERLYING MECHANISMS AND THE ROLE OF THE NTT-MMP-2 ISOFORM IN RENAL DYSFUNCTION, WHICH MAY HELP TO ESTABLISH IT AS A POTENTIAL THERAPEUTIC TARGET IN KIDNEY DISEASES. 2021 18 1728 28 DYSREGULATION OF MICRORNAS IN HYPERTROPHY AND OSSIFICATION OF LIGAMENTUM FLAVUM: NEW ADVANCES, CHALLENGES, AND POTENTIAL DIRECTIONS. PATHOLOGICAL CHANGES IN THE LIGAMENTUM FLAVUM (LF) CAN BE DEFINED AS A PROCESS OF CHRONIC PROGRESSIVE ABERRATIONS IN THE NATURE AND STRUCTURE OF LIGAMENTOUS TISSUES CHARACTERIZED BY INCREASED THICKNESS, REDUCED ELASTICITY, LOCAL CALCIFICATION, OR AGGRAVATED OSSIFICATION, WHICH MAY CAUSE SEVERE MYELOPATHY, RADICULOPATHY, OR BOTH. HYPERTROPHY OF LIGAMENTUM FLAVUM (HLF) AND OSSIFICATION OF LIGAMENTUM FLAVUM (OLF) ARE CLINICALLY COMMON ENTITIES. THOUGH ACCUMULATED EVIDENCE HAS INDICATED BOTH GENETIC AND ENVIRONMENTAL FACTORS COULD CONTRIBUTE TO THE INITIATION AND PROGRESSION OF HLF/OLF, THE DEFINITE PATHOGENESIS REMAINS FULLY UNCLEAR. MICRORNAS (MIRNAS), ONE OF THE IMPORTANT EPIGENETIC MODIFICATIONS, ARE SHORT SINGLE-STRANDED RNA MOLECULES THAT REGULATE PROTEIN-CODING GENE EXPRESSION AT POSTTRANSCRIPTIONAL LEVEL, WHICH CAN DISCLOSE THE MECHANISM UNDERLYING DISEASES, IDENTIFY VALUABLE BIOMARKERS, AND EXPLORE POTENTIAL THERAPEUTIC TARGETS. CONSIDERING THAT MIRNAS PLAY A CENTRAL ROLE IN REGULATING GENE EXPRESSION, WE SUMMARIZED CURRENT STUDIES FROM THE POINT OF VIEW OF MIRNA-RELATED MOLECULAR REGULATION NETWORKS IN HLF/OLF. EXPLORATORY STUDIES REVEALED A VARIETY OF MIRNA EXPRESSION PROFILES AND IDENTIFIED A BATTERY OF UPREGULATED AND DOWNREGULATED MIRNAS IN OLF/HLF PATIENTS THROUGH MICROARRAY DATASETS OR TRANSCRIPTOME SEQUENCING. EXPERIMENTAL STUDIES VALIDATED THE ROLES OF SPECIFIC MIRNAS (E.G., MIR-132-3P, MIR-199B-5P IN OLF, MIR-155, AND MIR-21 IN HLF) IN REGULATING FIBROSIS OR OSTEOGENESIS DIFFERENTIATION OF LF CELLS AND RELATED TARGET GENES OR MOLECULAR SIGNALING PATHWAYS. FINALLY, WE DISCUSSED THE PERSPECTIVES AND CHALLENGES OF MIRNA-BASED MOLECULAR MECHANISM, DIAGNOSTIC BIOMARKERS, AND THERAPEUTIC TARGETS OF HLF/OLF. 2021 19 1449 23 DIRECT LINEAGE REPROGRAMMING FOR INDUCED KERATINOCYTE STEM CELLS: A POTENTIAL APPROACH FOR SKIN REPAIR. SEVERE TRAUMA OR CHRONIC WOUNDS CAN DEPLETE THE KERATINOCYTE STEM CELLS (KSCS) PRESENT IN THE EPIDERMAL BASAL LAYER OR INHIBIT THEIR MIGRATION LEADING TO COMPROMISED WOUND HEALING. SUPPLEMENTING KSCS IS THE KEY TO SOLUTION WHILE LINEAGE REPROGRAMMING PROVIDES A NEW APPROACH TO ACQUIRING KSCS. THROUGH DIRECT LINEAGE REPROGRAMMING, INDUCED KSCS (IKSCS) CAN BE PRODUCED FROM SOMATIC CELLS, WHICH EXHIBIT GREAT APPLICATION POTENTIAL. TWO STRATEGIES ARE CURRENTLY BEING USED TO DIRECTLY GENERATE IKSCS, LINEAGE TRANSCRIPTION FACTOR (TF)-MEDIATED AND PLURIPOTENCY FACTORS-MEDIATED. THIS REVIEW FOCUSES ON LINEAGE TF-MEDIATED DIRECT REPROGRAMMING AND DESCRIBES THE CONVERSION PROCESS ALONG WITH THE UNDERLYING EPIGENETIC MECHANISMS. IT ALSO DISCUSSES OTHER POTENTIAL INDUCTION STRATEGIES TO GENERATE IKSCS AND CHALLENGES ASSOCIATED WITH IN SITU REPROGRAMMING FOR SKIN REPAIR. 2023 20 3390 22 HOPX PLAYS A CRITICAL ROLE IN ANTIRETROVIRAL DRUGS INDUCED EPIGENETIC MODIFICATION AND CARDIAC HYPERTROPHY. PEOPLE LIVING WITH HIV (PLWH) HAVE TO TAKE AN ANTIRETROVIRAL THERAPY (ART) FOR LIFE AND SHOW NONCOMMUNICABLE ILLNESSES SUCH AS CHRONIC INFLAMMATION, IMMUNE ACTIVATION, AND MULTIORGAN DYSREGULATION. RECENT STUDIES SUGGEST THAT LONG-TERM USE OF ART INDUCES COMORBID CONDITIONS AND IS ONE OF THE LEADING CAUSES OF HEART FAILURE IN PLWH. HOWEVER, THE MOLECULAR MECHANISM OF ANTIRETROVIRAL DRUGS (ARVS) INDUCED HEART FAILURE IS UNCLEAR. TO DETERMINE THE MECHANISM OF ARVS INDUCED CARDIAC DYSFUNCTION, WE PERFORMED GLOBAL TRANSCRIPTOMIC PROFILING OF ARVS TREATED NEONATAL RAT VENTRICULAR CARDIOMYOCYTES IN CULTURE. DIFFERENTIALLY EXPRESSED GENES WERE IDENTIFIED BY RNA-SEQUENCING. OUR DATA SHOW THAT ARVS TREATMENT CAUSES UPREGULATION OF SEVERAL BIOLOGICAL FUNCTIONS ASSOCIATED WITH CARDIOTOXICITY, HYPERTROPHY, AND HEART FAILURE. GLOBAL GENE EXPRESSION DATA WERE VALIDATED IN CARDIAC TISSUE ISOLATED FROM HIV PATIENTS HAVING A HISTORY OF ART. INTERESTINGLY, WE FOUND THAT HOMEODOMAIN-ONLY PROTEIN HOMEOBOX (HOPX) EXPRESSION WAS SIGNIFICANTLY INCREASED IN CARDIOMYOCYTES TREATED WITH ARVS AND IN THE HEART TISSUE OF HIV PATIENTS. FURTHERMORE, WE FOUND THAT HOPX PLAYS A CRUCIAL ROLE IN ARVS MEDIATED CELLULAR HYPERTROPHY. MECHANISTICALLY, WE FOUND THAT HOPX PLAYS A CRITICAL ROLE IN EPIGENETIC REGULATION, THROUGH DEACETYLATION OF HISTONE, WHILE THE HDAC INHIBITOR, TRICHOSTATIN A, CAN RESTORE THE ACETYLATION LEVEL OF HISTONE 3 IN THE PRESENCE OF ARVS. 2021